Combination Therapy for Multiple Myeloma

Not currently recruiting at 62 trial locations

Overseen By ABBVIE CALL CENTER

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: AbbVie

Must not be taking: BCL-2 inhibitors, Anti-CD38 therapy

Disqualifiers: CNS involvement, Active malignancies, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests new drug combinations to treat multiple myeloma (a type of blood cancer) that has returned or resisted treatment. It evaluates the safety and effectiveness of these combinations, using drugs like venetoclax (a targeted therapy), daratumumab (an immunotherapy), dexamethasone (a corticosteroid), and bortezomib (a proteasome inhibitor). The study has three parts, each focusing on different drug combinations based on specific genetic markers of the cancer. Individuals whose multiple myeloma has returned or not responded to previous treatments and who show certain genetic markers might be suitable for this trial. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot have had certain treatments like anti-myeloma chemotherapy or monoclonal antibodies within a specific time before starting the trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the combination of venetoclax, daratumumab, and dexamethasone (VenDd) is generally safe for patients with relapsed or refractory multiple myeloma. In earlier studies, many patients responded well to the treatment, indicating it was usually well-tolerated. Common side effects included nausea and tiredness, but these were manageable.

Early research on the combination of venetoclax, daratumumab, bortezomib, and dexamethasone (VenDVd) also found it to be generally safe with promising results. Patients handled the treatment well over about 20 months of follow-up.

The combination of daratumumab, bortezomib, and dexamethasone (DVd) has been extensively studied. Recent studies did not identify any new safety issues, and the treatment was usually well-tolerated. Common side effects included low blood cell counts and tiredness.

Overall, these treatment combinations have been reported to be well-tolerated, with manageable side effects, based on existing research. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard care for multiple myeloma, which often includes medications like lenalidomide and melphalan, the combination therapies in this trial are unique due to their targeted approach and novel combinations. Researchers are particularly excited about the addition of venetoclax, a BCL-2 inhibitor, which works by inducing apoptosis in cancer cells, potentially enhancing the effectiveness of existing treatments like daratumumab and bortezomib. Moreover, the combination of these drugs, including dexamethasone, is designed to act on different pathways, which might improve overall response rates and overcome resistance seen with current treatments. This multi-drug approach could offer a more powerful and comprehensive attack on multiple myeloma cells, potentially leading to improved outcomes for patients.

What evidence suggests that this trial's treatments could be effective for multiple myeloma?

Studies have shown promising results for the treatment combinations tested in this trial. Participants in different arms will receive various combinations of these treatments. The combination of venetoclax, daratumumab, and dexamethasone (VenDd), tested in several arms, achieved an overall response rate of 96%, indicating that most patients experienced a significant reduction in their cancer. In other arms, adding bortezomib to this mix (VenDVd) maintained a strong response rate at 92%. Research indicates that these combinations work particularly well for patients with a specific genetic marker called t(11;14). Additionally, the combination of daratumumab, bortezomib, and dexamethasone (DVd), tested in a separate arm, significantly extended the time patients live without their disease worsening. Overall, early data suggests these treatment combinations could be very effective in treating relapsed or hard-to-treat multiple myeloma. ^{1 5 6 7 8}

Who Is on the Research Team?

ABBVIE INC.

Principal Investigator

AbbVie

Are You a Good Fit for This Trial?

This trial is for adults with relapsed or refractory multiple myeloma, specifically those who have measurable disease and have undergone previous treatments. Participants must be t(11;14) positive for certain parts of the study and should have good blood, kidney, and liver function. People with recent high-dose steroid use, central nervous system involvement by myeloma, significant medical conditions, other active cancers in the last 3 years (with exceptions), allergies to study drugs or their components, prior BCL-2 inhibitor or anti-CD38 therapy (for some parts), or active COVID-19 are excluded.

Inclusion Criteria

My cancer can be measured by specific blood or urine tests.

My multiple myeloma has worsened or not responded to my last treatment.

My bone marrow samples have been collected.

Exclusion Criteria

I have taken corticosteroids in the last 2 weeks.

I have been treated with venetoclax or a similar drug before.

I have been treated with daratumumab or another anti-CD38 therapy.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive increasing doses of venetoclax with fixed doses of daratumumab and dexamethasone (Part 1a) or with fixed doses of daratumumab, bortezomib, and dexamethasone (Part 2a)

8 weeks

Open-label Expansion

Participants receive venetoclax in combination with daratumumab and dexamethasone or daratumumab, bortezomib, and dexamethasone in a single-arm, open-label setting

Up to 3.5 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

What Are the Treatments Tested in This Trial?

Interventions

• Bortezomib
• Daratumumab
• Dexamethasone
• Venetoclax

Trial Overview The trial tests combinations of venetoclax with daratumumab and dexamethasone—with or without bortezomib—to assess safety and effectiveness in treating multiple myeloma that has come back or hasn't responded to treatment. It's divided into three parts: two non-randomized phases exploring different drug combos at increasing doses followed by an expansion phase; the third part randomly assigns patients to one of two treatment groups.

How Is the Trial Designed?

Group I: Arm G: VenDd Dose Expansion Experimental Treatment 3 Interventions

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 II: Arm F: VenDd Dose Expansion Experimental Treatment 3 Interventions

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 III: Arm E, Part 2b: VenDVd Dose Expansion Experimental Treatment 4 Interventions

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 IV: Arm D, Part 2a: VenDVd Dose Escalation Experimental Treatment 4 Interventions

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 V: Arm B, Part 1b: VenDd Dose Expansion Experimental Treatment 3 Interventions

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 VI: Arm A, Part 1a: VenDd Dose Escalation Experimental Treatment 3 Interventions

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 VII: Arm H: DVd Dose Active Control 3 Interventions

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

Bortezomib is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Velcade for:

• Multiple myeloma
• Mantle cell lymphoma

Approved in United States as Velcade for:

• Multiple myeloma
• Mantle cell lymphoma

Approved in Canada as Velcade for:

• Multiple myeloma
• Mantle cell lymphoma

Approved in Japan as Velcade for:

• Multiple myeloma
• Mantle cell lymphoma

Who Is Running the Clinical Trial?

AbbVie

Lead Sponsor

Trials

1,079

Recruited

535,000+

Founded

2013

Headquarters

North Chicago, USA

Known For

Immunology treatments

Top Products

Humira (adalimumab), Skyrizi (risankizumab), Rinvoq (upadacitinib)

Dr. Roopal Thakkar

AbbVie

Chief Medical Officer since 2023

MD from Wayne State University School of Medicine

Robert A. Michael

AbbVie

Chief Executive Officer

Bachelor's degree in Finance from the University of Illinois

Janssen Research & Development, LLC

Industry Sponsor

Trials

1,022

Recruited

6,408,000+

Joaquin Duato

Janssen Research & Development, LLC

Chief Executive Officer since 2022

MBA from ESADE, Master of International Management from Thunderbird School of Global Management

Dr. Jijo James, MD

Janssen Research & Development, LLC

Chief Medical Officer since 2014

MD from St. Johns Medical College, MPH from Columbia University

Published Research Related to This Trial

In a study of 22 relapsed/refractory multiple myeloma patients, low-dose venetoclax (≤250 mg/day) combined with bortezomib, daratumumab, and dexamethasone showed an impressive overall response rate of 80% in patients with the t(11;14) chromosomal marker, indicating its efficacy as a salvage therapy.

The low-dose regimen significantly reduced the incidence of serious adverse events, particularly infections, which are commonly associated with higher doses of venetoclax, suggesting a safer treatment option for this specific patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low dose venetoclax in combination with bortezomib, daratumumab, and dexamethasone for the treatment of relapsed/refractory multiple myeloma patients-a single-center retrospective study. Regidor, B., Goldwater, MS., Wang, J., et al.[2021]

In a phase I study involving 48 patients with relapsed or refractory multiple myeloma (RRMM), the combination of venetoclax with daratumumab and dexamethasone (VenDd) showed a remarkable overall response rate of 96%, indicating its strong efficacy, especially in patients with the t(11;14) translocation.

The combination of venetoclax with bortezomib, daratumumab, and dexamethasone (VenDVd) also demonstrated significant efficacy, with a 92% overall response rate, and an 18-month progression-free survival rate of 66.7%, suggesting that these combinations could provide durable responses in RRMM treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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). Bahlis, NJ., Baz, R., Harrison, SJ., et al.[2022]

In a phase 3 trial involving 291 patients with relapsed or refractory multiple myeloma, venetoclax combined with bortezomib and dexamethasone significantly improved progression-free survival compared to placebo, with a median of 22.4 months versus 11.5 months (hazard ratio 0.63).

Despite its efficacy, the venetoclax group experienced higher rates of serious treatment-emergent adverse events, particularly infections, leading to increased mortality, which underscores the need for careful patient selection for this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax or placebo in combination with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma (BELLINI): a randomised, double-blind, multicentre, phase 3 trial. Kumar, SK., Harrison, SJ., Cavo, M., et al.[2021]

In a phase 2 study involving 49 adults with relapsed/refractory multiple myeloma, the combination of venetoclax, carfilzomib, and dexamethasone (VenKd) demonstrated an overall response rate of 80%, with even higher rates (92%) in patients with the t(11;14) genetic alteration.

The treatment was generally well tolerated, with a median progression-free survival of 22.8 months, although some patients experienced significant side effects, including diarrhea and fatigue.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 study of venetoclax plus carfilzomib and dexamethasone in patients with relapsed/refractory multiple myeloma. Costa, LJ., Davies, FE., Monohan, GP., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10022857/

Overall Survival With Daratumumab, Bortezomib, and ... At a median follow-up of 72.6 months, D-Vd significantly prolonged OS, with a 26% reduction in the risk of death versus bortezomib and dexamethasone alone ( ...

2. nejm.org nejm.org/doi/full/10.1056/NEJMoa1606038

Daratumumab, Bortezomib, and Dexamethasone for ... Daratumumab in combination with bortezomib and dexamethasone resulted in significantly longer progression-free survival than bortezomib and dexamethasone alone.

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.7543

Patient-reported outcomes (PROs) from the DREAMM-7 ... Overallquality of life, role functioning, physical functioning, fatigue, and pain were comparable in patients treated with BVd vs DVd.

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36822820/

A real-world multicentre UK retrospective analysis DVd with weekly bortezomib was effective in a heterogenous real-world population at first relapse with a low rate of peripheral neuropathy.

5. sciencedirect.com sciencedirect.com/science/article/pii/S0006497119836613

Daratumumab, Bortezomib, and Dexamethasone (DVd) ... Median duration of single-agent D in DVd arm after 8 cycles of Vd was 11.9 months. After median follow-up of 19.4 months, PFS was significantly prolonged and ...

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.2017.35.15_suppl.8036

Daratumumab, bortezomib and dexamethasone (DVd) vs ... DVd provided significant benefits with respect to PFS, ORR, depth of response, and MRD-negative rate vs Vd. No new safety signals were reported.

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36413710/

A Randomized, Open-Label, Phase III Trial Daratumumab plus bortezomib and dexamethasone (D-Vd) significantly prolonged progression-free survival versus bortezomib and dexamethasone (Vd) alone in ...

8. ashpublications.org ashpublications.org/blood/article/134/Supplement_1/3192/423938/Efficacy-and-Safety-of-Daratumumab-Bortezomib-and

Efficacy and Safety of Daratumumab, Bortezomib, and ... The most common (≥5%) grade 3/4 treatment-emergent adverse events (TEAEs) with D-Vd vs Vd included thrombocytopenia (46% vs 33%), anemia (16% vs ...