Venetoclax Combinations for Multiple Myeloma

Overseen By Clinical Trials Referral Office

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Mayo Clinic

Must not be taking: CYP3A inhibitors/inducers

Disqualifiers: Active malignancy, HIV, Hepatitis C, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 1

Duration: Up to 36 months

100 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial tests the safety, side effects, and best dose of venetoclax in combination with lenalidomide and dexamethasone, daratumumab and dexamethasone, or daratumumab, lenalidomide, and dexamethasone in treating patients with multiple myeloma. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Lenalidomide is a drug that is similar to thalidomide, and is used to treat multiple myeloma and certain types of anemia. Lenalidomide belongs to the family of drugs called angiogenesis inhibitors. Dexamethasone is in a class of medications called corticosteroids. It is used to reduce inflammation and lower the body's immune response to help lessen the side effects of chemotherapy drugs. Daratumumab is in a class of medications called monoclonal antibodies. It binds to a protein called CD38, which is found on some types of immune cells and cancer cells, including myeloma cells. Daratumumab may block CD38 and help the immune system kill cancer cells. Adding venetoclax to the other drug combinations may allow control of the cancer than is possible with the current treatments.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot take strong or moderate CYP3A inhibitors or inducers within 28 days before joining the trial.

What data supports the effectiveness of the drug combination including Venetoclax for treating multiple myeloma?

Research shows that Venetoclax, when combined with other drugs like bortezomib and dexamethasone, has shown promising results in treating multiple myeloma, especially in patients with specific genetic characteristics. Additionally, combining Venetoclax with Daratumumab enhances the ability of the immune system to kill cancer cells, suggesting this combination could be particularly effective for certain patients. ^{1 2 3 4 5}

Is the combination of Venetoclax and other drugs safe for treating multiple myeloma?

Venetoclax, when used in combination with other drugs like daratumumab and dexamethasone, has shown to be generally safe in treating multiple myeloma, especially at lower doses, with fewer serious infection-related side effects. However, higher doses of venetoclax can lead to serious side effects, particularly infections, when combined with certain drugs like bortezomib. ^{3 6 7 8 9}

What makes the drug combination of Venetoclax, Daratumumab, Dexamethasone, and Lenalidomide unique for treating multiple myeloma?

This drug combination is unique because Venetoclax, a BCL-2 inhibitor, is not yet FDA-approved for multiple myeloma but shows promise, especially in patients with a specific genetic marker (t(11;14)). The combination with Daratumumab, Dexamethasone, and Lenalidomide may enhance its effectiveness and is well-tolerated, offering a novel approach for relapsed or refractory multiple myeloma. ^{1 5 6 10 11}

Research Team

Shaji K. Kumar, M.D.

Principal Investigator

Mayo Clinic in Rochester

Eligibility Criteria

Adults with multiple myeloma, specifically those who have a certain genetic marker (t(11;14)) detected by a special test. Participants must be willing to follow strict birth control measures due to risks associated with lenalidomide. They should not have had more than one prior treatment cycle for newly diagnosed patients or any previous venetoclax treatments for others. Key organ functions must meet specific criteria and they cannot be planning stem cell transplants.

Inclusion Criteria

You have not received treatment for multiple myeloma (group 2), or you have received at least one treatment that did not include venetoclax (group 1).

Your alkaline phosphatase level in your blood should be less than 750 units per liter, and the test should have been done within the last 14 days before you join the study.

Your blood contains a high level of a specific type of protein.

Exclusion Criteria

You are currently receiving any experimental treatments or additional therapies.

Participation in other clinical trials, including those with other investigational agents not included in this trial, ≤ 30 days prior to registration

You have tested positive for hepatitis C within the last 3 months.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive venetoclax in combination with lenalidomide and dexamethasone, daratumumab and dexamethasone, or daratumumab, lenalidomide, and dexamethasone. Treatment repeats every 28 days for up to 36 cycles.

Up to 36 months

Multiple visits per cycle (in-person and virtual)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up at 30 days and then every 3 or 6 months for a total of 3 years.

3 years

Regular follow-up visits (in-person)

Treatment Details

Interventions

• Daratumumab
• Dexamethasone
• Lenalidomide
• Venetoclax

Trial Overview The trial is testing the safety and optimal dosing of venetoclax combined with other drugs: lenalidomide and dexamethasone, daratumumab and dexamethasone, or all three together in treating multiple myeloma. These combinations are being studied to see if they can better control cancer compared to current treatments.

Participant Groups

Group I: Arm C (Ven-DRd) Experimental Treatment 14 Interventions

Patients receive venetoclax PO QD on days 1-28 of each cycle, daratumumab SC on days 1, 8, 15, and 22 of cycles 1-2, days 1 and 15 of cycles 3-6, and day 1 of cycles 7+, lenalidomide PO QD on days 1-21 of each cycle, and dexamethasone PO on days 1, 8, 15, and 22 of cycles 1-12. Treatment repeats every 28 days for up to 36 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo chest x-ray and optional collection of blood samples during screening. In addition, patients undergo x-rays, WBLDCT, PET/CT or MRI scans during screening and on study, and bone marrow aspiration and biopsy during screening, on study, and during follow-up.

Group II: Arm B (Ven-Rd) Experimental Treatment 13 Interventions

Patients receive venetoclax PO QD on days 1-28 of each cycle, lenalidomide PO QD on days 1-21 of each cycle, and dexamethasone PO on days 1, 8, 15, 22 of cycles 1-12. Treatment repeats every 28 days for up to 36 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo chest x-ray and optional collection of blood samples during screening. In addition, patients undergo x-rays, WBLDCT, PET/CT or MRI scans during screening and on study, and bone marrow aspiration and biopsy during screening, and during follow-up.

Group III: Arm A (Ven-Dd) Experimental Treatment 13 Interventions

Patients receive venetoclax PO QD on days 1-28 of each cycle, daratumumab SC on days 1, 8, 15, and 22 of cycles 1-2, days 1 and 15 of cycles 3-6, and day 1 of cycles 7+, and dexamethasone PO on days 1, 8, 15, 22 of cycles 1-12. Treatment repeats every 28 days for up to 36 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo chest x-ray and optional collection of blood samples during screening. In addition, patients undergo x-rays, WBLDCT, PET/CT or MRI scans during screening and on study, and bone marrow aspiration and biopsy during screening, and during follow-up.

Daratumumab is already approved in European Union, United States for the following indications:

Approved in European Union as Darzalex for:

• Relapsed and refractory multiple myeloma
• Newly diagnosed multiple myeloma in combination with bortezomib, melphalan, and prednisone

Approved in United States as Darzalex for:

• Multiple myeloma in patients who have received at least three prior therapies
• Newly diagnosed multiple myeloma in combination with bortezomib, melphalan, and prednisone
• Relapsed or refractory multiple myeloma in combination with lenalidomide and dexamethasone

Who Is Running the Clinical Trial?

Mayo Clinic

Lead Sponsor

Trials

3,427

Recruited

3,221,000+

Findings from Research

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]

Daratumumab significantly improves overall survival (OS) compared to pomalidomide plus low-dose dexamethasone in patients with heavily pretreated multiple myeloma, with hazard ratios indicating a strong treatment benefit (0.56 and 0.51 for two different studies).

The survival advantage of daratumumab is even more pronounced in patients who have not previously been treated with pomalidomide, suggesting it may be particularly effective in this subgroup.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative Efficacy of Daratumumab Monotherapy and Pomalidomide Plus Low-Dose Dexamethasone in the Treatment of Multiple Myeloma: A Matching Adjusted Indirect Comparison. Van Sanden, S., Ito, T., Diels, J., et al.[2019]

The combination of venetoclax, a BCL-2 inhibitor, and daratumumab, an anti-CD38 antibody, shows enhanced effectiveness against multiple myeloma (MM) cell lines, particularly in those with the t(11;14) translocation and high BCL-2 expression.

This study suggests that this combination therapy could be a promising treatment option for MM patients who are resistant to existing therapies, as it enhances natural killer (NK) cell-mediated cytotoxicity against MM cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synergistic Effects of Venetoclax and Daratumumab on Antibody-Dependent Cell-Mediated Natural Killer Cytotoxicity in Multiple Myeloma. Nakamura, A., Suzuki, S., Kanasugi, J., et al.[2021]

Daratumumab, a monoclonal antibody targeting CD38, has shown significant anti-myeloma activity through various mechanisms, including direct apoptosis and immune system modulation, making it a key treatment for relapsed-refractory multiple myeloma (RRMM).

Clinical trials, such as CASTOR and POLLUX, demonstrated that daratumumab in combination with other therapies (like bortezomib and lenalidomide) significantly improves overall response rates and progression-free survival compared to standard treatments, leading to its approval and integration into clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab for the Management of Newly Diagnosed and Relapsed/Refractory Multiple Myeloma: Current and Emerging Treatments. Offidani, M., Corvatta, L., Morè, S., et al.[2021]

In a review of 7 clinical trials involving 482 patients with relapsed/refractory multiple myeloma, venetoclax demonstrated a high overall response rate of 76%, indicating it is an effective treatment option.

The study found that while venetoclax is associated with some adverse events, the overall rate of severe adverse events (Grade 3 or higher) was 84%, suggesting that while it is effective, careful monitoring for side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of venetoclax in patients with relapsed/refractory multiple myeloma: a meta-analysis. Gao, X., Zeng, H., Zhao, X., et al.[2023]

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 study of 103 patients with relapsed/refractory multiple myeloma, the combination of daratumumab, pomalidomide, and dexamethasone showed an overall response rate of 60%, indicating significant efficacy even in patients with a history of multiple prior therapies.

The safety profile of this combination treatment was similar to pomalidomide and dexamethasone alone, with the main exception being a higher incidence of neutropenia and infusion-related reactions, but without an increase in infection rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. Chari, A., Suvannasankha, A., Fay, JW., et al.[2022]

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]

Daratumumab combined with lenalidomide and dexamethasone showed an impressive overall response rate of 81% in patients with relapsed/refractory multiple myeloma, indicating its efficacy in this challenging patient population.

The treatment was well tolerated, with no dose-limiting toxicities observed and manageable infusion-related reactions, suggesting a favorable safety profile consistent with previous treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1/2 study of daratumumab, lenalidomide, and dexamethasone for relapsed multiple myeloma. Plesner, T., Arkenau, HT., Gimsing, P., et al.[2022]

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 II study involving 8 patients with relapsed/refractory multiple myeloma, the combination of venetoclax, pomalidomide, and dexamethasone (VenPd) showed that 63% of patients had a confirmed response, with a median duration of response of 12.9 months.

The study highlighted significant safety concerns, as all patients experienced grade ≥ 3 adverse events, primarily neutropenia, indicating that while there may be efficacy, careful monitoring and dosing adjustments will be necessary in future trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase II Study of Venetoclax in Combination With Pomalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma. Gasparetto, C., Bowles, KM., Abdallah, AO., et al.[2022]

References

1. England 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. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Comparative Efficacy of Daratumumab Monotherapy and Pomalidomide Plus Low-Dose Dexamethasone in the Treatment of Multiple Myeloma: A Matching Adjusted Indirect Comparison. [2019]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Synergistic Effects of Venetoclax and Daratumumab on Antibody-Dependent Cell-Mediated Natural Killer Cytotoxicity in Multiple Myeloma. [2021]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Daratumumab for the Management of Newly Diagnosed and Relapsed/Refractory Multiple Myeloma: Current and Emerging Treatments. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of venetoclax in patients with relapsed/refractory multiple myeloma: a meta-analysis. [2023]

6. Germany 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. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Phase 2 study of venetoclax plus carfilzomib and dexamethasone in patients with relapsed/refractory multiple myeloma. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Phase 1/2 study of daratumumab, lenalidomide, and dexamethasone for relapsed multiple myeloma. [2022]

10. United States 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). [2022]

11. United States pubmed.ncbi.nlm.nih.gov

A Phase II Study of Venetoclax in Combination With Pomalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma. [2022]