Venetoclax + Isatuximab + Dexamethasone for Multiple Myeloma

Recruiting at 1 trial location

Overseen By Yohana Sebhat

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: Oncotherapeutics

Must not be taking: Anti-CD38 antibodies, Venetoclax

Disqualifiers: Amyloidosis, HIV, Hepatitis B/C, 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

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

Compensation: Varies

Number of Visits: 4

Duration: 54 months

39 Participants Needed

Trial Summary

What is the purpose of this trial?

A phase 2 study of venetoclax in combination with isatuximab and dexamethasone for relapsed/refractory multiple myeloma patients with t(11;14)

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but it does exclude certain treatments like chemotherapy, corticosteroids, and some other therapies within a few weeks before starting the study drugs. It's best to discuss your current medications with the study team to see if any adjustments are needed.

What data supports the effectiveness of the drug Venetoclax when used in combination with Isatuximab and Dexamethasone for treating multiple myeloma?

Venetoclax has shown promising results in treating multiple myeloma, especially when combined with other drugs like bortezomib and dexamethasone, by inducing cell death in cancer cells. Isatuximab, when combined with other treatments, has also been effective in prolonging the time patients live without the disease getting worse and improving the response to treatment. ^{1 2 3 4 5}

Is the combination of Venetoclax, Isatuximab, and Dexamethasone safe for treating multiple myeloma?

Venetoclax, when used with other drugs like dexamethasone, has shown acceptable safety in treating multiple myeloma, with some studies noting serious side effects like infections, especially at higher doses. However, lower doses have been better tolerated, particularly in patients with specific genetic markers. ^{1 3 5 6 7}

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

This drug combination is unique because Venetoclax targets a specific protein that helps cancer cells survive, making it particularly effective for multiple myeloma patients with a specific genetic marker (t(11,14)(q13;q32)). Isatuximab, an antibody, works by targeting and killing cancer cells, and when combined with Dexamethasone, it enhances the overall treatment effect, offering a novel approach compared to standard therapies. ^{2 3 4 8 9}

Research Team

James Berenson, MD

Principal Investigator

Oncotherapeutics

Eligibility Criteria

This trial is for adults with relapsed/refractory multiple myeloma, specifically those who have a certain genetic change (t(11;14)). Participants must have measurable levels of the disease and meet specific blood count and kidney function criteria. They cannot join if they've had recent major surgery or other conditions that could interfere with the study.

Inclusion Criteria

My tests confirm I have the t(11;14) genetic marker.

My bone marrow has more than 10% plasma cells or I have a confirmed plasmacytoma.

Your serum calcium concentration is greater than 2.75 mmol/L (11 mg/dL) or higher than 0.25 mmol/L (1 mg/dL) above the upper limit of normal range.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive venetoclax, isatuximab, and dexamethasone in 28-day cycles

54 months

4 visits per 28-day cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Venetoclax

Trial Overview The study tests Venetoclax combined with Isatuximab and Dexamethasone in patients whose multiple myeloma has returned after treatment or didn't respond to previous treatments. It's a phase 2 trial, which means it focuses on effectiveness and side effects.

Participant Groups

Group I: open-label Experimental Treatment 1 Intervention

This is a Phase 2, multicenter, open-label study evaluating the safety and efficacy of venetoclax in combination with isatuximab and dexamethasone among RRMM patients who show the t(11;14) marker and currently show PD and have received at least 3 prior lines of therapy for multiple myeloma. All subjects in Dose Level 0 will receive 1) venetoclax, PO, at 400 mg every day (QD) on Days 1-28 of a 28-day cycle, 2) dexamethasone 40 mg IV, once weekly on Days 1, 8, 15, and 22 of a 28-day cycle where day 8 and 22 doses may be administered PO; and 3) isatuximab 10mg/kg, IV, on Days 1, 8, 15, and 22 of the first 28-day cycle, and then Days 1 and 15 during subsequent 28-day cycles. The primary safety analysis will focus on determining the DLTs for the study regimen, and occurrence of AEs throughout the study.

Who Is Running the Clinical Trial?

Oncotherapeutics

Lead Sponsor

Trials

23

Recruited

940+

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]

Isatuximab, an anti-CD38 monoclonal antibody, significantly improves progression-free survival and tumor response when combined with pomalidomide and dexamethasone in patients with relapsed and refractory multiple myeloma, based on phase III studies.

The combination therapies involving isatuximab were generally well tolerated, maintaining health-related quality of life and showing a manageable safety profile without new safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Isatuximab: A Review of Its Use in Multiple Myeloma. Frampton, JE.[2022]

Venetoclax, when combined with carfilzomib and dexamethasone, showed rapid initial effectiveness in two patients with multiple myeloma harboring the t(11,14)(q13;q32) genetic alteration, but the responses were short-lived, indicating a need for ongoing monitoring and potential adjustments in treatment.

The emergence of the t(11;14)(q13;q32) alteration during the disease progression highlights the importance of regular cytogenetic testing in multiple myeloma, as it can influence treatment strategies and outcomes in this challenging disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with carfilzomib and dexamethasone in relapsed/refractory multiple myeloma harboring t(11,14)(q13;q32): two case reports and a review of the literature. Abuelgasim, KA., Alherz, N., Alhejazi, A., et al.[2021]

In a phase 3 study involving 307 patients with relapsed and refractory multiple myeloma, the combination of isatuximab, pomalidomide, and dexamethasone significantly improved progression-free survival (11.5 months) compared to pomalidomide and dexamethasone alone (6.5 months).

The most common side effects included infusion reactions and upper respiratory infections, with a low incidence of treatment-related deaths, indicating that isatuximab is a relatively safe and effective treatment option for patients who have not responded to other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study. Attal, M., Richardson, PG., Rajkumar, SV., et al.[2020]

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 involving 117 patients with relapsed or refractory multiple myeloma, venetoclax showed a trend of improved progression-free survival (PFS) and overall survival (OS) with higher doses, particularly in patients with the t(11;14) genetic marker.

Importantly, increasing doses of venetoclax did not correlate with a rise in serious adverse effects, suggesting that an 800 mg daily dose combined with dexamethasone could enhance efficacy without compromising safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax in biomarker-selected multiple myeloma patients: Impact of exposure on clinical efficacy and safety. Badawi, M., Coppola, S., Eckert, D., 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 phase 3 study involving 302 patients with relapsed multiple myeloma, the addition of isatuximab to carfilzomib-dexamethasone significantly improved progression-free survival compared to carfilzomib-dexamethasone alone, with a hazard ratio of 0.53, indicating a 47% reduction in the risk of disease progression.

While the isatuximab group experienced a higher rate of treatment-emergent adverse events (77% vs. 67%), the overall safety profile was similar, with no significant difference in fatal adverse events, suggesting that isatuximab can be safely integrated into treatment regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial. Moreau, P., Dimopoulos, MA., Mikhael, J., et al.[2022]

In a study of 107 relapsed/refractory myeloma patients treated with isatuximab, pomalidomide, and dexamethasone (IsaPomDex), the overall response rate was 66.4%, indicating significant efficacy in a real-world setting.

The treatment was associated with a median progression-free survival of 10.9 months and a median overall survival of 18.8 months, although adverse events were common, with 87.9% of patients experiencing any grade adverse effects, primarily neutropenia and infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Isatuximab With Pomalidomide and Dexamethasone in Relapsed Myeloma: Results of a UK-Wide Real-World Dataset. Djebbari, F., Rampotas, A., Vallance, G., 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. France pubmed.ncbi.nlm.nih.gov

Isatuximab: A Review of Its Use in Multiple Myeloma. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with carfilzomib and dexamethasone in relapsed/refractory multiple myeloma harboring t(11,14)(q13;q32): two case reports and a review of the literature. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study. [2020]

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

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

6. England pubmed.ncbi.nlm.nih.gov

Venetoclax in biomarker-selected multiple myeloma patients: Impact of exposure on clinical efficacy and safety. [2023]

7. 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]

8. England pubmed.ncbi.nlm.nih.gov

Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial. [2022]

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

Efficacy of Isatuximab With Pomalidomide and Dexamethasone in Relapsed Myeloma: Results of a UK-Wide Real-World Dataset. [2022]