Selinexor Combination Therapy for Multiple Myeloma

Recruiting at 27 trial locations

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Strong CYP3A4 inhibitors, inducers

Disqualifiers: Uncontrolled illness, Allergic reactions, 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: 6

Duration: 16 weeks

70 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial compares the combination of selinexor, daratumumab, velcade (bortezomib), and dexamethasone (Dara-SVD) to the usual treatment of daratumumab, lenalidomide, bortezomib, and dexamethasone (Dara-RVD) in treating patients with high-risk newly diagnosed multiple myeloma. Selinexor is in a class of medications called selective inhibitors of nuclear export (SINE). It works by blocking a protein called CRM1, which may keep cancer cells from growing and may kill them. 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. Bortezomib blocks several molecular pathways in a cell and may cause cancer cells to die. It is a type of proteasome inhibitor and a type of dipeptidyl boronic acid. 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. Lenalidomide is in a class of medications called immunomodulatory agents. It works by helping the bone marrow to produce normal blood cells and by killing abnormal cells in the bone marrow. The drugs daratumumab, lenalidomide, bortezomib, dexamethasone and selinexor are already approved by the FDA for use in myeloma. But selinexor is not used until myeloma comes back (relapses) after initial treatment. Giving selinexor in the initial treatment may be a superior type of treatment for patients with high-risk newly diagnosed multiple myeloma.

Do I have to stop taking my current medications for the trial?

The trial does not specify if you need to stop taking your current medications, but it does prohibit the use of strong CYP3A4 inhibitors and inducers, as they can affect bortezomib exposure. Supportive care therapies like bone-directed therapies and antiviral agents are allowed.

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

Research shows that Selinexor, when combined with other drugs like bortezomib and dexamethasone, has been effective in treating multiple myeloma, especially in patients who have tried other treatments before. In one study, this combination led to a 63% overall response rate, meaning many patients saw their cancer shrink or stop growing. ^{1 2 3 4 5}

What is the safety profile of Selinexor combination therapy for multiple myeloma?

Selinexor combination therapy, including with bortezomib and dexamethasone, has a generally manageable safety profile with common side effects like low blood platelet count, low red and white blood cell counts, fatigue, nausea, and weight loss. Peripheral neuropathy (nerve damage) is less common, and the treatment is considered safe if side effects are managed proactively. ^{1 2 3 6 7}

What makes the Selinexor combination drug unique for treating multiple myeloma?

The Selinexor combination drug is unique because it includes Selinexor, a first-in-class oral drug that blocks exportin-1, a protein involved in cancer cell survival. This combination, given once weekly, has shown to prolong progression-free survival and reduce nerve damage compared to standard treatments, making it a valuable option for patients who have already tried other therapies. ^{1 2 3 7 8}

Research Team

Natalia Neparidze

Principal Investigator

Yale University Cancer Center LAO

Eligibility Criteria

This trial is for patients with newly diagnosed high-risk multiple myeloma who may have had one cycle of bortezomib-based therapy. They should not have severe liver or kidney issues, and their immune system must be functioning at a certain level. People with HIV can join if they're on effective treatment.

Inclusion Criteria

I have been recently diagnosed with multiple myeloma.

I am mostly self-sufficient and can carry out daily activities.

I have chronic hepatitis B but it's under control with medication.

Exclusion Criteria

I do not have any uncontrolled illnesses or significant conditions.

I have recovered from side effects of previous cancer treatments, except for hair loss.

I need urgent multiple myeloma therapy and can start after initial treatment.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either the Dara-SVD or Dara-RVD regimen for up to 4 cycles, with each cycle lasting 28 days

16 weeks

Weekly visits for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

2 years

Follow-up visits at 6 months, 1 year, and 2 years

Treatment Details

Interventions

• Bortezomib
• Daratumumab
• Dexamethasone
• Selinexor

Trial Overview The study compares Dara-SVD (selinexor, daratumumab, Velcade/bortezomib, dexamethasone) to the usual Dara-RVD (daratumumab, lenalidomide, Velcade/bortezomib, dexamethasone). It's testing whether adding selinexor early in treatment offers better outcomes for those with aggressive myeloma.

Participant Groups

Group I: Arm I (Dara-SVD) Experimental Treatment 11 Interventions

Patients receive daratumumab and hyaluronidase-fihj SC on days 1, 8, 15, \& 22 for cycles 1-2, then days 1 \& 15 for cycles 3-4, and selinexor PO, bortezomib SC, and dexamethasone PO on days 1, 8, 15, \& 22 of each cycle. Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo PET, MRI, or CT, and bone marrow aspiration and biopsy, and collection of blood and urine samples throughout the study.

Group II: Arm II (Dara-RVD) Active Control 11 Interventions

Patients receive daratumumab and hyaluronidase-fihj SC on days 1, 8, 15, \& 22 for cycles 1-2, then days 1 \& 15 for cycles 3-4, lenalidomide PO QD on days 1-21 of each cycle, and bortezomib SC and dexamethasone PO on days 1, 8, 15, \& 22 of each cycle. Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo PET, MRI, or CT, and bone marrow aspiration and biopsy, and collection of blood and urine samples throughout the study.

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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

Selinexor, when used in combination with dexamethasone or bortezomib and dexamethasone, showed an overall response rate of 29.5% in 44 patients with relapsed or refractory myeloma, indicating its efficacy as a treatment option.

The most common side effects included fatigue and thrombocytopenia, with 56% of patients requiring dose reductions; however, these adjustments did not negatively impact progression-free survival, suggesting that selinexor can be managed safely in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real World Efficacy and Toxicity of Selinexor: Importance of Patient Characteristics, Dose Intensity and Post Progression Outcomes. Kastritis, E., Gavriatopoulou, M., Solia, E., et al.[2023]

Selinexor, when combined with low-dose bortezomib and dexamethasone, showed a 63% overall response rate in treating relapsed or refractory multiple myeloma, with particularly high efficacy in patients not previously resistant to proteasome inhibitors (84% response rate).

The treatment was generally well-tolerated, with the most common severe side effects being thrombocytopenia (45%) and neutropenia (24%), while the recommended phase 2 dose was established as selinexor 100 mg once weekly, bortezomib 1.3 mg/m2 once weekly, and dexamethasone 40 mg once weekly.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selinexor plus low-dose bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma. Bahlis, NJ., Sutherland, H., White, D., et al.[2021]

In the phase 3 BOSTON trial, the combination of selinexor, bortezomib, and dexamethasone significantly improved progression-free survival in adults with previously treated multiple myeloma compared to the standard bortezomib-dexamethasone regimen.

This triplet therapy demonstrated a manageable safety profile, with a lower incidence of peripheral neuropathy compared to the standard treatment, making it a promising option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selinexor-Bortezomib-Dexamethasone: A Review in Previously Treated Multiple Myeloma. Syed, YY.[2023]

In a study of 34 patients with relapsed refractory multiple myeloma, the combination of selinexor, daratumumab, and dexamethasone showed a promising overall response rate of 73% and a median progression-free survival of 12.5 months in patients who had not previously received daratumumab.

The maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) for selinexor was determined to be 100 mg once weekly, with common side effects including thrombocytopenia and nausea, indicating that the treatment regimen is generally well tolerated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selinexor, daratumumab, and dexamethasone in patients with relapsed or refractory multiple myeloma. Gasparetto, C., Lentzsch, S., Schiller, G., et al.[2022]

Selinexor, a selective inhibitor of nuclear export (SINE) compound, has shown promising efficacy in treating multiple myeloma (MM), particularly in patients with 'penta-refractory' MM, which is resistant to the five most effective current treatments.

Early phase clinical trials have established a safety profile for selinexor, especially when used in combination with low-dose dexamethasone, indicating it could be a valuable addition to existing treatment strategies for MM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Implications of Targeting XPO1-mediated Nuclear Export in Multiple Myeloma. Gandhi, UH., Senapedis, W., Baloglu, E., et al.[2023]

Selinexor, a first-in-class selective inhibitor of nuclear export (XPO1), has shown significant efficacy in treating relapsed refractory multiple myeloma (RRMM), leading to its FDA approval in combination with dexamethasone based on results from the pivotal phase II STORM trial.

The phase III BOSTON trial demonstrated that selinexor combined with bortezomib and dexamethasone is superior to the standard treatment of bortezomib and dexamethasone alone, although it is associated with a predictable toxicity profile that requires careful management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting Nuclear Export Proteins in Multiple Myeloma Therapy. Richard, S., Jagannath, S.[2022]

Selinexor, an oral treatment that inhibits nuclear export of tumor suppressor proteins, showed efficacy in a case series of 3 heavily treated multiple myeloma patients, achieving partial or very good partial responses despite their advanced disease status.

The combination of selinexor with bortezomib and dexamethasone (XVd) resulted in positive outcomes similar to those seen in less heavily pretreated patients, indicating its potential as a valuable option for relapsed or refractory multiple myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selinexor in Patients from Argentina with Multiple Myeloma Treated with Multiple Prior Therapies: A Case Series. Remaggi, G., Ochoa, PA., Garate, GM.[2022]

Selinexor is an oral medication that targets exportin-1 (XPO1), which is overexpressed in multiple myeloma, and has shown significant anti-myeloma effects in preclinical studies, both alone and in combination with other treatments.

Selinexor-based therapies have been approved for treating relapsed/refractory multiple myeloma, including specific combinations like selinexor-dexamethasone for advanced cases, demonstrating its efficacy in patients who have undergone multiple prior therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selinexor: Targeting a novel pathway in multiple myeloma. Mo, CC., Yee, AJ., Midha, S., et al.[2023]

References

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

Real World Efficacy and Toxicity of Selinexor: Importance of Patient Characteristics, Dose Intensity and Post Progression Outcomes. [2023]

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

Selinexor plus low-dose bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma. [2021]

3. France pubmed.ncbi.nlm.nih.gov

Selinexor-Bortezomib-Dexamethasone: A Review in Previously Treated Multiple Myeloma. [2023]

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

Selinexor, daratumumab, and dexamethasone in patients with relapsed or refractory multiple myeloma. [2022]

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

Clinical Implications of Targeting XPO1-mediated Nuclear Export in Multiple Myeloma. [2023]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Targeting Nuclear Export Proteins in Multiple Myeloma Therapy. [2022]

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

Selinexor in Patients from Argentina with Multiple Myeloma Treated with Multiple Prior Therapies: A Case Series. [2022]

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

Selinexor: Targeting a novel pathway in multiple myeloma. [2023]