Selinexor Combination Therapy for Multiple Myeloma

Overseen By Derek Schatz

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Colorado, Denver

Must not be taking: XPO1 inhibitors

Disqualifiers: Uncontrolled hypertension, Diabetes, Infection, 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: 29

Duration: Variable (until progression or toxicity)

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination therapy for individuals with multiple myeloma, a type of blood cancer that has returned after treatment or hasn't responded well to previous treatments. The aim is to evaluate the effectiveness of the drug selinexor (a nuclear export inhibitor) when combined with other medications like pomalidomide, daratumumab, or carfilzomib. Participants will join one of three groups, each receiving a different combination of these drugs. This trial may suit those whose multiple myeloma progressed after previous treatments and who seek new options. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of people.

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

The trial protocol does not specify whether you need to stop taking your current medications. However, it does mention that you should not have received selinexor or another XPO1 inhibitor in a previous line of therapy. It's best to discuss your current medications with the trial team to ensure they don't interfere with the study.

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

A previous study found that the combination of selinexor, pomalidomide, and dexamethasone was generally well-tolerated by patients with relapsed or refractory multiple myeloma. Most patients managed the treatment without major issues, though some experienced side effects like nausea and low blood cell counts. Adjusting the selinexor dose reduced these side effects while maintaining treatment effectiveness.

Research has shown that the combination of selinexor, daratumumab, and dexamethasone also caused common side effects such as low platelet counts, nausea, and tiredness. These adverse events were common but manageable.

For the selinexor, carfilzomib, and dexamethasone combination, studies found it effective and generally well-tolerated, though side effects like tiredness and low blood cell counts were noted. The combination was adjusted in some cases to find the optimal dose that minimized these effects.

Overall, these treatments have been used in other studies and have demonstrated manageable safety profiles, meaning they are generally safe for most patients with some known side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for multiple myeloma because they combine existing medications with Selinexor, which has a unique way of working. Unlike most treatments that target the cancer cells directly, Selinexor works by blocking a protein that helps cancer cells grow and survive. This approach could potentially enhance the effectiveness of other drugs like Pomalidomide, Daratumumab, and Carfilzomib when used together. Additionally, these combinations offer diverse treatment options, allowing for personalized therapy based on patient needs. This versatility and novel action mechanism have the potential to improve outcomes for patients with multiple myeloma.

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

This trial will evaluate three different treatment combinations for multiple myeloma. Research has shown that the combination of selinexor, pomalidomide, and dexamethasone (SPd), which participants in one arm of this trial may receive, maintains an 83.3% response rate over 12 months. Another arm will test the selinexor, daratumumab, and dexamethasone (SDd) combination, with early results suggesting strong responses in patients who did not respond to lenalidomide, another treatment. The third arm will evaluate the selinexor, carfilzomib, and dexamethasone (SKd) combination, which demonstrated a 78% overall response rate, with many patients experiencing significant improvements. These combinations offer promising options for those with multiple myeloma that has returned or is not responding to other treatments. ^{3 4 6 7 8}

Who Is on the Research Team?

Daniel Sherbenou, MD

Principal Investigator

University of Colorado, Denver

Are You a Good Fit for This Trial?

This trial is for adults over 18 with relapsed or refractory multiple myeloma, who have measurable disease and whose cancer has progressed after treatment. They must be able to consent, have an ECOG Performance Status of ≤2, adequate organ function, and agree to use effective contraception. Excluded are those with certain heart conditions, uncontrolled medical issues, previous selinexor therapy, major surgery within the last month or active infections.

Inclusion Criteria

I can take care of myself but might not be able to do heavy physical work.

My liver is working well.

Patients must have a disease that can be measured.

Exclusion Criteria

Pregnant or breastfeeding females.

I have not had a heart attack in the last 3 months.

Patients unwilling or unable to comply with the protocol, including providing 24-hour urine samples for urine protein electrophoresis at the required time points.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive selinexor-based combination therapy in 28-day cycles until disease progression, unacceptable toxicity, or death

Variable (until progression or toxicity)

Weekly visits during each 28-day cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Regular visits as per study protocol

Open-label extension (optional)

Participants may opt into continuation of treatment long-term

Long-term

What Are the Treatments Tested in This Trial?

Interventions

• Carfilzomib
• Daratumumab
• Dexamethasone
• Pomalidomide
• Selinexor

Trial Overview

The trial tests Selinexor combined with other drugs in three different mixes (SPd: Selinexor + pomalidomide + dexamethasone; SDd: Selinexor + daratumumab + dexamethasone; SKd: Selinexor + carfilzomib + dexamethasone) against multiple myeloma. Participants will be assigned to one of these treatment arms based on physician's choice compared to drug sensitivity testing results.

How Is the Trial Designed?

Group I: Arm 3 SKd Experimental Treatment 3 Interventions

* Selinexor 80 mg PO days 1, 8, 15 * Carfilzomib IV infusion 20 mg/m2 cycle 1, day 1, 56 mg/m2 cycle 1 day 8, 15. Cycle 2+ days 1, 8, 15. * Dexamethasone 40 mg IV or PO days 1, 8, 15, 22 * 28 day treatment cycle

Group II: Arm 2 SDd Experimental Treatment 3 Interventions

* Selinexor 80 mg PO days 1, 8, 15 * Daratumumab 1,800mg/30,000 units subcutaneous injection on days 1, 8, 15, 22 of cycles 1 and 2, days 1, 15 of cycles 3-6, day 1 of cycles \>6 * Dexamethasone 40 mg PO or IV days 1, 8, 15, 22 * 28 day treatment cycle

Group III: Arm 1 SPd Experimental Treatment 3 Interventions

* Selinexor 60 mg PO days 1, 8, 15 * Pomalidomide 4 mg PO on days 1-21 * Dexamethasone 40 mg PO or IV on days 1, 8, 15, 22 * 28 day treatment cycles

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

Approved in United States as Kyprolis for:

• Multiple myeloma

Approved in European Union as Kyprolis for:

• Multiple myeloma

Approved in Canada as Kyprolis for:

• Multiple myeloma

Approved in Japan as Kyprolis for:

• Multiple myeloma

Who Is Running the Clinical Trial?

University of Colorado, Denver

Lead Sponsor

Trials

1,842

Recruited

3,028,000+

Karyopharm Therapeutics Inc

Industry Sponsor

Trials

89

Recruited

7,200+

Richard Paulson

Karyopharm Therapeutics Inc

Chief Executive Officer since 2021

MBA from the University of Toronto's Rotman School of Management

Reshma Rangwala

Karyopharm Therapeutics Inc

Chief Medical Officer since 2023

MD, PhD

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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]

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 a phase I trial involving 21 patients with relapsed/refractory multiple myeloma, the combination of selinexor, carfilzomib, and dexamethasone was found to be tolerable, with a recommended phase II dose established at selinexor 60 mg, carfilzomib 20/27 mg/m2, and dexamethasone 20 mg.

The treatment resulted in significant response rates, with 71% of patients achieving at least a minimal response and a median overall survival of 22.4 months, demonstrating its efficacy even in patients who were refractory to carfilzomib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 study of selinexor plus carfilzomib and dexamethasone for the treatment of relapsed/refractory multiple myeloma. Jakubowiak, AJ., Jasielec, JK., Rosenbaum, CA., et al.[2023]

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, 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]

The combination of selinexor, carfilzomib, and dexamethasone (XKd) demonstrated a high overall response rate of 78% in patients with relapsed refractory multiple myeloma, indicating strong efficacy.

The treatment was well-tolerated, with manageable side effects such as thrombocytopenia and nausea, and the maximum-tolerated dose was established as selinexor 80 mg, carfilzomib 56 mg/m2, and dexamethasone 40 mg, all administered weekly.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Once weekly selinexor, carfilzomib and dexamethasone in carfilzomib non-refractory multiple myeloma patients. Gasparetto, C., Schiller, GJ., Tuchman, SA., et al.[2022]

Selinexor (XPOVIO™) is a novel oral medication that inhibits Exportin-1 (XPO1) and has been approved for treating relapsed or refractory multiple myeloma (RRMM) in adults, marking a significant advancement in cancer therapy.

The drug is currently being tested for effectiveness in various other types of blood and solid tumors, indicating its potential as a versatile treatment option in oncology.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selinexor: First Global Approval. Syed, YY.[2023]

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]

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This phase I trial studies the side effects and best dose of selinexor and carfilzomib when given together with dexamethasone in treating patients with ...