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)

18 Participants Needed

Trial Summary

What is the purpose of this trial?

Selinexor (KPT-330, Xpovio) is a first in class selective inhibitor of nuclear export which has been approved for use in relapsed and refractory multiple myeloma (RRMM). This trial will seek to evaluate the outcomes achieved with selinexor based combination in RRMM selected by physician's choice and compared prospectively to ex vivo drug sensitivity testing results. Participants will be enrolled and assigned into one of the following treatment arms: Arm 1: Selinexor + pomalidomide + dexamethasone (SPd) Arm 2: Selinexor + daratumumab + dexamethasone (SDd) Arm 3: Selinexor + carfilzomib + dexamethasone (SKd)

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.

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

Research shows that the combination of Selinexor with other drugs like carfilzomib and dexamethasone can help control multiple myeloma, even in patients whose disease has returned or resisted other treatments. In a study, 71% of patients had at least a minimal response, and the combination was effective in patients who were resistant to carfilzomib, a key drug in the treatment. ^{1 2 3 4 5}

Is Selinexor combination therapy safe for humans?

Selinexor combination therapy has been tested in clinical trials for multiple myeloma, showing some common side effects like low blood cell counts (thrombocytopenia, anemia, neutropenia), fatigue, and infections. While generally tolerable, there was a case of cardiac failure as a dose-limiting toxicity, indicating the need for careful monitoring during treatment. ^{1 2 3 6 7}

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

The Selinexor combination therapy is unique because it includes Selinexor, an oral drug that targets a novel pathway by inhibiting exportin-1, which is overexpressed in multiple myeloma. This mechanism helps retain tumor suppressor proteins in the nucleus, enhancing the effectiveness of other drugs in the combination and offering a new option for patients with relapsed or refractory multiple myeloma. ^{1 2 3 6 8}

Research Team

Daniel Sherbenou, MD

Principal Investigator

University of Colorado, Denver

Eligibility Criteria

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 am 18 years old or older.

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

My liver is working well.

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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, 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, 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, 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, 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]

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 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. England pubmed.ncbi.nlm.nih.gov

Phase 1 study of selinexor plus carfilzomib and dexamethasone for the treatment of relapsed/refractory multiple myeloma. [2023]

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

Once weekly selinexor, carfilzomib and dexamethasone in carfilzomib non-refractory multiple myeloma patients. [2022]

3. 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]

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

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

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

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

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

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

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

Selinexor: First Global Approval. [2023]

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

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