Selinexor + Carfilzomib + Dexamethasone for Multiple Myeloma

(SINE Trial)

Recruiting at 4 trial locations

Overseen By Cancer Clinical Trials Office

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Chicago

Must not be taking: Anticancer therapy, Antivirals

Disqualifiers: Pregnancy, Heart failure, HIV, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 28 days per course

100 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial studies the side effects and best dose of selinexor and carfilzomib when given together with dexamethasone in treating patients with multiple myeloma that has returned or does not respond to treatment. Drugs used in chemotherapy, such as selinexor and dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Carfilzomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving selinexor, carfilzomib, and dexamethasone may be a better treatment for multiple myeloma.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have had radiation, chemotherapy, or immunotherapy within 2 weeks before starting the trial, and you cannot be on other anticancer therapies during the trial.

What data supports the effectiveness of the drug combination Selinexor, Carfilzomib, and Dexamethasone for treating multiple myeloma?

Research shows that the combination of Selinexor, Carfilzomib, and Dexamethasone can help control disease in patients with relapsed or refractory multiple myeloma, including those who are resistant to Carfilzomib. In a study, 71% of patients had at least a minimal response, and the median overall survival was 22.4 months. ^{1 2 3 4 5}

What makes the drug combination of Selinexor, Carfilzomib, and Dexamethasone unique for treating multiple myeloma?

This drug combination is unique because it includes Selinexor, which works by blocking a protein that helps cancer cells grow, making it different from other treatments that primarily target the cancer cells directly. This combination is used for patients with relapsed or refractory multiple myeloma, offering a novel approach by combining different mechanisms of action to tackle the disease. ^{6 7 8 9 10}

Research Team

Andrzej Jakubowiak, MD, PhD

Principal Investigator

University of Chicago

Eligibility Criteria

Adults with relapsed or refractory multiple myeloma, who have tried at least two prior therapies including a proteasome inhibitor and a cereblon-binding agent. They must have measurable disease, be able to follow the study schedule, and use effective contraception if of childbearing potential. Excluded are those with recent major surgery, known allergies to certain drug components, serious medical conditions that could interfere with treatment, previous Selinexor exposure, unstable heart conditions, active infections like HIV or hepatitis B/C.

Inclusion Criteria

Your bilirubin level is not too high, unless you have Gilbert's syndrome, in which case it can be a little higher.

Written informed consent in accordance with federal, local, and institutional guidelines

I have a measurable plasmacytoma that needs PI review before I join.

Exclusion Criteria

I am HIV positive.

I am allergic or cannot tolerate certain medications, including blood thinners, antiviral drugs, or fluids due to heart or lung problems.

I haven't had any bleeding issues or coagulation problems in the last month.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive selinexor, carfilzomib, and dexamethasone. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

28 days per course

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-ups at 30 days and then every 3 months for 2 years.

2 years

Treatment Details

Interventions

• Carfilzomib
• Dexamethasone
• Selinexor

Trial Overview The trial is testing the combination of selinexor and carfilzomib with dexamethasone to find the best dose and side effects for treating multiple myeloma that has returned after treatment or is not responding. Selinexor and dexamethasone are chemotherapy drugs while carfilzomib blocks enzymes needed for cancer cell growth.

Participant Groups

Group I: Selinexor, carfilzomib, dexamethasone Experimental Treatment 3 Interventions

Patients receive selinexor PO, carfilzomib IV, and dexamethasone PO QD or IV. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

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 Chicago

Lead Sponsor

Trials

1,086

Recruited

844,000+

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]

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]

In a study involving 122 patients with triple-class refractory myeloma, the combination of selinexor and dexamethasone resulted in a partial response or better in 26% of patients, demonstrating its potential efficacy as a treatment option for those who have not responded to existing therapies.

While selinexor was associated with common side effects like fatigue and nausea, it also led to significant thrombocytopenia in 73% of patients, highlighting the need for careful monitoring of blood cell counts during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral Selinexor-Dexamethasone for Triple-Class Refractory Multiple Myeloma. Chari, A., Vogl, DT., Gavriatopoulou, M., et al.[2023]

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]

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]

In a study comparing lenalidomide-dexamethasone (len/dex) and melphalan-prednisone-lenalidomide (MPR) in 89 elderly patients with myeloma, both treatments showed similar efficacy in terms of time to progression, progression-free survival, and overall survival, indicating that either regimen can be effective for this patient group.

However, MPR was associated with significantly higher rates of severe hematologic toxicities, such as neutropenia and thrombocytopenia, suggesting that while both treatments are effective, len/dex may be a safer option with fewer severe side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenalidomide plus dexamethasone vs. lenalidomide plus melphalan and prednisone: a retrospective study in newly diagnosed elderly myeloma. Gay, F., Vincent Rajkumar, S., Falco, P., et al.[2018]

In a study of 1671 rheumatoid arthritis patients, the combination of methotrexate (MTX) and leflunomide (LEF) showed a comparable safety profile to MTX or LEF alone, with no increased risk of serious adverse events (SAEs).

The MTX + LEF combination had a significantly lower risk of SAEs and serious infections compared to biologic DMARDs and Janus kinase inhibitors, suggesting it may be a safer alternative for patients starting treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of the Methotrexate-leflunomide Combination in Rheumatoid Arthritis: Results of a Multicentric, Registry-based, Cohort Study (BiobadaBrasil). Bredemeier, M., Ranza, R., Kakehasi, AM., et al.[2022]

In a study of 18 stable renal transplant patients, the combination of mycophenolate mofetil (MMF) and tacrolimus resulted in significantly higher levels of mycophenolic acid (MPA) compared to those receiving MMF with cyclosporine, indicating enhanced bioavailability and potential efficacy of MMF when used with tacrolimus.

The combination of tacrolimus and MMF showed a greater immunosuppressive effect in vitro, suggesting that this drug pairing may provide a more effective immunosuppressive strategy for renal transplant patients than previously understood.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Unexpected augmentation of mycophenolic acid pharmacokinetics in renal transplant patients receiving tacrolimus and mycophenolate mofetil in combination therapy, and analogous in vitro findings. Zucker, K., Rosen, A., Tsaroucha, A., et al.[2019]

Leflunomide, particularly its active metabolite A77 1726, has shown high tolerability and efficacy in treating advanced rheumatoid arthritis, with effective daily dosages of 10 mg and 25 mg, although the higher dose is linked to more side effects.

The drug works by inhibiting T- and B-cell proliferation and affecting cytokine signaling, with ongoing phase III trials aimed at confirming its effectiveness and safety in larger populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Leflunomide and malononitrilamides. Silva Júnior, HT., Morris, RE.[2021]

In a study of 75 patients with relapsed or refractory multiple myeloma, the combination of carfilzomib and dexamethasone (Kd56) showed a 60% overall response rate and a median progression-free survival (PFS) of 10 months, indicating its efficacy in a real-world clinical setting.

The treatment was well tolerated, with a low rate of adverse events, including no cases of neuropathy and only 10% of patients experiencing cardiovascular events above grade 3, suggesting a favorable safety profile for elderly and heavily pretreated patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carfilzomib plus dexamethasone in patients with relapsed and refractory multiple myeloma: A retro-prospective observational study. Del Giudice, ML., Gozzetti, A., Antonioli, E., 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. United States pubmed.ncbi.nlm.nih.gov

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

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

Oral Selinexor-Dexamethasone for Triple-Class Refractory Multiple Myeloma. [2023]

4. France pubmed.ncbi.nlm.nih.gov

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

5. 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]

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

Lenalidomide plus dexamethasone vs. lenalidomide plus melphalan and prednisone: a retrospective study in newly diagnosed elderly myeloma. [2018]

7. Canada pubmed.ncbi.nlm.nih.gov

Safety of the Methotrexate-leflunomide Combination in Rheumatoid Arthritis: Results of a Multicentric, Registry-based, Cohort Study (BiobadaBrasil). [2022]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Unexpected augmentation of mycophenolic acid pharmacokinetics in renal transplant patients receiving tacrolimus and mycophenolate mofetil in combination therapy, and analogous in vitro findings. [2019]

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

Leflunomide and malononitrilamides. [2021]

10. England pubmed.ncbi.nlm.nih.gov

Carfilzomib plus dexamethasone in patients with relapsed and refractory multiple myeloma: A retro-prospective observational study. [2023]