Selinexor + Ruxolitinib + Methylprednisolone for Multiple Myeloma

(KPT-IST-391 Trial)

Overseen By Yohana Sebhat

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: Oncotherapeutics

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: Ruxolitinib, Selinexor, Amyloidosis, 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 cycle

30 Participants Needed

Trial Summary

What is the purpose of this trial?

Selinexor, a first-in-class, oral selective exportin 1 (XPO1) inhibitor, has shown promise in pre-clinical and clinical studies. It functions by inhibiting the nuclear export protein XPO1, resulting in the accumulation of tumor suppressor proteins and inhibition of oncoprotein mRNAs, which is selectively lethal to myeloma cells. Selinexor has demonstrated activity in combination with various drugs, including glucocorticoids and proteasome inhibitors, leading to its FDA approval for the treatment of relapsed or refractory multiple myeloma.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot use certain drugs like strong CYP3A4 inhibitors or inducers, and some medications must be stopped a few weeks before starting the trial. It's best to discuss your current medications with the trial team.

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

Research shows that Ruxolitinib combined with steroids like methylprednisolone has shown significant clinical activity in heavily-treated multiple myeloma patients, with a 31% overall response rate. Additionally, Selinexor, when combined with dexamethasone, has demonstrated increased effectiveness in reducing multiple myeloma markers, suggesting potential benefits when used in combination therapies. ^{1 2 3 4 5}

Is the combination of Selinexor, Ruxolitinib, and Methylprednisolone safe for humans?

Selinexor and Ruxolitinib have been studied in combination with other drugs for multiple myeloma, showing manageable safety profiles. Common side effects include low blood cell counts and fatigue, but serious issues like infections can occur. Methylprednisolone, a steroid, is generally safe but can cause side effects like increased blood sugar and mood changes. ^{1 5 6 7 8}

What makes the drug combination of Selinexor, Ruxolitinib, and Methylprednisolone unique for treating multiple myeloma?

This drug combination is unique because it includes Selinexor, a first-in-class selective inhibitor of exportin-1, which has shown effectiveness in heavily pretreated multiple myeloma patients when combined with other agents. The addition of Ruxolitinib and Methylprednisolone may offer a novel approach by potentially enhancing the anti-cancer effects and providing a new option for patients who are resistant to traditional therapies. ^{3 4 6 8 9}

Research Team

James Berenson, MD

Principal Investigator

Oncotherapeutics

Eligibility Criteria

This trial is for adults over 18 with relapsed/refractory multiple myeloma who've had at least three prior treatments, including an IMiD and a PI. They must be able to consent, follow the visit schedule, and have specific levels of renal insufficiency, anemia, bone lesions or hypercalcemia. Those with certain severe health conditions are excluded.

Inclusion Criteria

I have multiple myeloma and have tried at least three different treatments.

I am taking or have taken an IMiD medication.

I am willing and able to give written consent for the trial before any screening procedures.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Selinexor, Ruxolitinib, and Methylprednisolone following a 3+3 dose escalation schedule

28 days per cycle

Weekly visits for dose administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

30 months

Treatment Details

Interventions

• Methylprednisolone
• Ruxolitinib
• Selinexor

Trial Overview The trial tests Selinexor combined with Ruxolitinib and Methylprednisolone in patients with multiple myeloma. Selinexor inhibits XPO1 to kill cancer cells; it's approved by FDA for this cancer type when used with other drugs.

Participant Groups

Group I: Experimental: Selinexor/Ruxolitinib/Steroids Experimental Treatment 3 Interventions

The regimen will follow a 3+3 dose escalation schedule starting at dose level 0. Subjects enrolled at dose level 0 will receive 1) selinexor (once weekly) starting at 40 mg, 2) ruxolitinib (twice a day (BID) on days 1-28) starting at 10 mg, and 3) oral methylprednisolone (every other day (QOD)) a set dose at 40 mg. Subjects at dose level 1 will receive 1) selinexor (once weekly) 60 mg, 2) ruxolitinib (BID) on days 1-28 10 mg, and 3) methylprednisolone (QOD) 40 mg. Subjects at dose level 2 will receive 1) selinexor (once weekly) 60 mg, 2) ruxolitinib (BID) on days 1-28 15 mg, and 3) oral methylprednisolone (QOD) 40 mg.

Who Is Running the Clinical Trial?

Oncotherapeutics

Lead Sponsor

Trials

23

Recruited

940+

Findings from Research

In a phase I trial involving 28 patients with relapsed/refractory multiple myeloma, ruxolitinib combined with lenalidomide and methylprednisolone showed a clinical benefit rate of 46% and an overall response rate of 38%, indicating its potential effectiveness in overcoming resistance to lenalidomide.

The trial reported no dose-limiting toxicities, suggesting that ruxolitinib is safe to use in this combination therapy, although some patients experienced grade 3 or 4 adverse events like anemia and thrombocytopenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase I Study of Ruxolitinib, Lenalidomide, and Steroids for Patients with Relapsed/Refractory Multiple Myeloma. Berenson, JR., To, J., Spektor, TM., et al.[2021]

In a study involving 29 patients with multiple myeloma who had undergone extensive prior treatments, the combination of ruxolitinib and methylprednisolone showed a 31% overall response rate, indicating significant clinical activity in this heavily-treated population.

The treatment was well tolerated, with a median duration of response of 13.1 months and median progression-free survival of 3.4 months, suggesting that JAK inhibitors may be a promising option for patients with multiple myeloma, including those with high-risk cytogenetics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib and methylprednisolone for treatment of patients with relapsed/refractory multiple myeloma. Berenson, JR., Martinez, D., Safaie, T., et al.[2023]

In a phase 1 study involving 84 patients with relapsed or refractory multiple myeloma, the combination of oral selinexor and dexamethasone showed a significant increase in efficacy, achieving a 50% objective response rate compared to a modest 4% with selinexor alone.

The most common side effects were manageable and primarily grade 1 or 2, with thrombocytopenia being the most notable severe adverse event at 45%, indicating that while selinexor is effective, monitoring for blood-related side effects is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of selinexor in relapsed or refractory multiple myeloma and Waldenstrom macroglobulinemia. Chen, C., Siegel, D., Gutierrez, M., 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]

Ruxolitinib, when combined with lenalidomide and methylprednisolone, shows potential to overcome resistance to lenalidomide in patients with relapsed/refractory multiple myeloma, achieving a clinical benefit rate of 49% and an overall response rate of 36% in a Phase I trial with 49 participants.

The trial demonstrated that ruxolitinib was safe, with no dose-limiting toxicities reported, although some patients experienced grade 3 or 4 adverse events, including anemia and decreased lymphocyte count, indicating a manageable safety profile for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1 study of ruxolitinib, steroids and lenalidomide for relapsed/refractory multiple myeloma patients. Berenson, JR., Kim, C., Bujarski, S., et al.[2022]

Selinexor-based treatments, particularly the combination of selinexor, dexamethasone, and proteasome inhibitors (SEL + DEX + PIs), showed higher efficacy in treating multiple myeloma, with an overall response rate of 54% compared to 24% for the SEL + DEX combination.

The SEL + DEX + PIs regimen also demonstrated lower incidences of severe adverse events, such as hyponatremia and anemia, indicating a better safety profile compared to the SEL + DEX treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy Analysis of Selinexor-Based Treatment in Multiple Myeloma, a Meta-Analysis Based on Prospective Clinical Trials. Tao, Y., Zhou, H., Niu, T.[2021]

Selinexor is a first-in-class oral medication that works by inhibiting nuclear export, leading to the retention of oncogene mRNAs and reactivation of tumor suppressor proteins, which triggers cell death in multiple myeloma (MM) cells.

In clinical studies, selinexor has shown manageable side effects and promising effectiveness in treating relapsed and refractory MM, indicating its potential to improve outcomes for patients with limited treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selinexor for the treatment of patients with previously treated multiple myeloma. Mo, CC., Jagannath, S., Chari, A., et al.[2022]

Selinexor combined with dexamethasone has shown improved response rates and duration in heavily pretreated multiple myeloma patients compared to traditional treatments, without causing excessive toxicity.

The combination of selinexor with other agents like bortezomib, carfilzomib, and IMiDs has demonstrated a durable response and a tolerable safety profile, making it a promising option for patients with relapsed and refractory multiple myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of selinexor-based regimens for relapsed/refractory multiple myeloma: a systematic review of literature. Masood, A., Iqbal, Q., Ehsan, H., et al.[2022]

In a phase 3 trial involving 402 patients with previously treated multiple myeloma, the combination of selinexor, bortezomib, and dexamethasone resulted in a median progression-free survival of 13.93 months, significantly longer than the 9.46 months observed with standard bortezomib and dexamethasone (p=0.0075).

The selinexor combination therapy was associated with lower rates of peripheral neuropathy (21%) compared to the standard treatment (34%), suggesting a safer profile regarding this common side effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Once-per-week selinexor, bortezomib, and dexamethasone versus twice-per-week bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a randomised, open-label, phase 3 trial. Grosicki, S., Simonova, M., Spicka, I., et al.[2022]

References

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

A Phase I Study of Ruxolitinib, Lenalidomide, and Steroids for Patients with Relapsed/Refractory Multiple Myeloma. [2021]

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

Ruxolitinib and methylprednisolone for treatment of patients with relapsed/refractory multiple myeloma. [2023]

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

Safety and efficacy of selinexor in relapsed or refractory multiple myeloma and Waldenstrom macroglobulinemia. [2021]

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

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

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

A phase 1 study of ruxolitinib, steroids and lenalidomide for relapsed/refractory multiple myeloma patients. [2022]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Safety and Efficacy Analysis of Selinexor-Based Treatment in Multiple Myeloma, a Meta-Analysis Based on Prospective Clinical Trials. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Selinexor for the treatment of patients with previously treated multiple myeloma. [2022]

8. Germany pubmed.ncbi.nlm.nih.gov

Efficacy and safety of selinexor-based regimens for relapsed/refractory multiple myeloma: a systematic review of literature. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Once-per-week selinexor, bortezomib, and dexamethasone versus twice-per-week bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a randomised, open-label, phase 3 trial. [2022]