Selinexor + Daratumumab + Carfilzomib + Dexamethasone for Multiple Myeloma

Recruiting at 3 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Academic and Community Cancer Research United

Disqualifiers: Uncontrolled hypertension, Significant cardiac disease, Hepatitis B, 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: 4

Duration: Up to 5 years

52 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies the effect of selinexor when combined with carfilzomib, daratumumab, and dexamethasone in treating patients with high-risk multiple myeloma that has come back (recurrent) or has not responded to treatment (refractory) and who have received 1-3 prior lines of therapy. Selinexor may stop the growth of cancer cells by blocking a protein called CRM1 that is needed for cell growth. Carfilzomib is a type of drug called a proteasome inhibitor. A proteasome is a protein found within cells that has the important role of identifying and marking damaged proteins that are needed to be destroyed by the cell for survival. The inhibition of the proteasome allows for damaged protein to accumulate within cells. This accumulation of damaged protein causes the cell to die. Daratumumab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Anti-inflammatory drugs, such as dexamethasone lower the body's immune response and are used with other drugs in the treatment of some types of cancer. Giving selinexor in combination with carfilzomib, daratumumab, and dexamethasone may work better than carfilzomib, daratumumab, and dexamethasone alone in treating patients with 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 any multiple myeloma therapy within 14 days before starting the trial treatment.

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

Research shows that combining Selinexor with Carfilzomib and Dexamethasone (SKd) was effective in controlling disease in patients with relapsed or refractory multiple myeloma, with a 71% rate of at least minimal response. Additionally, Selinexor with Daratumumab and Dexamethasone (SDd) showed a 73% overall response rate in patients who had not previously received Daratumumab, suggesting promising efficacy. ^{1 2 3 4 5}

Is the combination of Selinexor, Daratumumab, Carfilzomib, and Dexamethasone safe for humans?

The combination of Selinexor, Carfilzomib, and Dexamethasone has been studied in patients with relapsed or refractory multiple myeloma, showing some common side effects like low blood cell counts, fatigue, and nausea. The combination of Carfilzomib, Dexamethasone, and Daratumumab has also been found to have tolerable safety in similar patients. Overall, these treatments have shown manageable safety profiles, but they can cause significant side effects that need careful management. ^{1 2 3 4 6}

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

This drug combination is unique because it includes Selinexor, an oral selective inhibitor of nuclear export, which works with other drugs to overcome resistance in relapsed or refractory multiple myeloma. The combination targets different pathways, potentially offering a new option for patients who have not responded to other treatments. ^{1 2 5 7 8}

Research Team

Shebli Atrash

Principal Investigator

Academic and Community Cancer Research United

Eligibility Criteria

This trial is for adults with high-risk multiple myeloma that has returned or hasn't responded to treatment, having had 1-3 prior therapies. Participants must have adequate organ function and agree to use effective contraception. Those who've had certain toxic reactions to similar drugs, uncontrolled diseases, or specific infections can't join.

Inclusion Criteria

I have had 1 to 3 treatments for my condition before.

I signed the consent form less than 28 days ago.

Ability to complete questionnaire(s) by themselves or with assistance

Exclusion Criteria

You have tested positive for hepatitis C.

Receiving any other investigational agent considered as a treatment for the primary neoplasm

I have not taken daratumumab in the last 24 weeks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive carfilzomib, daratumumab, dexamethasone, and selinexor in 28-day cycles

Up to 5 years

Multiple visits per cycle, including days 1, 8, 15, and 22

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Every 3 months until progression, then every 6 months

Treatment Details

Interventions

• Carfilzomib
• Daratumumab
• Dexamethasone
• Selinexor

Trial Overview The study tests selinexor combined with carfilzomib, daratumumab, and dexamethasone in patients with recurrent or refractory multiple myeloma. It aims to see if this mix works better than the standard trio of drugs alone by blocking proteins that cancer cells need.

Participant Groups

Group I: Treatment (carfilzomib, daratumumab, dexamethasone, selinexor) Experimental Treatment 5 Interventions

Patients receive carfilzomib IV over 30 minutes on days 1, 8, and 15 and daratumumab IV on days 1 and 2 of cycle 1 then days 8, 15, and 22 of cycle 1, then, days 1, 8, 15, and 22 of cycle 2, days 1 and 15 of cycles 3-6, and day 1 of subsequent cycles. Patients also receive dexamethasone PO on days 1, 8 15, and 22, and selinexor PO on days 1, 8, and 15. Cycles 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?

Academic and Community Cancer Research United

Lead Sponsor

Trials

54

Recruited

4,900+

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]

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]

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]

In a phase 3 study involving 466 patients with relapsed or refractory multiple myeloma, the combination of carfilzomib, dexamethasone, and daratumumab (KdD) significantly improved progression-free survival compared to carfilzomib and dexamethasone alone (Kd), with a hazard ratio of 0.63, indicating a 37% reduction in the risk of disease progression.

Despite a higher incidence of grade 3 or higher adverse events in the KdD group (82%) compared to the Kd group (74%), the overall safety profile was considered favorable, with similar rates of treatment discontinuation due to adverse events in both groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): results from a randomised, multicentre, open-label, phase 3 study. Dimopoulos, M., Quach, H., Mateos, MV., et al.[2020]

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, 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, 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]

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

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

3. England pubmed.ncbi.nlm.nih.gov

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

4. England pubmed.ncbi.nlm.nih.gov

Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): results from a randomised, multicentre, open-label, phase 3 study. [2020]

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

8. France pubmed.ncbi.nlm.nih.gov

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