Selinexor + DRd for Multiple Myeloma

Recruiting in Palo Alto (17 mi)

+10 other locations

Overseen by Robert M Rifkin, MD, FACP

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Waitlist Available

Sponsor: US Oncology Research

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This is a single-arm, phase II, open-label trial to investigate the effects of selinexor (S) in combination with daratumumab, lenalidomide, and dexamethasone (DRd) for first-line treatment of multiple myeloma (MM). FDA has approved selinexor plus dexamethasone in multiple myeloma after four prior therapies, and DRd is also already approved by the FDA for multiple myeloma. This study will use all four (S-DRd) together to treat MM as an initial treatment.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop your current medications. However, since this is a first-line treatment for multiple myeloma, it's likely that you may need to adjust your current medications. Please consult with the trial investigators for specific guidance.

What data supports the idea that Selinexor + DRd for Multiple Myeloma is an effective drug?

The available research shows that the combination of Selinexor with Daratumumab and Dexamethasone (SDd) is effective for treating multiple myeloma. In a study with 34 patients, 73% of them responded positively to the treatment, and those who had not previously been treated with Daratumumab had a median time of 12.5 months before the disease worsened. This suggests that the combination is promising, especially for patients who have tried other treatments without success. Compared to another combination involving Selinexor, Bortezomib, and Dexamethasone (SVd), which had a 63% response rate, the SDd combination shows a higher response rate, indicating its potential effectiveness. ^{1 2 3 4 5}

What safety data exists for the treatment of Selinexor + DRd in multiple myeloma?

The combination of Selinexor, Daratumumab, and Dexamethasone (SDd) has been studied for safety in patients with relapsed or refractory multiple myeloma. In a study with 34 patients, common treatment-related adverse events included thrombocytopenia (70.6%), nausea (70.6%), fatigue (61.8%), anemia (61.8%), and neutropenia (50.0%). The maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) for Selinexor was determined to be 100 mg once weekly. The treatment was generally well tolerated, with no dose-limiting toxicities reported at this dose. Other studies have shown that Selinexor, when combined with other agents like bortezomib and dexamethasone, has a predictable toxicity profile, with common side effects including thrombocytopenia, anemia, neutropenia, fatigue, nausea, anorexia, and weight loss. These side effects are significant but manageable with aggressive and preemptive care. ^{1 2 3 4 6}

Is the drug combination of Selinexor, Daratumumab, Dexamethasone, and Lenalidomide promising for treating Multiple Myeloma?

Yes, the combination of Selinexor, Daratumumab, Dexamethasone, and Lenalidomide shows promise for treating Multiple Myeloma. It has a high overall response rate of 73% in patients who haven't been treated with Daratumumab before, and it helps patients live longer without the disease getting worse for about 12.5 months. This suggests it could be a valuable option for patients who have tried other treatments. ^{1 2 3 4 5}

Eligibility Criteria

Adults with untreated multiple myeloma can join this trial. They must be able to follow the study plan and use effective birth control if they can have children. People who've had major surgery recently, have brain involvement by myeloma, HIV, hepatitis B or C, serious heart issues, or certain blood conditions cannot participate.

Inclusion Criteria

I am 18 years old or older.

I am able to care for myself and perform daily activities.

You have a detectable disease that meets certain standards.

Exclusion Criteria

I do not have any health conditions that could affect the study.

You are thinking about getting pregnant.

My multiple myeloma has affected my brain or spinal cord.

Treatment Details

Interventions

• Daratumumab (Monoclonal Antibodies)
• Dexamethasone Oral (Corticosteroid)
• Lenalidomide (Immunomodulatory Agent)
• Selinexor (Selective Inhibitor of Nuclear Export (SINE))

Trial Overview The trial is testing a combination of four drugs: Selinexor plus Daratumumab, Lenalidomide, and Dexamethasone (S-DRd) as a first-line treatment for multiple myeloma. It's an open-label phase II study where everyone gets the same treatment.

Participant Groups

Group I: Selinexor plus DRd Experimental Treatment 4 Interventions

1. Lenalidomide 15 mg orally on Days 1-21 of each 28-day cycle 2. Dexamethasone 40 mg on Days 1, 8, 15, 22 of each cycle. However, those \>75 years old may be administered a weekly dose of 20 mg dexamethasone. 3. Daratumumab 1800 mg subcutaneous injection once weekly in Cycles 1 and 2, every 2 weeks in cycles 3 to 6, and every 4 weeks thereafter. 4. Selinexor 60 mg on Days 1, 8, 15, of cycles 1-3, with a planned dose-reduction to 40 mg on Days 1, 8, 15 for cycles beyond 3. If patient was previously dose reduced prior to cycle 4, then at cycle 4 planned dose reduction, you will again decrease dose by 1 level.

Daratumumab is already approved in European Union, United States for the following indications:

🇪🇺 Approved in European Union as Darzalex for:

• Relapsed and refractory multiple myeloma
• Newly diagnosed multiple myeloma in combination with bortezomib, melphalan, and prednisone

🇺🇸 Approved in United States as Darzalex for:

• Multiple myeloma in patients who have received at least three prior therapies
• Newly diagnosed multiple myeloma in combination with bortezomib, melphalan, and prednisone
• Relapsed or refractory multiple myeloma in combination with lenalidomide and dexamethasone

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Texas Oncology, P.A. San Antonio, TX

10 sites within US Oncology Network only (including TX, AZ, NY, and VA) Denver, CO

New York Oncology Hematology, P.C. Albany, NY

Texas Oncology, P.A. Tyler, TX

More Trial Locations

Who Is Running the Clinical Trial?

US Oncology Research Lead Sponsor

Karyopharm Therapeutics Inc Industry Sponsor

References

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

Selinexor, daratumumab, and dexamethasone in patients with relapsed or refractory multiple myeloma. [2022] We assessed the safety, efficacy, maximum tolerated dose (MTD), and the recommended phase 2 dose (RP2D) of selinexor, a first in class oral selective inhibitor of nuclear export (100 mg once weekly [QW] or 60 mg twice weekly), in combination with daratumumab (16 mg/kg per label) and dexamethasone (40 mg QW) (SDd) in patients with relapsed refractory multiple myeloma (RRMM). Thirty-four patients (median prior therapies, 3 [range, 2-10]) were enrolled; MM was refractory to proteasome inhibitor (PI) in 85%, immunomodulatory agent (IMiD) in 76%, both in 74%, and daratumumab in 6% of patients. Two dose-limiting toxicities (DLTs) were reported in the selinexor 60 mg twice-weekly cohort with no DLTs in the 100 mg QW cohort, making 100 mg QW the MTD and RP2D. Common treatment-related adverse events included thrombocytopenia (70.6%), nausea (70.6%), fatigue (61.8%), anemia (61.8%), and neutropenia (50.0%). Overall response rate was 73% and median progression-free survival 12.5 months in daratumumab-naïve patients. SDd was well tolerated and its promising efficacy suggests that further study of this PI- and IMiD-free regimen in RRMM patients who had at least one prior line of therapy including a PI and an IMiD but whose disease is naïve to daratumumab is warranted.

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

Selinexor plus low-dose bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma. [2021] Selinexor is an oral inhibitor of the nuclear export protein exportin 1. Preclinical studies demonstrated synergistic antimyeloma activity between selinexor and proteasome inhibitors (PI) through suppression of NF-κB signaling and nuclear retention of tumor suppressor proteins. We tested selinexor in combination with low-dose bortezomib and dexamethasone (SVd) for the treatment of relapsed or refractory multiple myeloma (MM). The primary objectives of this study were to determine the safety profile, overall response rate (ORR), and a recommended phase 2 dose (RP2D) of SVd. We enrolled 42 patients to receive selinexor (60, 80, or 100 mg orally) plus bortezomib (1.3 mg/m2 subcutaneously) and dexamethasone (20 mg orally) once or twice weekly in 21- or 35-day cycles. Patients had a median of 3 (range 1-11) prior lines of therapy, and 50% were refractory to a PI. Treatment-related grade 3 or 4 adverse events reported in ≥10% of patients were thrombocytopenia (45%), neutropenia (24%), fatigue (14%), and anemia (12%). Incidence (4 patients, 10%) and grade (≤2) of peripheral neuropathy were low. The ORR for the entire population was 63%: 84% ORR for PI nonrefractory and 43% for PI-refractory patients. The median progression-free survival for all patients was 9.0 months; 17.8 months for PI nonrefractory, and 6.1 months for PI refractory. SVd treatment produced high response rates in patients with relapsed or refractory MM, including borezomib-refractory MM, with no unexpected side effects. The RP2D is selinexor (100 mg once weekly), bortezomib (1.3 mg/m2 once weekly for 4 weeks), and dexamethasone (40 mg once weekly) per 35-day cycle. This trial was registered at www.clinicaltrials.gov as #NCT02343042.

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] Selinexor is an orally available selective inhibitor of exportin-1 that has offered a new treatment option in relapsed or refractory myeloma (RRMM) either in combination with dexamethasone (Sd) or with bortezomib and dexamethasone (SVd).

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

Targeting Nuclear Export Proteins in Multiple Myeloma Therapy. [2022] Nuclear export proteins such as exportin-1 (XPO1) transport tumor-suppressor proteins and other growth-regulatory proteins from the nucleus to the cytoplasm. Overexpression of XPO1 has been observed in several cancers and correlates with shorter event-free and overall survival in multiple myeloma. Selinexor was developed as an oral first-in-class selective inhibitor of nuclear export (SINE) that inhibits XPO1. Preclinical studies in tumor cell lines and mouse models have demonstrated the efficacy of selinexor both as a single agent and in various combinations with known active antimyeloma agents. Results from the pivotal phase II STORM trial led to the US FDA approval of selinexor with dexamethasone in penta-refractory myeloma. Because of the feasibility of combining selinexor with other active antimyeloma agents, the multiarm STOMP trial was initiated and is ongoing, with impressive response rates reported in some of the combination arms thus far. The registrational phase III BOSTON trial demonstrated the superiority of selinexor in combination with bortezomib and dexamethasone as compared with bortezomib and dexamethasone in patients with relapsed refractory multiple myeloma (RRMM) who have received one to three prior anti-MM regimens. The toxicity profile of selinexor is well established and predictable and may be significant unless managed aggressively and preemptively. The most common side effects are thrombocytopenia, anemia, neutropenia, fatigue, nausea, anorexia, and weight loss. Hyponatremia and cataracts seem to be class effects. Other SINE compounds are now being studied in efforts to discover agents that will potentially be better tolerated. Eltanexor is an investigational SINE compound that has shown a more positive toxicity profile in preclinical studies, with reduced central nervous system penetration and gastrointestinal side effects, and is now undergoing clinical investigation. These and other trials will further clarify the role of these innovative agents in the therapeutic advancement of RRMM.

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

Phase 1 study of selinexor plus carfilzomib and dexamethasone for the treatment of relapsed/refractory multiple myeloma. [2023] Selinexor, an oral Selective Inhibitor of Nuclear Export, targets Exportin 1 (XPO1, also termed CRM1). Non-clinical studies support combining selinexor with proteasome inhibitors (PIs) and corticosteroids to overcome resistance in relapsed/refractory multiple myeloma (RRMM). We conducted a phase I dose-escalation trial of twice-weekly selinexor in combination with carfilzomib and dexamethasone (SKd) to determine maximum tolerated dose in patients with RRMM (N = 21), with an expansion cohort to assess activity in carfilzomib-refractory disease and identify a recommended phase II dose (RP2D). During dose escalation, there was one dose-limiting toxicity (cardiac failure). The RP2D of twice-weekly SKd was selinexor 60 mg, carfilzomib 20/27 mg/m2 and dexamethasone 20 mg. The most common grade 3/4 treatment-emergent adverse events included thrombocytopenia (71%), anaemia (33%), lymphopenia (33%), neutropenia (33%) and infections (24%). Rates of ≥minimal response, ≥partial response and very good partial response were 71%, 48% and 14%, respectively; similar response outcomes were observed for dual-class refractory (PI and immunomodulatory drug)/quad-exposed (carfilzomib, bortezomib, lenalidomide and pomalidomide) patients (n = 17), and patients refractory to carfilzomib in last line of therapy (n = 13). Median progression-free survival was 3·7 months, and overall survival was 22·4 months in the overall population. SKd was tolerable and re-established disease control in RRMM patients, including carfilzomib-refractory patients. Registered at ClinicalTrials.gov (NCT02199665).

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

Safety and efficacy of selinexor in relapsed or refractory multiple myeloma and Waldenstrom macroglobulinemia. [2021] Novel therapies are needed for patients with relapsed or refractory multiple myeloma (MM). We conducted a multicenter, phase 1 study in advanced hematological malignancies to assess the safety, efficacy, and recommended phase 2 dose (RP2D) of oral selinexor, a selective inhibitor of the nuclear export protein XPO1. In the dose-escalation phase, 25 patients with heavily pretreated MM (22) or Waldenstrom macroglobulinemia (3) were administered selinexor (3-60 mg/m2) in 8 or 10 doses per 28-day cycle. In the dose-expansion phase, 59 patients with MM received selinexor at 45 or 60 mg/m2 with 20 mg dexamethasone, twice weekly in 28-day cycles, or selinexor (40 or 60 mg flat dose) without corticosteroids in 21-day cycles. The most common nonhematologic adverse events (AEs) were nausea (75%), fatigue (70%), anorexia (64%), vomiting (43%), weight loss (32%), and diarrhea (32%), which were primarily grade 1 or 2. The most common grade 3 or 4 AEs were hematologic, particularly thrombocytopenia (45%). Single-agent selinexor showed modest efficacy with an objective response rate (ORR) of 4% and clinical benefit rate of 21%. In contrast, the addition of dexamethasone increased the ORR with all responses of ≥partial response occurring in the 45 mg/m2 selinexor plus 20 mg dexamethasone twice weekly cohort (ORR = 50%). Furthermore, 46% of all patients showed a reduction in MM markers from baseline. Based on these findings, we conclude that selinexor in combination with dexamethasone is active in heavily pretreated MM and propose a RP2D of 45 mg/m2 (80 mg) plus 20 mg dexamethasone given twice weekly. This trial was registered at clinicaltrials.gov as #NCT01607892.