Selinexor Combination Therapy for Multiple Myeloma
Recruiting in Palo Alto (17 mi)
+27 other locations
Age: Any Age
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: National Cancer Institute (NCI)
Must not be taking: Strong CYP3A4 inhibitors, inducers
Disqualifiers: Uncontrolled illness, Allergic reactions, others
No Placebo Group
Prior Safety Data
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?This phase II trial compares the combination of selinexor, daratumumab, velcade (bortezomib), and dexamethasone (Dara-SVD) to the usual treatment of daratumumab, lenalidomide, bortezomib, and dexamethasone (Dara-RVD) in treating patients with high-risk newly diagnosed multiple myeloma. Selinexor is in a class of medications called selective inhibitors of nuclear export (SINE). It works by blocking a protein called CRM1, which may keep cancer cells from growing and may kill them. Daratumumab is in a class of medications called monoclonal antibodies. It binds to a protein called CD38, which is found on some types of immune cells and cancer cells, including myeloma cells. Daratumumab may block CD38 and help the immune system kill cancer cells. Bortezomib blocks several molecular pathways in a cell and may cause cancer cells to die. It is a type of proteasome inhibitor and a type of dipeptidyl boronic acid. Dexamethasone is in a class of medications called corticosteroids. It is used to reduce inflammation and lower the body's immune response to help lessen the side effects of chemotherapy drugs. Lenalidomide is in a class of medications called immunomodulatory agents. It works by helping the bone marrow to produce normal blood cells and by killing abnormal cells in the bone marrow. The drugs daratumumab, lenalidomide, bortezomib, dexamethasone and selinexor are already approved by the FDA for use in myeloma. But selinexor is not used until myeloma comes back (relapses) after initial treatment. Giving selinexor in the initial treatment may be a superior type of treatment for patients with high-risk newly diagnosed multiple myeloma.
Do I have to stop taking my current medications for the trial?
The trial does not specify if you need to stop taking your current medications, but it does prohibit the use of strong CYP3A4 inhibitors and inducers, as they can affect bortezomib exposure. Supportive care therapies like bone-directed therapies and antiviral agents are allowed.
What data supports the effectiveness of the drug combination therapy including Selinexor for treating multiple myeloma?
Research shows that Selinexor, when combined with other drugs like bortezomib and dexamethasone, has been effective in treating multiple myeloma, especially in patients who have tried other treatments before. In one study, this combination led to a 63% overall response rate, meaning many patients saw their cancer shrink or stop growing.
12345What is the safety profile of Selinexor combination therapy for multiple myeloma?
Selinexor combination therapy, including with bortezomib and dexamethasone, has a generally manageable safety profile with common side effects like low blood platelet count, low red and white blood cell counts, fatigue, nausea, and weight loss. Peripheral neuropathy (nerve damage) is less common, and the treatment is considered safe if side effects are managed proactively.
12367What makes the Selinexor combination drug unique for treating multiple myeloma?
The Selinexor combination drug is unique because it includes Selinexor, a first-in-class oral drug that blocks exportin-1, a protein involved in cancer cell survival. This combination, given once weekly, has shown to prolong progression-free survival and reduce nerve damage compared to standard treatments, making it a valuable option for patients who have already tried other therapies.
12378Eligibility Criteria
This trial is for patients with newly diagnosed high-risk multiple myeloma who may have had one cycle of bortezomib-based therapy. They should not have severe liver or kidney issues, and their immune system must be functioning at a certain level. People with HIV can join if they're on effective treatment.Inclusion Criteria
I have been recently diagnosed with multiple myeloma.
I am mostly self-sufficient and can carry out daily activities.
I have chronic hepatitis B but it's under control with medication.
+17 more
Exclusion Criteria
I do not have any uncontrolled illnesses or significant conditions.
I have recovered from side effects of previous cancer treatments, except for hair loss.
I need urgent multiple myeloma therapy and can start after initial treatment.
+5 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive either the Dara-SVD or Dara-RVD regimen for up to 4 cycles, with each cycle lasting 28 days
16 weeks
Weekly visits for drug administration and monitoring
Follow-up
Participants are monitored for safety and effectiveness after treatment completion
2 years
Follow-up visits at 6 months, 1 year, and 2 years
Participant Groups
The study compares Dara-SVD (selinexor, daratumumab, Velcade/bortezomib, dexamethasone) to the usual Dara-RVD (daratumumab, lenalidomide, Velcade/bortezomib, dexamethasone). It's testing whether adding selinexor early in treatment offers better outcomes for those with aggressive myeloma.
2Treatment groups
Experimental Treatment
Active Control
Group I: Arm I (Dara-SVD)Experimental Treatment11 Interventions
Patients receive daratumumab and hyaluronidase-fihj SC on days 1, 8, 15, \& 22 for cycles 1-2, then days 1 \& 15 for cycles 3-4, and selinexor PO, bortezomib SC, and dexamethasone PO on days 1, 8, 15, \& 22 of each cycle. Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo PET, MRI, or CT, and bone marrow aspiration and biopsy, and collection of blood and urine samples throughout the study.
Group II: Arm II (Dara-RVD)Active Control11 Interventions
Patients receive daratumumab and hyaluronidase-fihj SC on days 1, 8, 15, \& 22 for cycles 1-2, then days 1 \& 15 for cycles 3-4, lenalidomide PO QD on days 1-21 of each cycle, and bortezomib SC and dexamethasone PO on days 1, 8, 15, \& 22 of each cycle. Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo PET, MRI, or CT, and bone marrow aspiration and biopsy, and collection of blood and urine samples throughout the study.
Bortezomib is already approved in European Union, United States, Canada, Japan for the following indications:
🇪🇺 Approved in European Union as Velcade for:
- Multiple myeloma
- Mantle cell lymphoma
🇺🇸 Approved in United States as Velcade for:
- Multiple myeloma
- Mantle cell lymphoma
🇨🇦 Approved in Canada as Velcade for:
- Multiple myeloma
- Mantle cell lymphoma
🇯🇵 Approved in Japan as Velcade for:
- Multiple myeloma
- Mantle cell lymphoma
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Smilow Cancer Hospital Care Center - WesterlyWesterly, RI
Smilow Cancer Hospital Care Center - WaterfordWaterford, CT
Smilow Cancer Hospital Care Center at Saint FrancisHartford, CT
Yale-New Haven Hospital North Haven Medical CenterNorth Haven, CT
More Trial Locations
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Who Is Running the Clinical Trial?
National Cancer Institute (NCI)Lead Sponsor
References
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).
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.
Selinexor-Bortezomib-Dexamethasone: A Review in Previously Treated Multiple Myeloma. [2023]Selinexor [Nexpovio® (EU); Xpovio® (USA)] is a first-in-class, selective exportin-1 inhibitor. Oral selinexor once weekly in combination with subcutaneous bortezomib once weekly and oral dexamethasone twice weekly (selinexor-bortezomib-dexamethasone) is approved in the EU and USA for the treatment of adult patients with multiple myeloma who have received at least one prior therapy. In the open-label, randomized, phase 3 BOSTON trial, this regimen significantly prolonged progression-free survival (PFS) compared with the standard bortezomib-dexamethasone regimen in patients with previously treated multiple myeloma. Selinexor-bortezomib-dexamethasone had a generally manageable tolerability profile and an acceptable safety profile in BOSTON, with a lower incidence of peripheral neuropathy (a bortezomib-induced toxicity) compared with bortezomib-dexamethasone. The triplet regimen uses less bortezomib and dexamethasone during the first 24 weeks of treatment. The efficacy and safety profiles of selinexor-bortezomib-dexamethasone, combined with its once-weekly administration of selinexor and bortezomib, make it a useful additional triplet therapy option for previously treated multiple myeloma.
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.
Clinical Implications of Targeting XPO1-mediated Nuclear Export in Multiple Myeloma. [2023]Multiple myeloma (MM) is a malignancy of plasma cells that is typically chronic, and relapse is common. Current therapeutic strategies include combination and sequential treatments with corticosteroids, alkylating agents, proteasomal inhibitors, immunomodulators, and monoclonal antibodies. These drugs prolong survival but ultimately become ineffective. Exportin 1 (XPO1), a nuclear export protein, is overexpressed in MM cells, and knockdown studies have suggested that XPO1 is essential for MM cell survival. Selective inhibitor of nuclear export (SINE) compounds are novel, orally bioavailable class of agents that specifically inhibit XPO1. Selinexor (KPT-330) is the first-in-human SINE compound. Early phase clinical trials have established the safety profile of this agent and have shown promising efficacy in combination with low-dose dexamethasone and other anti-MM agents. The combination of selinexor and dexamethasone has demonstrated activity in "penta-refractory" MM, (ie, MM refractory to the 5 most active anti-MM agents currently used in treatment). We have reviewed the available data on the molecular implications of XPO1 inhibition in MM. We also reviewed the pertinent early phase clinical data with SINE compounds and discuss management strategies for common toxicities encountered with use of selinexor.
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.
Selinexor in Patients from Argentina with Multiple Myeloma Treated with Multiple Prior Therapies: A Case Series. [2022]BACKGROUND Numerous treatment options are available for patients with multiple myeloma (MM). Because of the course of the disease, most patients will experience serial relapse or the MM will become refractory to most of these treatments, leaving patients with few or no treatment options over time. Selinexor, a treatment with a novel mechanism of action, is an oral selective inhibitor of nuclear export (SINE) compound that blocks exportin 1, the major nuclear exporter of tumor suppressor proteins. CASE REPORT In this case series, we report on treatment with the weekly oral administration of selinexor combined with bortezomib and dexamethasone (XVd) in 3 patients from Argentina who were heavily treated (5-7 prior therapies) for MM that relapsed or was refractory to each previous treatment. Two patients had the high-risk cytogenetic abnormality del(17p). All 3 patients experienced efficacy with XVd reaching a best response of partial response or very good partial response. These responses were consistent with those of patients from the BOSTON study who were treated with XVd but were less heavily pretreated (1-3 prior therapies) and had a shorter median time since diagnosis of MM (7 years vs 3.7 years). The 3 patients experienced adverse events (AEs) that included nausea, thrombocytopenia, asthenia, and fatigue, which were similar to the most commonly reported AEs associated with selinexor treatment. CONCLUSIONS With its oral administration, novel mechanism of action, and responses in heavily pretreated patients, selinexor may help to address an important clinical need in the treatment of patients with relapsed/refractory MM.
Selinexor: Targeting a novel pathway in multiple myeloma. [2023]Selinexor is an orally bioavailable selective inhibitor of nuclear export compound that inhibits exportin-1 (XPO1), a novel therapeutic target that is overexpressed in multiple myeloma (MM) and is responsible for the transport of ∼220 nuclear proteins to the cytoplasm, including tumour suppressor proteins. Inhibition of this process has demonstrated substantial antimyeloma activity in preclinical studies, both alone and in combination with established MM therapeutics. Based on a clinical trial programme encompassing multiple combination regimens, selinexor-based therapy has been approved for the treatment of relapsed/refractory MM (RRMM), with selinexor-dexamethasone approved in the later-relapse setting for penta-refractory patients and selinexor-bortezomib-dexamethasone approved for patients who have received ≥1 prior therapy. Here, we provide a comprehensive review of the clinical data on selinexor-based regimens, including recent updates from the 2022 American Society of Hematology annual meeting, and summarise ongoing studies of this novel targeted agent in newly diagnosed MM and RRMM.