A Phase 3 Randomized, Controlled, Open-label Study of Selinexor, Bortezomib, and Dexamethasone (SVd) Versus Bortezomib and Dexamethasone (Vd) in Patients With Relapsed or Refractory Multiple Myeloma (RRMM)
Overview
- Phase
- Phase 3
- Intervention
- Selinexor
- Conditions
- Multiple Myeloma
- Sponsor
- Karyopharm Therapeutics Inc
- Enrollment
- 402
- Locations
- 156
- Primary Endpoint
- SVd/Vd Arm: Progression-free Survival (PFS) as Assessed by Independent Review Committee (IRC)
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
This Phase 3, 2-arm, randomized, active comparator-controlled, open-label, multicenter study will compare the efficacy and health-related quality of life (HR-QoL) and assess the safety of selinexor plus bortezomib (Velcade) plus low-dose dexamethasone (SVd) versus bortezomib plus low-dose dexamethasone (Vd) in adult patients with RRMM who have received 1 to 3 prior anti-multiple myeloma (MM) regimens. Crossover from the Vd Arm to a treatment that includes selinexor (i.e., SVdX or SdX) will be allowed at the point of IRC-confirmed objective disease progression per the IMWG criteria for patients in the Vd Arm.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Histologically confirmed MM with measurable disease per IMWG guidelines as defined by at least 1 of the following:
- •Serum M-protein ≥ 0.5 g/dL (\> 5 g/L) by serum protein electrophoresis (SPEP) or for immunoglobulin (Ig) A myeloma, by quantitative serum IgA levels; or
- •Urinary M-protein excretion at least 200 mg/24 hours; or
- •Serum free light chain (FLC) ≥ 100 mg/L, provided that the serum FLC ratio is abnormal (normal FLC ratio: 0.26 to 1.65).
- •Had at least 1 prior anti-MM regimen and no more than 3 prior anti-MM regimens. Induction therapy followed by stem cell transplant and consolidation/maintenance therapy will be considered as 1 anti-MM regimen.
- •Documented evidence of progressive MM (based on the Investigator's determination according to the modified IMWG response criteria) on or after their most recent regimen.
- •Prior treatment with bortezomib or other Proteasome Inhibitor (PI) is allowed, provided all of the following criteria are met:
- •Best response achieved with prior bortezomib at any time was ≥ PR and with the last PI (PI therapy (alone or in combination) was ≥ PR, AND
- •Participant did not discontinue bortezomib due to ≥ Grade 3 related toxicity, AND
- •Must have had at least a 6-month PI-treatment-free interval prior to Cycle 1 Day 1 (C1D1) of study treatment.
Exclusion Criteria
- •Prior exposure to a SINE compound (i.e. an XPO-1 inhibitor), including selinexor.
- •Prior malignancy that required treatment or has shown evidence of recurrence (except for non-melanoma skin cancer or adequately treated cervical carcinoma in situ) during the 5 years prior to randomization. Cancer treated with curative intent for \>5 years previously and without evidence of recurrence will be allowed.
- •Has any concurrent medical condition or disease (e.g., uncontrolled active hypertension, uncontrolled active diabetes, active systemic infection, etc.) that is likely to interfere with study procedures.
- •Uncontrolled active infection requiring parenteral antibiotics, antivirals, or antifungals within 1 week prior to C1D
- •Patients on prophylactic antibiotics or with a controlled infection within 1 week prior to C1D1 are acceptable.
- •Active plasma cell leukemia.
- •Documented systemic light chain amyloidosis.
- •MM involving the central nervous system.
- •Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome.
- •Spinal cord compression.
Arms & Interventions
SVd Arm: Selinexor + Bortezomib + Dexamethasone
Participants received a fixed oral dose of 100 milligrams (mg) selinexor tablets (5 tablets of 20 mg each) once weekly (QW) on Days 1, 8, 15, 22, and 29 of each 35-day cycle, along with subcutaneous (SC) injection of 1.3 milligrams per square meter (mg/m\^2) bortezomib QW on Days 1, 8, 15, and 22 of each 35-day cycle, and an oral dose of 20 mg of dexamethasone twice weekly (BIW) on Days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30 of each 35-day cycle until PD confirmed by the IRC, investigator or participant decision to discontinue study treatment, pregnancy, unacceptable AEs or toxicity that could not be managed by supportive care, withdrawal of consent, death, or sponsor decision to terminate the study.
Intervention: Selinexor
SVd Arm: Selinexor + Bortezomib + Dexamethasone
Participants received a fixed oral dose of 100 milligrams (mg) selinexor tablets (5 tablets of 20 mg each) once weekly (QW) on Days 1, 8, 15, 22, and 29 of each 35-day cycle, along with subcutaneous (SC) injection of 1.3 milligrams per square meter (mg/m\^2) bortezomib QW on Days 1, 8, 15, and 22 of each 35-day cycle, and an oral dose of 20 mg of dexamethasone twice weekly (BIW) on Days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30 of each 35-day cycle until PD confirmed by the IRC, investigator or participant decision to discontinue study treatment, pregnancy, unacceptable AEs or toxicity that could not be managed by supportive care, withdrawal of consent, death, or sponsor decision to terminate the study.
Intervention: Bortezomib
SVd Arm: Selinexor + Bortezomib + Dexamethasone
Participants received a fixed oral dose of 100 milligrams (mg) selinexor tablets (5 tablets of 20 mg each) once weekly (QW) on Days 1, 8, 15, 22, and 29 of each 35-day cycle, along with subcutaneous (SC) injection of 1.3 milligrams per square meter (mg/m\^2) bortezomib QW on Days 1, 8, 15, and 22 of each 35-day cycle, and an oral dose of 20 mg of dexamethasone twice weekly (BIW) on Days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30 of each 35-day cycle until PD confirmed by the IRC, investigator or participant decision to discontinue study treatment, pregnancy, unacceptable AEs or toxicity that could not be managed by supportive care, withdrawal of consent, death, or sponsor decision to terminate the study.
Intervention: Dexamethasone
Vd Arm: Bortezomib + Dexamethasone
Participants received SC injection of 1.3 mg/m\^2 bortezomib on Days 1, 4, 8, and 11 of each 21-day cycle for the first 8 cycles, followed by greater than or equal to (\>=) 9 cycles on Days 1, 8, 15, and 22 of each 35-day cycle, and received oral dose of 20 mg dexamethasone BIW on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle for the first 8 cycles and for cycles \>= 9 on Days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30 of each 35-day cycle until PD confirmed by the IRC, investigator or participant decision to discontinue study treatment, pregnancy, unacceptable AEs or toxicity that could not be managed by supportive care, withdrawal of consent, death, or sponsor decision to terminate the study.
Intervention: Bortezomib
Vd Arm: Bortezomib + Dexamethasone
Participants received SC injection of 1.3 mg/m\^2 bortezomib on Days 1, 4, 8, and 11 of each 21-day cycle for the first 8 cycles, followed by greater than or equal to (\>=) 9 cycles on Days 1, 8, 15, and 22 of each 35-day cycle, and received oral dose of 20 mg dexamethasone BIW on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle for the first 8 cycles and for cycles \>= 9 on Days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30 of each 35-day cycle until PD confirmed by the IRC, investigator or participant decision to discontinue study treatment, pregnancy, unacceptable AEs or toxicity that could not be managed by supportive care, withdrawal of consent, death, or sponsor decision to terminate the study.
Intervention: Dexamethasone
SVdX Arm: Selinexor + Bortezomib + Dexamethasone
Participants in the VD arm who had IRC-confirmed PD and were able to tolerate continued bortezomib treatment had crossed over to receive fixed oral dose of 100 mg selinexor tablets (5 tablets of 20 mg each) QW on Days 1, 8, 15, 22, and 29 of each 35-day cycle, along with SC injection of 1.3 mg/m\^2 bortezomib QW on Days 1, 8, 15, and 22 of each 35-day cycle, and an oral dose of 20 mg of dexamethasone BIW on Days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30 of each 35-day cycle until PD confirmed by the IRC, investigator or participant decision to discontinue study treatment, pregnancy, unacceptable AEs or toxicity that could not be managed by supportive care, withdrawal of consent, death, or sponsor decision to terminate the study.
Intervention: Selinexor
SVdX Arm: Selinexor + Bortezomib + Dexamethasone
Participants in the VD arm who had IRC-confirmed PD and were able to tolerate continued bortezomib treatment had crossed over to receive fixed oral dose of 100 mg selinexor tablets (5 tablets of 20 mg each) QW on Days 1, 8, 15, 22, and 29 of each 35-day cycle, along with SC injection of 1.3 mg/m\^2 bortezomib QW on Days 1, 8, 15, and 22 of each 35-day cycle, and an oral dose of 20 mg of dexamethasone BIW on Days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30 of each 35-day cycle until PD confirmed by the IRC, investigator or participant decision to discontinue study treatment, pregnancy, unacceptable AEs or toxicity that could not be managed by supportive care, withdrawal of consent, death, or sponsor decision to terminate the study.
Intervention: Bortezomib
SVdX Arm: Selinexor + Bortezomib + Dexamethasone
Participants in the VD arm who had IRC-confirmed PD and were able to tolerate continued bortezomib treatment had crossed over to receive fixed oral dose of 100 mg selinexor tablets (5 tablets of 20 mg each) QW on Days 1, 8, 15, 22, and 29 of each 35-day cycle, along with SC injection of 1.3 mg/m\^2 bortezomib QW on Days 1, 8, 15, and 22 of each 35-day cycle, and an oral dose of 20 mg of dexamethasone BIW on Days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30 of each 35-day cycle until PD confirmed by the IRC, investigator or participant decision to discontinue study treatment, pregnancy, unacceptable AEs or toxicity that could not be managed by supportive care, withdrawal of consent, death, or sponsor decision to terminate the study.
Intervention: Dexamethasone
SdX Arm: Selinexor + Dexamethasone
Participants in the VD arm who had IRC-confirmed PD and were unable to tolerate continued bortezomib treatment had crossed over to receive fixed oral dose of 100 mg selinexor tablets (5 tablets of 20 mg each) QW on Days 1, 8, 15, 22, and 29 of each 35-day cycle and an oral dose of 20 mg of dexamethasone BIW on Days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30 of each 35-day cycle until PD confirmed by the IRC, investigator or participant decision to discontinue study treatment, pregnancy, unacceptable AEs or toxicity that could not be managed by supportive care, withdrawal of consent, death, or sponsor decision to terminate the study.
Intervention: Selinexor
SdX Arm: Selinexor + Dexamethasone
Participants in the VD arm who had IRC-confirmed PD and were unable to tolerate continued bortezomib treatment had crossed over to receive fixed oral dose of 100 mg selinexor tablets (5 tablets of 20 mg each) QW on Days 1, 8, 15, 22, and 29 of each 35-day cycle and an oral dose of 20 mg of dexamethasone BIW on Days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30 of each 35-day cycle until PD confirmed by the IRC, investigator or participant decision to discontinue study treatment, pregnancy, unacceptable AEs or toxicity that could not be managed by supportive care, withdrawal of consent, death, or sponsor decision to terminate the study.
Intervention: Dexamethasone
Outcomes
Primary Outcomes
SVd/Vd Arm: Progression-free Survival (PFS) as Assessed by Independent Review Committee (IRC)
Time Frame: From date of randomization until IRC-confirmed documented PD or death, censored date, whichever occurred first (up to 33 months)
PFS was defined as time from date of randomization until the first date of IRC-confirmed PD, per International Myeloma Working Group (IMWG) response criteria, or death due to any cause, whichever occurs first. PD included increase of 25% from lowest confirmed response value in 1 or more of the following criteria: a) serum M-protein with absolute increase of \>= 0.5 gram per deciliter (g/dL); b) serum M-protein increase \>= 1 g/dL if the lowest M-component was \>=5 g/dL; c) urine M-protein (absolute increase must be \>= 200 mg per 24 hours); d) in participants without measurable serum and urine M-protein levels: the difference between involved and uninvolved free light chain (FLC) levels (absolute increase must be greater than \[\>\] 10 mg/dL); e) in participants without measurable serum and urine M-protein levels and without measurable involved FLC levels: bone marrow plasma cell percentage irrespective of baseline status (absolute increase must be \>=10%).
Secondary Outcomes
- SVd/Vd Arm: Number of Participants With at Least One Grade Greater Than or Equal to [>=] 2 Peripheral Neuropathy Events(From first dose of study treatment to 30 days after the last dose of study treatment inclusive, or the day before the start of new anti-MM treatment, whichever occurs first (up to 33 months))
- SVdX Arm: Overall Response Rate (ORR1) as Assessed by IRC During SVdX Treatment(From date of first SVdX treatment until disease progression or initiating a new MM treatment (up to 33 months))
- SVdX Arm: Progression Free Survival1 (PFS1) as Assessed by IRC During SVdX Treatment(From date of first SVdX treatment until IRC-confirmed documented PD or death or censored date, whichever occurred first (up to 33 months))
- SVd/Vd Arm: Percentage of Participants With Response Rate of Very Good Partial Response (VGPR) or Better Based on IRC Assessment(From date of randomization until confirmed PD or initiating a new MM treatment (up to 33 months))
- SVd/Vd Arm: Overall Response Rate (ORR) as Assessed by IRC(From date of randomization until disease progression or initiating a new MM treatment (up to 33 months))
- SVd/Vd Arm: Overall Survival (OS)(From date of randomization to the date of death or censored date, whichever occurred first (up to 45 months))
- SVd/Vd Arm: Duration of Response (DOR) as Assessed by IRC(From the first documentation of response to the first documentation of PD or death, whichever occurred first (up to 45 months))
- SVd/Vd Arm: Time-to-next-treatment (TTNT) in Participants Randomized to the SVd and Vd Arm Who Received Treatment After SVd/Vd(From date of randomization to start of next anti-MM treatment or death, whichever occurred first (up to 33 months))
- SVd/Vd Arm: Time To Response (TTR) in Participants Randomized to the SVd and Vd Arm(From randomization to the date of first IRC-confirmed PR or better (i.e., PR, VGPR, CR, or sCR), whichever occurred first (up to 33 months))
- SVd/Vd/SVdx Arm: Progression Free Survival 2 (PFS 2) in Participants Randomized to the SVd and Vd Arm Who Received Post-SVd/Vd/SVdX Treatment(From date of first dose of post-SVd/Vd/SVdX treatment to the date of first PD on post-SVd/Vd/SVdX treatment, or death due to any cause (up to 33 months))
- SVd/Vd Arm: Change From Baseline in Participant-Reported Peripheral Neuropathy (PN) Assessed by European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire- Chemotherapy-Induced PN 20 (EORTC- QLQ-CIPN20) Total Scores(Svd Arm: Baseline up to End of treatment (EOT) (at Day 820); Vd Arm: Baseline up to EOT (at Day 848))