Multiple Myeloma
Conditions
Keywords
Relapsed or Refractory Multiple Myeloma, RRMM, Bortezomib, Dexamethasone
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.
Interventions
DRUGSelinexor
oral 100 mg dose
DRUGBortezomib
subcutaneous dose of 1.3 mg/m2
DRUGDexamethasone
oral dose of 20mg
Sponsors
Karyopharm Therapeutics Inc
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Primary part is parallel (SVd vs Vd treatment arm). Participants who received Vd were allowed to cross-over to receive either SVd or SdX treatment arm.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Histologically confirmed MM with measurable disease per IMWG guidelines as defined by at least 1 of the following: 1. 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 2. Urinary M-protein excretion at least 200 mg/24 hours; or 3. Serum free light chain (FLC) ≥ 100 mg/L, provided that the serum FLC ratio is abnormal (normal FLC ratio: 0.26 to 1.65). 2. 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. 3. 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. 4. Prior treatment with bortezomib or other Proteasome Inhibitor (PI) is allowed, provided all of the following criteria are met: 1. 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 2. Participant did not discontinue bortezomib due to ≥ Grade 3 related toxicity, AND 3. Must have had at least a 6-month PI-treatment-free interval prior to Cycle 1 Day 1 (C1D1) of study treatment. 5. Must have an ECOG Status score of 0, 1, or 2. 6. Written informed consent in accordance with federal, local, and institutional guidelines. 7. Age ≥18 years. 8. Resolution of any clinically significant non-hematological toxicities (if any) from previous treatments to ≤ Grade 1 by C1D1. Patients with chronic, stable Grade 2 non-hematological toxicities may be included following approval from the Medical Monitor. 9. Adequate hepatic function within 28 days prior to C1D1. 1. Total bilirubin \<1.5 × upper limit of normal (ULN) (except patients with Gilbert's syndrome who must have a total bilirubin of \<3 × ULN), and 2. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) normal to \<2 × ULN. 10. Adequate renal function within 28 days prior to C1D1 (estimated creatinine clearance \[CrCl\] of ≥20 mL/min, calculated using the formula of Cockroft and Gault): (140-Age) × Mass (kg)/(72 × creatinine mg/dL) Multiply by 0.85 if the patient is female, or if CrCl is ≥20 mL/min as measured by 24-hour urine collection. 11\. Adequate hematopoietic function within 7 days prior to C1D1: total white blood cell (WBC) count ≥1500/mm3, absolute neutrophil count ≥1000/mm3, hemoglobin ≥8.5 g/dL and platelet count ≥75,000/mm3 (patients for whom \< 50% of bone marrow nucleated cells are plasma cells) or ≥50,000/mm3 (patients for whom ≥50% of bone marrow nucleated cells are plasma cells). 1. Patients receiving hematopoietic growth factor support, including erythropoietin, darbepoetin, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), and platelet stimulators (eg, eltrombopag, romiplostim, or interleukin-11) must have a 2-week interval between growth factor support and the Screening assessments, but they may receive growth factor support during the study. 2. Patients must have: * At least a 2-week interval from the last red blood cell (RBC) transfusion prior to the Screening hemoglobin assessment, and * At least a 1-week interval from the last platelet transfusion prior to the Screening platelet assessment. However, patients may receive RBC and/or platelet transfusions as clinically indicated per institutional guidelines during the study. 12\. Female patients of childbearing potential must have a negative serum pregnancy test at Screening. Female patients of childbearing potential and fertile male patients who are sexually active with a female of childbearing potential must use highly effective methods of contraception throughout the study and for 3 months following the last dose of study treatment.
Exclusion criteria
1. Prior exposure to a SINE compound (i.e. an XPO-1 inhibitor), including selinexor. 2. 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. 3. 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. 4. Uncontrolled active infection requiring parenteral antibiotics, antivirals, or antifungals within 1 week prior to C1D1. Patients on prophylactic antibiotics or with a controlled infection within 1 week prior to C1D1 are acceptable. 5. Active plasma cell leukemia. 6. Documented systemic light chain amyloidosis. 7. MM involving the central nervous system. 8. Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome. 9. Spinal cord compression. 10. Greater than Grade 2 neuropathy or ≥ Grade 2 neuropathy with pain at baseline, regardless of whether or not the patient is currently receiving medication 11. Known intolerance, hypersensitivity, or contraindication to glucocorticoids. 12. Radiation, chemotherapy, or immunotherapy or any other anticancer therapy (including investigational therapies) ≤ 2 weeks prior to C1D1. Localized radiation to a single site at least 1 week before C1D1 is permitted. Glucocorticoids within 2 weeks of C1D1 are permitted. Patients on long-term glucocorticoids during Screening do not require a washout period but must be able to tolerate the specified dexamethasone dose in this study. 13. Prior autologous stem cell transplantation \< 1 month or allogeneic stem cell transplantation \< 4 months prior to C1D1. 14. Active graft versus host disease (after allogeneic stem cell transplantation) at C1D1. 15. Pregnant or breastfeeding females. 16. Body Surface Area \< 1.4 m² at baseline, calculated by the Dubois or Mosteller method. 17. Life expectancy of \< 4 months. 18. Major surgery within 4 weeks prior to C1D1. 19. Active, unstable cardiovascular function: 1. Symptomatic ischemia, or 2. Uncontrolled clinically significant conduction abnormalities (e.g., patients with ventricular tachycardia on anti-arrhythmics are excluded; patients with first-degree atrioventricular block or asymptomatic left anterior fascicular block/right bundle branch block will not be excluded), or 3. Congestive heart failure of New York Heart Association Class ≥ 3 or known left ventricular ejection fraction \< 40%, or 4. Myocardial infarction within 3 months prior to C1D1. 20. Known active human immunodeficiency virus (HIV) infection or HIV seropositivity 21. Known active hepatitis A, B, or C infection; or known to be positive for hepatitis C virus ribonucleic acid (RNA) or hepatitis B virus surface antigen. 22. Any active gastrointestinal dysfunction interfering with the patient's ability to swallow tablets, or any active gastrointestinal dysfunction that could interfere with absorption of study treatment. 23. Any active, serious psychiatric, medical, or other conditions/situations that, in the opinion of the Investigator, could interfere with treatment, compliance, or the ability to give informed consent. 24. Contraindication to any of the required concomitant drugs or supportive treatments. 25. Patients unwilling or unable to comply with the protocol, including providing 24-hour urine samples for urine protein electrophoresis at the required time points.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| SVd/Vd Arm: Progression-free Survival (PFS) as Assessed by Independent Review Committee (IRC) | 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
| Measure | Time frame | Description |
|---|---|---|
| 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) | Response rate was defined as percentage of participants with responses of VGPR, at any time prior to IRC-confirmed PD or initiating a new MM treatment. VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level \< 100 mg per 24 hours. |
| 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) | Peripheral neuropathy events was assessed using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03. The grade ranges from Grade 1 (mild, asymptomatic, or mild symptoms) to Grade 5 (death related to an adverse event). Grade 2 indicates a moderate condition that may require minimal intervention and can limit certain daily activities. Grade 3 represents severe symptoms that are not immediately life-threatening but may lead to hospitalization and restrict self-care activities. Grade 4 denotes life-threatening consequences requiring urgent intervention. Number of participants experiencing at least one Grade \>= 2 peripheral neuropathy event have been reported. |
| 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) | OS was defined as the time from the date of randomization until either the date of death due to any cause or until the participant is lost to follow-up, for all participants. |
| 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) | DOR was defined as the duration of time from the first occurrence of an IRC confirmed response of at least (\>=) PR until the first date of IRC-confirmed PD or death due to any cause, whichever occurred first. PR: \>= 50% reduction of serum M-Protein and reduction in 24-hour urinary M-protein by \>= 90% or to \< 200 mg per 24 hours; PD: Increase of 25% from lowest confirmed response value in 1 or more of the following criteria: Serum M-protein with absolute increase of \>= 0.5 g/dL; Serum M-protein increase \>= 1 g/dL if the lowest M-component was \>= 5 g/dL; Urine M-protein (absolute increase must be \>= 200 mg per 24 hours). Analysis was performed using Kaplan-Meier method. |
| 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) | ORR was defined as the percentage of the participants who achieved a confirmed partial response or better (i.e., PR, VGPR, CR, or sCR) based on the IRC's response outcome assessments, according to the IMWG response criteria. PR: \>=50% reduction of serum M-Protein and reduction in 24-hour urinary M-protein by \>=90% or \<200 mg per 24 hours; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level \<100 mg per 24 hours; CR: Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and \<=5% plasma cells in bone marrow; or sCR: CR as defined as Normal FLC ratio+ Absence of clonal cells in bone marrow biopsy by immunohistochemistry. |
| 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) | ORR was defined as the percentage of the participants who achieved any confirmed partial response (PR) or better PR, complete response (CR), very good partial response (VGPR) or stringent complete response (sCR) based on the IRC's response outcome assessments, according to the International Myeloma Working Group (IMWG) response criteria, before IRC-confirmed PD or initiating a new MM treatment. PR: \>= 50% reduction of serum M-Protein and reduction in 24-hour urinary M-protein by \>= 90% or to \< 200 mg per 24 hours; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level \< 100 mg per 24 hours; CR: Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and \<= 5% plasma cells in bone marrow; or stringent complete response (sCR): CR as defined as Normal free light chain (FLC) ratio + Absence of clonal cells by immunohistochemistry. |
| 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) | TTNT is defined as the duration from date of randomization to start of next anti-MM treatment or death, whichever occurs first. For patients without an event, their follow-up time will be censored at the date of discontinuation from study, or last participating visit on or before database cutoff date, whichever occurs first. |
| 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) | TTR was defined as duration from randomization to the date of first IRC-confirmed PR or better (i.e., PR, VGPR, CR, or sCR) before IRC-confirmed PD or initiating a new MM treatment per IMWG response criteria. The participants who do not achieve IRC-confirmed PR or better response will be censored at the date of last disease assessment on or before database cutoff date. PR: \>= 50% reduction of serum M-Protein and reduction in 24-hour urinary M-protein by \>= 90% or to \< 200 mg per 24 hours; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level \< 100 mg per 24 hours; CR: Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and \<= 5% plasma cells in bone marrow; or sCR: Normal free light chain (FLC) ratio + Absence of clonal cells by immunohistochemistry. |
| 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) | PFS 2 was defined as the duration of time from the date of the first dose of the treatment after SVd/Vd/SVdX until the first date of PD on treatment after SVd/Vd/SVdX or death due to any cause, whichever occurred 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%). |
| 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) | The EORTC QLQ-CIPN20 instrument is a 20-item QoL instrument, which has been developed to elicit patients' experience of symptoms and functional limitations related to CIPN. The QLQ-CIPN20 contains 20 items assessing sensory (9 items), motor (8 items), and autonomic symptoms (3 items) containing a 4-point Likert scale (1= not at all, 2= a little, 3= quite a bit, and 4= very much), participants indicate the degree to which they have experienced sensory, motor, and autonomic symptoms during the past week. Sensory raw scale scores range from 1 to 36, motor raw scale scores range from 1 to 32, and autonomic raw scale scores range from 1 to 12 for men and 1-8 for women (erectile function item is excluded). All scale scores are linearly converted to a total score with range of 0-100 scale, with higher scores indicating more symptom burden. |
| 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) | PFS1 is defined as the duration of time from the date of the first dose of the SVd treatment after crossover from the Vd arm until the first date of PD or death due to any cause, whichever occurred 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%). |
Countries
Australia, Austria, Belgium, Bulgaria, Canada, Czechia, France, Germany, Greece, Hungary, India, Israel, Italy, Poland, Romania, Russia, Serbia, Spain, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted at 165 investigative sites in 21 countries. A total of 402 participants were enrolled and randomized, of which 399 participants received SVd treatment (195 participants) or Vd treatment (204 participants).
Pre-assignment details
Following confirmation of progressive disease (PD) by the Independent Review Committee (IRC), 204 participants in the safety population who received Vd treatment were allowed to cross over to receive either SVdX treatment (66 participants) or SdX treatment (14 participants).
Participants by arm
| Arm | Count |
|---|---|
| SVd Arm: Selinexor + Bortezomib + Dexamethasone Participants received a 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. | 195 |
| 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 \>= 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. | 207 |
| Total | 402 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Crossover Period | Death | 0 | 0 | 37 | 3 |
| Crossover Period | Disease Progression | 0 | 0 | 1 | 0 |
| Crossover Period | Lost to Follow-up | 0 | 0 | 0 | 1 |
| Crossover Period | Other | 0 | 0 | 1 | 1 |
| Crossover Period | Participants withdrawn due to company goals | 0 | 0 | 19 | 3 |
| Crossover Period | Withdrawal by Subject | 0 | 0 | 8 | 6 |
| Initial Treatment Period | Adverse Event | 1 | 0 | 0 | 0 |
| Initial Treatment Period | Death | 74 | 82 | 0 | 0 |
| Initial Treatment Period | Disease Progression | 1 | 1 | 0 | 0 |
| Initial Treatment Period | Lost to Follow-up | 13 | 8 | 0 | 0 |
| Initial Treatment Period | Other | 5 | 4 | 0 | 0 |
| Initial Treatment Period | Participants withdrawn due to company goals | 59 | 67 | 0 | 0 |
| Initial Treatment Period | Physician Decision | 2 | 1 | 0 | 0 |
| Initial Treatment Period | Protocol Deviation | 1 | 0 | 0 | 0 |
| Initial Treatment Period | Randomized but never treated | 0 | 3 | 0 | 0 |
| Initial Treatment Period | Withdrawal by Subject | 39 | 41 | 0 | 0 |
Baseline characteristics
| Characteristic | Vd Arm: Bortezomib + Dexamethasone | Total | SVd Arm: Selinexor + Bortezomib + Dexamethasone |
|---|---|---|---|
| Age, Continuous | 66.7 Years STANDARD_DEVIATION 9.35 | 66.0 Years STANDARD_DEVIATION 9.47 | 65.3 Years STANDARD_DEVIATION 9.56 |
| Race/Ethnicity, Customized Ethnicity Hispanic or Latino | 5 Participants | 11 Participants | 6 Participants |
| Race/Ethnicity, Customized Ethnicity Missing | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Ethnicity Not Hispanic or Latino | 188 Participants | 359 Participants | 171 Participants |
| Race/Ethnicity, Customized Ethnicity Not Reported | 11 Participants | 25 Participants | 14 Participants |
| Race/Ethnicity, Customized Ethnicity Unknown | 2 Participants | 6 Participants | 4 Participants |
| Race/Ethnicity, Customized Race Asian | 25 Participants | 50 Participants | 25 Participants |
| Race/Ethnicity, Customized Race Black or African American | 7 Participants | 11 Participants | 4 Participants |
| Race/Ethnicity, Customized Race Missing | 9 Participants | 14 Participants | 5 Participants |
| Race/Ethnicity, Customized Race Other | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Race White | 165 Participants | 326 Participants | 161 Participants |
| Sex: Female, Male Female | 92 Participants | 172 Participants | 80 Participants |
| Sex: Female, Male Male | 115 Participants | 230 Participants | 115 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 74 / 195 | 82 / 204 | 37 / 66 | 3 / 14 |
| other Total, other adverse events | 193 / 195 | 197 / 204 | 65 / 66 | 14 / 14 |
| serious Total, serious adverse events | 109 / 195 | 79 / 204 | 28 / 66 | 7 / 14 |
Outcome results
Primary
SVd/Vd Arm: Progression-free Survival (PFS) as Assessed by Independent Review Committee (IRC)
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%).
Time frame: From date of randomization until IRC-confirmed documented PD or death, censored date, whichever occurred first (up to 33 months)
Population: ITT population consisted of all participants who were randomized to the study treatment, regardless of whether or not they received the study treatment. Data was not planned to be reported for SVdx arm and Sdx arm.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| SVd Arm: Selinexor + Bortezomib + Dexamethasone | SVd/Vd Arm: Progression-free Survival (PFS) as Assessed by Independent Review Committee (IRC) | 13.93 Months |
| Vd Arm: Bortezomib + Dexamethasone | SVd/Vd Arm: Progression-free Survival (PFS) as Assessed by Independent Review Committee (IRC) | 9.46 Months |
p-value: 0.007595% CI: [0.5279, 0.9335]Stratified Log-rank Test
Secondary
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
The EORTC QLQ-CIPN20 instrument is a 20-item QoL instrument, which has been developed to elicit patients' experience of symptoms and functional limitations related to CIPN. The QLQ-CIPN20 contains 20 items assessing sensory (9 items), motor (8 items), and autonomic symptoms (3 items) containing a 4-point Likert scale (1= not at all, 2= a little, 3= quite a bit, and 4= very much), participants indicate the degree to which they have experienced sensory, motor, and autonomic symptoms during the past week. Sensory raw scale scores range from 1 to 36, motor raw scale scores range from 1 to 32, and autonomic raw scale scores range from 1 to 12 for men and 1-8 for women (erectile function item is excluded). All scale scores are linearly converted to a total score with range of 0-100 scale, with higher scores indicating more symptom burden.
Time frame: Svd Arm: Baseline up to End of treatment (EOT) (at Day 820); Vd Arm: Baseline up to EOT (at Day 848)
Population: The ITT population consisted of all patients who were randomized to the study treatment, regardless of whether or not they received the study treatment. Here, Overall number of participants analyzed signifies those participants who were evaluable for this outcome measure. Data was not planned to be reported for SVdx arm and Sdx arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| SVd Arm: Selinexor + Bortezomib + Dexamethasone | 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 | Total Sensory Score: Change at EOT | 3.38 Score on a Scale | Standard Deviation 12.436 |
| SVd Arm: Selinexor + Bortezomib + Dexamethasone | 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 | Total Motor Score: Change at EOT | 3.56 Score on a Scale | Standard Deviation 14.513 |
| SVd Arm: Selinexor + Bortezomib + Dexamethasone | 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 | Total Autonomic Score: Change at EOT | 10.41 Score on a Scale | Standard Deviation 22.201 |
| Vd Arm: Bortezomib + Dexamethasone | 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 | Total Sensory Score: Change at EOT | 11.17 Score on a Scale | Standard Deviation 19.069 |
| Vd Arm: Bortezomib + Dexamethasone | 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 | Total Motor Score: Change at EOT | 9.02 Score on a Scale | Standard Deviation 18.662 |
| Vd Arm: Bortezomib + Dexamethasone | 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 | Total Autonomic Score: Change at EOT | 10.92 Score on a Scale | Standard Deviation 25.306 |
Secondary
SVd/Vd Arm: Duration of Response (DOR) as Assessed by IRC
DOR was defined as the duration of time from the first occurrence of an IRC confirmed response of at least (\>=) PR until the first date of IRC-confirmed PD or death due to any cause, whichever occurred first. PR: \>= 50% reduction of serum M-Protein and reduction in 24-hour urinary M-protein by \>= 90% or to \< 200 mg per 24 hours; PD: Increase of 25% from lowest confirmed response value in 1 or more of the following criteria: Serum M-protein with absolute increase of \>= 0.5 g/dL; Serum M-protein increase \>= 1 g/dL if the lowest M-component was \>= 5 g/dL; Urine M-protein (absolute increase must be \>= 200 mg per 24 hours). Analysis was performed using Kaplan-Meier method.
Time frame: From the first documentation of response to the first documentation of PD or death, whichever occurred first (up to 45 months)
Population: ITT population consisted of all participants who were randomized to the study treatment, regardless of whether or not they received the study treatment. Data was not planned to be reported for SVdx arm and Sdx arm.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| SVd Arm: Selinexor + Bortezomib + Dexamethasone | SVd/Vd Arm: Duration of Response (DOR) as Assessed by IRC | 17.28 Months |
| Vd Arm: Bortezomib + Dexamethasone | SVd/Vd Arm: Duration of Response (DOR) as Assessed by IRC | 12.88 Months |
Secondary
SVd/Vd Arm: Number of Participants With at Least One Grade Greater Than or Equal to [>=] 2 Peripheral Neuropathy Events
Peripheral neuropathy events was assessed using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03. The grade ranges from Grade 1 (mild, asymptomatic, or mild symptoms) to Grade 5 (death related to an adverse event). Grade 2 indicates a moderate condition that may require minimal intervention and can limit certain daily activities. Grade 3 represents severe symptoms that are not immediately life-threatening but may lead to hospitalization and restrict self-care activities. Grade 4 denotes life-threatening consequences requiring urgent intervention. Number of participants experiencing at least one Grade \>= 2 peripheral neuropathy event have been reported.
Time frame: 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)
Population: Safety population included of all participants who had received at least 1 dose of the study treatment. Data was not planned to be reported for SVdx arm and Sdx arm.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SVd Arm: Selinexor + Bortezomib + Dexamethasone | SVd/Vd Arm: Number of Participants With at Least One Grade Greater Than or Equal to [>=] 2 Peripheral Neuropathy Events | 41 Participants |
| Vd Arm: Bortezomib + Dexamethasone | SVd/Vd Arm: Number of Participants With at Least One Grade Greater Than or Equal to [>=] 2 Peripheral Neuropathy Events | 70 Participants |
p-value: 0.001395% CI: [0.3216, 0.7906]Cochran-Mantel-Haenszel
Secondary
SVd/Vd Arm: Overall Response Rate (ORR) as Assessed by IRC
ORR was defined as the percentage of the participants who achieved any confirmed partial response (PR) or better PR, complete response (CR), very good partial response (VGPR) or stringent complete response (sCR) based on the IRC's response outcome assessments, according to the International Myeloma Working Group (IMWG) response criteria, before IRC-confirmed PD or initiating a new MM treatment. PR: \>= 50% reduction of serum M-Protein and reduction in 24-hour urinary M-protein by \>= 90% or to \< 200 mg per 24 hours; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level \< 100 mg per 24 hours; CR: Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and \<= 5% plasma cells in bone marrow; or stringent complete response (sCR): CR as defined as Normal free light chain (FLC) ratio + Absence of clonal cells by immunohistochemistry.
Time frame: From date of randomization until disease progression or initiating a new MM treatment (up to 33 months)
Population: ITT population consisted of all participants who were randomized to the study treatment, regardless of whether or not they received the study treatment. Data was not planned to be reported for SVdx arm and Sdx arm.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SVd Arm: Selinexor + Bortezomib + Dexamethasone | SVd/Vd Arm: Overall Response Rate (ORR) as Assessed by IRC | 76.4 Percentage of participants |
| Vd Arm: Bortezomib + Dexamethasone | SVd/Vd Arm: Overall Response Rate (ORR) as Assessed by IRC | 62.3 Percentage of participants |
p-value: 0.001295% CI: [1.2641, 3.0471]Cochran-Mantel-Haenszel
Secondary
SVd/Vd Arm: Overall Survival (OS)
OS was defined as the time from the date of randomization until either the date of death due to any cause or until the participant is lost to follow-up, for all participants.
Time frame: From date of randomization to the date of death or censored date, whichever occurred first (up to 45 months)
Population: ITT population consisted of all participants who were randomized to the study treatment, regardless of whether or not they received the study treatment. Data was not planned to be reported for SVdx arm and Sdx arm.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| SVd Arm: Selinexor + Bortezomib + Dexamethasone | SVd/Vd Arm: Overall Survival (OS) | 36.67 Months |
| Vd Arm: Bortezomib + Dexamethasone | SVd/Vd Arm: Overall Survival (OS) | 32.76 Months |
p-value: 0.215295% CI: [0.6313, 1.2168]Stratified log-rank test
Secondary
SVd/Vd Arm: Percentage of Participants With Response Rate of Very Good Partial Response (VGPR) or Better Based on IRC Assessment
Response rate was defined as percentage of participants with responses of VGPR, at any time prior to IRC-confirmed PD or initiating a new MM treatment. VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level \< 100 mg per 24 hours.
Time frame: From date of randomization until confirmed PD or initiating a new MM treatment (up to 33 months)
Population: ITT population consisted of all participants who were randomized to the study treatment, regardless of whether or not they received the study treatment. Data was not planned to be reported for SVdx arm and Sdx arm.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SVd Arm: Selinexor + Bortezomib + Dexamethasone | SVd/Vd Arm: Percentage of Participants With Response Rate of Very Good Partial Response (VGPR) or Better Based on IRC Assessment | 44.6 Percentage of participants |
| Vd Arm: Bortezomib + Dexamethasone | SVd/Vd Arm: Percentage of Participants With Response Rate of Very Good Partial Response (VGPR) or Better Based on IRC Assessment | 32.4 Percentage of participants |
p-value: 0.008295% CI: [1.0993, 2.5049]Cochran-Mantel-Haenszel
Secondary
SVd/Vd Arm: Time-to-next-treatment (TTNT) in Participants Randomized to the SVd and Vd Arm Who Received Treatment After SVd/Vd
TTNT is defined as the duration from date of randomization to start of next anti-MM treatment or death, whichever occurs first. For patients without an event, their follow-up time will be censored at the date of discontinuation from study, or last participating visit on or before database cutoff date, whichever occurs first.
Time frame: From date of randomization to start of next anti-MM treatment or death, whichever occurred first (up to 33 months)
Population: The ITT population consisted of all participants who were randomized to the study treatment, regardless of whether or not they received the study treatment. Data was not planned to be reported for SVdx arm and Sdx arm.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| SVd Arm: Selinexor + Bortezomib + Dexamethasone | SVd/Vd Arm: Time-to-next-treatment (TTNT) in Participants Randomized to the SVd and Vd Arm Who Received Treatment After SVd/Vd | 16.13 Months |
| Vd Arm: Bortezomib + Dexamethasone | SVd/Vd Arm: Time-to-next-treatment (TTNT) in Participants Randomized to the SVd and Vd Arm Who Received Treatment After SVd/Vd | 10.84 Months |
Secondary
SVd/Vd Arm: Time To Response (TTR) in Participants Randomized to the SVd and Vd Arm
TTR was defined as duration from randomization to the date of first IRC-confirmed PR or better (i.e., PR, VGPR, CR, or sCR) before IRC-confirmed PD or initiating a new MM treatment per IMWG response criteria. The participants who do not achieve IRC-confirmed PR or better response will be censored at the date of last disease assessment on or before database cutoff date. PR: \>= 50% reduction of serum M-Protein and reduction in 24-hour urinary M-protein by \>= 90% or to \< 200 mg per 24 hours; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level \< 100 mg per 24 hours; CR: Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and \<= 5% plasma cells in bone marrow; or sCR: Normal free light chain (FLC) ratio + Absence of clonal cells by immunohistochemistry.
Time frame: 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)
Population: The ITT population consisted of all patients who were randomized to the study treatment, regardless of whether or not they received the study treatment. Here, Overall number of participants analyzed signifies those participants who were evaluable for this outcome measure. Data was not planned to be reported for SVdx arm and Sdx arm.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| SVd Arm: Selinexor + Bortezomib + Dexamethasone | SVd/Vd Arm: Time To Response (TTR) in Participants Randomized to the SVd and Vd Arm | 1.41 Months |
| Vd Arm: Bortezomib + Dexamethasone | SVd/Vd Arm: Time To Response (TTR) in Participants Randomized to the SVd and Vd Arm | 1.61 Months |
Secondary
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
PFS 2 was defined as the duration of time from the date of the first dose of the treatment after SVd/Vd/SVdX until the first date of PD on treatment after SVd/Vd/SVdX or death due to any cause, whichever occurred 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%).
Time frame: 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)
Population: The ITT population consisted of all patients who were randomized to the study treatment, regardless of whether or not they received the study treatment. Here, Overall number of participants analyzed signifies those participants who were evaluable for this outcome measure. Data was not planned to be reported for Sdx arm.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| SVd Arm: Selinexor + Bortezomib + Dexamethasone | 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 | 6.60 Months |
| Vd Arm: Bortezomib + Dexamethasone | 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 | 8.84 Months |
| SVdX Arm: Selinexor + Bortezomib + Dexamethasone | 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 | 3.88 Months |
Secondary
SVdX Arm: Overall Response Rate (ORR1) as Assessed by IRC During SVdX Treatment
ORR was defined as the percentage of the participants who achieved a confirmed partial response or better (i.e., PR, VGPR, CR, or sCR) based on the IRC's response outcome assessments, according to the IMWG response criteria. PR: \>=50% reduction of serum M-Protein and reduction in 24-hour urinary M-protein by \>=90% or \<200 mg per 24 hours; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level \<100 mg per 24 hours; CR: Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and \<=5% plasma cells in bone marrow; or sCR: CR as defined as Normal FLC ratio+ Absence of clonal cells in bone marrow biopsy by immunohistochemistry.
Time frame: From date of first SVdX treatment until disease progression or initiating a new MM treatment (up to 33 months)
Population: The SVdX population consisted of a subset of participants in the Vd arm of the safety population who crossed over from the Vd arm to SVdX treatment after IRC confirmation of PD on Vd and had received at least 1 dose of selinexor. Here, Overall number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SVd Arm: Selinexor + Bortezomib + Dexamethasone | SVdX Arm: Overall Response Rate (ORR1) as Assessed by IRC During SVdX Treatment | 19.0 Percentage of participants |
Secondary
SVdX Arm: Progression Free Survival1 (PFS1) as Assessed by IRC During SVdX Treatment
PFS1 is defined as the duration of time from the date of the first dose of the SVd treatment after crossover from the Vd arm until the first date of PD or death due to any cause, whichever occurred 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%).
Time frame: From date of first SVdX treatment until IRC-confirmed documented PD or death or censored date, whichever occurred first (up to 33 months)
Population: The SVdX population consisted of a subset of participants in the Vd arm of the safety population who crossed over from the Vd arm to SVdX treatment after IRC confirmation of PD on Vd and had received at least 1 dose of selinexor. Here, Overall number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| SVd Arm: Selinexor + Bortezomib + Dexamethasone | SVdX Arm: Progression Free Survival1 (PFS1) as Assessed by IRC During SVdX Treatment | 3.91 Months |