Bortezomib, Selinexor, and Dexamethasone in Patients With Multiple Myeloma

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Selinexor
* Drug: Bortezomib
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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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. 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. Must have an ECOG Status score of 0, 1, or 2. Written informed consent in accordance with federal, local, and institutional guidelines. Age ≥18 years. Resolution of any clinically significant non-hematological toxicities (if any) from previous treatments to ≤ Grade 1 by C1D1. Adequate hepatic function within 28 days prior to C1D1. Adequate renal function within 28 days prior to C1D1. Adequate hematopoietic function within 7 days prior to C1D1. 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: 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. 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 C1D1. 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. Greater than Grade 2 neuropathy or ≥ Grade 2 neuropathy with pain at baseline, regardless of whether or not the patient is currently receiving medication Known intolerance, hypersensitivity, or contraindication to glucocorticoids. 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. Prior autologous stem cell transplantation < 1 month or allogeneic stem cell transplantation < 4 months prior to C1D1. Active graft versus host disease (after allogeneic stem cell transplantation) at C1D1. Pregnant or breastfeeding females. Body Surface Area < 1.4 m² at baseline, calculated by the Dubois or Mosteller method. Life expectancy of < 4 months. Major surgery within 4 weeks prior to C1D1. Active, unstable cardiovascular function: Symptomatic ischemia, or 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 Congestive heart failure of New York Heart Association Class ≥ 3 or known left ventricular ejection fraction < 40%, or Myocardial infarction within 3 months prior to C1D1. Known active human immunodeficiency virus (HIV) infection or HIV seropositivity 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. 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. 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. Contraindication to any of the required concomitant drugs or supportive treatments. Patients unwilling or unable to comply with the protocol, including providing 24-hour urine samples for urine protein electrophoresis at the required time points.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: selinexor+bortezomib+dexamethasone (SVd)<br>Selinexor will be given on Days 1, 8, 15, 22, and 29 of each 35-day cycle. Bortezomib will be given Days 1, 8, 15, and 22 of each 35-day cycle. Dexamethasone will be given Days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30 of each 35-day cycle. | Drug: Selinexor<br>* oral 100 mg dose<br>Drug: Bortezomib<br>* subcutaneous dose of 1.3 mg/m2<br>* Other names: Velcade®;Drug: Dexamethasone<br>* oral dose of 20mg<br>|
| Active Comparator: bortezomib+dexamethasone (Vd)<br>Bortezomib will be given Days 1, 4, 8, and 11 of each 21-day cycle for the first 8 cycles. For cycles ≥ 9, bortezomib will be given on Days 1, 8, 15, and 22 of each 35-day cycle. Dexamethasone will be given on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle for the first 8 cycles. For cycles ≥ 9, dexamethasone will be given on Days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30 of each 35-day cycle. | Drug: Bortezomib<br>* subcutaneous dose of 1.3 mg/m2<br>* Other names: Velcade®;Drug: Dexamethasone<br>* oral dose of 20mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) as Assessed by 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%). | From date of randomization until IRC-confirmed documented PD or death, censored date, whichever occurred first (up to 32 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) as Assessed by IRC |  | From date of randomization until disease progression or death, whichever occurred first (maximum duration up to 75 months) | 
| Percentage of Participants With Response Rates |  | From date of randomization until disease progression or death, whichever occurred first (maximum duration up to 75 months) | 
| Overall Survival (OS) |  | From date of randomization to the date of death or censored date, whichever occurred first (maximum duration of 75 months) | 
| Duration of Response (DOR) as Assessed by IRC |  | From the first documentation of response to the first documentation of PD or death or censored date, whichever occurred first (maximum duration up to 75 months) | 
| Time-to-next-treatment (TTNT) |  | From date of randomization to start of next anti-MM treatment or death, whichever occurs first (maximum duration of 75 months) | 
| Time-to-response (TTR) as Assessed by IRC |  | From date of randomization until the date of first IRC confirmed response (maximum duration up to 75 months) | 
| Number of Participants With Grade >= 2 Peripheral Neuropathy Events |  | From date of randomization up to 30 days after last dose of treatment (maximum duration of 75 months) | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs |  | From date of randomization up to 30 days after last dose of treatment (maximum duration up to 75 months) | 
| Patient-reported Peripheral Neuropathy Measured by European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-CIPN20 Instrument |  | Up to 75 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Relapsed or Refractory Multiple Myeloma, RRMM, Bortezomib, Dexamethasone