Bortezomib, Selinexor, and Dexamethasone in Patients With Multiple Myeloma
Condition: Multiple Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Intervention: Selinexor; Bortezomib; Dexamethasone
Intervention description: oral 100 mg dose; subcutaneous dose of 1.3 mg/m2; oral dose of 20mg
Intervention MeSH terms: Dexamethasone; Bortezomib
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Enrollment: 402.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Relapsed or Refractory Multiple Myeloma; RRMM; Bortezomib; Dexamethasone

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.
    

Eligibility criteria:

        Inclusion Criteria:

          1. 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.

          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:

               -  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.

          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.

          9. Adequate hepatic function within 28 days prior to C1D1.

         10. Adequate renal function within 28 days prior to C1D1.

         11. Adequate hematopoietic function within 7 days prior to C1D1.

         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.

          3. 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.

          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.