Phase 3 Study With Carfilzomib and Dexamethasone Versus Bortezomib and Dexamethasone for Relapsed Multiple Myeloma Patients
Condition: Multiple Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Intervention: Carfilzomib; Bortezomib; Dexamethasone
Intervention description: Carfilzomib is administered over 30 minutes as an infusion.; Bortezomib is administered as a 3-5 second bolus IV injection or SC injection (in accordance with regulatory approval); Tablet for oral administration; On days when carfilzomib or bortezomib was administered, the dexamethasone was to be given 30 minutes to 4 hours prior to the carfilzomib or bortezomib dose.
Intervention MeSH terms: Dexamethasone; Bortezomib
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 929.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: multiple myeloma; relapsed multiple myeloma

Summary:

      The primary objective of this study was to compare progression-free survival in patients with
      multiple myeloma who relapsed after 1 to 3 prior therapies treated with carfilzomib plus
      dexamethasone or bortezomib plus dexamethasone.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Multiple myeloma with relapsing or progressing disease at study entry.

          2. Patients must have evaluable multiple myeloma with, at least one of the following
             (assessed within 21 days prior to randomization):

               -  Serum M-protein ≥ 0.5 g/dL, or

               -  Urine M-protein ≥ 200 mg/24 hour, or

               -  In patients without detectable serum or urine M-protein, serum free light chain
                  (SFLC) > 100 mg/L (involved light chain) and an abnormal serum kappa/lamda ratio,
                  or

               -  For immunoglobulin (Ig) A patients whose disease can only be reliably measured by
                  serum quantitative immunoglobulin (qIgA) ≥ 750 mg/dL (0.75 g/dL).

          3. Patients must have documented at least partial response (PR) to at least 1 line of
             prior therapy. PR documentation can be based on Investigator assessment.

          4. Received 1, but no more than 3 prior treatment regimens or lines of therapy for
             multiple myeloma. (Induction therapy followed by stem cell transplant and
             consolidation/maintenance therapy will be considered as one line of therapy).

          5. Prior therapy with Velcade is allowed as long as the patient had at least a PR to
             prior Velcade therapy, was not removed from Velcade therapy due to toxicity, and will
             have at least a 6 month Velcade treatment-free interval from last dose received until
             first study treatment. (Patients may receive maintenance therapy with drugs that are
             not in the proteasome inhibitor class during this 6 month Velcade treatment-free
             interval).

          6. Prior therapy with carfilzomib is allowed as long as the patient had at least a PR to
             prior carfilzomib therapy, was not removed from carfilzomib therapy due to toxicity,
             and had at least a 6-month carfilzomib treatment-free interval from last dose received
             until first study treatment. (Patients may receive maintenance therapy with drugs that
             are not in the proteasome inhibitor class during this 6 month carfilzomib
             treatment-free interval). The exception to this is patients randomized or previously
             randomized in any other Onyx-Sponsored Phase 3 trial.

          7. Males and females ≥ 18 years of age.

          8. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2.

          9. Adequate hepatic function within 21 days prior to randomization, with bilirubin < 1.5
             times the upper limit of normal (ULN), and aspartate aminotransferase (AST) and
             alanine aminotransferase (ALT) < 3 times the ULN.

         10. Left ventricular ejection fraction (LVEF) ≥ 40%.

         11. Absolute neutrophil count (ANC) ≥ 1000/mm³ within 21 days prior to randomization.
             Screening ANC should be independent of growth factor support for ≥ 1 week.

         12. Hemoglobin ≥ 8.0 g/dL within 21 days prior to randomization. Use of erythropoietic
             stimulating factors and red blood cell (RBC) transfusions per institutional guidelines
             is allowed, however most recent RBC transfusion may not have been done within 7 days
             prior to obtaining screening hemoglobin.

         13. Platelet count ≥ 50,000/mm³ (≥ 30,000/mm³ if myeloma involvement in the bone marrow is
             > 50%) within 21 days prior to randomization. Patients should not have received
             platelet transfusions for at least 1 week prior to obtaining the screening platelet
             count.

         14. Calculated or measured creatinine clearance (CrCl) of ≥ 15 mL/min within 21 days prior
             to randomization. Calculation should be based on standard formula such as the
             Cockcroft and Gault:

             [(140 - Age) x Mass (kg) / (72 x Creatinine mg/dL)]; multiply result by 0.85 if
             female.

         15. Written informed consent in accordance with federal, local, and institutional
             guidelines.

         16. Female patients of child-bearing potential (FCBP) must have a negative serum pregnancy
             test within 21 days prior to randomization and agree to use an effective method of
             contraception during and for 3 months following last dose of drug (more frequent
             pregnancy tests may be conducted if required per local regulations). FCBP is defined
             as a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral
             oophorectomy or 2) has not been naturally postmenopausal (amenorrhea following cancer
             therapy does not rule out childbearing potential) for at least 12 consecutive months
             (i.e., has had menses at any time in the preceding 12 consecutive months).

         17. Male patients must use an effective barrier method of contraception during study and
             for 3 months following the last dose if sexually active with a FCBP.

        Exclusion Criteria:

          1. Multiple Myeloma of IgM subtype.

          2. Glucocorticoid therapy (prednisone > 30 mg/day or equivalent) within 14 days prior to
             randomization.

          3. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and
             skin changes).

          4. Plasma cell leukemia or circulating plasma cells ≥ 2 × 10^9/L.

          5. Waldenstrom's Macroglobulinemia.

          6. Patients with known amyloidosis.

          7. Chemotherapy with approved or investigational anticancer therapeutics within 21 days
             prior to randomization.

          8. Patients randomized or previously randomized in any other Onyx-Sponsored Phase 3
             trial.

          9. Focal radiation therapy within 7 days prior to randomization. Radiation therapy to an
             extended field involving a significant volume of bone marrow within 21 days prior to
             randomization (i.e., prior radiation must have been to less than 30% of the bone
             marrow).

         10. Immunotherapy within 21 days prior to randomization.

         11. Major surgery (excluding kyphoplasty) within 28 days prior to randomization.

         12. Active congestive heart failure (New York Heart Association [NYHA] Class III to IV),
             symptomatic ischemia, or conduction abnormalities uncontrolled by conventional
             intervention. Myocardial infarction within four months prior to randomization.

         13. Acute active infection requiring systemic antibiotics, antiviral (except antiviral
             therapy directed at hepatitis B) or antifungal agents within 14 days prior to
             randomization.

         14. Known human immunodeficiency (HIV) seropositive, hepatitis C infection, and/or
             hepatitis B (except for patients with hepatitis B surface antigen [SAg] or core
             antibody receiving and responding to antiviral therapy directed at hepatitis B: these
             patients are allowed).

         15. Patients with known cirrhosis.

         16. Second malignancy within the past 3 years except:

               -  adequately treated basal cell or squamous cell skin cancer

               -  carcinoma in situ of the cervix

               -  prostate cancer < Gleason score 6 with stable prostate-specific antigen (PSA)
                  over 12 months

               -  breast carcinoma in situ with full surgical resection

               -  treated medullary or papillary thyroid cancer

         17. Patients with myelodysplastic syndrome.

         18. Significant neuropathy (Grades 3 to 4, or Grade 2 with pain) within 14 days prior to
             randomization.

         19. Female patients who are pregnant or lactating.

         20. Known history of allergy to Captisol(a cyclodextrin derivative used to solubilize
             carfilzomib).

         21. Patients with hypersensitivity to carfilzomib, Velcade, boron, or mannitol.

         22. Patients with contraindication to dexamethasone.

         23. Contraindication to any of the required concomitant drugs or supportive treatments,
             including hypersensitivity to antiviral drugs, or intolerance to hydration due to
             preexisting pulmonary or cardiac impairment.

         24. Ongoing graft-vs-host disease.

         25. Patients with pleural effusions requiring thoracentesis or ascites requiring
             paracentesis within 14 days prior to randomization.