A Phase 3 Study Comparing Oral Ixazomib Plus Lenalidomide and Dexamethasone Versus Placebo Plus Lenalidomide and Dexamethasone in Adult Participants With Relapsed and/or Refractory Multiple Myeloma
Condition: Relapsed Multiple Myeloma; Refractory Multiple Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Intervention: Ixazomib; Lenalidomide; Dexamethasone; Placebo
Intervention description: Ixazomib capsules; Lenalidomide capsules; Dexamethasone tablets; Ixazomib placebo-matching capsules
Intervention MeSH terms: Dexamethasone; Lenalidomide; Ixazomib
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 722.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Drug therapy

Summary:

      The purpose of this study is to determine whether the addition of oral ixazomib to the
      background therapy of lenalidomide and dexamethasone improves progression free survival (PFS)
      in participants with relapsed and/or refractory multiple myeloma (RRMM).
    

Eligibility criteria:

        Inclusion Criteria:

          1. Male or female participants 18 years of age or older.

          2. Multiple myeloma diagnosed according to standard criteria either currently or at the
             time of initial diagnosis.

             NOTE: The initial diagnosis must have been symptomatic multiple myeloma, although the
             relapsed disease did not need to be symptomatic.

          3. Must have had measurable disease, defined by at least 1 of the following 3
             measurements:

               -  Serum M-protein ≥ 1 g/dL (≥ 10 g/L).

               -  Urine M-protein ≥ 200 mg/24 hours.

               -  Serum free light chain (FLC) assay: involved FLC level ≥ 10 mg/dL (≥ 100 mg/L),
                  provided that the serum FLC ratio was abnormal.

          4. Participants with relapsed and/or refractory multiple myeloma (RRMM) who had received
             1 to 3 prior therapies.

             NOTE: population included the following 3 categories of participants:

               -  Participants who relapsed from their previous treatment(s) but were not
                  refractory to any previous treatment.

               -  Participants who were refractory to all lines of previous treatment(s) (ie,
                  participants who had never responded to any therapies received).

               -  Participants who relapsed from at least 1 previous treatment AND additionally
                  were refractory to at least 1 previous treatment. For the purposes of this study,
                  refractory disease was defined as disease progression on treatment or progression
                  within 60 days after the last dose of a given therapy.

             A line of therapy was defined as 1 or more cycles of a planned treatment program. This
             may have consisted of 1 or more planned cycles of single-agent therapy or combination
             therapy, as well as a sequence of treatments administered in a planned manner. For
             example, a planned treatment approach of induction therapy followed by autologous stem
             cell transplantation, followed by maintenance was considered 1 line of therapy.
             Autologous and allogenic transplants were permitted.

          5. Must have met the following clinical laboratory criteria:

               -  Absolute neutrophil count (ANC) ≥ 1000/mm^3 and platelet count ≥ 75,000/mm^3.
                  Platelet transfusions to help participants meet eligibility criteria were not
                  allowed within 3 days prior to randomization.

               -  Total bilirubin ≤ 1.5 x the upper limit of the normal range (ULN).

               -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN.

               -  Calculated creatinine clearance ≥ 30 mL/min NOTE: Participants with a low
                  creatinine clearance ≤ 60 mL/min (or ≤ 50 mL/min, according to lenalidomide
                  prescribing information/local practice) were to receive a reduced lenalidomide
                  dose of 10 mg once daily (QD) on Days 1 through 21 of a 28-day cycle. The
                  lenalidomide dose may have been escalated to 15 mg QD after 2 cycles if the
                  participant was not responding to treatment and was tolerating the treatment. If
                  renal function normalized (ie, creatinine clearance >60 mL/min or >50 mL/min,
                  according to lenalidomide prescribing information/local practice) and the
                  participant continued to tolerate this treatment, lenalidomide may then have been
                  escalated to 25 mg QD.

          6. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.

          7. Participants who received prior allogenic transplant must have had no active
             graft-versus-host disease.

          8. Female participants who:

               -  Were postmenopausal for at least 24 months before the screening visit, OR

               -  Were surgically sterile, OR

               -  If they were of childbearing potential must have: had a negative pregnancy test
                  with a sensitivity of at least 25 mIU/mL within 10 to 14 days and again within 24
                  hours prior to starting Cycle 1 of lenalidomide; either agreed to practice true
                  abstinence, when this was in line with the preferred and usual lifestyle of the
                  participant. (Periodic abstinence [eg, calendar, ovulation, symptothermal,
                  post-ovulation methods] and withdrawal were not acceptable methods of
                  contraception.) OR begun 2 reliable methods of birth control (1 highly effective
                  method and 1 additional effective method) at the same time, at least 28 days
                  before starting study treatment through 90 days after the last dose of study
                  treatment; and agreed to ongoing pregnancy testing AND must have also adhered to
                  the guidelines of the RevAssist program (US participants), RevAid program
                  (Canadian participants), iAccess program (Australian participants), RevMate
                  program (Japanese participants) or The Lenalidomide Pregnancy Risk Minimisation
                  Plan as outlined in the Study Manual (all other participants who were not using
                  commercial supplies).

             Male patients, even if surgically sterilized (ie, status postvasectomy), who:

               -  Agreed to practice true abstinence, when this was in line with the preferred and
                  usual lifestyle of the participant. (Periodic abstinence [eg, calendar,
                  ovulation, symptothermal, post-ovulation methods] and withdrawal were not
                  acceptable methods of contraception.) OR

               -  Agreed to practice effective barrier contraception during the entire study
                  treatment period and 90 days after the last dose of study treatment if their
                  partner was of childbearing potential, even if they had a successful vasectomy,
                  AND

               -  Must have also adhered to the guidelines of the RevAssist program (US
                  participants), RevAid program (Canadian participants), iAccess program
                  (Australian participants), RevMate program (Japanese participants) or The
                  Lenalidomide Pregnancy Risk Minimisation Plan as outlined in the study Manual
                  (all other participants who were not using commercial supplies)

          9. Must have been able to take concurrent aspirin 81 to 325 mg daily (or enoxaparin 40 mg
             subcutaneously daily [or its equivalent] if allergic to aspirin), per published
             standard or institutional standard of care, as prophylactic anticoagulation.

             NOTE: For participants with prior history of deep vein thrombosis (DVT),
             low-molecular-weight heparin (LMWH) was mandatory.

         10. Voluntary written consent must have been given before performance of any study related
             procedure not part of standard medical care, with the understanding that consent may
             have been withdrawn by the participant at any time without prejudice to future medical
             care.

         11. Was willing and able to adhere to the study visit schedule and other protocol
             requirements.

        Exclusion Criteria:

          1. Was refractory to lenalidomide or proteasome inhibitor-based therapy at any line.

             NOTE: Refractory disease was defined as disease progression on treatment or
             progression within 60 days after the last dose of a given therapy. Participants who
             progressed after 60 days from the last dose of a given therapy were considered
             relapsed and were eligible for inclusion in the study.

             Participants who were refractory to thalidomide-based therapy were eligible.

          2. Female participants who were breast feeding or pregnant.

          3. Failure to have fully recovered (ie, Grade 1 toxicity) from the effects of prior
             chemotherapy (except for alopecia) regardless of the interval since last treatment.

          4. Major surgery within 14 days before randomization.

          5. Radiotherapy within 14 days before randomization.

          6. Central nervous system involvement.

          7. Infection requiring systemic antibiotic therapy or other serious infection within 14
             days before randomization.

          8. Diagnosis of Waldenstrom's macroglobulinemia, polyneuropathy, organomegaly,
             endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome, plasma cell
             leukemia, primary amyloidosis, myelodysplastic syndrome, or myeloproliferative
             syndrome.

          9. Evidence of current uncontrolled cardiovascular conditions, including uncontrolled
             hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure,
             unstable angina, or myocardial infarction within 6 months before randomization in the
             study.

         10. Systemic treatment with strong inhibitors of cytochrome P450 (CYP) 1A2 (CYP1A2)
             (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of CYP3A (clarithromycin,
             telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or
             strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin,
             phenobarbital), or use of Ginkgo biloba or St. John's wort within 14 days before
             randomization in the study.

         11. Ongoing or active systemic infection, active hepatitis B or C virus infection, or
             known human immunodeficiency virus positive.

         12. Comorbid systemic illnesses or other severe concurrent disease which, in the judgment
             of the investigator, would make the participant inappropriate for entry into this
             study or interfere significantly with the proper assessment of safety and toxicity of
             the prescribed regimens (eg, peripheral neuropathy that is Grade 1 with pain or Grade
             2 or higher of any cause).

         13. Psychiatric illness/social situation that would limit compliance with study
             requirements.

         14. Known allergy to any of the study medications, their analogues, or excipients in the
             various formulations of any agent.

         15. Inability to swallow oral medication, inability or unwillingness to comply with the
             drug administration requirements, or gastrointestinal condition that could interfere
             with the oral absorption or tolerance of treatment.

         16. Diagnosed or treated for another malignancy within 2 years before randomization or
             previously diagnosed with another malignancy and any evidence of residual disease.
             Participants with nonmelanoma skin cancer or carcinoma in situ of any type were not
             excluded if they had undergone complete resection.