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

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 thetime of initial diagnosis. NOTE: The initial diagnosis must have been symptomatic multiple myeloma, although therelapsed disease did not need to be symptomatic.
3. Must have had measurable disease, defined by at least 1 of the following 3measurements:

• 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 notrefractory 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 additionallywere refractory to at least 1 previous treatment. For the purposes of this study,refractory disease was defined as disease progression on treatment or progressionwithin 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. Thismay have consisted of 1 or more planned cycles of single-agent therapy or combinationtherapy, as well as a sequence of treatments administered in a planned manner. Forexample, a planned treatment approach of induction therapy followed by autologous stemcell 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 notallowed 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 lowcreatinine clearance ≤ 60 mL/min (or ≤ 50 mL/min, according to lenalidomideprescribing information/local practice) were to receive a reduced lenalidomidedose of 10 mg once daily (QD) on Days 1 through 21 of a 28-day cycle. Thelenalidomide dose may have been escalated to 15 mg QD after 2 cycles if theparticipant was not responding to treatment and was tolerating the treatment. Ifrenal function normalized (ie, creatinine clearance >60 mL/min or >50 mL/min,according to lenalidomide prescribing information/local practice) and theparticipant continued to tolerate this treatment, lenalidomide may then have beenescalated 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 activegraft-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 testwith a sensitivity of at least 25 mIU/mL within 10 to 14 days and again within 24hours prior to starting Cycle 1 of lenalidomide; either agreed to practice trueabstinence, when this was in line with the preferred and usual lifestyle of theparticipant. (Periodic abstinence [eg, calendar, ovulation, symptothermal,post-ovulation methods] and withdrawal were not acceptable methods ofcontraception.) OR begun 2 reliable methods of birth control (1 highly effectivemethod and 1 additional effective method) at the same time, at least 28 daysbefore starting study treatment through 90 days after the last dose of studytreatment; and agreed to ongoing pregnancy testing AND must have also adhered tothe guidelines of the RevAssist program (US participants), RevAid program (Canadian participants), iAccess program (Australian participants), RevMateprogram (Japanese participants) or The Lenalidomide Pregnancy Risk MinimisationPlan as outlined in the Study Manual (all other participants who were not usingcommercial supplies). Male patients, even if surgically sterilized (ie, status postvasectomy), who:
• Agreed to practice true abstinence, when this was in line with the preferred andusual lifestyle of the participant. (Periodic abstinence [eg, calendar,ovulation, symptothermal, post-ovulation methods] and withdrawal were notacceptable methods of contraception.) OR
• Agreed to practice effective barrier contraception during the entire studytreatment period and 90 days after the last dose of study treatment if theirpartner was of childbearing potential, even if they had a successful vasectomy,AND
• Must have also adhered to the guidelines of the RevAssist program (USparticipants), RevAid program (Canadian participants), iAccess program (Australian participants), RevMate program (Japanese participants) or TheLenalidomide 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 mgsubcutaneously daily [or its equivalent] if allergic to aspirin), per publishedstandard 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 relatedprocedure not part of standard medical care, with the understanding that consent mayhave been withdrawn by the participant at any time without prejudice to future medicalcare.
11. Was willing and able to adhere to the study visit schedule and other protocolrequirements.

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 orprogression within 60 days after the last dose of a given therapy. Participants whoprogressed after 60 days from the last dose of a given therapy were consideredrelapsed 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 priorchemotherapy (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 14days before randomization.
8. Diagnosis of Waldenstrom's macroglobulinemia, polyneuropathy, organomegaly,endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome, plasma cellleukemia, primary amyloidosis, myelodysplastic syndrome, or myeloproliferativesyndrome.
9. Evidence of current uncontrolled cardiovascular conditions, including uncontrolledhypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure,unstable angina, or myocardial infarction within 6 months before randomization in thestudy.
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) orstrong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin,phenobarbital), or use of Ginkgo biloba or St. John's wort within 14 days beforerandomization in the study.
11. Ongoing or active systemic infection, active hepatitis B or C virus infection, orknown human immunodeficiency virus positive.
12. Comorbid systemic illnesses or other severe concurrent disease which, in the judgmentof the investigator, would make the participant inappropriate for entry into thisstudy or interfere significantly with the proper assessment of safety and toxicity ofthe 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 studyrequirements.
14. Known allergy to any of the study medications, their analogues, or excipients in thevarious formulations of any agent.
15. Inability to swallow oral medication, inability or unwillingness to comply with thedrug administration requirements, or gastrointestinal condition that could interferewith the oral absorption or tolerance of treatment.
16. Diagnosed or treated for another malignancy within 2 years before randomization orpreviously diagnosed with another malignancy and any evidence of residual disease.Participants with nonmelanoma skin cancer or carcinoma in situ of any type were notexcluded if they had undergone complete resection.