A Phase 3 Study Comparing Oral Ixazomib Plus Lenalidomide and Dexamethasone Versus Placebo Plus Lenalidomide and Dexamethasone in Adult Patients With Relapsed and/or Refractory Multiple Myeloma

The drug being tested in this study is called Ixazomib. Ixazomib is being tested to treat
people who have relapsed and/or refractory multiple myeloma (RRMM). This study will look at
progression free survival (PFS), overall survival (OS) and safety in participants who take
ixazomib in addition to lenalidomide and dexamethasone compared to placebo in addition to
lenalidomide and dexamethasone.

The study enrolled 722 patients. Participants were randomly assigned (by chance, like
flipping a coin) to one of the two treatment groups—which will remain undisclosed to the
patient and study doctor during the study (unless there is an urgent medical need):

- Ixazomib 4 mg + lenalidomide + dexamethasone

- Placebo (dummy inactive pill) - this is a tablet that looks like the study drug but has
no active ingredient + lenalidomide + dexamethasone

All participants will receive treatment in 28 day cycles until disease progression or
unacceptable toxicity.

This multi-center trial will be conducted worldwide. The overall time to participate in this
study is approximately 80 months. Participants will make multiple visits to the clinic, and
will be contacted every 4 weeks for PFS and every 12 weeks for OS.

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.