An Effectiveness and Safety Study of Ixazomib in Combination With Lenalidomide and Dexamethasone (IRD) in Participants With Multiple Myeloma (MM) Previously Receiving a Bortezomib-based Induction Regimen (US MM-6)

The drug being tested in this study is called Ixazomib. Ixazomib is being tested to treat
people who have MM. This study will look at the effectiveness and safety in participants who
take ixazomib in addition to lenalidomide and dexamethasone.

The study will enroll approximately 160 participants. Participants will initially receive:

• Ixazomib 4 mg + lenalidomide 25 mg + dexamethasone 40 mg

Participants include MM participants who have received 3 cycles of a bortezomib-based
induction regimen (as defined by current National Comprehensive Cancer Network [NCCN]
guidelines) and have no evidence of PD following initial first-line therapy. All participants
will be asked to take ixazomib 4 mg on Days 1, 8 and 15 and lenalidomide 25 mg from Day 1
through 21 and dexamethasone 40 mg on Days 1, 8, 15 and 22 in 28 day cycles until disease
progression or unacceptable toxicity for up to 2 years. Dose modifications of ixazomib,
and/or lenalidomide and/or dexamethasone are allowed at the discretion of the physician.

This multi-center trial will be conducted in United States. It is anticipated that the
treatment phase of this study will last up to 36 months, including 12 months for enrollment,
and a 24-month IRD treatment period (26 cycles) with ixazomib and/or lenalidomide and/or
dexamethasone for the last participant enrolled.

Participants will make multiple visits to the clinic as per their standard of care, and will
be followed for PFS. After disease progression, participants will be followed-up for overall
survival every 6 months until death or termination of the study by the sponsor.

Inclusion Criteria:

1. Must have a diagnosis of a MM using current International Myeloma Working Group (IMWG)
diagnostic criteria and have received 1 prior line of therapy.

- Participants must have completed 3 cycles of a bortezomib-based induction regimen
(as defined by current NCCN guidelines) and have no evidence of disease
progression as defined by IMWG criteria.

- Participants with light chain and free light chain (FLC) only may be enrolled if
they meet all the criteria for a diagnosis of MM.

- Participants must be considered by their physician eligible to receiving the IRD
regimen.

2. Must be transplant ineligible as determined by their physician, or if transplant
eligible, not expect to undergo transplant for at least 24 months after study
enrollment.

• Stem cell harvest and mobilization regimen is acceptable if clinically indicated,
but must first be confirmed by the Takeda Medical Monitor.

3. Eastern Cooperative Oncology Group (ECOG) performance status and/or other performance
status 0, 1, or 2 at time of enrollment.

Exclusion Criteria:

1. Failure to have fully recovered (that is, less than or equal to [<=] Grade 1 toxicity)
from the reversible effects of prior chemotherapy.

2. Major surgery within 14 days before enrollment.

3. Radiotherapy within 14 days before enrollment (if the involved field is small, 7 days
will be considered a sufficient interval between treatment and administration of the
ixazomib.)

4. Central nervous system involvement.

5. Infection requiring systemic antibiotic therapy or other serious infection within 14
days before study enrollment.

6. Evidence of current uncontrolled cardiovascular conditions, including uncontrolled
hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure,
unstable angina, or myocardial infarction within the past 6 months.

7. Systemic treatment, within 14 days before the first dose of ixazomib, with strong
cytochrome P450 3A (CYP3A) inducers (rifampin, rifapentine, rifabutin, carbamazepine,
phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort.

8. Ongoing or active systemic infection, active hepatitis B or C virus infection, or
known human immunodeficiency virus positive.

9. Diagnosed or treated for another malignancy within 2 years before study enrollment or
previously diagnosed with another malignancy and have any evidence of residual
disease. Participants with non-melanoma skin cancer or carcinoma in situ of any type
are not excluded if they have undergone complete resection.

10. Has greater than or equal to (>=) Grade 2 peripheral neuropathy, or Grade 1 with pain
on clinical examination during the screening period.

11. PD on first-line therapy.

12. Participation in other interventional clinical trials, including those with other
investigational agents not included in this trial, within 30 days of the start of this
trial and throughout the duration of this trial. Non-interventional trials (that is,
observational trials) are permitted at any time point.