A Study of MLN9708 in Japanese Participants With Relapsed and/or Refractory Multiple Myeloma (RRMM)

• Sponsor: Takeda (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT04272775
• Collaborator: (none)
• Enrollment: 14
• Arms: 4
• Actual Duration (Months): 80.4

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the tolerability, safety, pharmacokinetics (PK) of ixazomib alone or in combination with lenalidomide and dexamethasone (Rd), and antitumor activity of ixazomib in participants with RRMM.

Condition or Disease	Intervention/Treatment	Phase
Relapsed and/or Refractory Multiple Myeloma	Drug: Ixazomib; Drug: Lenalidomide; Drug: Dexamethasone	Phase 1

Detailed Description

The drug being tested in this study is called ixazomib. This study will evaluate the tolerability, safety, and PK of ixazomib administered alone or in combination with lenalidomide and dexamethasone in participants with relapsed and/or refractory multiple myeloma.

This study will enroll approximately 24 participants (3 to 6 participants in each dose-escalation cohort). Participants will be assigned to receive treatment in one of the four treatment cohorts:

• Cohort 1: Ixazomib 4.0 mg

• Cohort 2: Ixazomib 4.0 mg + Lenalidomide and Dexamethasone

• Cohort 3: Ixazomib 5.5 mg

• Cohort 4: Ixazomib 5.5 mg + Lenalidomide and Dexamethasone

This multi-center trial will be conducted in Japan. The overall time to participate in this study is approximately 7 years. Participants will make a final visit 29 days after receiving their last dose of drug for a follow-up assessment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 14 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1 Study of MLN9708 in Japanese Patients With Relapsed and/or Refractory Multiple Myeloma
• Actual Study Start Date: Jun 5, 2012
• Actual Primary Completion Date: Feb 15, 2019
• Actual Study Completion Date: Feb 15, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort 1: Ixazomib 4.0 mg Ixazomib 4.0 milligram (mg), capsules, orally, once, on Days 1, 8, and 15 in 28-day treatment cycle for up to Cycle 87.	Drug: Ixazomib; Ixazomib capsules.; Other Names: MLN9708
Experimental: Cohort 2: Ixazomib 4.0 mg + Lenalidomide and Dexamethasone Ixazomib 4.0 mg, capsules, orally, once, on Days 1, 8, and 15 in 28-day treatment cycle along with lenalidomide 25 milligram per day (mg/day), capsules, orally, once, from Days 1 to 21 and dexamethasone 40 mg/day, tablets, orally, once, on Days 1, 8, 15, and 22 in 28-day treatment cycle for up to Cycle 62.	Drug: Ixazomib; Ixazomib capsules.; Other Names: MLN9708 ; Drug: Lenalidomide; Lenalidomide capsules.; Drug: Dexamethasone; Dexamethasone tablets.
Experimental: Cohort 3: Ixazomib 5.5 mg Ixazomib 5.5 mg, capsules, orally, once, on Days 1, 8, and 15 in 28-day treatment cycle for up to Cycle 87.	Drug: Ixazomib; Ixazomib capsules.; Other Names: MLN9708
Experimental: Cohort 4: Ixazomib 5.5 mg + Lenalidomide and Dexamethasone Ixazomib 5.5 mg, capsules, orally, once, on Days 1, 8, and 15 in 28-day treatment cycle along with lenalidomide 25 mg/day, capsules, orally, once, from Days 1 to 21 and dexamethasone 40 mg/day, tablets, orally, once, on Days 1, 8, 15, and 22 in 28-day treatment cycle for up to Cycle 87.	Drug: Ixazomib; Ixazomib capsules.; Other Names: MLN9708 ; Drug: Lenalidomide; Lenalidomide capsules.; Drug: Dexamethasone; Dexamethasone tablets.

Outcome Measures

Primary Outcome Measures

1. Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) [From Cycle 1 Day 1 until Cycle 2 Day 1 (Cycle length is equal to [=] 28 days)]

   DLT:Any following adverse events (AEs) possibly related to ixazomib assessed by Common Terminology Criteria for AEs (CTCAE) version 4.03; Grade 4 neutropenia/thrombocytopenia lasting >7 consecutive days; Grade 3/greater neutropenia with fever/infections; Grade 3/greater thrombocytopenia with clinically significant bleeding; platelet count less than (<)10,000 per cubic meter(/mm^3); Grade 2 peripheral neuropathy with pain/Grade 3 or greater peripheral neuropathy; Grade 3/greater nonhematologic toxicities with exceptions of arthralgia/myalgia, fatigue lasting <7 days manageable nausea/emesis with antiemetic prophylaxis, diarrhea that is controlled with supportive care; treatment delay of >14 days at start of Cycle 2 due to failure of hematologic/nonhematologic recovery; Other Grade 2/greater ixazomib related nonhematologic toxicities required permanent discontinuation of ixazomib;Inability to receive at least 80% of planned lenalidomide doses due to the AEs related to ixazomib.

2. Number of Participants Who Experienced at Least One Treatment-emergent Adverse Event (TEAE) [Baseline up to 29 days after last dose of study drug (up to Cycle 87 Day 44) (Each Cycle length=28 days)]

3. Number of Participants With Grade 3 or Higher TEAE Related to Body Weight [Baseline up to 29 days after last dose of study drug (up to Cycle 87 Day 44) (Each Cycle length=28 days)]

   Body weight abnormalities were graded using the CTCAE version 4.03. as: Grade 1 (Mild, asymptomatic or mild symptoms); Grade 2 (Moderate, minimal, local or noninvasive intervention indicated); Grade 3 (Severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated); Grade 4 (Life-threatening consequences, urgent intervention indicated); Grade 5 (Death related to AE).

4. Number of Participants With Grade 3 or Higher TEAE Related to Vital Signs [Baseline up to 29 days after last dose of study drug (up to Cycle 87 Day 44) (Each Cycle length=28 days)]

   Vital signs were graded using the CTCAE version 4.03. as: Grade 1 (Mild, asymptomatic or mild symptoms); Grade 2 (Moderate, minimal, local or noninvasive intervention indicated); Grade 3 (Severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated); Grade 4 (Life-threatening consequences, urgent intervention indicated); Grade 5 (Death related to AE).

5. Number of Participants With Grade 3 or Higher TEAE Related to 12-lead Electrocardiograms (ECGs) [Baseline up to 29 days after last dose of study drug (up to Cycle 87 Day 44) (Each Cycle length=28 days)]

   12-lead ECGs were graded using the CTCAE version 4.03. as: Grade 1 (Mild, asymptomatic or mild symptoms); Grade 2 (Moderate, minimal, local or noninvasive intervention indicated); Grade 3 (Severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated); Grade 4 (Life-threatening consequences, urgent intervention indicated); Grade 5 (Death related to AE).

6. Number of Participants With Grade 3 or Higher Laboratory Tests Abnormalities [Baseline up to 29 days after last dose of study drug (up to Cycle 87 Day 44) (Each Cycle length=28 days)]

   Laboratory tests abnormalities were graded using the CTCAE version 4.03. as: Grade 1 (Mild, asymptomatic or mild symptoms); Grade 2 (Moderate, minimal, local or noninvasive intervention indicated); Grade 3 (Severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated); Grade 4 (Life-threatening consequences, urgent intervention indicated); Grade 5 (Death related to AE).

7. Cmax: Maximum Observed Plasma Concentration for Ixazomib [Days 1 and 15 of Cycle 1: pre-dose and at multiple time points (15, 30, 60, and 90 minutes and 2, 4, 8, 24, 48, 96, and 168 hours) post-dose (Cycle length=28 days)]

Secondary Outcome Measures

1. Number of Participants Who Achieved Complete Response (CR), Very Good Partial Response (VGPR), and Partial Response (PR) [Baseline up to 29 days after last dose of study drug (up to Cycle 87 Day 44) (Each Cycle length=28 days)]

   Number of participants who achieved CR, PR, VGPR were assessed in accordance to International Myeloma Working Group Uniform Response Criteria for Multiple Myeloma. CR: No immunofixation on serum and urine, disappearance of soft tissue plasmacytomas and <5% plasma cells in bone marrow. Normal serum free light chain (SFLC) ratio if disease measurable only by SFLC. VGPR: Serum and urine M-protein detectable by immunofixation but not electrophoresis or greater than or equal to (>=) 90% decrease in serum M-protein with urine M-protein <100 milligram per 24 hours (mg/24 hrs). If disease measurable only by SFLC, >= 90% decrease in the difference between involved and uninvolved FLC levels (dFLC). PR: >= 50% reduction of serum M-protein and >= 90% reduction in urine M-protein or to <200 mg/24 hrs, or a >= 50% decrease in dFLC. A >=50% decrease in the size of soft tissue plasmacytomas present at baseline

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Japanese participants with multiple myeloma according to diagnostic criteria.

2. Previously treated with 2 or more regimens including all the following drugs; bortezomib, thalidomide or lenalidomide, corticosteroids.

3. Who have relapsed following the previous therapy or failed to continue the treatment due to their intolerability to the last treatment regimen for myeloma.

4. Measurable disease defined by at least one of the following 3 measurements; Serum M-protein: greater than or equal to (>=) 1 gram per deciliter (g/dL) (>= 10 gram per liter [g/L]), Urine M-protein: >= 200 mg/24 hours, Serum free light chain (FLC) assay: involved FLC level >= 10 milligram per deciliter (mg/dL) (>= 100 milligram per liter [mg/L]), provided that the serum FLC ratio is abnormal.

5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

6. 20 years or older at giving their informed consent.

7. Must be able to stay in the hospital for Cycle 1 treatment.

8. Must meet the following laboratory criteria at screening; Absolute neutrophil count (ANC): >=1,000 per cubic millimeter (/mm^{3), Platelet count: >=75,000/mm}3, Total bilirubin: <=1.5* the upper limit of normal range (ULN), Alanine aminotransferase (ALT) and aspartate aminotransferase (AST): less than or equal to (<=) 3* ULN, Creatinine clearance: calculated by using Cockcroft-Gault formula; MLN9708 monotherapy cohort: >=30 milliliter per minute (mL/min); MLN9708 with Rd cohort: >=60 mL/min.

9. Recovered (<= Grade 1) from the toxicities of the prior treatments. ANC >=1,000/mm^3.

10. Life expectancy of at least 3 months, in the judgment of the investigator.

11. Conforming to proper management guidelines of lenalidomide (MLN9708 with Rd cohort only).

Exclusion Criteria:

1. With plasmacytoma only.

2. With plasma cell leukemia.

3. With central nervous system invasion.

4. Radiotherapy within 14 days before enrollment.

5. Other anti-tumor drug administration within 21 days before enrollment.

6. Other investigational products administration within 21 days before enrollment (60 days from the last dose for carfilzomib).

7. Antibody treatment within 42 days before enrollment.

8. Systemic treatment with potent cytochrome P450 (CYP) isozyme 1A2 inhibitors (fluvoxamine, enoxacin), potent CYP3A inhibitors (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole), or potent CYP3A inducers (rifampin, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of foods containing Ginkgo biloba extract, St. John's Wort, or grapefruit within 14 days before enrollment.

9. Treatment with corticosteroids greater than (>) 10 mg of prednisolone per day. Inhaled and topical steroids are permitted.

10. Peripheral neuropathy >=Grade 2.

11. Diarrhea >= Grade 2.

12. Major surgery requiring general anesthesia within 14 days before enrollment.

13. Infection requiring systemic antibiotic treatment or other serious infections within 14 days before enrollment.

14. Evidence of concurrent uncontrolled cardiovascular conditions including hypertension, cardiac arrhythmias, New York Heart Association (NYHA) Class III or worse congestive heart failure, angina, myocardial infarction, or cerebral infarction within 6 months before enrollment.

15. Corrected QT interval (QTc) > 470 milliseconds on a 12-lead ECG obtained during the screening period.

16. Tested positive for human immunodeficiency virus (HIV) antibody, hepatitis B virus surface antigen (HBs antigen), or hepatitis C virus (HCV) antibody during the screening period.

17. Hypersensitivity to MLN9708 (including excipients), boron, or boron-containing drugs.

18. Hypersensitivity to lenalidomide, or dexamethasone, or excipients contained in the formulation of each drug (MLN9708 with Rd cohort only).

19. Known gastrointestinal diseases (difficulty swallowing, inflamed gastroenteritis, and Crohn disease), or gastrointestinal procedure (endoscopic procedure is permitted), that could interfere with the oral absorption or tolerance of the study treatment.

20. Uncontrolled diabetes mellitus.

21. A history of interstitial lung disease or lung fibrosis, or a current complication of interstitial lung disease or lung fibrosis diagnosed by diagnostic chest imaging.

22. Prior or current complications of deep vein thrombosis or pulmonary embolism (MLN9708 with Rd cohort only).

23 Diagnosed or treated for another malignancy within 2 years before the first dose or previously diagnosed with another malignancy and have any evidence of residual disease. Participants with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have complete resection.

1. Who do not consent to use adequate contraceptive precautions (example, condoms and oral contraceptives) during the following term:

• For women with childbearing potential, from when giving their consent through 3 months after the last dose of MLN9708, dexamethasone, or lenalidomide

• For men having their partners with childbearing potential, from giving their consent through 4 months after last dose of MLN9708, dexamethasone, or lenalidomide.

1. Pregnant (example, positive for pregnancy test) or lactating. Lactation is prohibited from the first dose through 6 months after the last dose of MLN9708, dexamethasone, and lenalidomide.

2. Use of an investigational medical device within 28 days before enrollment. 27. Any inabilities that could potentially interfere with the consent or completion of treatment according to this protocol.

3. Having difficulties in participation to this study by the investigator's judgment.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Takeda

Investigators

• Study Director: Medical Director, Takeda

Study Documents (Full-Text)

• Study Protocol - Nov 22, 2016
• Statistical Analysis Plan - Feb 12, 2014

More Information

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT04272775
• Other Study ID Numbers: TB-MC010034; JapicCTI-121822; U1111-1243-1737
• First Posted: Feb 17, 2020
• Last Update Posted: Mar 17, 2020
• Last Verified: Mar 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Takeda: Drug Therapy
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Dexamethasone; Lenalidomide; Ixazomib

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 5 investigative sites in Japan from 05 June 2012 to 15 February 2019.
Pre-assignment Detail	Relapsed and/or refractory multiple myeloma (RRMM) participants were enrolled to receive ixazomib 4.0 milligram (mg) in: Cohort 1 and along with lenalidomide 25 milligram per day (mg/day) and dexamethasone 40 mg/day (Rd) in Cohort 2. Study was terminated after completion of Cohorts 1 and 2 due to business decision; no safety or efficacy concerns.

Arm/Group Title	Cohort 1: Ixazomib 4.0 mg	Cohort 2: Ixazomib 4.0 mg + Lenalidomide and Dexamethasone
Arm/Group Description	Ixazomib 4.0 mg, capsules, orally, once, on Days 1, 8, and 15 in 28-day treatment cycle for up to Cycle 87.	Ixazomib 4.0 mg, capsules, orally, once, on Days 1, 8, and 15 in 28-day treatment cycle along with lenalidomide 25 mg/day, capsules, orally, once, from Days 1 to 21 and dexamethasone 40 mg/day, tablets, orally, once, on Days 1, 8, 15, and 22 in a 28-day treatment cycle for up to Cycle 62.
Period Title: Overall Study
STARTED	7	7
COMPLETED	0	0
NOT COMPLETED	7	7

Baseline Characteristics

Arm/Group Title	Cohort 1: Ixazomib 4.0 mg	Cohort 2: Ixazomib 4.0 mg + Lenalidomide and Dexamethasone	Total
Arm/Group Description	Ixazomib 4.0 mg, capsules, orally, once, on Days 1, 8, and 15 in 28-day treatment cycle for up to Cycle 87.	Ixazomib 4.0 mg, capsules, orally, once, on Days 1, 8, and 15 in 28-day treatment cycle along with lenalidomide 25 mg/day, capsules, orally, once, from Days 1 to 21 and dexamethasone 40 mg/day, tablets, orally, once, on Days 1, 8, 15, and 22 in a 28-day treatment cycle for up to Cycle 62.	Total of all reporting groups
Overall Participants	7	7	14
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63.4 (4.20)	60.3 (5.82)	61.9 (5.14)
Sex: Female, Male (Count of Participants)
Female	4 57.1%	2 28.6%	6 42.9%
Male	3 42.9%	5 71.4%	8 57.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	7 100%	7 100%	14 100%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	0 0%	0 0%	0 0%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
Japan	7 100%	7 100%	14 100%
Height (centimeter (cm)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeter (cm)]	156.49 (7.932)	165.29 (8.245)	160.89 (9.015)
Weight (kilogram (kg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram (kg)]	58.01 (8.477)	58.01 (9.688)	58.01 (8.745)
Body Surface Area (BSA) (square meter (m^2)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [square meter (m^2)]	1.585 (0.1438)	1.628 (0.1652)	1.607 (0.1504)
Eastern Cooperative Oncology Group Performance Status (Count of Participants)
0	6 85.7%	6 85.7%	12 85.7%
1	1 14.3%	0 0%	1 7.1%
2	0 0%	1 14.3%	1 7.1%
Medical and Surgical History (Count of Participants)
Had history	7 100%	7 100%	14 100%
No history	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Number of Participants Who Experienced Dose Limiting Toxicities (DLTs)
Description	DLT:Any following adverse events (AEs) possibly related to ixazomib assessed by Common Terminology Criteria for AEs (CTCAE) version 4.03; Grade 4 neutropenia/thrombocytopenia lasting >7 consecutive days; Grade 3/greater neutropenia with fever/infections; Grade 3/greater thrombocytopenia with clinically significant bleeding; platelet count less than (<)10,000 per cubic meter(/mm^3); Grade 2 peripheral neuropathy with pain/Grade 3 or greater peripheral neuropathy; Grade 3/greater nonhematologic toxicities with exceptions of arthralgia/myalgia, fatigue lasting <7 days manageable nausea/emesis with antiemetic prophylaxis, diarrhea that is controlled with supportive care; treatment delay of >14 days at start of Cycle 2 due to failure of hematologic/nonhematologic recovery; Other Grade 2/greater ixazomib related nonhematologic toxicities required permanent discontinuation of ixazomib;Inability to receive at least 80% of planned lenalidomide doses due to the AEs related to ixazomib.
Time Frame	From Cycle 1 Day 1 until Cycle 2 Day 1 (Cycle length is equal to [=] 28 days)

Outcome Measure Data

Analysis Population Description

The DLT analysis set consisted of DLT evaluable participants who received at least one dose of ixazomib.

Arm/Group Title	Cohort 1: Ixazomib 4.0 mg	Cohort 2: Ixazomib 4.0 mg + Lenalidomide and Dexamethasone
Arm/Group Description	Ixazomib 4.0 mg, capsules, orally, once, on Days 1, 8, and 15 in 28-day treatment cycle for up to Cycle 87.	Ixazomib 4.0 mg, capsules, orally, once, on Days 1, 8, and 15 in 28-day treatment cycle along with lenalidomide 25 mg/day, capsules, orally, once, from Days 1 to 21 and dexamethasone 40 mg/day, tablets, orally, once, on Days 1, 8, 15, and 22 in a 28-day treatment cycle for up to Cycle 62.
Measure Participants	6	6
Count of Participants [Participants]	1 14.3%	1 14.3%

2. Primary Outcome

Title	Number of Participants Who Experienced at Least One Treatment-emergent Adverse Event (TEAE)
Time Frame	Baseline up to 29 days after last dose of study drug (up to Cycle 87 Day 44) (Each Cycle length=28 days)

Outcome Measure Data

Analysis Population Description

The safety analysis set consisted of all participants who received at least one dose of ixazomib.

Arm/Group Title	Cohort 1: Ixazomib 4.0 mg	Cohort 2: Ixazomib 4.0 mg + Lenalidomide and Dexamethasone
Arm/Group Description	Ixazomib 4.0 mg, capsules, orally, once, on Days 1, 8, and 15 in 28-day treatment cycle for up to Cycle 87.	Ixazomib 4.0 mg, capsules, orally, once, on Days 1, 8, and 15 in 28-day treatment cycle along with lenalidomide 25 mg/day, capsules, orally, once, from Days 1 to 21 and dexamethasone 40 mg/day, tablets, orally, once, on Days 1, 8, 15, and 22 in a 28-day treatment cycle for up to Cycle 62.
Measure Participants	7	7
Count of Participants [Participants]	7 100%	7 100%

3. Primary Outcome

Title	Number of Participants With Grade 3 or Higher TEAE Related to Body Weight
Description	Body weight abnormalities were graded using the CTCAE version 4.03. as: Grade 1 (Mild, asymptomatic or mild symptoms); Grade 2 (Moderate, minimal, local or noninvasive intervention indicated); Grade 3 (Severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated); Grade 4 (Life-threatening consequences, urgent intervention indicated); Grade 5 (Death related to AE).
Time Frame	Baseline up to 29 days after last dose of study drug (up to Cycle 87 Day 44) (Each Cycle length=28 days)

Outcome Measure Data

Analysis Population Description

The safety analysis set consisted of all participants who received at least one dose of ixazomib.

Arm/Group Title	Cohort 1: Ixazomib 4.0 mg	Cohort 2: Ixazomib 4.0 mg + Lenalidomide and Dexamethasone
Arm/Group Description	Ixazomib 4.0 mg, capsules, orally, once, on Days 1, 8, and 15 in 28-day treatment cycle for up to Cycle 87.	Ixazomib 4.0 mg, capsules, orally, once, on Days 1, 8, and 15 in 28-day treatment cycle along with lenalidomide 25 mg/day, capsules, orally, once, from Days 1 to 21 and dexamethasone 40 mg/day, tablets, orally, once, on Days 1, 8, 15, and 22 in a 28-day treatment cycle for up to Cycle 62.
Measure Participants	7	7
Count of Participants [Participants]	0 0%	0 0%

4. Primary Outcome

Title	Number of Participants With Grade 3 or Higher TEAE Related to Vital Signs
Description	Vital signs were graded using the CTCAE version 4.03. as: Grade 1 (Mild, asymptomatic or mild symptoms); Grade 2 (Moderate, minimal, local or noninvasive intervention indicated); Grade 3 (Severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated); Grade 4 (Life-threatening consequences, urgent intervention indicated); Grade 5 (Death related to AE).
Time Frame	Baseline up to 29 days after last dose of study drug (up to Cycle 87 Day 44) (Each Cycle length=28 days)

Outcome Measure Data

Analysis Population Description

The safety analysis set consisted of all participants who received at least one dose of ixazomib.

Arm/Group Title	Cohort 1: Ixazomib 4.0 mg	Cohort 2: Ixazomib 4.0 mg + Lenalidomide and Dexamethasone
Arm/Group Description	Ixazomib 4.0 mg, capsules, orally, once, on Days 1, 8, and 15 in 28-day treatment cycle for up to Cycle 87.	Ixazomib 4.0 mg, capsules, orally, once, on Days 1, 8, and 15 in 28-day treatment cycle along with lenalidomide 25 mg/day, capsules, orally, once, from Days 1 to 21 and dexamethasone 40 mg/day, tablets, orally, once, on Days 1, 8, 15, and 22 in a 28-day treatment cycle for up to Cycle 62.
Measure Participants	7	7
Count of Participants [Participants]	1 14.3%	0 0%

5. Primary Outcome

Title	Number of Participants With Grade 3 or Higher TEAE Related to 12-lead Electrocardiograms (ECGs)
Description	12-lead ECGs were graded using the CTCAE version 4.03. as: Grade 1 (Mild, asymptomatic or mild symptoms); Grade 2 (Moderate, minimal, local or noninvasive intervention indicated); Grade 3 (Severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated); Grade 4 (Life-threatening consequences, urgent intervention indicated); Grade 5 (Death related to AE).
Time Frame	Baseline up to 29 days after last dose of study drug (up to Cycle 87 Day 44) (Each Cycle length=28 days)

Outcome Measure Data

Analysis Population Description

The safety analysis set consisted of all participants who received at least one dose of ixazomib.

Arm/Group Title	Cohort 1: Ixazomib 4.0 mg	Cohort 2: Ixazomib 4.0 mg + Lenalidomide and Dexamethasone
Arm/Group Description	Ixazomib 4.0 mg, capsules, orally, once, on Days 1, 8, and 15 in 28-day treatment cycle for up to Cycle 87.	Ixazomib 4.0 mg, capsules, orally, once, on Days 1, 8, and 15 in 28-day treatment cycle along with lenalidomide 25 mg/day, capsules, orally, once, from Days 1 to 21 and dexamethasone 40 mg/day, tablets, orally, once, on Days 1, 8, 15, and 22 in a 28-day treatment cycle for up to Cycle 62.
Measure Participants	7	7
Count of Participants [Participants]	0 0%	0 0%

6. Primary Outcome

Title	Number of Participants With Grade 3 or Higher Laboratory Tests Abnormalities
Description	Laboratory tests abnormalities were graded using the CTCAE version 4.03. as: Grade 1 (Mild, asymptomatic or mild symptoms); Grade 2 (Moderate, minimal, local or noninvasive intervention indicated); Grade 3 (Severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated); Grade 4 (Life-threatening consequences, urgent intervention indicated); Grade 5 (Death related to AE).
Time Frame	Baseline up to 29 days after last dose of study drug (up to Cycle 87 Day 44) (Each Cycle length=28 days)

Outcome Measure Data

Analysis Population Description

The safety analysis set consisted of all participants who received at least one dose of ixazomib.

Arm/Group Title	Cohort 1: Ixazomib 4.0 mg	Cohort 2: Ixazomib 4.0 mg + Lenalidomide and Dexamethasone
Arm/Group Description	Ixazomib 4.0 mg, capsules, orally, once, on Days 1, 8, and 15 in 28-day treatment cycle for up to Cycle 87.	Ixazomib 4.0 mg, capsules, orally, once, on Days 1, 8, and 15 in 28-day treatment cycle along with lenalidomide 25 mg/day, capsules, orally, once, from Days 1 to 21 and dexamethasone 40 mg/day, tablets, orally, once, on Days 1, 8, 15, and 22 in a 28-day treatment cycle for up to Cycle 62.
Measure Participants	7	7
Grade 4: Neutrophils low	0 0%	2 28.6%
Grade 4: Leukocytes low	0 0%	1 14.3%
Grade 4: Lymphocytes low	3 42.9%	0 0%
Grade 4: Platelets low	3 42.9%	2 28.6%
Grade 4: Sodium low	0 0%	1 14.3%
Grade 4: Potassium low	0 0%	1 14.3%
Grade 3: Neutrophils low	4 57.1%	2 28.6%
Grade 3: Hemoglobin low	2 28.6%	2 28.6%
Grade 3: Leukocytes low	3 42.9%	2 28.6%
Grade 3: Lymphocytes low	3 42.9%	3 42.9%
Grade 3: Platelets low	0 0%	2 28.6%
Grade 3: Albumin low	1 14.3%	1 14.3%
Grade 3: Corrected calcium high	0 0%	1 14.3%
Grade 3: Sodium low	1 14.3%	0 0%
Grade 3: Potassium low	1 14.3%	0 0%
Grade 3: Phosphate low	1 14.3%	1 14.3%

7. Primary Outcome

Title	Cmax: Maximum Observed Plasma Concentration for Ixazomib
Time Frame	Days 1 and 15 of Cycle 1: pre-dose and at multiple time points (15, 30, 60, and 90 minutes and 2, 4, 8, 24, 48, 96, and 168 hours) post-dose (Cycle length=28 days)

Outcome Measure Data

Analysis Population Description

The pharmacokinetic (PK) analysis set consisted of all participants who received at least one dose of ixazomib and has evaluable PK data. The PK analysis set where data at specified time points was available.

Arm/Group Title	Cohort 1: Ixazomib 4.0 mg	Cohort 2: Ixazomib 4.0 mg + Lenalidomide and Dexamethasone
Arm/Group Description	Ixazomib 4.0 mg, capsules, orally, once, on Days 1, 8, and 15 in 28-day treatment cycle for up to Cycle 87.	Ixazomib 4.0 mg, capsules, orally, once, on Days 1, 8, and 15 in 28-day treatment cycle along with lenalidomide 25 mg/day, capsules, orally, once, from Days 1 to 21 and dexamethasone 40 mg/day, tablets, orally, once, on Days 1, 8, 15, and 22 in a 28-day treatment cycle for up to Cycle 62.
Measure Participants	7	7
Day 1	65.3 (54.6)	32.9 (19.3)
Day 15	68.8 (59.9)	34.5 (42.0)

8. Secondary Outcome

Title	Number of Participants Who Achieved Complete Response (CR), Very Good Partial Response (VGPR), and Partial Response (PR)
Description	Number of participants who achieved CR, PR, VGPR were assessed in accordance to International Myeloma Working Group Uniform Response Criteria for Multiple Myeloma. CR: No immunofixation on serum and urine, disappearance of soft tissue plasmacytomas and <5% plasma cells in bone marrow. Normal serum free light chain (SFLC) ratio if disease measurable only by SFLC. VGPR: Serum and urine M-protein detectable by immunofixation but not electrophoresis or greater than or equal to (>=) 90% decrease in serum M-protein with urine M-protein <100 milligram per 24 hours (mg/24 hrs). If disease measurable only by SFLC, >= 90% decrease in the difference between involved and uninvolved FLC levels (dFLC). PR: >= 50% reduction of serum M-protein and >= 90% reduction in urine M-protein or to <200 mg/24 hrs, or a >= 50% decrease in dFLC. A >=50% decrease in the size of soft tissue plasmacytomas present at baseline
Time Frame	Baseline up to 29 days after last dose of study drug (up to Cycle 87 Day 44) (Each Cycle length=28 days)

Outcome Measure Data

Analysis Population Description

The response evaluable analysis set consisted of all participants who received at least one dose of ixazomib, have measurable disease at baseline, and at least one postbaseline response assessment.

Arm/Group Title	Cohort 1: Ixazomib 4.0 mg	Cohort 2: Ixazomib 4.0 mg + Lenalidomide and Dexamethasone
Arm/Group Description	Ixazomib 4.0 mg, capsules, orally, once, on Days 1, 8, and 15 in 28-day treatment cycle for up to Cycle 87.	Ixazomib 4.0 mg, capsules, orally, once, on Days 1, 8, and 15 in 28-day treatment cycle along with lenalidomide 25 mg/day, capsules, orally, once, from Days 1 to 21 and dexamethasone 40 mg/day, tablets, orally, once, on Days 1, 8, 15, and 22 in a 28-day treatment cycle for up to Cycle 62.
Measure Participants	7	6
Count of Participants [Participants]	0 0%	2 28.6%

Adverse Events

Time Frame	TEAEs are AEs that started after the first dose of study drug and no more than 29 days after the last dose of study drug (Cycle 87 Day 44)
Adverse Event Reporting Description	At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Arm/Group Title	Cohort 1: Ixazomib 4.0 mg		Cohort 2: Ixazomib 4.0 mg + Lenalidomide and Dexamethasone
Arm/Group Description	Ixazomib 4.0 mg, capsules, orally, once, on Days 1, 8, and 15 in 28-day treatment cycle for up to Cycle 87.		Ixazomib 4.0 mg, capsules, orally, once, on Days 1, 8, and 15 in 28-day treatment cycle along with lenalidomide 25 mg/day, capsules, orally, once, from Days 1 to 21 and dexamethasone 40 mg/day, tablets, orally, once, on Days 1, 8, 15, and 22 in a 28-day treatment cycle for up to Cycle 62.
All Cause Mortality
	Cohort 1: Ixazomib 4.0 mg		Cohort 2: Ixazomib 4.0 mg + Lenalidomide and Dexamethasone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/7 (0%)
Serious Adverse Events
	Cohort 1: Ixazomib 4.0 mg		Cohort 2: Ixazomib 4.0 mg + Lenalidomide and Dexamethasone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/7 (57.1%)		2/7 (28.6%)
Blood and lymphatic system disorders
Thrombocytopenia	1/7 (14.3%)		0/7 (0%)
Eye disorders
Retinal detachment	1/7 (14.3%)		0/7 (0%)
Infections and infestations
Bronchitis	1/7 (14.3%)		0/7 (0%)
Injury, poisoning and procedural complications
Femoral neck fracture	0/7 (0%)		1/7 (14.3%)
Spinal compression fracture	1/7 (14.3%)		0/7 (0%)
Metabolism and nutrition disorders
Hypokalaemia	1/7 (14.3%)		0/7 (0%)
Musculoskeletal and connective tissue disorders
Back pain	0/7 (0%)		1/7 (14.3%)
Bone pain	0/7 (0%)		1/7 (14.3%)
Other (Not Including Serious) Adverse Events
	Cohort 1: Ixazomib 4.0 mg		Cohort 2: Ixazomib 4.0 mg + Lenalidomide and Dexamethasone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/7 (100%)		7/7 (100%)
Blood and lymphatic system disorders
Neutropenia	6/7 (85.7%)		5/7 (71.4%)
Thrombocytopenia	6/7 (85.7%)		4/7 (57.1%)
Leukopenia	5/7 (71.4%)		4/7 (57.1%)
Lymphopenia	6/7 (85.7%)		2/7 (28.6%)
Anaemia	2/7 (28.6%)		1/7 (14.3%)
Cardiac disorders
Atrioventricular block first degree	1/7 (14.3%)		0/7 (0%)
Sinus tachycardia	0/7 (0%)		1/7 (14.3%)
Congenital, familial and genetic disorders
Epidermolysis	0/7 (0%)		1/7 (14.3%)
Ear and labyrinth disorders
Ear discomfort	1/7 (14.3%)		0/7 (0%)
Gastrointestinal disorders
Diarrhoea	6/7 (85.7%)		4/7 (57.1%)
Vomiting	5/7 (71.4%)		3/7 (42.9%)
Nausea	5/7 (71.4%)		2/7 (28.6%)
Constipation	1/7 (14.3%)		2/7 (28.6%)
Abdominal pain	2/7 (28.6%)		0/7 (0%)
Cheilitis	0/7 (0%)		1/7 (14.3%)
Haemorrhoids	0/7 (0%)		1/7 (14.3%)
Ileus	0/7 (0%)		1/7 (14.3%)
Perianal erythema	0/7 (0%)		1/7 (14.3%)
Stomatitis	0/7 (0%)		1/7 (14.3%)
General disorders
Pyrexia	3/7 (42.9%)		1/7 (14.3%)
Fatigue	2/7 (28.6%)		0/7 (0%)
Oedema peripheral	1/7 (14.3%)		1/7 (14.3%)
Face oedema	1/7 (14.3%)		0/7 (0%)
Malaise	0/7 (0%)		1/7 (14.3%)
Infections and infestations
Bronchitis	1/7 (14.3%)		3/7 (42.9%)
Nasopharyngitis	2/7 (28.6%)		2/7 (28.6%)
Influenza	1/7 (14.3%)		1/7 (14.3%)
Adenoviral conjunctivitis	0/7 (0%)		1/7 (14.3%)
Body tinea	0/7 (0%)		1/7 (14.3%)
Genital infection fungal	0/7 (0%)		1/7 (14.3%)
Laryngitis	1/7 (14.3%)		0/7 (0%)
Skin candida	1/7 (14.3%)		0/7 (0%)
Tinea pedis	0/7 (0%)		1/7 (14.3%)
Upper respiratory tract infection	0/7 (0%)		1/7 (14.3%)
Urethritis	0/7 (0%)		1/7 (14.3%)
Injury, poisoning and procedural complications
Chillblains	1/7 (14.3%)		0/7 (0%)
Contusion	0/7 (0%)		1/7 (14.3%)
Facial bones fracture	0/7 (0%)		1/7 (14.3%)
Rib fracture	0/7 (0%)		1/7 (14.3%)
Tooth fracture	1/7 (14.3%)		0/7 (0%)
Investigations
Aspartate aminotransferase increased	2/7 (28.6%)		1/7 (14.3%)
Alanine aminotransferase increased	1/7 (14.3%)		1/7 (14.3%)
Blood alkaline phosphatase increased	1/7 (14.3%)		1/7 (14.3%)
Blood lactate dehydrogenase increased	2/7 (28.6%)		0/7 (0%)
C-reactive protein increased	2/7 (28.6%)		0/7 (0%)
Blood magnesium decreased	1/7 (14.3%)		0/7 (0%)
Haemoglobin decreased	0/7 (0%)		1/7 (14.3%)
Lymphocyte count decreased	0/7 (0%)		1/7 (14.3%)
Weight decreased	1/7 (14.3%)		0/7 (0%)
Metabolism and nutrition disorders
Decreased appetite	3/7 (42.9%)		1/7 (14.3%)
Hypokalaemia	2/7 (28.6%)		1/7 (14.3%)
Hyponatraemia	1/7 (14.3%)		2/7 (28.6%)
Hyperkalaemia	1/7 (14.3%)		1/7 (14.3%)
Hypermagnesaemia	1/7 (14.3%)		1/7 (14.3%)
Abnormal loss of weight	1/7 (14.3%)		0/7 (0%)
Hypercalcaemia	0/7 (0%)		1/7 (14.3%)
Hyperuricaemia	1/7 (14.3%)		0/7 (0%)
Hypophosphataemia	0/7 (0%)		1/7 (14.3%)
Musculoskeletal and connective tissue disorders
Back pain	0/7 (0%)		1/7 (14.3%)
Muscle spasms	0/7 (0%)		1/7 (14.3%)
Muscular weakness	0/7 (0%)		1/7 (14.3%)
Musculoskeletal pain	1/7 (14.3%)		0/7 (0%)
Myalgia	0/7 (0%)		1/7 (14.3%)
Osteoporosis	1/7 (14.3%)		0/7 (0%)
Nervous system disorders
Dysgeusia	1/7 (14.3%)		1/7 (14.3%)
Headache	2/7 (28.6%)		0/7 (0%)
Neuropathy peripheral	0/7 (0%)		1/7 (14.3%)
Parkinson's disease	0/7 (0%)		1/7 (14.3%)
Seizure	1/7 (14.3%)		0/7 (0%)
Syncope	0/7 (0%)		1/7 (14.3%)
Tremor	1/7 (14.3%)		0/7 (0%)
Psychiatric disorders
Insomnia	3/7 (42.9%)		2/7 (28.6%)
Delirium	0/7 (0%)		1/7 (14.3%)
Renal and urinary disorders
Renal disorder	1/7 (14.3%)		0/7 (0%)
Respiratory, thoracic and mediastinal disorders
Hiccups	1/7 (14.3%)		1/7 (14.3%)
Cough	1/7 (14.3%)		0/7 (0%)
Dysphonia	1/7 (14.3%)		0/7 (0%)
Pleural effusion	1/7 (14.3%)		0/7 (0%)
Upper respiratory tract inflammation	0/7 (0%)		1/7 (14.3%)
Skin and subcutaneous tissue disorders
Rash maculo-papular	3/7 (42.9%)		0/7 (0%)
Decubitus ulcer	0/7 (0%)		1/7 (14.3%)
Eczema	0/7 (0%)		1/7 (14.3%)
Erythema	0/7 (0%)		1/7 (14.3%)
Haemorrhage subcutaneous	0/7 (0%)		1/7 (14.3%)
Ingrowing nail	0/7 (0%)		1/7 (14.3%)
Pruritus	1/7 (14.3%)		0/7 (0%)
Rash	0/7 (0%)		1/7 (14.3%)
Rash macular	0/7 (0%)		1/7 (14.3%)
Rash pruritic	0/7 (0%)		1/7 (14.3%)
Skin erosion	0/7 (0%)		1/7 (14.3%)
Urticaria	1/7 (14.3%)		0/7 (0%)
Vascular disorders
Hypertension	2/7 (28.6%)		0/7 (0%)
Hypotension	2/7 (28.6%)		0/7 (0%)
Phlebitis	0/7 (0%)		1/7 (14.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Research Organization shall not publish any articles or papers nor make any presentations, nor assist any other person in publishing any articles or papers or in making any presentations relating or referring to the Study or any results, data or insights from or any data, information or materials obtained or generated in the performance of its obligations without the prior written consent of Takeda, which consent may be granted or withheld in Takeda's sole discretion.