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

• Sponsor: Millennium Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01564537
• Collaborator: (none)
• Enrollment: 722
• Locations: 24
• Arms: 2
• Actual Duration (Months): 114.3
• Patients Per Site: 30.1
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief 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).

Condition or Disease	Intervention/Treatment	Phase
Relapsed Multiple Myeloma; Refractory Multiple Myeloma	Drug: Ixazomib; Drug: Lenalidomide; Drug: Dexamethasone; Drug: Placebo	Phase 3

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 722 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Randomized, Double-Blind, Multicenter Study Comparing Oral Ixazomib (MLN9708) Plus Lenalidomide and Dexamethasone Versus Placebo Plus Lenalidomide and Dexamethasone in Adult Patients With Relapsed and/or Refractory Multiple Myeloma
• Actual Study Start Date: Aug 1, 2012
• Actual Primary Completion Date: Oct 1, 2014
• Actual Study Completion Date: Feb 8, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ixazomib + Lenalidomide + Dexamethasone Ixazomib 4 mg, capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until progressive disease (PD) or unacceptable toxicity, whichever occurred first up to end of treatment (EOT) projected at 80 months.	Drug: Ixazomib; Ixazomib capsules; Other Names: MLN9708 NINLARO® ; Drug: Lenalidomide; Lenalidomide capsules; Drug: Dexamethasone; Dexamethasone tablets
Placebo Comparator: Placebo + Lenalidomide + Dexamethasone Ixazomib placebo-matching capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until progressive disease (PD) or unacceptable toxicity, whichever occurred first up to EOT projected at 80 months.	Drug: Lenalidomide; Lenalidomide capsules; Drug: Dexamethasone; Dexamethasone tablets; Drug: Placebo; Ixazomib placebo-matching capsules

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival (PFS) as Assessed by the Independent Review Committee (IRC) [From date of randomization until disease progression or death up to data cut-off: 30 October 2014 (approximate median follow-up 15 months)]

   Progression Free Survival (PFS) is defined as the time from the date of randomization to the date of first documentation of disease progression (PD) or death due to any cause, whichever occurs first. Response including PD was assessed by independent review committee (IRC) using the International Myeloma Working Group (IMWG) response criteria. PD requires 1 of the following: Increase of ≥ 25% from nadir in: Serum M-component (absolute increase ≥ 0.5 g/dl); Urine M-component (absolute increase ≥ 200 mg/24 hours); In patients without measurable serum and urine M-protein levels the difference between involved and uninvolved free light chain (FLC) levels (absolute increase > 10 mg/dl); Development of new or increase in the size of existing bone lesions or soft tissue plasmacytomas; Development of hypercalcemia (corrected serum calcium > 11.5 mg/dl) attributed solely to plasma cell proliferative disease. Status evaluated every 4 weeks until disease progression (PD) was confirmed.

Secondary Outcome Measures

1. Overall Survival (OS) [Date of randomization until death up to data cut-off: 30 October 2014 (approximate median follow-up 15 months)]

   Overall survival is defined as the time from the date of randomization to the date of death. Participants without documentation of death at the time of the analysis were censored at the date when they were last known to be alive.

2. Overall Survival in High-Risk Participants Carrying Deletion 17 [Del(17)] [At the time of screening; Day 1 of each cycle (every 4 weeks) until disease progression and thereafter every 12 weeks until death or study termination]

   Overall survival is defined as the time from the date of randomization to the date of death. The high-risk participants whose myeloma carried del(17) subgroup was defined as the cases reported as positive for del(17) by the central laboratory combined with those cases that lacked a central laboratory result but with known del (17) by local laboratory. Participants without documentation of death at the time of the analysis were censored at the date when they were last known to be alive.

3. Overall Response Rate (ORR) as Assessed by the IRC [Day 1 of each cycle (every 4 weeks) until disease progression up to data cut-off: 30 October 2014 (approximate median follow-up 15 months)]

   ORR was defined as the percentage of participants with Complete Response (CR) including stringent complete response (sCR), very good partial response (VGPR) and Partial Response (PR) assessed by the IRC using IMWG criteria.

4. Percentage of Participants With Complete Response (CR) and Very Good Partial Response (VGPR) as Assessed by the IRC [Day 1 of each cycle (every 4 weeks) until disease progression up to data cut-off: 30 October 2014 (approximate median follow-up 15 months)]

   Response was assessed by the IRC using International Myeloma Working Group (IMWG) Criteria. CR is defined as negative immunofixation on the serum and urine and; disappearance of any soft tissue plasmacytomas and; < 5% plasma cells in bone marrow. VGPR is defined as Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level < 100 mg per 24 hours.

5. Duration of Response (DOR) [Day 1 of each cycle (every 4 weeks) until disease progression up to data cut-off: 30 October 2014 (approximate median follow-up 15 months)]

   DOR was measured as the time in months from the date of first documentation of a confirmed response of PR or better (CR [including sCR] + PR+ VGPR) to the date of the first documented disease progression (PD) among participants who responded to the treatment. Response was assessed by the investigator using International Myeloma Working Group (IMWG) Criteria.

6. Time to Progression (TTP) as Assessed by the IRC [Day 1 of each cycle (every 4 weeks) until disease progression up to data cut-off: 30 October 2014 (approximate median follow-up 15 months)]

   TTP was measured as the time in months from the first dose of study treatment to the date of the first documented progressive disease (PD) as assessed by the IRC using IMWG criteria.

7. Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [From the date of signing of the informed consent form through 30 days after the last dose of study drug up to data cut-off: 30 October 2014 (approximate median follow-up 15 months)]

   Eastern Cooperative Oncology Group (ECOG) performance score, laboratory values, vital sign measurements and reported adverse events (AEs) were collected and assessed to evaluate the safety of therapy throughout the study. An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; or congenital anomaly; or a medically important event.

8. Percentage of Participants Achieving Pain Response [At screening; Day 1 of each cycle; and thereafter every 4 weeks until disease progression]

   Pain response was defined as 30% reduction from Baseline in Brief Pain Inventory-Short Form (BPI-SF) worst pain score over the last 24 hours without an increase in analgesic (oral morphine equivalents) use at 2 consecutive evaluations. The BPI-SF contains 15 items designed to capture the pain severity ("worst," "least," "average," and "now" [current pain]), pain location, medication to relieve the pain, and the interference of pain with various daily activities including general activity, mood, walking activity, normal work, relations with other people, sleep, and enjoyment of life. The pain severity items are rated on a 0 to 10 scale where: 0=no pain and 10=pain as bad as you can imagine and averaged for a total score of 0 (best) to 10 (Worst).

9. Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30) [Baseline and Every 2 Cycles beginning with Cycle 2 during treatment period, End of Treatment (EOT), and every 4 Weeks in follow-up]

   The EORTC-QLQ-C30 is a 30-question tool used to assess the overall quality of life in cancer participants. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact).The EORTC-QLQ-C30 Global Health Status/QOL Scale is scored between 0 and 100, where higher scores indicate better Global Health Status/QOL. Negative changes from baseline indicate deterioration in QOL or functioning and positive changes indicate improvement.

10. Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Multiple Myeloma Module (QLQ-MY-20) [Baseline and Every 2 Cycles beginning with Cycle 2 during treatment period, End of Treatment (EOT), and every 4 Weeks in follow-up]

    The EORTC-QLQ-MY-20 is a patient-completed, 20-question quality of life questionnaire that has 4 independent subscales, 2 functional subscales (body image, future perspective), and 2 symptoms scales (disease symptoms and side-effects of treatment). The participant answers questions about their health during the past week using a 4-point scale where 1=Not at All to 4=Very Much. A negative change from Baseline indicates improvement.

11. OS in High-Risk Participants [At the time of screening; Day 1 of each cycle; every 4 weeks until disease progression and thereafter every 12 weeks until death or study termination]

    Overall survival (OS) is defined as the time from the date of randomization to the date of death. High-risk participants are defined as participants carrying cytogenic abnormalities: del(17), translocation t(4;14), or t(14;16) as reported by the central laboratory combined with those cases that lacked a central laboratory result but with known del (17), t(4;14), or t(14;16) by local laboratory. Cytogenetic abnormalities of del(13) and +1q are no longer considered to be high-risk abnormalities and are not included in the analysis. Participants without documentation of death at the time of the analysis were censored at the date when they were last known to be alive.

12. PFS in High-Risk Participants [From date of randomization until disease progression or death up to data cut-off: 30 October 2014 (approximate median follow-up 15 months)]

    Progression Free Survival (PFS) is defined as the time from the date of randomization to the date of first documentation of disease progression or death due to any cause, whichever occurs first. Response was assessed by independent review committee (IRC) using IMWG response criteria. High-risk participants are defined as participants carrying cytogenic abnormalities: del(17), translocation t(4;14), or t(14;16) as reported by the central laboratory combined with those cases that lacked a central laboratory result but with known del (17), t(4;14), or t(14;16) by local laboratory. Cytogenetic abnormalities of del(13) and +1q are no longer considered to be high-risk abnormalities and are not included in the analysis.

13. Pharmacokinetic Parameters (Including Cmax, AUC and Tmax) of Ixazomib [Days 1 & 14 of Cycles 1 & 2. Day 1 of Cycles 3 to 10]

14. Association Between Response or Resistance to Ixazomib Treatment and Proteasome and Nuclear Factor-kB (NF-kB)-Related Genes [At the time of screening; Day 1 of each cycle; at EOT; every 4 weeks until disease progression and thereafter every 12 weeks until death or study termination]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

1. 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.

1. 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.

1. 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.

1. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.

2. Participants who received prior allogenic transplant must have had no active graft-versus-host disease.

3. 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)

1. 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.

1. 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.

2. 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.

1. Female participants who were breast feeding or pregnant.

2. 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.

3. Major surgery within 14 days before randomization.

4. Radiotherapy within 14 days before randomization.

5. Central nervous system involvement.

6. Infection requiring systemic antibiotic therapy or other serious infection within 14 days before randomization.

7. 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.

8. 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.

9. 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.

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

11. 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).

12. Psychiatric illness/social situation that would limit compliance with study requirements.

13. Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent.

14. 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.

15. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Arkansas Medical Sciences	Little Rock	Arkansas	United States	72205
2	Pacific Cancer Medical Center Inc	Anaheim	California	United States	92801
3	West Contra Costa Healthcare District	Berkeley	California	United States	94704
4	University of Florida	Gainesville	Florida	United States	32610
5	Cancer & Blood Disease Center	Lecanto	Florida	United States	34461
6	Northwest Georgia Oncology Center	Marietta	Georgia	United States	30060
7	John H. Stroger, Jr. Hospital of Cook County	Chicago	Illinois	United States	60612
8	Dana Farber Cancer Institute	Boston	Massachusetts	United States	2215
9	Mayo Clinic	Rochester	Minnesota	United States	55905
10	Hackensack University Medical Center	Hackensack	New Jersey	United States	7601
11	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
12	Columbia University Medical Center	New York	New York	United States	10032
13	Blood and Cancer Clinic	Fayetteville	North Carolina	United States	28303
14	Scranton Hematology Oncology	Scranton	Pennsylvania	United States	18510
15	MUSC Hollings Cancer Center	Charleston	South Carolina	United States	29425
16	Fred Hutchinson Cancer Research	Seattle	Washington	United States	98109
17	West Virginia University Hospitals and Clinic	Morgantown	West Virginia	United States	26506-9300
18	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
19	Tom Baker Cancer Centre	Calgary	Alberta	Canada	T2N 4N2
20	Cross Cancer Institute	Edmonton	Alberta	Canada	T6G 1Z2
21	Vancouver General Hospital	Vancouver	British Columbia	Canada	V5Z 1M9
22	Saint John Regional Hospital	Saint John	New Brunswick	Canada	E2L 4L2
23	CHUM Notre-Dame Hospital	Montreal	Quebec	Canada	H2L 4M1
24	MUHC Glen Site Cedars Cancer Centre	Montreal	Quebec	Canada	H4A 3J1

Sponsors and Collaborators

• Millennium Pharmaceuticals, Inc.

Investigators

• Study Director: Medical Monitor, Millennium Pharmaceuticals, Inc.

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Millennium Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT01564537
• Other Study ID Numbers: C16010; 2011-005496-17; CTR20130908; U1111-1164-7646; NL40132.018.12; 12/LO/0949; JapicCTI-132345; 1015042370; C16010CTIL
• First Posted: Mar 28, 2012
• Last Update Posted: Mar 9, 2022
• Last Verified: Feb 1, 2022

• Keywords provided by Millennium Pharmaceuticals, Inc.: Drug therapy
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Dexamethasone; Lenalidomide; Ixazomib

Study Results

Participant Flow

Recruitment Details	Participants enrolled in this study at 147 sites in Australia, Austria, Belgium, Canada, China, Czech Republic, Denmark, France, Germany, Hungary, Israel, Italy, Japan, Republic of Korea, Netherlands, New Zealand, Poland, Portugal, Romania, Russian Federation, Singapore, Spain, Sweden, Turkey, United Kingdom and US from 28 Aug 2012 to 27 May 2014.
Pre-assignment Detail	Participants with a diagnosis of relapsed and/or refractory multiple myeloma were enrolled in 1 of 2 treatment groups: Ixazomib 4 mg or Ixazomib placebo-matching tablets in combination with lenalidomide, and dexamethasone. Data cut-off for this first analysis was 30 October 2014. The study is continuing in a double-blind fashion.

Arm/Group Title	Ixazomib+ Lenalidomide + Dexamethasone	Placebo + Lenalidomide + Dexamethasone
Arm/Group Description	Ixazomib 4 mg, capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until progressive disease (PD) or unacceptable toxicity, whichever occurred first up to end of treatment (EOT) projected at 80 months.	Ixazomib placebo-matching capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until progressive disease (PD) or unacceptable toxicity, whichever occurred first up to EOT projected at 80 months.
Period Title: Overall Study
STARTED	360	362
Safety Population: Received Study Drug	360	360
COMPLETED	354	356
NOT COMPLETED	6	6

Baseline Characteristics

Arm/Group Title	Ixazomib+ Lenalidomide + Dexamethasone	Placebo + Lenalidomide + Dexamethasone	Total
Arm/Group Description	Ixazomib 4 mg, capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until progressive disease (PD) or unacceptable toxicity, whichever occurred first up to EOT projected at 80 months.	Ixazomib placebo-matching capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until progressive disease (PD) or unacceptable toxicity, whichever occurred first up to EOT projected at 80 months.	Total of all reporting groups
Overall Participants	360	362	722
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65.5 (9.13)	65.8 (9.70)	65.7 (9.41)
Age, Customized (participants) [Number]
≤65 years	168 46.7%	176 48.6%	344 47.6%
>65-≤75 years	145 40.3%	125 34.5%	270 37.4%
>75 years	47 13.1%	61 16.9%	108 15%
Sex: Female, Male (Count of Participants)
Female	153 42.5%	160 44.2%	313 43.4%
Male	207 57.5%	202 55.8%	409 56.6%
Race/Ethnicity, Customized (participants) [Number]
White	310 86.1%	301 83.1%	611 84.6%
Black or African American	7 1.9%	6 1.7%	13 1.8%
Native Hawaiian/Other Pacific Islander	2 0.6%	2 0.6%	4 0.6%
Asian	30 8.3%	34 9.4%	64 8.9%
American Indian/Alaska native	0 0%	1 0.3%	1 0.1%
Other	4 1.1%	3 0.8%	7 1%
Not reported	7 1.9%	15 4.1%	22 3%
Race/Ethnicity, Customized (participants) [Number]
Hispanic or Latino	9 2.5%	12 3.3%	21 2.9%
Not Hispanic or Latino	339 94.2%	333 92%	672 93.1%
Not Reported	10 2.8%	15 4.1%	25 3.5%
Missing	2 0.6%	2 0.6%	4 0.6%
Region of Enrollment (participants) [Number]
Russian Federation	21 5.8%	18 5%	39 5.4%
Singapore	2 0.6%	4 1.1%	6 0.8%
United States	28 7.8%	23 6.4%	51 7.1%
Portugal	7 1.9%	8 2.2%	15 2.1%
Austria	5 1.4%	4 1.1%	9 1.2%
Netherlands	3 0.8%	6 1.7%	9 1.2%
Sweden	15 4.2%	12 3.3%	27 3.7%
China	3 0.8%	3 0.8%	6 0.8%
Korea, Republic of	4 1.1%	2 0.6%	6 0.8%
Poland	21 5.8%	20 5.5%	41 5.7%
France	36 10%	45 12.4%	81 11.2%
Romania	6 1.7%	6 1.7%	12 1.7%
Hungary	18 5%	21 5.8%	39 5.4%
United Kingdom	12 3.3%	8 2.2%	20 2.8%
Spain	16 4.4%	14 3.9%	30 4.2%
New Zealand	28 7.8%	39 10.8%	67 9.3%
Canada	19 5.3%	26 7.2%	45 6.2%
Czech Republic	15 4.2%	21 5.8%	36 5%
Turkey	4 1.1%	3 0.8%	7 1%
Belgium	7 1.9%	7 1.9%	14 1.9%
Denmark	10 2.8%	7 1.9%	17 2.4%
Italy	24 6.7%	15 4.1%	39 5.4%
Israel	19 5.3%	14 3.9%	33 4.6%
Australia	9 2.5%	8 2.2%	17 2.4%
Germany	8 2.2%	7 1.9%	15 2.1%
Japan	20 5.6%	21 5.8%	41 5.7%
Stratification Factor: Lines of Prior Therapy (participants) [Number]
1 Line	212 58.9%	213 58.8%	425 58.9%
2 or 3 Lines	148 41.1%	149 41.2%	297 41.1%
Stratification Factor: Proteasome Inhibitor (participants) [Number]
Exposed	250 69.4%	253 69.9%	503 69.7%
Naïve	110 30.6%	109 30.1%	219 30.3%
Stratification Factor: International Staging System (ISS) Stag at Screening (participants) [Number]
Stage I or Stage II	314 87.2%	318 87.8%	632 87.5%
Stage III	46 12.8%	44 12.2%	90 12.5%

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival (PFS) as Assessed by the Independent Review Committee (IRC)
Description	Progression Free Survival (PFS) is defined as the time from the date of randomization to the date of first documentation of disease progression (PD) or death due to any cause, whichever occurs first. Response including PD was assessed by independent review committee (IRC) using the International Myeloma Working Group (IMWG) response criteria. PD requires 1 of the following: Increase of ≥ 25% from nadir in: Serum M-component (absolute increase ≥ 0.5 g/dl); Urine M-component (absolute increase ≥ 200 mg/24 hours); In patients without measurable serum and urine M-protein levels the difference between involved and uninvolved free light chain (FLC) levels (absolute increase > 10 mg/dl); Development of new or increase in the size of existing bone lesions or soft tissue plasmacytomas; Development of hypercalcemia (corrected serum calcium > 11.5 mg/dl) attributed solely to plasma cell proliferative disease. Status evaluated every 4 weeks until disease progression (PD) was confirmed.
Time Frame	From date of randomization until disease progression or death up to data cut-off: 30 October 2014 (approximate median follow-up 15 months)

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) population was defined as all randomized participants.

Arm/Group Title	Ixazomib+ Lenalidomide + Dexamethasone	Placebo + Lenalidomide + Dexamethasone
Arm/Group Description	Ixazomib 4 mg, capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until progressive disease (PD) or unacceptable toxicity, whichever occurred first up to EOT projected at 80 months.	Ixazomib placebo-matching capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until progressive disease (PD) or unacceptable toxicity, whichever occurred first up to EOT projected at 80 months.
Measure Participants	360	362
Median (95% Confidence Interval) [months]	20.6	14.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ixazomib+ Lenalidomide + Dexamethasone, Placebo + Lenalidomide + Dexamethasone
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.012
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.742
	Confidence Interval	(2-Sided) 95%; 0.587 to 0.939
	Parameter Dispersion	Type: Value:
	Estimation Comments	HR is estimated from Cox Regression.

2. Secondary Outcome

Title	Overall Survival (OS)
Description	Overall survival is defined as the time from the date of randomization to the date of death. Participants without documentation of death at the time of the analysis were censored at the date when they were last known to be alive.
Time Frame	Date of randomization until death up to data cut-off: 30 October 2014 (approximate median follow-up 15 months)

Outcome Measure Data

Analysis Population Description

ITT population was defined as all randomized participants.

Arm/Group Title	Ixazomib+ Lenalidomide + Dexamethasone	Placebo + Lenalidomide + Dexamethasone
Arm/Group Description	Ixazomib 4 mg, capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until progressive disease (PD) or unacceptable toxicity, whichever occurred first up to EOT projected at 80 months.	Ixazomib placebo-matching capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until progressive disease (PD) or unacceptable toxicity, whichever occurred first up to EOT projected at 80 months.
Measure Participants	360	362
Median (95% Confidence Interval) [months]	NA	NA

3. Secondary Outcome

Title	Overall Survival in High-Risk Participants Carrying Deletion 17 [Del(17)]
Description	Overall survival is defined as the time from the date of randomization to the date of death. The high-risk participants whose myeloma carried del(17) subgroup was defined as the cases reported as positive for del(17) by the central laboratory combined with those cases that lacked a central laboratory result but with known del (17) by local laboratory. Participants without documentation of death at the time of the analysis were censored at the date when they were last known to be alive.
Time Frame	At the time of screening; Day 1 of each cycle (every 4 weeks) until disease progression and thereafter every 12 weeks until death or study termination

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Overall Response Rate (ORR) as Assessed by the IRC
Description	ORR was defined as the percentage of participants with Complete Response (CR) including stringent complete response (sCR), very good partial response (VGPR) and Partial Response (PR) assessed by the IRC using IMWG criteria.
Time Frame	Day 1 of each cycle (every 4 weeks) until disease progression up to data cut-off: 30 October 2014 (approximate median follow-up 15 months)

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants.

Arm/Group Title	Ixazomib+ Lenalidomide + Dexamethasone	Placebo + Lenalidomide + Dexamethasone
Arm/Group Description	Ixazomib 4 mg, capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until progressive disease (PD) or unacceptable toxicity, whichever occurred first up to EOT projected at 80 months.	Ixazomib placebo-matching capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until progressive disease (PD) or unacceptable toxicity, whichever occurred first up to EOT projected at 80 months.
Measure Participants	360	362
Number [percentage of participants]	78.3 21.8%	71.5 19.8%

5. Secondary Outcome

Title	Percentage of Participants With Complete Response (CR) and Very Good Partial Response (VGPR) as Assessed by the IRC
Description	Response was assessed by the IRC using International Myeloma Working Group (IMWG) Criteria. CR is defined as negative immunofixation on the serum and urine and; disappearance of any soft tissue plasmacytomas and; < 5% plasma cells in bone marrow. VGPR is defined as Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level < 100 mg per 24 hours.
Time Frame	Day 1 of each cycle (every 4 weeks) until disease progression up to data cut-off: 30 October 2014 (approximate median follow-up 15 months)

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants.

Arm/Group Title	Ixazomib + Lenalidomide + Dexamethasone	Placebo + Lenalidomide + Dexamethasone
Arm/Group Description	Ixazomib 4 mg, capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until progressive disease (PD) or unacceptable toxicity, whichever occurred first up to EOT projected at 80 months.	Ixazomib placebo-matching capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until progressive disease (PD) or unacceptable toxicity, whichever occurred first up to EOT projected at 80 months.
Measure Participants	360	362
Number [percentage of participants]	48.1 13.4%	39.0 10.8%

6. Secondary Outcome

Title	Duration of Response (DOR)
Description	DOR was measured as the time in months from the date of first documentation of a confirmed response of PR or better (CR [including sCR] + PR+ VGPR) to the date of the first documented disease progression (PD) among participants who responded to the treatment. Response was assessed by the investigator using International Myeloma Working Group (IMWG) Criteria.
Time Frame	Day 1 of each cycle (every 4 weeks) until disease progression up to data cut-off: 30 October 2014 (approximate median follow-up 15 months)

Outcome Measure Data

Analysis Population Description

Response-Evaluable population included all participants who received at least 1 dose of study drug, had measurable disease at baseline, and at least 1 post-baseline response assessment, all responders.

Arm/Group Title	Ixazomib+ Lenalidomide + Dexamethasone	Placebo + Lenalidomide + Dexamethasone
Arm/Group Description	Ixazomib 4 mg, capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until progressive disease (PD) or unacceptable toxicity, whichever occurred first up to EOT projected at 80 months.	Ixazomib placebo-matching capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until progressive disease (PD) or unacceptable toxicity, whichever occurred first up to EOT projected at 80 months.
Measure Participants	279	255
Median (95% Confidence Interval) [months]	20.5	15.0

7. Secondary Outcome

Title	Time to Progression (TTP) as Assessed by the IRC
Description	TTP was measured as the time in months from the first dose of study treatment to the date of the first documented progressive disease (PD) as assessed by the IRC using IMWG criteria.
Time Frame	Day 1 of each cycle (every 4 weeks) until disease progression up to data cut-off: 30 October 2014 (approximate median follow-up 15 months)

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants

Arm/Group Title	Ixazomib+ Lenalidomide + Dexamethasone	Placebo + Lenalidomide + Dexamethasone
Arm/Group Description	Ixazomib 4 mg, capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until progressive disease (PD) or unacceptable toxicity, whichever occurred first up to EOT projected at 80 months.	Ixazomib placebo-matching capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until progressive disease (PD) or unacceptable toxicity, whichever occurred first up to EOT projected at 80 months.
Measure Participants	360	362
Median (95% Confidence Interval) [months]	21.4	15.7

8. Secondary Outcome

Title	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description	Eastern Cooperative Oncology Group (ECOG) performance score, laboratory values, vital sign measurements and reported adverse events (AEs) were collected and assessed to evaluate the safety of therapy throughout the study. An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; or congenital anomaly; or a medically important event.
Time Frame	From the date of signing of the informed consent form through 30 days after the last dose of study drug up to data cut-off: 30 October 2014 (approximate median follow-up 15 months)

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least 1 dose of ixazomib.

Arm/Group Title	Ixazomib+ Lenalidomide + Dexamethasone	Placebo + Lenalidomide + Dexamethasone
Arm/Group Description	Ixazomib 4 mg, capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until progressive disease (PD) or unacceptable toxicity, whichever occurred first up to EOT projected at 80 months.	Ixazomib placebo-matching capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until progressive disease (PD) or unacceptable toxicity, whichever occurred first up to EOT projected at 80 months.
Measure Participants	360	360
AEs	351 97.5%	355 98.1%
SAEs	143 39.7%	158 43.6%

9. Secondary Outcome

Title	Percentage of Participants Achieving Pain Response
Description	Pain response was defined as 30% reduction from Baseline in Brief Pain Inventory-Short Form (BPI-SF) worst pain score over the last 24 hours without an increase in analgesic (oral morphine equivalents) use at 2 consecutive evaluations. The BPI-SF contains 15 items designed to capture the pain severity ("worst," "least," "average," and "now" [current pain]), pain location, medication to relieve the pain, and the interference of pain with various daily activities including general activity, mood, walking activity, normal work, relations with other people, sleep, and enjoyment of life. The pain severity items are rated on a 0 to 10 scale where: 0=no pain and 10=pain as bad as you can imagine and averaged for a total score of 0 (best) to 10 (Worst).
Time Frame	At screening; Day 1 of each cycle; and thereafter every 4 weeks until disease progression

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Secondary Outcome

Title	Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30)
Description	The EORTC-QLQ-C30 is a 30-question tool used to assess the overall quality of life in cancer participants. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact).The EORTC-QLQ-C30 Global Health Status/QOL Scale is scored between 0 and 100, where higher scores indicate better Global Health Status/QOL. Negative changes from baseline indicate deterioration in QOL or functioning and positive changes indicate improvement.
Time Frame	Baseline and Every 2 Cycles beginning with Cycle 2 during treatment period, End of Treatment (EOT), and every 4 Weeks in follow-up

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

11. Secondary Outcome

Title	Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Multiple Myeloma Module (QLQ-MY-20)
Description	The EORTC-QLQ-MY-20 is a patient-completed, 20-question quality of life questionnaire that has 4 independent subscales, 2 functional subscales (body image, future perspective), and 2 symptoms scales (disease symptoms and side-effects of treatment). The participant answers questions about their health during the past week using a 4-point scale where 1=Not at All to 4=Very Much. A negative change from Baseline indicates improvement.
Time Frame	Baseline and Every 2 Cycles beginning with Cycle 2 during treatment period, End of Treatment (EOT), and every 4 Weeks in follow-up

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

12. Secondary Outcome

Title	OS in High-Risk Participants
Description	Overall survival (OS) is defined as the time from the date of randomization to the date of death. High-risk participants are defined as participants carrying cytogenic abnormalities: del(17), translocation t(4;14), or t(14;16) as reported by the central laboratory combined with those cases that lacked a central laboratory result but with known del (17), t(4;14), or t(14;16) by local laboratory. Cytogenetic abnormalities of del(13) and +1q are no longer considered to be high-risk abnormalities and are not included in the analysis. Participants without documentation of death at the time of the analysis were censored at the date when they were last known to be alive.
Time Frame	At the time of screening; Day 1 of each cycle; every 4 weeks until disease progression and thereafter every 12 weeks until death or study termination

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

13. Secondary Outcome

Title	PFS in High-Risk Participants
Description	Progression Free Survival (PFS) is defined as the time from the date of randomization to the date of first documentation of disease progression or death due to any cause, whichever occurs first. Response was assessed by independent review committee (IRC) using IMWG response criteria. High-risk participants are defined as participants carrying cytogenic abnormalities: del(17), translocation t(4;14), or t(14;16) as reported by the central laboratory combined with those cases that lacked a central laboratory result but with known del (17), t(4;14), or t(14;16) by local laboratory. Cytogenetic abnormalities of del(13) and +1q are no longer considered to be high-risk abnormalities and are not included in the analysis.
Time Frame	From date of randomization until disease progression or death up to data cut-off: 30 October 2014 (approximate median follow-up 15 months)

Outcome Measure Data

Analysis Population Description

Participants from the ITT population, all randomized participants, with cytogenic abnormalities.

Arm/Group Title	Ixazomib+ Lenalidomide + Dexamethasone	Placebo + Lenalidomide + Dexamethasone
Arm/Group Description	Ixazomib 4 mg, capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until progressive disease (PD) or unacceptable toxicity, whichever occurred first up to EOT projected at 80 months.	Ixazomib placebo-matching capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until progressive disease (PD) or unacceptable toxicity, whichever occurred first up to EOT projected at 80 months.
Measure Participants	75	62
Median (95% Confidence Interval) [months]	21.4	9.7

14. Secondary Outcome

Title	Pharmacokinetic Parameters (Including Cmax, AUC and Tmax) of Ixazomib
Time Frame	Days 1 & 14 of Cycles 1 & 2. Day 1 of Cycles 3 to 10

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

15. Secondary Outcome

Title	Association Between Response or Resistance to Ixazomib Treatment and Proteasome and Nuclear Factor-kB (NF-kB)-Related Genes
Time Frame	At the time of screening; Day 1 of each cycle; at EOT; every 4 weeks until disease progression and thereafter every 12 weeks until death or study termination

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Randomization until data cutoff of 30 October 2014 (approximate median follow-up 15 months)
Adverse Event Reporting Description	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. Safety population includes all enrolled participants who received at least one dose of study drug.
Arm/Group Title	Ixazomib+ Lenalidomide + Dexamethasone		Placebo + Lenalidomide + Dexamethasone
Arm/Group Description	Ixazomib 4 mg, capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until progressive disease (PD) or unacceptable toxicity up to EOT projected at 80 months.		Ixazomib placebo-matching capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until progressive disease (PD) or unacceptable toxicity, whichever occurred first up to EOT projected at 80 months.
All Cause Mortality
	Ixazomib+ Lenalidomide + Dexamethasone		Placebo + Lenalidomide + Dexamethasone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Ixazomib+ Lenalidomide + Dexamethasone		Placebo + Lenalidomide + Dexamethasone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	143/360 (39.7%)		158/360 (43.9%)
Blood and lymphatic system disorders
Thrombocytopenia	4/360 (1.1%)		5/360 (1.4%)
Idiopathic thrombocytopenic purpura	1/360 (0.3%)		0/360 (0%)
Febrile neutropenia	2/360 (0.6%)		7/360 (1.9%)
Neutropenia	2/360 (0.6%)		2/360 (0.6%)
Anaemia	3/360 (0.8%)		8/360 (2.2%)
Disseminated intravascular coagulation	2/360 (0.6%)		0/360 (0%)
Pancytopenia	1/360 (0.3%)		0/360 (0%)
Hyperviscosity syndrome	0/360 (0%)		1/360 (0.3%)
Leukopenia	0/360 (0%)		1/360 (0.3%)
Cardiac disorders
Atrial fibrillation	5/360 (1.4%)		6/360 (1.7%)
Atrial flutter	3/360 (0.8%)		0/360 (0%)
Cardiac failure	2/360 (0.6%)		4/360 (1.1%)
Cardiac failure congestive	2/360 (0.6%)		1/360 (0.3%)
Cardiac failure acute	1/360 (0.3%)		1/360 (0.3%)
Cardiogenic shock	0/360 (0%)		1/360 (0.3%)
Myocardial infarction	3/360 (0.8%)		1/360 (0.3%)
Angina pectoris	1/360 (0.3%)		0/360 (0%)
Myocardial ischaemia	1/360 (0.3%)		0/360 (0%)
Acute myocardial infarction	0/360 (0%)		2/360 (0.6%)
Acute coronary syndrome	0/360 (0%)		1/360 (0.3%)
Cardiac arrest	2/360 (0.6%)		0/360 (0%)
Cardio-respiratory arrest	1/360 (0.3%)		0/360 (0%)
Diastolic dysfunction	1/360 (0.3%)		0/360 (0%)
Left ventricular dysfunction	1/360 (0.3%)		0/360 (0%)
Coronary artery disease	1/360 (0.3%)		0/360 (0%)
Coronary artery thrombosis	0/360 (0%)		1/360 (0.3%)
Trifascicular block	1/360 (0.3%)		0/360 (0%)
Cardiovascular insufficiency	1/360 (0.3%)		0/360 (0%)
Arrhythmia	0/360 (0%)		1/360 (0.3%)
Ear and labyrinth disorders
Acute vestibular syndrome	0/360 (0%)		1/360 (0.3%)
Endocrine disorders
Hyperthyroidism	1/360 (0.3%)		0/360 (0%)
Eye disorders
Retinal vein thrombosis	1/360 (0.3%)		0/360 (0%)
Gastrointestinal disorders
Diarrhoea	7/360 (1.9%)		2/360 (0.6%)
Nausea	2/360 (0.6%)		0/360 (0%)
Vomiting	2/360 (0.6%)		0/360 (0%)
Constipation	1/360 (0.3%)		1/360 (0.3%)
Gastrooesophageal reflux disease	1/360 (0.3%)		0/360 (0%)
Dyspepsia	2/360 (0.6%)		0/360 (0%)
Ileus	1/360 (0.3%)		0/360 (0%)
Intestinal obstruction	1/360 (0.3%)		0/360 (0%)
Ileus paralytic	2/360 (0.6%)		0/360 (0%)
Colitis	1/360 (0.3%)		1/360 (0.3%)
Pancreatitis	1/360 (0.3%)		0/360 (0%)
Small intestinal obstruction	1/360 (0.3%)		0/360 (0%)
Femoral hernia, obstructive	1/360 (0.3%)		0/360 (0%)
Abdominal pain	1/360 (0.3%)		0/360 (0%)
Oesophageal achalasia	1/360 (0.3%)		0/360 (0%)
Inguinal hernia	1/360 (0.3%)		0/360 (0%)
Haematochezia	0/360 (0%)		1/360 (0.3%)
Melaena	0/360 (0%)		1/360 (0.3%)
Oesophageal ulcer	0/360 (0%)		1/360 (0.3%)
General disorders
Pyrexia	10/360 (2.8%)		14/360 (3.9%)
Malaise	2/360 (0.6%)		1/360 (0.3%)
Fatigue	2/360 (0.6%)		0/360 (0%)
Asthenia	1/360 (0.3%)		0/360 (0%)
General physical health deterioration	1/360 (0.3%)		2/360 (0.6%)
Multi-organ failure	1/360 (0.3%)		0/360 (0%)
Performance status decreased	1/360 (0.3%)		0/360 (0%)
Spinal pain	1/360 (0.3%)		2/360 (0.6%)
Non-cardiac chest pain	1/360 (0.3%)		0/360 (0%)
Oedema peripheral	1/360 (0.3%)		1/360 (0.3%)
Hyperthermia	1/360 (0.3%)		0/360 (0%)
Chills	1/360 (0.3%)		0/360 (0%)
Death	0/360 (0%)		1/360 (0.3%)
Soft tissue inflammation	0/360 (0%)		1/360 (0.3%)
Hepatobiliary disorders
Cholecystitis acute	1/360 (0.3%)		3/360 (0.8%)
Cholecystitis chronic	0/360 (0%)		1/360 (0.3%)
Hyperbilirubinaemia	0/360 (0%)		1/360 (0.3%)
Infections and infestations
Pneumonia	20/360 (5.6%)		27/360 (7.5%)
Bronchopneumonia	4/360 (1.1%)		2/360 (0.6%)
Lower respiratory tract infection	3/360 (0.8%)		4/360 (1.1%)
Lung infection	2/360 (0.6%)		4/360 (1.1%)
Lobar pneumonia	2/360 (0.6%)		2/360 (0.6%)
Bronchitis	1/360 (0.3%)		7/360 (1.9%)
Atypical pneumonia	0/360 (0%)		1/360 (0.3%)
Sepsis	3/360 (0.8%)		4/360 (1.1%)
Septic shock	2/360 (0.6%)		5/360 (1.4%)
Urosepsis	1/360 (0.3%)		1/360 (0.3%)
Bacterial sepsis	1/360 (0.3%)		0/360 (0%)
Infection	3/360 (0.8%)		2/360 (0.6%)
Respiratory tract infection	2/360 (0.6%)		3/360 (0.8%)
Postoperative wound infection	1/360 (0.3%)		0/360 (0%)
Localised infection	0/360 (0%)		2/360 (0.6%)
Influenza	5/360 (1.4%)		2/360 (0.6%)
Pneumonia influenzal	1/360 (0.3%)		0/360 (0%)
H1N1 influenza	0/360 (0%)		1/360 (0.3%)
Gastroenteritis	3/360 (0.8%)		0/360 (0%)
Gastrointestinal infection	1/360 (0.3%)		1/360 (0.3%)
Enterocolitis infectious	1/360 (0.3%)		0/360 (0%)
Appendicitis	0/360 (0%)		1/360 (0.3%)
Diarrhoea infectious	0/360 (0%)		1/360 (0.3%)
Arthritis bacterial	1/360 (0.3%)		0/360 (0%)
Bronchitis bacterial	1/360 (0.3%)		0/360 (0%)
Urinary tract infection bacterial	1/360 (0.3%)		0/360 (0%)
Cellulitis	0/360 (0%)		2/360 (0.6%)
Bacterial infection	0/360 (0%)		1/360 (0.3%)
Herpes zoster	3/360 (0.8%)		1/360 (0.3%)
Pharyngitis	1/360 (0.3%)		0/360 (0%)
Sinusitis	1/360 (0.3%)		0/360 (0%)
Upper respiratory tract infection	0/360 (0%)		2/360 (0.6%)
Chronic sinusitis	0/360 (0%)		1/360 (0.3%)
Gastroenteritis viral	2/360 (0.6%)		0/360 (0%)
Metapneumovirus infection	0/360 (0%)		1/360 (0.3%)
Haemophilus infection	1/360 (0.3%)		0/360 (0%)
Pneumonia haemophilus	1/360 (0.3%)		0/360 (0%)
Meningitis pneumococcal	1/360 (0.3%)		0/360 (0%)
Pneumonia pneumococcal	0/360 (0%)		2/360 (0.6%)
Pneumococcal infection	0/360 (0%)		1/360 (0.3%)
Pneumococcal sepsis	0/360 (0%)		1/360 (0.3%)
Staphylococcal bacteraemia	1/360 (0.3%)		0/360 (0%)
Endocarditis staphylococcal	0/360 (0%)		1/360 (0.3%)
Staphylococcal infection	0/360 (0%)		1/360 (0.3%)
Campylobacter gastroenteritis	1/360 (0.3%)		1/360 (0.3%)
Pneumonia moraxella	1/360 (0.3%)		0/360 (0%)
Moraxella infection	0/360 (0%)		1/360 (0.3%)
Bronchopulmonary aspergillosis	1/360 (0.3%)		0/360 (0%)
Intervertebral discitis	1/360 (0.3%)		0/360 (0%)
Candida pneumonia	1/360 (0.3%)		0/360 (0%)
Pneumonia fungal	1/360 (0.3%)		0/360 (0%)
Salmonella sepsis	1/360 (0.3%)		0/360 (0%)
Pulmonary tuberculosis	1/360 (0.3%)		0/360 (0%)
Urinary tract infection	0/360 (0%)		4/360 (1.1%)
Pyelonephritis	0/360 (0%)		1/360 (0.3%)
Skin infection	0/360 (0%)		2/360 (0.6%)
Dermo-hypodermitis	0/360 (0%)		1/360 (0.3%)
Pilonidal cyst	0/360 (0%)		1/360 (0.3%)
Subcutaneous abscess	0/360 (0%)		1/360 (0.3%)
Pseudomonal sepsis	0/360 (0%)		2/360 (0.6%)
Pneumonia pseudomonas aeruginosa	0/360 (0%)		1/360 (0.3%)
Rhinovirus infection	0/360 (0%)		3/360 (0.8%)
Parainfluenzae virus infection	0/360 (0%)		2/360 (0.6%)
Respiratory syncytial virus infection	0/360 (0%)		2/360 (0.6%)
Gastroenteritis caliciviral	0/360 (0%)		1/360 (0.3%)
Endocarditis	0/360 (0%)		1/360 (0.3%)
Clostridium difficile colitis	0/360 (0%)		1/360 (0.3%)
Cytomegalovirus colitis	0/360 (0%)		1/360 (0.3%)
Escherichia sepsis	0/360 (0%)		1/360 (0.3%)
Injury, poisoning and procedural complications
Femur fracture	2/360 (0.6%)		0/360 (0%)
Femoral neck fracture	1/360 (0.3%)		0/360 (0%)
Foot fracture	1/360 (0.3%)		0/360 (0%)
Overdose	2/360 (0.6%)		3/360 (0.8%)
Accidental overdose	1/360 (0.3%)		0/360 (0%)
Spinal compression fracture	1/360 (0.3%)		5/360 (1.4%)
Spinal fracture	1/360 (0.3%)		0/360 (0%)
Thoracic vertebral fracture	0/360 (0%)		1/360 (0.3%)
Road traffic accident	1/360 (0.3%)		0/360 (0%)
Fall	0/360 (0%)		2/360 (0.6%)
Ligament rupture	1/360 (0.3%)		0/360 (0%)
Tendon rupture	0/360 (0%)		1/360 (0.3%)
Rib fracture	1/360 (0.3%)		0/360 (0%)
Sternal fracture	0/360 (0%)		1/360 (0.3%)
Procedural pain	1/360 (0.3%)		0/360 (0%)
Concussion	0/360 (0%)		1/360 (0.3%)
Humerus fracture	0/360 (0%)		1/360 (0.3%)
Investigations
Platelet count decreased	2/360 (0.6%)		1/360 (0.3%)
Weight decreased	1/360 (0.3%)		0/360 (0%)
Blood creatinine increased	0/360 (0%)		1/360 (0.3%)
Influenza A virus test positive	0/360 (0%)		1/360 (0.3%)
Metabolism and nutrition disorders
Hypercalcaemia	3/360 (0.8%)		1/360 (0.3%)
Hyponatraemia	2/360 (0.6%)		0/360 (0%)
Hyperglycaemia	1/360 (0.3%)		3/360 (0.8%)
Hypokalaemia	1/360 (0.3%)		1/360 (0.3%)
Gout	1/360 (0.3%)		0/360 (0%)
Diabetes mellitus	0/360 (0%)		1/360 (0.3%)
Diabetes mellitus inadequate control	0/360 (0%)		1/360 (0.3%)
Decreased appetite	0/360 (0%)		1/360 (0.3%)
Musculoskeletal and connective tissue disorders
Pathological fracture	4/360 (1.1%)		1/360 (0.3%)
Back pain	1/360 (0.3%)		6/360 (1.7%)
Pain in extremity	1/360 (0.3%)		0/360 (0%)
Musculoskeletal pain	0/360 (0%)		1/360 (0.3%)
Neck pain	0/360 (0%)		1/360 (0.3%)
Bone pain	2/360 (0.6%)		1/360 (0.3%)
Osteolysis	1/360 (0.3%)		1/360 (0.3%)
Groin pain	0/360 (0%)		2/360 (0.6%)
Arthritis reactive	0/360 (0%)		1/360 (0.3%)
Arthralgia	0/360 (0%)		1/360 (0.3%)
Osteoarthritis	0/360 (0%)		1/360 (0.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Plasma cell myeloma	5/360 (1.4%)		8/360 (2.2%)
Plasmacytoma	4/360 (1.1%)		0/360 (0%)
Plasma cell leukaemia	0/360 (0%)		2/360 (0.6%)
Adenocarcinoma of colon	2/360 (0.6%)		0/360 (0%)
Myelodysplastic syndrome	1/360 (0.3%)		1/360 (0.3%)
Metastatic gastric cancer	1/360 (0.3%)		0/360 (0%)
Neoplasm malignant	1/360 (0.3%)		0/360 (0%)
Prostate cancer metastatic	0/360 (0%)		1/360 (0.3%)
Skin cancer	0/360 (0%)		1/360 (0.3%)
Nervous system disorders
Syncope	4/360 (1.1%)		2/360 (0.6%)
Lethargy	0/360 (0%)		1/360 (0.3%)
Cerebrovascular accident	1/360 (0.3%)		0/360 (0%)
Haemorrhagic stroke	1/360 (0.3%)		0/360 (0%)
Ischaemic stroke	0/360 (0%)		2/360 (0.6%)
Cerebral haemorrhage	0/360 (0%)		1/360 (0.3%)
Spinal cord compression	2/360 (0.6%)		0/360 (0%)
Vascular encephalopathy	1/360 (0.3%)		0/360 (0%)
Coma	1/360 (0.3%)		0/360 (0%)
Neuralgia	1/360 (0.3%)		0/360 (0%)
Transient ischaemic attack	1/360 (0.3%)		0/360 (0%)
Acute polyneuropathy	0/360 (0%)		1/360 (0.3%)
Central nervous system lesion	0/360 (0%)		1/360 (0.3%)
Convulsion	0/360 (0%)		1/360 (0.3%)
Psychiatric disorders
Delirium	1/360 (0.3%)		0/360 (0%)
Confusional state	0/360 (0%)		2/360 (0.6%)
Psychotic disorder	0/360 (0%)		1/360 (0.3%)
Completed suicide	0/360 (0%)		1/360 (0.3%)
Renal and urinary disorders
Renal failure acute	5/360 (1.4%)		4/360 (1.1%)
Renal failure	1/360 (0.3%)		3/360 (0.8%)
Renal impairment	0/360 (0%)		2/360 (0.6%)
Renal failure chronic	0/360 (0%)		1/360 (0.3%)
Nephrolithiasis	2/360 (0.6%)		0/360 (0%)
Urinary retention	0/360 (0%)		2/360 (0.6%)
Urinary tract obstruction	0/360 (0%)		1/360 (0.3%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	1/360 (0.3%)		0/360 (0%)
Endometrial hyperplasia	0/360 (0%)		1/360 (0.3%)
Bartholin's cyst	0/360 (0%)		1/360 (0.3%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	6/360 (1.7%)		8/360 (2.2%)
Pulmonary microemboli	1/360 (0.3%)		0/360 (0%)
Chronic obstructive pulmonary disease	2/360 (0.6%)		1/360 (0.3%)
Interstitial lung disease	1/360 (0.3%)		0/360 (0%)
Organising pneumonia	1/360 (0.3%)		0/360 (0%)
Dyspnoea	1/360 (0.3%)		3/360 (0.8%)
Orthopnoea	0/360 (0%)		1/360 (0.3%)
Pneumonia aspiration	1/360 (0.3%)		1/360 (0.3%)
Pneumonitis	0/360 (0%)		2/360 (0.6%)
Pulmonary congestion	1/360 (0.3%)		0/360 (0%)
Acute respiratory distress syndrome	0/360 (0%)		1/360 (0.3%)
Respiratory failure	1/360 (0.3%)		1/360 (0.3%)
Haemoptysis	1/360 (0.3%)		0/360 (0%)
Pleural effusion	1/360 (0.3%)		0/360 (0%)
Pulmonary hypertension	1/360 (0.3%)		0/360 (0%)
Epistaxis	0/360 (0%)		1/360 (0.3%)
Lung disorder	0/360 (0%)		1/360 (0.3%)
Skin and subcutaneous tissue disorders
Psoriasis	1/360 (0.3%)		0/360 (0%)
Cutaneous vasculitis	1/360 (0.3%)		0/360 (0%)
Vascular disorders
Deep vein thrombosis	4/360 (1.1%)		5/360 (1.4%)
Thrombophlebitis	0/360 (0%)		1/360 (0.3%)
Thrombophlebitis superficial	0/360 (0%)		1/360 (0.3%)
Hypotension	2/360 (0.6%)		0/360 (0%)
Orthostatic hypotension	1/360 (0.3%)		1/360 (0.3%)
Aortic aneurysm	1/360 (0.3%)		0/360 (0%)
Aortic dissection	0/360 (0%)		1/360 (0.3%)
Haematoma	1/360 (0.3%)		0/360 (0%)
Peripheral artery aneurysm	1/360 (0.3%)		0/360 (0%)
Phlebitis superficial	1/360 (0.3%)		0/360 (0%)
Aortic thrombosis	0/360 (0%)		1/360 (0.3%)
Hypovolaemic shock	0/360 (0%)		1/360 (0.3%)
Peripheral vascular disorder	0/360 (0%)		1/360 (0.3%)
Other (Not Including Serious) Adverse Events
	Ixazomib+ Lenalidomide + Dexamethasone		Placebo + Lenalidomide + Dexamethasone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	335/360 (93.1%)		322/360 (89.4%)
Eye disorders
Vision blurred	20/360 (5.6%)		12/360 (3.3%)
Conjunctivitis	20/360 (5.6%)		5/360 (1.4%)
Gastrointestinal disorders
Dry mouth	15/360 (4.2%)		23/360 (6.4%)
Abdominal pain upper	21/360 (5.8%)		13/360 (3.6%)
Infections and infestations
Nasopharyngitis	71/360 (19.7%)		66/360 (18.3%)
Investigations
Neutrophil count decreased	20/360 (5.6%)		20/360 (5.6%)
Metabolism and nutrition disorders
Hypocalcaemia	20/360 (5.6%)		16/360 (4.4%)
Musculoskeletal and connective tissue disorders
Muscle spasms	63/360 (17.5%)		91/360 (25.3%)
Musculoskeletal chest pain	23/360 (6.4%)		31/360 (8.6%)
Muscular weakness	16/360 (4.4%)		18/360 (5%)
Nervous system disorders
Peripheral sensory neuropathy	67/360 (18.6%)		50/360 (13.9%)
Dizziness	48/360 (13.3%)		34/360 (9.4%)
Headache	38/360 (10.6%)		37/360 (10.3%)
Neuropathy peripheral	37/360 (10.3%)		29/360 (8.1%)
Dysgeusia	30/360 (8.3%)		27/360 (7.5%)
Tremor	21/360 (5.8%)		33/360 (9.2%)
Paraesthesia	28/360 (7.8%)		14/360 (3.9%)
Psychiatric disorders
Insomnia	70/360 (19.4%)		90/360 (25%)
Anxiety	15/360 (4.2%)		19/360 (5.3%)
Depression	18/360 (5%)		14/360 (3.9%)
Respiratory, thoracic and mediastinal disorders
Cough	49/360 (13.6%)		54/360 (15%)
Dyspnoea exertional	12/360 (3.3%)		20/360 (5.6%)
Dysphonia	7/360 (1.9%)		18/360 (5%)
Skin and subcutaneous tissue disorders
Pruritus	36/360 (10%)		25/360 (6.9%)
Rash macular	22/360 (6.1%)		22/360 (6.1%)
Rash maculo-papular	32/360 (8.9%)		12/360 (3.3%)
Vascular disorders
Hypertension	18/360 (5%)		13/360 (3.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

In general, Investigators may publish clinical data after the earlier of (i) publication by the Sponsor or (ii) 12 months following the abandonment, early termination or database lock; provided a copy of the publication provided to Sponsor at least 30 days ahead of publication, the Sponsor's confidential information is removed as may be requested by Sponsor and Investigator defers publication for up to 60 days in the event Sponsor provides notice that it intends to file a patent application.