Phase 1 Pharmacokinetic Study of Oral Ixazomib Plus Lenalidomide and Dexamethasone in Adult Asian Participants With Relapsed and/or Refractory Multiple Myeloma

• Sponsor: Millennium Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01645930
• Collaborator: (none)
• Enrollment: 43
• Locations: 5
• Arm: 1
• Actual Duration (Months): 51.8
• Patients Per Site: 8.6
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this Phase 1 study is to characterize the pharmacokinetic (PK) and tolerability of oral ixazomib (MLN9708) when administered in combination with lenalidomide and dexamethasone in adult Asian participants with relapsed and/or refractory multiple myeloma.

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

Detailed Description

The drug being tested in this study was ixazomib. Ixazomib was tested to treat adult Asian people who had relapsed and/or refractory multiple myeloma.

The study enrolled 43 patients. Participants were enrolled to receive:

• Ixazomib 4 mg + Lenalidomide 25 mg + Dexamethasone 40 mg.

All participants were asked to take ixazomib capsules orally on Days 1, 8, and 15; lenalidomide capsules, orally, on Days 1 through 21; and dexamethasone tablets, orally, on Days 1, 8, 15, and 22 of a 28-day treatment cycle until progressive disease (PD) or unacceptable toxicity (up to 20 cycles).

This multi-center trial was conducted in Singapore, Hong Kong and South Korea. The overall time to participate in this study was up to 577 days. Participants made multiple visits to the clinic, and were contacted 30 days after last dose of study drug for a follow-up assessment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 43 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1 Pharmacokinetic and Tolerability Study of Oral MLN9708 Plus Lenalidomide and Dexamethasone in Adult Asian Patients With Relapsed and/or Refractory Multiple Myeloma
• Actual Study Start Date: Dec 17, 2012
• Actual Primary Completion Date: Jul 14, 2014
• Actual Study Completion Date: Apr 11, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ixazomib+Lenalidomide+Dexamethasone Ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15; lenalidomide 25 mg, capsules, orally, once on Days 1 through 21; and dexamethasone 40 mg, tablets, orally, once on Days 1, 8, 15, and 22 of a 28-day treatment cycle until progressive disease (PD) or unacceptable toxicity (up to 20 cycles)	Drug: Ixazomib; Ixazomib capsules; Drug: Lenalidomide; Lenalidomide capsules; Drug: Dexamethasone; Dexamethasone tablets

Outcome Measures

Primary Outcome Measures

1. Cmax: Maximum Observed Plasma Concentration for Ixazomib [Cycle 1, Day 1 pre-dose and multiple time-points (up to 168 hours) post-dose]

2. Cmax: Maximum Observed Plasma Concentration for Ixazomib [Cycle 1, Day 15 pre-dose and multiple time-points (up to 336 hours) post-dose]

3. Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib [Cycle 1, Day 1 pre-dose and multiple time-points (up to 168 hours) post-dose]

4. Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib [Cycle 1, Day 15 pre-dose and multiple time-points (up to 336 hours) post-dose]

5. AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to Time of the Last Quantifiable Concentration for Ixazomib [Cycle 1, Day 1 pre-dose and multiple time-points (up to 168 hours) post-dose]

6. AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to Time of the Last Quantifiable Concentration for Ixazomib [Cycle 1, Day 15 pre-dose and multiple time-points (up to 336 hours) post-dose]

7. Number of Participants With Dose Limiting Toxicities (DLTs) [Cycle 1 (up to Day 28)]

   DLT was defined as any of the following AEs that were considered by investigator to be possibly related to therapy: 1. Grade 4 neutropenia lasting at least 7 consecutive days; 2. Grade 3 neutropenia with fever and/or infection; 3. Grade 4 thrombocytopenia at least 7 consecutive days; 4. Grade 3 thrombocytopenia with clinically significant bleeding; 5. Platelet count <10,000/mm^3; 6. Grade 2 peripheral neuropathy with pain or ≥Grade 3 peripheral neuropathy; 7. Grade 3 or greater nausea and / or emesis despite the use of optimal anti-emetic prophylaxis; 8. Grade 3 or greater diarrhea that occurred despite maximal supportive therapy; 9. Any other Grade 3 or greater nonhematologic toxicity with the following exceptions: Grade 3 arthralgia/myalgia, <1 week Grade 3 fatigue; 10. A delay of >2 weeks in the subsequent cycle of treatment; 11. Other combination study drug-related nonhematologic toxicities ≥Grade 2 that, in the opinion of the investigator, required discontinuation of study drug.

8. Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [From the first dose of study drug through 30 days after the last dose of study drug (up to 577 days)]

   An Adverse Event (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. A SAE is defined as any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or was a medically important event.

9. Number of Participants With Clinically Significant Laboratory Abnormalities Reported as Adverse Events of ≥Grade 3 Intensity [From the first dose of study drug through 30 days after the last dose of study drug (up to 577 days)]

   Clinically significant laboratory abnormalities were defined as any test results which were observed beyond the clinically acceptable limits as per the discretion of investigator. Clinical laboratory tests included chemistry, hematology and urinalysis tests.

10. Number of Participants With Clinically Significant Vital Signs Reported as Adverse Events [From the first dose of study drug through 30 days after the last dose of study drug (up to 577 days)]

    The number of participants who meet markedly abnormal criteria for vital signs, included diastolic and systolic blood pressure, heart rate, oral temperature, respiratory rate, and body weight.

Secondary Outcome Measures

1. Percentage of Participants With Confirmed Best Response Category [From Cycle 1, Day 1 to Cycle 3, Day 1 until disease progression (approximately 20 months)]

   Percentage of participants who achieve or maintain any best response category during the treatment period were reported. Best response includes complete response (CR), very good partial response (VGPR), and partial response (PR). Response was assessed according to IMWG criteria. CR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas and ≤5% plasma cells in bone marrow; PR: ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to <200 mg per 24 hours. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein plus urine M-protein level <100 mg per 24 hour.

2. Duration of Response (DOR) [From date of documentation of a confirmed response to date of progressive disease, (approximately 20 months)]

   DOR was defined as the length of time between the date of first documented response (PR, VGPR, or CR) and the date of first documented progressive disease (PD). According to IMWG criteria: CR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas and ≤5% plasma cells in bone marrow; PR: ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to <200 mg per 24 hours. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein plus urine M-protein level <100 mg per 24 hour.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Male or female East Asian participants 18 years or older

• Diagnosed Multiple Myeloma according to standard criteria

• Measurable disease as specified in study protocol

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

• Participants with relapsed and/or refractory Multiple Myeloma who have received 1 to 3 prior therapies

• Meet the clinical laboratories criteria as specified in the protocol

• Female participants who are post menopausal, surgically sterile, or agree to practice 2 effective methods of contraception or agree to abstain from heterosexual intercourse; must also adhere to the guidelines of the lenalidomide pregnancy prevention program

• Male participants who agree to practice effective barrier contraception or agree to abstain from heterosexual intercourse and must adhere to the guidelines of the lenalidomide pregnancy prevention program

• Must be able to take concurrent aspirin 325 mg daily

• Voluntary written consent

Exclusion Criteria:

• Female participants who are lactating or pregnant

• Major surgery or radiotherapy within 14 days before enrollment

• Infection requiring systematic antibiotics within 14 days before study enrollment

• Central nervous system involvement

• Failure to have fully recovered from the effects of prior chemotherapy regardless of the interval since last treatment

• Systemic treatment with strong inhibitors of cytochrome P450 1A2 (CYP1A2), strong inhibitors of CYP3A, or strong CYP3A inducers, or use of Ginko biloba or St. John's wort within 14 days before study enrollment

• Diagnosis of Waldenstrom's macroglobulinemia, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) syndrome, plasma cell leukemia, primary amyloidosis, myelodysplastic syndrome, or myeloproliferative syndrome

• Evidence of current uncontrolled cardiovascular conditions

• Serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to the protocol

• Known allergy to any of the study medications

• Known gastrointestinal condition or procedure that could interfere with swallowing or the oral absorption of tolerance of ixazomib

• Diagnosed or treated for another malignancy within 2 years before study enrollment or previously diagnosed with another malignancy and have any evidence of residual disease with the exception of nonmelanoma skin cancer or any completely resected carcinoma in situ

• Ongoing or active systemic infection, active hepatitis B virus infect, active hepatitis C infection, or known human immunodeficiency virus (HIV) positive

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Pokfulam		Hong Kong
2		Shatin		Hong Kong
3		Incheon		Korea, Republic of
4		Seoul		Korea, Republic of
5		Singapore		Singapore

Sponsors and Collaborators

• Millennium Pharmaceuticals, Inc.

Investigators

• Study Director: Medical Director Clinical Science, Millennium Pharmaceuticals, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Millennium Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT01645930
• Other Study ID Numbers: C16013; U1111-1155-5943; HKUCTR-1593
• First Posted: Jul 20, 2012
• Last Update Posted: Nov 8, 2018
• Last Verified: Mar 1, 2018

• 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 took part in the study at 8 investigative sites in Singapore, Hong Kong and South Korea from 17 December 2012 to 11 April 2017. Data cut-off for the analysis was 14 July 2014.
Pre-assignment Detail	Asian participants with a diagnosis of relapsed and/or refractory multiple myeloma were enrolled and received a combination of ixazomib, lenalidomide and dexamethasone.

Arm/Group Title	Ixazomib+Lenalidomide+Dexamethasone
Arm/Group Description	Ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15; lenalidomide 25 mg, capsules, orally, once on Days 1 through 21; and dexamethasone 40 mg, tablets, orally, once on Days 1, 8, 15, and 22 of a 28-day treatment cycle until progressive disease (PD) or unacceptable toxicity (up to 20 cycles)
Period Title: Overall Study
STARTED	43
COMPLETED	0
NOT COMPLETED	43

Baseline Characteristics

Arm/Group Title	Ixazomib+Lenalidomide+Dexamethasone
Arm/Group Description	Ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15; lenalidomide 25 mg, capsules, orally, once on Days 1 through 21; and dexamethasone 40 mg, tablets, orally, once on Days 1, 8, 15, and 22 of a 28-day treatment cycle until progressive disease (PD) or unacceptable toxicity (up to 20 cycles)
Overall Participants	43
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.5 (9.84)
Sex: Female, Male (Count of Participants)
Female	16 37.2%
Male	27 62.8%
Race/Ethnicity, Customized (Count of Participants)
Not Hispanic or Latino	43 100%
Race/Ethnicity, Customized (Count of Participants)
Asian	43 100%
Region of Enrollment (Count of Participants)
Singapore	21 48.8%
Hong Kong	6 14%
Korea, Republic Of	16 37.2%
Height at Baseline (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	160.2 (7.80)
Weight at Baseline (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	60.6 (10.47)

Outcome Measures

1. Primary Outcome

Title	Cmax: Maximum Observed Plasma Concentration for Ixazomib
Time Frame	Cycle 1, Day 1 pre-dose and multiple time-points (up to 168 hours) post-dose

Outcome Measure Data

Analysis Population Description

Participants from the Pharmacokinetic (PK)-evaluable population, all participants who received protocol-specified dosing during Cycle 1, did not receive any excluded concomitant medications and had sufficient concentration-time data to permit reliable estimation of PK parameters, with data available for analysis.

Arm/Group Title	Ixazomib+Lenalidomide+Dexamethasone
Arm/Group Description	Ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15; lenalidomide 25 mg, capsules, orally, once on Days 1 through 21; and dexamethasone 40 mg, tablets, orally, once on Days 1, 8, 15, and 22 of a 28-day treatment cycle until progressive disease (PD) or unacceptable toxicity (up to 20 cycles)
Measure Participants	22
Mean (Standard Deviation) [ng/mL]	37.57 (31.701)

2. Primary Outcome

Title	Cmax: Maximum Observed Plasma Concentration for Ixazomib
Time Frame	Cycle 1, Day 15 pre-dose and multiple time-points (up to 336 hours) post-dose

Outcome Measure Data

Analysis Population Description

PK-evaluable population included all participants who received protocol-specified dosing during Cycle 1, did not receive any excluded concomitant medications and had sufficient concentration-time data to permit reliable estimation of PK parameters.

Arm/Group Title	Ixazomib+Lenalidomide+Dexamethasone
Arm/Group Description	Ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15; lenalidomide 25 mg, capsules, orally, once on Days 1 through 21; and dexamethasone 40 mg, tablets, orally, once on Days 1, 8, 15, and 22 of a 28-day treatment cycle until progressive disease (PD) or unacceptable toxicity (up to 20 cycles)
Measure Participants	24
Mean (Standard Deviation) [ng/mL]	57.57 (38.507)

3. Primary Outcome

Title	Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib
Time Frame	Cycle 1, Day 1 pre-dose and multiple time-points (up to 168 hours) post-dose

Outcome Measure Data

Analysis Population Description

Participants from the PK-evaluable population, all participants who received protocol-specified dosing during Cycle 1, did not receive any excluded concomitant medications and had sufficient concentration-time data to permit reliable estimation of PK parameters, with data available for analysis.

Arm/Group Title	Ixazomib+Lenalidomide+Dexamethasone
Arm/Group Description	Ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15; lenalidomide 25 mg, capsules, orally, once on Days 1 through 21; and dexamethasone 40 mg, tablets, orally, once on Days 1, 8, 15, and 22 of a 28-day treatment cycle until progressive disease (PD) or unacceptable toxicity (up to 20 cycles)
Measure Participants	22
Median (Full Range) [hours]	1.5

4. Primary Outcome

Title	Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib
Time Frame	Cycle 1, Day 15 pre-dose and multiple time-points (up to 336 hours) post-dose

Outcome Measure Data

Analysis Population Description

PK-evaluable population included all participants who received protocol-specified dosing during Cycle 1, did not receive any excluded concomitant medications and had sufficient concentration-time data to permit reliable estimation of PK parameters.

Arm/Group Title	Ixazomib+Lenalidomide+Dexamethasone
Arm/Group Description	Ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15; lenalidomide 25 mg, capsules, orally, once on Days 1 through 21; and dexamethasone 40 mg, tablets, orally, once on Days 1, 8, 15, and 22 of a 28-day treatment cycle until progressive disease (PD) or unacceptable toxicity (up to 20 cycles)
Measure Participants	24
Median (Full Range) [hours]	2.0

5. Primary Outcome

Title	AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to Time of the Last Quantifiable Concentration for Ixazomib
Time Frame	Cycle 1, Day 1 pre-dose and multiple time-points (up to 168 hours) post-dose

Outcome Measure Data

Analysis Population Description

Participants from the PK-evaluable population, all participants who received protocol-specified dosing during Cycle 1, did not receive any excluded concomitant medications and had sufficient concentration-time data to permit reliable estimation of PK parameters, with data available for analysis.

Arm/Group Title	Ixazomib+Lenalidomide+Dexamethasone
Arm/Group Description	Ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15; lenalidomide 25 mg, capsules, orally, once on Days 1 through 21; and dexamethasone 40 mg, tablets, orally, once on Days 1, 8, 15, and 22 of a 28-day treatment cycle until progressive disease (PD) or unacceptable toxicity (up to 20 cycles)
Measure Participants	20
Mean (Standard Deviation) [hr*ng/mL]	685.9 (246.35)

6. Primary Outcome

Title	AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to Time of the Last Quantifiable Concentration for Ixazomib
Time Frame	Cycle 1, Day 15 pre-dose and multiple time-points (up to 336 hours) post-dose

Outcome Measure Data

Analysis Population Description

PK-evaluable population included all participants who received protocol-specified dosing during Cycle 1, did not receive any excluded concomitant medications and had sufficient concentration-time data to permit reliable estimation of PK parameters.

Arm/Group Title	Ixazomib+Lenalidomide+Dexamethasone
Arm/Group Description	Ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15; lenalidomide 25 mg, capsules, orally, once on Days 1 through 21; and dexamethasone 40 mg, tablets, orally, once on Days 1, 8, 15, and 22 of a 28-day treatment cycle until progressive disease (PD) or unacceptable toxicity (up to 20 cycles)
Measure Participants	24
Mean (Standard Deviation) [hr*ng/mL]	1746.0 (798.60)

7. Primary Outcome

Title	Number of Participants With Dose Limiting Toxicities (DLTs)
Description	DLT was defined as any of the following AEs that were considered by investigator to be possibly related to therapy: 1. Grade 4 neutropenia lasting at least 7 consecutive days; 2. Grade 3 neutropenia with fever and/or infection; 3. Grade 4 thrombocytopenia at least 7 consecutive days; 4. Grade 3 thrombocytopenia with clinically significant bleeding; 5. Platelet count <10,000/mm^3; 6. Grade 2 peripheral neuropathy with pain or ≥Grade 3 peripheral neuropathy; 7. Grade 3 or greater nausea and / or emesis despite the use of optimal anti-emetic prophylaxis; 8. Grade 3 or greater diarrhea that occurred despite maximal supportive therapy; 9. Any other Grade 3 or greater nonhematologic toxicity with the following exceptions: Grade 3 arthralgia/myalgia, <1 week Grade 3 fatigue; 10. A delay of >2 weeks in the subsequent cycle of treatment; 11. Other combination study drug-related nonhematologic toxicities ≥Grade 2 that, in the opinion of the investigator, required discontinuation of study drug.
Time Frame	Cycle 1 (up to Day 28)

Outcome Measure Data

Analysis Population Description

DLT-evaluable population consisted of participants who either had a DLT during Cycle 1 or received all scheduled doses and completed all study procedures in Cycle 1 without having a DLT.

Arm/Group Title	Ixazomib+Lenalidomide+Dexamethasone
Arm/Group Description	Ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15; lenalidomide 25 mg, capsules, orally, once on Days 1 through 21; and dexamethasone 40 mg, tablets, orally, once on Days 1, 8, 15, and 22 of a 28-day treatment cycle until progressive disease (PD) or unacceptable toxicity (up to 20 cycles)
Measure Participants	24
Number [participants]	2 4.7%

8. Primary Outcome

Title	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description	An Adverse Event (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. A SAE is defined as any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or was a medically important event.
Time Frame	From the first dose of study drug through 30 days after the last dose of study drug (up to 577 days)

Outcome Measure Data

Analysis Population Description

Safety population was defined as all participants who received at least 1 dose of study drug.

Arm/Group Title	Ixazomib+Lenalidomide+Dexamethasone
Arm/Group Description	Ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15; lenalidomide 25 mg, capsules, orally, once on Days 1 through 21; and dexamethasone 40 mg, tablets, orally, once on Days 1, 8, 15, and 22 of a 28-day treatment cycle until progressive disease (PD) or unacceptable toxicity (up to 20 cycles)
Measure Participants	43
AEs	43 100%
SAEs	18 41.9%

9. Primary Outcome

Title	Number of Participants With Clinically Significant Laboratory Abnormalities Reported as Adverse Events of ≥Grade 3 Intensity
Description	Clinically significant laboratory abnormalities were defined as any test results which were observed beyond the clinically acceptable limits as per the discretion of investigator. Clinical laboratory tests included chemistry, hematology and urinalysis tests.
Time Frame	From the first dose of study drug through 30 days after the last dose of study drug (up to 577 days)

Outcome Measure Data

Analysis Population Description

Safety population was defined as all participants who received at least 1 dose of study drug.

Arm/Group Title	Ixazomib+Lenalidomide+Dexamethasone
Arm/Group Description	Ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15; lenalidomide 25 mg, capsules, orally, once on Days 1 through 21; and dexamethasone 40 mg, tablets, orally, once on Days 1, 8, 15, and 22 of a 28-day treatment cycle until progressive disease (PD) or unacceptable toxicity (up to 20 cycles)
Measure Participants	43
Alanine Aminotransferase Increased	2 4.7%
Aspartate Aminotransferase Increased	1 2.3%
Blood Creatinine Increased	1 2.3%
Haemoglobin Decreased	1 2.3%
Neutrophil Count Decreased	2 4.7%
Platelet Count Decreased	4 9.3%
Anaemia	6 14%
Febrile Neutropenia	1 2.3%
Neutropenia	12 27.9%
Thrombocytopenia	8 18.6%
Hyperglycaemia	1 2.3%
Hypocalcaemia	3 7%
Hypokalaemia	5 11.6%
Hypomagnesaemia	1 2.3%
Hyponatraemia	1 2.3%
Hypophosphataemia	2 4.7%

10. Primary Outcome

Title	Number of Participants With Clinically Significant Vital Signs Reported as Adverse Events
Description	The number of participants who meet markedly abnormal criteria for vital signs, included diastolic and systolic blood pressure, heart rate, oral temperature, respiratory rate, and body weight.
Time Frame	From the first dose of study drug through 30 days after the last dose of study drug (up to 577 days)

Outcome Measure Data

Analysis Population Description

Safety population was defined as all participants who received at least 1 dose of study drug.

Arm/Group Title	Ixazomib+Lenalidomide+Dexamethasone
Arm/Group Description	Ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15; lenalidomide 25 mg, capsules, orally, once on Days 1 through 21; and dexamethasone 40 mg, tablets, orally, once on Days 1, 8, 15, and 22 of a 28-day treatment cycle until progressive disease (PD) or unacceptable toxicity (up to 20 cycles)
Measure Participants	43
Grade 1 or 2 Hypertension	4 9.3%
Grade 2 Hypotension	1 2.3%

11. Secondary Outcome

Title	Percentage of Participants With Confirmed Best Response Category
Description	Percentage of participants who achieve or maintain any best response category during the treatment period were reported. Best response includes complete response (CR), very good partial response (VGPR), and partial response (PR). Response was assessed according to IMWG criteria. CR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas and ≤5% plasma cells in bone marrow; PR: ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to <200 mg per 24 hours. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein plus urine M-protein level <100 mg per 24 hour.
Time Frame	From Cycle 1, Day 1 to Cycle 3, Day 1 until disease progression (approximately 20 months)

Outcome Measure Data

Analysis Population Description

Safety population was defined as all participants who received at least 1 dose of study drug.

Arm/Group Title	Ixazomib+Lenalidomide+Dexamethasone
Arm/Group Description	Ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15; lenalidomide 25 mg, capsules, orally, once on Days 1 through 21; and dexamethasone 40 mg, tablets, orally, once on Days 1, 8, 15, and 22 of a 28-day treatment cycle until progressive disease (PD) or unacceptable toxicity (up to 20 cycles)
Measure Participants	43
Number [percentage of participants]	53.5 124.4%

12. Secondary Outcome

Title	Duration of Response (DOR)
Description	DOR was defined as the length of time between the date of first documented response (PR, VGPR, or CR) and the date of first documented progressive disease (PD). According to IMWG criteria: CR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas and ≤5% plasma cells in bone marrow; PR: ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to <200 mg per 24 hours. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein plus urine M-protein level <100 mg per 24 hour.
Time Frame	From date of documentation of a confirmed response to date of progressive disease, (approximately 20 months)

Outcome Measure Data

Analysis Population Description

Safety population was defined as all participants who received at least 1 dose of study drug.

Arm/Group Title	Ixazomib+Lenalidomide+Dexamethasone
Arm/Group Description	Ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15; lenalidomide 25 mg, capsules, orally, once on Days 1 through 21; and dexamethasone 40 mg, tablets, orally, once on Days 1, 8, 15, and 22 of a 28-day treatment cycle until progressive disease (PD) or unacceptable toxicity (up to 20 cycles)
Measure Participants	43
Median (Full Range) [months]	12.9

Adverse Events

Time Frame	First dose of study drug through 30 days after the last dose of study drug (up to 577 days)
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	Ixazomib+Lenalidomide+Dexamethasone
Arm/Group Description	Ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15; lenalidomide 25 mg, capsules, orally, once on Days 1 through 21; and dexamethasone 40 mg, tablets, orally, once on Days 1, 8, 15, and 22 of a 28-day treatment cycle until progressive disease (PD) or unacceptable toxicity (up to 20 cycles)
All Cause Mortality
	Ixazomib+Lenalidomide+Dexamethasone
	Affected / at Risk (%)	# Events
Total	0/43 (0%)
Serious Adverse Events
	Ixazomib+Lenalidomide+Dexamethasone
	Affected / at Risk (%)	# Events
Total	18/43 (41.9%)
Blood and lymphatic system disorders
Thrombocytopenia	1/43 (2.3%)
Gastrointestinal disorders
Diarrhoea	3/43 (7%)
Gastritis atrophic	1/43 (2.3%)
Vomiting	1/43 (2.3%)
General disorders
Pyrexia	1/43 (2.3%)
General physical health deterioration	1/43 (2.3%)
Immune system disorders
Drug hypersensitivity	1/43 (2.3%)
Food allergy	1/43 (2.3%)
Infections and infestations
Pneumonia	3/43 (7%)
Lung infection	2/43 (4.7%)
Diarrhoea infectious	1/43 (2.3%)
Gastroenteritis	1/43 (2.3%)
Upper respiratory tract infection	2/43 (4.7%)
Injury, poisoning and procedural complications
Laceration	1/43 (2.3%)
Spinal fracture	1/43 (2.3%)
Investigations
Platelet count decreased	1/43 (2.3%)
Blood creatinine increased	1/43 (2.3%)
Metabolism and nutrition disorders
Hypophagia	1/43 (2.3%)
Hypokalaemia	1/43 (2.3%)
Musculoskeletal and connective tissue disorders
Back pain	2/43 (4.7%)
Osteoporotic fracture	1/43 (2.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Plasmacytoma	2/43 (4.7%)
Renal cell carcinoma	1/43 (2.3%)
Nervous system disorders
Presyncope	1/43 (2.3%)
Spinal cord compression	1/43 (2.3%)
Renal and urinary disorders
Renal impairment	1/43 (2.3%)
Other (Not Including Serious) Adverse Events
	Ixazomib+Lenalidomide+Dexamethasone
	Affected / at Risk (%)	# Events
Total	43/43 (100%)
Blood and lymphatic system disorders
Neutropenia	13/43 (30.2%)
Thrombocytopenia	13/43 (30.2%)
Anaemia	12/43 (27.9%)
Eye disorders
Cataract	7/43 (16.3%)
Gastrointestinal disorders
Diarrhoea	23/43 (53.5%)
Vomiting	15/43 (34.9%)
Nausea	12/43 (27.9%)
Constipation	10/43 (23.3%)
Abdominal pain	5/43 (11.6%)
Abdominal discomfort	4/43 (9.3%)
Dyspepsia	4/43 (9.3%)
Abdominal pain upper	3/43 (7%)
Stomatitis	3/43 (7%)
General disorders
Fatigue	14/43 (32.6%)
Pyrexia	8/43 (18.6%)
Oedema peripheral	6/43 (14%)
Asthenia	5/43 (11.6%)
Influenza like illness	5/43 (11.6%)
Infections and infestations
Upper respiratory tract infection	15/43 (34.9%)
Influenza	3/43 (7%)
Nasopharyngitis	3/43 (7%)
Pneumonia	3/43 (7%)
Urinary tract infection	3/43 (7%)
Injury, poisoning and procedural complications
Spinal compression fracture	3/43 (7%)
Investigations
Alanine aminotransferase increased	7/43 (16.3%)
Platelet count decreased	7/43 (16.3%)
Blood creatinine increased	6/43 (14%)
Aspartate aminotransferase increased	5/43 (11.6%)
Neutrophil count decreased	4/43 (9.3%)
Weight decreased	4/43 (9.3%)
Blood alkaline phosphatase increased	3/43 (7%)
Gamma-glutamyltransferase increased	3/43 (7%)
Metabolism and nutrition disorders
Decreased appetite	12/43 (27.9%)
Hypokalaemia	12/43 (27.9%)
Hypocalcaemia	6/43 (14%)
Hypomagnesaemia	4/43 (9.3%)
Hypophosphataemia	4/43 (9.3%)
Hypercalcaemia	3/43 (7%)
Musculoskeletal and connective tissue disorders
Back pain	6/43 (14%)
Muscle spasms	4/43 (9.3%)
Myalgia	4/43 (9.3%)
Muscular weakness	3/43 (7%)
Musculoskeletal chest pain	3/43 (7%)
Musculoskeletal pain	3/43 (7%)
Nervous system disorders
Dizziness	12/43 (27.9%)
Neuropathy peripheral	9/43 (20.9%)
Hypoaesthesia	5/43 (11.6%)
Headache	4/43 (9.3%)
Lethargy	3/43 (7%)
Peripheral sensory neuropathy	4/43 (9.3%)
Psychiatric disorders
Insomnia	13/43 (30.2%)
Respiratory, thoracic and mediastinal disorders
Cough	13/43 (30.2%)
Productive cough	5/43 (11.6%)
Rhinorrhoea	4/43 (9.3%)
Dyspnoea	3/43 (7%)
Skin and subcutaneous tissue disorders
Pruritus	6/43 (14%)
Rash maculo-papular	6/43 (14%)
Rash pruritic	6/43 (14%)
Dry skin	5/43 (11.6%)
Rash macular	5/43 (11.6%)
Skin hyperpigmentation	4/43 (9.3%)
Pruritus generalised	3/43 (7%)
Vascular disorders
Hypertension	4/43 (9.3%)

Limitations/Caveats

[Not Specified]

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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