Trial Outcomes & Findings for Phase 1 Pharmacokinetic Study of Oral Ixazomib Plus Lenalidomide and Dexamethasone in Adult Asian Participants With Relapsed and/or Refractory Multiple Myeloma (NCT NCT01645930)

NCT ID: NCT01645930

Last Updated: 2018-11-08

Results Overview

• Recruitment status: COMPLETED
• Study phase: PHASE1
• Target enrollment: 43 participants
• Primary outcome timeframe: Cycle 1, Day 1 pre-dose and multiple time-points (up to 168 hours) post-dose
• Results posted on: 2018-11-08

Participant Flow

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.

Asian participants with a diagnosis of relapsed and/or refractory multiple myeloma were enrolled and received a combination of ixazomib, lenalidomide and dexamethasone.

Participant milestones

Measure	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)
Overall Study STARTED	43
Overall Study COMPLETED	0
Overall Study NOT COMPLETED	43

Reasons for withdrawal

Measure	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)
Overall Study Participants Ongoing on Study Treatment	22
Overall Study Progressive Disease	12
Overall Study Adverse Event	4
Overall Study Unsatisfactory Therapeutic Response	2
Overall Study Withdrawal by Participant	2
Overall Study Reason not Defined	1

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Ixazomib+Lenalidomide+Dexamethasone n=43 Participants 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)
Age, Continuous	61.5 years STANDARD_DEVIATION 9.84 • n=93 Participants
Sex: Female, Male Female	16 Participants n=93 Participants
Sex: Female, Male Male	27 Participants n=93 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	43 Participants n=93 Participants
Race/Ethnicity, Customized Asian	43 Participants n=93 Participants
Region of Enrollment Singapore	21 Participants n=93 Participants
Region of Enrollment Hong Kong	6 Participants n=93 Participants
Region of Enrollment Korea, Republic Of	16 Participants n=93 Participants
Height at Baseline	160.2 cm STANDARD_DEVIATION 7.80 • n=93 Participants
Weight at Baseline	60.6 kg STANDARD_DEVIATION 10.47 • n=93 Participants

PRIMARY outcome

Timeframe: Cycle 1, Day 1 pre-dose and multiple time-points (up to 168 hours) post-dose

Population: 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.

Outcome measures

Measure	Ixazomib+Lenalidomide+Dexamethasone n=22 Participants 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)
Cmax: Maximum Observed Plasma Concentration for Ixazomib	37.57 ng/mL Standard Deviation 31.701

PRIMARY outcome

Timeframe: Cycle 1, Day 15 pre-dose and multiple time-points (up to 336 hours) post-dose

Population: 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.

Outcome measures

Measure	Ixazomib+Lenalidomide+Dexamethasone n=24 Participants 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)
Cmax: Maximum Observed Plasma Concentration for Ixazomib	57.57 ng/mL Standard Deviation 38.507

PRIMARY outcome

Timeframe: Cycle 1, Day 1 pre-dose and multiple time-points (up to 168 hours) post-dose

Population: 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.

Outcome measures

Measure	Ixazomib+Lenalidomide+Dexamethasone n=22 Participants 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)
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib	1.5 hours Interval 0.5 to 7.0

PRIMARY outcome

Timeframe: Cycle 1, Day 15 pre-dose and multiple time-points (up to 336 hours) post-dose

Population: 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.

Outcome measures

Measure	Ixazomib+Lenalidomide+Dexamethasone n=24 Participants 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)
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib	2.0 hours Interval 0.5 to 7.97

PRIMARY outcome

Timeframe: Cycle 1, Day 1 pre-dose and multiple time-points (up to 168 hours) post-dose

Population: 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.

Outcome measures

Measure	Ixazomib+Lenalidomide+Dexamethasone n=20 Participants 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)
AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to Time of the Last Quantifiable Concentration for Ixazomib	685.9 hr*ng/mL Standard Deviation 246.35

PRIMARY outcome

Timeframe: Cycle 1, Day 15 pre-dose and multiple time-points (up to 336 hours) post-dose

Population: 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.

Outcome measures

Measure	Ixazomib+Lenalidomide+Dexamethasone n=24 Participants 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)
AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to Time of the Last Quantifiable Concentration for Ixazomib	1746.0 hr*ng/mL Standard Deviation 798.60

PRIMARY outcome

Timeframe: Cycle 1 (up to Day 28)

Population: 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.

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.

Outcome measures

Measure	Ixazomib+Lenalidomide+Dexamethasone n=24 Participants 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)
Number of Participants With Dose Limiting Toxicities (DLTs)	2 participants

PRIMARY outcome

Timeframe: From the first dose of study drug through 30 days after the last dose of study drug (up to 577 days)

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

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.

Outcome measures

Measure	Ixazomib+Lenalidomide+Dexamethasone n=43 Participants 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)
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) AEs	43 participants
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) SAEs	18 participants

PRIMARY outcome

Timeframe: From the first dose of study drug through 30 days after the last dose of study drug (up to 577 days)

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

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.

Outcome measures

Measure	Ixazomib+Lenalidomide+Dexamethasone n=43 Participants 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)
Number of Participants With Clinically Significant Laboratory Abnormalities Reported as Adverse Events of ≥Grade 3 Intensity Alanine Aminotransferase Increased	2 participants
Number of Participants With Clinically Significant Laboratory Abnormalities Reported as Adverse Events of ≥Grade 3 Intensity Aspartate Aminotransferase Increased	1 participants
Number of Participants With Clinically Significant Laboratory Abnormalities Reported as Adverse Events of ≥Grade 3 Intensity Blood Creatinine Increased	1 participants
Number of Participants With Clinically Significant Laboratory Abnormalities Reported as Adverse Events of ≥Grade 3 Intensity Haemoglobin Decreased	1 participants
Number of Participants With Clinically Significant Laboratory Abnormalities Reported as Adverse Events of ≥Grade 3 Intensity Neutrophil Count Decreased	2 participants
Number of Participants With Clinically Significant Laboratory Abnormalities Reported as Adverse Events of ≥Grade 3 Intensity Platelet Count Decreased	4 participants
Number of Participants With Clinically Significant Laboratory Abnormalities Reported as Adverse Events of ≥Grade 3 Intensity Anaemia	6 participants
Number of Participants With Clinically Significant Laboratory Abnormalities Reported as Adverse Events of ≥Grade 3 Intensity Febrile Neutropenia	1 participants
Number of Participants With Clinically Significant Laboratory Abnormalities Reported as Adverse Events of ≥Grade 3 Intensity Neutropenia	12 participants
Number of Participants With Clinically Significant Laboratory Abnormalities Reported as Adverse Events of ≥Grade 3 Intensity Thrombocytopenia	8 participants
Number of Participants With Clinically Significant Laboratory Abnormalities Reported as Adverse Events of ≥Grade 3 Intensity Hyperglycaemia	1 participants
Number of Participants With Clinically Significant Laboratory Abnormalities Reported as Adverse Events of ≥Grade 3 Intensity Hypocalcaemia	3 participants
Number of Participants With Clinically Significant Laboratory Abnormalities Reported as Adverse Events of ≥Grade 3 Intensity Hypokalaemia	5 participants
Number of Participants With Clinically Significant Laboratory Abnormalities Reported as Adverse Events of ≥Grade 3 Intensity Hypomagnesaemia	1 participants
Number of Participants With Clinically Significant Laboratory Abnormalities Reported as Adverse Events of ≥Grade 3 Intensity Hyponatraemia	1 participants
Number of Participants With Clinically Significant Laboratory Abnormalities Reported as Adverse Events of ≥Grade 3 Intensity Hypophosphataemia	2 participants

PRIMARY outcome

Timeframe: From the first dose of study drug through 30 days after the last dose of study drug (up to 577 days)

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

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.

Outcome measures

Measure	Ixazomib+Lenalidomide+Dexamethasone n=43 Participants 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)
Number of Participants With Clinically Significant Vital Signs Reported as Adverse Events Grade 1 or 2 Hypertension	4 participants
Number of Participants With Clinically Significant Vital Signs Reported as Adverse Events Grade 2 Hypotension	1 participants

SECONDARY outcome

Timeframe: From Cycle 1, Day 1 to Cycle 3, Day 1 until disease progression (approximately 20 months)

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

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.

Outcome measures

Measure	Ixazomib+Lenalidomide+Dexamethasone n=43 Participants 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)
Percentage of Participants With Confirmed Best Response Category	53.5 percentage of participants

SECONDARY outcome

Timeframe: From date of documentation of a confirmed response to date of progressive disease, (approximately 20 months)

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

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.

Outcome measures

Measure	Ixazomib+Lenalidomide+Dexamethasone n=43 Participants 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)
Duration of Response (DOR)	12.9 months Interval 1.8 to 15.0

Adverse Events

Ixazomib+Lenalidomide+Dexamethasone

Serious events: 18 serious events

Other events: 43 other events

Deaths: 0 deaths

Serious adverse events

Measure	Ixazomib+Lenalidomide+Dexamethasone n=43 participants at risk 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)
Infections and infestations Pneumonia	7.0% 3/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Infections and infestations Lung infection	4.7% 2/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Infections and infestations Diarrhoea infectious	2.3% 1/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Infections and infestations Gastroenteritis	2.3% 1/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Infections and infestations Upper respiratory tract infection	4.7% 2/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Gastrointestinal disorders Diarrhoea	7.0% 3/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Gastrointestinal disorders Gastritis atrophic	2.3% 1/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Gastrointestinal disorders Vomiting	2.3% 1/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Musculoskeletal and connective tissue disorders Back pain	4.7% 2/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Musculoskeletal and connective tissue disorders Osteoporotic fracture	2.3% 1/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Plasmacytoma	4.7% 2/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Renal cell carcinoma	2.3% 1/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
General disorders Pyrexia	2.3% 1/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
General disorders General physical health deterioration	2.3% 1/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Immune system disorders Drug hypersensitivity	2.3% 1/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Immune system disorders Food allergy	2.3% 1/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Injury, poisoning and procedural complications Laceration	2.3% 1/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Injury, poisoning and procedural complications Spinal fracture	2.3% 1/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Investigations Platelet count decreased	2.3% 1/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Investigations Blood creatinine increased	2.3% 1/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Metabolism and nutrition disorders Hypophagia	2.3% 1/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Metabolism and nutrition disorders Hypokalaemia	2.3% 1/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Nervous system disorders Presyncope	2.3% 1/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Nervous system disorders Spinal cord compression	2.3% 1/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Blood and lymphatic system disorders Thrombocytopenia	2.3% 1/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Renal and urinary disorders Renal impairment	2.3% 1/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.

Other adverse events

Measure	Ixazomib+Lenalidomide+Dexamethasone n=43 participants at risk 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)
Blood and lymphatic system disorders Neutropenia	30.2% 13/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Blood and lymphatic system disorders Thrombocytopenia	30.2% 13/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Blood and lymphatic system disorders Anaemia	27.9% 12/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Eye disorders Cataract	16.3% 7/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Gastrointestinal disorders Diarrhoea	53.5% 23/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Gastrointestinal disorders Vomiting	34.9% 15/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Gastrointestinal disorders Nausea	27.9% 12/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Gastrointestinal disorders Constipation	23.3% 10/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Gastrointestinal disorders Abdominal pain	11.6% 5/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Gastrointestinal disorders Abdominal discomfort	9.3% 4/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Gastrointestinal disorders Dyspepsia	9.3% 4/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Gastrointestinal disorders Abdominal pain upper	7.0% 3/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Gastrointestinal disorders Stomatitis	7.0% 3/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
General disorders Fatigue	32.6% 14/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
General disorders Pyrexia	18.6% 8/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
General disorders Oedema peripheral	14.0% 6/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
General disorders Asthenia	11.6% 5/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
General disorders Influenza like illness	11.6% 5/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Infections and infestations Upper respiratory tract infection	34.9% 15/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Infections and infestations Influenza	7.0% 3/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Infections and infestations Nasopharyngitis	7.0% 3/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Infections and infestations Pneumonia	7.0% 3/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Infections and infestations Urinary tract infection	7.0% 3/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Injury, poisoning and procedural complications Spinal compression fracture	7.0% 3/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Investigations Alanine aminotransferase increased	16.3% 7/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Investigations Platelet count decreased	16.3% 7/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Investigations Blood creatinine increased	14.0% 6/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Investigations Aspartate aminotransferase increased	11.6% 5/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Investigations Neutrophil count decreased	9.3% 4/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Investigations Weight decreased	9.3% 4/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Investigations Blood alkaline phosphatase increased	7.0% 3/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Investigations Gamma-glutamyltransferase increased	7.0% 3/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Metabolism and nutrition disorders Decreased appetite	27.9% 12/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Metabolism and nutrition disorders Hypokalaemia	27.9% 12/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Metabolism and nutrition disorders Hypocalcaemia	14.0% 6/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Metabolism and nutrition disorders Hypomagnesaemia	9.3% 4/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Metabolism and nutrition disorders Hypophosphataemia	9.3% 4/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Metabolism and nutrition disorders Hypercalcaemia	7.0% 3/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Musculoskeletal and connective tissue disorders Back pain	14.0% 6/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Musculoskeletal and connective tissue disorders Muscle spasms	9.3% 4/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Musculoskeletal and connective tissue disorders Myalgia	9.3% 4/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Musculoskeletal and connective tissue disorders Muscular weakness	7.0% 3/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	7.0% 3/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	7.0% 3/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Nervous system disorders Dizziness	27.9% 12/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Nervous system disorders Neuropathy peripheral	20.9% 9/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Nervous system disorders Hypoaesthesia	11.6% 5/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Nervous system disorders Headache	9.3% 4/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Nervous system disorders Lethargy	7.0% 3/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Nervous system disorders Peripheral sensory neuropathy	9.3% 4/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Psychiatric disorders Insomnia	30.2% 13/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Respiratory, thoracic and mediastinal disorders Cough	30.2% 13/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Respiratory, thoracic and mediastinal disorders Productive cough	11.6% 5/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	9.3% 4/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Respiratory, thoracic and mediastinal disorders Dyspnoea	7.0% 3/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Skin and subcutaneous tissue disorders Pruritus	14.0% 6/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Skin and subcutaneous tissue disorders Rash maculo-papular	14.0% 6/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Skin and subcutaneous tissue disorders Rash pruritic	14.0% 6/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Skin and subcutaneous tissue disorders Dry skin	11.6% 5/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Skin and subcutaneous tissue disorders Rash macular	11.6% 5/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Skin and subcutaneous tissue disorders Skin hyperpigmentation	9.3% 4/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Skin and subcutaneous tissue disorders Pruritus generalised	7.0% 3/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.
Vascular disorders Hypertension	9.3% 4/43 • First dose of study drug through 30 days after the last dose of study drug (up to 577 days) 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.

Additional Information

Medical Director

Takeda

Phone: +1-877-825-3327

Email: trialdisclosures@takeda.com

Results disclosure agreements

• Principal investigator is a sponsor employee 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
• Publication restrictions are in place

Restriction type: OTHER