Download PDF

Clinical Trial Results:
An Open-Label, Phase 2 Study to Evaluate the Oral Combination of MLN9708 With Cyclophosphamide and Dexamethasone In Patients With Newly Diagnosed or Relapsed and/or Refractory Multiple Myeloma Requiring Systemic Treatment

Summary
EudraCT number	2013-003113-17
Trial protocol	SE GR PL
Global end of trial date	29 Jun 2018

Results information
Results version number	v1(current)
This version publication date	10 Jul 2019
First version publication date	10 Jul 2019
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

C16020

ISRCTN number

US NCT number

NCT02046070

WHO universal trial number (UTN)

U1111-1158-2714

Sponsor organisation name

Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited

Sponsor organisation address

40 Landsdowne Street, Cambridge, United States, MA 02139

Public contact

Medical Director, Clinical Science, Takeda Oncology, +1 877-825-3327, clinicaltrialregistry@tpna.com

Scientific contact

Medical Director, Clinical Science, Takeda Oncology, +1 877-825-3327, clinicaltrialregistry@tpna.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

29 Jun 2018

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

29 Jun 2018

Was the trial ended prematurely?

Main objective of the trial

This is a phase 2, multicenter, open-label study in patients with Newly Diagnosed Multiple Myeloma (NDMM) who have not received prior systemic treatment for multiple myeloma (MM) and who are ineligible for high-dose therapy (HDT)-stem cell transplantation (SCT) due to age (ie, ≥ 65 years) or comorbid disease(s) or with Relapsed and/or Refractory Multiple Myeloma (RRMM).

Protection of trial subjects

All study participants were required to read and sign an Informed Consent Form.

Background therapy

Evidence for comparator

Actual start date of recruitment

05 Mar 2014

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

45 Months

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 16

Country: Number of subjects enrolled

Greece: 52

Country: Number of subjects enrolled

Poland: 47

Country: Number of subjects enrolled

Sweden: 20

Country: Number of subjects enrolled

United States: 13

Worldwide total number of subjects

148

EEA total number of subjects

119

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

102

85 years and over

Subject disposition

Top of page

Recruitment details

Participants took part in the study at 23 investigative sites in Australia, Greece, Poland, Sweden and the United States from 05 March 2014 to 29 June 2018.

Screening details

Participants with NDMM were enrolled in 1 of 2 arms to receive 4.0 mg ixazomib in combination with 300 or 400 mg cyclophosphamide and 40 mg dexamethasone (CCd); participants with RRMM were enrolled in 1 arm to receive ixazomib 4.0 mg CCd. All arms included a safety lead-in cohort for pharmacokinetics (PK) analysis.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM)

Arm description

Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15 of a 28-day cycle until progressive disease (PD)/death or unacceptable toxicity [13 cycles in the Induction Phase continuing in the Maintenance Phase for up to 36 Months] and cyclophosphamide (CYC) 300 mg/m^2, tablets, orally, on Days 1, 8 and 15 of a 28-day cycle for 13 cycles or until PD/death or unacceptable toxicity and dexamethasone (DEX) 40 mg, tablets, orally, on Days 1, 8, 15 and 22 (dose reduced to 20 mg for patients >75 years) of a 28-day cycle for 13 cycles or until PD/death or unacceptable toxicity in participants with NDMM.

Arm type

Experimental

Investigational medicinal product name

Cyclophosphamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Cyclophosphamide tablets.

Investigational medicinal product name

Dexamethasone

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Dexamethasone tablets.

Investigational medicinal product name

Ixazomib

Investigational medicinal product code

Other name

MLN9708

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Ixazomib capsules.

Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM)

Arm description

Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15 of a 28-day cycle until PD/death or unacceptable toxicity [13 cycles in the Induction Phase continuing in the Maintenance Phase for up to 36 Months] and cyclophosphamide (CYC) 400 mg/m^2, tablets, orally, on Days 1, 8 and 15 of a 28-day cycle for 13 cycles or until PD/death or unacceptable toxicity and dexamethasone (DEX) 40 mg, tablets, orally, on Days 1, 8, 15 and 22 (dose reduced to 20 mg for patients >75 years) of a 28-day cycle for 13 cycles or until PD/death or unacceptable toxicity in participants with NDMM.

Arm type

Experimental

Investigational medicinal product name

Cyclophosphamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Cyclophosphamide tablets.

Investigational medicinal product name

Dexamethasone

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Dexamethasone tablets.

Investigational medicinal product name

Ixazomib

Investigational medicinal product code

Other name

MLN9708

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Ixazomib capsules.

Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (RRMM)

Arm description

Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15 of a 28-day cycle and cyclophosphamide (CYC) 300 mg/m^2, tablets, orally, on Days 1, 8 and 15 of a 28-day cycle and dexamethasone (DEX) 40 mg, tablets, orally, on Days 1, 8, 15 and 22 (dose reduced to 20 mg for patients >75 years) of a 28-day cycle until PD/death or unacceptable toxicity in participants with RRMM.

Arm type

Experimental

Investigational medicinal product name

Cyclophosphamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Cyclophosphamide tablets.

Investigational medicinal product name

Ixazomib

Investigational medicinal product code

Other name

MLN9708

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Ixazomib capsules.

Investigational medicinal product name

Dexamethasone

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Dexamethasone tablets.

Number of subjects in period 1	Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM)	Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM)	Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (RRMM)
Started	36	34	78
Completed	4	6	8
Not completed	32	28	70
Consent withdrawn by subject	1	2	6
Adverse event, non-fatal	8	10	17
Progressive Disease	18	11	40
Study Terminated by Sponsor	1	1	1
Reason not Specified	4	4	6

Baseline characteristics

Top of page

Reporting group title

Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM)

Reporting group description

Reporting group title

Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM)

Reporting group description

Reporting group title

Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (RRMM)

Reporting group description

Reporting group values	Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM)	Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM)	Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (RRMM)	Total
Number of subjects	36	34	78	148
Age categorical
Units: Subjects
Adults (18-64 years)	0	2	41	43
From 65-84 years	34	32	36	102
85 years and over	2	0	1	3
Age Continuous
Units: years
arithmetic mean (standard deviation)	73.4 ( 5.48 )	74.1 ( 5.80 )	63.5 ( 9.85 )	-
Sex: Female, Male
Units: Subjects
Female	21	16	37	74
Male	15	18	41	74
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	1	0	0	1
Not Hispanic or Latino	35	33	75	143
Unknown or Not Reported	0	1	3	4
Race/Ethnicity, Customized
Units: Subjects
White	35	34	74	143
Other	1	0	2	3
Asian	0	0	1	1
Black or African American	0	0	1	1
Height
Units: centimeters (cm)
arithmetic mean (standard deviation)	163.5 ( 11.35 )	163.5 ( 12.47 )	165.9 ( 10.47 )	-
Weight
Units: kilograms (kg)
arithmetic mean (standard deviation)	73.6 ( 11.8 )	73.0 ( 17.54 )	78.1 ( 16.80 )	-
Body Surface Area (BSA)
BSA = square root (height(cm) x weight (kg) / 3600.
Units: meters squared (m^2)
arithmetic mean (standard deviation)	1.8 ( 0.17 )	1.8 ( 0.26 )	1.9 ( 0.23 )	-

End points

Top of page

Reporting group title

Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM)

Reporting group description

Reporting group title

Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM)

Reporting group description

Reporting group title

Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (RRMM)

Reporting group description

Primary: Combined Response Rate during the Induction Phase in Newly Diagnosed Multiple Myeloma (NDMM) Participants

Top of page

End point title

Combined Response Rate during the Induction Phase in Newly Diagnosed Multiple Myeloma (NDMM) Participants ^[1] ^[2]

End point description

Combined Response Rate is the percentage of participants with Complete Response (CR), including stringent Complete Response (sCR), and Very Good Partial Response (VGPR) according to the International Myeloma Working Group (IMWG) criteria during the Induction Phase (Cycles 1-13, 28-day cycles). CR=negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow. VGPR=serum and urine M-component detectable by immunofixation but not on electrophoresis or 90% reduction in serum M-component plus urine M-component <100 mg/24 hour. Response Evaluable Population was defined as participants who received at least 2 of the 3 ixazomib doses during Cycle 1, had measurable disease at Baseline, and at least 1 postbaseline response assessment.

End point type

Primary

End point timeframe

Day 1 of Cycles 1-13, 28-day cycles (Up to 1 year)

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses are reported for this endpoint.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable to the NDMM arms.

End point values	Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM)	Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM)
Number of subjects analysed	33	34
Units: percentage of participants
number (confidence interval 95%)	27 (13 to 46)	24 (11 to 41)

No statistical analyses for this end point

Primary: Overall Response Rate (ORR) in Relapsed and/or Refractory Multiple Myeloma (RRMM) Participants

Top of page

End point title

Overall Response Rate (ORR) in Relapsed and/or Refractory Multiple Myeloma (RRMM) Participants ^[3] ^[4]

End point description

ORR is the percentage of participants with CR, VGPR or PR according to IMWG criteria. CR=negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas and <5% plasma cells (PC) in bone marrow. VGPR=serum and urine M-component detectable by immunofixation but not on electrophoresis or 90% reduction in serum M-component plus urine M-component <100 mg/24 hour. PR=50% reduction of serum M-protein and reduction in 24 hour urine M-protein by 90% or <200 mg/24 hour or decrease 50% difference between involved free light chain (FLC) levels or 50% reduction in bone marrow plasma cells if baseline percentage was 30%; and if present at Baseline, 50% reduction in the size of soft tissue plasmacytomas. Response Evaluable Population was defined as participants who received at least 2 of the 3 ixazomib doses during Cycle 1, had measurable disease at Baseline, and at least 1 postbaseline response assessment.

End point type

Primary

End point timeframe

Day 1 of each 28 day cycle (Up to 45 months)

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses are reported for this endpoint.
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable to the RRMM arm.

End point values	Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (RRMM)
Number of subjects analysed	73
Units: percentage of participants
arithmetic mean (confidence interval 95%)	49 (37 to 61)

No statistical analyses for this end point

Secondary: Number of Participants with Adverse Events (AEs), Grade 3 or Higher AEs, AEs Resulting in Treatment Discontinuation, AEs Resulting in Dose Reduction and Serious Adverse Events (SAEs) in NDMM Participants

Top of page

End point title

Number of Participants with Adverse Events (AEs), Grade 3 or Higher AEs, AEs Resulting in Treatment Discontinuation, AEs Resulting in Dose Reduction and Serious Adverse Events (SAEs) in NDMM Participants ^[5]

End point description

An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product whether or not it is related to the medicinal product. This includes any newly occurring event, or a previous condition that has increased in severity or frequency since the administration of study drug. A SAE is any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly/birth defect or is a medically important event. Relationship of each AE to study drug was determined by the Investigator. Safety Population was defined as all participants who receive at least 1 dose of any study drug.

End point type

Secondary

End point timeframe

First dose of study drug through 30 days after last dose of drug (Up to 45 months)

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable to the NDMM arms.

End point values	Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM)	Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM)
Number of subjects analysed	36	34
Units: participants
Any AE	35	34
Grade 3 or Higher AEs	27	27
AEs Resulting in Treatment Discontinuation	9	11
AEs Resulting in Dose Reduction	11	10
SAEs	17	20

No statistical analyses for this end point

Secondary: Percentage of Participants with CR + VGPR + PR (ORR), CR, VGPR, PR and Stable Disease (SD), Progressive Disease (PD) during the Induction Phase

Top of page

End point title

Percentage of Participants with CR + VGPR + PR (ORR), CR, VGPR, PR and Stable Disease (SD), Progressive Disease (PD) during the Induction Phase ^[6]

End point description

Percentage of participants with CR+VGPR+PR(ORR),CR,VGPR,PR,SD,PD (IMWG criteria). CR=negative immunofixation of serum+urine; disappearance of soft tissue plasmacytomas;<5%PC in bone marrow. VGPR=serum+urine M-component by immunofixation but not on electrophoresis or 90% reduction in serum +urine M-component <100mg/24hr. PR=50% serum M-protein and 24hr urine M-protein reduction by 90% or <200mg/24hr or decrease 50% difference in FLC levels or 50% reduction in bone marrow plasma cells if baseline=30%; and if present at Baseline, 50% reduction in size of soft tissue plasmacytomas. SD=not meeting criteria for VGPR,PR or PD. PD=25% increase in lowest value of: serum+urine M-component, difference in involved+uninvolved FLC levels, bone marrow PC%; new or increased size of existing bone lesions or soft tissue plasmacytomas. Response Evaluable Population: participants received 2 of 3 ixazomib doses during Cycle 1, had measurable disease at Baseline and 1 postbaseline response assessment.

End point type

Secondary

End point timeframe

Day 1 of Cycles 1-13, 28-day cycles (Up to 1 year)

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable to the NDMM arms.

End point values	Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM)	Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM)
Number of subjects analysed	33	34
Units: percentage of participants
number (confidence interval 95%)
CR + VGPR + PR	79 (61 to 91)	71 (53 to 85)
CR	12 (3 to 28)	9 (2 to 24)
VGPR	15 (5 to 32)	15 (5 to 31)
PR	67 (48 to 82)	62 (44 to 78)
SD	12 (3 to 28)	18 (7 to 35)
PD	0 (0 to 0)	3 (1 to 15)

No statistical analyses for this end point

Secondary: Percentage of Participants with CR + VGPR + PR (ORR), CR + VGPR, CR, VGPR, PR, SD and PD Throughout the Entire Treatment Period in NDMM Participants

Top of page

End point title

Percentage of Participants with CR + VGPR + PR (ORR), CR + VGPR, CR, VGPR, PR, SD and PD Throughout the Entire Treatment Period in NDMM Participants ^[7]

End point description

End point type

Secondary

End point timeframe

Day 1 of each 28-day Cycle (Up to 45 months)

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable to the NDMM arms.

End point values	Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM)	Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM)
Number of subjects analysed	33	34
Units: percentage of participants
number (confidence interval 95%)
CR + VGPR + PR	82 (65 to 93)	71 (53 to 85)
CR + VGPR	36 (20 to 55)	32 (17 to 51)
CR	15 (5 to 32)	12 (3 to 27)
VGPR	21 (9 to 39)	21 (9 to 38)
PR	67 (48 to 82)	59 (41 to 75)
SD	18 (7 to 35)	18 (7 to 35)
PD	0 (0 to 0)	6 (1 to 20)

No statistical analyses for this end point

Secondary: Time to Response (TTR) in NDMM Participants during the Induction Phase

Top of page

End point title

Time to Response (TTR) in NDMM Participants during the Induction Phase ^[8]

End point description

TTR is defined as the time interval from the date of the first dose of study treatment to the date of the first documented confirmed response of PR or better up to the initiation of alternative therapy in a participant who responded. Participants from the Response Evaluable Population, defined as participants who received at least 2 of the 3 ixazomib doses during Cycle 1, had measurable disease at Baseline, and at least 1 postbaseline response assessment, who responded.

End point type

Secondary

End point timeframe

Up to 1 year

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable to the NDMM arms.

End point values	Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM)	Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM)
Number of subjects analysed	26	23
Units: months
median (confidence interval 95%)	2.2 (0.95 to 2.92)	1.9 (0.95 to 1.9)

No statistical analyses for this end point

Secondary: Duration of Response (DOR) in NDMM Participants

Top of page

End point title

Duration of Response (DOR) in NDMM Participants ^[9]

End point description

DOR is defined as the time from the date of first documentation of a confirmed PR or better to the date of first documented PD up to the initiation of alternative therapy. Participants from the Response Evaluable Population, participants who received at least 2 of the 3 ixazomib doses during Cycle 1, had measurable disease at Baseline and at least 1 postbaseline response assessment, who responded. Responders without PD were censored at the date of SD or better prior to the date of alternative therapy. 99999 indicates 95% Confidence Interval (CI) Upper Limit was not estimable due to the low number of participants with events.

End point type

Secondary

End point timeframe

Up to 45 Months

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable to the NDMM arms.

End point values	Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM)	Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM)
Number of subjects analysed	26	23
Units: months
median (confidence interval 95%)	32.2 (18.66 to 99999)	36.6 (19.75 to 99999)

No statistical analyses for this end point

Secondary: Time to Progression (TTP) in NDMM Participants

Top of page

End point title

Time to Progression (TTP) in NDMM Participants ^[10]

End point description

TTP is defined as the time from the date of first dose of study treatment to the date of first documentation of disease progression. Safety Population was defined as all participants who received at least 1 dose of any study drug. Participants without documentation of PD were censored at the date of last response assessment that is SD or better prior to the date of the alternative therapy. 99999 indicates 95% CI Upper Limit was not estimable due to the low number of participants with events.

End point type

Secondary

End point timeframe

Up to 45 months

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable to the NDMM arms.

End point values	Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM)	Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM)
Number of subjects analysed	36	34
Units: months
median (confidence interval 95%)	30.9 (19.58 to 41.66)	32.2 (20.27 to 99999)

No statistical analyses for this end point

Secondary: Progression Free Survival (PFS) in NDMM Participants

Top of page

End point title

Progression Free Survival (PFS) in NDMM Participants ^[11]

End point description

PFS is defined as the time from the date of first dose of study treatment to the date of the first documented disease progression or death. Safety Population was defined as all participants who received at least 1 dose of any study drug. Participants without documentation of PD or death were censored at the date of last response assessment that is SD or better prior to the date of the alternative therapy. 99999 indicates 95% CI Upper Limit was not estimable due to the low number of participants with events.

End point type

Secondary

End point timeframe

Up to 45 months

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable to the NDMM arms.

End point values	Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM)	Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM)
Number of subjects analysed	36	34
Units: months
median (confidence interval 95%)	23.5 (15.67 to 39.59)	23.0 (15.90 to 99999)

No statistical analyses for this end point

Secondary: Number of Participants with AEs, SAEs, AEs Resulting in Discontinuation and AEs Resulting in Dose Reduction in NDMM Participants Remaining on Treatment after 13 Cycles

Top of page

End point title

Number of Participants with AEs, SAEs, AEs Resulting in Discontinuation and AEs Resulting in Dose Reduction in NDMM Participants Remaining on Treatment after 13 Cycles ^[12]

End point description

End point type

Secondary

End point timeframe

First dose of study drug through 30 days after the last dose of drug (Up to 45 months)

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable to the NDMM arms.

End point values	Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM)	Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM)
Number of subjects analysed	24	22
Units: participants
Any AE	22	20
SAE	6	4
AEs Resulting in Treatment Discontinuation	1	2
AEs Resulting in Dose Reduction	5	4

No statistical analyses for this end point

Secondary: Change from Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) during the Induction Phase in NDMM Participants

Top of page

End point title

Change from Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) during the Induction Phase in NDMM Participants ^[13]

End point description

EORTC QLQ-C30 is a 30 item questionnaire that consists of 5 functional scales(physical, role, emotional, cognitive, and social functioning), 1 global health status scale, 3 symptom scales(fatigue, nausea and vomiting, and pain), 6 single items(dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Patient evaluates their health status over previous week. 28 questions answered on a 4-point scale where:1=Not at all(best) to 4=Very Much(worst), 2 questions answered on 7-point scale where 1=Very poor(worst) to 7=Excellent(best). All scales and single-item measures transformed to score:0-100. For functioning scales and global QOL higher scores indicate better functioning (a positive change from Baseline indicates improvement); for symptom scales higher scores indicate more severe symptoms (a negative change from Baseline indicates improvement). Safety Population:participants who received at least 1 dose of any study drug, with data available for analysis.

End point type

Secondary

End point timeframe

Baseline (BL) (Day 1 of Cycle 1), Day 1 of Cycle 13 (Up to 1 year)

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable to the NDMM arms.

End point values	Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM)	Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM)
Number of subjects analysed	24	23
Units: score on a scale
arithmetic mean (standard deviation)
Global Health Status/QoL, Change from BL; Cycle 13	3.47 ( 30.783 )	-5.43 ( 24.180 )
Physical functioning, Change from BL at Cycle 13	14.17 ( 35.675 )	17.97 ( 20.640 )
Role functioning, Change from BL at Cycle 13	8.33 ( 43.127 )	6.52 ( 35.441 )
Emotional functioning, Change from BL at Cycle 13	11.34 ( 27.837 )	2.54 ( 15.977 )
Cognitive functioning, Change from BL at Cycle 13	2.78 ( 22.877 )	-7.25 ( 14.058 )
Social functioning, Change from BL at Cycle 13	9.03 ( 39.921 )	-11.59 ( 29.914 )
Fatigue, Change from BL at Cycle 13	-10.88 ( 35.307 )	-6.76 ( 30.473 )
Nausea/Vomiting, Change from BL at Cycle 13	-4.86 ( 26.228 )	-4.35 ( 19.603 )
Pain, Change from BL at Cycle 13	-13.89 ( 52.628 )	-10.87 ( 39.443 )
Dyspnea, Change from BL at Cycle 13	-11.11 ( 37.644 )	-7.25 ( 40.147 )
Insomnia, Change from BL at Cycle 13	-16.67 ( 46.104 )	-10.14 ( 35.441 )
Appetite Loss, Change from BL at Cycle 13	-18.06 ( 42.822 )	-7.25 ( 24.529 )
Constipation, Change from BL at Cycle 13	-13.89 ( 39.215 )	-5.80 ( 41.013 )
Diarrhea, Change from BL at Cycle 13	-2.78 ( 30.954 )	5.80 ( 19.207 )
Financial Difficulties, Change from BL at Cycle 13	4.17 ( 26.580 )	1.45 ( 30.942 )

No statistical analyses for this end point

Secondary: Percentage of Participants with CR + VGR + PR (ORR), CR, VGPR, and PR in NDMM Participants Remaining on Treatment after 13 Cycles

Top of page

End point title

Percentage of Participants with CR + VGR + PR (ORR), CR, VGPR, and PR in NDMM Participants Remaining on Treatment after 13 Cycles ^[14]

End point description

Percentage of participants with Overall Response (CR + VGPR + PR), CR, VGPR and PR according to IMWG criteria. CR=negative immunofixation of serum and urine; disappearance of soft tissue plasmacytomas;<5% PC in bone marrow. VGPR=serum and urine M-component detectable by immunofixation but not on electrophoresis or 90% reduction in serum M-component plus urine M-component <100 mg/24 hour. PR=50% reduction of serum M-protein and reduction in 24 hour urine M-protein by 90% or <200 mg/24 hour or decrease 50% difference between involved FLC levels or 50% reduction in bone marrow plasma cells if baseline percentage was 30%; and if present at Baseline, 50% reduction in the size of soft tissue plasmacytomas. Participants from the Response Evaluable Population, participants who received at least 2 of the 3 ixazomib doses during Cycle 1, had measurable disease at Baseline and at least 1 postbaseline response assessment, with both an Induction and Maintenance response.

End point type

Secondary

End point timeframe

Day 1 of each 28-day Cycle (Up to 45 months)

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable to the NDMM arms.

End point values	Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM)	Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM)
Number of subjects analysed	24	21
Units: percentage of participants
number (not applicable)
CR + VGPR + PR	75.0	85.7
CR	16.7	19.0
VGPR	20.8	28.6
PR	37.5	38.1

No statistical analyses for this end point

Secondary: Cmax: Maximum Observed Plasma Concentration for Ixazomib in NDMM Participants

Top of page

End point title

Cmax: Maximum Observed Plasma Concentration for Ixazomib in NDMM Participants ^[15]

End point description

PK-Evaluable Population was defined as participants in the safety lead-in cohort who have sufficient dosing data and ixazomib concentration-time data to permit calculation of PK parameters. Number analyzed is the number of participants with data available for analysis at the given time-point.

End point type

Secondary

End point timeframe

Cycle 1 Days 1 and 15 predose and at multiple timepoints (up to 168 hours) postdose

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable to the NDMM arms.

End point values	Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM)	Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM)
Number of subjects analysed	6	6
Units: nanogram/mL (ng/mL)
arithmetic mean (standard deviation)
Cycle 1 Day 1 (n=6,6)	64.283 ( 36.283 )	46.600 ( 34.7722 )
Cycle 1 Day 15 (n=6,5)	53.145 ( 46.3782 )	62.280 ( 39.4249 )

No statistical analyses for this end point

Secondary: Tmax: Time to First Occurrence of Cmax for Ixazomib in NDMM Participants

Top of page

End point title

Tmax: Time to First Occurrence of Cmax for Ixazomib in NDMM Participants ^[16]

End point description

End point type

Secondary

End point timeframe

Cycle 1 Days 1 and 15 predose and at multiple timepoints (up to 168 hours) postdose

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable to the NDMM arms.

End point values	Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM)	Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM)
Number of subjects analysed	6	6
Units: hour (hr)
median (full range (min-max))
Cycle 1 Day 1 (n=6,6)	1.250 (0.92 to 1.58)	1.040 (0.50 to 2.00)
Cycle 1 Day 15 (n=6,5)	1.000 (0.45 to 4.00)	1.000 (0.50 to 1.50)

No statistical analyses for this end point

Secondary: AUCtau: Area Under the Concentration-time Curve during a Dosing Interval for Ixazomib in NDMM Participants

Top of page

End point title

AUCtau: Area Under the Concentration-time Curve during a Dosing Interval for Ixazomib in NDMM Participants ^[17]

End point description

End point type

Secondary

End point timeframe

Cycle 1 Days 1 and 15 predose and at multiple timepoints (up to 168 hours) postdose

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable to the NDMM arms.

End point values	Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM)	Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM)
Number of subjects analysed	6	6
Units: hr*ng/mL
arithmetic mean (standard deviation)
Cycle 1 Day 1 (n=6,5)	885.167 ( 354.1465 )	792.600 ( 650.5665 )
Cycle 1 Day 15 (n=6,5)	1338.333 ( 746.2902 )	1226.600 ( 527.5792 )

No statistical analyses for this end point

Secondary: Number of Participants with AEs, Grade 3 or Higher AEs, AEs Resulting in Treatment Discontinuation, AEs Resulting in Dose Reduction, SAEs in RRMM Participants

Top of page

End point title

Number of Participants with AEs, Grade 3 or Higher AEs, AEs Resulting in Treatment Discontinuation, AEs Resulting in Dose Reduction, SAEs in RRMM Participants ^[18]

End point description

An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal relationship with this treatment. A SAE is any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly/birth defect or is a medically important event. Relationship of each AE to study drug was determined by the Investigator. Safety population was defined as all participants who received at least 1 dose of any study drug.

End point type

Secondary

End point timeframe

First dose of study drug through 30 days after last dose of drug (Up to 45 months)

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable to the RRMM arm.

End point values	Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (RRMM)
Number of subjects analysed	78
Units: participants
Any AE	72
Grade 3 or Higher AE	49
AEs Resulting in Treatment Discontinuation	19
AEs Resulting in Dose Reduction	30
SAEs	30

No statistical analyses for this end point

Secondary: Cmax: Maximum Observed Plasma Concentration for Ixazomib in RRMM Participants

Top of page

End point title

Cmax: Maximum Observed Plasma Concentration for Ixazomib in RRMM Participants ^[19]

End point description

End point type

Secondary

End point timeframe

Cycle 1 Days 1 and 15 predose and at multiple timepoints (up to 168 hours) postdose

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable to the RRMM arm.

End point values	Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (RRMM)
Number of subjects analysed	7
Units: ng/mL
arithmetic mean (standard deviation)
Cycle 1 Day 1 (n=6)	47.400 ( 36.7083 )
Cycle 1 Day 15 (n=7)	52.229 ( 39.6006 )

No statistical analyses for this end point

Secondary: Tmax: Time to First Occurrence of Cmax for Ixazomib in RRMM Participants

Top of page

End point title

Tmax: Time to First Occurrence of Cmax for Ixazomib in RRMM Participants ^[20]

End point description

End point type

Secondary

End point timeframe

Cycle 1 Days 1 and 15 predose and at multiple timepoints (up to 168) hours postdose

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable to the RRMM arm.

End point values	Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (RRMM)
Number of subjects analysed	7
Units: hr
median (full range (min-max))
Cycle 1 Day 1 (n=6)	1.225 (0.50 to 3.42)
Cycle 1 Day 15 (n=7)	2.000 (0.50 to 8.00)

No statistical analyses for this end point

Secondary: AUCtau: Area Under the Concentration-time Curve during a Dosing Interval for Ixazomib in RRMM Participants

Top of page

End point title

AUCtau: Area Under the Concentration-time Curve during a Dosing Interval for Ixazomib in RRMM Participants ^[21]

End point description

End point type

Secondary

End point timeframe

Cycle 1 Days 1 and 15 predose and at multiple timepoints (up to 168 hours) postdose

Notes
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable to the RRMM arm.

End point values	Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (RRMM)
Number of subjects analysed	7
Units: hr*ng/mL
arithmetic mean (standard deviation)
Cycle 1 Day 1 (n=6)	518.167 ( 78.8274 )
Cycle 1 Day 15 (n=7)	1241.000 ( 657.4978 )

No statistical analyses for this end point

Secondary: Percentage of Participants with (CR + VGPR), CR, VGPR, PR, SD and PD in RRMM Participants

Top of page

End point title

Percentage of Participants with (CR + VGPR), CR, VGPR, PR, SD and PD in RRMM Participants ^[22]

End point description

End point type

Secondary

End point timeframe

Day 1 of each 28-day Cycle (Up to 45 months)

Notes
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable to the RRMM arm.

End point values	Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (RRMM)
Number of subjects analysed	73
Units: percentage of participants
number (confidence interval 95%)
CR + VGPR	19 (11 to 30)
CR	5 (2 to 13)
VGPR	14 (7 to 24)
PR	44 (32 to 56)
SD	37 (26 to 49)
PD	10 (4 to 19)

No statistical analyses for this end point

Secondary: Time to Response (TTR) in RRMM Participants

Top of page

End point title

Time to Response (TTR) in RRMM Participants ^[23]

End point description

TTR is defined as the time interval from the date of the first dose of study treatment to the date of the first documented confirmed response of PR or better up to the alternative therapy in a participant who responded. Participants from the Response Evaluable Population, defined as participants who received at least 2 of the 3 ixazomib doses during Cycle 1, had measurable disease at Baseline, and at least 1 postbaseline response assessment, who responded.

End point type

Secondary

End point timeframe

Up to 45 months

Notes
[23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable to the RRMM arm.

End point values	Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (RRMM)
Number of subjects analysed	36
Units: months
median (confidence interval 95%)	2.1 (0.95 to 3.12)

No statistical analyses for this end point

Secondary: Duration of Response (DOR) in RRMM Participants

Top of page

End point title

Duration of Response (DOR) in RRMM Participants ^[24]

End point description

DOR is defined as the time from the date of first documentation of a confirmed PR or better to the date of first documented PD up to the alternative therapy. Participants from the Response Evaluable Population, participants who received at least 2 of the 3 ixazomib doses during Cycle 1, had measurable disease at Baseline and at least 1 postbaseline response assessment, who responded. Responders without PD were censored at the date of SD or better prior to the date of the alternative therapy. 99999 indicates 95% CI Upper Limit was not estimable due to the low number of participants with events.

End point type

Secondary

End point timeframe

Up to 45 months

Notes
[24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable to the RRMM arm.

End point values	Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (RRMM)
Number of subjects analysed	36
Units: months
median (confidence interval 95%)	26.3 (12.22 to 99999)

No statistical analyses for this end point

Secondary: Time to Progression (TTP) in RRMM Participants

Top of page

End point title

Time to Progression (TTP) in RRMM Participants ^[25]

End point description

End point type

Secondary

End point timeframe

Up to 45 months

Notes
[25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable to the RRMM arm.

End point values	Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (RRMM)
Number of subjects analysed	78
Units: months
median (confidence interval 95%)	16.8 (11.30 to 24.67)

No statistical analyses for this end point

Secondary: Progression Free Survival (PFS) in RRMM Participants

Top of page

End point title

Progression Free Survival (PFS) in RRMM Participants ^[26]

End point description

PFS is defined as the time from the date of first dose of study treatment to the date of the first documented disease progression or death. Safety Population was defined as all participants who received at least 1 dose of any study drug. Participants without documentation of PD or death were censored at the date of last response assessment that was SD or better prior to the date of the alternative therapy.

End point type

Secondary

End point timeframe

Up to 45 months

Notes
[26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable to the RRMM arm.

End point values	Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (RRMM)
Number of subjects analysed	78
Units: months
median (confidence interval 95%)	14.2 (9.69 to 20.57)

No statistical analyses for this end point

Secondary: Change from Baseline in EORTC Quality of Life Questionnaire (QLQ-C30) in RRMM Participants

Top of page

End point title

Change from Baseline in EORTC Quality of Life Questionnaire (QLQ-C30) in RRMM Participants ^[27]

End point description

EORTC QLQ-C30 is a 30 item questionnaire that consists of 5 functional scales(physical, role, emotional, cognitive, and social functioning), 1 global health status scale, 3 symptom scales(fatigue, nausea and vomiting, and pain), 6 single items(dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Patient evaluates their health status over previous week. 28 questions answered on 4-point scale where:1=Not at all(best) to 4=Very Much(worst), 2 questions answered on 7-point scale where 1=Very poor(worst) to 7=Excellent(best). All scales and single-item measures transformed to score:0-100. For functioning scales and global QOL higher scores indicate better functioning (a positive change from Baseline indicates improvement); for symptom scales higher scores indicate more severe symptoms (a negative change from Baseline indicates improvement). Safety Population: participants who received at least 1 dose of any study drug, with data available for analysis.

End point type

Secondary

End point timeframe

Baseline (Day 1 of Cycle 1), Day 1 of End of Treatment (EOT) (Up to 45 months)

Notes
[27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable to the RRMM arm.

End point values	Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (RRMM)
Number of subjects analysed	50
Units: score on a scale
arithmetic mean (standard deviation)
Global Health Status/QoL, Change from BL at EOT	-5.50 ( 20.798 )
Physical functioning, Change from BL at EOT	-6.00 ( 19.806 )
Role functioning, Change from BL at EOT	-7.67 ( 30.344 )
Emotional functioning, Change from BL at EOT	-5.00 ( 23.023 )
Cognitive functioning, Change from BL at EOT	-5.33 ( 19.760 )
Social functioning, Change from BL at EOT	-11.33 ( 26.177 )
Fatigue, Change from BL at EOT	5.11 ( 22.695 )
Nausea/Vomiting, Change from BL at EOT	3.33 ( 14.677 )
Pain, Change from BL at EOT	5.00 ( 28.621 )
Dyspnea, Change from BL at EOT	10.00 ( 27.970 )
Insomnia, Change from BL at EOT	-6.00 ( 27.512 )
Appetite Loss, Change from BL at EOT	4.67 ( 24.290 )
Constipation, Change from BL at EOT	2.00 ( 18.332 )
Diarrhea, Change from BL at EOT	6.00 ( 19.852 )
Financial Difficulties, Change from BL at EOT	4.00 ( 20.909 )

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

First dose of study drug through 30 days after last dose of drug (Up to 45 months)

Adverse event reporting additional 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.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.0

Reporting group title

Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM)

Reporting group description

Reporting group title

Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM)

Reporting group description

Reporting group title

Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (RRMM)

Reporting group description

Serious adverse events	Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM)	Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM)	Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (RRMM)
Total subjects affected by serious adverse events
subjects affected / exposed	17 / 36 (47.22%)	20 / 34 (58.82%)	30 / 78 (38.46%)
number of deaths (all causes)	3	2	5
number of deaths resulting from adverse events	0	0	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Plasma cell myeloma
subjects affected / exposed	0 / 36 (0.00%)	0 / 34 (0.00%)	2 / 78 (2.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bladder cancer
subjects affected / exposed	0 / 36 (0.00%)	0 / 34 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Benign bone neoplasm
subjects affected / exposed	0 / 36 (0.00%)	0 / 34 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rectal adenocarcinoma
subjects affected / exposed	0 / 36 (0.00%)	1 / 34 (2.94%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastric cancer
subjects affected / exposed	1 / 36 (2.78%)	0 / 34 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myelodysplastic syndrome
subjects affected / exposed	0 / 36 (0.00%)	0 / 34 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Brain neoplasm benign
subjects affected / exposed	0 / 36 (0.00%)	1 / 34 (2.94%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Oesophageal carcinoma
subjects affected / exposed	1 / 36 (2.78%)	0 / 34 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypotension
subjects affected / exposed	0 / 36 (0.00%)	0 / 34 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	1 / 36 (2.78%)	1 / 34 (2.94%)	2 / 78 (2.56%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fatigue
subjects affected / exposed	0 / 36 (0.00%)	1 / 34 (2.94%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pulmonary oedema
Additional description: 1 TE death occurred during treatment with Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM), 1 with Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) and 1 with Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (RRMM) and all 3 are not related.
subjects affected / exposed	1 / 36 (2.78%)	1 / 34 (2.94%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	0 / 1	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 1
Pulmonary embolism
subjects affected / exposed	0 / 36 (0.00%)	2 / 34 (5.88%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 36 (0.00%)	0 / 34 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory failure
Additional description: One treatment-emergent death occurred during treatment with Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) and is not related.
subjects affected / exposed	1 / 36 (2.78%)	0 / 34 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Investigations
Light chain analysis increased
subjects affected / exposed	0 / 36 (0.00%)	0 / 34 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Femur fracture
subjects affected / exposed	0 / 36 (0.00%)	1 / 34 (2.94%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tendon rupture
subjects affected / exposed	1 / 36 (2.78%)	0 / 34 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	3 / 36 (8.33%)	1 / 34 (2.94%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	0 / 7	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	0 / 36 (0.00%)	2 / 34 (5.88%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	1 / 36 (2.78%)	0 / 34 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Acute coronary syndrome
subjects affected / exposed	0 / 36 (0.00%)	0 / 34 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	0 / 36 (0.00%)	1 / 34 (2.94%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	0 / 36 (0.00%)	1 / 34 (2.94%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac arrest
Additional description: One treatment-emergent (TE) death occurred during treatment with Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (RRMM) and is not related.
subjects affected / exposed	0 / 36 (0.00%)	0 / 34 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Nervous system disorders
Cerebral haemorrhage
Additional description: One treatment-emergent death occurred during treatment with Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (RRMM) and is related.
subjects affected / exposed	0 / 36 (0.00%)	0 / 34 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1
Haemorrhage intracranial
Additional description: One treatment-emergent death occurred during treatment with Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (RRMM) and is not related.
subjects affected / exposed	0 / 36 (0.00%)	0 / 34 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Syncope
subjects affected / exposed	1 / 36 (2.78%)	1 / 34 (2.94%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Carpal tunnel syndrome
subjects affected / exposed	0 / 36 (0.00%)	0 / 34 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Pancytopenia
subjects affected / exposed	0 / 36 (0.00%)	2 / 34 (5.88%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Anaemia
subjects affected / exposed	2 / 36 (5.56%)	0 / 34 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	1 / 10	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	1 / 36 (2.78%)	0 / 34 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 36 (0.00%)	0 / 34 (0.00%)	2 / 78 (2.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bone marrow failure
subjects affected / exposed	0 / 36 (0.00%)	1 / 34 (2.94%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Eye disorders
Cataract
subjects affected / exposed	0 / 36 (0.00%)	0 / 34 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Constipation
subjects affected / exposed	1 / 36 (2.78%)	1 / 34 (2.94%)	2 / 78 (2.56%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	2 / 36 (5.56%)	0 / 34 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	1 / 2	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 36 (0.00%)	0 / 34 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haematemesis
subjects affected / exposed	0 / 36 (0.00%)	0 / 34 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Melaena
subjects affected / exposed	0 / 36 (0.00%)	0 / 34 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
Additional description: One treatment-emergent death occurred during treatment with Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) and is not related.
subjects affected / exposed	1 / 36 (2.78%)	0 / 34 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	0 / 36 (0.00%)	1 / 34 (2.94%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	0 / 36 (0.00%)	0 / 34 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rectal ulcer
subjects affected / exposed	1 / 36 (2.78%)	0 / 34 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal distension
subjects affected / exposed	0 / 36 (0.00%)	1 / 34 (2.94%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	0 / 36 (0.00%)	0 / 34 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	1 / 36 (2.78%)	0 / 34 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 36 (0.00%)	1 / 34 (2.94%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mouth haemorrhage
subjects affected / exposed	0 / 36 (0.00%)	0 / 34 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Pemphigus
subjects affected / exposed	0 / 36 (0.00%)	0 / 34 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rash macular
subjects affected / exposed	1 / 36 (2.78%)	0 / 34 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 36 (0.00%)	0 / 34 (0.00%)	2 / 78 (2.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	0 / 36 (0.00%)	1 / 34 (2.94%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 36 (0.00%)	1 / 34 (2.94%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal chest pain
subjects affected / exposed	0 / 36 (0.00%)	1 / 34 (2.94%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bone pain
subjects affected / exposed	1 / 36 (2.78%)	0 / 34 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteolysis
subjects affected / exposed	0 / 36 (0.00%)	0 / 34 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Pneumonia
Additional description: One treatment-emergent death occurred during treatment with Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) and is not related.
subjects affected / exposed	4 / 36 (11.11%)	2 / 34 (5.88%)	3 / 78 (3.85%)
occurrences causally related to treatment / all	1 / 4	0 / 3	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Bronchitis
subjects affected / exposed	0 / 36 (0.00%)	0 / 34 (0.00%)	2 / 78 (2.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	1 / 36 (2.78%)	1 / 34 (2.94%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 36 (0.00%)	2 / 34 (5.88%)	2 / 78 (2.56%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sinusitis
subjects affected / exposed	0 / 36 (0.00%)	0 / 34 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	0 / 36 (0.00%)	1 / 34 (2.94%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Localised infection
subjects affected / exposed	0 / 36 (0.00%)	0 / 34 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	0 / 36 (0.00%)	0 / 34 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 36 (0.00%)	0 / 34 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 36 (0.00%)	0 / 34 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 36 (0.00%)	0 / 34 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pseudomembranous colitis
subjects affected / exposed	0 / 36 (0.00%)	1 / 34 (2.94%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Escherichia sepsis
subjects affected / exposed	1 / 36 (2.78%)	0 / 34 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 36 (0.00%)	0 / 34 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumocystis jirovecii pneumonia
subjects affected / exposed	0 / 36 (0.00%)	0 / 34 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pseudomonal sepsis
Additional description: One treatment-emergent death occurred during treatment with Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (RRMM) and is related.
subjects affected / exposed	0 / 36 (0.00%)	0 / 34 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1
Pneumonia respiratory syncytial viral
subjects affected / exposed	0 / 36 (0.00%)	0 / 34 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cystitis
subjects affected / exposed	0 / 36 (0.00%)	0 / 34 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	0 / 36 (0.00%)	1 / 34 (2.94%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Hypokalaemia
subjects affected / exposed	0 / 36 (0.00%)	0 / 34 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM)	Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM)	Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (RRMM)
Total subjects affected by non serious adverse events
subjects affected / exposed	34 / 36 (94.44%)	34 / 34 (100.00%)	69 / 78 (88.46%)
Vascular disorders
Hypertension
subjects affected / exposed	2 / 36 (5.56%)	7 / 34 (20.59%)	2 / 78 (2.56%)
occurrences all number	2	8	2
Hypotension
subjects affected / exposed	1 / 36 (2.78%)	2 / 34 (5.88%)	2 / 78 (2.56%)
occurrences all number	1	2	2
General disorders and administration site conditions
Fatigue
subjects affected / exposed	8 / 36 (22.22%)	7 / 34 (20.59%)	15 / 78 (19.23%)
occurrences all number	10	10	22
Oedema peripheral
subjects affected / exposed	8 / 36 (22.22%)	9 / 34 (26.47%)	5 / 78 (6.41%)
occurrences all number	9	11	12
Pyrexia
subjects affected / exposed	4 / 36 (11.11%)	6 / 34 (17.65%)	4 / 78 (5.13%)
occurrences all number	6	16	5
Influenza like illness
subjects affected / exposed	1 / 36 (2.78%)	1 / 34 (2.94%)	4 / 78 (5.13%)
occurrences all number	1	1	5
Non-cardiac chest pain
subjects affected / exposed	1 / 36 (2.78%)	1 / 34 (2.94%)	4 / 78 (5.13%)
occurrences all number	1	1	6
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	3 / 36 (8.33%)	4 / 34 (11.76%)	7 / 78 (8.97%)
occurrences all number	4	5	7
Dyspnoea
subjects affected / exposed	2 / 36 (5.56%)	0 / 34 (0.00%)	6 / 78 (7.69%)
occurrences all number	2	0	7
Psychiatric disorders
Insomnia
subjects affected / exposed	1 / 36 (2.78%)	3 / 34 (8.82%)	10 / 78 (12.82%)
occurrences all number	1	3	16
Anxiety
subjects affected / exposed	1 / 36 (2.78%)	2 / 34 (5.88%)	0 / 78 (0.00%)
occurrences all number	1	2	0
Confusional state
subjects affected / exposed	0 / 36 (0.00%)	2 / 34 (5.88%)	1 / 78 (1.28%)
occurrences all number	0	3	1
Investigations
Weight decreased
subjects affected / exposed	4 / 36 (11.11%)	3 / 34 (8.82%)	1 / 78 (1.28%)
occurrences all number	4	3	1
Blood creatinine increased
subjects affected / exposed	3 / 36 (8.33%)	2 / 34 (5.88%)	0 / 78 (0.00%)
occurrences all number	3	4	0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	1 / 36 (2.78%)	2 / 34 (5.88%)	2 / 78 (2.56%)
occurrences all number	1	2	2
Fall
subjects affected / exposed	1 / 36 (2.78%)	2 / 34 (5.88%)	1 / 78 (1.28%)
occurrences all number	1	2	1
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	1 / 36 (2.78%)	3 / 34 (8.82%)	1 / 78 (1.28%)
occurrences all number	1	5	1
Nervous system disorders
Peripheral sensory neuropathy
subjects affected / exposed	6 / 36 (16.67%)	10 / 34 (29.41%)	10 / 78 (12.82%)
occurrences all number	7	17	17
Dizziness
subjects affected / exposed	3 / 36 (8.33%)	2 / 34 (5.88%)	7 / 78 (8.97%)
occurrences all number	3	3	9
Hypoaesthesia
subjects affected / exposed	4 / 36 (11.11%)	3 / 34 (8.82%)	5 / 78 (6.41%)
occurrences all number	4	3	6
Headache
subjects affected / exposed	3 / 36 (8.33%)	3 / 34 (8.82%)	3 / 78 (3.85%)
occurrences all number	3	3	4
Neuropathy peripheral
subjects affected / exposed	4 / 36 (11.11%)	1 / 34 (2.94%)	3 / 78 (3.85%)
occurrences all number	6	1	3
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	11 / 36 (30.56%)	11 / 34 (32.35%)	19 / 78 (24.36%)
occurrences all number	16	19	32
Neutropenia
subjects affected / exposed	6 / 36 (16.67%)	16 / 34 (47.06%)	15 / 78 (19.23%)
occurrences all number	16	59	33
Thrombocytopenia
subjects affected / exposed	4 / 36 (11.11%)	4 / 34 (11.76%)	18 / 78 (23.08%)
occurrences all number	15	8	54
Leukopenia
subjects affected / exposed	1 / 36 (2.78%)	1 / 34 (2.94%)	4 / 78 (5.13%)
occurrences all number	1	1	6
Lymphopenia
subjects affected / exposed	0 / 36 (0.00%)	1 / 34 (2.94%)	4 / 78 (5.13%)
occurrences all number	0	1	6
Iron deficiency anaemia
subjects affected / exposed	2 / 36 (5.56%)	1 / 34 (2.94%)	1 / 78 (1.28%)
occurrences all number	2	1	1
Eye disorders
Cataract
subjects affected / exposed	0 / 36 (0.00%)	2 / 34 (5.88%)	5 / 78 (6.41%)
occurrences all number	0	2	9
Glaucoma
subjects affected / exposed	0 / 36 (0.00%)	2 / 34 (5.88%)	0 / 78 (0.00%)
occurrences all number	0	3	0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	11 / 36 (30.56%)	9 / 34 (26.47%)	26 / 78 (33.33%)
occurrences all number	13	14	50
Nausea
subjects affected / exposed	8 / 36 (22.22%)	10 / 34 (29.41%)	19 / 78 (24.36%)
occurrences all number	16	12	34
Vomiting
subjects affected / exposed	6 / 36 (16.67%)	9 / 34 (26.47%)	9 / 78 (11.54%)
occurrences all number	13	11	16
Constipation
subjects affected / exposed	8 / 36 (22.22%)	7 / 34 (20.59%)	8 / 78 (10.26%)
occurrences all number	11	8	11
Dyspepsia
subjects affected / exposed	1 / 36 (2.78%)	3 / 34 (8.82%)	6 / 78 (7.69%)
occurrences all number	1	3	9
Abdominal pain upper
subjects affected / exposed	2 / 36 (5.56%)	2 / 34 (5.88%)	4 / 78 (5.13%)
occurrences all number	3	2	7
Flatulence
subjects affected / exposed	0 / 36 (0.00%)	0 / 34 (0.00%)	4 / 78 (5.13%)
occurrences all number	0	0	5
Gastritis
subjects affected / exposed	2 / 36 (5.56%)	1 / 34 (2.94%)	1 / 78 (1.28%)
occurrences all number	2	1	1
Skin and subcutaneous tissue disorders
Rash erythematous
subjects affected / exposed	2 / 36 (5.56%)	2 / 34 (5.88%)	3 / 78 (3.85%)
occurrences all number	3	2	5
Rash maculo-papular
subjects affected / exposed	4 / 36 (11.11%)	0 / 34 (0.00%)	3 / 78 (3.85%)
occurrences all number	6	0	4
Pruritus
subjects affected / exposed	2 / 36 (5.56%)	1 / 34 (2.94%)	3 / 78 (3.85%)
occurrences all number	2	1	5
Rash macular
subjects affected / exposed	1 / 36 (2.78%)	2 / 34 (5.88%)	3 / 78 (3.85%)
occurrences all number	1	2	6
Alopecia
subjects affected / exposed	1 / 36 (2.78%)	3 / 34 (8.82%)	1 / 78 (1.28%)
occurrences all number	1	3	1
Erythema
subjects affected / exposed	2 / 36 (5.56%)	0 / 34 (0.00%)	1 / 78 (1.28%)
occurrences all number	4	0	1
Erythema multiforme
subjects affected / exposed	0 / 36 (0.00%)	2 / 34 (5.88%)	1 / 78 (1.28%)
occurrences all number	0	2	1
Rash pruritic
subjects affected / exposed	2 / 36 (5.56%)	0 / 34 (0.00%)	0 / 78 (0.00%)
occurrences all number	3	0	0
Renal and urinary disorders
Chronic kidney disease
subjects affected / exposed	1 / 36 (2.78%)	3 / 34 (8.82%)	3 / 78 (3.85%)
occurrences all number	2	7	4
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	4 / 36 (11.11%)	6 / 34 (17.65%)	6 / 78 (7.69%)
occurrences all number	7	9	9
Back pain
subjects affected / exposed	3 / 36 (8.33%)	5 / 34 (14.71%)	7 / 78 (8.97%)
occurrences all number	3	6	7
Musculoskeletal pain
subjects affected / exposed	5 / 36 (13.89%)	4 / 34 (11.76%)	2 / 78 (2.56%)
occurrences all number	6	6	2
Bone pain
subjects affected / exposed	4 / 36 (11.11%)	0 / 34 (0.00%)	6 / 78 (7.69%)
occurrences all number	4	0	6
Musculoskeletal chest pain
subjects affected / exposed	0 / 36 (0.00%)	1 / 34 (2.94%)	4 / 78 (5.13%)
occurrences all number	0	1	5
Pain in extremity
subjects affected / exposed	0 / 36 (0.00%)	1 / 34 (2.94%)	4 / 78 (5.13%)
occurrences all number	0	1	4
Osteoarthritis
subjects affected / exposed	2 / 36 (5.56%)	1 / 34 (2.94%)	0 / 78 (0.00%)
occurrences all number	2	1	0
Groin pain
subjects affected / exposed	2 / 36 (5.56%)	0 / 34 (0.00%)	0 / 78 (0.00%)
occurrences all number	2	0	0
Infections and infestations
Upper respiratory tract infection
subjects affected / exposed	9 / 36 (25.00%)	3 / 34 (8.82%)	21 / 78 (26.92%)
occurrences all number	10	3	42
Bronchitis
subjects affected / exposed	5 / 36 (13.89%)	4 / 34 (11.76%)	12 / 78 (15.38%)
occurrences all number	8	4	18
Nasopharyngitis
subjects affected / exposed	5 / 36 (13.89%)	4 / 34 (11.76%)	6 / 78 (7.69%)
occurrences all number	12	8	8
Respiratory tract infection
subjects affected / exposed	3 / 36 (8.33%)	4 / 34 (11.76%)	8 / 78 (10.26%)
occurrences all number	3	8	15
Herpes zoster
subjects affected / exposed	6 / 36 (16.67%)	3 / 34 (8.82%)	5 / 78 (6.41%)
occurrences all number	6	3	6
Influenza
subjects affected / exposed	3 / 36 (8.33%)	0 / 34 (0.00%)	6 / 78 (7.69%)
occurrences all number	3	0	6
Conjunctivitis
subjects affected / exposed	2 / 36 (5.56%)	1 / 34 (2.94%)	5 / 78 (6.41%)
occurrences all number	2	1	5
Urinary tract infection
subjects affected / exposed	2 / 36 (5.56%)	3 / 34 (8.82%)	3 / 78 (3.85%)
occurrences all number	2	3	3
Lower respiratory tract infection
subjects affected / exposed	1 / 36 (2.78%)	0 / 34 (0.00%)	5 / 78 (6.41%)
occurrences all number	1	0	7
Pharyngitis
subjects affected / exposed	2 / 36 (5.56%)	1 / 34 (2.94%)	3 / 78 (3.85%)
occurrences all number	2	1	5
Pneumonia
subjects affected / exposed	1 / 36 (2.78%)	1 / 34 (2.94%)	4 / 78 (5.13%)
occurrences all number	1	1	4
Oral herpes
subjects affected / exposed	2 / 36 (5.56%)	0 / 34 (0.00%)	3 / 78 (3.85%)
occurrences all number	2	0	4
Cellulitis
subjects affected / exposed	2 / 36 (5.56%)	0 / 34 (0.00%)	1 / 78 (1.28%)
occurrences all number	2	0	1
Gastroenteritis
subjects affected / exposed	0 / 36 (0.00%)	2 / 34 (5.88%)	1 / 78 (1.28%)
occurrences all number	0	2	1
Viral upper respiratory tract infection
subjects affected / exposed	0 / 36 (0.00%)	2 / 34 (5.88%)	0 / 78 (0.00%)
occurrences all number	0	2	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 36 (0.00%)	4 / 34 (11.76%)	2 / 78 (2.56%)
occurrences all number	0	4	2
Hypokalaemia
subjects affected / exposed	0 / 36 (0.00%)	3 / 34 (8.82%)	3 / 78 (3.85%)
occurrences all number	0	3	3
Hypocalcaemia
subjects affected / exposed	0 / 36 (0.00%)	1 / 34 (2.94%)	4 / 78 (5.13%)
occurrences all number	0	1	9
Diabetes mellitus
subjects affected / exposed	2 / 36 (5.56%)	1 / 34 (2.94%)	1 / 78 (1.28%)
occurrences all number	2	1	1

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

06 May 2014

Amendment 1: The protocol was amended to allow the enrollment of patients with relapsed and/or refractory multiple myeloma (RRMM) into the study. The evaluation of oral ixazomib when added to a regimen of cyclophosphamide and low-dose dexamethasone (Cd) in this patient population. Study objectives and endpoints were added, and study procedures described for this patient population. The amendment also contained minor. Updates in study procedures to improve protocol clarity and compliance and align the study conduct with the sponsor’s current guidelines and practices.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Clinical Trial Results: An Open-Label, Phase 2 Study to Evaluate the Oral Combination of MLN9708 With Cyclophosphamide and Dexamethasone In Patients With Newly Diagnosed or Relapsed and/or Refractory Multiple Myeloma Requiring Systemic Treatment

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Combined Response Rate during the Induction Phase in Newly Diagnosed Multiple Myeloma (NDMM) Participants

Primary: Combined Response Rate during the Induction Phase in Newly Diagnosed Multiple Myeloma (NDMM) Participants

Primary: Overall Response Rate (ORR) in Relapsed and/or Refractory Multiple Myeloma (RRMM) Participants

Primary: Overall Response Rate (ORR) in Relapsed and/or Refractory Multiple Myeloma (RRMM) Participants

Secondary: Number of Participants with Adverse Events (AEs), Grade 3 or Higher AEs, AEs Resulting in Treatment Discontinuation, AEs Resulting in Dose Reduction and Serious Adverse Events (SAEs) in NDMM Participants

Secondary: Number of Participants with Adverse Events (AEs), Grade 3 or Higher AEs, AEs Resulting in Treatment Discontinuation, AEs Resulting in Dose Reduction and Serious Adverse Events (SAEs) in NDMM Participants

Secondary: Percentage of Participants with CR + VGPR + PR (ORR), CR, VGPR, PR and Stable Disease (SD), Progressive Disease (PD) during the Induction Phase

Secondary: Percentage of Participants with CR + VGPR + PR (ORR), CR, VGPR, PR and Stable Disease (SD), Progressive Disease (PD) during the Induction Phase

Secondary: Percentage of Participants with CR + VGPR + PR (ORR), CR + VGPR, CR, VGPR, PR, SD and PD Throughout the Entire Treatment Period in NDMM Participants

Secondary: Percentage of Participants with CR + VGPR + PR (ORR), CR + VGPR, CR, VGPR, PR, SD and PD Throughout the Entire Treatment Period in NDMM Participants

Secondary: Time to Response (TTR) in NDMM Participants during the Induction Phase

Secondary: Time to Response (TTR) in NDMM Participants during the Induction Phase

Secondary: Duration of Response (DOR) in NDMM Participants

Secondary: Duration of Response (DOR) in NDMM Participants

Secondary: Time to Progression (TTP) in NDMM Participants

Secondary: Time to Progression (TTP) in NDMM Participants

Secondary: Progression Free Survival (PFS) in NDMM Participants

Secondary: Progression Free Survival (PFS) in NDMM Participants

Secondary: Number of Participants with AEs, SAEs, AEs Resulting in Discontinuation and AEs Resulting in Dose Reduction in NDMM Participants Remaining on Treatment after 13 Cycles

Secondary: Number of Participants with AEs, SAEs, AEs Resulting in Discontinuation and AEs Resulting in Dose Reduction in NDMM Participants Remaining on Treatment after 13 Cycles

Secondary: Change from Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) during the Induction Phase in NDMM Participants

Secondary: Change from Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) during the Induction Phase in NDMM Participants

Secondary: Percentage of Participants with CR + VGR + PR (ORR), CR, VGPR, and PR in NDMM Participants Remaining on Treatment after 13 Cycles

Secondary: Percentage of Participants with CR + VGR + PR (ORR), CR, VGPR, and PR in NDMM Participants Remaining on Treatment after 13 Cycles

Secondary: Cmax: Maximum Observed Plasma Concentration for Ixazomib in NDMM Participants

Secondary: Cmax: Maximum Observed Plasma Concentration for Ixazomib in NDMM Participants

Secondary: Tmax: Time to First Occurrence of Cmax for Ixazomib in NDMM Participants

Secondary: Tmax: Time to First Occurrence of Cmax for Ixazomib in NDMM Participants

Secondary: AUCtau: Area Under the Concentration-time Curve during a Dosing Interval for Ixazomib in NDMM Participants

Secondary: AUCtau: Area Under the Concentration-time Curve during a Dosing Interval for Ixazomib in NDMM Participants

Secondary: Number of Participants with AEs, Grade 3 or Higher AEs, AEs Resulting in Treatment Discontinuation, AEs Resulting in Dose Reduction, SAEs in RRMM Participants

Secondary: Number of Participants with AEs, Grade 3 or Higher AEs, AEs Resulting in Treatment Discontinuation, AEs Resulting in Dose Reduction, SAEs in RRMM Participants

Secondary: Cmax: Maximum Observed Plasma Concentration for Ixazomib in RRMM Participants

Secondary: Cmax: Maximum Observed Plasma Concentration for Ixazomib in RRMM Participants

Secondary: Tmax: Time to First Occurrence of Cmax for Ixazomib in RRMM Participants

Secondary: Tmax: Time to First Occurrence of Cmax for Ixazomib in RRMM Participants

Secondary: AUCtau: Area Under the Concentration-time Curve during a Dosing Interval for Ixazomib in RRMM Participants

Secondary: AUCtau: Area Under the Concentration-time Curve during a Dosing Interval for Ixazomib in RRMM Participants

Secondary: Percentage of Participants with (CR + VGPR), CR, VGPR, PR, SD and PD in RRMM Participants

Secondary: Percentage of Participants with (CR + VGPR), CR, VGPR, PR, SD and PD in RRMM Participants

Secondary: Time to Response (TTR) in RRMM Participants

Secondary: Time to Response (TTR) in RRMM Participants

Secondary: Duration of Response (DOR) in RRMM Participants

Secondary: Duration of Response (DOR) in RRMM Participants

Secondary: Time to Progression (TTP) in RRMM Participants

Secondary: Time to Progression (TTP) in RRMM Participants

Secondary: Progression Free Survival (PFS) in RRMM Participants

Secondary: Progression Free Survival (PFS) in RRMM Participants

Secondary: Change from Baseline in EORTC Quality of Life Questionnaire (QLQ-C30) in RRMM Participants

Secondary: Change from Baseline in EORTC Quality of Life Questionnaire (QLQ-C30) in RRMM Participants

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
An Open-Label, Phase 2 Study to Evaluate the Oral Combination of MLN9708 With Cyclophosphamide and Dexamethasone In Patients With Newly Diagnosed or Relapsed and/or Refractory Multiple Myeloma Requiring Systemic Treatment