Study of Oral Ixazomib in Adult Participants With Relapse... | NCT01318902

ID	Type	Description	Link
2010-022497-13	EudraCT Number
U1111-1168-1192	Registry Identifier	WHO (UTN )

Label	Type	Description	Intervention Names
Dose Escalation Cohort: Ixazomib 4.0 mg	Experimental	Ixazomib 4.0 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone 40 mg, tablet, orally was added once on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. If there was no hematologic response the participant was discontinued. Participants with hematologic response continued treatment up to maximum 12 cycles.	Drug: Ixazomib Drug: Dexamethasone
Dose Escalation Cohort: Ixazomib 5.5 mg	Experimental	Ixazomib 5.5 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone 40 mg, tablet, orally was added once on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. If there was no hematologic response the participant was discontinued. Participants with hematologic response continued treatment up to maximum 12 cycles.	Drug: Ixazomib Drug: Dexamethasone
Dose Expansion Cohort: Ixazomib 4.0 mg (PI Naive)	Experimental	Ixazomib 4.0 mg, capsule, orally, on Days 1, 8 and 15 during a 28-day treatment cycle until progressive disease (PD) or unacceptable toxicity, for participants with relapsed or refractory amyloidosis and who were not treated with any other proteasome inhibitor (PI). Duration of treatment was up to 12 months unless the investigator and sponsor determined the participant would benefit from therapy beyond 12 months.	Drug: Ixazomib
Dose Expansion Cohort: Ixazomib 4.0 mg (PI Exposed)

Name	Type	Description	Arm Group Labels	Other Names
Ixazomib	Drug	Ixazomib capsules.	Dose Escalation Cohort: Ixazomib 4.0 mg Dose Escalation Cohort: Ixazomib 5.5 mg Dose Expansion Cohort: Ixazomib 4.0 mg (PI Exposed)

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Number of Participants With at Least One Treatment Emergent Adverse Event (TEAE) and Serious Adverse Event (SAE)	An AE is any untoward medical occurrence in a participant administered a medicinal investigational drug. The untoward medical occurrence does not necessarily have to have a causal relationship with treatment. An SAE is any untoward medical occurrence that results in death; is life-threatening; requires inpatient hospitalization or prolongation of present hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect or is a medically important event that may not be immediately life-threatening or result in death or hospitalization, but may jeopardize the participant or may require intervention to prevent one of other outcomes listed in definition above, or involves suspected transmission via a medicinal product of an infectious agent. A TEAE is defined as an AE that occurs after administration of first dose of study drug and through 30 days after last dose of study drug or until start of subsequent antineoplastic therapy.	From the first dose of study drug plus 30 days after last dose of study drug or until the initiation of subsequent antineoplastic therapy (Up to approximately 13 months)
Number of Participants With Clinically Significant Abnormal Laboratory Values Reported as TEAE	The number of participants with any clinically significant abnormal standard safety laboratory values collected throughout the study reported as TEAEs. Parameters assessed were hematology, serum chemistry and urinalysis. Abnormal laboratory values were assessed as an AE if that value leads to discontinuation or delay in treatment, dose modification, therapeutic intervention, or is considered by the investigator to be a clinically significant change from baseline.	From the first dose of study drug plus 30 days after last dose of study drug or until the initiation of subsequent antineoplastic therapy (Up to approximately 13 months)
Number of Participants With Peripheral Neuropathy Reported as a TEAE	Neurotoxicity was assessed as the number of participants with the TEAE of peripheral neuropathy.	From the first dose of study drug plus 30 days after last dose of study drug or until the initiation of subsequent antineoplastic therapy (Up to approximately 13 months)

Secondary Outcomes

Measure	Description	Time Frame
Cmax: Maximum Observed Plasma Concentration for Ixazomib		Cycle 1: Day 1 (MTD cohort participants only, 4.0 mg) and Day 15 (all participants enrolled in the study): predose (within 1 hour (hr) before dosing), and postdose at multiple timepoints up to 168 hr
Tmax: Time of First Occurrence of Cmax for Ixazomib

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Male or female participants 18 years or older
Biopsy-proven systemic relapsed or refractory light-chain (AL) amyloidosis, which after at least 1 prior therapy, in the investigator's opinion, requires further treatment
If received stem cell transplant, must be at least 3 months posttransplantation and recovered from side effects
Must have measurable disease defined as serum differential free light chain concentration ≥ 40 mg/L
Must have objective measurable organ (heart or kidney) amyloid involvement
Must have cardiac biomarker risk stage I or II disease
Must have adequate hematologic, hepatic, and renal function
Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
Female participants who are postmenopausal, surgically sterile, or agree to practice 2 effective methods of contraception or agree to abstain from heterosexual intercourse
Male participants who agree to practice effective barrier contraception or agree to abstain from heterosexual intercourse
Voluntary written consent

Exclusion Criteria

Peripheral neuropathy that is greater or equal to Grade 2
Cardiac status as described in protocol
Severe diarrhea (≥ Grade 3) not controllable with medication or requires administration of total parenteral nutrition
Known gastrointestinal condition or procedure that could interfere with swallowing or the oral absorption of tolerance of MLN9708
Uncontrolled infection requiring systematic antibiotics
Known human immunodeficiency virus (HIV) positive, hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection
Presence of other active malignancy with the exception of nonmelanoma skin cancer, cervical cancer, treated early-stage prostate cancer provided that prostate-specific antigen is within normal limit, or any completely resected carcinoma in situ
Female participants who are lactating or pregnant
Major surgery within 14 days before the first dose of study drug
Serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to the protocol

Name	Affiliation	Role
Medical Monitor	Millennium Pharmaceuticals, Inc.	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Tufts Medical Center		Boston	Massachusetts	02111	United States
Boston Medical Center

PubMed Identifier	Type	Citation
	Result	Sanchorawala V, Comenzo R, Zonder J, Kukreti V, Cohen A, Dispenzieri A, et al. MLN9708, an investigational oral proteasome inhibitor (PI), in relapsed or refractory lightchain (AL) amyloidosis. Clinical Lymphoma Myeloma and Leukemia 2013;13(suppl 1):S153-4; abstr P-229.
	Result	Sanchorawala V, Zonder J, Comenzo R, Schönland S, Dispenzieri A, Berg D, et al. Poster Presentation: Phase 1 study of MLN9708, a novel, investigational oral proteasome inhibitor, in patients with relapsed or refractory light-chain amyloidosis. XIII International Symposium on Amyloidosis, Groningen, The Netherlands 2012.
	Result	Merlini G, Sanchorawala V, Zonder J, Kukreti V, Schonland S, Jaccard A, et al. MLN9708, a novel, investigational oral proteasome inhibitor, in patients with relapsed or refractory light-chain amyloidosis (AL): results of a phase 1 study. In: 54th ASH Annual Meeting and Exposition; 2012 8-11 December; Atlanta, GA; p. abstr 731.
28550039

ID	Title	Description
FG000	Dose Escalation Cohort: Ixazomib 4.0 mg	Ixazomib 4.0 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone 40 mg, tablet, orally was added once on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. If there was no hematologic response the participant was discontinued. Participants with hematologic response continued treatment up to maximum 12 cycles.

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
SAP	No	Yes	No	Statistical Analysis Plan	Nov 6, 2012	Nov 13, 2019

Arm/Group Information

ID	Title	Description
BG000	Dose Escalation Cohort: Ixazomib 4.0 mg	Ixazomib 4.0 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone 40 mg, tablet, orally was added once on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. If there was no hematologic response the participant was discontinued. Participants with hematologic response continued treatment up to maximum 12 cycles.
BG001	Dose Escalation Cohort: Ixazomib 5.5 mg	Ixazomib 5.5 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone 40 mg, tablet, orally was added once on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. If there was no hematologic response the participant was discontinued. Participants with hematologic response continued treatment up to maximum 12 cycles.
BG002	Dose Expansion Cohort: Ixazomib 4.0 mg (PI Naive)	Ixazomib 4.0 mg, capsule, orally, on Days 1, 8 and 15 during a 28-day treatment cycle until progressive disease (PD) or unacceptable toxicity, for participants with relapsed or refractory amyloidosis and who were not treated with any other proteasome inhibitor (PI). Duration of treatment was up to 12 months unless the investigator and sponsor determined the participant would benefit from therapy beyond 12 months.
BG003	Dose Expansion Cohort: Ixazomib 4.0 mg (PI Exposed)	Ixazomib 4.0 mg, capsule, orally, on Days 1, 8 and 15 during a 28-day treatment cycle until PD or unacceptable toxicity, for participants with relapsed or refractory amyloidosis and who were previously treated with any other PI. Duration of treatment was up to 12 months unless the investigator and sponsor determined the participant would benefit from therapy beyond 12 months.
BG004	Total	Total of all reporting groups

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Number of Participants With at Least One Treatment Emergent Adverse Event (TEAE) and Serious Adverse Event (SAE)

An AE is any untoward medical occurrence in a participant administered a medicinal investigational drug. The untoward medical occurrence does not necessarily have to have a causal relationship with treatment. An SAE is any untoward medical occurrence that results in death; is life-threatening; requires inpatient hospitalization or prolongation of present hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect or is a medically important event that may not be immediately life-threatening or result in death or hospitalization, but may jeopardize the participant or may require intervention to prevent one of other outcomes listed in definition above, or involves suspected transmission via a medicinal product of an infectious agent. A TEAE is defined as an AE that occurs after administration of first dose of study drug and through 30 days after last dose of study drug or until start of subsequent antineoplastic therapy.

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

Posted

Count of Participants

Participants

From the first dose of study drug plus 30 days after last dose of study drug or until the initiation of subsequent antineoplastic therapy (Up to approximately 13 months)

ID	Title	Description
OG000	Dose Escalation Cohort: Ixazomib 4.0 mg	Ixazomib 4.0 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone 40 mg, tablet, orally was added once on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. If there was no hematologic response the participant was discontinued. Participants with hematologic response continued treatment up to maximum 12 cycles.
OG001	Dose Escalation Cohort: Ixazomib 5.5 mg	Ixazomib 5.5 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone 40 mg, tablet, orally was added once on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. If there was no hematologic response the participant was discontinued. Participants with hematologic response continued treatment up to maximum 12 cycles.
OG002	Dose Expansion Cohort: Ixazomib 4.0 mg (PI Naive)	Ixazomib 4.0 mg, capsule, orally, on Days 1, 8 and 15 during a 28-day treatment cycle until progressive disease (PD) or unacceptable toxicity, for participants with relapsed or refractory amyloidosis and who were not treated with any other proteasome inhibitor (PI). Duration of treatment was up to 12 months unless the investigator and sponsor determined the participant would benefit from therapy beyond 12 months.
OG003	Dose Expansion Cohort: Ixazomib 4.0 mg (PI Exposed)	Ixazomib 4.0 mg, capsule, orally, on Days 1, 8 and 15 during a 28-day treatment cycle until PD or unacceptable toxicity, for participants with relapsed or refractory amyloidosis and who were previously treated with any other PI. Duration of treatment was up to 12 months unless the investigator and sponsor determined the participant would benefit from therapy beyond 12 months.

Units	Counts
Participants	OG0006 OG0015 OG0025 OG003

Title

Denominators

Categories

TEAE

Title	Measurements
	OG0006 OG0015 OG0025 OG003

Primary

Number of Participants With Clinically Significant Abnormal Laboratory Values Reported as TEAE

The number of participants with any clinically significant abnormal standard safety laboratory values collected throughout the study reported as TEAEs. Parameters assessed were hematology, serum chemistry and urinalysis. Abnormal laboratory values were assessed as an AE if that value leads to discontinuation or delay in treatment, dose modification, therapeutic intervention, or is considered by the investigator to be a clinically significant change from baseline.

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

Posted

Count of Participants

Participants

From the first dose of study drug plus 30 days after last dose of study drug or until the initiation of subsequent antineoplastic therapy (Up to approximately 13 months)

ID	Title	Description
OG000	Dose Escalation Cohort: Ixazomib 4.0 mg	Ixazomib 4.0 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone 40 mg, tablet, orally was added once on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. If there was no hematologic response the participant was discontinued. Participants with hematologic response continued treatment up to maximum 12 cycles.
OG001	Dose Escalation Cohort: Ixazomib 5.5 mg	Ixazomib 5.5 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone 40 mg, tablet, orally was added once on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. If there was no hematologic response the participant was discontinued. Participants with hematologic response continued treatment up to maximum 12 cycles.

Primary

Number of Participants With Peripheral Neuropathy Reported as a TEAE

Neurotoxicity was assessed as the number of participants with the TEAE of peripheral neuropathy.

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

Posted

Count of Participants

Participants

From the first dose of study drug plus 30 days after last dose of study drug or until the initiation of subsequent antineoplastic therapy (Up to approximately 13 months)

ID	Title	Description
OG000	Dose Escalation Cohort: Ixazomib 4.0 mg	Ixazomib 4.0 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone 40 mg, tablet, orally was added once on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. If there was no hematologic response the participant was discontinued. Participants with hematologic response continued treatment up to maximum 12 cycles.
OG001	Dose Escalation Cohort: Ixazomib 5.5 mg	Ixazomib 5.5 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone 40 mg, tablet, orally was added once on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. If there was no hematologic response the participant was discontinued. Participants with hematologic response continued treatment up to maximum 12 cycles.

Primary

Maximum Tolerated Dose (MTD) of Ixazomib

MTD was highest dose of Ixazomib, at which <=1 of 6 participants experienced dose-limiting toxicity (DLT). DLT was defined using National Cancer Institute Common Terminology Criteria for Adverse Events, v 4.03 as: Grade 4 neutropenia (absolute neutrophil count <500 cells/mm^3) for >7 days;Grade 3 neutropenia with fever or infection;Grade 4 thrombocytopenia (platelets < 25,000/mm^3) for >7 days;Grade 3 thrombocytopenia with clinically significant bleeding;platelet count <10,000/mm^3;Grade 2 peripheral neuropathy with pain or >=Grade 3 peripheral neuropathy; >=Grade 3 nausea/emesis, diarrhea controlled by supportive therapy;Grade 3 QTc prolongation (QTc >500 msec);any >=Grade 3 nonhematologic toxicity except Grade 3 arthralgia/myalgia;or <1 week Grade 3 fatigue;delay in initiation of the subsequent therapy cycle by >2 weeks;other >=Grade 2 study drug-related nonhematologic toxicities requiring therapy discontinuation, considered possibly related to therapy as assessed by Investigator.

DLT-evaluable population included all participants who received all Cycle 1 doses of ixazomib or experienced a DLT in Cycle 1.

Posted

Number

Cycle 1 (28 days)

ID	Title	Description
OG000	Dose Escalation Cohort: Ixazomib 4.0 mg	Ixazomib 4.0 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone 40 mg, tablet, orally was added once on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. If there was no hematologic response the participant was discontinued. Participants with hematologic response continued treatment up to maximum 12 cycles.

Primary

Recommended Phase 2 Dose (RP2D) of Ixazomib

The RP2D is the maximum tolerated dose (MTD) or less. The MTD is defined as the dose range at which ≤ 1 of 6 evaluable participants experience dose limiting toxicities (DLT) within the first 28 days of treatment (end of Cycle 1). The RP2D of Ixazomib was determined in dose escalation group on the basis of the totality of safety, tolerability, pharmacokinetics (PK) and pharmacodynamic (PD) data observed in Cycle 1.

DLT-evaluable population included all participants who received all Cycle 1 doses of ixazomib or experienced a DLT in Cycle 1.

Posted

Number

Cycle 1 (28 days)

ID	Title	Description
OG000	Dose Escalation Cohort: Ixazomib 4.0 mg	Ixazomib 4.0 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone 40 mg, tablet, orally was added once on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. If there was no hematologic response the participant was discontinued. Participants with hematologic response continued treatment up to maximum 12 cycles.
OG001	Dose Escalation Cohort: Ixazomib 5.5 mg	Ixazomib 5.5 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone 40 mg, tablet, orally was added once on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. If there was no hematologic response the participant was discontinued. Participants with hematologic response continued treatment up to maximum 12 cycles.

Secondary

Cmax: Maximum Observed Plasma Concentration for Ixazomib

Pharmacokinetic (PK) analysis population included all participants who received at least 1 dose of ixazomib and had sufficient ixazomib concentration-time data and dosing data to permit calculation of ixazomib plasma PK parameters. Number analyzed is the number of participants with evaluable data at the given time-point.

Posted

Mean

Full Range

ng/mL

Cycle 1: Day 1 (MTD cohort participants only, 4.0 mg) and Day 15 (all participants enrolled in the study): predose (within 1 hour (hr) before dosing), and postdose at multiple timepoints up to 168 hr

ID	Title	Description
OG000	Ixazomib 4.0 mg	Ixazomib 4.0 mg, capsule, orally, once weekly on Days 1 and 15 during each 28-day treatment cycle for all the participants from dose escalation and expansion cohorts were evaluated in this arm group. Duration of treatment was up to 12 months unless the investigator and sponsor determined the participant would benefit from therapy beyond 12 months.
OG001	Ixazomib 5.5 mg	Ixazomib 5.5 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone was added on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. The maximum duration of treatment was up to 12 cycles.

Secondary

Tmax: Time of First Occurrence of Cmax for Ixazomib

PK analysis population included all participants who received at least 1 dose of ixazomib and had sufficient ixazomib concentration-time data and dosing data to permit calculation of ixazomib plasma PK parameters. Number analyzed is the number of participants with evaluable data at the given time-point.

Posted

Median

Full Range

hours

Cycle 1: Day 1 (MTD cohort participants only, 4.0 mg) and Day 15 (all participants enrolled in the study): predose (within 1 hour (hr) before dosing), and postdose at multiple timepoints up to 168 hr

ID	Title	Description
OG000	Ixazomib 4.0 mg	Ixazomib 4.0 mg, capsule, orally, once weekly on Days 1 and 15 during each 28-day treatment cycle for all the participants from dose escalation and expansion cohorts were evaluated in this arm group. Duration of treatment was up to 12 months unless the investigator and sponsor determined the participant would benefit from therapy beyond 12 months.
OG001	Ixazomib 5.5 mg	Ixazomib 5.5 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone was added on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. The maximum duration of treatment was up to 12 cycles.

Secondary

Ctrough: Plasma Concentration Immediately Prior to Dosing for Ixazomib

Posted

Mean

Full Range

ng/mL

Cycle 1: Day 1 (MTD cohort participants only, 4.0 mg) and Day 15 (all participants enrolled in the study): predose (within 1 hour (hr) before dosing), and postdose at multiple timepoints up to 168 hr

ID	Title	Description
OG000	Ixazomib 4.0 mg	Ixazomib 4.0 mg, capsule, orally, once weekly on Days 1 and 15 during each 28-day treatment cycle for all the participants from dose escalation and expansion cohorts were evaluated in this arm group. Duration of treatment was up to 12 months unless the investigator and sponsor determined the participant would benefit from therapy beyond 12 months.
OG001	Ixazomib 5.5 mg	Ixazomib 5.5 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone was added on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. The maximum duration of treatment was up to 12 cycles.

Secondary

AUC0-168: Area Under the Plasma Concentration-time Curve From Time 0 to 168 Hours Post-dose for Ixazomib

Posted

Mean

Full Range

hr*ng/mL

Cycle 1: Day 1 (MTD cohort participants only, 4.0 mg) and Day 15 (all participants enrolled in the study): predose (within 1 hour (hr) before dosing), and postdose at multiple timepoints up to 168 hr

ID	Title	Description
OG000	Ixazomib 4.0 mg	Ixazomib 4.0 mg, capsule, orally, once weekly on Days 1 and 15 during each 28-day treatment cycle for all the participants from dose escalation and expansion cohorts were evaluated in this arm group. Duration of treatment was up to 12 months unless the investigator and sponsor determined the participant would benefit from therapy beyond 12 months.
OG001	Ixazomib 5.5 mg	Ixazomib 5.5 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone was added on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. The maximum duration of treatment was up to 12 cycles.

Secondary

Emax: Maximum Observed Percent Inhibition of Whole Blood 20S Proteasome

Pharmacodynamic (PD) analysis population: all participants who received at least 1 dose of ixazomib and had whole blood 20S proteasome inhibition-time data and dosing data to permit calculation of PD parameters. Data was only collected for ixazomib 4.0 mg arm group. Number analyzed is number of participants with evaluable data at given time-point.

Posted

Mean

Standard Deviation

percentage of inhibition

Cycle 1: Day 1 (MTD cohort participants only, 4.0 mg) and Day 15 (all participants enrolled in the study): predose (within 1 hour (hr) before dosing), and postdose at multiple timepoints up to 168 hr

ID	Title	Description
OG000	Ixazomib 4.0 mg	Ixazomib 4.0 mg, capsule, orally, once weekly on Days 1 and 15 during each 28-day treatment cycle for all the participants from dose escalation and expansion cohorts were evaluated in this arm group. Duration of treatment was up to 12 months unless the investigator and sponsor determined the participant would benefit from therapy beyond 12 months.

Units	Counts
Participants	OG000

Secondary

TEmax: Time to Maximum Observed Effect (Emax) of Whole Blood 20S Proteasome Inhibition for Ixazomib

PD analysis population: all participants who received at least 1 dose of ixazomib and had whole blood 20S proteasome inhibition-time data and dosing data to permit calculation of PD parameters. Data was only collected for ixazomib 4.0 mg arm group. Number analyzed is number of participants with evaluable data at given time-point.

Posted

Median

Full Range

hours

Cycle 1: Day 1 (MTD cohort participants only, 4.0 mg) and Day 15 (all participants enrolled in the study): predose (within 1 hour (hr) before dosing), and postdose at multiple timepoints up to 168 hr

ID	Title	Description
OG000	Ixazomib 4.0 mg	Ixazomib 4.0 mg, capsule, orally, once weekly on Days 1 and 15 during each 28-day treatment cycle for all the participants from dose escalation and expansion cohorts were evaluated in this arm group. Duration of treatment was up to 12 months unless the investigator and sponsor determined the participant would benefit from therapy beyond 12 months.

Units	Counts
Participants	OG000

Secondary

AUE0-168: Area Under Effect Curve of Whole Blood 20S Proteasome Inhibition From Zero to Concentration at 168 Hours for Ixazomib

Posted

Mean

Standard Deviation

hr*percentage of inhibition

Cycle 1: Day 1 (MTD cohort participants only, 4.0 mg) and Day 15 (all participants enrolled in the study): predose (within 1 hour (hr) before dosing), and postdose at multiple timepoints up to 168 hr

ID	Title	Description
OG000	Ixazomib 4.0 mg	Ixazomib 4.0 mg, capsule, orally, once weekly on Days 1 and 15 during each 28-day treatment cycle for all the participants from dose escalation and expansion cohorts were evaluated in this arm group. Duration of treatment was up to 12 months unless the investigator and sponsor determined the participant would benefit from therapy beyond 12 months.

Units	Counts
Participants	OG000

Secondary

Number of Participants With Best Organ Response to Treatment Based on Investigators Assessment

Organ response rate was estimated as the number of participants with documented organ response (ie. Heart or kidney ). Treatment response of amyloid-related organs were identified based on national cancer institute, common terminology criteria for adverse events (NCI CTCAE) Version 4.02 criteria.

Organ response-evaluable population included all participants who received at least 1 cycle of ixazomib, had amyloid involvement of at least kidney or heart at baseline, and had at least 1 postbaseline organ response assessment.

Posted

Count of Participants

Participants

At Cycles 3, 6, 9, and 12; every 6 months thereafter until disease progression or the initiation of subsequent antineoplastic therapy and at end of treatment (EOT) visit (Up to approximately 12 months)

ID	Title	Description
OG000	Dose Escalation Cohort: Ixazomib 4.0 mg	Ixazomib 4.0 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone 40 mg, tablet, orally was added once on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. If there was no hematologic response the participant was discontinued. Participants with hematologic response continued treatment up to maximum 12 cycles.
OG001	Dose Escalation Cohort: Ixazomib 5.5 mg	Ixazomib 5.5 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone 40 mg, tablet, orally was added once on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. If there was no hematologic response the participant was discontinued. Participants with hematologic response continued treatment up to maximum 12 cycles.

Secondary

Number of Participants With Best Hematologic Response to Treatment Based on Investigators Assessment

The overall hematologic response rate is defined as number of participants with complete response (CR) or partial response (PR) or very good partial response (VGPR) as assessed by the investigator. Response is determined according to standardized criteria using a central laboratory. CR=serum and urine negative for monoclonal protein by immunofixation; or free light chain ratio normal; < 5% plasma cells in bone marrow without clonal dominance. PR=reduction in dFLC > 50%. VGPR= dFLC < 40 mg/L.

Hematologic response-evaluable population included all participants who received at least 1 cycle of ixazomib, had measureable disease at baseline, and had at least 1 postbaseline hematologic response assessment.

Posted

Count of Participants

Participants

Day 22 to 28 in each cycle and end of treatment visit; then every 6 weeks thereafter until disease progression or initiation of subsequent antineoplastic therapy (Up to approximately 12 months)

ID	Title	Description
OG000	Dose Escalation Cohort: Ixazomib 4.0 mg	Ixazomib 4.0 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone 40 mg, tablet, orally was added once on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. If there was no hematologic response the participant was discontinued. Participants with hematologic response continued treatment up to maximum 12 cycles.
OG001

Secondary

Time to First Hematologic Response

Time to first hematologic response, measured as the time from the first dose of ixazomib to the date of first documentation of a hematologic response.

Hematologic response-evaluable population: all participants who received at least 1 cycle of ixazomib, had measureable disease at baseline, had >=1 postbaseline hematologic response. No participants had hematologic response for ixazomib 5.5 mg arm group thus were not analyzed. Data is reported for participants evaluable for this outcome measure.

Posted

Median

Full Range

months

From the date of the first dose of ixazomib to the date of first documentation of a hematologic response (Up to approximately 12 months)

ID	Title	Description
OG000	Dose Escalation Cohort: Ixazomib 4.0 mg	Ixazomib 4.0 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone 40 mg, tablet, orally was added once on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. If there was no hematologic response the participant was discontinued. Participants with hematologic response continued treatment up to maximum 12 cycles.
OG001	Dose Escalation Cohort: Ixazomib 5.5 mg	Ixazomib 5.5 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone 40 mg, tablet, orally was added once on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. If there was no hematologic response the participant was discontinued. Participants with hematologic response continued treatment up to maximum 12 cycles.

Secondary

Time to First Organ Response

Time to first organ response, measured as the time from the first dose of ixazomib to the date of first documentation of a organ response.

Organ Response-Evaluable population included participants who received at least 1 cycle of ixazomib, who had amyloid involvement of at least kidney or heart at baseline, and who had at least 1 postbaseline organ response assessment.

Posted

Median

Full Range

months

From the date of the first dose of ixazomib to the date of first documentation of a organ response (Up to approximately 12 months)

ID	Title	Description
OG000	Dose Escalation Cohort: Ixazomib 4.0 mg	Ixazomib 4.0 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone 40 mg, tablet, orally was added once on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. If there was no hematologic response the participant was discontinued. Participants with hematologic response continued treatment up to maximum 12 cycles.
OG001	Dose Escalation Cohort: Ixazomib 5.5 mg	Ixazomib 5.5 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone 40 mg, tablet, orally was added once on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. If there was no hematologic response the participant was discontinued. Participants with hematologic response continued treatment up to maximum 12 cycles.

Secondary

Duration of Hematologic Response

Duration of hematologic response, measured as the time from the date of first documentation of a hematologic response to the date of hematologic disease progression.

Posted

Median

Full Range

months

From the date of first documentation of a hematologic response to the date of hematologic disease progression (Up to approximately 12 months)

ID	Title	Description
OG000	Dose Escalation Cohort: Ixazomib 4.0 mg	Ixazomib 4.0 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone 40 mg, tablet, orally was added once on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. If there was no hematologic response the participant was discontinued. Participants with hematologic response continued treatment up to maximum 12 cycles.
OG001	Dose Escalation Cohort: Ixazomib 5.5 mg	Ixazomib 5.5 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone 40 mg, tablet, orally was added once on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. If there was no hematologic response the participant was discontinued. Participants with hematologic response continued treatment up to maximum 12 cycles.

Secondary

Duration of Organ Response

Duration of organ response, measured as the time from the date of first documentation of a organ response to the date of organ disease progression.

Posted

Median

Full Range

months

From the date of first documentation of a organ response to the date of organ disease progression (Up to approximately 12 months)

ID	Title	Description
OG000	Dose Escalation Cohort: Ixazomib 4.0 mg	Ixazomib 4.0 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone 40 mg, tablet, orally was added once on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. If there was no hematologic response the participant was discontinued. Participants with hematologic response continued treatment up to maximum 12 cycles.
OG001	Dose Escalation Cohort: Ixazomib 5.5 mg	Ixazomib 5.5 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone 40 mg, tablet, orally was added once on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. If there was no hematologic response the participant was discontinued. Participants with hematologic response continued treatment up to maximum 12 cycles.

Secondary

Time to Hematologic Disease Progression

Time to hematologic progression, measured as the time from the date of the first dose of ixazomib to the date of first documented hematologic disease progression.

Safety population included all participants who received at least 1 dose of ixazomib. Data is reported for participants evaluable for this outcome measure.

Posted

Median

Full Range

months

From the date of the first dose of ixazomib to the date of first documented hematologic disease progression (Up to approximately 12 months)

ID	Title	Description
OG000	Dose Escalation Cohort: Ixazomib 4.0 mg	Ixazomib 4.0 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone 40 mg, tablet, orally was added once on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. If there was no hematologic response the participant was discontinued. Participants with hematologic response continued treatment up to maximum 12 cycles.
OG001	Dose Escalation Cohort: Ixazomib 5.5 mg	Ixazomib 5.5 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone 40 mg, tablet, orally was added once on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. If there was no hematologic response the participant was discontinued. Participants with hematologic response continued treatment up to maximum 12 cycles.

Secondary

Time to Organ Disease Progression

Time to organ disease progression, measured as the time from the date of the first dose of ixazomib to the date of first documented organ disease progression.

Posted

Median

Full Range

months

From the date of the first dose of ixazomib to the date of first documented organ disease progression (Up to approximately 12 months)

ID	Title	Description
OG000	Dose Escalation Cohort: Ixazomib 4.0 mg	Ixazomib 4.0 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone 40 mg, tablet, orally was added once on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. If there was no hematologic response the participant was discontinued. Participants with hematologic response continued treatment up to maximum 12 cycles.
OG001	Dose Escalation Cohort: Ixazomib 5.5 mg	Ixazomib 5.5 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone 40 mg, tablet, orally was added once on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. If there was no hematologic response the participant was discontinued. Participants with hematologic response continued treatment up to maximum 12 cycles.

Secondary

Hematologic Disease Progression-Free Survival (PFS)

Hematologic disease PFS, measured as the time from the date of the first dose of ixazomib to the date of hematologic disease progression or death.

Safety population included all participants who received at least 1 dose of ixazomib. Data is reported for participants evaluable for this outcome measure.

Posted

Median

Full Range

months

From the date of the first dose of ixazomib to the date of hematologic disease progression or death (Up to approximately 12 months)

ID	Title	Description
OG000	Dose Escalation Cohort: Ixazomib 4.0 mg	Ixazomib 4.0 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone 40 mg, tablet, orally was added once on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. If there was no hematologic response the participant was discontinued. Participants with hematologic response continued treatment up to maximum 12 cycles.
OG001	Dose Escalation Cohort: Ixazomib 5.5 mg	Ixazomib 5.5 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone 40 mg, tablet, orally was added once on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. If there was no hematologic response the participant was discontinued. Participants with hematologic response continued treatment up to maximum 12 cycles.

Secondary

Organ Disease Progression-Free Survival (PFS)

Organ disease PFS, measured as the time from the date of the first dose of ixazomib to the date of organ disease progression or death.

Posted

Median

Full Range

months

From the date of the first dose of ixazomib to the date of organ disease progression or death (Up to approximately 12 months)

ID	Title	Description
OG000	Dose Escalation Cohort: Ixazomib 4.0 mg	Ixazomib 4.0 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone 40 mg, tablet, orally was added once on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. If there was no hematologic response the participant was discontinued. Participants with hematologic response continued treatment up to maximum 12 cycles.
OG001	Dose Escalation Cohort: Ixazomib 5.5 mg	Ixazomib 5.5 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone 40 mg, tablet, orally was added once on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. If there was no hematologic response the participant was discontinued. Participants with hematologic response continued treatment up to maximum 12 cycles.

Secondary

Percentage of Participants With One Year Hematologic Disease PFS

One-year survival, defined as the patient survival probability at 1 year after the date of first dose of ixazomib.

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

Posted

Number

percentage of participants

From the date of the first dose of ixazomib to the date of hematologic disease progression or death (Up to 1 year)

ID	Title	Description
OG000	Dose Escalation Cohort: Ixazomib 4.0 mg	Ixazomib 4.0 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone 40 mg, tablet, orally was added once on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. If there was no hematologic response the participant was discontinued. Participants with hematologic response continued treatment up to maximum 12 cycles.
OG001	Dose Escalation Cohort: Ixazomib 5.5 mg	Ixazomib 5.5 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone 40 mg, tablet, orally was added once on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. If there was no hematologic response the participant was discontinued. Participants with hematologic response continued treatment up to maximum 12 cycles.

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Dose Escalation Cohort: Ixazomib 4.0 mg	Ixazomib 4.0 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone 40 mg, tablet, orally was added once on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. If there was no hematologic response the participant was discontinued. Participants with hematologic response continued treatment up to maximum 12 cycles.	0	6	3	6	6	6
EG001	Dose Escalation Cohort: Ixazomib 5.5 mg	Ixazomib 5.5 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone 40 mg, tablet, orally was added once on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. If there was no hematologic response the participant was discontinued. Participants with hematologic response continued treatment up to maximum 12 cycles.	0	5	5	5	5	5
EG002	Dose Expansion Cohort: Ixazomib 4.0 mg (PI Naive)	Ixazomib 4.0 mg, capsule, orally, on Days 1, 8 and 15 during a 28-day treatment cycle until progressive disease (PD) or unacceptable toxicity, for participants with relapsed or refractory amyloidosis and who were not treated with any other proteasome inhibitor (PI). Duration of treatment was up to 12 months unless the investigator and sponsor determined the participant would benefit from therapy beyond 12 months.	1	5	5	5	5	5
EG003	Dose Expansion Cohort: Ixazomib 4.0 mg (PI Exposed)	Ixazomib 4.0 mg, capsule, orally, on Days 1, 8 and 15 during a 28-day treatment cycle until PD or unacceptable toxicity, for participants with relapsed or refractory amyloidosis and who were previously treated with any other PI. Duration of treatment was up to 12 months unless the investigator and sponsor determined the participant would benefit from therapy beyond 12 months.	0	11	5	11	10	11

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Atrial fibrillation	Cardiac disorders	MedDRA 21.0	Systematic Assessment		EG0000 affected6 at risk EG0012 affected5 at risk EG0020 affected5 at risk EG0030 affected11 at risk
Cardiac failure congestive	Cardiac disorders	MedDRA 21.0	Systematic Assessment	One treatment-emergent death occurred during treatment with Dose Expansion Cohort: Ixazomib 4 mg (PI Naive) and is not related.	EG0001 affected6 at risk EG0010 affected5 at risk EG0021 affected5 at risk EG003
Pleural effusion	Respiratory, thoracic and mediastinal disorders	MedDRA 21.0	Systematic Assessment		EG0001 affected6 at risk EG0011 affected5 at risk EG0020 affected5 at risk EG003
Abdominal pain	Gastrointestinal disorders	MedDRA 21.0	Systematic Assessment		EG0000 affected6 at risk EG0011 affected5 at risk EG0020 affected5 at risk EG003
Acute kidney injury	Renal and urinary disorders	MedDRA 21.0	Systematic Assessment		EG0000 affected6 at risk EG0010 affected5 at risk EG0020 affected5 at risk EG003
Angina pectoris	Cardiac disorders	MedDRA 21.0	Systematic Assessment		EG0000 affected6 at risk EG0011 affected5 at risk EG0020 affected5 at risk EG003
Basal cell carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 21.0	Systematic Assessment		EG0000 affected6 at risk EG0010 affected5 at risk EG0021 affected5 at risk EG003
Cardiac arrest	Cardiac disorders	MedDRA 21.0	Systematic Assessment		EG0000 affected6 at risk EG0011 affected5 at risk EG0020 affected5 at risk EG003
Cardiac failure	Cardiac disorders	MedDRA 21.0	Systematic Assessment		EG0000 affected6 at risk EG0010 affected5 at risk EG0020 affected5 at risk EG003
Cholecystitis	Hepatobiliary disorders	MedDRA 21.0	Systematic Assessment		EG0000 affected6 at risk EG0011 affected5 at risk EG0020 affected5 at risk EG003
Dehydration	Metabolism and nutrition disorders	MedDRA 21.0	Systematic Assessment		EG0001 affected6 at risk EG0010 affected5 at risk EG0020 affected5 at risk EG003
Diarrhoea	Gastrointestinal disorders	MedDRA 21.0	Systematic Assessment		EG0000 affected6 at risk EG0011 affected5 at risk EG0020 affected5 at risk EG003
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA 21.0	Systematic Assessment		EG0000 affected6 at risk EG0011 affected5 at risk EG0020 affected5 at risk EG003
Facial pain	General disorders	MedDRA 21.0	Systematic Assessment		EG0000 affected6 at risk EG0010 affected5 at risk EG0020 affected5 at risk EG003
Fall	Injury, poisoning and procedural complications	MedDRA 21.0	Systematic Assessment		EG0000 affected6 at risk EG0010 affected5 at risk EG0021 affected5 at risk EG003
Haemothorax	Respiratory, thoracic and mediastinal disorders	MedDRA 21.0	Systematic Assessment		EG0000 affected6 at risk EG0010 affected5 at risk EG0021 affected5 at risk EG003
Hyperkalaemia	Metabolism and nutrition disorders	MedDRA 21.0	Systematic Assessment		EG0000 affected6 at risk EG0011 affected5 at risk EG0020 affected5 at risk EG003
Hypokalaemia	Metabolism and nutrition disorders	MedDRA 21.0	Systematic Assessment		EG0001 affected6 at risk EG0010 affected5 at risk EG0020 affected5 at risk EG003
Hyponatraemia	Metabolism and nutrition disorders	MedDRA 21.0	Systematic Assessment		EG0001 affected6 at risk EG0010 affected5 at risk EG0020 affected5 at risk EG003
Hypotension	Vascular disorders	MedDRA 21.0	Systematic Assessment		EG0000 affected6 at risk EG0010 affected5 at risk EG0021 affected5 at risk EG003
Hypoxia	Respiratory, thoracic and mediastinal disorders	MedDRA 21.0	Systematic Assessment		EG0000 affected6 at risk EG0011 affected5 at risk EG0020 affected5 at risk EG003
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA 21.0	Systematic Assessment		EG0001 affected6 at risk EG0010 affected5 at risk EG0020 affected5 at risk EG003
Plasmacytoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 21.0	Systematic Assessment		EG0000 affected6 at risk EG0010 affected5 at risk EG0020 affected5 at risk EG003
Pneumonia	Infections and infestations	MedDRA 21.0	Systematic Assessment		EG0000 affected6 at risk EG0010 affected5 at risk EG0021 affected5 at risk EG003
Presyncope	Nervous system disorders	MedDRA 21.0	Systematic Assessment		EG0000 affected6 at risk EG0010 affected5 at risk EG0021 affected5 at risk EG003
Renal failure	Renal and urinary disorders	MedDRA 21.0	Systematic Assessment		EG0000 affected6 at risk EG0011 affected5 at risk EG0020 affected5 at risk EG003
Respiratory failure	Respiratory, thoracic and mediastinal disorders	MedDRA 21.0	Systematic Assessment		EG0000 affected6 at risk EG0011 affected5 at risk EG0020 affected5 at risk EG003
Squamous cell carcinoma of skin	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 21.0	Systematic Assessment		EG0000 affected6 at risk EG0010 affected5 at risk EG0021 affected5 at risk EG003
Influenza	Infections and infestations	MedDRA 21.0	Systematic Assessment		EG0000 affected6 at risk EG0010 affected5 at risk EG0020 affected5 at risk EG003
Nausea	Gastrointestinal disorders	MedDRA 21.0	Systematic Assessment		EG0001 affected6 at risk EG0010 affected5 at risk EG0020 affected5 at risk EG003

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Nausea	Gastrointestinal disorders	MedDRA 21.0	Systematic Assessment	EG0004 affected6 at risk EG0014 affected5 at risk EG0023 affected5 at risk EG0034 affected11 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA 21.0	Systematic Assessment	EG0003 affected6 at risk EG0013 affected5 at risk EG0023 affected5 at risk EG003
Fatigue	General disorders	MedDRA 21.0	Systematic Assessment	EG0002 affected6 at risk EG0013 affected5 at risk EG0023 affected5 at risk EG003
Constipation	Gastrointestinal disorders	MedDRA 21.0	Systematic Assessment	EG0001 affected6 at risk EG0013 affected5 at risk EG0022 affected5 at risk EG003
Decreased appetite	Metabolism and nutrition disorders	MedDRA 21.0	Systematic Assessment	EG0002 affected6 at risk EG0012 affected5 at risk EG0021 affected5 at risk EG003
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA 21.0	Systematic Assessment	EG0001 affected6 at risk EG0012 affected5 at risk EG0023 affected5 at risk EG003
Pyrexia	General disorders	MedDRA 21.0	Systematic Assessment	EG0001 affected6 at risk EG0011 affected5 at risk EG0021 affected5 at risk EG003
Oedema peripheral	General disorders	MedDRA 21.0	Systematic Assessment	EG0003 affected6 at risk EG0010 affected5 at risk EG0022 affected5 at risk EG003
Upper respiratory tract infection	Infections and infestations	MedDRA 21.0	Systematic Assessment	EG0002 affected6 at risk EG0010 affected5 at risk EG0023 affected5 at risk EG003
Asthenia	General disorders	MedDRA 21.0	Systematic Assessment	EG0000 affected6 at risk EG0011 affected5 at risk EG0020 affected5 at risk EG003
Hypotension	Vascular disorders	MedDRA 21.0	Systematic Assessment	EG0001 affected6 at risk EG0011 affected5 at risk EG0021 affected5 at risk EG003
Insomnia	Psychiatric disorders	MedDRA 21.0	Systematic Assessment	EG0001 affected6 at risk EG0011 affected5 at risk EG0022 affected5 at risk EG003
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA 21.0	Systematic Assessment	EG0003 affected6 at risk EG0010 affected5 at risk EG0020 affected5 at risk EG003
Rash maculo-papular	Skin and subcutaneous tissue disorders	MedDRA 21.0	Systematic Assessment	EG0001 affected6 at risk EG0011 affected5 at risk EG0022 affected5 at risk EG003
Thrombocytopenia	Blood and lymphatic system disorders	MedDRA 21.0	Systematic Assessment	EG0002 affected6 at risk EG0010 affected5 at risk EG0022 affected5 at risk EG003
Headache	Nervous system disorders	MedDRA 21.0	Systematic Assessment	EG0001 affected6 at risk EG0010 affected5 at risk EG0022 affected5 at risk EG003
Muscular weakness	Musculoskeletal and connective tissue disorders	MedDRA 21.0	Systematic Assessment	EG0000 affected6 at risk EG0010 affected5 at risk EG0022 affected5 at risk EG003
Pruritus	Skin and subcutaneous tissue disorders	MedDRA 21.0	Systematic Assessment	EG0000 affected6 at risk EG0011 affected5 at risk EG0022 affected5 at risk EG003
Vomiting	Gastrointestinal disorders	MedDRA 21.0	Systematic Assessment	EG0001 affected6 at risk EG0012 affected5 at risk EG0021 affected5 at risk EG003
Abdominal pain	Gastrointestinal disorders	MedDRA 21.0	Systematic Assessment	EG0001 affected6 at risk EG0012 affected5 at risk EG0020 affected5 at risk EG003
Anaemia	Blood and lymphatic system disorders	MedDRA 21.0	Systematic Assessment	EG0002 affected6 at risk EG0010 affected5 at risk EG0022 affected5 at risk EG003
Back pain	Musculoskeletal and connective tissue disorders	MedDRA 21.0	Systematic Assessment	EG0000 affected6 at risk EG0010 affected5 at risk EG0021 affected5 at risk EG003
Contusion	Injury, poisoning and procedural complications	MedDRA 21.0	Systematic Assessment	EG0001 affected6 at risk EG0010 affected5 at risk EG0021 affected5 at risk EG003
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA 21.0	Systematic Assessment	EG0001 affected6 at risk EG0010 affected5 at risk EG0021 affected5 at risk EG003
Dizziness	Nervous system disorders	MedDRA 21.0	Systematic Assessment	EG0001 affected6 at risk EG0010 affected5 at risk EG0021 affected5 at risk EG003
Dysgeusia	Nervous system disorders	MedDRA 21.0	Systematic Assessment	EG0001 affected6 at risk EG0010 affected5 at risk EG0022 affected5 at risk EG003
Peripheral sensory neuropathy	Nervous system disorders	MedDRA 21.0	Systematic Assessment	EG0001 affected6 at risk EG0010 affected5 at risk EG0022 affected5 at risk EG003
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA 21.0	Systematic Assessment	EG0000 affected6 at risk EG0010 affected5 at risk EG0021 affected5 at risk EG003
Blood creatinine increased	Investigations	MedDRA 21.0	Systematic Assessment	EG0001 affected6 at risk EG0010 affected5 at risk EG0021 affected5 at risk EG003
Cardiac failure	Cardiac disorders	MedDRA 21.0	Systematic Assessment	EG0001 affected6 at risk EG0010 affected5 at risk EG0021 affected5 at risk EG003
Cellulitis	Infections and infestations	MedDRA 21.0	Systematic Assessment	EG0000 affected6 at risk EG0010 affected5 at risk EG0022 affected5 at risk EG003
Chills	General disorders	MedDRA 21.0	Systematic Assessment	EG0001 affected6 at risk EG0010 affected5 at risk EG0021 affected5 at risk EG003
Fall	Injury, poisoning and procedural complications	MedDRA 21.0	Systematic Assessment	EG0000 affected6 at risk EG0010 affected5 at risk EG0021 affected5 at risk EG003
Fluid retention	Metabolism and nutrition disorders	MedDRA 21.0	Systematic Assessment	EG0000 affected6 at risk EG0011 affected5 at risk EG0020 affected5 at risk EG003
Hyponatraemia	Metabolism and nutrition disorders	MedDRA 21.0	Systematic Assessment	EG0001 affected6 at risk EG0010 affected5 at risk EG0021 affected5 at risk EG003
Increased tendency to bruise	Blood and lymphatic system disorders	MedDRA 21.0	Systematic Assessment	EG0000 affected6 at risk EG0010 affected5 at risk EG0022 affected5 at risk EG003
Muscle spasms	Musculoskeletal and connective tissue disorders	MedDRA 21.0	Systematic Assessment	EG0001 affected6 at risk EG0010 affected5 at risk EG0021 affected5 at risk EG003
Nasal congestion	Respiratory, thoracic and mediastinal disorders	MedDRA 21.0	Systematic Assessment	EG0001 affected6 at risk EG0010 affected5 at risk EG0021 affected5 at risk EG003
Nasopharyngitis	Infections and infestations	MedDRA 21.0	Systematic Assessment	EG0000 affected6 at risk EG0010 affected5 at risk EG0022 affected5 at risk EG003
Neuropathy peripheral	Nervous system disorders	MedDRA 21.0	Systematic Assessment	EG0001 affected6 at risk EG0010 affected5 at risk EG0021 affected5 at risk EG003
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	MedDRA 21.0	Systematic Assessment	EG0001 affected6 at risk EG0010 affected5 at risk EG0022 affected5 at risk EG003
Abdominal distension	Gastrointestinal disorders	MedDRA 21.0	Systematic Assessment	EG0000 affected6 at risk EG0010 affected5 at risk EG0021 affected5 at risk EG003
Abdominal pain upper	Gastrointestinal disorders	MedDRA 21.0	Systematic Assessment	EG0000 affected6 at risk EG0010 affected5 at risk EG0020 affected5 at risk EG003
Angina pectoris	Cardiac disorders	MedDRA 21.0	Systematic Assessment	EG0000 affected6 at risk EG0010 affected5 at risk EG0021 affected5 at risk EG003
Atrial flutter	Cardiac disorders	MedDRA 21.0	Systematic Assessment	EG0000 affected6 at risk EG0011 affected5 at risk EG0021 affected5 at risk EG003
Bronchitis	Infections and infestations	MedDRA 21.0	Systematic Assessment	EG0001 affected6 at risk EG0010 affected5 at risk EG0020 affected5 at risk EG003
Conjunctivitis	Eye disorders	MedDRA 21.0	Systematic Assessment	EG0001 affected6 at risk EG0010 affected5 at risk EG0020 affected5 at risk EG003
Dehydration	Metabolism and nutrition disorders	MedDRA 21.0	Systematic Assessment	EG0000 affected6 at risk EG0011 affected5 at risk EG0021 affected5 at risk EG003
Dry eye	Eye disorders	MedDRA 21.0	Systematic Assessment	EG0000 affected6 at risk EG0010 affected5 at risk EG0022 affected5 at risk EG003
Dry mouth	Gastrointestinal disorders	MedDRA 21.0	Systematic Assessment	EG0000 affected6 at risk EG0010 affected5 at risk EG0021 affected5 at risk EG003
Dry skin	Skin and subcutaneous tissue disorders	MedDRA 21.0	Systematic Assessment	EG0001 affected6 at risk EG0010 affected5 at risk EG0021 affected5 at risk EG003
Dyspepsia	Gastrointestinal disorders	MedDRA 21.0	Systematic Assessment	EG0000 affected6 at risk EG0010 affected5 at risk EG0020 affected5 at risk EG003
Epistaxis	Respiratory, thoracic and mediastinal disorders	MedDRA 21.0	Systematic Assessment	EG0000 affected6 at risk EG0010 affected5 at risk EG0020 affected5 at risk EG003
Gait disturbance	General disorders	MedDRA 21.0	Systematic Assessment	EG0000 affected6 at risk EG0010 affected5 at risk EG0021 affected5 at risk EG003
Hyperglycaemia	Metabolism and nutrition disorders	MedDRA 21.0	Systematic Assessment	EG0000 affected6 at risk EG0010 affected5 at risk EG0022 affected5 at risk EG003
Hypertension	Vascular disorders	MedDRA 21.0	Systematic Assessment	EG0001 affected6 at risk EG0010 affected5 at risk EG0020 affected5 at risk EG003
Hypokalaemia	Metabolism and nutrition disorders	MedDRA 21.0	Systematic Assessment	EG0001 affected6 at risk EG0010 affected5 at risk EG0020 affected5 at risk EG003
Influenza like illness	General disorders	MedDRA 21.0	Systematic Assessment	EG0000 affected6 at risk EG0010 affected5 at risk EG0021 affected5 at risk EG003
Mood altered	Psychiatric disorders	MedDRA 21.0	Systematic Assessment	EG0000 affected6 at risk EG0010 affected5 at risk EG0021 affected5 at risk EG003
Myalgia	Musculoskeletal and connective tissue disorders	MedDRA 21.0	Systematic Assessment	EG0000 affected6 at risk EG0010 affected5 at risk EG0021 affected5 at risk EG003
Neutropenia	Blood and lymphatic system disorders	MedDRA 21.0	Systematic Assessment	EG0000 affected6 at risk EG0010 affected5 at risk EG0021 affected5 at risk EG003
Ocular hyperaemia	Eye disorders	MedDRA 21.0	Systematic Assessment	EG0000 affected6 at risk EG0010 affected5 at risk EG0022 affected5 at risk EG003
Paraesthesia	Nervous system disorders	MedDRA 21.0	Systematic Assessment	EG0001 affected6 at risk EG0010 affected5 at risk EG0021 affected5 at risk EG003
Platelet count decreased	Investigations	MedDRA 21.0	Systematic Assessment	EG0000 affected6 at risk EG0012 affected5 at risk EG0020 affected5 at risk EG003
Rash macular	Skin and subcutaneous tissue disorders	MedDRA 21.0	Systematic Assessment	EG0000 affected6 at risk EG0010 affected5 at risk EG0021 affected5 at risk EG003
Rash pruritic	Skin and subcutaneous tissue disorders	MedDRA 21.0	Systematic Assessment	EG0000 affected6 at risk EG0010 affected5 at risk EG0020 affected5 at risk EG003
Skin lesion	Skin and subcutaneous tissue disorders	MedDRA 21.0	Systematic Assessment	EG0001 affected6 at risk EG0010 affected5 at risk EG0021 affected5 at risk EG003

ID	Term
D054219	Neoplasms, Plasma Cell
D009370	Neoplasms by Histologic Type
D009369	Neoplasms
D000686	Amyloidosis
D057165	Proteostasis Deficiencies
D008659	Metabolic Diseases
D009750	Nutritional and Metabolic Diseases
D008232	Lymphoproliferative Disorders
D007160	Immunoproliferative Disorders
D007154	Immune System Diseases
D010265	Paraproteinemias

ID	Term
D011246	Pregnadienetriols
D011245	Pregnadienes
D011278	Pregnanes
D013256	Steroids
D000072473	Fused-Ring Compounds
D011083	Polycyclic Compounds
D013259	Steroids, Fluorinated