Study of Oral Ixazomib Maintenance Therapy After Initial... | NCT03748953

ID	Type	Description	Link
2014-001394-13	EudraCT Number

Description Module

Detailed Description

The drug being tested in this study is called ixazomib. Ixazomib is being tested to slow disease progression and improve overall survival in Chinese participants who have newly diagnosed multiple myeloma (NDMM) who have had a major positive response to initial therapy and have not undergone stem cell transplantation (SCT). This study will look at the effect of ixazomib has on the length of time that participants are free of disease progression and their overall survival. After the implementation of Amendment 8, participants who received placebo-matching capsules before unblinding and have not yet experienced disease progression will cross over to receive ixazomib.

The study will enroll approximately 37 patients. Participants will be assigned to a single treatment group

• Ixazomib

All participants will be asked to take one capsule on Days 1, 8, and 15 of every 28-day cycle, for up to approximately 24 months (equivalent to 26 cycles [if no cycle delays], to the nearest complete cycle) or until documented progressive disease (PD) or intolerable toxicity, whichever occurs first.

This multi-center trial will be conducted in China. The overall time to participate in this study is until a total of approximately up to 60 months. Participants will make multiple visits to the clinic, and every 4 weeks until the next line of therapy begins for a follow-up assessment.

Label	Type	Description	Intervention Names
Ixazomib	Experimental	Participants received ixazomib 3 milligrams (mg), capsules, orally, once on Days 1, 8, and 15 for Cycles 1 through 4, during which if the participants tolerated the initial dose, the dose was escalated to ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15 for Cycles 5 through 26, or until documented PD or intolerable toxicity, whichever occurred first (cycle length=28 days).	Drug: Ixazomib

Name	Type	Description	Arm Group Labels	Other Names
Ixazomib	Drug	Ixazomib Capsules	Ixazomib

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Number of Participants Categorized According to Performance Status (PS) Based on Eastern Cooperative Oncology Group (ECOG) PS	ECOG PS was used to assess physical health of participants. ECOG PS grade:0= fully active, able to carry on all pre-disease performance without restriction,1= restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature 2= ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours, 3= capable of only limited self-care, 4= completely disabled, cannot carry on any selfcare, totally confined to bed or chair confined to bed or chair more than 50% of waking hours and 5= dead. Only those categories with non-zero values were reported.	Month 25
Percentage of Participants Receiving Ixazomib With Treatment-emergent Adverse Events (TEAEs)	Adverse events (AEs) were defined as any unfavorable and unintended sign, symptom or disease temporally associated with the use of a medicinal product reported from first dose of study drug through 30 days after the last dose of study drug. A TEAE was defined as an AE that started or worsened after first study drug administration and within 30 days of last dose of study drug. Percentages are rounded off to the nearest whole number.	Up to 58.4 months
Percentage of Participants Receiving Ixazomib With Treatment-emergent Serious Adverse Events (SAEs)	AEs were defined as any unfavorable and unintended sign, symptom or disease temporally associated with the use of a medicinal product reported from first dose of study drug through 30 days after the last dose of study drug. A TEAE was defined as an AE that started or worsened after first study drug administration and within 30 days of last dose of study drug. An SAE was defined as any untoward medical occurrence that at any dose resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability or incapacity, was a congenital abnormality or birth defect, or is an important medical event. Percentages are rounded off to the nearest whole number.	Up to 58.4 months

Secondary Outcomes

Measure	Description	Time Frame
Progression-Free Survival (PFS)	PFS was defined as the time from the date of first dose of study drug to the first occurrence of PD as evaluated by the investigator or death from any cause, whichever occurred first. PD was defined as ≥25% increase from lowest value in serum M component or urine M-component; difference between involved and uninvolved free light chain (FLC) levels (absolute increase >10 milligrams per deciliter [mg/dL]); bone marrow plasma cell percent ≥10%; new bone lesions or soft tissue plasmacytomas development or definite increase in existing bone lesions/soft tissue plasmacytomas size; hypercalcaemia development.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Adult male or female participants aged 18 years or older with a confirmed diagnosis of symptomatic NDMM according to standard criteria.
Has completed 6 to 12 months (±2 weeks) of initial therapy, during which the participant was treated to best response, defined as the best response maintained for 2 cycles after the M-protein nadir is reached.
Has documented major response (partial response [PR], very good partial response [VGPR], complete response [CR]) according to the international myeloma working group (IMWG) uniform response criteria, version 2011, after this initial therapy.
Female participants who:

Are postmenopausal for at least 1 year before the screening visit, OR Are surgically sterile, OR If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 90 days after the last dose of study drug, or Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence [e.g., calendar, ovulation,symptothermal, postovulation methods] and withdrawal are not acceptable methods of contraception.)

Male participants, even if surgically sterilized (i.e., status postvasectomy), who:

Agree to practice effective barrier contraception during the entire study Treatment period and through 90 days after the last dose of study drug, or Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods for the female partner] and withdrawal are not acceptable methods of contraception.)
Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to future medical care.
Has availability of complete documentation for:
1. Details of initial disease state, initial therapy, and response
2. Cytogenetic assessment at diagnosis (cytogenetic assessment performed after diagnosis must be approved by a Takeda project clinician or designee)
3. International Staging System (ISS) staging at diagnosis (requiring beta 2-microglobulin and serum albumin results).
Has Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2.
Suitable venous access for the study-required blood sampling and consent for the specific amounts that will be taken.
Participant is willing and able to adhere to the study visit schedule and other protocol requirements including blood sampling and bone marrow aspiration.
Participants must meet the following clinical laboratory criteria at study entry:

1. Absolute neutrophil count (ANC) ≥1,000/mm^3 without growth factor support and platelet count ≥ 75,000/mm^3. Platelet transfusions to help participants meet eligibility criteria are not allowed within 3 days before enrollment.

2. Total bilirubin ≤1.5*the upper limit of the normal range (ULN). 3. Alanine aminotransferase and aspartate aminotransferase ≤3*ULN. 4. Calculated creatinine clearance ≥30 mL/min (using the Cockroft-Gault equation).

Exclusion Criteria:

Has multiple myeloma that relapsed after, or was not responsive to, initial therapy.
Had prior stem-cell transplantation (SCT).
Has radiotherapy within 14 days before enrollment.
Had been diagnosed or treated for another malignancy within 5 years before enrollment or previously diagnosed with another malignancy with evidence of residual disease. Participants with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
Female participants who are lactating and breastfeeding or have a positive serum pregnancy test during the Screening period.
Has major surgery within 14 days before enrollment.
Has central nervous system involvement.
Infection requiring intravenous (IV) antibiotic therapy or other serious infection within 14 days before enrollment.
Has diagnosis of Waldenstrom's macroglobulinemia, polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome, plasma cell leukemia, primary amyloidosis, myelodysplastic syndrome, or myeloproliferative syndrome.
Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, uncontrolled congestive heart failure, unstable angina, or myocardial infarction within the past 6 months.
Systemic treatment with strong cytochrome P450 (CYP3A) inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital) or use of St. John's wort within 14 days before enrollment.
Ongoing or active infection, known human immunodeficiency virus positive, active hepatitis B or C infection.
Has comorbid systemic illnesses or other severe concurrent disease that, in the judgment of the investigator, would make the participant inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens (e.g., peripheral neuropathy (PN) that is Grade 1 with pain or Grade 2 or higher of any cause).
Psychiatric illness/social situation that would limit compliance with study requirements.
Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent.
Inability to swallow oral medication, inability or unwillingness to comply with the drug administration requirements, or gastrointestinal (GI) procedure that could interfere with the oral absorption or tolerance of treatment.
Treatment with any investigational products within 30 days before enrollment.

Name	Affiliation	Role
Medical Director	Takeda	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Beijing Chaoyang Hospital Capital Medical University		Beijing	Beijing Municipality	100020	China

Label	URL
To obtain more information about this study, click this link.	View source

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Ixazomib	Participants received ixazomib 3 mg, capsules, orally, once on Days 1, 8, and 15 for Cycles 1 through 4, during which if the participants tolerated the initial dose, the dose was escalated to ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15 for Cycles 5 through 26, or until documented progressive disease (PD) or intolerable toxicity, whichever occurred first (cycle length=28 days).

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Aug 26, 2022	Nov 28, 2024

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 Categorized According to Performance Status (PS) Based on Eastern Cooperative Oncology Group (ECOG) PS

ECOG PS was used to assess physical health of participants. ECOG PS grade:0= fully active, able to carry on all pre-disease performance without restriction,1= restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature 2= ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours, 3= capable of only limited self-care, 4= completely disabled, cannot carry on any selfcare, totally confined to bed or chair confined to bed or chair more than 50% of waking hours and 5= dead. Only those categories with non-zero values were reported.

Ixazomib Safety Population (ISP) included all participants who received at least 1 dose of ixazomib. As prespecified in the SAP, the ISP contained only one arm i.e., Ixazomib (participants originally randomized to ixazomib + participants who were randomized to the placebo arm prior to implementation of Amendment 08 and who crossed over to ixazomib arm contributing data for this outcome measure from the time they initiated ixazomib onward), thus data is presented accordingly.

Posted

Count of Participants

Participants

Month 25

ID	Title	Description
OG000	Ixazomib	Participants received ixazomib 3 mg, capsules, orally, once on Days 1, 8, and 15 for Cycles 1 through 4, during which if the participants tolerated the initial dose, the dose was escalated to ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15 for Cycles 5 through 26, or until documented progressive disease (PD) or intolerable toxicity, whichever occurred first (cycle length=28 days).

Units	Counts
Participants	OG00035

Title

Denominators

Categories

ECOG Score 0

Title	Measurements
	OG00034

ECOG Score 1

Title	Measurements
	OG0001

Primary

Percentage of Participants Receiving Ixazomib With Treatment-emergent Adverse Events (TEAEs)

Adverse events (AEs) were defined as any unfavorable and unintended sign, symptom or disease temporally associated with the use of a medicinal product reported from first dose of study drug through 30 days after the last dose of study drug. A TEAE was defined as an AE that started or worsened after first study drug administration and within 30 days of last dose of study drug. Percentages are rounded off to the nearest whole number.

ISP included all participants who received at least 1 dose of ixazomib. As prespecified in the SAP, the ISP contained only one arm i.e., Ixazomib (participants originally randomized to ixazomib + participants who were randomized to the placebo arm prior to implementation of Amendment 08 and who crossed over to ixazomib arm contributing data for this outcome measure from the time they initiated ixazomib onward), thus data is presented accordingly.

Posted

Number

percentage of participants

Up to 58.4 months

ID	Title	Description
OG000	Ixazomib	Participants received ixazomib 3 mg, capsules, orally, once on Days 1, 8, and 15 for Cycles 1 through 4, during which if the participants tolerated the initial dose, the dose was escalated to ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15 for Cycles 5 through 26, or until documented progressive disease (PD) or intolerable toxicity, whichever occurred first (cycle length=28 days).

Primary

Percentage of Participants Receiving Ixazomib With Treatment-emergent Serious Adverse Events (SAEs)

AEs were defined as any unfavorable and unintended sign, symptom or disease temporally associated with the use of a medicinal product reported from first dose of study drug through 30 days after the last dose of study drug. A TEAE was defined as an AE that started or worsened after first study drug administration and within 30 days of last dose of study drug. An SAE was defined as any untoward medical occurrence that at any dose resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability or incapacity, was a congenital abnormality or birth defect, or is an important medical event. Percentages are rounded off to the nearest whole number.

Posted

Number

percentage of participants

Up to 58.4 months

ID	Title	Description
OG000	Ixazomib	Participants received ixazomib 3 mg, capsules, orally, once on Days 1, 8, and 15 for Cycles 1 through 4, during which if the participants tolerated the initial dose, the dose was escalated to ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15 for Cycles 5 through 26, or until documented progressive disease (PD) or intolerable toxicity, whichever occurred first (cycle length=28 days).

Primary

Number of Participants Receiving Ixazomib With Clinically Significant Changes in Safety Laboratory Values

Clinical laboratory assessments included hematology, serum chemistry, and urinalysis. Any clinically significant changes in the clinical laboratory value over time based on the investigator's interpretation were reported.

Posted

Count of Participants

Participants

Up to 58.4 months

ID	Title	Description
OG000	Ixazomib	Participants received ixazomib 3 mg, capsules, orally, once on Days 1, 8, and 15 for Cycles 1 through 4, during which if the participants tolerated the initial dose, the dose was escalated to ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15 for Cycles 5 through 26, or until documented progressive disease (PD) or intolerable toxicity, whichever occurred first (cycle length=28 days).

Units	Counts
Participants

Secondary

Progression-Free Survival (PFS)

PFS was defined as the time from the date of first dose of study drug to the first occurrence of PD as evaluated by the investigator or death from any cause, whichever occurred first. PD was defined as ≥25% increase from lowest value in serum M component or urine M-component; difference between involved and uninvolved free light chain (FLC) levels (absolute increase >10 milligrams per deciliter [mg/dL]); bone marrow plasma cell percent ≥10%; new bone lesions or soft tissue plasmacytomas development or definite increase in existing bone lesions/soft tissue plasmacytomas size; hypercalcaemia development.

Efficacy Population included all participants who received ixazomib treatment for the duration of their study participation. As prespecified in the SAP, the Efficacy Population contained only one arm i.e., Ixazomib (efficacy outcomes data for the participants who received placebo before Protocol Amendment 8 was not collected per statistical analysis plan), thus data is presented accordingly.

Posted

Median

95% Confidence Interval

months

From the first dose of study drug to every 4 weeks until PD or death from any cause (up to 58.4 months)

ID	Title	Description
OG000	Ixazomib	Participants received ixazomib 3 mg, capsules, orally, once on Days 1, 8, and 15 for Cycles 1 through 4, during which if the participants tolerated the initial dose, the dose was escalated to ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15 for Cycles 5 through 26, or until documented progressive disease (PD) or intolerable toxicity, whichever occurred first (cycle length=28 days).

Secondary

Overall Survival (OS)

OS was measured as the time from the date of first dose of study drug to the date of death.

Posted

Median

95% Confidence Interval

months

From the first dose of study drug to every 12 weeks during follow-up after PD or next line therapy or death whichever occurred later (up to 58.4 months)

ID	Title	Description
OG000	Ixazomib	Participants received ixazomib 3 mg, capsules, orally, once on Days 1, 8, and 15 for Cycles 1 through 4, during which if the participants tolerated the initial dose, the dose was escalated to ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15 for Cycles 5 through 26, or until documented progressive disease (PD) or intolerable toxicity, whichever occurred first (cycle length=28 days).

Units	Counts
Participants	OG000

Secondary

Percentage of Participants Who Achieved or Maintained Best Response Before PD or up to Subsequent Therapy

Response was assessed according to International Myeloma Working Group (IMWG) criteria. Best response includes partial response (PR), very good partial response (VGPR), and complete response (CR). PR as per IMWG criteria is 50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to less than (<)200 mg per 24 hours. VGPR is serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein plus urine M-protein level <100 mg per 24 hours. CR is negative immunofixation of serum and urine and disappearance of soft tissue plasmacytomas and <5% plasma cells in bone marrow. Percentages are rounded off to the nearest whole number.

Response-evaluable Population included a subset of the Efficacy Population and consisted of all participants who had a baseline&at least 1 postbaseline response assessment. As prespecified in the SAP, this population contained only one arm i.e., Ixazomib (efficacy outcomes data for the participants who received placebo before Protocol Amendment 8 was not collected per SAP), thus data is presented accordingly.

Posted

Number

percentage of participants

Up to 58.4 months

ID	Title	Description
OG000	Ixazomib	Participants received ixazomib 3 mg, capsules, orally, once on Days 1, 8, and 15 for Cycles 1 through 4, during which if the participants tolerated the initial dose, the dose was escalated to ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15 for Cycles 5 through 26, or until documented progressive disease (PD) or intolerable toxicity, whichever occurred first (cycle length=28 days).

Secondary

Duration of Complete Response (CR)

Duration of CR was defined as the time from the date of first dose of study drug or the date of CR to the date of first documentation of PD. CR was defined as negative immunofixation on the serum and urine; soft tissue plasmacytomas disappearance; <5% plasma cells (PCs) in bone marrow.

Posted

Median

95% Confidence Interval

months

Up to 58.4 months

ID	Title	Description
OG000	Ixazomib	Participants received ixazomib 3 mg, capsules, orally, once on Days 1, 8, and 15 for Cycles 1 through 4, during which if the participants tolerated the initial dose, the dose was escalated to ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15 for Cycles 5 through 26, or until documented progressive disease (PD) or intolerable toxicity, whichever occurred first (cycle length=28 days).

Units	Counts
Participants

Secondary

Time to Progression (TTP)

TTP was defined as the time from the date of first dose of study drug to the date of first documentation of PD. PD was defined as ≥25% increase from lowest value in serum M component or urine M-component; difference between involved and uninvolved FLC levels (absolute increase >10 mg/dL); bone marrow plasma cell percent ≥10%; new bone lesions or soft tissue plasmacytomas development or definite increase in existing bone lesions/soft tissue plasmacytomas size; hypercalcaemia development.

Posted

Median

95% Confidence Interval

months

Up to 58.4 months

ID	Title	Description
OG000	Ixazomib	Participants received ixazomib 3 mg, capsules, orally, once on Days 1, 8, and 15 for Cycles 1 through 4, during which if the participants tolerated the initial dose, the dose was escalated to ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15 for Cycles 5 through 26, or until documented progressive disease (PD) or intolerable toxicity, whichever occurred first (cycle length=28 days).

Units	Counts

Secondary

Time to Next-Line Therapy (TTNT)

TTNT was defined as the time from the date of first dose of study drug to the date of the first dose of next-line of antineoplastic therapy.

Posted

Median

95% Confidence Interval

months

Up to 58.4 months

ID	Title	Description
OG000	Ixazomib	Participants received ixazomib 3 mg, capsules, orally, once on Days 1, 8, and 15 for Cycles 1 through 4, during which if the participants tolerated the initial dose, the dose was escalated to ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15 for Cycles 5 through 26, or until documented progressive disease (PD) or intolerable toxicity, whichever occurred first (cycle length=28 days).

Units	Counts
Participants	OG000

Secondary

Percentage of Participants With A New Primary Malignancy

ISP=all participants who received atleast 1 dose of ixazomib. As prespecified in SAP,ISP had only 1 arm:Ixazomib (participants originally randomized to ixazomib + participants randomized to placebo arm prior to implementation of Amendment 08 & crossed over to ixazomib arm contributing data for this OM from time they initiated ixazomib onward), thus data is presented accordingly.

Posted

Number

percentage of participants

Up to 58.4 months

ID	Title	Description
OG000	Ixazomib	Participants received ixazomib 3 mg, capsules, orally, once on Days 1, 8, and 15 for Cycles 1 through 4, during which if the participants tolerated the initial dose, the dose was escalated to ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15 for Cycles 5 through 26, or until documented progressive disease (PD) or intolerable toxicity, whichever occurred first (cycle length=28 days).

Units	Counts
Participants	OG000

Secondary

Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 as Measured by the Global Health Status (GHS)

The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. The change from baseline in GHS (EORTC QLQ-C30) score is presented. Participant responses to the question "How would you rate your overall health during the past week?" are scored on a 7-point scale (1=very poor to 7=excellent). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score indicates a better overall GHS.

Efficacy Population included all participants who received ixazomib treatment for the duration of their study participation. Overall number of participants analyzed is the number of participants with data available for analyses. As prespecified in the SAP, the Efficacy Population contained only one arm i.e., Ixazomib (efficacy outcomes data for the participants who received placebo before Protocol Amendment 8 was not collected per SAP), thus data is presented accordingly.

Posted

Mean

Standard Deviation

score on a scale

Baseline, Cycle 26 (cycle length=28 days)

ID	Title	Description
OG000	Ixazomib	Participants received ixazomib 3 mg, capsules, orally, once on Days 1, 8, and 15 for Cycles 1 through 4, during which if the participants tolerated the initial dose, the dose was escalated to ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15 for Cycles 5 through 26, or until documented progressive disease (PD) or intolerable toxicity, whichever occurred first (cycle length=28 days).

Secondary

Correlation Between Frailty Status and PFS

Participant's frailty status is classified as fit, unfit, or frail on the basis of 4 components: age, the Charlson comorbidity scoring system without age weighting, the Katz index of independence in activities of daily living, and the Lawton instrumental activities of daily living scale. The sum of the 4 frailty scores equals the total frailty score. A total frailty score of 0 corresponds to a frailty status of fit; a total score of 1, to unfit; and a total score of 2 or more, to frail. PFS is defined as the time from the date of first dose of study drug to the first occurrence of PD as evaluated by the investigator.

Efficacy Population included all participants who received ixazomib treatment for the duration of their study participation. Number analyzed is the number of participants with data available for analysis for the specified category. As prespecified in the SAP, the Efficacy Population contained only one arm i.e., Ixazomib (efficacy outcomes data for the participants who received placebo before Protocol Amendment 8 was not collected per SAP), thus data is presented accordingly.

Posted

Median

95% Confidence Interval

months

Up to 58.4 months

ID	Title	Description
OG000	Ixazomib	Participants received ixazomib 3 mg, capsules, orally, once on Days 1, 8, and 15 for Cycles 1 through 4, during which if the participants tolerated the initial dose, the dose was escalated to ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15 for Cycles 5 through 26, or until documented progressive disease (PD) or intolerable toxicity, whichever occurred first (cycle length=28 days).

Secondary

Correlation Between Frailty Status and OS

Participant's frailty status is classified as fit, unfit, or frail on the basis of 4 components: age, the Charlson comorbidity scoring system without age weighting, the Katz index of independence in activities of daily living, and the Lawton instrumental activities of daily living scale. The sum of the 4 frailty scores equals the total frailty score. A total frailty score of 0 corresponds to a frailty status of fit; a total score of 1, to unfit; and a total score of 2 or more, to frail. OS was measured as the time from the date of first dose of study drug to the date of death.

Posted

Median

95% Confidence Interval

months

Up to 58.4 months

ID	Title	Description
OG000	Ixazomib	Participants received ixazomib 3 mg, capsules, orally, once on Days 1, 8, and 15 for Cycles 1 through 4, during which if the participants tolerated the initial dose, the dose was escalated to ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15 for Cycles 5 through 26, or until documented progressive disease (PD) or intolerable toxicity, whichever occurred first (cycle length=28 days).

Secondary

Plasma Concentration of Ixazomib

Plasma concentrations of the complete hydrolysis product of ixazomib citrate (ixazomib) were measured using a validated liquid chromatography-tandem mass spectrometry (LC/MS/MS) assay.

ISP=all participants who received atleast 1 dose of ixazomib. Number analyzed=participants with data available for analysis at specified time point. As prespecified in SAP, ISP had only 1 arm:Ixazomib (participants originally randomized to ixazomib + participants randomized to placebo arm prior to implementation of Amendment 08 & crossed over to ixazomib arm contributing data for this OM from time they initiated ixazomib onward), thus data is presented accordingly.

Posted

Geometric Mean

Geometric Coefficient of Variation

nanograms per milliliter (ng/mL)

Cycle 1 (1 and 4 hours post-dose Day 1, Days 8 and 15 pre-dose); Cycle 2 and 5 (Days 1 and 8 pre-dose) and Cycles 3, 4, 6 to 10 (Day 1 pre-dose) (cycle length=28 days)

ID	Title	Description
OG000	Ixazomib	Participants received ixazomib 3 mg, capsules, orally, once on Days 1, 8, and 15 for Cycles 1 through 4, during which if the participants tolerated the initial dose, the dose was escalated to ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15 for Cycles 5 through 26, or until documented progressive disease (PD) or intolerable toxicity, whichever occurred first (cycle length=28 days).

Units	Counts

Secondary

Time to Resolution of Peripheral Neuropathy (PN) Events

PN is defined as the event in the high-level term of peripheral neuropathies not elsewhere classified (NEC) according to the medical dictionary for regulatory activities (MedDRA). A PN event was considered as resolved if its final outcome was resolved with no subsequent PN event of the same preferred term occurring on the resolution date or the day before and after. Time to resolution was defined as the time from the initial onset date (inclusive) to the resolution date for resolved events.

ISP=all participants who received atleast 1 dose of ixazomib. Overall number of participants analyzed=participants with PN events. As prespecified in SAP,ISP had only 1 arm:Ixazomib (participants originally randomized to ixazomib+participants randomized to placebo prior to Amendment 08 &crossed over to ixazomib arm contributing data for this OM from time they initiated ixazomib onward),& is presented accordingly.

Posted

Median

95% Confidence Interval

days

Up to 58.4 months

ID	Title	Description
OG000	Ixazomib	Participants received ixazomib 3 mg, capsules, orally, once on Days 1, 8, and 15 for Cycles 1 through 4, during which if the participants tolerated the initial dose, the dose was escalated to ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15 for Cycles 5 through 26, or until documented progressive disease (PD) or intolerable toxicity, whichever occurred first (cycle length=28 days).

Secondary

Time to Improvement of PN Events

PN is defined as the event in the high-level term of peripheral neuropathies NEC according to the MedDRA. A PN event is considered to be improved if the event improves from the maximum grade; that is, all the grades recorded after the maximum grade are less than the maximum grade. Time to improvement is defined as the time from the initial onset date (inclusive) of the maximum grade to the first onset date that the toxicity grade is below the maximum grade with no higher grade thereafter, or the resolution date, whichever occurs first.

ISP=all participants who received atleast 1 dose of ixazomib. Overall number of participants analyzed=participants with PN events. As prespecified in SAP,ISP had only 1 arm:Ixazomib (participants originally randomized to ixazomib + participants randomized to placebo arm prior to implementation of Amendment 08 & crossed over to ixazomib arm contributing data for this OM from time they initiated ixazomib onward), thus data is presented accordingly.

Posted

Median

95% Confidence Interval

days

Up to 58.4 months

ID	Title	Description
OG000	Ixazomib	Participants received ixazomib 3 mg, capsules, orally, once on Days 1, 8, and 15 for Cycles 1 through 4, during which if the participants tolerated the initial dose, the dose was escalated to ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15 for Cycles 5 through 26, or until documented progressive disease (PD) or intolerable toxicity, whichever occurred first (cycle length=28 days).

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Cardiac failure congestive	Cardiac disorders	MedDRA26.0	Systematic Assessment	EG0001 affected35 at risk EG0010 affected4 at risk
Cataract	Eye disorders	MedDRA26.0	Systematic Assessment	EG0001 affected35 at risk EG0010 affected4 at risk
Chest discomfort	General disorders	MedDRA26.0	Systematic Assessment	EG0001 affected35 at risk EG0010 affected4 at risk
Cholelithiasis	Hepatobiliary disorders	MedDRA26.0	Systematic Assessment	EG0001 affected35 at risk EG0010 affected4 at risk
COVID-19	Infections and infestations	MedDRA26.0	Systematic Assessment	EG0002 affected35 at risk EG0010 affected4 at risk
Pneumonia	Infections and infestations	MedDRA26.0	Systematic Assessment	EG0001 affected35 at risk EG0010 affected4 at risk
Femur fracture	Injury, poisoning and procedural complications	MedDRA26.0	Systematic Assessment	EG0001 affected35 at risk EG0010 affected4 at risk
Post procedural haemorrhage	Injury, poisoning and procedural complications	MedDRA26.0	Systematic Assessment	EG0001 affected35 at risk EG0010 affected4 at risk
Periarthritis	Musculoskeletal and connective tissue disorders	MedDRA26.0	Systematic Assessment	EG0001 affected35 at risk EG0010 affected4 at risk
Rotator cuff syndrome	Musculoskeletal and connective tissue disorders	MedDRA26.0	Systematic Assessment	EG0001 affected35 at risk EG0010 affected4 at risk
Cerebral infarction	Nervous system disorders	MedDRA26.0	Systematic Assessment	EG0001 affected35 at risk EG0010 affected4 at risk
Angioedema	Skin and subcutaneous tissue disorders	MedDRA26.0	Systematic Assessment	EG0001 affected35 at risk EG0010 affected4 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Anaemia	Blood and lymphatic system disorders	MedDRA26.0	Systematic Assessment	EG0004 affected35 at risk EG0010 affected4 at risk
Leukopenia	Blood and lymphatic system disorders	MedDRA26.0	Systematic Assessment	EG0003 affected35 at risk EG0010 affected4 at risk
Neutropenia	Blood and lymphatic system disorders	MedDRA26.0	Systematic Assessment	EG0002 affected35 at risk EG0010 affected4 at risk
Thrombocytopenia	Blood and lymphatic system disorders	MedDRA26.0	Systematic Assessment	EG0003 affected35 at risk EG0010 affected4 at risk
Abdominal distension	Gastrointestinal disorders	MedDRA26.0	Systematic Assessment	EG0002 affected35 at risk EG0010 affected4 at risk
Abdominal pain	Gastrointestinal disorders	MedDRA26.0	Systematic Assessment	EG0002 affected35 at risk EG0010 affected4 at risk
Breath odour	Gastrointestinal disorders	MedDRA26.0	Systematic Assessment	EG0000 affected35 at risk EG0011 affected4 at risk
Constipation	Gastrointestinal disorders	MedDRA26.0	Systematic Assessment	EG0002 affected35 at risk EG0010 affected4 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA26.0	Systematic Assessment	EG00012 affected35 at risk EG0011 affected4 at risk
Gastritis	Gastrointestinal disorders	MedDRA26.0	Systematic Assessment	EG0002 affected35 at risk EG0011 affected4 at risk
Mouth ulceration	Gastrointestinal disorders	MedDRA26.0	Systematic Assessment	EG0002 affected35 at risk EG0010 affected4 at risk
Nausea	Gastrointestinal disorders	MedDRA26.0	Systematic Assessment	EG0006 affected35 at risk EG0010 affected4 at risk
Tongue ulceration	Gastrointestinal disorders	MedDRA26.0	Systematic Assessment	EG0000 affected35 at risk EG0011 affected4 at risk
Toothache	Gastrointestinal disorders	MedDRA26.0	Systematic Assessment	EG0004 affected35 at risk EG0010 affected4 at risk
Vomiting	Gastrointestinal disorders	MedDRA26.0	Systematic Assessment	EG0009 affected35 at risk EG0010 affected4 at risk
Fatigue	General disorders	MedDRA26.0	Systematic Assessment	EG0003 affected35 at risk EG0010 affected4 at risk
Peripheral swelling	General disorders	MedDRA26.0	Systematic Assessment	EG0003 affected35 at risk EG0010 affected4 at risk
Pyrexia	General disorders	MedDRA26.0	Systematic Assessment	EG0006 affected35 at risk EG0010 affected4 at risk
Hepatic steatosis	Hepatobiliary disorders	MedDRA26.0	Systematic Assessment	EG0002 affected35 at risk EG0010 affected4 at risk
Bronchitis	Infections and infestations	MedDRA26.0	Systematic Assessment	EG0004 affected35 at risk EG0010 affected4 at risk
COVID-19	Infections and infestations	MedDRA26.0	Systematic Assessment	EG0008 affected35 at risk EG0010 affected4 at risk
Herpes zoster	Infections and infestations	MedDRA26.0	Systematic Assessment	EG0002 affected35 at risk EG0010 affected4 at risk
Nasopharyngitis	Infections and infestations	MedDRA26.0	Systematic Assessment	EG0005 affected35 at risk EG0011 affected4 at risk
Pneumonia	Infections and infestations	MedDRA26.0	Systematic Assessment	EG0005 affected35 at risk EG0010 affected4 at risk
Upper respiratory tract infection	Infections and infestations	MedDRA26.0	Systematic Assessment	EG00014 affected35 at risk EG0011 affected4 at risk
Aspartate aminotransferase increased	Investigations	MedDRA26.0	Systematic Assessment	EG0003 affected35 at risk EG0010 affected4 at risk
Blood creatine phosphokinase increased	Investigations	MedDRA26.0	Systematic Assessment	EG0002 affected35 at risk EG0010 affected4 at risk
Blood lactate dehydrogenase increased	Investigations	MedDRA26.0	Systematic Assessment	EG0002 affected35 at risk EG0010 affected4 at risk
Lymphocyte count decreased	Investigations	MedDRA26.0	Systematic Assessment	EG0005 affected35 at risk EG0010 affected4 at risk
Neutrophil count decreased	Investigations	MedDRA26.0	Systematic Assessment	EG0003 affected35 at risk EG0010 affected4 at risk
Platelet count decreased	Investigations	MedDRA26.0	Systematic Assessment	EG0008 affected35 at risk EG0010 affected4 at risk
Weight decreased	Investigations	MedDRA26.0	Systematic Assessment	EG0004 affected35 at risk EG0010 affected4 at risk
Weight increased	Investigations	MedDRA26.0	Systematic Assessment	EG0002 affected35 at risk EG0011 affected4 at risk
White blood cell count decreased	Investigations	MedDRA26.0	Systematic Assessment	EG0005 affected35 at risk EG0010 affected4 at risk
Decreased appetite	Metabolism and nutrition disorders	MedDRA26.0	Systematic Assessment	EG0004 affected35 at risk EG0010 affected4 at risk
Hypercholesterolaemia	Metabolism and nutrition disorders	MedDRA26.0	Systematic Assessment	EG0003 affected35 at risk EG0010 affected4 at risk
Hyperglycaemia	Metabolism and nutrition disorders	MedDRA26.0	Systematic Assessment	EG0003 affected35 at risk EG0010 affected4 at risk
Hypertriglyceridaemia	Metabolism and nutrition disorders	MedDRA26.0	Systematic Assessment	EG0002 affected35 at risk EG0010 affected4 at risk
Hyperuricaemia	Metabolism and nutrition disorders	MedDRA26.0	Systematic Assessment	EG0002 affected35 at risk EG0010 affected4 at risk
Hypocalcaemia	Metabolism and nutrition disorders	MedDRA26.0	Systematic Assessment	EG0003 affected35 at risk EG0010 affected4 at risk
Hypokalaemia	Metabolism and nutrition disorders	MedDRA26.0	Systematic Assessment	EG0002 affected35 at risk EG0010 affected4 at risk
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA26.0	Systematic Assessment	EG0005 affected35 at risk EG0012 affected4 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA26.0	Systematic Assessment	EG0003 affected35 at risk EG0011 affected4 at risk
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA26.0	Systematic Assessment	EG0002 affected35 at risk EG0010 affected4 at risk
Spinal osteoarthritis	Musculoskeletal and connective tissue disorders	MedDRA26.0	Systematic Assessment	EG0000 affected35 at risk EG0011 affected4 at risk
Cerebrovascular insufficiency	Nervous system disorders	MedDRA26.0	Systematic Assessment	EG0000 affected35 at risk EG0011 affected4 at risk
Dizziness	Nervous system disorders	MedDRA26.0	Systematic Assessment	EG0004 affected35 at risk EG0010 affected4 at risk
Headache	Nervous system disorders	MedDRA26.0	Systematic Assessment	EG0004 affected35 at risk EG0010 affected4 at risk
Hypoaesthesia	Nervous system disorders	MedDRA26.0	Systematic Assessment	EG0002 affected35 at risk EG0011 affected4 at risk
Neuropathy peripheral	Nervous system disorders	MedDRA26.0	Systematic Assessment	EG0003 affected35 at risk EG0010 affected4 at risk
Insomnia	Psychiatric disorders	MedDRA26.0	Systematic Assessment	EG0001 affected35 at risk EG0011 affected4 at risk
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA26.0	Systematic Assessment	EG0003 affected35 at risk EG0010 affected4 at risk
Dermatitis acneiform	Skin and subcutaneous tissue disorders	MedDRA26.0	Systematic Assessment	EG0004 affected35 at risk EG0010 affected4 at risk
Eczema	Skin and subcutaneous tissue disorders	MedDRA26.0	Systematic Assessment	EG0004 affected35 at risk EG0010 affected4 at risk
Papule	Skin and subcutaneous tissue disorders	MedDRA26.0	Systematic Assessment	EG0002 affected35 at risk EG0010 affected4 at risk
Pruritus	Skin and subcutaneous tissue disorders	MedDRA26.0	Systematic Assessment	EG0001 affected35 at risk EG0012 affected4 at risk
Rash	Skin and subcutaneous tissue disorders	MedDRA26.0	Systematic Assessment	EG0002 affected35 at risk EG0010 affected4 at risk
Hypertension	Vascular disorders	MedDRA26.0	Systematic Assessment	EG0003 affected35 at risk EG0011 affected4 at risk

ID	Term
D054219	Neoplasms, Plasma Cell
D009370	Neoplasms by Histologic Type
D009369	Neoplasms
D020141	Hemostatic Disorders
D014652	Vascular Diseases
D002318	Cardiovascular Diseases
D010265	Paraproteinemias
D001796	Blood Protein Disorders
D006402	Hematologic Diseases
D006425	Hemic and Lymphatic Diseases
D006474	Hemorrhagic Disorders
D008232	Lymphoproliferative Disorders
D007160	Immunoproliferative Disorders
D007154	Immune System Diseases

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Ixazomib	Participants received ixazomib 3 mg, capsules, orally, once on Days 1, 8, and 15 for Cycles 1 through 4, during which if the participants tolerated the initial dose, the dose was escalated to ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15 for Cycles 5 through 26, or until documented progressive disease (PD) or intolerable toxicity, whichever occurred first (cycle length=28 days).	1	35	11	35	33	35
EG001	Placebo	Participants received ixazomib placebo-matching capsules, orally, once on Days 1, 8, and 15 of each cycle until Protocol Amendment 08 was implemented (cycle length=28 days).	0	4	0	4	4	4