glycine and Multiple Myeloma

glycine has been researched along with Multiple Myeloma in 162 studies

Multiple Myeloma: A malignancy of mature PLASMA CELLS engaging in monoclonal immunoglobulin production. It is characterized by hyperglobulinemia, excess Bence-Jones proteins (free monoclonal IMMUNOGLOBULIN LIGHT CHAINS) in the urine, skeletal destruction, bone pain, and fractures. Other features include ANEMIA; HYPERCALCEMIA; and RENAL INSUFFICIENCY.

Research

Studies (162)

Authors

Clinical Trials (25)

Trial Overview

Trial Outcomes

Clinical Benefit Rate (CBR)

Disease response status is based on the IMWG criteria being held for two consecutive evaluations at least 4 weeks apart. Clinical benefit rate (CBR) is defined as proportion of patients with minimal response (MR) and better according to International Myeloma Working Group (IMWG) Uniform Response Criteria (Phase II) (NCT02004275)
Timeframe: 3 years

Disease Control Rate (DCR), Defined as Stable Disease (SD) and Better According to International Myeloma Working Group (IMWG) Uniform Response Criteria (Phase II)

Proportion of patients that went two of more cycles of treatment without discontinuing treatment for progression or intolerability. (NCT02004275)
Timeframe: 42 days

Duration of Response (DOR), Calculated for All Patients Achieving an Objective Response, Partial Response (PR) or Better (Phase II)

(NCT02004275)
Timeframe: Up to 3 years

Incidence and Type of Dose Limiting Toxicities (DLTs) Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 (Phase I)

These events are reported in the adverse events section of this report. (NCT02004275)
Timeframe: 44.5 months

Incidence of Dose Reductions/Delays (Phase I)

(NCT02004275)
Timeframe: 39 months

Incidence, Type and Severity of Adverse Events, Graded According to National Cancer Institute (NCI) Common Terminology Criteria Adverse Events (CTCAE) Version 4.0 (Phase II)

The count of paitents that experenced an adverse event is reported in this section. A full table of these events is reported in the adverse event section of this report. (NCT02004275)
Timeframe: 92 months

Maximum Tolerated Dose (MTD) of Pomalidomide and Ixazomib, Determined According to Incidence of Dose Limiting Toxicity (DLT) Graded Using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 (Phase I)

For this protocol, dose-limiting toxicity (DLT) will be defined by the following adverse events at least possibly related to study therapy: Grade 3 or higher non-hematologic toxicity, with the following exceptions: Alopecia is not expected but would not be considered a DLT. Nausea, vomiting and diarrhea will only be considered a DLT if it cannot be adequately managed with optimal supportive care. Grade 3 or 4 hyperglycemia due to dexamethasone will only be considered a DLT if it cannot be controlled with appropriate therapy Grade 4 hematologic toxicity, with the following exceptions: Grade 4 lymphopenia is expected with this regimen and will not be construed as a DLT. Grade 4 neutropenia will only be considered a DLT if it lasts longer than 7 days despite appropriate supportive care. Grade 4 thrombocytopenia will only be considered a DLT if it lasts longer than 7 days or is associated with greater then or equal to grade 3 bleeding event (NCT02004275)
Timeframe: 28 days

Overall Response Rate (ORR)

ORR is defined as partial response (PR), very good partial response (VGPR), complete response (CR), or stringent complete response (sCR) according to International Myeloma Working Group (IMWG) Uniform Response Criteria (NCT02004275)
Timeframe: 3 years

Overall Survival (OS) (Phase II)

Overall survival was analyzed from the time of registration to the date of death or last known date living. Due to median OS time not being reached due to lack of deaths at the time of this report by either arm, the 2 year OS rate has been reported. This analysis censors living patients at 2 years. (NCT02004275)
Timeframe: 2 years

Progression Free Survival (PFS) (Phase II)

progression-free survival (PFS), defined as the time from randomization to the date the International Myeloma Working Group (IMWG) criteria for disease progression is met. If a patient initiates another anti-cancer treatment prior to disease progression, they will be censored at the date of initiation of this treatment. Patients will be randomized to treatment using the Pocock-Simon algorithm balancing the distribution of the following stratification factors between the two treatment arms: 1) ISS 1-2 disease vs. ISS 3 disease (current ISS stage based off screening beta 2 microglobulin and albumin) 2) High risk cytogenetics features: yes vs. no High risk cytogenetics features include: del(1p), gain of 1q, t(4;14), t(14;16), t(14; 20), del(17p) 3) Prior treatment with a proteasome inhibitor: yes vs. no (NCT02004275)
Timeframe: 3 years

Progression Free Survival (PFS) for All Patients on the Pomalidomide/Dexamethasone Arm at the Time of Cross-over to Pomalidomide/Dexamethasone/Ixazomib (Phase II)

(NCT02004275)
Timeframe: Up to 3 years post-registration (at crossover)

Baseline Level of Perceived Fatigue and QOL, Assessed Using the Registration Fatigue/Uniscale Assessment Form (Phase II)

Pre-treatment patient-report of fatigue and overall quality of life (based on a 10-point Likert scale). A higher number indicates a better quality of life where 10 is the best outcome and 0 is the worst. (NCT02004275)
Timeframe: baseline

Response Rates (Overall Response Rate (ORR), Clinical Benefit Rate (CBR), Disease Control Rate (DCR) for All Patients on the Pomalidomide/Dexamethasone Arm at the Time of Cross-over to Pomalidomide/Dexamethasone/Ixazomib (Phase II)

(NCT02004275)
Timeframe: Up to 3 years

Number of Participants With One or More Treatment-emergent Adverse Events (TEAEs)

An adverse event (AE) is any unfavorable or unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product whether or not it was related to the medicinal product. A TEAE is defined as any AE that occurred after administration of the first dose of any study drug through 30 days after the last dose of any study drug. (NCT02917941)
Timeframe: Up to approximately 33 months

Overall Response Rate (ORR)

ORR:percentage of participants with CR including stringent complete response(sCR),VGPR,partial response(PR) per independent review committee(IRC)by IMWG criteria.CR: serum,urine -ve immunofixation; disappearance of soft tissue plasmacytomas,<5%plasma cells in bone marrow(CR in those with only measurable disease by serum FLC levels=normal FLC ratio 0.26 to 1.65+CR criteria).sCR:CR+normal FLC ratio,absence of clonal plasma cells(immunohistochemistry)or 2-to 4-color flow cytometry.VGPR:serum,urine M-protein detectable by immunofixation,not by electrophoresis or ≥90%reduction,<100mg/24hrs(VGPR in those with only measurable disease by serum FLC levels,requires>90%decrease in involved-uninvolved FLC level difference).PR: ≥50%reduction of serum M protein+reduction in 24-hr urinary M protein by≥90%/ to<200mg/24-hr or ≥50%decrease in difference between involved-uninvolved FLC levels/≥50%reduction in bone marrow plasma cells,if≥30%at baseline/≥50%soft tissue plasmacytoma size reduction. (NCT02917941)
Timeframe: Up to approximately 33 months

Overall Survival (OS)

OS was defined as the time from the date of first study drug administration to the date of death. (NCT02917941)
Timeframe: Up to approximately 33 months

Percentage of Participants With Very Good Partial Response (VGPR) or Better Response (Complete Response (CR) + VGPR)

Response was assessed using International Myeloma Working Group (IMWG) Criteria. CR was defined as negative immunofixation in serum and urine and disappearance of any soft tissue plasmacytomas and < 5% plasma cells in bone marrow. VGPR was defined as serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level < 100 mg per 24 hours. (NCT02917941)
Timeframe: Up to approximately 33 months

Progression-free Survival (PFS)

PFS was defined as the time in months from the date of first study drug administration to the date of first documentation of PD or death from any cause, whichever occurred first. PD required one of the following: increase of ≥ 25% from nadir in: serum M-component (absolute increase ≥ 0.5 g/dl); urine M-component (absolute increase ≥ 200 mg/24 hours); in participants without measurable serum and urine M-protein levels the difference between involved and uninvolved free light chain (FLC) levels (absolute increase > 10 mg/dl); development of new or increase in the size of existing bone lesions or soft tissue plasmacytomas; development of hypercalcemia (corrected serum calcium > 11.5 mg/dl) attributed solely to plasma cell proliferative disease. (NCT02917941)
Timeframe: Up to approximately 33 months

Time to Progression (TTP)

TTP was measured as the time in months from the first dose of study treatment to the date of the first documented PD as assessed using IMWG criteria. PD required one of the following: increase of ≥ 25% from nadir in: serum M-component (absolute increase ≥ 0.5 g/dL); urine M-component (absolute increase ≥ 200 mg/24 hours); in participants without measurable serum and urine M-protein levels the difference between involved and uninvolved FLC levels (absolute increase > 10 mg/dL); development of new or increase in the size of existing bone lesions or soft tissue plasmacytomas; development of hypercalcemia (corrected serum calcium > 11.5 mg/dL) attributed solely to plasma cell proliferative disease. (NCT02917941)
Timeframe: Up to approximately 33 months

Duration of Response (DOR)

DOR was measured as time in months from date of first documentation of response, VGPR or better, and ORR (CR+PR (including sCR and VGPR) or better, to date of first documented PD among participants who responded to treatment. Response was assessed by investigator using IMWG Criteria. CR:negative immunofixation in serum and urine and; disappearance of any soft tissue plasmacytomas and;<5% plasma cells in bone marrow. sCR:CR plus normal FLC ratio, absence of clonal plasma cells by immunohistochemistry or 2- to 4-color flow cytometry. VGPR:serum and urine M-protein detectable by immunofixation but not on electrophoresis/≥90% reduction in serum M-protein plus urine M-protein level <100 mg/24 hours. PR:≥50% reduction of serum M protein+reduction in 24-hour urinary M protein by ≥90%/ to <200 mg/24-hour or ≥50% decrease in difference between involved and uninvolved FLC levels/≥50% reduction in bone marrow plasma cells, if ≥30% at baseline/≥50% reduction in size of soft tissue plasmacytomas. (NCT02917941)
Timeframe: Up to approximately 33 months

Number of Participants With NCI CTCAE Grade 3 or Higher TEAEs Related Laboratory Parameters

Laboratory parameters included chemistry and hematology. An AE is any unfavorable or unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product whether or not it was related to the medicinal product. A TEAE is defined as any AE that occurred after administration of the first dose of any study drug through 30 days after the last dose of any study drug. An AE was graded as per NCI CTCAE. (NCT02917941)
Timeframe: Up to approximately 33 months

Number of Participants With NCI CTCAE Grade 3 or Higher TEAEs Related to Vital Signs

Vital signs included temperature, blood pressure, heart rate, and respiratory rate. An AE is any unfavorable or unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product whether or not it was related to the medicinal product. A TEAE is defined as any AE that occurred after administration of the first dose of any study drug through 30 days after the last dose of any study drug. An AE was graded as per NCI CTCAE. (NCT02917941)
Timeframe: Up to approximately 33 months

Duration of Response (DOR)

DOR: Time from first documentation of CR/PR/VGPR to first documentation of PD. Per IMWG criteria, PR:>=50% reduction of serum M protein+reduction in 24-hour urinary M protein by >=90% to <200 mg/24-hour or >=50% decrease in difference between involved and uninvolved FLC levels/ >=50% reduction in bone marrow plasma cells, if >=30% at Baseline/ >=50% reduction in size of soft tissue plasmacytomas. VGPR: serum+urine M-protein detectable by immunofixation but not on electrophoresis/ >=90% reduction in serum M-protein + urine M-protein level <100 mg/24-hour. CR:negative immunofixation on serum + urine+disappearance of soft tissue plasmacytomas+<5% plasma cells in bone marrow. PD:serum M-component increase >=0.5 g/dl or urine M-component increase >=200 mg/24-hour/ difference between involved and uninvolved FLC levels increase >10 mg/dl or bone marrow plasma cell >=10%/development of new/ increase in size of existing bone lesions or soft tissue plasmacytoma or development of hypercalcemia. (NCT03170882)
Timeframe: From date of first documentation of CR, VGPR or PR until first occurrence of confirmed disease progression or death due to any cause, whichever occurs first (Up to approximately 3 years)

Overall Survival (OS)

OS was defined as the time from randomization to death from any cause, up to 3 years are reported. (NCT03170882)
Timeframe: From date of randomization to death due to any cause (Up to approximately 3 years)

Percentage of Participants With Overall Response

Overall Response Rate (ORR) was defined as the percentage of participants who achieved partial response (PR), very good partial response (VGPR), or complete response (CR) based on laboratory results and IRC assessment using modified IMWG criteria. PR: >=50% reduction of serum M protein + reduction in 24-hour urinary M protein by >=90% or to <200 mg/24-hour; if M protein is not measurable, >=50% decrease in difference between involved and uninvolved FLC levels is required; if not measurable by FLC, >=50% reduction in bone marrow plasma cells, when baseline value >=30% and; if present at baseline, >=50% reduction in size of soft tissue plasmacytomas is required. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis or >=90% reduction in serum M-protein + urine M-protein level <100 mg/24-hour. CR: negative immunofixation on serum + urine; disappearance of soft tissue plasmacytomas; <5 % plasma cells in bone marrow. (NCT03170882)
Timeframe: From date of randomization until first documentation of CR, VGPR or PR (Up to approximately 3 years)

Progression Free Survival (PFS)

PFS: Time from randomization to first occurrence of confirmed progressive disease (PD) as assessed by investigator by International Myeloma Working Group(IMWG) response criteria/death from any cause, whichever occurs first. PD requires following: Increase of >=25 % from nadir in: Serum M component (increase must be >=0.5 gram per deciliter [g/dl]); Urine M-component (increase must be >=200 milligram [mg]/24-hour); In participants without measurable serum and urine M-protein levels difference between involved and uninvolved free light chain (FLC) increase of >10 mg/dl; In participants without measurable serum and urine M protein levels and without measurable disease by FLC level: bone marrow plasma cell percentage must be >=10%; Development of new/increase in size of existing bone lesions/soft tissue plasmacytomas; development of hypercalcemia (>11.5mg/dL corrected serum calcium) attributed solely to plasma cell proliferative disease. (NCT03170882)
Timeframe: From date of randomization until first occurrence of confirmed disease progression or death due to any cause, whichever occurs first (Up to approximately 3 years)

Time to Progression (TTP)

TTP was defined as the time from the date of randomization to first documentation of PD. Per IMWG criteria, PD required 1 of the following: Increase of >=25% from nadir in: Serum M-component (increase must be >=0.5 g/dl; Urine M-component (increase must be >=200 mg/24-hour); In participants without measurable serum and urine M-protein levels difference between involved and uninvolved FLC levels increase of >10 mg/dl; In participants without measurable serum and urine M protein levels and without measurable disease by FLC level: Bone marrow plasma cell percentage must be >=10%; Development of new or increase in size of existing bone lesions or soft tissue plasmacytomas; Development of hypercalcemia (>11.5 mg/dL corrected serum calcium) attributed solely to plasma cell proliferative disease. (NCT03170882)
Timeframe: From date of randomization until first occurrence of confirmed disease progression or death due to any cause, whichever occurs first (Up to approximately 3 years)

Time to Response

Time to response was defined as the time from randomization to the first documentation of PR/VGPR/CR. Per IMWG criteria, PR: >=50% reduction of serum M protein + reduction in 24-hour urinary M protein by >=90% or to <200 mg/24-hour; if M-protein is not measurable, >=50% decrease in difference between involved and uninvolved FLC levels is required; if not measurable by FLC, >=50% reduction in bone marrow plasma cells, when Baseline value >=30% and; if present at Baseline, >=50% reduction in size of soft tissue plasmacytomas is required. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis or >=90% reduction in serum M-protein + urine M-protein level <100 mg/24-hour. CR: negative immunofixation on serum + urine; disappearance of soft tissue plasmacytomas; <5% plasma cells in bone marrow. (NCT03170882)
Timeframe: From date of randomization until first documentation of CR, VGPR or PR (Up to approximately 3 years)

Health Care Utilization (HU): Number of Participants With at Least One Medical Encounter

Healthcare resources used during medical encounters included hospitalizations, emergency room stays, or outpatient visits. A hospitalization was defined as at least 1 overnight stay in an Intensive Care Unit and/or non-Intensive Care Unit (acute care unit, palliative care unit, and hospice). (NCT03170882)
Timeframe: Up to approximately 3 years

Health-Related Quality of Life (HRQOL) Based on European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 (EORTC QLQ-C30) Physical Domain Score

The EORTC QLQ-C30 contains 30 items across 5 functional scales (physical, role, cognitive, emotional, and social), 9 symptom scales (fatigue, nausea and vomiting, pain, dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial difficulties) and a global health status/quality of life (QOL) scale. The physical domain consisted of 5 items covering participant's daily physical activities on a scale from 1 (not at all) to 4 (very much). Raw scores were linearly transformed to a total score between 0-100, with a high score indicating better physical functioning. (NCT03170882)
Timeframe: Baseline and End of Treatment (Up to 28 cycles, each cycle was of 28 days)

HRQOL Based on EORTC Multiple Myeloma Module 20 (EORTC QLQ-MY20) Score

The EORTC QLQ-MY20 has 20 items across 4 independent subscales, 2 symptoms scales (disease symptoms, side effects of treatment), and 2 functional subscales (body image, future perspective). Scores were averaged and transformed to 0-100 scale. Higher scores for the future perspective scale indicate better perspective of the future, for the body image scale indicate better body image and for the disease symptoms scale indicate higher level of symptomatology. (NCT03170882)
Timeframe: Baseline and End of Treatment (Up to 28 cycles, each cycle was of 28 days)

HRQOL Based on EORTC QLQ-C30 SubScale Score

The EORTC QLQ-C30 contains 30 items across 5 functional scales (physical, role, cognitive, emotional, and social), 9 symptom scales (fatigue, nausea and vomiting, pain, dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial difficulties) and a QOL scale. Most of the 30 items had 4 response levels (not at all, a little, quite a bit, and very much), with 2 questions relying on a 7-point numeric rating scale. Each subscale raw score were linearly transformed to a total score between 0 to 100. For the functional scales and the global health status/QOL scale, higher scores represent better QOL; for the symptom scales, lower scores represent better QOL. The Physical domain of the functional subscale is reported in the secondary outcome measure 7. (NCT03170882)
Timeframe: Baseline and End of Treatment (Up to 28 cycles, each cycle was of 28 days)

HRQOL Based on EuroQol Visual Analogue Scale (EQ VAS) Score

The EQ VAS records the respondent's self-rated health on a 20 centimeter (cm), vertical, visual analogue scale ranging from 0 (worst imaginable health state) to 100 (best imaginable health state). The scores from all dimensions were combined into a single index score that was reported, where higher score was better quality of life. (NCT03170882)
Timeframe: Baseline and End of Treatment (Up to 28 cycles, each cycle was of 28 days)

HU: Duration of Medical Encounters

Duration of healthcare resources used during medical encounters including hospitalizations, emergency room stays, or outpatient visits was reported in days. A hospitalization was defined as at least 1 overnight stay in an Intensive Care Unit and/or non-Intensive Care Unit (acute care unit, palliative care unit, and hospice). (NCT03170882)
Timeframe: Up to approximately 3 years

Number of Participants With Responses to HRQOL Based on 5-level Classification System of the EuroQol 5-Dimensional Health Questionnaire (EQ-5D-5L) Score

EQ-5D-5L comprises of 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), each rated on 5 levels: 1= no problems, 2= slight problems, 3= moderate problems, 4= severe problems, 5= extremely severe problems. Higher scores indicated greater levels of problems across the five dimensions. (NCT03170882)
Timeframe: End of Treatment (Up to 28 cycles, each cycle was of 28 days)

Maximum Tolerated (MTD) Dose of Cyclophosphamide (Phase I)

Will be defined as the dose level below the lowest dose that induces dose-limiting toxicity in at least 1/3 of patients, as assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. (NCT01864018)
Timeframe: At 28 days

Number of Patients Experiencing a Grade 3 or Greater Adverse Event at Least Possibly Related to Treatment as Assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0

The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration. Adverse events will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. A grade 3 event is one that is severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. (NCT01864018)
Timeframe: Up to 5 years

Percentage of Patients With Complete Response or Very Good Partial Response (Phase II, Cohort A)

The percentage of successes will be estimated by the number of successes divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true success proportion will be calculated. (NCT01864018)
Timeframe: Up to 48 weeks

Progression-free Survival (PFS)

The distribution of PFS will be estimated using the method of Kaplan Meier. (NCT01864018)
Timeframe: Time from registration to the earliest date of documentation of disease progression or death due to any cause, assessed up to 5 years

Rate of Complete Response, Very Good Partial Response, or Partial Response (Phase II, Cohort B)

The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true success proportion will be calculated. (NCT01864018)
Timeframe: Up to 48 weeks

Survival Time

The distribution of survival time will be estimated using the method of Kaplan-Meier. (NCT01864018)
Timeframe: Time from registration to death due to any cause, assessed up to 5 years

Maximum Tolerated (MTD) Dose of Cyclophosphamide With Ixazomib and Dexamethasone (Phase I)

Will be defined as the dose level below the lowest dose that induces dose-limiting toxicity in at least 1/3 of patients, as assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. (NCT01864018)
Timeframe: At 28 days

Progression Free Survival (PFS)

PFS was defined as the time from the date of randomization to the date of first documentation of progressive disease (PD), as evaluated by an independent review committee according to International Myeloma Working Group (IMWG) criteria, or death due to any cause, whichever occured first. PD was defined as ≥25% increase from lowest value in: serum/urine M component; participants without measurable serum and urine M-protein levels, the difference between involved and uninvolved free light chain (FLC) levels must be >10 mg/dL; participants without measurable serum, urine M-protein levels and FLC levels, bone marrow plasma cell percent must have been ≥10%; new bone lesions/soft tissue plasmacytomas development/existing bone lesions/soft tissue plasmacytomas size increase; hypercalcemia development. (NCT02181413)
Timeframe: Randomization up to End of treatment (EOT) (24 months); thereafter followed up every 4 weeks until progression of disease or death (to data cutoff: approximately 4 years)

Duration of Response (DOR)

DOR was measured as the time in months from the date of first documentation of a confirmed response of PR or better (CR [including sCR] + PR+ VGPR) to the date of the first documented disease progression (PD) among participants who responded to the treatment. Response was assessed by the investigator using International Myeloma Working Group (IMWG) Criteria. (NCT01564537)
Timeframe: Day 1 of each cycle (every 4 weeks) until disease progression up to approximately 38 months

OS in High-Risk Participants

Overall survival (OS) is defined as the time from the date of randomization to the date of death. High-risk participants are defined as participants carrying cytogenic abnormalities: del(17), translocation t(4;14), or t(14;16) as reported by the central laboratory combined with those cases that lacked a central laboratory result but with known del (17), t(4;14), or t(14;16) by local laboratory. Cytogenetic abnormalities of del(13) and +1q are not included in the analysis. Participants without documentation of death at the time of the analysis were censored at the date when they were last known to be alive. Data is only reported for high-risk participants. (NCT01564537)
Timeframe: From the time of screening until disease progression and thereafter every 12 weeks until death or study termination (up to approximately 97 months)

Overall Response Rate (ORR) as Assessed by the IRC

ORR was defined as the percentage of participants with Complete Response (CR) including stringent complete response (sCR), very good partial response (VGPR) and Partial Response (PR) assessed by the IRC using IMWG criteria. Percentages are rounded off to single decimal. (NCT01564537)
Timeframe: Day 1 of each cycle (every 4 weeks) until disease progression up to approximately 27 months(approximate median follow-up 15 months)

Overall Response Rate in Participants Defined by Polymorphism

Data is reported for percentage of participants defined by polymorphism defined by polymorphisms in proteasome genes, such as polymorphism P11A in PSMB1 gene. Percentages are rounded off to single decimal. (NCT01564537)
Timeframe: Day 1 of each cycle (every 4 weeks) until disease progression up to approximately 27 months (approximate median follow-up 15 months)

Overall Survival (OS)

Overall survival is defined as the time from the date of randomization to the date of death. Participants without documentation of death at the time of the analysis were censored at the date when they were last known to be alive. (NCT01564537)
Timeframe: From date of randomization until death (up to approximately 97 months)

Overall Survival in High-Risk Participants Carrying Deletion 17 [Del(17)]

Overall survival is defined as the time from the date of randomization to the date of death. The high-risk participants whose myeloma carried del(17) subgroup was defined as the cases reported as positive for del(17) by the central laboratory combined with those cases that lacked a central laboratory result but with known del (17) by local laboratory. Participants without documentation of death at the time of the analysis were censored at the date when they were last known to be alive. Data is only reported high-risk participants with Del(17). (NCT01564537)
Timeframe: From the time of screening until disease progression and thereafter every 12 weeks until death or study termination (up to approximately 97 months)

Percentage of Participants With Complete Response (CR) and Very Good Partial Response (VGPR) as Assessed by the IRC

Response was assessed by the IRC using International Myeloma Working Group (IMWG) Criteria. CR is defined as negative immunofixation on the serum and urine and; disappearance of any soft tissue plasmacytomas and; < 5% plasma cells in bone marrow. VGPR is defined as Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level < 100 mg per 24 hours. Percentages are rounded off to single decimal. (NCT01564537)
Timeframe: Day 1 of each cycle (every 4 weeks) until disease progression up to approximately 27 months (approximate median follow-up 15 months)

PFS in High-Risk Participants

Progression Free Survival (PFS) is defined as the time from the date of randomization to the date of first documentation of disease progression or death due to any cause, whichever occurs first. Response was assessed by independent review committee (IRC) using IMWG response criteria. High-risk participants are defined as participants carrying cytogenic abnormalities: del(17), translocation t(4;14), or t(14;16) as reported by the central laboratory combined with those cases that lacked a central laboratory result but with known del (17), t(4;14), or t(14;16) by local laboratory. Cytogenetic abnormalities of del(13) and +1q are not included in the analysis. (NCT01564537)
Timeframe: From date of randomization until disease progression or death up to approximately 38 months (approximate median follow-up 15 months)

Progression Free Survival (PFS) as Assessed by the Independent Review Committee (IRC)

Progression Free Survival (PFS) is defined as the time from the date of randomization to the date of first documentation of disease progression (PD) or death due to any cause, whichever occurs first. Response including PD was assessed by independent review committee (IRC) using the International Myeloma Working Group (IMWG) response criteria. PD requires 1 of the following: Increase of ≥ 25% from nadir in: Serum M-component (absolute increase ≥ 0.5 g/dl); Urine M-component (absolute increase ≥ 200 mg/24 hours); In patients without measurable serum and urine M-protein levels the difference between involved and uninvolved free light chain (FLC) levels (absolute increase > 10 mg/dl); Development of new or increase in the size of existing bone lesions or soft tissue plasmacytomas; Development of hypercalcemia (corrected serum calcium > 11.5 mg/dl) attributed solely to plasma cell proliferative disease. Status evaluated every 4 weeks until disease progression (PD) was confirmed. (NCT01564537)
Timeframe: From date of randomization until disease progression or death up to approximately 27 months (approximate median follow-up 15 months)

Time to Progression (TTP) as Assessed by the IRC

TTP was measured as the time in months from the first dose of study treatment to the date of the first documented progressive disease (PD) as assessed by the IRC using IMWG criteria. (NCT01564537)
Timeframe: Day 1 of each cycle (every 4 weeks) until disease progression up to approximately 27 months (approximate median follow-up 15 months)

Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30)

The EORTC-QLQ-C30 is a 30-question tool used to assess the overall quality of life in cancer participants. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact).The EORTC-QLQ-C30 Global Health Status/QOL Scale is scored between 0 and 100, where higher scores indicate better Global Health Status/QOL. Negative changes from baseline indicate deterioration in QOL or functioning and positive changes indicate improvement. Scores are linearly transformed to a 0-100 scale. High scores for the global and functional domains indicate higher quality of life or functioning. Higher scores on the symptom scales represent higher levels of symptomatology or problems. (NCT01564537)
Timeframe: Baseline, EOT and follow-up (up to approximately 97 months)

Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30)

The EORTC-QLQ-C30 is a 30-question tool used to assess the overall quality of life in cancer participants. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact).The EORTC-QLQ-C30 Global Health Status/QOL Scale is scored between 0 and 100, where higher scores indicate better Global Health Status/QOL. Negative changes from baseline indicate deterioration in QOL or functioning and positive changes indicate improvement. Scores are linearly transformed to a 0-100 scale. High scores for the global and functional domains indicate higher quality of life or functioning. Higher scores on the symptom scales represent higher levels of symptomatology or problems. (NCT01564537)
Timeframe: Baseline, EOT and follow-up (up to approximately 97 months)

Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Multiple Myeloma Module (QLQ-MY-20)

The EORTC-QLQ-MY-20 is a patient-completed, 20-question quality of life questionnaire that has 4 independent subscales, 2 functional subscales (body image, future perspective), and 2 symptoms scales (disease symptoms and side-effects of treatment). The participant answers questions about their health during the past week using a 4-point scale where 1=Not at All to 4=Very Much. A negative change from Baseline indicates improvement. Scores are linearly transformed to a 0-100 scale. Higher scores on the symptom scales (e.g. Disease Symptoms, Side Effects of Treatment) represent higher levels of symptomatology or problems. High scores for Body Image and Future Perspective represent better quality of life or functioning. (NCT01564537)
Timeframe: Baseline, EOT and follow-up (up to approximately 97 months)

Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Multiple Myeloma Module (QLQ-MY-20)

The EORTC-QLQ-MY-20 is a patient-completed, 20-question quality of life questionnaire that has 4 independent subscales, 2 functional subscales (body image, future perspective), and 2 symptoms scales (disease symptoms and side-effects of treatment). The participant answers questions about their health during the past week using a 4-point scale where 1=Not at All to 4=Very Much. A negative change from Baseline indicates improvement. Scores are linearly transformed to a 0-100 scale. Higher scores on the symptom scales (e.g. Disease Symptoms, Side Effects of Treatment) represent higher levels of symptomatology or problems. High scores for Body Image and Future Perspective represent better quality of life or functioning. (NCT01564537)
Timeframe: Baseline, EOT and follow-up (up to approximately 97 months)

Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

Eastern Cooperative Oncology Group (ECOG) performance score, laboratory values, vital sign measurements and reported adverse events (AEs) were collected and assessed to evaluate the safety of therapy throughout the study. An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; or congenital anomaly; or a medically important event. (NCT01564537)
Timeframe: From the date of signing of the informed consent form through 30 days after the last dose of study drug up to approximately 115 months

Number of Participants With Change From Baseline in Pain Response

"Pain response was defined as 30% reduction from Baseline in Brief Pain Inventory-Short Form (BPI-SF) worst pain score over the last 24 hours without an increase in analgesic (oral morphine equivalents) use at 2 consecutive evaluations. The BPI-SF contains 15 items designed to capture the pain severity (worst, least, average, and now [current pain]), pain location, medication to relieve the pain, and the interference of pain with various daily activities including general activity, mood, walking activity, normal work, relations with other people, sleep, and enjoyment of life. The pain severity items are rated on a 0 to 10 scale where: 0=no pain and 10=pain as bad as you can imagine and averaged for a total score of 0 (best) to 10 (Worst)." (NCT01564537)
Timeframe: Baseline and end of treatment (EOT) (up to approximately 38 months)

Plasma Concentration Over Time for Ixazomib

(NCT01564537)
Timeframe: Pre-dose and post-dose at multiple timepoints up to Cycle 10 Day 1 (each cycle length = 28 days)

Plasma Concentration Over Time for Ixazomib

(NCT01564537)
Timeframe: Pre-dose and post-dose at multiple timepoints up to Cycle 10 Day 1 (each cycle length = 28 days)

Duration of Next-line Therapy

Duration of next-line therapy is defined as the time from the date of the first dose of the next line of antineoplastic therapy coming after study treatment to the date of the last dose. (NCT02312258)
Timeframe: From randomization until PD or death (up to 52 months)

OS in a High-risk Population

High-risk population included but not be limited to participants carrying cytogenetic deletion (del)17, translocation [t](4;14), t(14;16). OS was measured as the time from the date of randomization to the date of death. (NCT02312258)
Timeframe: From the date of randomization and every 12 weeks after PD on next-line therapy until death (up to 88 months)

Overall Survival (OS)

OS was measured as the time from the date of randomization to the date of death. (NCT02312258)
Timeframe: From the date of randomization and every 12 weeks after PD on next-line therapy until death (up to 88 months)

Percentage of Participants Who Develop a New Primary Malignancy

(NCT02312258)
Timeframe: From randomization until PD or death (up to 52 months)

Percentage of Participants With Conversion From Minimal Residual Disease (MRD) Positive to MRD Negative

Bone marrow aspirates and blood samples were sent to a central laboratory and were assessed for MRD using flow cytometry. MRD negativity was defined as absence of MRD and MRD positivity was defined as presence of MRD. MRD was assessed by 8-color flow cytometry with the IMWG recommended sensitivity of 10^-5. (NCT02312258)
Timeframe: Up to 52 months

PFS in a High-risk Population

High-risk population included but not be limited to participants carrying del17, t(4;14), t(14;16). PFS was defined as the time from the date of randomization to the date of first documentation of PD or death from any cause. (NCT02312258)
Timeframe: From randomization until PD or death (up to 52 months)

Progression Free Survival (PFS)

PFS is defined as the time from the date of randomization to the date of first documentation of progressive disease (PD) or death from any cause, as evaluated by an independent review committee (IRC) according to International Myeloma Working Group (IMWG) criteria, or death due to any cause, whichever occurs first. Per IMWG criteria, PD is defined as, increase of 25% of lowest response value in one or more of following criteria: serum M-component (absolute increase ≥0.5 g/ deciliter (dL)); or urine M-component (absolute increase ≥200 mg/24-hour); difference between involved and uninvolved free light chains (FLC) levels (absolute increase >10 mg/dL); or bone marrow plasma cell percentage (absolute plasma cell percentage ≥10%); development of new/ increase in size of existing bone lesions or soft tissue plasmacytoma; or development of hypercalcemia (corrected serum calcium >11.5mg/dL). (NCT02312258)
Timeframe: From randomization until PD or death (up to 52 months)

Progression Free Survival 2 (PFS2)

PFS2 is defined as the time from the date of randomization to objective PD on next-line treatment using IMWG criteria, or death due to any cause, whichever occurred first. (NCT02312258)
Timeframe: From the date of randomization to every 12 weeks until second PD or death (up to 88 months)

Time to End of the Next-line of Therapy After Study Treatment

Time to end of the next line of therapy is defined as the time from the date of randomization to the date of last dose of the next line of antineoplastic therapy following study treatment. (NCT02312258)
Timeframe: From randomization until PD or death (up to 52 months)

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 was considered as resolved if its final outcome was resolved with no subsequent PN event of the same preferred term occurring on the improvement date or the day before and after. Time to improvement was defined as the time from the initial onset date (inclusive) to the improvement of event. (NCT02312258)
Timeframe: Up to 52 months

Time to Next Line Therapy (TTNT)

TTNT is defined as the time from the date of randomization to the date of the first dose of next-line antineoplastic therapy. (NCT02312258)
Timeframe: From randomization until PD or death (up to 52 months)

Time to Progression (TTP)

TTP is defined as the time from the date of randomization to the date of first documentation of PD, using IMWG criteria. (NCT02312258)
Timeframe: From randomization until PD or death (up to 52 months)

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. (NCT02312258)
Timeframe: Up to 52 months

Change From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status

ECOG performance status assesses a participant's performance status on a 6-point scale ranging from 0=fully active/able to carry on all pre-disease activities without restriction; 1=restricted in physically strenuous activity, ambulatory/able to carry out light or sedentary work; 2=ambulatory (>50% of waking hours), capable of all self-care, unable to carry out any work activities; 3=capable of only limited self-care, confined to bed/chair >50% of waking hours; 4=completely disabled, cannot carry on any self-care, totally confined to bed/chair; 5=dead. Lower grades indicate improvement. (NCT02312258)
Timeframe: Baseline, Day 1 of Cycles 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, and 26, progression free survival follow-up (PFSFU)- Visit 37 and progressive disease follow-up (PDFU)- Visit 26 (cycle length=28 days)

Change From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status

ECOG performance status assesses a participant's performance status on a 6-point scale ranging from 0=fully active/able to carry on all pre-disease activities without restriction; 1=restricted in physically strenuous activity, ambulatory/able to carry out light or sedentary work; 2=ambulatory (>50% of waking hours), capable of all self-care, unable to carry out any work activities; 3=capable of only limited self-care, confined to bed/chair >50% of waking hours; 4=completely disabled, cannot carry on any self-care, totally confined to bed/chair; 5=dead. Lower grades indicate improvement. (NCT02312258)
Timeframe: Baseline, Day 1 of Cycles 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, and 26, progression free survival follow-up (PFSFU)- Visit 37 and progressive disease follow-up (PDFU)- Visit 26 (cycle length=28 days)

Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC 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." (NCT02312258)
Timeframe: Baseline, Cycles 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, and 26 (cycle length=28 days)

Correlation Between Frailty Status and PFS and OS

Participant's frailty status is classified as fit, unfit or frail on the bases 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 randomization to the date of first documentation of PD or death from any cause, as evaluated by an IRC according to IMWG criteria, or death due to any cause, whichever occurs first, assessed for up to 52 months in this outcome measure. OS will be measured as the time from the date of randomization to the date of death, assessed for up to 52 months in this outcome measure. (NCT02312258)
Timeframe: From randomization up to 52 months

Correlation of MRD Status With PFS and OS

PFS is defined as the time from the date of randomization to the date of first documentation of PD or death from any cause, as evaluated by an IRC according to IMWG criteria, or death due to any cause, whichever occurred first, assessed for up to 52 months in this outcome measure. OS was measured as the time from the date of randomization to the date of death, assessed for up to 52 months in this outcome measure. Participants with various types of known MRD status were pooled together for analysis of overall survival in this outcome measure. (NCT02312258)
Timeframe: From randomization up to 52 months

Percentage of Participants Who Achieve or Maintain Any Best Response Category During the Treatment Period

Response was assessed according to IMWG criteria based on IRC assessment. Best response included PR, VGPR and CR. PR= >=50% reduction of serum M protein and >=90% or <200 mg reduction urinary M protein in 24-hour, or >50% decrease in difference between involved and uninvolved FLC levels, or >50% reduction in bone marrow plasma cells, if bone marrow plasma cells >30% and >50% reduction in size of soft tissue plasmacytomas at baseline. VGPR= >90% reduction (<100 mg/24-hour) in serum M-protein + urine M-protein detectable by immunofixation but not on electrophoresis. Complete response= >5% plasma cells in myelogram with absence of paraprotein in serum and urine according to immunofixation. (NCT02312258)
Timeframe: Up to 27 months

Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

An adverse event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (e.g., a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. TEAEs were defined as events that occurred after administration of the first dose of ixazomib or placebo through 30 days after the last dose of ixazomib or placebo. A SAE means any untoward medical occurrence that resulted in death, was life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect or was considered medically significant. (NCT02312258)
Timeframe: First dose of study drug through 30 days after last dose of study drug (up to 88 months)

Pharmacokinetic Parameter: 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. (NCT02312258)
Timeframe: 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)

Complete Response (CR) Rate

CR rate was defined as the percentage of participants who achieve CR assessed by an IRC relative to the intent-to-treat (ITT) population during the treatment period. Percentage of participants with CR, as assessed by IMWG disease assessment criteria were reported. CR was defined as negative immunofixation of serum and urine along with the disappearance of any soft tissue plasmacytomas and <5 % plasma cells (PC's) in bone marrow. (NCT01850524)
Timeframe: Up to approximately 9 years

Duration of Response

Duration of response was measured as the time from the date of first documentation of PR or better to the date of first documented progression (PD) for responders, as measured by IMWG criteria. (NCT01850524)
Timeframe: Up to approximately 9 years

OS in High-risk Population Carrying Del(17p), t(4;14), or t(14;16) Mutations

OS was defined as the time from the date of randomization to the date of death, as assessed in high-risk population carrying del(17p), t(4;14), or t(14;16) mutations. High risk category includes t(4;14), t(14;16), or del(17) abnormalities. (NCT01850524)
Timeframe: From the date of randomization to death due to any cause (Up to approximately 9 years)

Overall Response Rate (ORR)

ORR was defined as the percentage of participants who achieved CR + partial response (PR) + very good partial response (VGPR) (including sCR) or better relative to the ITT population during treatment period. CR was defined as negative immunofixation of serum and urine along with the disappearance of any soft tissue plasmacytomas and <5 % PC's in bone marrow. PR was defined as ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% along with ≥50% reduction in the size of soft tissue plasmacytomas. VGPR was defined as ≥90% in serum M-component plus urine M-component <100 mg/24. sCR is defined as stringent complete response. Percentages are rounded off to nearest whole numbers. (NCT01850524)
Timeframe: Up to approximately 9 years

Overall Survival (OS)

OS was defined as the time from the date of randomization to the date of death. Participants without documented death at the time of analysis are censored at the date last known to be alive. (NCT01850524)
Timeframe: From the date of randomization to death due to any cause (Up to approximately 9 years)

Pain Response Rate as Assessed by the Brief Pain Inventory- Short Form (BPI-SF) and Analgesic Use

Pain response rate was defined as percentage of participants with pain response. Pain response was defined as the occurrence of at least a 30% reduction from baseline in BPI-SF worst pain score over the last 24 hours without an increase in analgesic use for 2 consecutive measurements > 28 days apart, were reported. Brief Pain Inventory - Short Form (m-BPI-SF) is a participant rated 11-point Likert rating scale ranged from 0 (no pain) to 10 (worst pain imaginable). Percentages are rounded off to the nearest single decimal. (NCT01850524)
Timeframe: Up to approximately 9 years

Percentage of Participants With MRD-Negative Status as Assessed by Flow Cytometry

The absence of minimal residual disease (MRD negativity) was tested in all participants who achieve a CR and maintained it until Cycle 18, using bone marrow aspirates. (NCT01850524)
Timeframe: Up to Cycle 18 (cycle length = 28 days)

Percentage of Participants With New or Worsening of Existing Skeletal-related Events (SREs)

SRE is defined as new fractures [including vertebral compression fractures], irradiation of or surgery on bone, or spinal cord compression. (NCT01850524)
Timeframe: From the date of randomization through 30 days after the last dose of study drug up to end of study (up to approximately 9 years)

PFS in High-risk Population Carrying Del(17p), t(4;14), or t(14;16) Mutations

PFS was defined as the time from the date of randomization to the date of first documentation of progressive disease based on central laboratory results and IMWG criteria as evaluated by an independent review committee (IRC) or death due to any cause, whichever occurs first, as assessed in high-risk population carrying del(17p), t(4;14), or t(14;16) mutations. (NCT01850524)
Timeframe: Up to approximately 9 years

Progression Free Survival (PFS)

PFS was defined as the time from the date of randomization to the date of first documentation of progressive disease (PD) or death due to any cause according to International Myeloma Working Group (IMWG) criteria whichever occurs first. PD required one of the following: Increase of >=25% from nadir in: Serum M-component and/or (the absolute increase must be >=0.5 g/dL); Urine M-component and/or (the absolute increase must be >=200 mg/24 hours); in participants without measurable serum and urine M-protein levels: the difference between involved and uninvolved free light chain (FLC) levels (absolute increase must be > 10 mg/dL); Bone marrow plasma cell percentage: the absolute % must be >10%; development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas; hypercalcemia (corrected serum calcium > 11.5 mg/dL or 2.85 mmol/L). (NCT01850524)
Timeframe: Up to approximately 79 months

Progression Free Survival (PFS)-2

PFS2 was defined as the time from the date of randomization to the date of documentation of disease progression on the subsequent line of anticancer therapy, as assessed by the investigator in accordance with IMWG criteria, or death due to any cause, whichever occurs first. (NCT01850524)
Timeframe: Up to approximately 9 years

Time to Pain Progression

Time to pain progression was assessed as the time from randomization to the date of initial progression classification. Pain progression was defined as the occurrence of 1 of the following and confirmed by 2 consecutive evaluations (To qualify as progression, the participant must have a BPI-SF worst pain score > 4 during pain progression): 1) a ≥ 2 point and 30% increase from Baseline in BPI-SF worst pain score without an increase in analgesic use, or 2) a 25% or more increase in analgesic use from Baseline without a decrease in BPI-SF worst pain score from Baseline. Brief Pain Inventory - Short Form (m-BPI-SF) is a participant rated 11-point Likert rating scale ranged from 0 (no pain) to 10 (worst pain imaginable). (NCT01850524)
Timeframe: Up to approximately 9 years

Time to Progression (TTP)

Time to progression was defined as the time from randomization to the date of first documented disease progression. (NCT01850524)
Timeframe: Up to approximately 9 years

Time to Response

Time to response was defined as the time from the date of randomization to the first documentation of PR or better, as measured by IMWG criteria. (NCT01850524)
Timeframe: Up to approximately 9 years

Change From Baseline in Health-Related Quality of Life (HRQOL) Measured by European Organisation for Research and Treatment of Cancer-Quality of Life Questionnaire (EORTC-QLQ)-C30 Scale Total Score

EORTC-QLQ-C30 scale was used to assess HRQOL in cancer participants and contains 30 items. Subscale with individual items include physical functioning items 1-5, role functioning items 6-7, emotional functioning items 21-24, cognitive functioning items 20, 25, social functioning items 26-27, quality of life items 29-30, fatigue items 10, 12, 18, nausea and vomiting items 14-15, pain items 9, 19, dyspnoea item 8, insomnia item 11, appetite loss item 13, constipation item 16, diarrhoea item 17, financial difficulties item 28. Raw scores were converted into scale scores ranging from 0 to 100. For the functional scales and the global health status scale, higher scores represent better HRQOL; whereas for the symptom scales lower scores represent better HRQOL. Positive change in functional and global health status scale indicated improvement; negative change for the symptom scales indicates improvement. (NCT01850524)
Timeframe: Baseline to approximately 9 years

Change From Baseline in HRQOL Measured by EORTC-QLQ-MY20 Scale

EORTC QLQ-MY20 was a validated questionnaire to assess the overall quality of life in participants with multiple myeloma. The scale has 20 questions. Subscale and individual items include future perspective items 18-20, body image item 17, disease symptoms items 1-6, side effects of treatment items 7-16. Raw scores are averaged, and transformed to 0-100 scale, where higher score is better quality of life. Positive change indicates improvement. (NCT01850524)
Timeframe: Baseline to approximately 9 years

Cmax: Maximum Plasma Concentration for Ixazomib

(NCT01850524)
Timeframe: Cycle 1 Day 1: Post-dose at multiple timepoints up to 4 hours; Pre-dose at Cycle 1 Day 14, Cycles 2-3 Day 1 and Day 14, Cycles 4-11 Day 1 (Each cycle length = 28 days)

Number of Participants With Abnormal Serum Chemistry and Hematology Laboratory Values Based on Treatment-emergent Adverse Events (TEAEs)

The laboratory values assessment included serum chemistry and hematology. The Serum chemistry assessment included blood urea nitrogen (BUN), creatinine, bilirubin (total), urate, lactate dehydrogenase, phosphate, albumin, alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), glucose, sodium, potassium, calcium, chloride, carbon dioxide (CO2), magnesium, thyroid stimulating hormone (TSH). Hematology assessment included hemoglobin, hematocrit, platelet (count), leukocytes with differential neutrophils (ANC). Participants with abnormal serum chemistry laboratory values reported as TEAEs are reported. TEAEs were defined as events that occurred after administration of the first dose of any agent in the study drug regimen and through 30 days after the last dose of any agent in the study drug regimen. (NCT01850524)
Timeframe: From the date of randomization through 30 days after the last dose of study drug up to end of study (up to approximately 9 years)

Number of Participants With Shifts From Baseline to Worst Value in Eastern Cooperative Oncology Group (ECOG) Performance Score

Eastern Cooperative Oncology Group (ECOG) scale score ranged from 0 to 5, where 0 indicated normal activity and 5 indicated death. The data is reported for those categories where at least 1 participant had worst post-baseline value for each ECOG score. (NCT01850524)
Timeframe: Up to approximately 9 years

Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

An AE was 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. (NCT01850524)
Timeframe: From the date of randomization through 30 days after the last dose of study drug up to end of study (up to approximately 9 years)

Part A: Change From Baseline in 12-lead Electrocardiogram (ECG) Findings: QT Interval - Fridericia's Correction Formula

12-lead ECG were recorded after the participants have rested for at least 15 minutes in supine position. Change from baseline in 12-Lead ECG findings that is QT interval - Fridericia's correction formula at pre-dose on Cycle 2 Day 1 were reported. (NCT04075721)
Timeframe: Cycle 1 Day 1 pre-dose (Baseline), pre-dose on Cycle 2 Day 1 (each Cycle is of 28 days)

Part A: Mutilple Dose: Maximum Observed Plasma Concentration (Cmax) of M3258

Cmax was obtained directly from the concentration versus time curve. (NCT04075721)
Timeframe: Cycle 1 Day 8 or Cycle 1 Day 15: Pre-dose 1, 2, 3, 4, 5, 6, and 8 hours post-dose (each Cycle is of 28 days)

Part A: Number of Participants With Dose-Limiting Toxicities (DLTs) as Per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0

DLT: any of adverse events (AEs), assessed by Investigator and/Sponsor at any dose, regimen, and judged not to be related to underlying disease/any previous/concomitant medication/concurrent condition during first cycle of study treatment. DLT was confirmed by Safety Monitoring Committee. DLTs: Grade (Gr) greater than/equal to (>=) 3 nonhematologic AE with exception of: Single laboratory values out of abnormal range; Gr3 diarrhea persisting less than or equal to [<=] 72 hour (hr); Nausea and vomiting <= 72 hr; Transient Gr3 fatigue, local reactions, flu-like symptoms <= 72 hr; Gr3 nonrecurrent skin toxicity; Asymptomatic Gr >= 3 lipase/amylase elevation. Any Gr >= 4 hematologic AE: Gr >= 3 febrile neutropenia with Absolute Neutrophil Count (ANC) <1000 per cube millimeter and temperature of >38.3 Celsius (°C); Gr >= 3 thrombocytopenia; Gr4 thrombocytopenia lasting >7 days. (NCT04075721)
Timeframe: Day 1 up to Day 28

Part A: Number of Participants With Treatment-Emergent Adverse Event (TEAEs) Outside of Dose-Limiting Toxicity (DLT) Period That Safety Monitoring Committee Deems Relevant for Determination of the Maximum Tolerated Dose

Adverse Event (AE): any untoward medical occurrence in a participant administered with a study drug, which does not necessarily have a causal relationship with this treatment. TEAEs: events that started from first dose of study intervention to 30 days after end of study intervention, or the cutoff date, whichever occurred first. TEAEs included both serious TEAEs (Serious AE: AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect) and non-serious TEAEs. TRAEs are defined as those AEs which are reasonably related to the study intervention. (NCT04075721)
Timeframe: Day 29 up to 20.1 weeks

Part A: Single Dose: Area Under Plasma Concentration-Time Curve (AUC) From Time Zero to Last Sampling Time (AUC0-t) of M3258

Area under the plasma concentration versus time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-t was calculated according to the mixed log-linear trapezoidal rule. Single dose PK data on Day 1 were summarized by dose level, such that all 10 mg arms were combined as descriptive statistics of PK were only calculated for N greater than (>) 2 in which a measurement of greater than (>) lower limit of quantification (LLOQ) represents a valid measurement. (NCT04075721)
Timeframe: Cycle 1 Day 1: Pre-dose 1, 2, 3, 4, 5, 6, 8 and 24 hours post-dose (each Cycle is of 28 days)

Part A: Single Dose: Maximum Observed Plasma Concentration (Cmax) of M3258

Cmax was obtained directly from the concentration versus time curve. Single dose PK data on Day 1 were summarized by dose level, such that all 10 mg arms were combined as descriptive statistics of PK were only calculated for N greater than (>) 2 in which a measurement of greater than (>) lower limit of quantification (LLOQ) represents a valid measurement. (NCT04075721)
Timeframe: Cycle 1 Day 1: Pre-dose 1, 2, 3, 4, 5, 6, 8 and 24 hours post-dose (each Cycle is of 28 days)

Number of Participants With Shift From Baseline Grade Less Than (<) 3 in Clinical Laboratory Parameters to Grade Greater Than or Equal to (>=) 3 on Treatment

Laboratory parameters included hematology, chemistry, and coagulation. Number of participants with shifts from baseline (Grade <3) to >= Grade 3 were reported as per NCI-CTCAE, v5.0 graded from Grade 1 to 5. Grade 1: Mild, Grade 2: Moderate; Grade 3: Severe. Grade 4: Life-threatening and Grade 5: Death. (NCT04075721)
Timeframe: Time from first treatment up to 30 days after end of study intervention (assessed up to 24.3 weeks)

Part A: Change From Baseline in Free Light Chain Ratio

Change from baseline in free light chain ratio was reported at Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1 and end of study intervention. (NCT04075721)
Timeframe: Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1 and end of study intervention (Week 20.1) (each Cycle is of 28 days)

Part A: Change From Baseline in Free Light Chain Ratio

Change from baseline in free light chain ratio was reported at Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1 and end of study intervention. (NCT04075721)
Timeframe: Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1 and end of study intervention (Week 20.1) (each Cycle is of 28 days)

Part A: Change From Baseline in Free Light Chain Ratio

Change from baseline in free light chain ratio was reported at Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1 and end of study intervention. (NCT04075721)
Timeframe: Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1 and end of study intervention (Week 20.1) (each Cycle is of 28 days)

Part A: Change From Baseline in Serum Monoclonal (M)-Protein Level Measured Using Electrophoresis

Change from baseline in serum monoclonal (M)-protein level was measured by using electrophoresis at Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1 and end of study intervention. (NCT04075721)
Timeframe: Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1 and end of study intervention (Week 20.1) (each Cycle is of 28 days)

Part A: Change From Baseline in Serum Monoclonal (M)-Protein Level Measured Using Electrophoresis

Change from baseline in serum monoclonal (M)-protein level was measured by using electrophoresis at Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1 and end of study intervention. (NCT04075721)
Timeframe: Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1 and end of study intervention (Week 20.1) (each Cycle is of 28 days)

Part A: Change From Baseline in Serum Monoclonal (M)-Protein Level Measured Using Electrophoresis

Change from baseline in serum monoclonal (M)-protein level was measured by using electrophoresis at Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1 and end of study intervention. (NCT04075721)
Timeframe: Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1 and end of study intervention (Week 20.1) (each Cycle is of 28 days)

Part A: Change From Baseline in Urine M-protein Level Using Electrophoresis

Change from baseline in urine M-protein level was measured by using electrophoresis at Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1 and end of study intervention. (NCT04075721)
Timeframe: Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1 and end of study intervention (Week 20.1) (each Cycle is of 28 days)

Part A: Change From Baseline in Urine M-protein Level Using Electrophoresis

Change from baseline in urine M-protein level was measured by using electrophoresis at Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1 and end of study intervention. (NCT04075721)
Timeframe: Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1 and end of study intervention (Week 20.1) (each Cycle is of 28 days)

Part A: Multiple Dose: Ratio to Baseline in Large Multifunctional Protease 7 (LMP7) Activity at Cycle 1 Day 8 (or Day 15)

Ratio to baseline was calculated dividing post-baseline measurements by the baseline measurement. (NCT04075721)
Timeframe: Cycle 1 Day 1 pre-dose (Baseline), Pre-dose, 2 and 6 hours post-dose on Cycle 1 Day 8 (or Day 15) (each Cycle is of 28 days)

Part A: Multiple Dose: Ratio to Baseline in Large Multifunctional Protease 7 (LMP7) Activity at Cycle 1 Day 8 (or Day 15)

Ratio to baseline was calculated dividing post-baseline measurements by the baseline measurement. (NCT04075721)
Timeframe: Cycle 1 Day 1 pre-dose (Baseline), Pre-dose, 2 and 6 hours post-dose on Cycle 1 Day 8 (or Day 15) (each Cycle is of 28 days)

Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score

ECOG performance status measured to assess participant's performance status on a scale of 0 to 5, where 0 = Fully active, able to carry on all pre-disease activities without restriction; 1 = Restricted in physically strenuous activity, ambulatory and able to carry out light or sedentary work; 2 = Ambulatory and capable of all selfcare but unable to carry out any work activities; 3 = Capable of only limited self-care, confined to bed/chair for more than 50 percent of waking hours; 4 = Completely disabled, cannot carry on any self-care, totally confined to bed/chair; 5 = dead. ECOG performance status was reported in terms of number of participants with shifts in score from baseline value vs worst post-baseline value (that is [i.e.] highest score). (NCT04075721)
Timeframe: Time from first treatment up to 30 days after end of study intervention (assessed up to 24.3 weeks)

Part A: Number of Participants With Overall Response (OR) as Assessed by Investigator Using International Myeloma Working Group (IMWG) Criteria

OR is defined as a best overall response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR) or partial response (PR) based on the IMWG Criteria: sCR: CR (negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and < 5% plasma cells in bone marrow); normal free light chain (FLC) ratio and no clonal cells in bone marrow; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis/>= 90% reduction in serum M-protein and urine M-protein level < 100 mg/24 hours; PR: >= 50% reduction of serum M-Protein and reduction in urinary M-protein by >= 90%/to < 200 mg/24 hours. In addition to the above, if present at baseline a >= 50% reduction in the size of soft tissue plasmacytomas is also required. (NCT04075721)
Timeframe: Time from first dose of study treatment up to 18.2 months

Part A: Number of Participants With Treatment-Emergent Adverse Event (TEAEs) and Treatment-Related Adverse Event (TRAEs)

Adverse Event (AE): any untoward medical occurrence in a participant administered with a study drug, which does not necessarily have a causal relationship with this treatment. TEAEs: events that started from first dose of study intervention to 30 days after end of study intervention, or the cutoff date, whichever occurred first. TEAEs included both serious TEAEs (Serious AE: AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect) and non-serious TEAEs. TRAEs are defined as those AEs which are reasonably related to the study intervention. (NCT04075721)
Timeframe: Time from first treatment up to 30 days after end of study intervention (assessed up to 24.3 weeks)

Part A: Number of Participants With Treatment-Emergent Changes From Baseline in Vital Signs - Maximal Body Temperature Increase

The number of participants with treatment-emergent changes from baseline in increased Body Temperature (degree Celsius [°C]) were reported by using criteria: Baseline temperature (temp.) less than (<) 37°C, on treatment change <1°C, 1 - <2°C, 2 - <3°C and greater than or equal to (>=)3°C; Baseline temp. 37 - <38°C, on treatment change <1°C, 1 - <2°C, 2 - <3°C and >=3°C; Baseline temp. 38 - <39°C, on treatment change <1°C, 1 - <2°C, 2 - <3°C and >=3°C; Baseline temp. 39-<40°C, on treatment change <1°C, 1 - <2°C, 2 - <3°C and >=3°C; Baseline temp. >=40°C, on treatment change <1°C, 1 - <2°C, 2 - <3°C and >=3°C. (NCT04075721)
Timeframe: Time from first treatment up to 30 days after end of study intervention (assessed up to 24.3 weeks)

Part A: Number of Participants With Treatment-Emergent Changes From Baseline in Vital Signs - Maximal Respiration Rate Increase/Decrease

The number of participants with treatment-emergent changes from baseline in Increase (Ic.)/Decrease (Dc.) maximal Respiration Rate (RR) were reported by using criteria: Ic./Dc. BS RR <20 breaths per minute (breaths/min), on TR change (ch) =<5 breaths/min, >5 - =<10 breaths/min and >10 breaths/min. Ic./Dc. BS RR >=20 breaths/min, on TR ch =<5 breaths/min, >5 - =<10 breaths/min and >10 breaths/min. (NCT04075721)
Timeframe: Time from first treatment up to 30 days after end of study intervention (assessed up to 24.3 weeks)

Part A: Number of Participants With Treatment-Emergent Changes From Baseline in Vital Signs - Maximal Systolic Blood Pressure Increase/Decrease and Maximal Diastolic Blood Pressure Increase/Decrease

The number of participants with treatment-emergent changes from baseline (BS) in Increase (Ic.)/Decrease (Dc.) Systolic Blood Pressure (SBP) and diastolic blood pressure (DBP) (millimeter of mercury [mmHg]) were reported by using criteria: Ic./Dc. BS SBP/DBP <140/<90 mmHg, on maximal treatment (TR) change =<20 mmHg, >20 - =<40 mmHg and >40 mmHg; Ic./Dc. BS SBP/DBP >=140/>=90 mmHg, on maximal TR change =<20 mmHg, >20 - =<40 mmHg and >40 mmHg. (NCT04075721)
Timeframe: Time from first treatment up to 30 days after end of study intervention (assessed up to 24.3 weeks)

Part A: Single Dose: Ratio to Baseline in Large Multifunctional Protease 7 (LMP7) Activity at Cycle 1 Day 1

Ratio to baseline was calculated dividing post-baseline measurements by the baseline measurement. Single dose Pd data on Day 1 were summarized by dose level, such that all 10 mg arms were combined as descriptive statistics of PK were only calculated for N greater than (>) 2 in which a measurement of greater than (>) lower limit of quantification (LLOQ) represents a valid measurement. (NCT04075721)
Timeframe: Baseline (Pre-dose), 2, 6 and 24 hours post-dose on Cycle 1 Day 1 (each Cycle is of 28 days)

Accumulation Ratio: Day 15 AUC0-168 / Day 1 AUC0-168 for MLN2238

MLN2238 is the complete hydrolysis product of the study drug ixazomib citrate (MLN9708). (NCT00963820)
Timeframe: Day 15 of Cycle 1