Multiple Myeloma
Conditions
Keywords
Drug Therapy
Brief summary
The purpose of this study is to determine the long-term safety and tolerability of ixazomib maintenance therapy.
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.
Interventions
DRUGIxazomib
Ixazomib Capsules
Sponsors
Millennium Pharmaceuticals, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Adult male or female participants aged 18 years or older with a confirmed diagnosis of symptomatic NDMM according to standard criteria. 2. 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. 3. 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. 4. 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.) 5. 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. 6. 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). 7. Has Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2. 8. Suitable venous access for the study-required blood sampling and consent for the specific amounts that will be taken. 9. Participant is willing and able to adhere to the study visit schedule and other protocol requirements including blood sampling and bone marrow aspiration. 10. 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
1. Has multiple myeloma that relapsed after, or was not responsive to, initial therapy. 2. Had prior stem-cell transplantation (SCT). 3. Has radiotherapy within 14 days before enrollment. 4. 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. 5. Female participants who are lactating and breastfeeding or have a positive serum pregnancy test during the Screening period. 6. Has major surgery within 14 days before enrollment. 7. Has central nervous system involvement. 8. Infection requiring intravenous (IV) antibiotic therapy or other serious infection within 14 days before enrollment. 9. 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. 10. 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. 11. 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. 12. Ongoing or active infection, known human immunodeficiency virus positive, active hepatitis B or C infection. 13. 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). 14. Psychiatric illness/social situation that would limit compliance with study requirements. 15. Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent. 16. 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. 17. Treatment with any investigational products within 30 days before enrollment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Categorized According to Performance Status (PS) Based on Eastern Cooperative Oncology Group (ECOG) PS | Month 25 | 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. |
| Percentage of Participants Receiving Ixazomib With Treatment-emergent Adverse Events (TEAEs) | Up to 58.4 months | 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. |
| Percentage of Participants Receiving Ixazomib With Treatment-emergent Serious Adverse Events (SAEs) | Up to 58.4 months | 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. |
| Number of Participants Receiving Ixazomib With Clinically Significant Changes in Safety Laboratory Values | Up to 58.4 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | 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) | OS was measured as the time from the date of first dose of study drug to the date of death. |
| Percentage of Participants Who Achieved or Maintained Best Response Before PD or up to Subsequent Therapy | Up to 58.4 months | 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. |
| Duration of Complete Response (CR) | Up to 58.4 months | 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. |
| 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) | Baseline, Cycle 26 (cycle length=28 days) | 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. |
| Time to Next-Line Therapy (TTNT) | Up to 58.4 months | 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. |
| Correlation Between Frailty Status and OS | Up to 58.4 months | 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. |
| Plasma Concentration of Ixazomib | 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) | 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. |
| Time to Resolution of Peripheral Neuropathy (PN) Events | Up to 58.4 months | 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. |
| Time to Improvement of PN Events | Up to 58.4 months | 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. |
| Correlation Between Frailty Status and PFS | Up to 58.4 months | 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. |
| Percentage of Participants With A New Primary Malignancy | Up to 58.4 months | — |
| Time to Progression (TTP) | Up to 58.4 months | 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. |
| Progression-Free Survival (PFS) | From the first dose of study drug to every 4 weeks until PD or death from any cause (up to 58.4 months) | 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. |
Countries
China
Participant flow
Recruitment details
A total of 37 participants (31 enrolled in this study and 6 rolled over from study C16021\[NCT02312258\]) with a diagnosis of newly diagnosed multiple myeloma (NDMM) not treated with stem cell transplantation (SCT) took part in the study at investigative sites in China from 24 January 2019 to 06 December 2023.
Pre-assignment details
Of the 31 participants who newly enrolled in this study, 10 (4 randomized to placebo and 6 to ixazomib) were enrolled before the implementation of Protocol Amendment 08, and 21 under the amendment, with all 21 receiving ixazomib as the study design was changed to a single-arm study. After Amendment 08, 2 of the 4 participants who were initially randomized to placebo crossed over to the ixazomib arm. As per planned analysis, these 4 participants were not included in the Efficacy Population.
Participants by arm
| Arm | Count |
|---|---|
| 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). | 33 |
| Total | 33 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Treatment Post Amendment 08 | Lost to Follow-up | 1 | 0 |
| Treatment Post Amendment 08 | Reason not Specified | 16 | 0 |
| Treatment Post Amendment 08 | Withdrawal by Subject | 18 | 0 |
| Treatment Prior to Amendment 08 | Discontinued to Switch to Ixazomib | 0 | 2 |
| Treatment Prior to Amendment 08 | Reason not Specified | 0 | 2 |
Baseline characteristics
| Characteristic | Ixazomib |
|---|---|
| Age, Continuous | 65.80 years STANDARD_DEVIATION 7.551 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 33 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 33 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 35 | 0 / 4 |
| other Total, other adverse events | 33 / 35 | 4 / 4 |
| serious Total, serious adverse events | 11 / 35 | 0 / 4 |
Outcome results
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.
Time frame: Month 25
Population: 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.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ixazomib | Number of Participants Categorized According to Performance Status (PS) Based on Eastern Cooperative Oncology Group (ECOG) PS | ECOG Score 0 | 34 Participants |
| Ixazomib | Number of Participants Categorized According to Performance Status (PS) Based on Eastern Cooperative Oncology Group (ECOG) PS | ECOG Score 1 | 1 Participants |
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.
Time frame: Up to 58.4 months
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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ixazomib | Number of Participants Receiving Ixazomib With Clinically Significant Changes in Safety Laboratory Values | 0 Participants |
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.
Time frame: Up to 58.4 months
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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ixazomib | Percentage of Participants Receiving Ixazomib With Treatment-emergent Adverse Events (TEAEs) | 97 percentage of participants |
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.
Time frame: Up to 58.4 months
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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ixazomib | Percentage of Participants Receiving Ixazomib With Treatment-emergent Serious Adverse Events (SAEs) | 31 percentage of participants |
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.
Time frame: Baseline, Cycle 26 (cycle length=28 days)
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ixazomib | 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) | -5.3 score on a scale | Standard Deviation 15.49 |
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.
Time frame: Up to 58.4 months
Population: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Ixazomib | Correlation Between Frailty Status and OS | Frailty Status: Fit | NA months |
| Ixazomib | Correlation Between Frailty Status and OS | Frailty Status: Unfit | NA months |
| Ixazomib | Correlation Between Frailty Status and OS | Frailty Status: Frail | NA months |
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.
Time frame: Up to 58.4 months
Population: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Ixazomib | Correlation Between Frailty Status and PFS | Frailty Status: Fit | NA months |
| Ixazomib | Correlation Between Frailty Status and PFS | Frailty Status: Unfit | 20.9 months |
| Ixazomib | Correlation Between Frailty Status and PFS | Frailty Status: Frail | 6.5 months |
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.
Time frame: Up to 58.4 months
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ixazomib | Duration of Complete Response (CR) | NA months |
Secondary
Overall Survival (OS)
OS was measured as the time from the date of first dose of study drug to the date of death.
Time frame: 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)
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ixazomib | Overall Survival (OS) | NA months |
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.
Time frame: Up to 58.4 months
Population: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ixazomib | Percentage of Participants Who Achieved or Maintained Best Response Before PD or up to Subsequent Therapy | CR | 76 percentage of participants |
| Ixazomib | Percentage of Participants Who Achieved or Maintained Best Response Before PD or up to Subsequent Therapy | PR | 3 percentage of participants |
| Ixazomib | Percentage of Participants Who Achieved or Maintained Best Response Before PD or up to Subsequent Therapy | VGPR | 12 percentage of participants |
Secondary
Percentage of Participants With A New Primary Malignancy
Time frame: Up to 58.4 months
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ixazomib | Percentage of Participants With A New Primary Malignancy | 0 percentage of participants |
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.
Time frame: 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)
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Ixazomib | Plasma Concentration of Ixazomib | Cycle 5 Day 8: Pre-dose | 5.29 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 36.9 |
| Ixazomib | Plasma Concentration of Ixazomib | Cycle 6 Day 1: Pre-dose | 3.58 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 41.3 |
| Ixazomib | Plasma Concentration of Ixazomib | Cycle 1 Day 1: 1 Hour Post-dose | 15.3 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 181 |
| Ixazomib | Plasma Concentration of Ixazomib | Cycle 1 Day 1: 4 Hours Post-dose | 16.6 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 94.4 |
| Ixazomib | Plasma Concentration of Ixazomib | Cycle 1 Day 8: Pre-dose | 2.25 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 51.5 |
| Ixazomib | Plasma Concentration of Ixazomib | Cycle 1 Day 15: Pre-dose | 4 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 53.6 |
| Ixazomib | Plasma Concentration of Ixazomib | Cycle 2 Day 1: Pre-dose | 2.92 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 46.8 |
| Ixazomib | Plasma Concentration of Ixazomib | Cycle 2 Day 8: Pre-dose | 4.37 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 42.5 |
| Ixazomib | Plasma Concentration of Ixazomib | Cycle 3 Day 1: Pre-dose | 3.15 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 41.9 |
| Ixazomib | Plasma Concentration of Ixazomib | Cycle 4 Day 1: Pre-dose | 3.16 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 59.4 |
| Ixazomib | Plasma Concentration of Ixazomib | Cycle 5 Day 1: Pre-dose | 3.25 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 42.1 |
| Ixazomib | Plasma Concentration of Ixazomib | Cycle 7 Day 1: Pre-dose | 4.04 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 48.5 |
| Ixazomib | Plasma Concentration of Ixazomib | Cycle 8 Day 1: Pre-dose | 3.28 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 64.7 |
| Ixazomib | Plasma Concentration of Ixazomib | Cycle 9 Day 1: Pre-dose | 3.7 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 31.3 |
| Ixazomib | Plasma Concentration of Ixazomib | Cycle 10 Day 1: Pre-dose | 2.99 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 37.6 |
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.
Time frame: From the first dose of study drug to every 4 weeks until PD or death from any cause (up to 58.4 months)
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ixazomib | Progression-Free Survival (PFS) | 21.3 months |
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.
Time frame: Up to 58.4 months
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ixazomib | Time to Improvement of PN Events | 8.0 days |
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.
Time frame: Up to 58.4 months
Population: 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 SAP), thus data is presented accordingly.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ixazomib | Time to Next-Line Therapy (TTNT) | NA months |
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.
Time frame: Up to 58.4 months
Population: 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 SAP), thus data is presented accordingly.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ixazomib | Time to Progression (TTP) | 21.3 months |
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.
Time frame: Up to 58.4 months
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ixazomib | Time to Resolution of Peripheral Neuropathy (PN) Events | 24.0 days |