Multiple Myeloma
Conditions
Keywords
MLN9708, Newly diagnosed, NDMM, IXAZOMIB, RRMM
Brief summary
This is a phase 2, multicenter, open-label study in patients with Newly Diagnosed Multiple Myeloma (NDMM) who have not received prior systemic treatment for multiple myeloma (MM) and who are ineligible for high-dose therapy (HDT)-stem cell transplantation (SCT) due to age (ie, ≥ 65 years) or comorbid disease(s) or with Relapsed and/or Refractory Multiple Myeloma (RRMM).
Detailed description
The investigational drug being tested in this study is called MLN9708 also known as Ixazomib. This study will look at disease response rates and safety in people who take ixazomib in addition to cyclophosphamide and dexamethasone. NDMM participants will be randomly assigned (by chance, like flipping a coin) to one of two treatment groups and RRMM participants will be assigned to a third group: * NDMM - ixazomib (MLN9708) 4.0 mg + cyclophosphamide 300 mg/m\^2 + dexamethasone 40 mg * NDMM - ixazomib (MLN9708) 4.0 mg + cyclophosphamide 400 mg/m\^2 + dexamethasone 40 mg * RRMM - ixazomib (MLN9708) 4.0 mg + cyclophosphamide 300 mg/m\^2 + dexamethasone 40 mg The study enrolled 148 participants. This multi-centre trial will be conducted in the United States, European Union, and Australia.
Interventions
DRUGCyclophosphamide
Cyclophosphamide tablets
DRUGIxazomib
Ixazomib capsules
DRUGDexamethasone
Dexamethasone tablets
Sponsors
Millennium Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Each participant with newly diagnosed multiple myeloma (NDMM) must meet all of the following inclusion criteria to be enrolled in the study: 1. Adult male or female participants 18 years of age or older with a confirmed diagnosis of symptomatic multiple myeloma (MM) according to standard criteria. 2. Participants for whom cyclophosphamide and dexamethasone treatment is appropriate and who are considered not eligible for high-dose therapy (HDT)-stem cell transplantation (SCT) for 1 or more of the following reasons: * The participant is 65 years of age or older. * The participant is less than 65 years of age but has significant comorbid condition(s) that are, in the opinion of the investigator, likely to have a negative impact on tolerability of HDT-SCT. Each participant with relapsed and/or refractory multiple myeloma (RRMM) must meet all of the following inclusion criteria to be enrolled in the study: 1. Adult male or female participants 18 years or older with a confirmed diagnosis of symptomatic MM either currently or at the time of initial diagnosis, according to standard criteria, and relapsed and/or refractory disease after 1 to 3 lines of prior therapy. A participant is considered to have refractory disease if disease progression occurred during the treatment period or within 60 days of receiving the last dose of a given therapy. A line of therapy is defined as 1 or more cycles of a single-agent or combination therapy or a sequence of planned treatments such as induction therapy followed by autologous stem cell transplantation (ASCT) and then maintenance therapy. 2. No evidence of graft-versus-host disease for participants who have undergone prior allogeneic stem cell transplantation. In addition, all participants (NDMM and RRMM) must meet all of the remaining criteria: 1. Participants must have measurable disease defined by at least 1 of the following 3 measurements: * Serum M-protein ≥ 1 g/dL (≥ 10 g/L). * Urine M-protein ≥ 200 mg/24 hours. * Serum free light chain assay: involved free light chain level ≥ 10 mg/dL (≥ 100 mg/L), provided that the serum free light chain ratio is abnormal. 2. Participants must meet all of the following clinical laboratory criteria: * Absolute neutrophil count (ANC) ≥ 1000/mm\^3 and platelet count ≥ 75,000/mm\^3. Platelet transfusions to help participants meet eligibility criteria are not allowed within 3 days prior to administration of the study drug. * Total bilirubin ≤ 1.5 x the upper limit of the normal range (ULN). * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN. * Calculated creatinine clearance (CrCL) ≥ 30 mL/min. 3. Eastern Cooperative Oncology Group performance status of 0, 1, or 2. 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 over the period previously described, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence \[ie, calendar, ovulation, symptothermal, postovulation methods\] and withdrawal are not acceptable methods of contraception.), and * adhere to any treatment-specific pregnancy prevention guidelines for cyclophosphamide and dexamethasone. 5. Male participants, even if surgically sterilized (ie, status post-vasectomy), 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 over the period previously described, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence \[eg, calendar, ovulation, symptothermal, postovulation methods for the female partner\] and withdrawal are not acceptable methods of contraception.), and * adhere to any treatment-specific pregnancy prevention guidelines for cyclophosphamide and dexamethasone. 6. 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. 7. Suitable venous access for the study-required blood sampling. 8. Is willing and able to adhere to the study visit schedule and other protocol requirements.
Exclusion criteria
1. Prior treatment for multiple myeloma with either standard of care treatment or investigational regimen (for participants with NDMM only). NOTE: Prior treatment with corticosteroids (maximum dose of corticosteroids should not exceed the equivalent of 160 mg of dexamethasone over 14 days. Localized radiation is permitted as long as it is below a therapeutic level and administered at least 14 days prior to the first dose of study treatment. 2. Diagnosis of smoldering MM, Waldenström's macroglobulinemia, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome, plasma cell leukemia, primary amyloidosis, myelodysplastic syndrome, or myeloproliferative syndrome. 3. Central nervous system involvement. 4. Diagnosed or treated for another malignancy within 2 years before the first dose or previously diagnosed with another malignancy and have any 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. Peripheral neuropathy Grade 1 with pain or Grade 2 or higher peripheral neuropathy of any cause on clinical examination during the Screening period. 6. Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of study drug, including difficulty swallowing. 7. Infection requiring intravenous (IV) antibiotic therapy or other serious infection within 14 days before the first dose of study drug. 8. Ongoing or active infection, known human immunodeficiency virus (HIV) positive, active hepatitis B or C infection. 9. Systemic treatment with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort within 14 days before the first dose of study treatment. 10. Known allergy to any of the study medications, their analogues, or excipients in the various formulations. 11. Major surgery within 14 days before the first dose of study drug. (Note: kyphoplasty or vertebroplasty is not considered major surgery.) 12. Female participants who are lactating and breastfeeding or have a positive serum pregnancy test during the Screening period. 13. Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol. 14. Comorbid systemic illnesses or other severe concurrent disease which, 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. 15. Treatment with any investigational products for reasons other than MM within 30 days before the first dose of study drug.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Combined Response Rate During the Induction Phase in Newly Diagnosed Multiple Myeloma (NDMM) Participants | Day 1 of Cycles 1-13, 28-day cycles (Up to 1 year) | Combined Response Rate is the percentage of participants with Complete Response (CR), including stringent Complete Response (sCR), and Very Good Partial Response (VGPR) according to the International Myeloma Working Group (IMWG) criteria during the Induction Phase (Cycles 1-13, 28-day cycles). CR=negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas and \<5% plasma cells in bone marrow. VGPR=serum and urine M-component detectable by immunofixation but not on electrophoresis or 90% reduction in serum M-component plus urine M-component \<100 mg/24 hour. |
| Overall Response Rate (ORR) in Relapsed and/or Refractory Multiple Myeloma (RRMM) Participants | Day 1 of each 28 day cycle (Up to 45 months) | ORR is the percentage of participants with CR, VGPR or PR according to IMWG criteria. CR=negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas and \<5% plasma cells (PC) in bone marrow. VGPR=serum and urine M-component detectable by immunofixation but not on electrophoresis or 90% reduction in serum M-component plus urine M-component \<100 mg/24 hour. PR=50% reduction of serum M-protein and reduction in 24 hour urine M-protein by 90% or \<200 mg/24 hour or decrease 50% difference between involved free light chain (FLC) levels or 50% reduction in bone marrow plasma cells if baseline percentage was 30%; and if present at Baseline, 50% reduction in the size of soft tissue plasmacytomas. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With CR + VGPR + PR (ORR), CR + VGPR, CR, VGPR, PR, SD and PD Throughout the Entire Treatment Period in NDMM Participants | Day 1 of each 28-day Cycle (Up to 45 months) | Percentage of participants with CR + VGPR + PR (ORR), CR, VGPR, PR, SD, PD according to IMWG criteria. CR=negative immunofixation of serum and urine; disappearance of soft tissue plasmacytomas;\<5% PC in bone marrow. VGPR=serum and urine M-component detectable by immunofixation but not on electrophoresis or 90% reduction in serum M-component plus urine M-component \<100 mg/24 hour. PR=50% reduction of serum M-protein and reduction in 24 hour urine M-protein by 90% or \<200 mg/24 hour or decrease 50% difference between involved FLC levels or 50% reduction in bone marrow plasma cells if baseline percentage was 30%; and if present at Baseline, 50% reduction in the size of soft tissue plasmacytomas. SD=not meeting criteria for VGPR, PR or PD. PD=25% increase in lowest value any of the following: serum M-component, urine M-component, difference between involved and uninvolved FLC levels, bone marrow PC percentage; new or increase in size of existing bone lesions or soft tissue plasmacytomas. |
| Time to Response (TTR) in NDMM Participants During the Induction Phase | Up to 1 year | TTR is defined as the time interval from the date of the first dose of study treatment to the date of the first documented confirmed response of PR or better up to the initiation of alternative therapy in a participant who responded. |
| Duration of Response (DOR) in NDMM Participants | Up to 45 Months | DOR is defined as the time from the date of first documentation of a confirmed PR or better to the date of first documented PD up to the initiation of alternative therapy. |
| Time to Progression (TTP) in NDMM Participants | Up to 45 months | TTP is defined as the time from the date of first dose of study treatment to the date of first documentation of disease progression. |
| Progression Free Survival (PFS) in NDMM Participants | Up to 45 months | PFS is defined as the time from the date of first dose of study treatment to the date of the first documented disease progression or death. |
| Number of Participants With AEs, SAEs, AEs Resulting in Discontinuation and AEs Resulting in Dose Reduction in NDMM Participants Remaining on Treatment After 13 Cycles | First dose of study drug through 30 days after the last dose of drug (Up to 45 months) | An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product whether or not it is related to the medicinal product. This includes any newly occurring event, or a previous condition that has increased in severity or frequency since the administration of study drug. A SAE is any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly/birth defect or is a medically important event. Relationship of each AE to study drug was determined by the Investigator. |
| Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) During the Induction Phase in NDMM Participants | Baseline (BL) (Day 1 of Cycle 1), Day 1 of Cycle 13 (Up to 1 year) | EORTC QLQ-C30 is a patient completed 30 item questionnaire that consists of 5 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning), 1 global health status scale, 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The patient evaluates their health status over the previous week. There are 28 questions answered on a 4-point scale where1=Not at all (best) to 4=Very Much (worst) and 2 questions answered on a 7-point scale where 1=Very poor (worst) to 7= Excellent (best). All of the scales and single-item measures are transformed to a score:0 to 100. For functioning scales and global QOL higher scores indicate better functioning (a positive change from Baseline indicates improvement); for symptom scales higher scores indicate more severe symptoms (a negative change from Baseline indicates improvement). |
| Percentage of Participants With CR + VGR + PR (ORR), CR, VGPR, and PR in NDMM Participants Remaining on Treatment After 13 Cycles | Day 1 of each 28-day Cycle (Up to 45 months) | Percentage of participants with Overall Response (CR + VGPR + PR), CR, VGPR and PR according to IMWG criteria. CR=negative immunofixation of serum and urine; disappearance of soft tissue plasmacytomas;\<5% PC in bone marrow. VGPR=serum and urine M-component detectable by immunofixation but not on electrophoresis or 90% reduction in serum M-component plus urine M-component \<100 mg/24 hour. PR=50% reduction of serum M-protein and reduction in 24 hour urine M-protein by 90% or \<200 mg/24 hour or decrease 50% difference between involved FLC levels or 50% reduction in bone marrow plasma cells if baseline percentage was 30%; and if present at Baseline, 50% reduction in the size of soft tissue plasmacytomas. |
| Cmax: Maximum Observed Plasma Concentration for Ixazomib in NDMM Participants | Cycle 1 Days 1 and 15 predose and at multiple timepoints (up to 168 hours) postdose | — |
| Tmax: Time to First Occurrence of Cmax for Ixazomib in NDMM Participants | Cycle 1 Days 1 and 15 predose and at multiple timepoints (up to 168 hours) postdose | — |
| Number of Participants With Adverse Events (AEs), Grade 3 or Higher AEs, AEs Resulting in Treatment Discontinuation, AEs Resulting in Dose Reduction and Serious Adverse Events (SAEs) in NDMM Participants | First dose of study drug through 30 days after last dose of drug (Up to 45 months) | An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product whether or not it is related to the medicinal product. This includes any newly occurring event, or a previous condition that has increased in severity or frequency since the administration of study drug. A SAE is any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly/birth defect or is a medically important event. Relationship of each AE to study drug was determined by the Investigator. |
| Number of Participants With AEs, Grade 3 or Higher AEs, AEs Resulting in Treatment Discontinuation, AEs Resulting in Dose Reduction, SAEs in RRMM Participants | First dose of study drug through 30 days after last dose of drug (Up to 45 months) | An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal relationship with this treatment. A SAE is any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly/birth defect or is a medically important event. Relationship of each AE to study drug was determined by the Investigator. |
| Cmax: Maximum Observed Plasma Concentration for Ixazomib in RRMM Participants | Cycle 1 Days 1 and 15 predose and at multiple timepoints (up to 168 hours) postdose | — |
| Tmax: Time to First Occurrence of Cmax for Ixazomib in RRMM Participants | Cycle 1 Days 1 and 15 predose and at multiple timepoints (up to 168) hours postdose | — |
| AUCtau: Area Under the Concentration-time Curve During a Dosing Interval for Ixazomib in RRMM Participants | Cycle 1 Days 1 and 15 predose and at multiple timepoints (up to 168 hours) postdose | — |
| Percentage of Participants With (CR + VGPR), CR, VGPR, PR, SD and PD in RRMM Participants | Day 1 of each 28-day Cycle (Up to 45 months) | Percentage of participants with CR + VGPR + PR (ORR), CR, VGPR, PR, SD, PD according to IMWG criteria. CR=negative immunofixation of serum and urine; disappearance of soft tissue plasmacytomas;\<5% PC in bone marrow. VGPR=serum and urine M-component detectable by immunofixation but not on electrophoresis or 90% reduction in serum M-component plus urine M-component \<100 mg/24 hour. PR=50% reduction of serum M-protein and reduction in 24 hour urine M-protein by 90% or \<200 mg/24 hour or decrease 50% difference between involved FLC levels or 50% reduction in bone marrow plasma cells if baseline percentage was 30%; and if present at Baseline, 50% reduction in the size of soft tissue plasmacytomas. SD=not meeting criteria for VGPR, PR or PD. PD=25% increase in lowest value any of the following: serum M-component, urine M-component, difference between involved and uninvolved FLC levels, bone marrow PC percentage; new or increase in size of existing bone lesions or soft tissue plasmacytomas. |
| Time to Response (TTR) in RRMM Participants | Up to 45 months | TTR is defined as the time interval from the date of the first dose of study treatment to the date of the first documented confirmed response of PR or better up to the alternative therapy in a participant who responded. |
| Duration of Response (DOR) in RRMM Participants | Up to 45 months | DOR is defined as the time from the date of first documentation of a confirmed PR or better to the date of first documented PD up to the alternative therapy. |
| Time to Progression (TTP) in RRMM Participants | Up to 45 months | TTP is defined as the time from the date of first dose of study treatment to the date of first documentation of disease progression. |
| Progression Free Survival (PFS) in RRMM Participants | Up to 45 months | PFS is defined as the time from the date of first dose of study treatment to the date of the first documented disease progression or death. |
| Change From Baseline in EORTC Quality of Life Questionnaire (QLQ-C30) in RRMM Participants | Baseline (Day 1 of Cycle 1), Day 1 of End of Treatment (EOT) (Up to 45 months) | EORTC QLQ-C30 is a patient completed 30 item questionnaire that consists of 5 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning), 1 global health status scale, 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The patient evaluates their health status over the previous week. There are 28 questions answered on a 4-point scale where1=Not at all (best) to 4=Very Much (worst) and 2 questions answered on a 7-point scale where 1=Very poor (worst) to 7= Excellent (best). All of the scales and single-item measures are transformed to a score:0 to 100. For functioning scales and global QOL higher scores indicate better functioning (a positive change from Baseline indicates improvement); for symptom scales higher scores indicate more severe symptoms (a negative change from Baseline indicates improvement). |
| AUCtau: Area Under the Concentration-time Curve During a Dosing Interval for Ixazomib in NDMM Participants | Cycle 1 Days 1 and 15 predose and at multiple timepoints (up to 168 hours) postdose | — |
| Percentage of Participants With CR + VGPR + PR (ORR), CR, VGPR, PR and Stable Disease (SD), Progressive Disease (PD) During the Induction Phase | Day 1 of Cycles 1-13, 28-day cycles (Up to 1 year) | Percentage of participants with CR + VGPR + PR (ORR), CR, VGPR, PR, SD, PD according to IMWG criteria. CR=negative immunofixation of serum and urine; disappearance of soft tissue plasmacytomas;\<5% PC in bone marrow. VGPR=serum and urine M-component detectable by immunofixation but not on electrophoresis or 90% reduction in serum M-component plus urine M-component \<100 mg/24 hour. PR=50% reduction of serum M-protein and reduction in 24 hour urine M-protein by 90% or \<200 mg/24 hour or decrease 50% difference between involved FLC levels or 50% reduction in bone marrow plasma cells if baseline percentage was 30%; and if present at Baseline, 50% reduction in the size of soft tissue plasmacytomas. SD=not meeting criteria for VGPR, PR or PD. PD=25% increase in lowest value any of the following: serum M-component, urine M-component, difference between involved and uninvolved FLC levels, bone marrow PC percentage; new or increase in size of existing bone lesions or soft tissue plasmacytomas. |
Countries
Australia, Greece, Poland, Sweden, United States
Participant flow
Recruitment details
Participants took part in the study at 23 investigative sites in Australia, Greece, Poland, Sweden and the United States from 05 March 2014 to 29 June 2018.
Pre-assignment details
Participants with NDMM were enrolled in 1 of 2 arms to receive 4.0 mg ixazomib in combination with 300 or 400 mg cyclophosphamide and 40 mg dexamethasone (CCd); participants with RRMM were enrolled in 1 arm to receive ixazomib 4.0 mg CCd. All arms included a safety lead-in cohort for pharmacokinetics (PK) analysis.
Participants by arm
| Arm | Count |
|---|---|
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15 of a 28-day cycle until progressive disease (PD)/death or unacceptable toxicity \[13 cycles in the Induction Phase continuing in the Maintenance Phase for up to 36 Months\] and cyclophosphamide (CYC) 300 mg/m\^2, tablets, orally, on Days 1, 8 and 15 of a 28-day cycle for 13 cycles or until PD/death or unacceptable toxicity and dexamethasone (DEX) 40 mg, tablets, orally, on Days 1, 8, 15 and 22 (dose reduced to 20 mg for patients \>75 years) of a 28-day cycle for 13 cycles or until PD/death or unacceptable toxicity in participants with NDMM. | 36 |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15 of a 28-day cycle until PD/death or unacceptable toxicity \[13 cycles in the Induction Phase continuing in the Maintenance Phase for up to 36 Months\] and cyclophosphamide (CYC) 400 mg/m\^2, tablets, orally, on Days 1, 8 and 15 of a 28-day cycle for 13 cycles or until PD/death or unacceptable toxicity and dexamethasone (DEX) 40 mg, tablets, orally, on Days 1, 8, 15 and 22 (dose reduced to 20 mg for patients \>75 years) of a 28-day cycle for 13 cycles or until PD/death or unacceptable toxicity in participants with NDMM. | 34 |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (RRMM) Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15 of a 28-day cycle and cyclophosphamide (CYC) 300 mg/m\^2, tablets, orally, on Days 1, 8 and 15 of a 28-day cycle and dexamethasone (DEX) 40 mg, tablets, orally, on Days 1, 8, 15 and 22 (dose reduced to 20 mg for patients \>75 years) of a 28-day cycle until PD/death or unacceptable toxicity in participants with RRMM. | 78 |
| Total | 148 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 8 | 10 | 17 |
| Overall Study | Progressive Disease | 18 | 11 | 40 |
| Overall Study | Reason not Specified | 4 | 4 | 6 |
| Overall Study | Study Terminated by Sponsor | 1 | 1 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 2 | 6 |
Baseline characteristics
| Characteristic | Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (RRMM) | Total |
|---|---|---|---|---|
| Age, Continuous | 73.4 years STANDARD_DEVIATION 5.48 | 74.1 years STANDARD_DEVIATION 5.8 | 63.5 years STANDARD_DEVIATION 9.85 | 68.3 years STANDARD_DEVIATION 9.59 |
| Body Surface Area (BSA) | 1.8 meters squared (m^2) STANDARD_DEVIATION 0.17 | 1.8 meters squared (m^2) STANDARD_DEVIATION 0.26 | 1.9 meters squared (m^2) STANDARD_DEVIATION 0.23 | 1.8 meters squared (m^2) STANDARD_DEVIATION 0.23 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 35 Participants | 33 Participants | 75 Participants | 143 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 3 Participants | 4 Participants |
| Height | 163.5 centimeters (cm) STANDARD_DEVIATION 11.35 | 163.5 centimeters (cm) STANDARD_DEVIATION 12.47 | 165.9 centimeters (cm) STANDARD_DEVIATION 10.47 | 164.8 centimeters (cm) STANDARD_DEVIATION 11.16 |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 0 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 35 Participants | 34 Participants | 74 Participants | 143 Participants |
| Sex: Female, Male Female | 21 Participants | 16 Participants | 37 Participants | 74 Participants |
| Sex: Female, Male Male | 15 Participants | 18 Participants | 41 Participants | 74 Participants |
| Weight | 73.6 kilograms (kg) STANDARD_DEVIATION 11.8 | 73.0 kilograms (kg) STANDARD_DEVIATION 17.54 | 78.1 kilograms (kg) STANDARD_DEVIATION 16.8 | 75.8 kilograms (kg) STANDARD_DEVIATION 15.99 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 36 | 2 / 34 | 5 / 78 |
| other Total, other adverse events | 34 / 36 | 34 / 34 | 69 / 78 |
| serious Total, serious adverse events | 17 / 36 | 20 / 34 | 30 / 78 |
Outcome results
Primary
Combined Response Rate During the Induction Phase in Newly Diagnosed Multiple Myeloma (NDMM) Participants
Combined Response Rate is the percentage of participants with Complete Response (CR), including stringent Complete Response (sCR), and Very Good Partial Response (VGPR) according to the International Myeloma Working Group (IMWG) criteria during the Induction Phase (Cycles 1-13, 28-day cycles). CR=negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas and \<5% plasma cells in bone marrow. VGPR=serum and urine M-component detectable by immunofixation but not on electrophoresis or 90% reduction in serum M-component plus urine M-component \<100 mg/24 hour.
Time frame: Day 1 of Cycles 1-13, 28-day cycles (Up to 1 year)
Population: Response Evaluable Population was defined as participants who received at least 2 of the 3 ixazomib doses during Cycle 1, had measurable disease at Baseline, and at least 1 postbaseline response assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Combined Response Rate During the Induction Phase in Newly Diagnosed Multiple Myeloma (NDMM) Participants | 27 percentage of participants |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Combined Response Rate During the Induction Phase in Newly Diagnosed Multiple Myeloma (NDMM) Participants | 24 percentage of participants |
Comparison: P-value tests the null hypothesis: CR+VGPR rate=27% in treatment arms obtained using the one-sided Chi-Square test with alpha=0.10.p-value: 0.4859Chi-squared
Comparison: P-value tests the null hypothesis: CR+VGPR rate=27% in treatment arms obtained using the one-sided Chi-Square test with alpha=0.10.p-value: 0.6757Chi-squared
Primary
Overall Response Rate (ORR) in Relapsed and/or Refractory Multiple Myeloma (RRMM) Participants
ORR is the percentage of participants with CR, VGPR or PR according to IMWG criteria. CR=negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas and \<5% plasma cells (PC) in bone marrow. VGPR=serum and urine M-component detectable by immunofixation but not on electrophoresis or 90% reduction in serum M-component plus urine M-component \<100 mg/24 hour. PR=50% reduction of serum M-protein and reduction in 24 hour urine M-protein by 90% or \<200 mg/24 hour or decrease 50% difference between involved free light chain (FLC) levels or 50% reduction in bone marrow plasma cells if baseline percentage was 30%; and if present at Baseline, 50% reduction in the size of soft tissue plasmacytomas.
Time frame: Day 1 of each 28 day cycle (Up to 45 months)
Population: Response Evaluable Population was defined as participants who received at least 2 of the 3 ixazomib doses during Cycle 1, had measurable disease at Baseline, and at least 1 postbaseline response assessment.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Overall Response Rate (ORR) in Relapsed and/or Refractory Multiple Myeloma (RRMM) Participants | 49 percentage of participants |
Comparison: P-value tests the null hypothesis: CR+VGPR+PR rate=60% obtained using the one-sided Chi-Square test with alpha=0.10.p-value: 0.9688Chi-squared
Secondary
AUCtau: Area Under the Concentration-time Curve During a Dosing Interval for Ixazomib in NDMM Participants
Time frame: Cycle 1 Days 1 and 15 predose and at multiple timepoints (up to 168 hours) postdose
Population: PK-Evaluable Population was defined as participants in the safety lead-in cohort who have sufficient dosing data and ixazomib concentration-time data to permit calculation of PK parameters. Number analyzed is the number of participants with data available for analysis at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | AUCtau: Area Under the Concentration-time Curve During a Dosing Interval for Ixazomib in NDMM Participants | Cycle 1 Day 1 | 885.167 hr*ng/mL | Standard Deviation 354.1465 |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | AUCtau: Area Under the Concentration-time Curve During a Dosing Interval for Ixazomib in NDMM Participants | Cycle 1 Day 15 | 1338.333 hr*ng/mL | Standard Deviation 746.2902 |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | AUCtau: Area Under the Concentration-time Curve During a Dosing Interval for Ixazomib in NDMM Participants | Cycle 1 Day 1 | 792.600 hr*ng/mL | Standard Deviation 650.5665 |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | AUCtau: Area Under the Concentration-time Curve During a Dosing Interval for Ixazomib in NDMM Participants | Cycle 1 Day 15 | 1226.600 hr*ng/mL | Standard Deviation 527.5792 |
Secondary
AUCtau: Area Under the Concentration-time Curve During a Dosing Interval for Ixazomib in RRMM Participants
Time frame: Cycle 1 Days 1 and 15 predose and at multiple timepoints (up to 168 hours) postdose
Population: PK-Evaluable Population was defined as participants in the safety lead-in cohort who have sufficient dosing data and ixazomib concentration-time data to permit calculation of PK parameters. Number analyzed is the number of participants with data available for analysis at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | AUCtau: Area Under the Concentration-time Curve During a Dosing Interval for Ixazomib in RRMM Participants | Cycle 1 Day 1 | 518.167 hr*ng/mL | Standard Deviation 78.8274 |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | AUCtau: Area Under the Concentration-time Curve During a Dosing Interval for Ixazomib in RRMM Participants | Cycle 1 Day 15 | 1241.000 hr*ng/mL | Standard Deviation 657.4978 |
Secondary
Change From Baseline in EORTC Quality of Life Questionnaire (QLQ-C30) in RRMM Participants
EORTC QLQ-C30 is a patient completed 30 item questionnaire that consists of 5 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning), 1 global health status scale, 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The patient evaluates their health status over the previous week. There are 28 questions answered on a 4-point scale where1=Not at all (best) to 4=Very Much (worst) and 2 questions answered on a 7-point scale where 1=Very poor (worst) to 7= Excellent (best). All of the scales and single-item measures are transformed to a score:0 to 100. For functioning scales and global QOL higher scores indicate better functioning (a positive change from Baseline indicates improvement); for symptom scales higher scores indicate more severe symptoms (a negative change from Baseline indicates improvement).
Time frame: Baseline (Day 1 of Cycle 1), Day 1 of End of Treatment (EOT) (Up to 45 months)
Population: Participants from the Safety Population, defined as all participants who received at least 1 dose of any study drug, with data available for analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Change From Baseline in EORTC Quality of Life Questionnaire (QLQ-C30) in RRMM Participants | Global Health Status/QoL, Change from BL at EOT | -5.50 score on a scale | Standard Deviation 20.798 |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Change From Baseline in EORTC Quality of Life Questionnaire (QLQ-C30) in RRMM Participants | Physical functioning, Change from BL at EOT | -6.00 score on a scale | Standard Deviation 19.806 |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Change From Baseline in EORTC Quality of Life Questionnaire (QLQ-C30) in RRMM Participants | Role functioning, Change from BL at EOT | -7.67 score on a scale | Standard Deviation 30.344 |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Change From Baseline in EORTC Quality of Life Questionnaire (QLQ-C30) in RRMM Participants | Emotional functioning, Change from BL at EOT | -5.00 score on a scale | Standard Deviation 23.023 |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Change From Baseline in EORTC Quality of Life Questionnaire (QLQ-C30) in RRMM Participants | Cognitive functioning, Change from BL at EOT | -5.33 score on a scale | Standard Deviation 19.76 |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Change From Baseline in EORTC Quality of Life Questionnaire (QLQ-C30) in RRMM Participants | Social functioning, Change from BL at EOT | -11.33 score on a scale | Standard Deviation 26.177 |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Change From Baseline in EORTC Quality of Life Questionnaire (QLQ-C30) in RRMM Participants | Fatigue, Change from BL at EOT | 5.11 score on a scale | Standard Deviation 22.695 |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Change From Baseline in EORTC Quality of Life Questionnaire (QLQ-C30) in RRMM Participants | Nausea/Vomiting, Change from BL at EOT | 3.33 score on a scale | Standard Deviation 14.677 |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Change From Baseline in EORTC Quality of Life Questionnaire (QLQ-C30) in RRMM Participants | Pain, Change from BL at EOT | 5.00 score on a scale | Standard Deviation 28.621 |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Change From Baseline in EORTC Quality of Life Questionnaire (QLQ-C30) in RRMM Participants | Dyspnea, Change from BL at EOT | 10.00 score on a scale | Standard Deviation 27.97 |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Change From Baseline in EORTC Quality of Life Questionnaire (QLQ-C30) in RRMM Participants | Insomnia, Change from BL at EOT | -6.00 score on a scale | Standard Deviation 27.512 |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Change From Baseline in EORTC Quality of Life Questionnaire (QLQ-C30) in RRMM Participants | Appetite Loss, Change from BL at EOT | 4.67 score on a scale | Standard Deviation 24.29 |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Change From Baseline in EORTC Quality of Life Questionnaire (QLQ-C30) in RRMM Participants | Constipation, Change from BL at EOT | 2.00 score on a scale | Standard Deviation 18.332 |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Change From Baseline in EORTC Quality of Life Questionnaire (QLQ-C30) in RRMM Participants | Diarrhea, Change from BL at EOT | 6.00 score on a scale | Standard Deviation 19.852 |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Change From Baseline in EORTC Quality of Life Questionnaire (QLQ-C30) in RRMM Participants | Financial Difficulties, Change from BL at EOT | 4.00 score on a scale | Standard Deviation 20.909 |
Secondary
Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) During the Induction Phase in NDMM Participants
EORTC QLQ-C30 is a patient completed 30 item questionnaire that consists of 5 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning), 1 global health status scale, 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The patient evaluates their health status over the previous week. There are 28 questions answered on a 4-point scale where1=Not at all (best) to 4=Very Much (worst) and 2 questions answered on a 7-point scale where 1=Very poor (worst) to 7= Excellent (best). All of the scales and single-item measures are transformed to a score:0 to 100. For functioning scales and global QOL higher scores indicate better functioning (a positive change from Baseline indicates improvement); for symptom scales higher scores indicate more severe symptoms (a negative change from Baseline indicates improvement).
Time frame: Baseline (BL) (Day 1 of Cycle 1), Day 1 of Cycle 13 (Up to 1 year)
Population: Participants from the Safety Population, defined as all participants who received at least 1 dose of any study drug, with data available for analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) During the Induction Phase in NDMM Participants | Cognitive functioning, Change from BL at Cycle 13 | 2.78 score on a scale | Standard Deviation 22.877 |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) During the Induction Phase in NDMM Participants | Pain, Change from BL at Cycle 13 | -13.89 score on a scale | Standard Deviation 52.628 |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) During the Induction Phase in NDMM Participants | Physical functioning, Change from BL at Cycle 13 | 14.17 score on a scale | Standard Deviation 35.675 |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) During the Induction Phase in NDMM Participants | Dyspnea, Change from BL at Cycle 13 | -11.11 score on a scale | Standard Deviation 37.644 |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) During the Induction Phase in NDMM Participants | Social functioning, Change from BL at Cycle 13 | 9.03 score on a scale | Standard Deviation 39.921 |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) During the Induction Phase in NDMM Participants | Insomnia, Change from BL at Cycle 13 | -16.67 score on a scale | Standard Deviation 46.104 |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) During the Induction Phase in NDMM Participants | Emotional functioning, Change from BL at Cycle 13 | 11.34 score on a scale | Standard Deviation 27.837 |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) During the Induction Phase in NDMM Participants | Appetite Loss, Change from BL at Cycle 13 | -18.06 score on a scale | Standard Deviation 42.822 |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) During the Induction Phase in NDMM Participants | Fatigue, Change from BL at Cycle 13 | -10.88 score on a scale | Standard Deviation 35.307 |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) During the Induction Phase in NDMM Participants | Constipation, Change from BL at Cycle 13 | -13.89 score on a scale | Standard Deviation 39.215 |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) During the Induction Phase in NDMM Participants | Role functioning, Change from BL at Cycle 13 | 8.33 score on a scale | Standard Deviation 43.127 |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) During the Induction Phase in NDMM Participants | Diarrhea, Change from BL at Cycle 13 | -2.78 score on a scale | Standard Deviation 30.954 |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) During the Induction Phase in NDMM Participants | Nausea/Vomiting, Change from BL at Cycle 13 | -4.86 score on a scale | Standard Deviation 26.228 |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) During the Induction Phase in NDMM Participants | Financial Difficulties, Change from BL at Cycle 13 | 4.17 score on a scale | Standard Deviation 26.58 |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) During the Induction Phase in NDMM Participants | Global Health Status/QoL, Change from BL; Cycle 13 | 3.47 score on a scale | Standard Deviation 30.783 |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) During the Induction Phase in NDMM Participants | Financial Difficulties, Change from BL at Cycle 13 | 1.45 score on a scale | Standard Deviation 30.942 |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) During the Induction Phase in NDMM Participants | Global Health Status/QoL, Change from BL; Cycle 13 | -5.43 score on a scale | Standard Deviation 24.18 |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) During the Induction Phase in NDMM Participants | Physical functioning, Change from BL at Cycle 13 | 17.97 score on a scale | Standard Deviation 20.64 |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) During the Induction Phase in NDMM Participants | Role functioning, Change from BL at Cycle 13 | 6.52 score on a scale | Standard Deviation 35.441 |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) During the Induction Phase in NDMM Participants | Emotional functioning, Change from BL at Cycle 13 | 2.54 score on a scale | Standard Deviation 15.977 |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) During the Induction Phase in NDMM Participants | Cognitive functioning, Change from BL at Cycle 13 | -7.25 score on a scale | Standard Deviation 14.058 |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) During the Induction Phase in NDMM Participants | Social functioning, Change from BL at Cycle 13 | -11.59 score on a scale | Standard Deviation 29.914 |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) During the Induction Phase in NDMM Participants | Fatigue, Change from BL at Cycle 13 | -6.76 score on a scale | Standard Deviation 30.473 |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) During the Induction Phase in NDMM Participants | Nausea/Vomiting, Change from BL at Cycle 13 | -4.35 score on a scale | Standard Deviation 19.603 |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) During the Induction Phase in NDMM Participants | Pain, Change from BL at Cycle 13 | -10.87 score on a scale | Standard Deviation 39.443 |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) During the Induction Phase in NDMM Participants | Dyspnea, Change from BL at Cycle 13 | -7.25 score on a scale | Standard Deviation 40.147 |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) During the Induction Phase in NDMM Participants | Insomnia, Change from BL at Cycle 13 | -10.14 score on a scale | Standard Deviation 35.441 |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) During the Induction Phase in NDMM Participants | Appetite Loss, Change from BL at Cycle 13 | -7.25 score on a scale | Standard Deviation 24.529 |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) During the Induction Phase in NDMM Participants | Constipation, Change from BL at Cycle 13 | -5.80 score on a scale | Standard Deviation 41.013 |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) During the Induction Phase in NDMM Participants | Diarrhea, Change from BL at Cycle 13 | 5.80 score on a scale | Standard Deviation 19.207 |
Secondary
Cmax: Maximum Observed Plasma Concentration for Ixazomib in NDMM Participants
Time frame: Cycle 1 Days 1 and 15 predose and at multiple timepoints (up to 168 hours) postdose
Population: PK-Evaluable Population was defined as participants in the safety lead-in cohort who have sufficient dosing data and ixazomib concentration-time data to permit calculation of PK parameters. Number analyzed is the number of participants with data available for analysis at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Cmax: Maximum Observed Plasma Concentration for Ixazomib in NDMM Participants | Cycle 1 Day 1 | 64.283 nanogram/mL (ng/mL) | Standard Deviation 36.283 |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Cmax: Maximum Observed Plasma Concentration for Ixazomib in NDMM Participants | Cycle 1 Day 15 | 53.145 nanogram/mL (ng/mL) | Standard Deviation 46.3782 |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Cmax: Maximum Observed Plasma Concentration for Ixazomib in NDMM Participants | Cycle 1 Day 1 | 46.600 nanogram/mL (ng/mL) | Standard Deviation 34.7722 |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Cmax: Maximum Observed Plasma Concentration for Ixazomib in NDMM Participants | Cycle 1 Day 15 | 62.280 nanogram/mL (ng/mL) | Standard Deviation 39.4249 |
Secondary
Cmax: Maximum Observed Plasma Concentration for Ixazomib in RRMM Participants
Time frame: Cycle 1 Days 1 and 15 predose and at multiple timepoints (up to 168 hours) postdose
Population: PK-Evaluable Population was defined as participants in the safety lead-in cohort who have sufficient dosing data and ixazomib concentration-time data to permit calculation of PK parameters. Number analyzed is the number of participants with data available for analysis at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Cmax: Maximum Observed Plasma Concentration for Ixazomib in RRMM Participants | Cycle 1 Day 1 | 47.400 ng/mL | Standard Deviation 36.7083 |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Cmax: Maximum Observed Plasma Concentration for Ixazomib in RRMM Participants | Cycle 1 Day 15 | 52.229 ng/mL | Standard Deviation 39.6006 |
Secondary
Duration of Response (DOR) in NDMM Participants
DOR is defined as the time from the date of first documentation of a confirmed PR or better to the date of first documented PD up to the initiation of alternative therapy.
Time frame: Up to 45 Months
Population: Participants from the Response Evaluable Population, participants who received at least 2 of the 3 ixazomib doses during Cycle 1, had measurable disease at Baseline and at least 1 postbaseline response assessment, who responded. Responders without PD were censored at the date of SD or better prior to the date of alternative therapy.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Duration of Response (DOR) in NDMM Participants | 32.2 months |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Duration of Response (DOR) in NDMM Participants | 36.6 months |
Secondary
Duration of Response (DOR) in RRMM Participants
DOR is defined as the time from the date of first documentation of a confirmed PR or better to the date of first documented PD up to the alternative therapy.
Time frame: Up to 45 months
Population: Participants from the Response Evaluable Population, participants who received at least 2 of the 3 ixazomib doses during Cycle 1, had measurable disease at Baseline and at least 1 postbaseline response assessment, who responded. Responders without PD were censored at the date of SD or better prior to the date of the alternative therapy.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Duration of Response (DOR) in RRMM Participants | 26.3 months |
Secondary
Number of Participants With Adverse Events (AEs), Grade 3 or Higher AEs, AEs Resulting in Treatment Discontinuation, AEs Resulting in Dose Reduction and Serious Adverse Events (SAEs) in NDMM Participants
An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product whether or not it is related to the medicinal product. This includes any newly occurring event, or a previous condition that has increased in severity or frequency since the administration of study drug. A SAE is any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly/birth defect or is a medically important event. Relationship of each AE to study drug was determined by the Investigator.
Time frame: First dose of study drug through 30 days after last dose of drug (Up to 45 months)
Population: Safety Population was defined as all participants who receive at least 1 dose of any study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Number of Participants With Adverse Events (AEs), Grade 3 or Higher AEs, AEs Resulting in Treatment Discontinuation, AEs Resulting in Dose Reduction and Serious Adverse Events (SAEs) in NDMM Participants | Grade 3 or Higher AEs | 27 Participants |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Number of Participants With Adverse Events (AEs), Grade 3 or Higher AEs, AEs Resulting in Treatment Discontinuation, AEs Resulting in Dose Reduction and Serious Adverse Events (SAEs) in NDMM Participants | AEs Resulting in Dose Reduction | 11 Participants |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Number of Participants With Adverse Events (AEs), Grade 3 or Higher AEs, AEs Resulting in Treatment Discontinuation, AEs Resulting in Dose Reduction and Serious Adverse Events (SAEs) in NDMM Participants | AEs Resulting in Treatment Discontinuation | 9 Participants |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Number of Participants With Adverse Events (AEs), Grade 3 or Higher AEs, AEs Resulting in Treatment Discontinuation, AEs Resulting in Dose Reduction and Serious Adverse Events (SAEs) in NDMM Participants | SAEs | 17 Participants |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Number of Participants With Adverse Events (AEs), Grade 3 or Higher AEs, AEs Resulting in Treatment Discontinuation, AEs Resulting in Dose Reduction and Serious Adverse Events (SAEs) in NDMM Participants | Any AE | 35 Participants |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Number of Participants With Adverse Events (AEs), Grade 3 or Higher AEs, AEs Resulting in Treatment Discontinuation, AEs Resulting in Dose Reduction and Serious Adverse Events (SAEs) in NDMM Participants | SAEs | 20 Participants |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Number of Participants With Adverse Events (AEs), Grade 3 or Higher AEs, AEs Resulting in Treatment Discontinuation, AEs Resulting in Dose Reduction and Serious Adverse Events (SAEs) in NDMM Participants | Any AE | 34 Participants |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Number of Participants With Adverse Events (AEs), Grade 3 or Higher AEs, AEs Resulting in Treatment Discontinuation, AEs Resulting in Dose Reduction and Serious Adverse Events (SAEs) in NDMM Participants | Grade 3 or Higher AEs | 27 Participants |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Number of Participants With Adverse Events (AEs), Grade 3 or Higher AEs, AEs Resulting in Treatment Discontinuation, AEs Resulting in Dose Reduction and Serious Adverse Events (SAEs) in NDMM Participants | AEs Resulting in Treatment Discontinuation | 11 Participants |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Number of Participants With Adverse Events (AEs), Grade 3 or Higher AEs, AEs Resulting in Treatment Discontinuation, AEs Resulting in Dose Reduction and Serious Adverse Events (SAEs) in NDMM Participants | AEs Resulting in Dose Reduction | 10 Participants |
Secondary
Number of Participants With AEs, Grade 3 or Higher AEs, AEs Resulting in Treatment Discontinuation, AEs Resulting in Dose Reduction, SAEs in RRMM Participants
An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal relationship with this treatment. A SAE is any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly/birth defect or is a medically important event. Relationship of each AE to study drug was determined by the Investigator.
Time frame: First dose of study drug through 30 days after last dose of drug (Up to 45 months)
Population: Safety population was defined as all participants who received at least 1 dose of any study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Number of Participants With AEs, Grade 3 or Higher AEs, AEs Resulting in Treatment Discontinuation, AEs Resulting in Dose Reduction, SAEs in RRMM Participants | Any AE | 72 Participants |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Number of Participants With AEs, Grade 3 or Higher AEs, AEs Resulting in Treatment Discontinuation, AEs Resulting in Dose Reduction, SAEs in RRMM Participants | Grade 3 or Higher AE | 49 Participants |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Number of Participants With AEs, Grade 3 or Higher AEs, AEs Resulting in Treatment Discontinuation, AEs Resulting in Dose Reduction, SAEs in RRMM Participants | AEs Resulting in Treatment Discontinuation | 19 Participants |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Number of Participants With AEs, Grade 3 or Higher AEs, AEs Resulting in Treatment Discontinuation, AEs Resulting in Dose Reduction, SAEs in RRMM Participants | AEs Resulting in Dose Reduction | 30 Participants |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Number of Participants With AEs, Grade 3 or Higher AEs, AEs Resulting in Treatment Discontinuation, AEs Resulting in Dose Reduction, SAEs in RRMM Participants | SAEs | 30 Participants |
Secondary
Number of Participants With AEs, SAEs, AEs Resulting in Discontinuation and AEs Resulting in Dose Reduction in NDMM Participants Remaining on Treatment After 13 Cycles
An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product whether or not it is related to the medicinal product. This includes any newly occurring event, or a previous condition that has increased in severity or frequency since the administration of study drug. A SAE is any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly/birth defect or is a medically important event. Relationship of each AE to study drug was determined by the Investigator.
Time frame: First dose of study drug through 30 days after the last dose of drug (Up to 45 months)
Population: Safety Population was defined as all participants who receive at least 1 dose of any study drug. Number of participants analyzed is the number of participants who remained on treatment after 13 cycles.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Number of Participants With AEs, SAEs, AEs Resulting in Discontinuation and AEs Resulting in Dose Reduction in NDMM Participants Remaining on Treatment After 13 Cycles | Any AE | 22 Participants |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Number of Participants With AEs, SAEs, AEs Resulting in Discontinuation and AEs Resulting in Dose Reduction in NDMM Participants Remaining on Treatment After 13 Cycles | SAE | 6 Participants |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Number of Participants With AEs, SAEs, AEs Resulting in Discontinuation and AEs Resulting in Dose Reduction in NDMM Participants Remaining on Treatment After 13 Cycles | AEs Resulting in Treatment Discontinuation | 1 Participants |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Number of Participants With AEs, SAEs, AEs Resulting in Discontinuation and AEs Resulting in Dose Reduction in NDMM Participants Remaining on Treatment After 13 Cycles | AEs Resulting in Dose Reduction | 5 Participants |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Number of Participants With AEs, SAEs, AEs Resulting in Discontinuation and AEs Resulting in Dose Reduction in NDMM Participants Remaining on Treatment After 13 Cycles | AEs Resulting in Dose Reduction | 4 Participants |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Number of Participants With AEs, SAEs, AEs Resulting in Discontinuation and AEs Resulting in Dose Reduction in NDMM Participants Remaining on Treatment After 13 Cycles | Any AE | 20 Participants |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Number of Participants With AEs, SAEs, AEs Resulting in Discontinuation and AEs Resulting in Dose Reduction in NDMM Participants Remaining on Treatment After 13 Cycles | AEs Resulting in Treatment Discontinuation | 2 Participants |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Number of Participants With AEs, SAEs, AEs Resulting in Discontinuation and AEs Resulting in Dose Reduction in NDMM Participants Remaining on Treatment After 13 Cycles | SAE | 4 Participants |
Secondary
Percentage of Participants With (CR + VGPR), CR, VGPR, PR, SD and PD in RRMM Participants
Percentage of participants with CR + VGPR + PR (ORR), CR, VGPR, PR, SD, PD according to IMWG criteria. CR=negative immunofixation of serum and urine; disappearance of soft tissue plasmacytomas;\<5% PC in bone marrow. VGPR=serum and urine M-component detectable by immunofixation but not on electrophoresis or 90% reduction in serum M-component plus urine M-component \<100 mg/24 hour. PR=50% reduction of serum M-protein and reduction in 24 hour urine M-protein by 90% or \<200 mg/24 hour or decrease 50% difference between involved FLC levels or 50% reduction in bone marrow plasma cells if baseline percentage was 30%; and if present at Baseline, 50% reduction in the size of soft tissue plasmacytomas. SD=not meeting criteria for VGPR, PR or PD. PD=25% increase in lowest value any of the following: serum M-component, urine M-component, difference between involved and uninvolved FLC levels, bone marrow PC percentage; new or increase in size of existing bone lesions or soft tissue plasmacytomas.
Time frame: Day 1 of each 28-day Cycle (Up to 45 months)
Population: Response Evaluable Population was defined as participants who received at least 2 of the 3 ixazomib doses during Cycle 1, had measurable disease at Baseline, and at least 1 postbaseline response assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Percentage of Participants With (CR + VGPR), CR, VGPR, PR, SD and PD in RRMM Participants | CR + VGPR | 19 percentage of participants |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Percentage of Participants With (CR + VGPR), CR, VGPR, PR, SD and PD in RRMM Participants | CR | 5 percentage of participants |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Percentage of Participants With (CR + VGPR), CR, VGPR, PR, SD and PD in RRMM Participants | VGPR | 14 percentage of participants |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Percentage of Participants With (CR + VGPR), CR, VGPR, PR, SD and PD in RRMM Participants | PR | 44 percentage of participants |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Percentage of Participants With (CR + VGPR), CR, VGPR, PR, SD and PD in RRMM Participants | SD | 37 percentage of participants |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Percentage of Participants With (CR + VGPR), CR, VGPR, PR, SD and PD in RRMM Participants | PD | 10 percentage of participants |
Secondary
Percentage of Participants With CR + VGPR + PR (ORR), CR + VGPR, CR, VGPR, PR, SD and PD Throughout the Entire Treatment Period in NDMM Participants
Percentage of participants with CR + VGPR + PR (ORR), CR, VGPR, PR, SD, PD according to IMWG criteria. CR=negative immunofixation of serum and urine; disappearance of soft tissue plasmacytomas;\<5% PC in bone marrow. VGPR=serum and urine M-component detectable by immunofixation but not on electrophoresis or 90% reduction in serum M-component plus urine M-component \<100 mg/24 hour. PR=50% reduction of serum M-protein and reduction in 24 hour urine M-protein by 90% or \<200 mg/24 hour or decrease 50% difference between involved FLC levels or 50% reduction in bone marrow plasma cells if baseline percentage was 30%; and if present at Baseline, 50% reduction in the size of soft tissue plasmacytomas. SD=not meeting criteria for VGPR, PR or PD. PD=25% increase in lowest value any of the following: serum M-component, urine M-component, difference between involved and uninvolved FLC levels, bone marrow PC percentage; new or increase in size of existing bone lesions or soft tissue plasmacytomas.
Time frame: Day 1 of each 28-day Cycle (Up to 45 months)
Population: Response Evaluable Population was defined as participants who received at least 2 of the 3 ixazomib doses during Cycle 1, had measurable disease at Baseline, and at least 1 postbaseline response assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Percentage of Participants With CR + VGPR + PR (ORR), CR + VGPR, CR, VGPR, PR, SD and PD Throughout the Entire Treatment Period in NDMM Participants | CR | 15 percentage of participants |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Percentage of Participants With CR + VGPR + PR (ORR), CR + VGPR, CR, VGPR, PR, SD and PD Throughout the Entire Treatment Period in NDMM Participants | PR | 67 percentage of participants |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Percentage of Participants With CR + VGPR + PR (ORR), CR + VGPR, CR, VGPR, PR, SD and PD Throughout the Entire Treatment Period in NDMM Participants | CR + VGPR | 36 percentage of participants |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Percentage of Participants With CR + VGPR + PR (ORR), CR + VGPR, CR, VGPR, PR, SD and PD Throughout the Entire Treatment Period in NDMM Participants | SD | 18 percentage of participants |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Percentage of Participants With CR + VGPR + PR (ORR), CR + VGPR, CR, VGPR, PR, SD and PD Throughout the Entire Treatment Period in NDMM Participants | VGPR | 21 percentage of participants |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Percentage of Participants With CR + VGPR + PR (ORR), CR + VGPR, CR, VGPR, PR, SD and PD Throughout the Entire Treatment Period in NDMM Participants | PD | 0 percentage of participants |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Percentage of Participants With CR + VGPR + PR (ORR), CR + VGPR, CR, VGPR, PR, SD and PD Throughout the Entire Treatment Period in NDMM Participants | CR + VGPR + PR | 82 percentage of participants |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Percentage of Participants With CR + VGPR + PR (ORR), CR + VGPR, CR, VGPR, PR, SD and PD Throughout the Entire Treatment Period in NDMM Participants | PD | 6 percentage of participants |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Percentage of Participants With CR + VGPR + PR (ORR), CR + VGPR, CR, VGPR, PR, SD and PD Throughout the Entire Treatment Period in NDMM Participants | CR + VGPR + PR | 71 percentage of participants |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Percentage of Participants With CR + VGPR + PR (ORR), CR + VGPR, CR, VGPR, PR, SD and PD Throughout the Entire Treatment Period in NDMM Participants | CR + VGPR | 32 percentage of participants |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Percentage of Participants With CR + VGPR + PR (ORR), CR + VGPR, CR, VGPR, PR, SD and PD Throughout the Entire Treatment Period in NDMM Participants | CR | 12 percentage of participants |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Percentage of Participants With CR + VGPR + PR (ORR), CR + VGPR, CR, VGPR, PR, SD and PD Throughout the Entire Treatment Period in NDMM Participants | VGPR | 21 percentage of participants |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Percentage of Participants With CR + VGPR + PR (ORR), CR + VGPR, CR, VGPR, PR, SD and PD Throughout the Entire Treatment Period in NDMM Participants | PR | 59 percentage of participants |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Percentage of Participants With CR + VGPR + PR (ORR), CR + VGPR, CR, VGPR, PR, SD and PD Throughout the Entire Treatment Period in NDMM Participants | SD | 18 percentage of participants |
Secondary
Percentage of Participants With CR + VGPR + PR (ORR), CR, VGPR, PR and Stable Disease (SD), Progressive Disease (PD) During the Induction Phase
Percentage of participants with CR + VGPR + PR (ORR), CR, VGPR, PR, SD, PD according to IMWG criteria. CR=negative immunofixation of serum and urine; disappearance of soft tissue plasmacytomas;\<5% PC in bone marrow. VGPR=serum and urine M-component detectable by immunofixation but not on electrophoresis or 90% reduction in serum M-component plus urine M-component \<100 mg/24 hour. PR=50% reduction of serum M-protein and reduction in 24 hour urine M-protein by 90% or \<200 mg/24 hour or decrease 50% difference between involved FLC levels or 50% reduction in bone marrow plasma cells if baseline percentage was 30%; and if present at Baseline, 50% reduction in the size of soft tissue plasmacytomas. SD=not meeting criteria for VGPR, PR or PD. PD=25% increase in lowest value any of the following: serum M-component, urine M-component, difference between involved and uninvolved FLC levels, bone marrow PC percentage; new or increase in size of existing bone lesions or soft tissue plasmacytomas.
Time frame: Day 1 of Cycles 1-13, 28-day cycles (Up to 1 year)
Population: Response Evaluable Population was defined as participants who received at least 2 of the 3 ixazomib doses during Cycle 1, had measurable disease at Baseline, and at least 1 postbaseline response assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Percentage of Participants With CR + VGPR + PR (ORR), CR, VGPR, PR and Stable Disease (SD), Progressive Disease (PD) During the Induction Phase | PD | 0 percentage of participants |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Percentage of Participants With CR + VGPR + PR (ORR), CR, VGPR, PR and Stable Disease (SD), Progressive Disease (PD) During the Induction Phase | CR + VGPR + PR | 79 percentage of participants |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Percentage of Participants With CR + VGPR + PR (ORR), CR, VGPR, PR and Stable Disease (SD), Progressive Disease (PD) During the Induction Phase | CR | 12 percentage of participants |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Percentage of Participants With CR + VGPR + PR (ORR), CR, VGPR, PR and Stable Disease (SD), Progressive Disease (PD) During the Induction Phase | VGPR | 15 percentage of participants |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Percentage of Participants With CR + VGPR + PR (ORR), CR, VGPR, PR and Stable Disease (SD), Progressive Disease (PD) During the Induction Phase | PR | 67 percentage of participants |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Percentage of Participants With CR + VGPR + PR (ORR), CR, VGPR, PR and Stable Disease (SD), Progressive Disease (PD) During the Induction Phase | SD | 12 percentage of participants |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Percentage of Participants With CR + VGPR + PR (ORR), CR, VGPR, PR and Stable Disease (SD), Progressive Disease (PD) During the Induction Phase | PR | 62 percentage of participants |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Percentage of Participants With CR + VGPR + PR (ORR), CR, VGPR, PR and Stable Disease (SD), Progressive Disease (PD) During the Induction Phase | PD | 3 percentage of participants |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Percentage of Participants With CR + VGPR + PR (ORR), CR, VGPR, PR and Stable Disease (SD), Progressive Disease (PD) During the Induction Phase | VGPR | 15 percentage of participants |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Percentage of Participants With CR + VGPR + PR (ORR), CR, VGPR, PR and Stable Disease (SD), Progressive Disease (PD) During the Induction Phase | CR + VGPR + PR | 71 percentage of participants |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Percentage of Participants With CR + VGPR + PR (ORR), CR, VGPR, PR and Stable Disease (SD), Progressive Disease (PD) During the Induction Phase | SD | 18 percentage of participants |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Percentage of Participants With CR + VGPR + PR (ORR), CR, VGPR, PR and Stable Disease (SD), Progressive Disease (PD) During the Induction Phase | CR | 9 percentage of participants |
Secondary
Percentage of Participants With CR + VGR + PR (ORR), CR, VGPR, and PR in NDMM Participants Remaining on Treatment After 13 Cycles
Percentage of participants with Overall Response (CR + VGPR + PR), CR, VGPR and PR according to IMWG criteria. CR=negative immunofixation of serum and urine; disappearance of soft tissue plasmacytomas;\<5% PC in bone marrow. VGPR=serum and urine M-component detectable by immunofixation but not on electrophoresis or 90% reduction in serum M-component plus urine M-component \<100 mg/24 hour. PR=50% reduction of serum M-protein and reduction in 24 hour urine M-protein by 90% or \<200 mg/24 hour or decrease 50% difference between involved FLC levels or 50% reduction in bone marrow plasma cells if baseline percentage was 30%; and if present at Baseline, 50% reduction in the size of soft tissue plasmacytomas.
Time frame: Day 1 of each 28-day Cycle (Up to 45 months)
Population: Participants from the Response Evaluable Population, participants who received at least 2 of the 3 ixazomib doses during Cycle 1, had measurable disease at Baseline and at least 1 postbaseline response assessment, with both an Induction and Maintenance response.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Percentage of Participants With CR + VGR + PR (ORR), CR, VGPR, and PR in NDMM Participants Remaining on Treatment After 13 Cycles | CR + VGPR + PR | 75.0 percentage of participants |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Percentage of Participants With CR + VGR + PR (ORR), CR, VGPR, and PR in NDMM Participants Remaining on Treatment After 13 Cycles | CR | 16.7 percentage of participants |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Percentage of Participants With CR + VGR + PR (ORR), CR, VGPR, and PR in NDMM Participants Remaining on Treatment After 13 Cycles | VGPR | 20.8 percentage of participants |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Percentage of Participants With CR + VGR + PR (ORR), CR, VGPR, and PR in NDMM Participants Remaining on Treatment After 13 Cycles | PR | 37.5 percentage of participants |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Percentage of Participants With CR + VGR + PR (ORR), CR, VGPR, and PR in NDMM Participants Remaining on Treatment After 13 Cycles | PR | 38.1 percentage of participants |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Percentage of Participants With CR + VGR + PR (ORR), CR, VGPR, and PR in NDMM Participants Remaining on Treatment After 13 Cycles | CR + VGPR + PR | 85.7 percentage of participants |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Percentage of Participants With CR + VGR + PR (ORR), CR, VGPR, and PR in NDMM Participants Remaining on Treatment After 13 Cycles | VGPR | 28.6 percentage of participants |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Percentage of Participants With CR + VGR + PR (ORR), CR, VGPR, and PR in NDMM Participants Remaining on Treatment After 13 Cycles | CR | 19.0 percentage of participants |
Secondary
Progression Free Survival (PFS) in NDMM Participants
PFS is defined as the time from the date of first dose of study treatment to the date of the first documented disease progression or death.
Time frame: Up to 45 months
Population: Safety Population was defined as all participants who received at least 1 dose of any study drug. Participants without documentation of PD or death were censored at the date of last response assessment that is SD or better prior to the date of the alternative therapy.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Progression Free Survival (PFS) in NDMM Participants | 23.5 months |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Progression Free Survival (PFS) in NDMM Participants | 23.0 months |
Secondary
Progression Free Survival (PFS) in RRMM Participants
PFS is defined as the time from the date of first dose of study treatment to the date of the first documented disease progression or death.
Time frame: Up to 45 months
Population: Safety Population was defined as all participants who received at least 1 dose of any study drug. Participants without documentation of PD or death were censored at the date of last response assessment that was SD or better prior to the date of the alternative therapy.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Progression Free Survival (PFS) in RRMM Participants | 14.2 months |
Secondary
Time to Progression (TTP) in NDMM Participants
TTP is defined as the time from the date of first dose of study treatment to the date of first documentation of disease progression.
Time frame: Up to 45 months
Population: Safety Population was defined as all participants who received at least 1 dose of any study drug. Participants without documentation of PD were censored at the date of last response assessment that is SD or better prior to the date of the alternative therapy.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Time to Progression (TTP) in NDMM Participants | 30.9 months |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Time to Progression (TTP) in NDMM Participants | 32.2 months |
Secondary
Time to Progression (TTP) in RRMM Participants
TTP is defined as the time from the date of first dose of study treatment to the date of first documentation of disease progression.
Time frame: Up to 45 months
Population: Safety Population was defined as all participants who received at least 1 dose of any study drug. Participants without documentation of PD were censored at the date of last response assessment that is SD or better prior to the date of the alternative therapy.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Time to Progression (TTP) in RRMM Participants | 16.8 months |
Secondary
Time to Response (TTR) in NDMM Participants During the Induction Phase
TTR is defined as the time interval from the date of the first dose of study treatment to the date of the first documented confirmed response of PR or better up to the initiation of alternative therapy in a participant who responded.
Time frame: Up to 1 year
Population: Participants from the Response Evaluable Population, defined as participants who received at least 2 of the 3 ixazomib doses during Cycle 1, had measurable disease at Baseline, and at least 1 postbaseline response assessment, who responded.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Time to Response (TTR) in NDMM Participants During the Induction Phase | 2.2 months |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Time to Response (TTR) in NDMM Participants During the Induction Phase | 1.9 months |
Secondary
Time to Response (TTR) in RRMM Participants
TTR is defined as the time interval from the date of the first dose of study treatment to the date of the first documented confirmed response of PR or better up to the alternative therapy in a participant who responded.
Time frame: Up to 45 months
Population: Participants from the Response Evaluable Population, defined as participants who received at least 2 of the 3 ixazomib doses during Cycle 1, had measurable disease at Baseline, and at least 1 postbaseline response assessment, who responded.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Time to Response (TTR) in RRMM Participants | 2.1 months |
Secondary
Tmax: Time to First Occurrence of Cmax for Ixazomib in NDMM Participants
Time frame: Cycle 1 Days 1 and 15 predose and at multiple timepoints (up to 168 hours) postdose
Population: PK-Evaluable Population was defined as participants in the safety lead-in cohort who have sufficient dosing data and ixazomib concentration-time data to permit calculation of PK parameters. Number analyzed is the number of participants with data available for analysis at the given time-point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Tmax: Time to First Occurrence of Cmax for Ixazomib in NDMM Participants | Cycle 1 Day 1 | 1.250 hour (hr) |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Tmax: Time to First Occurrence of Cmax for Ixazomib in NDMM Participants | Cycle 1 Day 15 | 1.000 hour (hr) |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Tmax: Time to First Occurrence of Cmax for Ixazomib in NDMM Participants | Cycle 1 Day 1 | 1.040 hour (hr) |
| Ixazomib 4.0 mg + CYC 400 mg/m^2 + DEX 40 mg (NDMM) | Tmax: Time to First Occurrence of Cmax for Ixazomib in NDMM Participants | Cycle 1 Day 15 | 1.000 hour (hr) |
Secondary
Tmax: Time to First Occurrence of Cmax for Ixazomib in RRMM Participants
Time frame: Cycle 1 Days 1 and 15 predose and at multiple timepoints (up to 168) hours postdose
Population: PK-Evaluable Population was defined as participants in the safety lead-in cohort who have sufficient dosing data and ixazomib concentration-time data to permit calculation of PK parameters. Number analyzed is the number of participants with data available for analysis at the given time-point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Tmax: Time to First Occurrence of Cmax for Ixazomib in RRMM Participants | Cycle 1 Day 1 | 1.225 hr |
| Ixazomib 4.0 mg + CYC 300 mg/m^2 + DEX 40 mg (NDMM) | Tmax: Time to First Occurrence of Cmax for Ixazomib in RRMM Participants | Cycle 1 Day 15 | 2.000 hr |