Study of Oral IXAZOMIB in Combination With Lenalidomide and Dexamethasone in Participants With Newly Diagnosed Multiple Myeloma

MTD was highest dose of ixazomib given with combination drugs, at which \<=1 of 6 participants experienced dose-limiting toxicity (DLT) during Cycle 1 of Phase 1. DLT defined as any of following considered possibly related to therapy: Grade 4 neutropenia (absolute neutrophil count \[ANC\] \<500 cell per cubic millimeter \[cells/mm\^3\]) for \>7 days; Grade 3 neutropenia with fever or infection; Grade 4 thrombocytopenia for \>7 days; Grade 3 thrombocytopenia with clinically significant bleeding; platelet count \<10,000/mm\^3; Grade 2 peripheral neuropathy with pain or \>=Grade 3 peripheral neuropathy; \>=Grade 3 nausea/emesis, diarrhea controlled by supportive therapy; any \>=Grade 3 nonhematologic toxicity except Grade 3 arthralgia/myalgia; or \<1 week Grade 3 fatigue; delay in initiation of the subsequent therapy cycle by \>14 days; \<=80% lenalidomide doses administered due to other \>=Grade 2 combination study drug-related nonhematologic toxicities requiring therapy discontinuation.

Time frame: Cycle 1 (21 days)

Population: DLT-evaluable population included all participants who received all Cycle 1 doses of MLN9708 and completed Cycle 1 procedures, or experienced a DLT in Cycle 1 in Phase 1.

Vital signs included body temperature, blood pressure and heart rate.

Time frame: Baseline up to 30 days after last dose of study drug (Up to Cycle 83 - approximately 2067 days)

Population: Safety population included all participants who received at least 1 dose of any study drug.

Laboratory tests included chemistry, hematology and urinalysis. Abnormal laboratory value was assessed as an AE if the value lead to discontinuation or delay in treatment, dose modification, therapeutic intervention, or was considered by the investigator to be a clinically significant change from baseline. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.

Time frame: Baseline up to 30 days after last dose of study drug (Up to Cycle 83 - approximately 2067 days)

Population: Safety population included all participants who received at least 1 dose of any study drug and reported baseline and at least 1 post-baseline value.

TEAE related to neurotoxicity grading based on common terminology criteria for adverse events (CTACE) version 4.03 are reported. Grade 1= mild; Grade 2= moderate; within normal limits, Grade 3= severe or medically significant but not immediately life-threatening; Grade 4= life-threatening consequences; urgent intervention indicated; Grade 5= death. Only TEAEs related to neurotoxicity with values are reported.

Time frame: Baseline up to 30 days after last dose of study drug (Up to Cycle 83 - approximately 2067 days)

Population: Safety population included all participants who received at least 1 dose of any study drug and reported baseline and at least 1 post-baseline value.

An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; or congenital anomaly; or a medically important event. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug.

Time frame: Baseline up to 30 days after last dose of study drug (Up to Cycle 83 - approximately 2067 days)

Population: Safety population included all participants who received at least 1 dose of any study drug.

The RP2D of ixazomib was determined after the evaluation of the available data from the phase 1 portion of the trial which included, but was not limited to analyses of efficacy results, toxicity characterization, all grades peripheral neuropathy, and treatment discontinuation. The maximum number of cycles received was 83 cycles (approximately up to 2037 days).

Time frame: Cycle 1 (21 days)

Population: Safety population included all participants who received at least 1 dose of any study drug.

A SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; or congenital anomaly; or a medically important event.

Time frame: Baseline up to 30 days after the last dose of study drug (approximately 1905 days)

Population: Safety population included all participants who received at least one dose of any study drug.

CR as per International Myeloma Working Group (IMWG) uniform criteria is defined as negative immunofixation on the serum and urine and disappearance of soft tissue plasmacytomas and \<5% plasma cells in bone marrow. VGPR as per IMWG criteria is defined as serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level \<100 mg per 24 hours. VGPR was applicable only to participants who had measurable disease defined by at least 1 of the following 3 measurements: Serum M-protein greater than or equal to (\>=)1 g/dL; Urine M-protein \>=200 mg/24 hours; Serum FLC assay level \>=10 mg/dL, provided serum FLC ratio was abnormal.

Time frame: Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)

Population: Response-evaluable population included all participants who received at least 1 dose of study drug, had measurable disease at baseline, and at least 1 post-baseline response assessment.

An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. As per Common Terminology Criteria for Adverse Events v4.0 (CTCAE), Grade 3 = AE with severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living. Grade 4 = AE with life-threatening consequences; urgent intervention indicated and Grade 5 = Death related to AE.

Time frame: Baseline up to 30 days after the last dose of study drug (approximately 1905 days)

Population: Safety population included all participants who received at least 1 dose of any study drug.

An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug.

Time frame: Baseline up to 30 days after the last dose of study drug (approximately 1905 days)

Population: Safety population included all participants who received at least 1 dose of any study drug.

The Kaplan-Meier estimate reports the percentage of participants surviving at Year 1.

Time frame: 1 year after the first dose of study treatment

Population: mITT population included all participants who received at least 1 dose of any study drug in Phase 2 or who received at least 1 dose of any study drug and were treated at the phase 2 dose level during Phase 1.

Overall survival was measured as the time from the date of first dose of study treatment to the time of death plus 1 day. For participants who did not die, survival was censored at the date of last contact. Overall Survival was analyzed using standard survival analysis techniques based on Kaplan-Meier estimates.

Time frame: Baseline up to a follow-up of 62.1 months

Population: mITT population included all participants who received at least 1 dose of any study drug in Phase 2 or who received at least 1 dose of any study drug and were treated at the phase 2 dose level during Phase 1.

AUC(0-72) is a measure of the area under the plasma concentration time-curve from time zero to 72 hours post-dose for ixazomib.

Time frame: Cycle 1, Days 1 and 11

Population: PK analysis population included all participants, who had sufficient dosing data and ixazomib concentration-time data to permit calculation of PK parameters where Days 1 and 11 assessments were available.

Maximum observed plasma concentration (Cmax) is the peak plasma concentration of ixazomib, obtained directly from the plasma concentration-time curve.

Time frame: Cycle 1, Days 1 and 11

Population: Pharmacokinetic (PK) analysis population included all participants who had sufficient dosing data and ixazomib concentration-time data to permit calculation of PK parameters where Days 1 and 11 assessments were available.

CR as per International Myeloma Working Group (IMWG) uniform criteria is defined as negative immunofixation on the serum and urine and disappearance of soft tissue plasmacytomas and \<5% plasma cells in bone marrow. Partial response(PR):\>=50% reduction of serum M-protein,urinary M-protein by \>=90%/to \<200 mg/24 hr reduction.Near CR(nCR):positive immunofixation of serum/urine;soft tissue plasmacytomas disappearance;\<=5% plasma cells in bone marrow. VGPR as per IMWG criteria is defined as serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level \<100 mg per 24 hours. VGPR was applicable only to participants who had measurable disease defined by at least 1 of the following 3 measurements: Serum M-protein greater than or equal to (\>=)1 g/dL; Urine M-protein \>=200 mg/24 hours; Serum FLC assay level \>=10 mg/dL, provided serum FLC ratio was abnormal.

Time frame: Baseline until end of study treatment (Up to treatment Cycle 83 - approximately 2037 days)

Population: Response-evaluable population included all participants who received at least 1 dose of ixazomib, had measurable disease at baseline, and at least 1 post-baseline disease assessment. Results were summarized together for all Phase 1 participants, as per planned analysis.

The accumulation ratio (Rac) was estimated as the ratio of AUC (0-72) on Day 11 to the AUC (0-72) on Day 1. AUC (0-72) is the area under the plasma concentration-time curve from time zero to 72 hours post-dose for ixazomib.

Time frame: Cycle 1, Days 1 and 11

Population: PK analysis population included all participants, who had sufficient dosing data and ixazomib concentration-time data to permit calculation of PK parameters where Days 1 and 11 assessments were available.

Tmax: Time to reach the first maximum plasma concentration (Cmax), equal to time (hours) to Cmax of ixazomib after administration, obtained directly from the plasma concentration-time curve.

Time frame: Cycle 1, Days 1 and 11

Population: PK analysis population included all participants, who had sufficient dosing data and ixazomib concentration-time data to permit calculation of PK parameters where Days 1 and 11 assessments were available.

DOR was measured as the time from the date of first documentation of a confirmed response to the date of first documented PD. PD is defined as \>=25% increase from lowest value in: serum/urine M-component; difference between involved, uninvolved FLC levels; bone marrow plasma cell percent; development of new bone lesions or soft tissue plasmacytomas development or increase in the size of existing bone lesions or soft tissue plasmacytomas; hypercalcaemia development.

Time frame: Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)

Population: Included a subset of response-evaluable population who achieved response.

CR as per IMWG criteria is negative immunofixation on serum and urine and disappearance of soft tissue plasmacytomas and \<5% plasma cells in bone marrow.

Time frame: Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)

Population: Response-evaluable population included all participants who received at least 1 dose of ixazomib, had measurable disease at baseline, and at least 1 post-baseline disease assessment.

CR as per IMWG criteria is defined as negative immunofixation on the serum and urine and disappearance of soft tissue plasmacytomas and \<5% plasma cells in bone marrow. VGPR as per IMWG criteria is defined as serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level \<100 mg per 24 hours. VGPR were applicable only to participants who had measurable disease defined by at least 1 of the following 3 measurements: Serum M-protein; Urine M-protein; Serum FLC assay.

Time frame: Cycles 4, 8, and 16

Population: Response-evaluable population included all participants who received at least one 1 dose of ixazomib, had measurable disease at baseline, and at least one 1 post-baseline disease assessment.

MR as per IMWG criteria is 25%-49% reduction in serum paraprotein and 50%-89% reduction in urine light chain excretion for 6 weeks.

Time frame: Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)

Population: Response-evaluable population included all participants who received at least 1 dose of ixazomib, had measurable disease at baseline, and at least 1 post-baseline disease assessment.

nCR as per IMWG criteria is positive immunofixation analysis of serum or urine as the only evidence of disease; appearance of any soft tissue plasmacytomas and \<=5% plasma cells in bone marrow.

Time frame: Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)

Population: Response-evaluable population included all participants who received at least 1 dose of ixazomib, had measurable disease at baseline, and at least 1 post-baseline disease assessment.

Overall response is defined as CR, VGPR or PR based on IMWG Response Criteria for malignant lymphoma. CR: disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. VGPR: serum, urine M-protein detectable by immunofixation but not on electrophoresis or \>=90% reduction in serum M-protein+urine M-protein level \<100 mg/24h. Partial response (PR) is a minimum of 50% decrease in sum of the product of the diameters of up to 6 of the largest dominant nodes or nodal masses and no increase in the size of other nodes.

Time frame: Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)

Population: Response-evaluable population included all participants who received at least 1 dose of ixazomib, had measurable disease at baseline, and at least 1 post-baseline disease assessment.

PR as per IMWG criteria is 50% reduction of serum M-protein and reduction in 24-hr urinary M-protein by 90% or to \<200 mg per 24 hours.

Time frame: Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)

Population: Response-evaluable population included all participants who received at least 1 dose of ixazomib, had measurable disease at baseline, and at least 1 post-baseline disease assessment.

sCR as per IMWG criteria is CR plus normal FLC ratio and absence of clonal cells in bone marrow. CR is negative immunofixation on serum and urine and disappearance of soft tissue plasmacytomas and \<5% plasma cells in bone marrow.

Time frame: Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)

Population: Response-evaluable population included all participants who received at least one 1 dose of ixazomib, had measurable disease at baseline, and at least one 1 post-baseline disease assessment.

VGPR as per IMWG criteria 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.

Time frame: Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)

Population: Response-evaluable population included all participants who received at least 1 dose of ixazomib, had measurable disease at baseline, and at least 1 post-baseline disease assessment.

Time to first response is defined as the time from the date of first dose of study treatment to the date of the first documentation of a confirmed response (PR or better) in a participant who responded + 1 day. PR as per IMWG criteria is 50% reduction of serum M-protein and reduction in 24-h urinary M-protein by 90% or to \<200 mg per 24 hours.

Time frame: Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)

Population: Response-evaluable population included all participants who received at least 1 dose of study drug, had measurable disease at baseline, and at least 1 post-baseline response assessment.

PFS was defined as the time from the date of first dose of study treatment to the date of first documentation of progressive disease or to death due to any cause, whichever occurred first plus 1. PD: \>=25% increase from lowest value in:serum/urine M-component; difference between involved,uninvolved FLC levels; bone marrow plasma cell percent; new bone lesions/soft tissue plasmacytomas development/existing bone lesions/soft tissue plasmacytomas size rise; hypercalcaemia development. SD: not meeting criteria for CR, VGPR, PR, or PD. Participants who received ASCT or an alternate anticancer therapy were censored at the last response assessment that was SD or better before initiation of therapy. Participants without a response assessment were censored at the date of first dose. PFS was analyzed using standard survival analysis techniques based on Kaplan-Meier estimates.

Time frame: Baseline up to a follow-up of 62.1 months

Population: mITT population included all participants who received at least 1 dose of any study drug in Phase 2 or who received at least 1 dose of any study drug and were treated at the phase 2 dose level during Phase 1.

Time to progression was defined as the time from the date of first dose of study treatment to the date of first documentation of PD + 1 day. Participants that did not experience PD will be censored at the last response assessment that is SD or better. PD: \>=25% increase from lowest value in:serum/urine M-component; difference between involved, uninvolved FLC levels; bone marrow plasma cell percent; new bone lesions/soft tissue plasmacytomas development/existing bone lesions/soft tissue plasmacytomas size rise; hypercalcaemia development. SD: not meeting criteria for CR, VGPR, PR, or PD. Participants that received Autologous Stem Cell Transplantation (ASCT) or an alternate cancer therapy were also be censored at the last response assessment that is, SD or better prior to initiation of therapy. Participants without response assessment will be censored at the date of first dose. TTP was analyzed using standard survival analysis techniques based on Kaplan-Meier estimates.

Time frame: Baseline up to a follow-up of 62.1 months

Population: modified-intent-to-treat (mITT) population included all participants who received at least one dose of any study drug in Phase 2 or who received at least 1 dose of any study drug and were treated at the phase 2 dose level during Phase 1.