An Open-Label, Dose-Escalation, Phase 1/2 Study of the Oral Formulation of IXAZOMIB (MLN9708), Administered Twice-weekly in Combination With Lenalidomide and Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma Requiring Systemic Treatment

Phase 1: Maximum Tolerated Dose (MTD)

时间窗: Cycle 1 (21 days)

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.

Phase 1: Number of Participants With Treatment-Emergent Adverse Events (TEAE) Related to Neurotoxicity

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

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.

Phase 1: Recommended Phase 2 Dose (RP2D)

时间窗: Cycle 1 (21 days)

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).

Phase 1: Number of Participants With Markedly Abnormal Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs)

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

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.

Phase 2: Percentage of Participants With Complete Response (CR) + Very Good Partial Response (VGPR)

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

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.

Phase 2: Percentage of Participants With Grade 3 or Higher Adverse Events

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

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.

Phase 1: Percentage of Participants Experiencing 1 or More Treatment-Emergent Adverse Events (TEAEs) or Serious Adverse Events (SAEs)

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

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.

Phase 1: Number of Participants With Clinically Significant Change From Baseline in Vital Signs

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

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

Phase 2: Percentage of Participants Experiencing Serious Adverse Events

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

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.

Phase 2: Percentage of Participants With Treatment-Emergent Adverse Events Resulting in Study Drug Discontinuation

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

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.