Study Evaluating the Safety and Tolerability of Weekly Dosing of Oral IXAZOMIB in Adult Patients With Relapsed and Refractory Multiple Myeloma

Neurotoxicity is graded using participant responses to 11 functional questions on a 5-point scale, where 0=Not at all and 4=Very much, using the Functional Assessment of Cancer Therapy/Gynecology Oncology Group - Neurotoxicity Questionnaire, Version 4.0(14). Neurotoxicity subscale is a sum of 11 reversed item scores where each original score is transformed as (4 - score). The highest possible score is 44, and a higher score indicates more neurotoxicity.

Time frame: Cycle 1 Day 1 and End of Study (Up to 354 days)

Population: Safety Population included all randomized participants who received study drug.

An Adverse Event 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 (eg, 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 treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. A Serious Adverse Event (SAE) was any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant.

Time frame: From the first dose through 30 days after last dose of ixazomib citrate or until the start of subsequent antineoplastic therapy (Up to 354 days)

Population: Safety Population included all randomized participants who received study drug.

MLN2238 is the complete hydrolysis product of the study drug ixazomib citrate (MLN9708).

Time frame: Day 15 of Cycle 1

Population: Participants from the PK Analysis Population, all participants who had sufficient dosing data to calculate PK parameters, with data available for calculation of accumulation ratio.

AUC(0-168) is a measure of the area under the plasma concentration-time curve over the dosing interval (tau) (AUC\[0-tau\]), where tau is the length of the dosing interval - 168 hours in this study). MLN2238 is the complete hydrolysis product of the study drug ixazomib citrate (MLN9708).

Time frame: Days 1 and 15 of Cycle 1

Population: Participants from the PK Analysis Population, all participants who had sufficient dosing data to calculate PK parameters, with data available for calculation of AUC(0-168).

Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve. MLN2238 is the complete hydrolysis product of the study drug ixazomib citrate (MLN9708).

Time frame: Days 1 and 15 of Cycle 1

Population: Participants from the Pharmacokinetic (PK) Analysis Population, all participants who had sufficient dosing data to calculate PK parameters, with data available for calculation of Cmax.

A Whole Blood 20S Proteasome Inhibition Parameter. There were no subjects in the Pharmacodynamic (PD) Analysis Set for the 2.23 mg/m\^2 cohort, so PD tables do not include that arm.

Time frame: Days 1 and 15 of Cycle 1

Population: PD analysis Population included all participants who had sufficient dosing data to calculate PD parameters

Responses were based on International Myeloma Working Group Uniform Criteria. Complete Response (CR)=Negative immunofixation on serum and urine and disappearance of any soft tissue plasmacytomas and \<5% plasma cells in bone marrow. Partial Response (PR)= reduction in M-Protein ≥50% in serum and ≥90% in 24-hour urine. If M-protein unmeasurable, ≥50% decrease in difference of involved and uninvolved Free Light Chain (FLC). If M-protein and FLC unmeasurable, ≥50% reduction in plasma cells is required, if baseline bone marrow plasma cell ≥30%. And ≥50% reduction in the size of soft tissue plasmacytomas. Minimal Response (MR)= 25-49% reduction in serum paraprotein for 6 weeks. 50-89% reduction in 24 hour urinary light chain excretion for 6 weeks. For Non-secretory myeloma patients, 25-49 % reduction in plasma cells in bone marrow and trephine biopsy for a 6 weeks. 25-49% reduction in the size of soft tissue plasmacytomas. No increase in the size or number of lytic bone lesions.

Time frame: Up to 354 days

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

Time frame: Days 1 and 15 of Cycle 1

Population: PD analysis population included all participants who had sufficient dosing data to calculate PD parameters

Terminal elimination rate constant (λz) is the rate at which drugs are eliminated from the body and the values were used for calculation of T1/2. MLN2238 is the complete hydrolysis product of the study drug ixazomib citrate (MLN9708).

Time frame: Day 15 of Cycle 1

Population: Participants from the PK Analysis Population, all participants who had sufficient dosing data to calculate PK parameters, with data available for calculation of terminal elimination rate constant.

Terminal phase elimination half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma. MLN2238 is the complete hydrolysis product of the study drug ixazomib citrate (MLN9708).

Time frame: Day 15 of Cycle 1

Population: Participants from the PK Analysis Population, all participants who had sufficient dosing data to calculate PK parameters, with data available for calculation of terminal phase elimination half-life.

Tmax: Time to reach the maximum observed plasma concentration (Cmax), equal to time to Cmax. MLN2238 is the complete hydrolysis product of the study drug ixazomib citrate (MLN9708).

Time frame: Days 1 and 15 of Cycle 1

Population: Participants from the PK Analysis Population, all participants who had sufficient dosing data to calculate PK parameters, with data available for analysis of Tmax.