Study of Oral Ixazomib in Combination With Melphalan and Prednisone in Participants With Newly Diagnosed Multiple Myeloma

The RP2D is the maximum tolerated dose (MTD) or less. The MTD is defined as the dose range at which ≤ 1 of 6 evaluable participants experience dose limiting toxicities (DLT) within the first 28 days of treatment (end of Cycle 1).

Time frame: Cycle 1, phase 1 (Up to 42 days)

Population: Dose Limiting Toxicity population included participants who received at least 80% of doses of MLN9708 and melphalan during Cycle 1 in Arms A or all doses of MLN9708 and melphalan during Cycle 1 in Arm B, C, D, or experience a DLT in Cycle 1 in the phase 1 dose escalation portion.

VGPR or better response rate is defined as percentage of participants with a complete response (CR) and very good partial response (VGPR). Per International Myeloma Working Group Uniform Response Criteria (IMWG), CR: 1) Negative immunofixation on the serum and urine, 2) Disappearance of any soft tissue plasmacytomas and 3) \< 5% plasma cells in bone marrow. VGPR: 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 hour.

Time frame: Day 1 of every other cycle from Day 1 of Cycle 2 (each cycle of 28 days) until death (Up to 5.5 years)

Population: The response-evaluable population is defined as participants who received at least 5 of 8 MLN9708 doses in Arm A, at least 2 of 3 MLN9708 doses in Arm B, at least 4 of 5 MLN9708 doses in Arm C, or at least 3 of 4 MLN9708 doses in Arm D and had measurable disease at baseline and at least 1 post-baseline response assessment.

Time frame: Baseline, Day 1 of each treatment cycle, and Day 1 of each maintenance cycle, up to 5.5 years

Population: Assessments of quality of life parameters were not analyzed due to change in planned analysis.

Time frame: Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D

Population: The PK population consisted of all participants who had sufficient dosing data and ixazomib concentration-time data to permit calculation of ixazomib PK parameters.

Time frame: Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D

Population: The pharmacokinetics (PK) population consisted of all participants who had sufficient dosing data and ixazomib concentration-time data to permit calculation of ixazomib PK parameters.

DOR is defined as time of first documentation of a confirmed PR or better response to first documented PD or start of alternative therapy. DOR was presented for those achieving CR+VGPR+PR. Per IMWG criteria, CR:1)Negative immunofixation on serum+urine, 2)Disappearance of any soft tissue plasmacytomas, 3)\< 5% plasma cells in bone marrow. VGPR: Serum+urine M-protein detectable by immunofixation but not on electrophoresis/ 90% or \>reduction in serum M-protein + urine M-protein level \< 100 mg/ 24-hour. PR:1)≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to \<200 mg/24-hour. If serum+urine M-protein are unmeasurable, ≥50% decrease in difference between involved and uninvolved FLC levels is required. Else, ≥50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma cell percentage was ≥30%. In addition, if present at baseline, a ≥50% reduction in size of soft tissue plasmacytomas is required.

Time frame: From the time from the date of first documentation of PR or better to the date of first documented disease progression for up to 5.5 years

Population: The safety population consisted of participants who received at least 1 dose of any study drug.

Whole blood 20S proteasome inhibition parameters

Time frame: At multiple time points during Cycles 1-3 of each phase and arm of the study, throughout approximately 84-126 days depending on the arm of the study

Population: Due to the change in the planned analysis, the efficacy endpoint of maximum inhibition rate was not performed.

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.

Time frame: From first dose of study drug through 30 days after last dose of study drug or until the start of subsequent antineoplastic therapy for up to 5.6 years

Population: The safety population consisted of participants who received at least 1 dose of any study drug.

Accumulation ratio for AUCtau (Rac) was calculated as area under the curve from time zero to end of dosing interval (AUCtau) on Day 14 divided by area under the curve from time zero to end of dosing interval (AUCtau) on Day 1.

Time frame: Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D

Population: The PK population consisted of all participants who had sufficient dosing data and ixazomib concentration-time data to permit calculation of ixazomib PK parameters.

ORR is defined as percentage of participants with overall response including CR, VGPR, and partial response (PR). Per IMWG criteria, CR:1)Negative immunofixation on serum and urine, 2)Disappearance of any soft tissue plasmacytomas, 3)\< 5% plasma cells in bone marrow. VGPR: Serum+urine M-protein detectable by immunofixation but not on electrophoresis/ 90% or \>reduction in serum M-protein + urine M-protein level \< 100 mg/ 24-hour. PR:1)≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to \<200 mg/24-hour. If serum+urine M-protein are unmeasurable, ≥50% decrease in difference between involved and uninvolved FLC levels is required. If serum+urine M-protein are unmeasurable and serum free light assay is also unmeasurable, ≥50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma cell percentage was ≥30%. In addition, if present at baseline, a ≥50% reduction in size of soft tissue plasmacytomas is required.

Time frame: Day 1 of every other cycle from Day 1 of Cycle 2 (each cycle of 28 days) up to 61 cycles, at end of treatment (Up to 5.5 years)

Population: The response-evaluable population is defined as participants who received at least 5 of 8 MLN9708 doses in Arm A, at least 2 of 3 MLN9708 doses in Arm B, at least 4 of 5 MLN9708 doses in Arm C, or at least 3 of 4 MLN9708 doses in Arm D and had measurable disease at baseline and at least 1 post-baseline response assessment.

Overall Survival is the time in months from start of study treatment to date of death due to any cause.

Time frame: From date of enrollment to date of death, approximately 5.5 years (Approximate median follow-up: 43.6 months)

Population: The safety population consisted of participants who received at least 1 dose of any study drug.

Progression Free Survival is defined as time in months from start of study treatment to first documentation of objective tumor progression per investigator assessment or up to death due to any cause, whichever occurs first. Per IMWG criteria, progressive disease requires any 1 or more of following: Increase of ≥25% from nadir in serum M-component and/or (absolute increase must be ≥0.5 g/dL), urine M-component and/or (absolute increase must be ≥200 mg/24 hour. Participants without measurable serum+urine M-protein levels: difference between involved and uninvolved FLC levels. The absolute increase must be \>10 mg/dL. Bone marrow plasma cell percentage: absolute % must be ≥10%. Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in size of existing bone lesions or soft tissue plasmacytomas. Development of hypercalcemia (corrected serum calcium \>11.5 mg/dL or 2.85 mmol/L) that can be attributed solely to plasma cell proliferative disorder.

Time frame: From the date of enrollment to the date of the first documented disease progression or death due to any cause for up to 5.5 years

Population: The safety population consisted of participants who received at least 1 dose of any study drug.

Terminal elimination rate constant, calculated as the negative of the slope of the log-linear regression of the natural logarithm concentration-time curve during the terminal phase.

Time frame: Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D

Population: The PK population consisted of all participants who had sufficient dosing data and ixazomib concentration-time data to permit calculation of ixazomib PK parameters.

Terminal phase elimination half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma.

Time frame: Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D

Population: The PK population consisted of all participants who had sufficient dosing data and ixazomib concentration-time data to permit calculation of ixazomib PK parameters.

Whole blood 20S proteasome inhibition parameters

Time frame: At multiple time points during Cycles 1-3 of each phase and arm of the study, throughout approximately 84-126 days depending on the arm of the study

Population: The efficacy endpoint of maximum inhibition rate was not performed due to the change in the planned analysis.

Response is defined as CR, VGPR and PR. Per IMWG criteria, CR:1)Negative immunofixation on serum+urine, 2)Disappearance of any soft tissue plasmacytomas, 3)\< 5% plasma cells in bone marrow. VGPR: Serum+urine M-protein detectable by immunofixation but not on electrophoresis/ 90% or \>reduction in serum M-protein + urine M-protein level \< 100 mg/ 24-hour. PR:1)≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to \<200 mg/24-hour. If serum+urine M-protein are unmeasurable, ≥50% decrease in difference between involved and uninvolved FLC levels is required. Else, ≥50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma cell percentage was ≥30%. In addition, if present at baseline, a ≥50% reduction in size of soft tissue plasmacytomas is required.

Time frame: From the date of enrollment to the date of the first documented response for up to 5.5 years

Population: The safety population consisted of participants who received at least 1 dose of any study drug.

Time to Next Therapy is defined as time from the date of enrollment to the date of subsequent antineoplastic therapy.

Time frame: From the date of enrollment to the date of subsequent antineoplastic therapy for up to 5.5 years

Population: Time to next therapy was not analyzed due to the change in the planned analysis.

TTP is defined as time from date of enrollment to date of first documented disease progression (PD). Per IMWG criteria, progressive disease requires any 1 or more of following: Increase of ≥25% from nadir in serum M-component and/or (absolute increase must be ≥0.5 g/dL), urine M-component and/or (absolute increase must be ≥200 mg/24 hour. Participants without measurable serum+urine M-protein levels: difference between involved and uninvolved FLC levels. The absolute increase must be \>10 mg/dL. Bone marrow plasma cell percentage: absolute % must be ≥10%. Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in size of existing bone lesions or soft tissue plasmacytomas. Development of hypercalcemia (corrected serum calcium \>11.5 mg/dL or 2.85 mmol/L) that can be attributed solely to plasma cell proliferative disorder.

Time frame: From the date of enrollment to the date of the first documented disease progression for up to 5.5 years

Population: The safety population consisted of participants who received at least 1 dose of any study drug.

Time frame: Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D

Population: The PK population consisted of all participants who had sufficient dosing data and ixazomib concentration-time data to permit calculation of ixazomib PK parameters.