A Study of Ixazomib Administered in Combination With Lenalidomide and Low-Dose Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma

MTD of ixazomib will be determined by assessing adverse events and serious adverse events, clinical laboratory values, neurotoxicity grading, and vital sign measurements.

Time frame: Until occurrence of progressive disease or unacceptable toxicity (Up to 336 days)

Population: All Phase 1 participants.

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 serious adverse event (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: Until occurrence of progressive disease or unacceptable toxicity (Up to 336 days)

Population: The safety population was defined as all patients who received at least one dose of any of the 3 study drugs.

RP2D will be determined based on number and type of adverse event and serious adverse events, assessments of clinical laboratory values, neurotoxicity grading, and treatment discontinuation.

Time frame: Until occurrence of progressive disease or unacceptable toxicity (Up to 336 days)

Population: All Phase 1 participants.

ORR was defined as the percentage of participants with Complete (CR) + Very Good Partial Response (VGPR) assessed by the investigatory using International Myeloma Working Group (IMWG) Criteria. CR=Negative immunofixation on the serum and urine and; disappearance of any soft tissue plasmacytomas and; \< 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 hours.

Time frame: Until occurrence of progressive disease or unacceptable toxicity (Up to 787 days)

Population: Participants from the response-evaluable population, defined as all patients who received at least one dose of ixazomib, had measurable disease at baseline, and at least one post-baseline disease assessment, with available data.

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 serious adverse event (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: Until occurrence of progressive disease or unacceptable toxicity (Up to 787 days)

Population: The safety population was defined as all patients who received at least one dose of any of the 3 study drugs.

AUC(0-168) is a measure of the area under the plasma concentration-time curve from time 0 to 168 hours postdose for Ixazomib.

Time frame: Cycle 1, Days 1 and 15

Population: The Pharmacokinetic (PK) analysis population, defined as all patients enrolled in the phase 1 portion of the study who had sufficient dosing data and ixazomib concentration-time data to permit calculation of ixazomib pharmacokinetic parameters, with available data.

Cmax: 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 15

Population: The Pharmacokinetic (PK) analysis population, defined as all patients enrolled in the phase 1 portion of the study who had sufficient dosing data and ixazomib concentration-time data to permit calculation of ixazomib pharmacokinetic parameters, with available data.

Emax is the maximum observed inhibition of whole blood 20S proteasome. The pharmacodynamics 20S Proteasome samples were collected and the assays were performed; however, concerns about the third-party laboratory's performance of the blood 20S proteasome activity assay were identified that precluded the ability to confirm the accuracy of the data so no data is reported.

Time frame: Day 1 predose and at multiple time points (up to 168 hours) postdose and Day 15 predose and at multiple time points (up to 336 hours) postdose

The accumulation ratio (Rac) was estimated as the ratio of AUC(0-168) on Day 15 to the AUC(0-168) on Day 1. AUC(0-168) is the area under the plasma concentration-time curve from time 0 to 168 hours postdose for ixazomib.

Time frame: Cycle 1, Day 15

Population: The Pharmacokinetic (PK) analysis population, defined as all patients enrolled in the phase 1 portion of the study who had sufficient dosing data and ixazomib concentration-time data to permit calculation of ixazomib pharmacokinetic parameters, with available data.

TEmax is the time to the maximum observed inhibition of whole blood 20S proteasome. The pharmacodynamics 20S Proteasome samples were collected and the assays were performed; however, concerns about the third-party laboratory's performance of the blood 20S proteasome activity assay were identified that precluded the ability to confirm the accuracy of the data so no data is reported.

Time frame: Day 1 predose and at multiple time points (up to 168 hours) postdose and Day 15 predose and at multiple time points (up to 336 hours) postdose

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

Time frame: Cycle 1, Days 1 and 15

Population: The Pharmacokinetic (PK) analysis population, defined as all patients enrolled in the phase 1 portion of the study who had sufficient dosing data and ixazomib concentration-time data to permit calculation of ixazomib pharmacokinetic parameters, with data available.

1-year survival rate is defined as the percentage of participants still alive at year after the first dose of stud drug.

Time frame: 1 year after first dose of study drug

DOR was measured as the time in months from the date of first documentation of a confirmed response (CR + PR+ VGPR) to the date of the first documented disease progression (PD). Response was assessed by the investigator using International Myeloma Working Group (IMWG) Criteria. CR=negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and \< 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 hours.

Time frame: Up to 787 days

Population: Participants from the Response Evaluable Population, defined as all patients who received at least one dose of ixazomib, had measurable disease at baseline, and at least one post-baseline disease assessment, with data available for analysis. Patients who did not experience PD were censored at the last response assessment that was SD or better.

ORR was defined as the percentage of participants with CR, VGPR and Partial Response (PR) assessed by the investigator using IMWG criteria. CR=Negative immunofixation on the serum and urine + Disappearance of any soft tissue plasmacytomas and \< 5% plasma cells in bone marrow. PR=50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by 90% or to \< 200 mg per 24 hours. 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 hours.

Time frame: Up to 787 days

Population: The response-evaluable population was defined as all patients who received at least one dose of ixazomib, had measurable disease at baseline, and at least one post-baseline disease assessment.

OS was measured as the time in months from the first dose of study treatment to the date of death + 1 day.

Time frame: From the first dose of study treatment to the date of death (up to 787 days)

Population: Safety Population included al participants who received 1 of the 3 study drugs. Participants who did not die were censored at the last study visit.

Response was assessed by the investigator using International Myeloma Working Group (IMWG) Criteria. CR is defined as negative immunofixation on the serum and urine and; disappearance of any soft tissue plasmacytomas and; \< 5% plasma cells in bone marrow. VGPR 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.

Time frame: After Cycles 3, 6 and 9 (Up to 787 days)

Population: The response-evaluable population was defined as all patients who received at least one dose of ixazomib, had measurable disease at baseline, and at least one post-baseline disease assessment.

Response was assessed by the investigator using International Myeloma Working Group (IMWG) Criteria. CR=Negative immunofixation on the serum and urine + Disappearance of any soft tissue plasmacytomas and \< 5% plasma cells in bone marrow. sCR= CR + Normal free light chain (FLC) ratio and Absence of clonal cells in bone marrow. PR=≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to \< 200 mg per 24 hours. 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 hours. nCR=Positive immunofixation analysis of serum or urine as the only evidence of disease. Disappearance of any soft tissue plasmacytomas and \< 5% plasma cells in bone marrow. MR=25% to 49% reduction in serum paraprotein and 50% to 89% reduction in urine light chain excretion for 6 weeks.

Time frame: Cycles 3, 6, 9 and 12 (Up to 787 days)

Population: The response-evaluable population was defined as all patients who received at least one dose of ixazomib, had measurable disease at baseline, and at least one post-baseline disease assessment.

PFS was measured as the time in months from the first dose of study treatment to the date of the first documented PD or death.

Time frame: Up to 787 days

Population: The mITT population was defined as all patients who received at least one dose of any study drug in phase 2 or who received at least one dose of any study drug and were treated at the phase 2 dose level during phase 1.

Time to Best Response was measured as the time in months from the first dose of study treatment to the date of first documented documentation of a confirmed response of partial response (PR) or better.

Time frame: Up to 787 days

Population: Participants form the response-evaluable population, defined as all patients who received at least one dose of ixazomib, had measurable disease at baseline, and at least one post-baseline disease assessment, with available data.

TTP was measured as the time in months from the first dose of study treatment to the date of the first documented progressive disease (PD).

Time frame: From the first dose of study treatment to the date of first documented progressive disease (Up to 787 days)

Population: The modified Intent-to-Treat (mITT) population was defined as all patients who received at least one dose of any study drug in phase 2 or who received at least one dose of any study drug and were treated at the phase 2 dose level during phase 1.