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Ixazomib 4 mg, days 1, 8, 15.

Dexamethasone 40 mg oral weekly.

Bendamustine dose levels: 70 mg/m\^2, 80mg/m\^2, or 90 mg/m\^2 given on days 1 and 2

Ixazomib 4 mg, days 1, 8, 15.

Dexamethasone 40 mg oral weekly.

Bendamustine dose levels: MTD given on days 1 and 2

4 mg of MLN9708 delivered on days 1, 8 and 15 of a 28 day cycle.

MLN9708

40 mg oral on Days 1, 8, 15 of each 28 day cycle.

70 mg/m\^2, 80 mg/m\^2, or 90 mg/m\^2 on days 1 and 2

Bendamustine (multiple dose levels)

Bendamustine (MTD)

Parameswaran Hari, MD, MRCP, MS

This Phase I/II study is designed to first identify doses of MLN9708 and bendamustine that are associated with an acceptable adverse event profile when delivered together in 28-day cycles. Additionally, the study aims to assess the efficacy of the combination in patients with relapsed/refractory multiple myeloma. Responders (stable disease or more), will continue to receive up to eight cycles total in the absence of further progressive disease.

OVERVIEW: This Phase I/II study is designed to first identify doses of MLN9708 and bendamustine that are associated with an acceptable adverse event profile when delivered together in 28-day cycles. Additionally, the study aims to assess the efficacy of the combination in patients with relapsed/refractory multiple myeloma. Responders (stable disease or more),will continue to receive up to eight cycles total in the absence of further progressive disease.

OVERVIEW OF THE DOSE ESCALATION/DE-ESCALATION: This study aims to assess the combination's efficacy in patients with relapsed/refractory multiple myeloma. Responders (stable disease or more) will continue to receive up to eight cycles total in the absence of further progressive disease. The dose of MLN9708 will be fixed at 4 mg given on days 1, 8 and 15. Dexamethasone will be administered at 40 mg (oral) on Days 1, 8, 15 of each 28 day cycle. Dexamethasone administered as 40 mg oral on Days 1, 8, 15 of each 28 day cycle. Three doses of bendamustine will be evaluated (Dose 1: 70 mg/m\^2, days 1 and 2; Dose 2: 80 mg/m\^2. days 1 and 2; and Dose 3: 90 mg/m\^2, days 1 and 2).

PHASE 1 DESIGN: A 3+3 design was employed. At each dose, three patients were initially evaluated. When no dose limiting toxicities were observed, the bendamustine dose will be increased.

PHASE 2 DESIGN: Design for Phase II portion of study: The MTD or a recommended phase 2 dose (RP2D) for the combination. The plan is to treat additional patients at that dose to assess efficacy and response to treatment. The investigators plan to enroll 19 patients (including those treated at the MTD in Phase I).

Study of Bendamustine and IXAZOMIB (MLN9708) Plus Dexamethasone in Relapsed/Refractory Multiple Myeloma

Phase I/II Study of Bendamustine and IXAZOMIB (MLN9708) Plus Dexamethasone in Relapsed/Refractory Multiple Myeloma

Maximum tolerated dose of bendamustine in combination with fixed doses of ixazomib (MLN9708) and dexamethasone will be determined from the incidence of dose limiting toxicities at each dosage.

Objective response rate was defined as the number of subjects achieving a complete response (CR) or partial response (PR) after at least four cycles of ixazomib (MLN9708) and bendamustine plus dexamethasone.

Overall survival was determined as the average number of months subjects survived following enrollment.

This measure is the number of months participants remain free from evidence of disease.

Percentage of subject response rates at any point during the eight cycles.

Median time in months participants maintain CR, PR or stable disease.

A 3+3 design was employed. At each dose, three patients were initially evaluated. If no dose limiting toxicities were observed, the bendamustine dose was increased; if one dose limiting toxicity is observed, three additional patients were treated at that dose. A dose at which 2 DLTs were observed in 3 or 6 patients were judged to be too toxic and the lower dose was defined as the maximally tolerated dose (MTD).

Parameswaran Hari

Section Head, Hematological Malignancies Director, Adult Blood and Marrow Transplant Program

MLN9708: 4 mg of MLN9708 delivered on days 1, 8 and 15 of a 28 day cycle.

Dexamethasone: 40 mg oral on Days 1, 8, 15 of each 28 day cycle.

Bendamustine: 70 mg/m\^2 on days 1 and 2

Bendamustine (70 mg/m^2), MLN9708 and Dexamethasone

MLN9708: 4 mg of MLN9708 delivered on days 1, 8 and 15 of a 28 day cycle.

Dexamethasone: 40 mg oral on Days 1, 8, 15 of each 28 day cycle.

Bendamustine: 80 mg/m\^2 on days 1 and 2.

This reporting group includes subjects from both the Dose Escalation and Fixed Dose Phases who received Bendamustine at 80 mg/m\^2.

Bendamustine (80 mg/m^2), MLN9708 and Dexamethasone

MLN9708: 4 mg of MLN9708 delivered on days 1, 8 and 15 of a 28 day cycle.

Dexamethasone: 40 mg oral on Days 1, 8, 15 of each 28 day cycle.

Bendamustine: 90 mg/m\^2 on days 1 and 2

Bendamustine (90 mg/m^2), MLN9708 and Dexamethasone

MLN9708: 4 mg of MLN9708 delivered on days 1, 8 and 15 of a 28 day cycle.

Dexamethasone: 40 mg oral on Days 1, 8, 15 of each 28 day cycle.

Bendamustine: 70 mg/m\^2 days 1 and 2

Dose Escalation Phase: Bendamustine (70 mg/m^2), MLN9708, Dex.

MLN9708: 4 mg of MLN9708 delivered on days 1, 8 and 15 of a 28 day cycle.

Dexamethasone: 40 mg oral on Days 1, 8, 15 of each 28 day cycle.

Bendamustine: 80 mg/m\^2 days 1 and 2

Dose Escalation Phase: Bendamustine (80 mg/m^2), MLN9708, Dex.

MLN9708: 4 mg of MLN9708 delivered on days 1, 8 and 15 of a 28 day cycle.

Dexamethasone: 40 mg oral on Days 1, 8, 15 of each 28 day cycle.

Bendamustine: 90 mg/m\^2 days 1 and 2

Dose Escalation Phase: Bendamustine (90 mg/m^2), MLN9708, Dex.

Fixed Dose Phase

Total

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

MLN9708: 4 mg of MLN9708 delivered on days 1, 8 and 15 of a 28 day cycle.

Dexamethasone: 40 mg oral on Days 1, 8, 15 of each 28 day cycle.

Bendamustine:70 mg/m\^2, 80 mg/m\^2, or 90 mg/m\^2 on days 1 and 2

MLN9708, Bendamustine and Dexamethasone

All participants received at least ne dose of Bendamustine at either 70 mg/m\^2, 80 mg\^2 or 90 mg/m\^2.

Maximum Tolerated Dose of Bendamustine

Ixazomib 4 mg, days 1, 8, 15.

Dexamethasone 40 mg oral weekly.

Bendamustine dose levels: 80mg/m2 days 1,2

MLN9708: 4 mg of MLN9708 delivered on days 1, 8 and 15 of a 28 day cycle.

Dexamethasone: 40 mg oral on Days 1, 8, 15 of each 28 day cycle.

Bendamustine: 80mg/m2 days 1,2

Subjects receiving the fixed dose of 80 mg/m\^2 Bendamustine were included in this analysis. Results from five of the subjects in the Dose Escalation Phase of this study who also received 80 mg/m\^2 Bendamustine were included in the analysis. One of the Dose Expansion Phase subjects did not complete sufficient dosing cycles for inclusion.

Objective Response Rate

MLN9708: 4 mg of MLN9708 delivered on days 1, 8 and 15 of a 28 day cycle.

Dexamethasone: 40 mg oral on Days 1, 8, 15 of each 28 day cycle.

Bendamustine: 80 mg/m\^2 days 1,2

Overall Survival (OS)

For this analysis, all 20 participants who received the fixed dose of 80 mg/m\^2 Bendamustine and all 8 participants who received Bendamustine (80 mg/m\^2) in the Dose Escalation phase, were combined.

Progression Free Survival (PFS)

Cumulative Response Rates in Patients After Eight Cycles.

Duration of Response (DoR)

MLN9708 : 4 mg, days 1, 8, 15.

Dexamethasone: 40 mg oral weekly.

Bendamustine: 70 mg/m\^2 days 1 and 2

Bendamustine (70 mg/m^2), MLN9708, Dexamethasone

MLN9708 : 4 mg, days 1, 8, 15.

Dexamethasone: 40 mg oral weekly.

Bendamustine: 80 mg/m\^2 days 1 and 2

Bendamustine (80 mg/m^2), MLN9708, Dexamethasone

MLN9708 : 4 mg, days 1, 8, 15.

Dexamethasone: 40 mg oral weekly.

Bendamustine: 90 mg/m\^2 days 1 and 2

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Study of Bendamustine and IXAZOMIB (MLN9708) Plus Dexamethasone in Relapsed/Refractory Multiple Myeloma	NCT02477215	Multiple Myelom...	MLN9708 Dexamethasone Bendamustine (m... Bendamustine (M...	18 Years -	Medical College of Wisconsin
Study of Bendamustine and IXAZOMIB (MLN9708) Plus Dexamethasone in Relapsed/Refractory Multiple Myeloma	NCT02477215	Multiple Myelom...	MLN9708 Dexamethasone Bendamustine (m... Bendamustine (M...	18 Years -	Medical College of Wisconsin

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