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

• Sponsor: Parameswaran Hari (Other)
• Overall Status: Completed
• CT.gov ID: NCT02477215
• Collaborator: (none)
• Enrollment: 38
• Location: 1
• Arms: 2
• Actual Duration (Months): 59.3
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Drug: MLN9708; Drug: Dexamethasone; Drug: Bendamustine (multiple dose levels); Drug: Bendamustine (MTD)	Phase 1/Phase 2

Detailed Description

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 Design

• Study Type: Interventional
• Actual Enrollment: 38 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I/II Study of Bendamustine and IXAZOMIB (MLN9708) Plus Dexamethasone in Relapsed/Refractory Multiple Myeloma
• Actual Study Start Date: Oct 9, 2015
• Actual Primary Completion Date: May 2, 2018
• Actual Study Completion Date: Sep 17, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: MLN9708, Bendamustine and Dexamethasone Dose Escalation 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	Drug: MLN9708; 4 mg of MLN9708 delivered on days 1, 8 and 15 of a 28 day cycle.; Other Names: Ixazomib ; Drug: Dexamethasone; 40 mg oral on Days 1, 8, 15 of each 28 day cycle.; Other Names: Decadron ; Drug: Bendamustine (multiple dose levels); 70 mg/m^2, 80 mg/m^2, or 90 mg/m^2 on days 1 and 2; Other Names: Treanda Treakisym Ribomustin
Experimental: MLN9708, Bendamustine and Dexamethasone MTD Ixazomib 4 mg, days 1, 8, 15. Dexamethasone 40 mg oral weekly. Bendamustine dose levels: MTD given on days 1 and 2	Drug: MLN9708; 4 mg of MLN9708 delivered on days 1, 8 and 15 of a 28 day cycle.; Other Names: Ixazomib ; Drug: Dexamethasone; 40 mg oral on Days 1, 8, 15 of each 28 day cycle.; Other Names: Decadron ; Drug: Bendamustine (MTD); 80 mg/m^2 on days 1 and 2; Other Names: Treanda Treakisym Ribomustin

Outcome Measures

Primary Outcome Measures

1. Maximum Tolerated Dose of Bendamustine [Six months for each dosing cohort]

   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.

2. Objective Response Rate [18 months]

   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.

Secondary Outcome Measures

1. Overall Survival (OS) [36 months]

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

2. Progression Free Survival (PFS) [18 months]

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

3. Cumulative Response Rates in Patients After Eight Cycles. [18 months]

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

4. Duration of Response (DoR) [36 months]

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

5. Number of Participants Experiencing Dose-Limiting Toxicity (DLT) [Six months]

   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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

INCLUSION CRITERIA:

1. Male or female patients 18 years or older.

2. Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.

3. Female patients who:

• Are postmenopausal for at least one year before the screening visit, OR

• Are surgically sterile, OR

• If they are of childbearing potential, agree to practice two effective methods of contraception, at the same time, from the time of signing the informed consent form through 90 days after the last dose of study drug, OR • Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.)

Male patients, even if surgically sterilized (ie, status post-vasectomy), must agree to one of the following:

• Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, OR

• Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods] and withdrawal are not acceptable methods of contraception.)

1. Patients must have have histologically or cytologically confirmed symptomatic Multiple Myeloma, who are non-responsive to or ineligible for autologous stem cell transplant, and who progress after prior exposure to proteasome inhibitor (bortezomib, carfilzomib) and lenalidomide or pomalidomide or thalidomide (IMID); and refractory/progressing to at least one of these agents and must meet at least one of the following parameters of measurable disease:

• Measurable levels of monoclonal protein (M protein): > 1 g/dL of immunoglobin G (IgG) or immunoglobin M (IgM) M-protein or > 0.5 g/dL immunoglobin A (IgA) or immunoglobin D (IgD) M protein on serum protein electrophoresis OR > 200 mg/24h of free light chain proteinuria on a 24 hour urine protein electrophoresis which must be obtained within 4 weeks prior to registration OR > 10 mg/dL involved free light chain on serum free light chain testing with an abnormal kappa:lambda light chain ratio.

• Patients with lytic bone disease, defined as at least one lytic lesion that can be accurately measured in at least one dimension.

1. Eastern Cooperative Oncology Group (ECOG) performance status and/or other performance status 0, 1, or 2.

2. Patients are eligible after autologous or allogeneic stem cell transplantation. Allogeneic transplantation can be enrolled only if they have no ongoing transplant related side effects.

3. Patients must be at least 2 weeks from major surgery, radiation therapy, participation in other investigational trials and have recovered from clinically significant toxicities of these prior treatments

4. Patients must meet the following clinical laboratory criteria:

• Absolute neutrophil count (ANC) ≥ 1,000/mm3 and platelet count ≥ 75,000/mm3. Platelet transfusions or granulocyte-colony stimulating factor (G-CSF) can be used to help patients meet eligibility criteria but are not allowed within 3 days before study enrollment.

• Total bilirubin < 1.5 x the upper limit of the normal range (ULN), , OR, direct bilirubin within normal limits (WNL), when total bilirubin is >>< 1.5 x the ULN.

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3 x ULN.

• Calculated creatinine clearance ≥ 30 mL/min.

EXCLUSION CRITERIA

Patients meeting any of the following exclusion criteria are not to be enrolled in the study:

1. Female patients who are lactating or have a positive serum pregnancy test during the screening period.

2. Failure to have fully recovered (ie, ≤ Grade 1 toxicity) from the reversible effects of prior chemotherapy except for peripheral neuropathy, which is addressed in exclusion criteria no. #14.

3. Major surgery within 14 days before enrollment.

4. Radiotherapy within 14 days before enrollment. If the involved field is limited (single disease focus not involving pelvis and involving <36 Gy radiation), 7 days will be considered a sufficient interval between treatment and administration of Ixazomib provided hematologic inclusion parameters are met.

5. Central nervous system involvement.

6. Infection requiring systemic antibiotic therapy or other serious infection within 14 days before study enrollment.

7. Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within the past 6 months.

8. Systemic treatment, within 14 days before the first dose of IXAZOMIB, with strong inhibitors of cytochrome P1A2 (CYP1A2) (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of cytochrome P3A (CYP3A) (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort.

9. Ongoing or active systemic infection, active hepatitis B or C virus infection, or known human immunodeficiency virus (HIV) positive.

10. Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.

11. Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent.

12. Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of IXAZOMIB including difficulty swallowing.

13. Diagnosed or treated for another malignancy where the expected survival is less than two years will be excluded. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.

14. Patient has ≥ Grade 2 peripheral neuropathy, or Grade 2 with pain on clinical examination during the screening period.

15. Participation in other clinical trials, including those with other investigational agents not included in this trial, within 30 days of the start of this trial and throughout the duration of this trial.

16. Patients that have previously been treated with IXAZOMIB, or participated in a study with IXAZOMIB whether treated with IXAZOMIB or not.

17. Patients with a history of severe chronic obstructive pulmonary disease requiring ongoing oxygen support or those with a resting oxygen saturation <92% on room air irrespective of the cause.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Froedtert Hospital and the Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226

Sponsors and Collaborators

• Parameswaran Hari

Investigators

• Principal Investigator: Parameswaran Hari, MD, MRCP, MS, Medical College of Wisconsin

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 28, 2017

More Information

Publications

None provided.

• Responsible Party: Parameswaran Hari, Section Head, Hematological Malignancies Director, Adult Blood and Marrow Transplant Program, Medical College of Wisconsin
• ClinicalTrials.gov Identifier: NCT02477215
• Other Study ID Numbers: PRO00024991
• First Posted: Jun 22, 2015
• Last Update Posted: Oct 22, 2020
• Last Verified: Sep 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Parameswaran Hari, Section Head, Hematological Malignancies Director, Adult Blood and Marrow Transplant Program, Medical College of Wisconsin: Multiple Myeloma
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Dexamethasone; Bendamustine Hydrochloride; Ixazomib

Study Results

Participant Flow

Arm/Group Title	Bendamustine (70 mg/m^2), MLN9708, Dexamethasone	Bendamustine (80 mg/m^2), MLN9708, Dexamethasone	Bendamustine (90 mg/m^2), MLN9708, Dexamethasone
Arm/Group Description	MLN9708 : 4 mg, days 1, 8, 15. Dexamethasone: 40 mg oral weekly. Bendamustine: 70 mg/m^2 days 1 and 2	MLN9708 : 4 mg, days 1, 8, 15. Dexamethasone: 40 mg oral weekly. Bendamustine: 80 mg/m^2 days 1 and 2	MLN9708 : 4 mg, days 1, 8, 15. Dexamethasone: 40 mg oral weekly. Bendamustine: 90 mg/m^2 days 1 and 2
Period Title: Dose Escalation Phase
STARTED	4	8	6
COMPLETED	3	6	6
NOT COMPLETED	1	2	0
Period Title: Dose Escalation Phase
STARTED	0	20	0
COMPLETED	0	13	0
NOT COMPLETED	0	7	0

Baseline Characteristics

Arm/Group Title	Dose Escalation Phase: Bendamustine (70 mg/m^2), MLN9708, Dex.	Dose Escalation Phase: Bendamustine (80 mg/m^2), MLN9708, Dex.	Dose Escalation Phase: Bendamustine (90 mg/m^2), MLN9708, Dex.	Fixed Dose Phase	Total
Arm/Group Description	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	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	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	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	Total of all reporting groups
Overall Participants	4	8	6	20	38
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	1 25%	2 25%	1 16.7%	10 50%	14 36.8%
>=65 years	3 75%	6 75%	5 83.3%	10 50%	24 63.2%
Sex: Female, Male (Count of Participants)
Female	2 50%	2 25%	4 66.7%	7 35%	15 39.5%
Male	2 50%	6 75%	2 33.3%	13 65%	23 60.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%	1 5%	1 2.6%
Not Hispanic or Latino	4 100%	8 100%	6 100%	19 95%	37 97.4%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	1 12.5%	0 0%	0 0%	1 2.6%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	1 16.7%	7 35%	8 21.1%
White	4 100%	7 87.5%	5 83.3%	13 65%	29 76.3%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	4 100%	8 100%	6 100%	20 100%	38 100%

Outcome Measures

1. Primary Outcome

Title	Maximum Tolerated Dose of Bendamustine
Description	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.
Time Frame	Six months for each dosing cohort

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	MLN9708, Bendamustine and Dexamethasone
Arm/Group Description	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
Measure Participants	15
Number [mg/m^2]	80

2. Primary Outcome

Title	Objective Response Rate
Description	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.
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	MLN9708, Bendamustine and Dexamethasone
Arm/Group Description	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
Measure Participants	18
Number [participants]	11 275%

3. Secondary Outcome

Title	Overall Survival (OS)
Description	Overall survival was determined as the average number of months subjects survived following enrollment.
Time Frame	36 months

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	MLN9708, Bendamustine and Dexamethasone
Arm/Group Description	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
Measure Participants	18
Median (95% Confidence Interval) [MONTHS]	23.2

4. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	This measure is the number of months participants remain free from evidence of disease.
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	MLN9708, Bendamustine and Dexamethasone
Arm/Group Description	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
Measure Participants	28
Median (95% Confidence Interval) [MONTHS]	5.2

5. Secondary Outcome

Title	Cumulative Response Rates in Patients After Eight Cycles.
Description	Percentage of subject response rates at any point during the eight cycles.
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	MLN9708, Bendamustine and Dexamethasone
Arm/Group Description	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
Measure Participants	18
Number [percentage of participants]	28 700%

6. Secondary Outcome

Title	Duration of Response (DoR)
Description	Median time in months participants maintain CR, PR or stable disease.
Time Frame	36 months

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	MLN9708, Bendamustine and Dexamethasone
Arm/Group Description	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
Measure Participants	18
Median (Full Range) [MONTHS]	5.1

7. Secondary Outcome

Title	Number of Participants Experiencing Dose-Limiting Toxicity (DLT)
Description	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).
Time Frame	Six months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bendamustine (70 mg/m^2), MLN9708, Dexamethasone	Bendamustine (80 mg/m^2), MLN9708, Dexamethasone	Bendamustine (90 mg/m^2), MLN9708, Dexamethasone
Arm/Group Description	MLN9708 : 4 mg, days 1, 8, 15. Dexamethasone: 40 mg oral weekly. Bendamustine: 70 mg/m^2 days 1 and 2	MLN9708 : 4 mg, days 1, 8, 15. Dexamethasone: 40 mg oral weekly. Bendamustine: 80 mg/m^2 days 1 and 2	MLN9708 : 4 mg, days 1, 8, 15. Dexamethasone: 40 mg oral weekly. Bendamustine: 90 mg/m^2 days 1 and 2
Measure Participants	3	6	6
Count of Participants [Participants]	0 0%	1 12.5%	2 33.3%

Adverse Events

Time Frame	3 years
Arm/Group Title	Bendamustine (70 mg/m^2), MLN9708 and Dexamethasone		Bendamustine (80 mg/m^2), MLN9708 and Dexamethasone		Bendamustine (90 mg/m^2), MLN9708 and Dexamethasone
Arm/Group Description	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		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.		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
All Cause Mortality
	Bendamustine (70 mg/m^2), MLN9708 and Dexamethasone		Bendamustine (80 mg/m^2), MLN9708 and Dexamethasone		Bendamustine (90 mg/m^2), MLN9708 and Dexamethasone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/3 (66.7%)		8/19 (42.1%)		2/6 (33.3%)
Serious Adverse Events
	Bendamustine (70 mg/m^2), MLN9708 and Dexamethasone		Bendamustine (80 mg/m^2), MLN9708 and Dexamethasone		Bendamustine (90 mg/m^2), MLN9708 and Dexamethasone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/3 (66.7%)		8/19 (42.1%)		0/6 (0%)
Blood and lymphatic system disorders
Anemia	1/3 (33.3%)	1	0/19 (0%)	0	0/6 (0%)	0
Cardiac disorders
Mobitz type 1	0/3 (0%)	0	1/19 (5.3%)	1	0/6 (0%)	0
Gastrointestinal disorders
Fecal incontinence	0/3 (0%)	0	1/19 (5.3%)	1	0/6 (0%)	0
Colitis	0/3 (0%)	0	2/19 (10.5%)	2	0/6 (0%)	0
Nausea	0/3 (0%)	0	1/19 (5.3%)	1	0/6 (0%)	0
Vomiting	0/3 (0%)	0	1/19 (5.3%)	1	0/6 (0%)	0
Diarrhea	0/3 (0%)	0	1/19 (5.3%)	1	0/6 (0%)	0
Gastric hemorrhage	0/3 (0%)	0	1/19 (5.3%)	1	0/6 (0%)	0
General disorders
Non-cardiac chest pain	0/3 (0%)	0	1/19 (5.3%)	1	0/6 (0%)	0
Fever	0/3 (0%)	0	1/19 (5.3%)	1	0/6 (0%)	0
Edema limbs	0/3 (0%)	0	1/19 (5.3%)	1	0/6 (0%)	0
Infections and infestations
Sepsis	0/3 (0%)	0	2/19 (10.5%)	2	0/6 (0%)	0
Lung infection	1/3 (33.3%)	1	0/19 (0%)	0	0/6 (0%)	0
Injury, poisoning and procedural complications
Fall	0/3 (0%)	0	1/19 (5.3%)	1	0/6 (0%)	0
Investigations
Creatinine increased	0/3 (0%)	0	1/19 (5.3%)	1	0/6 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	0/3 (0%)	0	1/19 (5.3%)	1	0/6 (0%)	0
Pain in extremity	0/3 (0%)	0	1/19 (5.3%)	1	0/6 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Progressive disease	0/3 (0%)	0	1/19 (5.3%)	1	0/6 (0%)	0
Psychiatric disorders
Suicidal ideation	0/3 (0%)	0	1/19 (5.3%)	1	0/6 (0%)	0
Renal and urinary disorders
Urinary incontinence	0/3 (0%)	0	1/19 (5.3%)	1	0/6 (0%)	0
Hematuria	0/3 (0%)	0	1/19 (5.3%)	1	0/6 (0%)	0
Respiratory, thoracic and mediastinal disorders
Respiratory failure	0/3 (0%)	0	1/19 (5.3%)	1	0/6 (0%)	0
Pneumonitis	0/3 (0%)	0	1/19 (5.3%)	1	0/6 (0%)	0
Exacerbated COPD	0/3 (0%)	0	1/19 (5.3%)	1	0/6 (0%)	0
Vascular disorders
Thromboembolic event	0/3 (0%)	0	1/19 (5.3%)	1	0/6 (0%)	0
Other (Not Including Serious) Adverse Events
	Bendamustine (70 mg/m^2), MLN9708 and Dexamethasone		Bendamustine (80 mg/m^2), MLN9708 and Dexamethasone		Bendamustine (90 mg/m^2), MLN9708 and Dexamethasone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/19 (0%)		0/6 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.