Clinical trial NCT02477215
Conditions: Multiple Myeloma
Keywords: Multiple Myeloma
Sponsor: Parameswaran Hari
Start date: 2015-10-09; Completion date: 2020-09-17
Enrollment: 38 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

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.

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).

Arms: arm 1: 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 arm 2: Ixazomib 4 mg, days 1, 8, 15.

Dexamethasone 40 mg oral weekly.

Bendamustine dose levels: MTD given on days 1 and 2
Interventions: intervention 1: MLN9708 intervention 2: Dexamethasone intervention 3: Bendamustine (multiple dose levels) intervention 4: Bendamustine (MTD)
Intervention descriptions: intervention 1: 4 mg of MLN9708 delivered on days 1, 8 and 15 of a 28 day cycle. intervention 2: 40 mg oral on Days 1, 8, 15 of each 28 day cycle. intervention 3: 70 mg/m\^2, 80 mg/m\^2, or 90 mg/m\^2 on days 1 and 2 intervention 4: 80 mg/m\^2 on days 1 and 2

Protocol documents:
Prot_SAP_000.pdf: 
 
CLINICAL STUDY PROTOCOL 
X16069 
Phase I/II Study of Bendamustine and IXAZOMIB (MLN9708) Plus Dexamethasone in 
Relapsed/Refractory Multiple Myeloma 
 
 
 
 
 
Indication: 
Relapsed/Refractory multiple myeloma 
Phase: 
Phase I/II 
 
 
 
Protocol History 
Original 
 
10/10/2014 
Amendment 1 
 
10/02/2015 
Amendment 2  
 
03/21/2016 
Amendment 3 
 
06/01/2016 
Amendment 4 
 
10/06/2016 
Amendment 5 
 
02/14/2017 
Amendment 6 
 
08-28-2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidentiality Statement: 
This protocol may not be used, published or otherwise disclosed without the written 
consent of the Medical College of Wisconsin 
 
 
 
 
 
 
 
 
 


2 
 
Investigator and Study Center: 
 
Parameswaran Hari, MD, MRCP, MS 
Professor 
Department of Medicine 
Division of Hematology and Oncology 
Medical College of Wisconsin 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
414.805.4600 
Email address: phari@mcw.edu 
 
Co-Investigator:  Binod Dhakal, MD, MS 
Assistant Professor of Medicine 
Division of Hematology and Oncology 
Medical College of Wisconsin 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
414.805.4600 
 
Sub-I:  Ehab Atallah, MD 
Associate Professor 
Department of Medicine 
Division of Hematology and Oncology 
Medical College of Wisconsin 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
414.805.4600 
 
Sub-I: Timothy Fenske, MD 
Associate Professor 
Department of Medicine 
Division of Hematology and Oncology 
Medical College of Wisconsin 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
414.805.4600 
 
Sub-I: Laura Michaelis, MD 
Associate Professor 
Department of Medicine 
Division of Hematology and Oncology 
Medical College of Wisconsin 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
414.805.4600 


3 
 
Sub-I: Karen-Sue Carlson, MD 
Assistant Professor 
Department of Medicine 
Division of Hematology and Oncology 
Medical College of Wisconsin 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
414.805.4600 
 
 
Sub-I: Marcelo Pasquini, MD 
Associate Professor 
Department of Medicine 
Division of Hematology and Oncology 
Medical College of Wisconsin 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
414.805.4600 
 
 
Sub-I: Mehdi Hamadani, MD 
Associate Professor 
Department of Medicine 
Division of Hematology and Oncology 
Medical College of Wisconsin 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
414.805.4600 
 
Sub-I: Carlos Arce-Lara, MD 
Assistant Professor 
Department of Medicine 
Division of Hematology and Oncology 
Medical College of Wisconsin 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
414.805.4600 
 
Sub-I: Anita D’Souza, MD 
Assistant Professor 
Department of Medicine 
Division of Hematology and Oncology 
Medical College of Wisconsin 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
414.805.4600 


4 
 
 
Investigational Pharmacy: 
Emily Hoefing, Pharm D, BCPS 
Froedtert Hospital 
9200 W. Wisconsin Ave. 
Milwaukee, WI  53226 
 
Research Coordinator: 
Daniel Schmoller 
Medical College of Wisconsin 
9200 W. Wisconsin Ave. 
Milwaukee, WI  53226 
 
 
Biostatistics: 
James Anderson, PhD 
Professor 
Division of Biostatistics 
Medical College of Wisconsin 
9200 W. Wisconsin Avenue 
Milwaukee, WI  53226 
 
 
This is an investigator-initiated study. The principal investigator Parameswaran Hari, (who 
may also be referred to as the sponsor-investigator), is conducting the study and acting as 
the sponsor. Therefore, the legal/ethical obligations of the principal investigator include both 
those of a sponsor and those of an investigator. 


5 
 
PROTOCOL SUMMARY  
Study Title:  Phase I/II study of bendamustine and IXAZOMIB (MLN9708) plus 
dexamethasone in relapsed/refractory multiple myeloma 
Phase:  Phase I//II 
Total Number of Patients:  28 (Maximum:15 in Phase I and 19 in Phase II [including 
phase 1 patients treated at recommended phase 2 dosing]) 
Study Objectives  
Primary 
 Phase I:  To determine the maximum tolerated dose (MTD) of the combination of 
IXAZOMIB (MLN9708) and bendamustine plus dexamethasone in patients with 
relapsed/refractory multiple myeloma. 
 Phase II:  To determine the objective response rate(ORR) after four cycles of 
IXAZOMIB (MLN9708) and bendamustine plus dexamethasone. 
Secondary 
 To determine the overall survival (OS) of patients treated with IXAZOMIB 
(MLN9708) and bendamustine plus dexamethasone. 
 To determine the progression free survival (PFS) of patients treated with 
IXAZOMIB (MLN9708) and bendamustine plus dexamethasone. 
 To determine the cumulative response rates in patients after 8 cycles. 
 To determine the duration of response (DoR). 
 To determine the minimal residual disease status (MRD) in patients who achieve a 
complete response. 
 
Overview of Study Design:   
This Phase I/II study is designed to first identify doses of IXAZOMIB (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 8 cycles total in the absence of further 
progressive disease. 
Dose escalation/de-escalation:  Because 4 mg of MLN9708 delivered on days 1, 8 and 15 
of a 28 day cycle is known to have an acceptable toxicity profile, as a single agent and in 
combination with some other agents, the Phase I portion of the study will be designed as 
follows: 
The dose of MLN9708 will be fixed at 4 mg, days 1, 8 and 15.  


6 
 
Dexamethasone administered as 40 mg oral on Days 1, 8, 15 of each 28 day cycle.  At 
physician discretion, patients may be reduced to a minimum of 20mg. 
 
Three doses of bendamustine will be evaluated. 
Bendamustine dose levels: 
 
Dose 1: 70 mg/m2, days 1 and 2 
Dose 2: 80 mg/ m 2. days 1 and 2 
Dose 3: 90 mg/ m 2, days 1 and 2 
 
A 3+3 design will be employed. At each dose, three patients will be initially evaluated. If 
no dose limiting toxicities are observed, the bendamustine dose will be increased; if one 
dose limiting toxicity is observed, three additional patients will be treated at that dose and 
escalation will occur only of no additional DLTs are observed. A dose at which 2 DLTs 
are observed in 3 or 6 patients will be judged to be too toxic and the lower dose will be 
defined as the maximally tolerated dose (MTD). 
 
Should the first dose combination be found to have 2 DLTs in three patients, MLN9708 
would be de-escalated to 3 mg, days 1, 8 and 15 (with bendamustine at 70 mg/m2). If this 
is achieved with no DLTs, the bendamustine dose will then be escalated to 80 mg/m2 and 
then 90 mg/m2 days 1 and 2. 
The Phase I portion of the study is expected to be completed with the enrollment of no 
more than 15 patients. Should more patients be required, the protocol will be amended. 
Design for Phase II portion of study: Once an MTD or a recommended Phase 2 dose 
(RP2D) for the combination is identified, the plan is to treat additional patients at that 
dose to assess efficacy and response to treatment. We plan to enroll 14 patients (including 
those treated at the MTD in Phase I) and continue enrollment only if the observed overall 
response rate is at least 28.6% (4/14); 
If enrollment continues we will treat an additional 5 patients (19 in total) and consider the 
combination “interesting” for further development only if at least 6/19 patients (35.31%) 
achieve a response. 
 
From the statistical section: 
Enroll 14 patients (including those treated at the MTD in Phase I) and continue 
enrollment only if the observed response rate is at least 28.6% (4/14); 
If enrollment continues, treat an additional 5 patients (19 in total) and consider the 
combination worthy of further development only if at least 6/19 patients (35.31%) 
achieve a response. 
 
 


7 
 
Study Population:   
Inclusion Criteria 
Each patient must meet all of the following inclusion criteria to be enrolled in the study: 
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 [e.g., calendar, ovulation, 
symptothermal, postovulation methods] and withdrawal are not acceptable 
methods of contraception.) 
Male patients, even if surgically sterilized (i.e., 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, post-ovulation methods] and withdrawal are not acceptable 
methods of contraception.) 
4. Patients must have histologically or cytologically confirmed symptomatic 
Multiple Myeloma. They must be non-responsive to or ineligible for autologous 
stem cell transplant, and must progress after prior exposure to both proteasome 


8 
 
inhibitor (bortezomib, carfilzomib) and IMID (lenalidomide or pomalidomide or 
thalidomide); and refractory/progressive to at least one of the agents and must 
meet at least one of the following parameters of measurable disease: 
1. Measurable levels of monoclonal protein (M protein): > 1 g/dL of IgG or IgM 
M-protein > 0.5 g/dL, IgA or 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 four 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. 
2. Patients with lytic bone disease, defined as at least one lytic lesion that can be 
accurately measured in at least one dimension. 
5. Eastern Cooperative Oncology Group (ECOG) performance status and/or other 
performance status 0, 1 or 2.  
6. 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. (No GVHD or treatment for GVHD). 
7. Patients must be at least two weeks from major surgery, radiation therapy, 
participation in other investigational trials and have recovered from clinically 
significant toxicities of these prior treatments 
8. Patients must meet the following clinical laboratory criteria: 
 Absolute neutrophil count (ANC)  1,000/mm3 and platelet count 
 75,000/mm3. Platelet transfusions or 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  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  ULN. 
 Calculated creatinine clearance  30 mL/min. 


9 
 
 
   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 (i.e.,  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), seven 
days will be considered a sufficient interval between treatment and administration 
of IXAZOMIB provided hematologic inclusion parameters are met. 
5. Myeloma-related central nervous system involvement. 
6. Serious infection within 14 days of study treatment start and has not clinically 
resolved. 
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 
six months. 
8. Systemic treatment, within 14 days before the first dose of IXAZOMIB, with 
strong inhibitors of CYP1A2 (fluvoxamine, enoxacin, ciprofloxacin), strong 
inhibitors of 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. Active hepatitis B or C virus infection, or known human immunodeficiency virus 
(HIV) positive. 


10 
 
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 1with 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 two weeks 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. 
 
Duration of Study:  The treatment will be given for four cycles (28-day cycles) and up to 
four more cycles, if there is clinical benefit (no evidence of progression of disease). The 
study follow up will continue until after the last patient has progressed with myeloma. All 
patients will be followed for survival.  
 
 


11 
 
1. SCHEDULE OF EVENTS    
Days 
Screening 
days -21 
to -11 
Cycle 1 of study 
q28 days10, 11 
Cycle 2 and 3 of 
study q28 days11 
Cycle 4 of study 
q28 days9, 11 
Post treatment follow up 
phase 
 
 
D1 
D2 
D8 
D 
15 
D1 
D2 
D8 
D 
15 
D1 
D2 
D8 
D 
15 
End of study8 
Study entry 
assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication history 
X 
X 
 
 
 
X  
 
 
X  
 
 
X 
Physical 
examination 
X 
X 
 
 
 
X  
 
 
X  
 
 
X 
ECOG PS 
X 
X 
 
 
 
X  
 
 
X  
 
 
X 
Vitals2 
X 
X 
 
 
 
X  
 
 
X  
 
 
X 
Height and 
Weight12 
X 
X 
 
 
 
X  
 
 
X  
 
 
X 
CBC and 
differential 
X 
X 
 
X X X  
X X X  
X X X 
Serum chemistry 
panel3 
X 
X 
 
X X X  
X X X  
X X X 
Serum pregnancy 
test4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Multiple myeloma 
panel5 
X 
X 
 
 
 
X  
 
 
X  
 
 
X 
Bone marrow 
aspiration and 
biopsy6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 Survival7 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Treatment l13 
 
X 
X X X X X X X X X X X  
Adverse event 
reporting 
 
 
 
 
Recorded from consent through 30 days after last dose of study drug 
Notes: 
1. 
Screening procedures to occur up to 21 days before Cycle 1 Week 1 Visit, except for serum pregnancy test (within seven days prior 
to Week 1 Visit). BM aspirates and biopsies performed up to 12 weeks before Cycle 1 Week 1 Visit do not need to be repeated 
2. 
Vital signs: blood pressure, pulse rate, respiratory rate and temperature. 
3. 
Serum chemistries panel: Including albumin, total protein, total bilirubin, ALT, AST, LDH, alkaline phosphatase, bicarbonate, sodium, 
potassium, chloride, creatinine, BUN and glucose. 
4. 
Females of reproductive potential only. 
5. 
Multiple myeloma panel includes serum protein electrophoresis and immunofixation, 24‐hour urine protein electrophoresis and 
immunofixation, serum‐free light chains, quantitative immunoglobulins. For patients who do not have measurable disease in the 
urine (involved light chain <200 mg/24 hours) at screening, 24‐hour urine protein electrophoresis and immunofixation are only to 
be performed as clinically indicated or to confirm complete remission. 
6. 
Bone marrow aspirate and/or biopsy and cytogenetics will be performed as clinically indicated during the trial. 


12 
 
7. 
Follow‐up will be every eight weeks for the first year or until disease relapse/progression and every 12 weeks for the second year or 
until disease relapse/progression. 
8. 
Perform end‐of‐study procedures four weeks after study completion or at time of early withdrawal. If study procedure cannot be 
performed on the scheduled day, the procedure must be performed within 48 hours. 
9. 
The treatment will be given for a total of four cycles and will be given for four more cycles if response is demonstrated (SD or 
better). Subsequent cycles will follow the same treatment format and schedules, when performed. 
10. Multiple myeloma panel does not need to be repeated at Cycle 1, if the screening panel was performed within one week prior to 
Cycle 1 Day 1. All other screening assessments performed within 72 hours prior to Cycle 1 Day 1 do not need to be repeated.  
11. For all cycles, Day 1 exam, disease and lab assessments may be performed up to 72 hours prior to Day 1. For all cycles and dose 
dates, a treatment window of + 1 day is allowed to accommodate holidays and scheduling conflicts. 
12. Height and weight to be performed at screening and follow‐up. Weight to be performed on Day 1 of each cycle. 
13. Treatment will be as follows: Bendamustine on days 1 and 2, Ixazomib on days 1, 8, and 15, and Dexamethasone on days 1, 8, and 
15. 
 


13 
 
TABLE OF CONTENTS 
PROTOCOL SUMMARY ........................................................................................................5 
Inclusion Criteria ..................................................................................................................7 
Exclusion Criteria .................................................................................................................9 
1. SCHEDULE OF EVENTS .................................................................................................11 
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS ............................................15 
2. BACKGROUND AND STUDY RATIONALE ................................................................19 
2.1 Scientific Background ..................................................................................................19 
2.1.1 Disease Under Treatment .......................................................................................19 
2.1.2 Ixazomib (MLN9708) ............................................................................................20 
2.2 Preclinical Experience ..................................................................................................20 
2.3 Clinical Experience .......................................................................................................20 
2.4 Pharmacokinetics and Drug Metabolism ......................................................................22 
2.5 Clinical Trial Experience Using the Oral Formulation of Ixazomib ............................23 
2.6 Relapsed and/or Refractory Multiple Myeloma ...........................................................29 
2.7 Newly Diagnosed Multiple Myeloma (NDMM) ..........................................................30 
2.8 Clinical Trial Experience Using the Intravenous Formulation of Ixazomib ................30 
2.9 Study Rationale .............................................................................................................30 
2.10 Potential Risks and Benefits .......................................................................................31 
3. STUDY OBJECTIVES ......................................................................................................33 
3.1 Primary Objectives .......................................................................................................33 
3.2 Secondary Objectives ...................................................................................................33 
4. STUDY END POINTS .......................................................................................................33 
4.1 Primary end point: ........................................................................................................33 
4.2 Secondary end points: ...................................................................................................33 
5. STUDY DESIGN ...............................................................................................................34 
5.1 Overview of Study Design ...........................................................................................34 
5.2   Dose Escalation Rules ................................................................................................36 
5.3  Number of Patients ......................................................................................................37 
5.4 Duration of Study .........................................................................................................37 
6. STUDY POPULATION .....................................................................................................37 
6.1 Inclusion Criteria ..........................................................................................................37 
6.2 Exclusion Criteria .........................................................................................................39 
7. STUDY DRUG ...................................................................................................................41 
7.1 Description of Investigational Agents ..........................................................................41 
7.2 Study Drug Administration ..........................................................................................41 
7.2.1  Ixazomib Administration ......................................................................................41 
7.2.2 Bendamustine: .......................................................................................................42 
7.2.3 Dexamethasone: .....................................................................................................45 
7.2.4  Definition of MTD: ...............................................................................................47 
7.2.5   Definition of Dose-limiting toxicity: ...................................................................47 
7.3 Dose-Modification Guidelines .....................................................................................48 
7.4 Excluded Concomitant Medications and Procedures ...................................................53 
7.5 Permitted Concomitant Medications and Procedures ...................................................54 
7.6 Precautions and Restrictions .........................................................................................55 


14 
 
7.7 Management of Clinical Events ...................................................................................56 
7.8 Preparation, Reconstitution, and Dispensing ................................................................59 
7.9 Packaging and Labeling ................................................................................................60 
7.10 Storage, Handling, and Accountability .......................................................................60 
7.11 Study Compliance .......................................................................................................61 
7.12 Termination of Treatment and/or Study Participation ................................................61 
8. STUDY PROCEDURES: ...................................................................................................62 
8.1 Study procedures: .........................................................................................................62 
8.1.1 Administrative procedures: ....................................................................................62 
8.1.2 Clinical Procedures/Assessments ..........................................................................64 
8.1.3 Other procedures: ...................................................................................................65 
8.1.4 Study definitions ....................................................................................................65 
9. STATISTICAL AND QUANTITATIVE ANALYSES .....................................................67 
9.1 Statistical Methods .......................................................................................................67 
9.2 General considerations .................................................................................................68 
9.3 Determination of sample size .......................................................................................68 
9.4 Statistical analysis .........................................................................................................69 
9.4.1 Demographics and Baseline characteristics ...........................................................69 
9.4.2 Safety analysis .......................................................................................................69 
9.4.3 Efficacy analysis ....................................................................................................70 
10. ADVERSE EVENTS ........................................................................................................71 
10.1 Definitions ..................................................................................................................71 
10.1.1 Adverse Event Definition ....................................................................................71 
10.1.2 Serious Adverse Event Definition .......................................................................71 
10.2 Procedures for Reporting Serious Adverse Events .....................................................72 
10.3 Procedures for Reporting Drug Exposure During Pregnancy and Birth Events ........75 
11. ADMINISTRATIVE REQUIREMENTS ........................................................................75 
11.1 Product Complaints ....................................................................................................75 
11.2 Data safety monitoring: ..............................................................................................75 
11.3 Clinical trials management system .............................................................................77 
11.4 Monitoring ..................................................................................................................77 
12. REFERENCES .................................................................................................................79 
13. APPENDICES ..................................................................................................................82 
13.1 Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status ..........82 
13.2 Cockcroft-Gault Equation ...........................................................................................83 
13.3 Response criteria in Multiple myeloma ......................................................................84 
13.4 Enrollment Worksheet ................................................................................................85 
 


15 
 
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS 
Common abbreviations used in oncology protocols are provided below. Program-specific or 
protocol-specific abbreviations must be added to this list, and unnecessary abbreviations 
removed, as applicable. Abbreviations that are retained should not be changed.  
Abbreviation 
Term 
5-HT3 
5-hydroxytryptamine 3 serotonin receptor 
AE 
adverse event 
ALL 
acute lymphoblastic leukemia 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AML 
acute myelogenous leukemia 
ANC 
absolute neutrophil count 
API 
active pharmaceutical ingredient 
aPTT 
activated partial thromboplastin time 
Ara-C 
Cytarabine 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration versus time curve 
AUC24 hr 
area under the plasma concentration versus time curve from zero to 24 hours 
AUCinf 
area under the plasma concentration versus time curve from zero to infinity 
AUCτ 
area under the plasma concentration versus time curve from zero to next dose 
BCRP 
breast cancer resistance protein 
hCG
beta-human chorionic gonadotropin 
BID 
bis in die; twice a day 
BM 
bone marrow 
BSA 
body surface area 
BUN 
blood urea nitrogen 
BZD 
Benzodiazepines 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CL 
clearance, IV dosing 
CLP 
plasma clearance 
CLTotal 
total clearance 
Cmax 
single-dose maximum (peak) concentration   
CNS 
central nervous system 


16 
 
Abbreviation 
Term 
CO2 
carbon dioxide 
CR 
complete remission  
CRM 
continual reassessment method 
CRP 
C-reactive protein 
CSF-1R 
colony-stimulating factor 1 receptor 
CT 
computed tomography 
Ctrough 
single-dose end of dosing interval (trough) concentration 
CV 
Cradiovascular 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
DLT 
dose-limiting toxicity 
DME 
drug metabolizing enzymes 
DNA 
deoxyribonucleic acid 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ELISA 
enzyme-linked immunosorbent assay 
EOS 
End of Study (visit) 
EOT 
End of Treatment (visit) 
EU 
European Union 
FDA 
United States Food and Drug Administration 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony stimulating factor 
GGT 
gamma glutamyl transferase 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practices 
GM-CSF 
granulocyte macrophage-colony stimulating factor 
GMP 
Good Manufacturing Practice 
Hb 
Hemoglobin 
Hct 
Hematocrit 
HDPE 
high-density polyethylene 
hERG 
human ether-à-go-go related gene 
HIV 
human immunodeficiency virus 


17 
 
Abbreviation 
Term 
HNSTD 
highest nonseverely toxic dose 
IB 
Investigator’s Brochure 
IC50 
concentration producing 50% inhibition 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
IRB 
institutional review board 
ITT 
intent-to-treat 
IV 
intravenous; intravenously 
IVRS 
interactive voice response system 
Ki 
inhibition constant 
KPS 
Karnofsky Performance Status 
LDH 
lactate dehydrogenase 
LFT 
liver function test(s) 
MedDRA 
Medical Dictionary for Regulatory Activities 
Millennium 
Millennium Pharmaceuticals, Inc., and its affiliates 
MRI 
magnetic resonance imaging 
MRU 
medical resource utilization 
MTD 
maximum tolerated dose 
MUGA 
multiple gated acquisition (scan) 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NPO 
nothing by mouth 
NYHA 
New York Heart Association 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
PD 
progressive disease (disease progression) 
Progressive disease 
Pgp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
PO 
per os; by mouth (orally) 
PR 
partial response 
PRO 
patient-reported outcome 
PSA 
prostate-specific antigen 


18 
 
Abbreviation 
Term 
QD 
quaque die; each day; once daily 
QID 
quater in die; 4 times a day 
QOD 
quaque altera die; every other day 
QOL 
quality of life 
QTc 
rate-corrected QT interval (millisec) of electrocardiograph 
RBC 
red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SC 
Subcutaneous 
SD 
stable disease 
SmPC 
Summary of Product Characteristics 
t1/2 
terminal disposition half-life 
TGI 
tumor growth inhibition 
Tmax 
single-dose time to reach maximum (peak) concentration 
UK 
United Kingdom 
ULN 
upper limit of the normal range 
US 
United States 
Vz 
volume of distribution in the terminal phase 
WBC 
white blood cell 
WHO 
World Health Organization 
 


19 
 
2.    
BACKGROUND AND STUDY RATIONALE 
2.1    Scientific Background 
2.1.1    Disease Under Treatment 
Multiple Myeloma is a neoplastic plasma cell disorder that is characterized by clonal 
proliferation of malignant plasma cells in the bone marrow, monoclonal protein in the blood 
or urine and associated organ dysfunction (1). As a result of the development of novel anti-
myeloma agents, autologous stem cell transplantation and the supportive care there has been 
significant improvement in the survival of patients with multiple myeloma (2-4). Multiple 
myeloma still remains an incurable disease despite advances in these treatment modalities in 
the recent years (1). The standard of treatment involves induction with novel agents 
followed by autologous stem cell transplant. Multiple studies have shown that with current 
induction, there is 35-60% in vGPR or better response rates. Irrespective of induction 
agents, there is response augmentation of 20% after the autologous stem cell transplantation 
(3, 5, 6). The median progression free survival with this strategy is more than 50 months and 
5 year overall survival is less than 40%. Despite these the great majorities of patients relapse 
and need effective second line or further therapies. There are few effective salvage regimens 
available for patients with disease resistant to novel agents. The available options include 
bortezomib retreatment resulting in the response rates of 40% (7). Lenalidomide and 
dexamethasone has shown significant improvement in overall response rate (ORR 60.6% vs. 
21.9%, p< 0.001) complete response rate (CR 15% vs. 2%, p<0.001) and median overall 
survival (OS, 38 m vs. 31.6 m, p=0.045) when compared to dexamethasone alone (8). 
Bendamustine in Multiple myeloma: 
 Bendamustine is a bifunctional mechlorethamine derivative with alkylating and anti-purine 
activities (9). Bendamustine with prednisone in previously untreated multiple myeloma 
patients had comparable ORR with melphalan and prednisone; however, significantly higher 
number of patients achieved CR in bendamustine group (32% vs. 13%; p=0.007) (10). 
Bendamustine has shown very promising results in both Phase1 and 2 studies in patients 
with relapsed/refractory multiple myeloma. In a Phase 1 study, bendamustine at maximum 
tolerated dose of 100mg/m2 resulted in ORR of 55% in patients with relapsed multiple 
myeloma after autologous SCT (11). In a similar group of patients, bendamustine at a lower 
dose (60mg/m2), when combined with thalidomide and prednisone, resulted in ORR of 86% 
(12) . Combination of bendamustine (at MTD of 75 mg/ m2) with lenalidomide (10 mg/d) 
and dexamethasone in Phase1/2 study resulted in ORR of 76% (13). There are two Phase1/2 


20 
 
studies looking at the combination of bendamustine with bortezomib in patients with 
relapsed/refractory multiple myeloma. In one study, 36 patients with relapsed/refractory 
multiple myeloma and light chain induced renal failure were treated with bendamustine 
(60mg/m2), bortezomib (1.3 mg) and prednisone, which resulted in ORR of 67%(14). 
Similarly, in another Phase I study, 79 patients with relapsed /refractory multiple myeloma 
were treated with bendamustine (70 mg/m2), bortezomib (1.3 mg/m2) resulted in the ORR of 
75.9% (15). Bendamustine, in combination with immunmodulators (IMIDs) or proteasome 
inhibitor, is active in patients with relapsed/refractory multiple myeloma. In this study, we 
seek to improve the efficacy of bendamustine by combining the novel proteasome inhibitor 
IXAZOMIB (MLN9708) to bendamustine and dexamethasone in patients with 
relapsed/refractory multiple myeloma. 
2.1.2         Ixazomib (MLN9708)  
2.2    Preclinical Experience 
Please refer to the current IXAZOMIB Investigator’s Brochure (IB) and Safety 
Management Attachment (SMA). 
2.3    Clinical Experience 
Ixazomib has been evaluated as an oral single agent in Phase 1 studies that included patients 
with advanced solid tumors, lymphoma, relapse/refractory MM (RRMM), and relapsed or 
refractory light-chain (AL) amyloidosis and demonstrated early signs of activity. Ongoing 
studies continue to investigate both single-agent IXAZOMIB and IXAZOMIB in 
combination with standard treatments. Based on encouraging preliminary data observed in 
patients with MM requiring systemic treatment, two Phase 3 trials in newly diagnosed MM 
(NDMM) (C16014) and RRMM (C16010) patient populations are currently evaluating 
IXAZOMIB in combination with Revlimid and Dexamethasone (RevDex) versus 
placebo/RevDex. Both trials are combining IXAZOMIB at a weekly dose of 4.0 mg on 
Days 1, 8, and 15 in a 28-day cycle to a standard dose of lenalidomide with a weekly 
dexamethasone dose of 40 mg. In addition, ongoing clinical pharmacology studies include 
evaluation of drug-drug interactions with ketoconazole and rifampin, effect of food, and oral 
bioavailability. Studies evaluating the safety and pharmacokinetic (PK) of IXAZOMIB 
alone (in Japanese patients) and in combination with lenalidomide and dexamethasone in 
Asian adult patients (including Japanese patients) with a diagnosis of NDMM are ongoing. 
 


21 
 
As of 27 March 2013, preliminary clinical data is available for a total of 653 patients across 
13 studies. The emerging safety profile indicates that IXAZOMIB is generally well 
tolerated. The adverse events (AEs) are consistent with the class-based effects of proteasome 
inhibition and are similar to what has been previously reported with VELCADE though the 
severity of some, for example peripheral neuropathy, is less. While some of these potential 
toxicities may be severe, they can be managed by clinical monitoring and standard medical 
intervention, or, as needed, dose modification or discontinuation. 
 
Fatigue was the most common AE reported among 384 patients treated in the oral (PO) 
studies (47%). Other common AEs reported in the pooled intravenous (IV) and PO safety 
populations included nausea, thrombocytopenia, diarrhea and vomiting. Rash is also a 
commonly reported treatment-emergent event; however, there is some variety in its 
characterization and causality resulting in different preferred terms to describe it. A high-
level term outline of rash events includes rashes, eruptions and exanthems NEC; pruritus 
NEC; erythemas; papulosquamous conditions; and exfoliative conditions. The dose 
escalation phases of most trials reported in the IB have now completed enrollment, and 
gastrointestinal (GI) symptoms were the common dose-limiting toxicities (DLTs) when the 
use of prophylactic anti-emetics was not permitted per protocol. In the expansion cohorts or 
Phase 2 cohorts (as per each study), the incidence and severity of GI symptoms was 
mitigated by the use of the lower maximum tolerated dose (MTD)/recommended Phase 2 
dose (RP2D) (as per each study) and standard clinical usage of anti-emetics and/or 
antidiarrheal medications as deemed appropriate. Prophylactic use of antiemetics has not 
been required as with other agents but (as outlined in Section 6.7) has been used according 
to standard practice and are effective. 
 
The most frequent (at least 20%) treatment-emergent adverse events (TEAEs) reported with 
the PO formulation pooled from single-agent studies (n = 201) irrespective of causality to 
IXAZOMIB, include nausea (53%), fatigue (51%), diarrhea (44%), thrombocytopenia 
(34%), vomiting (38%), decreased appetite (32%), fever (21%), and anemia (21%). The 
most frequent (at least 20%) TEAEs reported with the PO formulation pooled from 
combination trials (irrespective of the combination) (n = 173), irrespective of causality to 
IXAZOMIB, include diarrhea (47%), fatigue (44%), nausea (38%), peripheral edema 
(35%), constipation (33%), insomnia (29%), thrombocytopenia (28%), anemia (26%), 
vomiting (26%), neutropenia (25%), back pain (24%), pyrexia (23%), peripheral edema 
(21%, each), fever (20%), cough (20%), hypokalemia (20%), neutropenia (20%) and upper 
respiratory tract infection (20%). Overall rash of all grades is reported in approximately 50% 


22 
 
of patients and is more common when IXAZOMIB is given in combination with 
lenalidomide where rash is an overlapping toxicity. 
 
Additional detailed information regarding the clinical experience of IXAZOMIB may be 
found in the IB, including information on the IV formulation.  
2.4   Pharmacokinetics and Drug Metabolism 
Clinical IV and PO PK data show that IXAZOMIB citrate (measured as the biologically 
active boronic acid form of IXAZOMIB [MLN2238]) has multi-exponential disposition 
with a rapid initial phase that is largely over by four hours. Oral IXAZOMIB citrate is 
rapidly absorbed with a median single-dose first time of occurrence of maximum (peak) 
concentration (Tmax) of approximately 0.5 to 2.0 hours and a terminal disposition half-life 
(t1/2) after multiple dosing of approximately 5 to 7 days (16). Results of a population PK 
analysis (n = 137) show that there is no relationship between body surface area (BSA) or 
body weight and clearance (CL). Also, based on stochastic simulations for fixed dose, 
exposures are independent of the individual patient’s BSA (17). Based on these data, a 
recommendation was made for fixed dosing in clinical trials. An absolute bioavailability of 
67% was determined for IXAZOMIB using the population PK analysis. Please refer to the 
current IXAZOMIB IB and Safety Management Attachment (SMA) for information on the 
PK for IV doses of IXAZOMIB. 
 
Metabolism appears to be the major route of elimination for IXAZOMIB, and urinary 
excretion of the parent drug is negligible (< 5% of dose). In vitro studies indicate that 
IXAZOMIB is metabolized by multiple cytochrome P450s (CYPs) and non-CYP 
enzymes/proteins. The rank order of relative biotransformation activity of the five major 
human CYP isozymes was 3A4 (34.2%) > 1A2 (30.7%) > 2D6 (14.7%) > 2C9 (12.1%) > 
2C19 (< 1%). Ixazomib is not an inhibitor of CYPs 1A2, 2C9, 2C19, 2D6, or 3A4 nor a 
time-dependent inhibitor of CYP3A4/5. The potential for IXAZOMIB treatment to produce 
drug-drug interactions (DDIs) via CYP inhibition is inferred to be low. However, there may 
be a potential for DDIs with a concomitant strong CYP3A4 or CYP1A2 inhibitor or inducer 
because of the potential for first-pass metabolism when IXAZOMIB is administered via the 
PO route and because of the moderate contribution of CYP3A4- and CYP1A2-mediated 
metabolism of IXAZOMIB in human liver microsomes. Ixazomib may be a weak substrate 
of P-glycoprotein (Pgp), breast cancer resistance protein (BCRP), and multidrug resistance 
associated protein (MRP2) efflux pump transporters. Ixazomib is not an inhibitor of Pgp, 
BCRP, and MRP2. The potential for DDIs with substrates or inhibitors of Pgp, BCRP, and 


23 
 
MRP2 is, therefore, inferred to be low. Clinical Study C16009 (Arm 1) with ketoconazole, a 
strong CYP3A4 inhibitor, showed a 2-fold increase in area under the plasma concentration 
versus time curve (AUC) in the presence of ketoconazole. This resulted in the continued 
exclusion of strong CYP3A4 inhibitors in ongoing/planned clinical studies. 
 
Further details on these studies are provided in the IB. 
 
2.5    Clinical Trial Experience Using the Oral Formulation of Ixazomib 
As of 27 March 2013, a total of 507 patients with differing malignancies (multiple myeloma, 
AL amyloidosis, nonhematologic cancers, and lymphoma) have been treated in studies 
evaluating the oral IXAZOMIB formulation. These patients have been treated with different 
doses of IXAZOMIB either as a single-agent treatment (in 201 patients) or in combination 
with currently clinically available treatments (in 306 patients). Information regarding the 
ongoing studies, patient populations, and doses investigated is included in Table 1-1. 
 


24 
 
Table 2-1    
Clinical Studies of Oral Ixazomib 
Trial/ 
Population 
Description 
Doses Investigated 
C16003 
RRMM 
N = 60 
PO, TW, single agent 
0.24-2.23 mg/m2 TW 
MTD:  2.0 mg/m2 
DLT:  rash, thrombocytopenia 
Closed to enrollment 
C16004 
RRMM 
N = 60 
PO, W, single agent 
0.24-3.95 mg/m2 W 
MTD:  2.97 mg/m2 
DLT:  rash, nausea, vomiting, diarrhea 
Closed to enrollment 
C16005 
NDMM 
N = 65 
PO, W, combination with LenDex 
28-day cycle 
1.68-3.95 mg/m2 W 
MTD:  2.97 mg/m2 
DLT:  nausea, vomiting, diarrhea, syncope 
RP2Da:  4.0 mg fixed (switched to fixed dosing in 
Phase 2, equivalent to 2.23mg/m2) 
Closed to enrollment 
C16006 
NDMM 
N = 20 
PO, TW (Arm A- 42 day cycle) and 
W (Arm B- 28 day cycle), 
combination with Melphalan and 
Prednisone 
Arm Aa:  3-3.7-mg fixed dose TW 
DLT:  rash, thrombocytopenia, subileus 
Arm Ba:  3-5.5-mg fixed dose, W 
DLT:  Esophageal ulcer nausea, vomiting, 
hematemesis, thrombocytopenia, ileus, 
neurogenic bladder 
MTD = 3.0 mg 
C16007 
RRAL 
N = 27 
PO, W, single agent 
4-5.5-mg fixed dosea W 
DLT:  thrombocytopenia, diarrhea, dyspnea, acute 
rise in creatinine, cardiac arrest  
MTD:  4.0 mg W 
 
C16008 
NDMM 
N = 64 
PO, TW, combination with LenDex 
21-day cycle 
3.0-3.7-mg fixed dosea W 
MTD:  3.0 mg 
Closed to enrollment 
C16009 
Solid tumors, 
Lymphomas 
N = 54 
PO, W, single agent 
5.5-mg fixed dosea W 
C16010 
RRMM 
N = 200 
PO, W, with LenDex versus placebo-
LenDex 
4.0 mg W 
C16011 
RRAL 
N = 4 
PO, W, with Dex versus physician’s 
choice of a Dex-based regimen 
4.0 mg W 
C16013 
RRMM 
N = 9 
PO, W, with LenDex 
4.0 mg W 


25 
 
Table 2-1    
Clinical Studies of Oral Ixazomib 
Trial/ 
Population 
Description 
Doses Investigated 
C16014 
Symptomatic 
MM 
N=701 
PO, combination with LenDex 
IXAZOMIB 4.0 mg or matching placebo on 
Days 1, 8, and 15, plus Len 25 mg on Days 1-21 
(10 mg if low creatinine clearance, with escalation 
to 15 mg if tolerated) and Dex 40 mg (or 20 mg if 
>75 years old) on Days 1, 8, 15, and 22 
C16015 
Symptomatic 
MM with 
normal renal 
function or 
severe renal 
impairment 
N=28 
PO, combination with Dex 
Part A: IXAZOMIB 3.0 mg on Day 1 
Part B: IXAZOMIB 4.0 mg on Days 1, 8, and 15, 
plus Dex 40 mg (or 20 mg if >75 years old) on 
Days 1, 8, 15 and 22 of a 28-day cycle 
 
C16017 
RR follicular 
lymphoma 
N=58 
PO, W 
4.0, 5.3, and 7.0 mg, W 
Treatment at RP2D once determined. 
 
C16018 
Advanced 
solid tumors 
or 
hematologic 
malignancies 
with varying 
degrees of 
liver 
dysfunction 
N=45 
Part A: PO, Day 1 of 15-day cycle 
Part B: PO, W 
1.5 mg (severe hepatic impairment), 2.3 mg 
(moderate hepatic impairment), or 4.0 mg (normal 
hepatic function) 
 
TB-
MC010034 
RRMM 
N = 10 
PO, W 
4.0 mg, W 
Single agent: 4.0 mg 
Combination with Rd 
Abbreviations:  RRAL = Relapsed and/or refractory Primary systemic light chain (AL) amyloidosis; BSA = 
body surface area; Dex=dexamethasone; DLT = dose-limiting toxicity; IV = intravenously; LenDex = 
lenalidomide plus dexamethasone; MTD = maximum tolerated dose; NDMM = newly diagnosed multiple 
myeloma; PO = orally; RR= relapsed and/or refractory; RRAL= relapsed and/or refractory systemic light 
chain amyloidosis RRMM = relapsed and/or refractory multiple myeloma; TBD = to be determined; TW 
= twice weekly; W = weekly; RP2D= recommended Phase 2 dose. 
Note that blinded data from pivotal Studies C16010 and C16011 are not included.  
a Approximate BSA and fixed dosing equivalence:  3 mg~ equivalent to 1.68 mg/m2 BSA dosing; 4.0 mg ~ 
equivalent to 2.23 mg/m2 BSA dosing; and 5.5 mg~ equivalent to 2.97 mg/m2 BSA dosing. 
 
 
 


26 
 
Overview of the Oral Formulation of Ixazomib 
The emerging safety profile indicates that IXAZOMIB is generally well tolerated. The 
adverse events (AEs) are consistent with the class-based effects of proteasome inhibition 
and are similar to what has been previously reported with VELCADE though the severity of 
some, for example peripheral neuropathy, is less. While some of these potential toxicities 
may be severe, they can be managed by clinical monitoring and standard medical 
intervention, or, as needed, dose modification or discontinuation.  
In the four ongoing studies (C16003, C16004, C16007, and C16009) investigating single-
agent oral IXAZOMIB in patients with differing malignancies (multiple myeloma, AL 
amyloidosis, nonhematologic cancers, and lymphoma), a total of 201 patients have been 
treated as of 27 March 2013. These patients have been treated with different doses of 
IXAZOMIB as they are all Phase 1 trials. An overview of the most frequent (at least 10%) 
AEs occurring in the pooled safety population from single-agent oral IXAZOMIB Studies 
(C16003, C16004, C16007, and C16009) is shown in Table 1-2. 
Table 2-2 Most Common (At Least 10% of Total) Treatment-Emergent 
Adverse Events in Oral Single-Agent Studies 
Primary System Organ Class 
Preferred Term 
IV Studiesa 
N = 146 
Oral Studiesb 
N = 491 
Total 
N = 637 
General disorders and administration 
site conditions 
118 (81) 
363 (74) 
481 (76) 
Fatigue 
89 (61) 
223 (45) 
312 (49) 
Pyrexia 
45 (31) 
112 (23) 
157 (25) 
Oedema peripheral 
31 (21) 
122 (25) 
153 (24) 
Asthenia 
10 (7) 
74 (15) 
84 (13) 
Nervous system disorders 
87 (60) 
272 (55) 
359 (56) 
Dizziness 
25 (17) 
85 (17) 
110 (17) 
Headache 
31 (21) 
74 (15) 
105 (16) 
Neuropathy peripheral 
17 (12) 
81 (16) 
98 (15) 
Metabolism and nutrition disorders 
89 (61) 
267 (54) 
356 (56) 
Decreased appetite 
56 (38) 
120 (24) 
176 (28) 
Dehydration 
25 (17) 
61 (12) 
86 (14) 
Hypokalaemia 
11 (8) 
57 (12) 
68 (11) 
Blood and lymphatic system disorders 
88 (60) 
256 (52) 
344 (54) 
Thrombocytopenia 
65 (45) 
161 (33) 
226 (35) 
Anaemia 
28 (19) 
114 (23) 
142 (22) 
Neutropenia 
16 (11) 
103 (21) 
119 (19) 
Lymphopenia 
16 (11) 
61 (12) 
77 (12) 


27 
 
Table 2-2 Most Common (At Least 10% of Total) Treatment-Emergent 
Adverse Events in Oral Single-Agent Studies 
Skin and subcutaneous tissue disorders 
84 (58) 
255 (52) 
339 (53) 
Rash (all terms) 
73 (50) 
197 (40) 
270 (42) 
Rash maculo-papular 
21 (14) 
60 (12) 
81 (13) 
Rash macular 
15 (10) 
56 (11) 
71 (11) 
Musculoskeletal and connective tissue 
disorders 
78 (53) 
249 (51) 
327 (51) 
Back pain 
27 (18) 
88 (18) 
115 (18) 
Arthralgia 
17 (12) 
72 (15) 
89 (14) 
Pain in extremity 
21 (14) 
66 (13) 
87 (14) 
Respiratory, thoracic and mediastinal 
disorders 
87 (60) 
228 (46) 
315 (49) 
Cough 
32 (22) 
94 (19) 
126 (20) 
Dyspnoea 
31 (21) 
80 (16) 
111 (17) 
Infections and infestations 
48 (33) 
244 (50) 
292 (46) 
Upper respiratory tract infection 
12 (8) 
94 (19) 
106 (17) 
Psychiatric disorders 
32 (22) 
151 (31) 
183 (29) 
Insomnia 
14 (10) 
89 (18) 
103 (16) 
Source:  Ixazomib Investigator’s Brochure Edition 8 
 
Treatment emergent is defined as any AE that occurs after administration of the first dose of any study drug 
through 30 days after the last dose of any study drug. 
A subject counts once for each preferred term and system organ class. Percentages use the number of treated 
subjects as the denominator. 
a  Studies C16001 and C16002. 
b  Studies C16003, C16004, C16005, C16006, C16007, C16008, C16009, C16013, C16015, C16017,     
C16018, and TB-MC010034. 
 
 
As of 13 April 2015, there are 12 studies actively enrolling patients with multiple myeloma 
to investigate oral IXAZOMIB in combination with standard combination regimens.  
The most frequent (at least 10%) AEs occurring in the pooled safety population from 
Studies C16005, C16006, C16008, and C16013 are shown for all grades (Table 1-3). Note 
that in combination trials, related is defined as related to any study drug in the combination 
regimen. 
 
 


28 
 
Table 2-3    
Most Common (At Least 10% of Total) Treatment-Emergent Adverse 
Events in Oral Combination Studies 
Primary System Organ Class 
      Preferred Term 
Total Oral Combo Agent 
(5/6/8/13) 
n = 173 
n (%) 
Subjects with at Least One Adverse Event 
163 (94) 
Gastrointestinal disorders 
139 (80) 
 Nausea 
65 (38) 
 Diarrhoea 
81 (47) 
 Vomiting 
51 (29) 
 Constipation 
57 (33) 
General disorders and administration site 
conditions 
132 (76) 
 Fatigue 
76 (44) 
 Pyrexia 
39 (23) 
 Oedema peripheral 
61 (35) 
 Asthenia 
20 (12) 
Nervous system disorders 
115 (66) 
 Headache 
28 (16) 
 Dizziness 
34 (20) 
 Neuropathy peripheral 
45 (26) 
Metabolism and nutrition disorders 
91 (53) 
 Decreased appetite 
25 (14) 
 Hypokalaemia 
34 (20) 
Blood and lymphatic system disorders 
88 (51) 
 Thrombocytopenia 
49 (28) 
 Anaemia 
45 (26) 
 Neutropenia 
43 (25) 
 Lymphopenia 
20 (12) 
Skin and subcutaneous tissue disorders 
102 (59) 
 Rash maculopapulara 
29 (17) 
 Rash maculara 
22 (13) 
Musculoskeletal and connective tissue 
disorders 
99 (57) 
 Back pain 
42 (24) 
 Pain in extremity 
31 (18) 
 Arthralgia 
22 (13) 
Respiratory, thoracic and mediastinal 
disorders 
80 (46) 
 Cough 
36 (21) 
 Dyspnoea 
26 (15) 


29 
 
Table 2-3    
Most Common (At Least 10% of Total) Treatment-Emergent Adverse 
Events in Oral Combination Studies 
Primary System Organ Class 
      Preferred Term 
Total Oral Combo Agent 
(5/6/8/13) 
n = 173 
n (%) 
Infections and infestations 
92 (53) 
 Upper respiratory tract infection 
35 (20) 
Psychiatric disorders 
73 (42) 
 Insomnia 
50 (29) 
Source:  Ixazomib Investigator’s Brochure Edition 7 
Abbreviations:  MedDRA = Medical Dictionary for Regulatory Activities, version 15.0. 
Subject Incidence:  A subject counts once for each preferred term. Percentages use the number of treated 
subjects as the denominator.  
Data from ongoing blinded pivotal trials (C16010) are not included. 
a Note that rash maculopapular and rash macular represent the 2 most common terms used to describe rash.  
 
 
The clinical experience with IXAZOMIB also shows early signs of antitumor activity as 
evidenced by at least a 50% reduction in disease burden in some patients and prolonged 
disease stabilization in others across all ongoing trials. The antitumor activity has been seen 
with single-agent IXAZOMIB, when combined with established therapies, and across the 
malignancies studied (advanced solid tumors (18), non-Hodgkin’s disease, Hodgkin’s 
disease (19), relapsed and/or refractory multiple myeloma [RRMM; (20, 21)], relapsed or 
refractory systemic light chain amyloidosis [RRAL;(22)], and newly diagnosed multiple 
myeloma [NDMM; (23-25)]) to date. 
 
Though additional data are needed to characterize the clinical benefit of this drug, the 
emerging data supports the ongoing development of IXAZOMIB. 
 
2.6    Relapsed and/or Refractory Multiple Myeloma 
The early development of IXAZOMIB in patients with RRMM involves two studies 
(C16003 and C16004) with similar objectives, but each investigated one of the two dosing 
schedules commonly used with the first-in-class proteasome inhibitor, VELCADE. 
Study C16003 is an open-label, dose escalation, Phase 1 study of IXAZOMIB dosing on a 
twice-weekly schedule on Days 1, 4, 8, and 11 of a 21-day cycle in adult patients with 
RRMM.((26, 27))  Study C16004 is an open-label, dose escalation, Phase 1 study of 
IXAZOMIB dosing on a weekly schedule on Days 1, 8, and 15 of a 28-day cycle in adults 


30 
 
patients with RRMM.((28-30))  Both studies have now completed enrollment. The DLTs in 
Study C16003 were rash macular and thrombocytopenia and the DLTs in C16004 were 
nausea, diarrhea, vomiting and erythema multiforme. 
In the dose escalation component of both studies, patients had multiple myeloma that had 
relapsed following at least two lines of therapy that must have included bortezomib, 
thalidomide (or lenalidomide), and corticosteroids. In both studies, when the MTD was 
established, cohorts of patients representing the heterogeneous patient population currently 
seen in clinical practice were to be enrolled into one of four expansion cohorts, including a 
relapsed and refractory cohort, a carfilzomib cohort, a proteasome inhibitor-naïve cohort, 
and a VELCADE-relapsed cohort. 
Final study results are currently being analyzed, but preliminary data suggest that 
IXAZOMIB has anti-tumor activity in heavily pretreated MM patients, with durable 
responses/disease control, and is generally well tolerated. Please refer to the IXAZOMIB IB 
and SMA for further information.  
2.7    Newly Diagnosed Multiple Myeloma (NDMM) 
Multiple research paths are being explored in patients with NDMM with a focus on 
evaluating IXAZOMIB in combination with agents commonly used across treatment 
settings. The development of IXAZOMIB in combination with lenalidomide with 
dexamethasone (LenDex) in patients with NDMM who are transplant eligible or ineligible 
involves two studies (C16005 and C16008) with similar study designs except for a few key 
differences, namely the schedules of IXAZOMIB and dexamethasone. Ixazomib is also 
being evaluated in combination with melphalan and prednisone (MP) for patients who are 
not transplant eligible due to age or coexisting morbidity (in Study C16006).  
All 3 studies are Phase 1/2, with Phase 1 focusing on safety and Phase 2 on efficacy (and 
further characterization of safety). Please refer to the IXAZOMIB IB and SMA for further 
information.  
2.8      Clinical Trial Experience Using the Intravenous Formulation of Ixazomib 
See the IB for descriptions of the two studies that investigated IV IXAZOMIB in advanced 
solid tumors and advanced lymphoma (Studies C16001 and C16002, respectively). 
2.9 
Study Rationale 
Despite very good response with the novel agents, great majorities of patients with multiple 


31 
 
myeloma relapse and need effective second line or further therapies. There are few effective 
salvage regimens available for patients with disease resistant to novel agents. The available 
options include bortezomib retreatment resulting in the response rates of 40%. Lenalidomide 
and dexamethasone has shown significant improvement in overall response rate (ORR 
60.6% vs. 21.9%, p< 0.001) complete response rate (CR 15% vs. 2%, p<0.001) and median 
overall survival (OS, 38 m vs. 31.6 m, p=0.045) when compared to dexamethasone alone 
(8). Bendamustine is a bifunctional mechlorethamine derivative with alkylating and anti-
purine activities (9). Bendamustine with prednisone in previously untreated multiple 
myeloma patients had comparable ORR with melphalan and prednisone; however, 
significantly higher number of patients achieved CR in bendamustine group (32% vs. 13%; 
p=0.007) (10). Bendamustine has shown very promising results in both Phase1 and 2 studies 
in patients with relapsed/refractory multiple myeloma. In Phase 1 study, bendamustine at 
maximum tolerated dose of 100mg/m2 resulted in ORR of 55% in patients with relapsed 
multiple myeloma after autologous SCT (11). In a similar group of patients, bendamustine at 
a lower dose (60mg/m2) when combined with thalidomide and prednisone resulted in ORR 
of 86% (12). Combination of bendamustine (at MTD of 75 mg/m2) with lenalidomide (10 
mg/d) and dexamethasone in Phase1/2 study resulted in ORR of 76% (13). There are two 
Phase1/2 studies looking at the combination of bendamustine with bortezomib in patients 
with 
relapsed/refractory 
multiple 
myeloma. 
In 
one 
study, 
36 
patients 
with 
relapsed/refractory multiple myeloma and light chain induced renal failure were treated with 
bendamustine (60mg/m2), bortezomib (1.3 mg) and prednisone, which resulted in ORR of 
67%(14). Similarly, in another Phase I study. 79 patients with relapsed /refractory multiple 
myeloma were treated with bendamustine (70 mg/m2), bortezomib (1.3 mg/ m2) resulted in 
the ORR of 75.9% (15). Bendamustine, in combination with immunmodulators (IMIDs) or 
proteasome inhibitor, is active in patients with relapsed/refractory multiple myeloma. In this 
study, we seek to improve the efficacy of bendamustine by adding IXAZOMIB (MLN9708) 
to bendamustine and dexamethasone in patients with relapsed/refractory multiple myeloma. 
It is worthwhile to look into the new proteasome inhibitor in combination with 
bendamustine in relapsed/refractory multiple myeloma. In this study, we seek to combine 
bendamustine with IXAZOMIB (MLN9708), a new proteasome inhibitor in patients with 
relapsed/refractory multiple myeloma.  
2.10    
Potential Risks and Benefits 
Please refer to the current IXAZOMIB IB and SMA. 


32 
 
The clinical benefit of IXAZOMIB continues to be studied in a comprehensive and global 
development plan that involves studies sponsored by Millennium. Ixazomib appears to show 
early signs of anti-tumor activity as evidenced by at least 50% reduction in disease burden in 
some patients, including patients that have been heavily pretreated, as well as those with 
newly diagnosed MM. It prolongs stabilization of the underlying disease in other patients 
across all ongoing trials. The preliminary findings are favorable when considering historical 
and currently available therapies for the patient populations evaluated. Though additional 
data are needed to characterize the clinical benefit of this drug, the emerging data supports 
expanded development of IXAZOMIB for the treatment of patients with advanced 
malignancy. 
This study will be conducted in compliance with the protocol, good clinical practice (GCP), 
applicable regulatory requirements, and International Conference on Harmonisation (ICH) 
guidelines. 
We anticipate additional risks of nausea, diarrhea, cytopenias especially thrombocytopenia, 
in addition to neuropathy and hepatotoxicity when IXAZOMIB (MLN9708) is used in 
combination with bendamustine. 
Rationale for combining Proteasome inhibitor with Bendamustine/Dexamethasone: 
The BVD (bendamustine/VELCADE and dexamethasone) combination was able to induce a 
rapid and high response rate (almost 70%) in a recent study by Rodon et al (31). This 
compares favorably with those achieved with bortezomib-dexamethasone, showing an ORR 
between 50% and 54.6% or with lenalidomide-dexamethasone. The best options for future 
treatment of relapsed MM are likely to consist of triplet combinations, which have, up to 
now, been reported in only few Phase 3 trials. Ludwig reported the results of 8 cycles of 
BVD combination in patients with relapsed MM. The ORR was 61%, and a PFS of 10 
months, even allowing for the inclusion of patients previously exposed to bortezomib, 
previously treated with ASCT, and having received more than 1 prior line of therapy (15). 
Offidani et al. evaluated the BVD regimen in patients treated with ASCT as part of frontline 
therapy, patients previously exposed to bortezomib,and patients who had experienced more 
than 1 relapse. The ORR (71.5%) reported by Offidani is identical to the one in study by 
Rodon et al., while the median PFS was longer (15.5 months) (32). These compare 
extremely favorably with recently approved agents in this setting —  Carfilzomib and 
pomalidomide. With the widespread use of MPT in frontline in elderly patients and, in the 
future of Len-Dex, the results by Rodon et al. obtained in a homogenous population of 


33 
 
patients treated at the time of first relapse, suggest that bendamustine, in combination with 
proteasome inhibitor, could form the basis for future studies. 
3.    
STUDY OBJECTIVES 
3.1    Primary Objectives 
Phase I -To determine the maximum tolerated dose of the combination of IXAZOMIB 
(MLN9708) and bendamustine plus dexamethasone in patients with relapsed/refractory 
multiple myeloma. 
Phase II - To determine the objective response rate (ORR) after four cycles of IXAZOMIB 
(MLN9708) and bendamustine plus dexamethasone. 
3.2    Secondary Objectives 
To determine the overall survival (OS) of patients treated with oral IXAZOMIB 
(MLN9708) and bendamustine plus dexamethasone 
To determine the progression free survival (PFS) of patients treated with oral IXAZOMIB 
(MLN9708) and benadmustine plus dexamethasone. 
To determine the cumulative response rates in patients after 8 cycles. 
To determine the duration of response(DoR). 
To determine the minimal residual disease status(MRD) in patients who achieve a complete 
response at the end of the study. 
4. STUDY END POINTS 
4.1  Primary end point: 
MTD of bendamsutine when combined with IXAZOMIB plus dexamethasone up to 
maximum bednamustine dose of 90 mg/m2. 
 
ORR: CR + PR (IMWG response criteria, Appendix 12.3) 
 
4.2  Secondary end points: 
PFS: Measured as time from enrollment to progression of myeloma or death. Patients 
surviving without progression will be censored at the last follow up. 
 


34 
 
OS: Measured as time from enrollment to death from any cause. 
 
Cumulative response rate and duration of response 
 
Minimal residual status (MRD)  
 
 
5.    
STUDY DESIGN  
5.1    Overview of Study Design 
This is a Phase I/II, single-arm, open-label, study evaluating the efficacy and safety of the 
combination of IXAZOMIB, bendamustine, and dexamethasone in subjects with relapsed 
or refractory multiple myeloma, who have previously been treated with proteasome 
inhibitors or immunomodulators either alone or both. Phase I portion of the study will look 
into the safety of combination of bendamustine and MLN9708. Subject participation will 
include a screening period, treatment period, and a follow-up period. The treatment period 
for all subjects will extend from the first dose of study drug combination on Day 1 Cycle 1 
until the completion of four cycles of therapy or up to 8 cycles if a response is observed, PD, 
unacceptable AE, decision by the subject or by the investigator to discontinue treatment, or 
death.  
On days when more than one study drug is administered, MLN9708 before bendamustine. 
When possible, dexamethasone should be given prior to MLN9708, as this may lessen the 
experience of nausea. Subjects will be assigned to a single treatment arm which will consist 
of: 
 Ixazomib initially administered as 4 mg oral on days 1 ,8 and 15 of each 28 day 
cycle. 
 Bendamustine administered after Ixazomib on Days 1 and 2 of each cycle at 70mg/ 
m2, 80 mg/m2 or 90 mg/m2 IV during the Phase I portion of the study, and at the 
MTD or a maximum dose of 90 mg/m2 IV during the Phase II portion of the study. 
 Dexamethasone administered as 40 mg oral or IV on Days 1, 8, 15 of each 28 day 
cycle. At physician discretion, patients may be reduced to a minimum of 20 mg. 
A 3+3 design will be employed. At each dose three patients will be initially evaluated. If no 
dose limiting toxicities are observed, the bendamustine dose will be increased; if one dose 
limiting toxicity is observed, three additional patients will be treated at that dose and 


35 
 
escalation will occur only if no additional DLTs are observed. A dose at which 2 DLTs are 
observed in three or six patients will be judged to be too toxic and the lower dose will be 
defined as the maximally tolerated dose (MTD). 
Should the first dose combination be found to be too toxic, IXAZOMIB (MLN9708) would 
be deescalated to 3 mg oral, days 1, 8 and 15 (with bendamustine at 70 mg/m2). If this were 
safe, the bendamustine dose will then be escalated to 80 mg/m2 and then 90 mg/m2 days 1 
and 2 if found safe. No intra-patient dose escalation is permitted. 
DLT observation period will be one cycle from the first dose of MLN9708 and 
bendamustine on Cycle 1 Day 1 to 28 days after the first dose or the start of Cycle 2. Dose 
escalation to higher dose level will require the last patient on the previous dose level to be 
out of DLT observation period. 
Once acceptable doses for the combination are identified, the plan is to treat additional 
patients at the maximally tolerated doses to assess response to treatment. 
Phase 2 study: 
A Simon 2-stage design will be used for the Phase 2 portion of the study. The study will 
enroll 14 patients (including those treated at the MTD in Phase I) and continue enrollment 
only if the observed response rate is at least 28.6% (4/14); If enrollment continues, the study 
will treat an additional 5 patients (19 in total) and consider the combination “interesting” 
only if at least 6/19 patients (31.6%) achieve a response. 
The study will terminate for futility if there is no objective partial response once 11 patients 
have been treated at recommended Phase 2 dose (3 up to 6 in Phase I and 5 up to 8 in Phase 
II). 
DSMC will have authority to stop study for any unexpected adverse events during the entire 
course of the study. During the phase 2 portion of the study, in the event of development of 
Garde 3-5 non-hematological toxicity in 6 or more (out of 19) patients, the study will be 
suspended. The DSMC will be asked to review the Grade 3-5 events and their attribution to 
trial intervention and make a final determination of safety. This would suspend the study 
16% of the time when the true rate of Grade 3-5 non-hematological toxicity was 20% but 
92% of the time if the true rate was 45%. 
Summary of the schedule is as follows: 


36 
 
 
 
 
5.2  Dose Escalation Rules 
Dose escalation will proceed as follows: 
• If 0 of 3 subjects at a dose level experiences a DLT, dose escalation will proceed, and 3 
subjects will be treated at the next dose level. 
• If 1 of 3 subjects experiences a DLT, up to 3 more subjects will be enrolled at the same 
dose level. 
• If 1 of 6 subjects experiences a DLT, dose escalation will proceed and 3 subjects will be 
treated at the next dose level. 
• If 2 or more subjects experience a DLT, the prior dose level will be considered the MTD, 
and the Phase 2 portion of the study will begin at that dose level. However, if 2 or more 
subjects experience a DLT at the 70 mg/m² dose of bendamustine, then MLN9708 would be 
deescalated to 3 mg, days 1, 8 and 15 (with bendamustine at 70 mg/m2). If this is safe, the 
bendamustine dose will then be escalated to 80 mg/m2 and then 90 mg/m2 days 1 and 2 if 
found safe. 
• If the MTD is not achieved, the Phase 2 portion of the study will proceed at 90 mg/m² dose 
level and 4 mg dose of Ixazomib level which will be considered the recommended Phase 2 
dose(RP2D). 
• There will be no intrapatient dose escalation 
Cycle 
(28 days) 
Cycle 1 of Study 
Cycles 2,3 and 4 of study 
Dexamethasone 
D1,8,15 
D1,8,15 
Bendamustine 
D1, D2 
D1,D2 
IXAZOMIB (MLN9708) 
D 1, 8, 15 
D 1, 8, 15 


37 
 
The study team will provide the results from each dosing cohort to the DSMC for review. 
The study will not enroll any additional patients until the last patient on the previous dose 
level is out of the DLT observation period and the DSMC has reviewed the cohort’s results. 
5.3 Number of Patients 
  A maximum sample size of 28 patients will be enrolled. 
 
After Phase 1 is completed and a recommended Phase 2 dose established, if there are no 
objective responses in the first 14 pts treated at recommended Phase 2 dose (including those 
treated at these doses in Phase 1) the study will be terminated for futility. 
 
DSMC will have authority to stop study for any unexpected adverse events during the entire 
course of the study. 
 
 
5.4    Duration of Study 
The treatment will be given for 4 cycles (28 d cycles) and up to 4 more cycles if there is 
clinical benefit (stable disease or better). The study follow up will continue until after the 
last patient has progressed with myeloma. All patients will be followed for survival.  
6.    
STUDY POPULATION 
6.1    Inclusion Criteria 
Each patient must meet all of the following inclusion criteria to be enrolled in the study: 
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 1 year before the screening visit, OR 
 Are surgically sterile, OR 
 If they are of childbearing potential, agree to practice 2 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 


38 
 
 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, post-ovulation methods] and withdrawal are not acceptable 
methods of contraception.) 
4. Patients must have histologically or cytologically confirmed symptomatic Multiple 
Myeloma. They must be non-responsive to or ineligible for autologous stem cell 
transplant, and must progress after prior exposure to both proteasome inhibitor 
(bortezomib, carfilzomib) and IMID (lenalidomide or pomalidomide or thalidomide); 
and refractory/progressing to at least one of the 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 IgG or IgM 
M-protein or > 0.5 g/dL IgA or 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. 
5. Eastern Cooperative Oncology Group (ECOG) performance status and/or other 
performance status 0, 1, or 2.  
6. 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. (No GVHD or treatment for GVHD). 


39 
 
7. 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 
8. Patients must meet the following clinical laboratory criteria: 
 Absolute neutrophil count (ANC)  1,000/mm3 and platelet count  75,000/mm3. 
Platelet transfusions or 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  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  ULN. 
 Calculated creatinine clearance  30 mL/min. 
6.2    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. Myeloma-related central nervous system involvement. 
6. Serious infection within 14 days of study treatment start and has not clinically 
resolved. 


40 
 
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 CYP1A2 (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of 
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. 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 surbvival is less 
than 2 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 1 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 two weeks 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. 


41 
 
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. 
 
7.    
STUDY DRUG 
7.1 Description of Investigational Agents 
Ixazomib Capsules 
The IXAZOMIB drug product is provided in strengths of 4.0-, 3.0-, and 2.3-mg and 2.0-, 
0.5-, and 0.2 mg capsules as the active boronic acid. The different dose strengths are 
differentiated by both capsule size and color as described below: 
Dose Strength 
Capsule Size 
Capsule Color 
4.0 mg 
Size 4 
Ivory 
3.0 mg 
Size 3 
Light gray 
 2.3 mg 
Size 2 
Light pink 
2.0 mg 
Size 2 
Swedish orange 
0.5 mg 
Size 3 
Dark green 
0.2 mg 
Size 4 
White opaque 
 
 
7.2    Study Drug Administration 
7.2.1 Ixazomib Administration 
All protocol-specific criteria for administration of study drug must be met and documented 
before drug administration. Study drug will be administered or dispensed only to eligible 
patients under the supervision of the investigator or identified subinvestigator(s). Patients 
should be monitored for toxicity, as necessary, and doses of IXAZOMIB should be 
modified as needed to accommodate patient tolerance to treatment; this may include 
symptomatic treatment, dose interruptions, and adjustments of IXAZOMIB dose (see 
Section 6.3). 
Capsules of IXAZOMIB will also be referred to as study drug. Study drug will be supplied 
by Millennium as capsules of 0.2-, 0.5-, and 2.0 mg, or as capsules of 2.3-, 3.0- and 4.0 mg 
IXAZOMIB.  
The prescribed administration of IXAZOMIB doses in this study is 4mg IXAZOMIB in a 
day 1,8 and 15 cycle.  


42 
 
Patients should be instructed to swallow IXAZOMIB capsules whole, with water, and not to 
break, chew, or open the capsules. Study drug should be taken on an empty stomach. . . Each 
capsule should be swallowed separately with a sip of water. A total of approximately 8 
ounces (240 mL) of water should be taken with the capsules.  
Missed doses can be taken as soon as the patient remembers if the next scheduled dose is 
72 hours or more away. A double dose should not be taken to make up for a missed dose. If 
the patient vomits after taking a dose, the patient should not repeat the dose but should 
resume dosing at the time of the next scheduled dose. 
Ixazomib Destruction 
Investigational IXAZOMIB (expired or end of study) should be destroyed on site according 
to the institution’s standard operating procedure. Be sure to document removal and 
destruction on drug accountability logs. 
7.2.2Bendamustine: 
Source and Pharmacology: 
Bendamustine (Treanda) is a bifunctional mechlorethamine derivative containing a purine-
like benzimidazole ring. The chemical name of bendamustine hydrochloride is 1H-
benzimidazole-2-butanoic acid, 5-[bis(2-chloroethyl)amino]-1 methyl-, monohydrochloride. 
Mechlorethamine and its derivatives form electrophilic alkyl groups. These groups form 
covalent bonds with electron-rich nucleophilic moieties, resulting in interstrand DNA 
crosslinks. The bifunctional covalent linkage can lead to cell death via several pathways. 
Bendamustine is cytotoxic in both quiescent and dividing cells.  
Bendamustine hydrochloride for injection (Treamda) was the initial formulation used in the 
study and was available in individual cartons containing amber 8-mL or 20-mL single-use 
vials. T 
In December 2015, the FDA approved a new formulation of Bendamustine (Bendeka 
Injection). Bendeka is a low-volume and short-time infusion (10 minutes) formulation of 
bendamustine. It was approved by the Food and Drug Administration based on 
pharmacokinetic equivalence to the previous available formulation (Treanda). In a 
pharmacokinetic study, a single IV dose of Bendeka (bendamustine hydrochloride) Injection 


43 
 
(120 mg/m2; administered as a 10 minute infusion), resulted in a higher maximum plasma 
concentration (Cmax) and equivalent systemic exposure (AUC), compared to a single dose 
of Treanda (120 mg/m2) infused over 60 minutes.  
Since Bendamustine for this study was obtained commercially, the Treanda formulation was 
used initially.  However, with the availability of the new formulation and commercial 
phasing out of Treanda, the study will switch over to using the newer Bendeka formulation.  
This formulation is supplied as a 100mg/4mL strength solution multi-dose vials and will 
obtained commercially. Bendamustine and will not be supplied by the study supporter.  
The amount of drug to be administered will be based on BSA calculated using the Mosteller 
formula. The same BSA will be used for each dose calculation unless the subjects 
experiences a >10% change in body weight from the weight used for the most recent BSA 
calculation. 
Storage and Stability 
BENDEKA (bendamustine hydrochloride) Injection should be stored in refrigerator, 2° to 
8°C (36° to 46°F).  Bendamustine should be stored in the original containers until the time 
of use in order to protect the drug from light. Bendamustine contains no antimicrobial 
preservative. The admixture should be prepared as close as possible to the time of patient 
administration. Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% 
Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours 
when stored refrigerated (2-8°C or 36-47°F) or for 3 hours when stored at room temperature 
(15-30°C or 59-86°F) in room light. Drug administration should be completed within the 
established periods of stability for the admixed solution. 
Solution Preparation and Dispensing 
Bendamustine hydrochloride for injection is intended for intravenous infusion only after 
reconstitution. Please follow the reconstitution instructions in the package insert of 
bendamustine (Bendeka).  The volume needed for the required dose should be aseptically 
withdrawn from the 25 mg/mL solution and immediately transferred to a 50 mL infusion 
bag of the diluent.  The resulting final concentration of bendamustine hydrochloride in the 
infusion bag should be within 1.85 mg/mL – 5.6 mg/mL.  After transferring, thoroughly mix 


44 
 
the contents of the infusion bag. The admixture should be a clear, and colorless to yellow 
solution 
 
Adverse Effects:  Please refer to package insert 
Hematologic: neutropenia (Grade 3 or 4 neutropenia in up to 25% of treated patients), 
thrombocytopenia infrequently requiring transfusions, and anemia. 
Infections: increased risk of infections (e.g., pneumonia) and sepsis have been reported 
following treatment with bendamustine. 
Infusion reactions and anaphylaxis: have been reported commonly in clinical trials with 
symptoms including fever, chills, pruritis, and rash. Rare reports of anaphylactic or 
anaphylactoid reactions have occurred. 
Tumor lysis syndrome: reported in several patients treated with bendamustine, primarily 
during the first cycle of therapy. 
Skin reactions: reported reactions include rash, toxic skin reactions, and bullous exanthema 
Elevated LFT’s: reported increase in total bilirubin and transaminases in up to 30% of 
patients in some clinical trials. 
Gastrointestinal: frequent reporting of nausea, vomiting, and stomatitis. 
Frequent adverse events: asthenia, fatigue, malaise, and weakness; dry mouth; 
somnolence; cough; constipation; headache; mucosal inflammation and stomatitis; nausea, 
vomiting, and diarrhea. Hematologic toxicity is very frequent including Grade 3 and 4 
neutropenia and thrombocytopenia. Mild elevation of liver function tests (total bilirubin and 
transaminases). 
Less common adverse events: hypersensitivity reactions, skin eruptions, fevers, chills, 
hypertension, pyrexia, and neutropenic infection. 
Nursing/patient implications 
Patients require close monitoring during the first infusion for evidence of hypersensitivity 
reaction, which is an uncommon but serious side effect with bendamustine. 


45 
 
Hematologic toxicity is the primary dose-limiting toxicity, and hematologic nadirs should be 
expected in the third week of therapy. 
Infection, including pneumonia and sepsis, have been reported following treatment with 
bendamustine, usually in combination with myelosuppression. 
Patients with myelosuppression need education regarding monitoring for signs of fever or 
infection. 
Prophylaxis for tumor lysis syndrome should be considered in patients with high tumor 
burden, or elevated uric acid and/or LDH. 
Patients should be educated on supportive measures for management of nausea, vomiting, 
diarrhea, constipation, and stomatitis. 
7.2.3  Dexamethasone: 
Source and Pharmacology: Dexamethasone is a synthetic fluorinated glucocorticoid 
devoid of mineralocorticoid effects. Dexamethasone, 0.75 mg, has potent anti-inflammatory 
activity equivalent to approximately 5 mg of prednisone. Glucocorticoids produce 
widespread and diverse physiologic effects on carbohydrate, protein, and lipid metabolism, 
electrolyte and water balance, functions of the cardiovascular system, kidney, skeletal 
muscle, and the nervous systems. Glucocorticoids reduce the concentration of thymus-
dependent lymphocytes (T-lymphocytes), monocytes, and eosinophils. Glucocorticoids 
selectively bind to the cortisol receptors on human lymphoid cells which are found in larger 
numbers on leukemic lymphoblasts. They also decrease binding of immunoglobulin to cell 
surface receptors and inhibit the synthesis and/or release of interleukins, thereby decreasing 
T-lymphocyte blastogenesis and reducing expansion of the primary immune response. The 
specific cellular mechanisms that act to halt DNA synthesis are thought to be related to 
inhibition of glucose transport or phosphorylation, retardation of mitosis, and inhibition of 
protein synthesis. Elimination half-lives for the following age groups have been reported to 
be: infants and children under 2 years of age: 2.3 to 9.5 hours, 8 to 16 years: 2.82 to 7.5 
hours, and adults (age not specified): 3 to 6 hours. The biologic half-life is 36- 72 hours. It is 
primarily metabolized in the liver and excreted by the kidneys. 
Formulation and Stability:  
Available in 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 4 mg, and 6 mg tablets; liquid 
formulations are available in 0.5 mg/5 mL and 0.5 mg/0.5 mL concentration. Inactive 


46 
 
ingredients vary depending on manufacturer but tablet formulations may include: calcium or 
magnesium stearate, corn starch, lactose, and various dyes. Liquid formulations may 
include: 5%-30% alcohol, benzoic acid, sorbitol, sodium saccharin, glycerin, purified water, 
and various dyes. Dexamethasone Sodium Phosphate Solution for Injection is available as 4 
mg/mL, 10 mg/mL, 20 mg/mL and 24 mg/mL. Four milligrams of dexamethasone sodium 
phosphate is equivalent to 3.33 mg of dexamethasone. Vial sizes include 1 mL, 5 mL, 10 
mL, 25 mL, and 30 mL and are available in multi-dose vials as well as unit of use vials and 
syringes. Inactive ingredients vary depending on manufacturer but include creatinine, 
sodium and propyl paraben, benzyl alcohol, and EDTA. 
Guidelines for Administration:  
See Treatment and Dose Modifications section of the protocol. 
Commercially available from various manufacturers. See package insert for further 
information 
Adverse effects: 
Cardiovascular: Arrhythmia, bradycardia, cardiac arrest, cardiomyopathy, CHF, circulatory 
collapse, edema, hypertension, myocardial rupture (post-MI), syncope, thromboembolism, 
vasculitis 
Central nervous system: Depression, emotional instability, euphoria, headache, intracranial 
pressure increased, insomnia, malaise, mood swings, neuritis, personality changes, 
pseudotumor cerebri (usually following discontinuation), psychic disorders, seizure, vertigo 
Dermatologic: Acne, allergic dermatitis, alopecia, angioedema, bruising, dry skin, erythema, 
fragile skin, hirsutism, hyper-/hypopigmentation, hypertrichosis, perianal pruritus (following 
I.V. injection), petechiae, rash, skin atrophy, skin test reaction impaired, striae, urticaria, 
wound healing impaired 
Endocrine & metabolic: Adrenal suppression, carbohydrate tolerance decreased, Cushing's 
syndrome, diabetes mellitus, glucose intolerance decreased, growth suppression (children), 
hyperglycemia, hypokalemic alkalosis, menstrual irregularities, negative nitrogen balance, 
pituitary-adrenal axis suppression, protein catabolism, sodium retention 


47 
 
Gastrointestinal: Abdominal distention, appetite increased, gastrointestinal hemorrhage, 
gastrointestinal perforation, nausea, pancreatitis, peptic ulcer, ulcerative esophagitis, weight 
gain 
Genitourinary: Altered (increased or decreased) spermatogenesis 
Hepatic: Hepatomegaly, transaminases increased 
Local: Postinjection flare (intra-articular use), thrombophlebitis 
Neuromuscular & skeletal: Arthropathy, aseptic necrosis (femoral and humoral heads), 
fractures, muscle mass loss, myopathy (particularly in conjunction with neuromuscular 
disease or neuromuscular-blocking agents), neuropathy, osteoporosis, parasthesia, tendon 
rupture, vertebral compression fractures, weakness 
Ocular: Cataracts, exophthalmos, glaucoma, intraocular pressure increased 
Renal: Glucosuria 
Respiratory: Pulmonary edema 
Miscellaneous: Abnormal fat deposition, anaphylactoid reaction, anaphylaxis, avascular 
necrosis, diaphoresis, hiccups, hypersensitivity, impaired wound healing, infections, 
Kaposi's sarcoma, moon face, secondary malignancy 
7.2.4 Definition of MTD: 
The MTD is defined as the highest dose of bendamustine, up to a maximum of 90 mg/m², in 
combination with IXAZOMIB and dexamethasone that causes DLT during Cycle 1 in 0 of 
3 or 0 to 1 of 6 subjects. 
7.2.5  Definition of Dose-limiting toxicity: 
Toxicity will be evaluated according to the National Cancer Institute’s Common 
Terminology Criteria for Adverse Events, version 4.0(CTCAEv4). DLT observation period 
will be one cycle, from the first dose of MLN9708 and bendamustine on cycle 1 day 1 to 28 
days after the first dose or the start of cycle 2. Dose escalation to higher dose level will 
require the last patient on the previous dose level to be out of DLT observation period.  
Dose limiting toxicity will be defined as any of the following events that are considered, by 
the investigator, to be related to therapy with bendamustine and IXAZOMIB: 


48 
 
• Grade 4 neutropenia (ANC <500 cells/mm3) lasting more than 7 consecutive days 
• Grade 3 neutropenia with fever and/or infection, where fever is defined as an oral 
temperature ≥38.5°C 
• Platelet count <10,000/mm3 or Grade 4 thrombocytopenia (platelet count <25,000/mm3) 
lasting more than 7 days or Grade 3 thrombocytopenia with clinically significant bleeding 
• Grade 3 or greater nausea and/or emesis despite the use of optimal anti-emetic prophylaxis. 
Optimal anti-emetic prophylaxis is defined as an anti-emetic regimen that employs a 5-HT3 
antagonist given in standard doses and according to standard schedules. 
• Grade 3 or greater diarrhea that occurs despite maximal supportive therapy with 
loperamide or comparable antidiarrheal agents 
• Any other Grade 3 or greater nonhematologic toxicity 
• Treatment delay of more than 1 week because of a lack of adequate hematologic or 
nonhematologic recovery of drug-related toxicities experienced in the previous cycle of 
treatment. 
• Other treatment-related nonhematologic toxicities Grade 2 or greater that, in the opinion of 
the investigator, require a dose reduction or discontinuation of therapy in Cycle 1. 
7.3    Dose-Modification Guidelines   
If the first dose of study drug in a cycle is missed due to study-drug-related toxicity or 
another reason, the start of the cycle is delayed and the next dose will be considered Day 1 
of that cycle. All efforts should be made to deliver all study drugs on the specified schedule. 
If one or more of the drugs must be delayed during a cycle for study-drug-related toxicity or 
another reason, they must be delivered within 3 days of the scheduled dose; otherwise the 
dose must be skipped. Subsequent doses during the cycle should remain on schedule based 
on Day 1 of the cycle. For example, if the Cycle 2, Day 8 dose of IXAZOMIB cannot be 
administered on the scheduled day, it must be delivered no later than Day 11, or it must be 
skipped. If the Cycle 2, Day 8 dose is delayed to Day 11, the subsequent dose of 
IXAZOMIB should be delivered on Cycle 2, Day 15, as previously scheduled. If a dose is 
not given, all assessments should be completed and the dose noted as missed. 
 


49 
 
Bendamustine and Ixazomib: 
On the first day of each new treatment cycle and before each IXAZOMIB, or bendamustine 
dose, the subject will be evaluated for possible toxicities that may have occurred after the 
previous doses(s). Toxicities are to be assessed according to the CTCAEv4. 
Any toxicity that requires a treatment delay of more than 2 weeks from the scheduled startof 
a given cycle will result in the discontinuation of IXAZOMIB, bendamustine and 
dexamethasone. See Table 7-1  


50 
 
Dosage adjustments for hematologic toxicity are outlined in Table 7-1a and 7-1b. 
Table 7-1a  
Ixazomib and Bendamustine Dose Adjustments for Hematologic 
Toxicities 
Criteria 
Action 
Within-Cycle Dose Modifications 
 
 
If platelet count  30  109/L or ANC ≤ 0.50  
109/L on a IXAZOMIB dosing day (other than 
Day 1)  
 
Study treatment should be withheld.  
 
Complete blood count (CBC) with differential 
should be repeated until the ANC and/or platelet 
counts have exceeded the prespecified values on 
at least 2 occasions.  
 
Upon recovery, bendamustine may be reinitiated 
with 1 dose level reduction and upon recurrence 
of same toxicity lower IXAZOMIB dose to 1 
dose level. 
Dose Modifications for Subsequent Treatment Cycles 
 
 
Delay up to 2 weeks in the start of a 
subsequent cycle due to lack of related toxicity 
recovery  
 
ANC < 1.0  109/L, platelet count < 75  
109/L, related to the investigational agent(s) or 
other related nonhematologic toxicities > 
Grade 1 or not to the patient’s baseline 
condition 
 
Hold both drugs until resolution  
 
Upon recovery, reduce bendamustine first and 
then IXAZOMIB to 1 dose level. 
 
The maximum delay before treatment should be 
discontinued will be > 2 weeks or at the 
discretion of the PI. 
Dose Modifications for Subsequent Treatment Cycles 
 
 
All hematologic toxicities 
 
For hematologic toxicity that occurs during a 
cycle but recover in time for the start of the 
next cycle: 
o 
 If dose was reduced for 
bendamustine or IXAZOMIB 
within the cycle, start the next 
cycle at that lowered dose. 
o 
If due to toxicity timing, ie, after 
Day 15 dosing thus a dose 
reduction was not required at that 
point in the cycle, reduce 
IXAZOMIB only by 1 dose level 
at the start of that cycle. 
o 
Do not reduce the dose both within 
a cycle and at the start of the cycle 
next cycle for the same toxicity. 
 
 
 
 
 


51 
 
 
Treatment modifications due to IXAZOMIB and bendamustine-related AEs are 
outlined in Table 7-2. 
Table 7-2    
Ixazomib and Bendamustine Treatment Modification (Delays, 
Reductions, and Discontinuations) Due to Adverse Events (Non-
Hematologic Toxicities) 
Adverse Event (Severity) 
Action on Study Drug 
Further Considerations 
Peripheral Neuropathy: 
Grade 1 peripheral neuropathy 
 
 No action 
 
Grade 1 signs and symptoms:  
asymptomatic; without pain or loss 
of function; clinical or diagnostic 
observations only (29) 
 
 
New or worsening Grade 1 
peripheral neuropathy with pain or 
Grade 2 
 Hold IXAZOMIB alone until 
resolution to Grade ≤ 1 without 
pain or baseline 
Grade 2 signs and symptoms:  
Moderate symptoms; limiting 
instrumental activities of daily 
living (ADL) (29) 
 
 
New or worsening Grade 2 
peripheral neuropathy with pain or 
Grade 3 
 Hold IXAZOMIB alone until 
resolution to Grade ≤ 1 without 
pain or baseline 
 Reduce IXAZOMIB to next 
lower dose upon recovery 
 
Grade 3 signs and symptoms:  
severe symptoms; limiting self-
care ADL; assistive device 
indicated (29) 
New or worsening Grade 4 
peripheral neuropathy 
 Discontinue IXAZOMIB 
 
 
 
Grade 2 Rash 
 
Symptomatic 
recommendations as per 
section 7.7 
 
 Stevens Johnson Syndrome is a 
contraindication to further 
Ixazomib use.  
Table 7-
1b  
Criteria for Related Hematological and Nonhematological Recovery  
To Start a New Cycle (Day 1)  
To Redose Within a Cycle (Days 8 and 15)  
ANC  
ANC must be ≥ 1,000/mm3  
ANC must be ≥ 500/mm3  
Platelet  
Platelet count must be ≥ 
75,000/mm3  
Platelet count must be ≥ 30,000/mm3  
Nonhematological  
All other nonhematologic 
toxicities  
Neuropathy must be ≤ Grade 1 (with no 
pain)  
 
(except for alopecia) must have  
Other nonhematologic toxicities should be  
 
resolved to ≤ Grade 1 or to the 
patient’s baseline condition  
< Grade 3.  
Abbreviation: ANC = absolute neutrophil count.  
 


52 
 
Table 7-2    
Ixazomib and Bendamustine Treatment Modification (Delays, 
Reductions, and Discontinuations) Due to Adverse Events (Non-
Hematologic Toxicities) 
Adverse Event (Severity) 
Action on Study Drug 
Further Considerations 
Grade 3 Rash 
 
Hold IXAZOMIB until 
resolution to < Grade 2 
along with symptom 
management (first 
occurrence) 
 
For second or subsequent 
occurrence of rash dose 
reduce Ixazomib by one 
dose level when 
restarting. 
Non resolving Grade 3 rash or any 
Grade 4 rash will need skin biopsy 
and stoppage of Ixazomib use. 
Nausea, emesis, or 
diarrhea with maximal 
prophylaxis ≥Grade 3 
 
Hold bendamustine and 
IXAZOMIB for up to 2 
weeks or until the 
toxicity returns to ≤Grade 
2, and restart at the next 
lower dose of 
benadmustine. If 
treatment is delayed by 
more than 2 weeks, 
bendamustine and 
IXAZOMIB must be 
discontinued. Additional 
dexamethasone is not 
permitted as an 
antiemetic. 
 
 
Grade ≥3 nonhematologic toxicity 
. 
 
 Determine attribution of 
toxicity. Hold appropriatey 
attributed agent until resolution 
to Grade < 1 or baseline 
 
Symptomatic recommendations 
noted in Section 6.7 
If not recovered to < Grade 1 or 
baseline within 4 weeks 
 
 Reduce attributed therapy to 
next lower dose upon return to 
< Grade 1 or baseline 
 
 
Subsequent recurrence Grade 3 
that does not recover to < Grade 1 
or baseline within 4 weeks 
 Hold attributed therapy until 
resolution to Grade < 1 or 
baseline 
 Reduce attribiuted therapy to 
next lower dose level 
Monitor closely, take appropriate 
medical precautions, and provide 
appropriate symptomatic care 
 
Grade 4 nonhematologic toxicities 
judged to be related either 
bendamutine or IXAZOMIB or 
both 
 
 Consider permanently 
discontinuing the drug 
attributed to cause toxicity 
 
Exceptions are cases in which the 
investigator determines the patient 
is obtaining a significant clinical 
benefit and toxicity has declined to 


53 
 
Table 7-2    
Ixazomib and Bendamustine Treatment Modification (Delays, 
Reductions, and Discontinuations) Due to Adverse Events (Non-
Hematologic Toxicities) 
Adverse Event (Severity) 
Action on Study Drug 
Further Considerations 
Grade 2 
 
7.4    Excluded Concomitant Medications and Procedures 
The following medications and procedures are prohibited during the study. 
Systemic treatment with any of the following metabolizing enzyme inhibitors is not 
permitted in this study. (A drug-drug interaction [DDI] with a strong inhibitor would 
increase the IXAZOMIB and bendamustine exposure and could lead to a higher probability 
of an AE.): 
 Strong inhibitors of CYP1A2:  fluvoxamine, enoxacin, ciprofloxacin 
 Strong inhibitors of CYP3A:  clarithromycin, telithromycin, itraconazole, 
voriconazole, ketoconazole, nefazodone, and posaconazole 
Systemic treatment with any of the following metabolizing enzyme inducers should be 
avoided, unless there is no appropriate alternative medication for the patient’s use 
(Rationale:  Unlike with inhibitors, if there were to be a DDI with an inducer, IXAZOMIB 
exposure would be less; therefore, there would be a reduced chance of an AE. However, 
there may be less chance for an antitumor effect, but that is not an absolute reason to be 
taken off IXAZOMIB): 
 Strong CYP3A inducers:  rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, 
and phenobarbital 
 Excluded foods and dietary supplements include St. John’s wort and Ginkgo biloba 
The following procedures are prohibited during the study. 
 Any antineoplastic treatment, including the antihormonal drugs other than study 
drugs 
 Radiation therapy (note that, in general, the requirement for local radiation therapy 
indicates disease progression). Patients may be enrolled into a study 2 weeks after 


54 
 
finishing the radiation if they meet eligibility criteria. Study therapy can be 
interrupted for up to 3 weeks to allow for radiation to symptomatic plasmacytomas/ 
lytic lesion. 
 Platelet transfusions to help patients meet eligibility criteria are not allowed within 
3 days prior to study drug dosing for any dosing day 
7.5    Permitted Concomitant Medications and Procedures  
The following medications and procedures are permitted during the study: 
 Antiemetics, including 5-HT3 serotonin receptor antagonists, may be used at the 
discretion of the investigator. 
 Loperamide or other antidiarrheal should be used for symptomatic diarrhea at 
discretion of the investigator. The dose and regimen will be according to institutional 
guidelines. IVF should be given to prevent volume depletion. Note additional 
dexamethsaone is not permitted in the treatment of these symptoms. 
 Growth factors (eg, granulocyte colony stimulating factor [G-CSF], granulocyte 
macrophage-colony stimulating factor [GM-CSF], recombinant erythropoietin) are 
permitted. Their use should follow published guidelines and/or institutional practice. 
Erythropoietin will be allowed in this study. Their use should follow published 
guidelines and/or institutional practice. 
 Patients should be transfused with red cells and platelets as clinically indicated and 
according to institutional guidelines. 
 Antiviral therapy such as acyclovir may be administered if medically appropriate. 
 Concomitant treatment with bisphosphonates will be permitted, as appropriate. 
 Patients who experience worsening neuropathy from baseline may be observed for 
recovery, and have dose reductions/delays as indicated in the protocol, and any 
supportive therapy or intervention may be initiated as appropriate at the discretion of 
the investigator. 
 Supportive measures consistent with optimal patient care may be given throughout 
the study. 


55 
 
 Prophylaxis for tumor lysis syndrome for high risk is permitted. 
7.6    Precautions and Restrictions  
 Fluid deficit should be corrected before initiation of treatment and during treatment. 
Nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided with impaired renal 
function given reported NSAID-induced renal failure in patients with decreased renal 
function. 
Pregnancy 
It is not known what effects IXAZOMIB has on human pregnancy or development of the 
embryo or fetus. Bendamustine has been assigned to pregnancy category D by FDA. Animal 
studies have revealed skeletal and visceral malformations (exencephaly, cleft palates, 
accessory rib, and spinal deformities), decreased fetal body weights, a significant increase in 
external and internal malformations, as well as embryo and fetal lethality as indicated by 
increased resorptions and a decrease in live fetuses. There are no controlled data in human 
pregnancy. Therefore, female patients participating in this study should avoid becoming 
pregnant, and male patients should avoid impregnating a female partner. Nonsterilized 
female patients of reproductive age group and male patients should use effective methods of 
contraception through defined periods during and after study treatment as specified below. 
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 2 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: 


56 
 
 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, post-ovulation methods] and withdrawal are not acceptable 
methods of contraception.) 
7.7   Management of Clinical Events  
Adverse drug reactions such as thrombocytopenia, diarrhea, fatigue, nausea, vomiting, and 
rash have been associated with IXAZOMIB treatment. Infusion reactions and tumor lysis 
syndrome have been reported with bendamustine. Management guidelines regarding these 
events are outlined below. Further details of management of IXAZOMIB AEs are described 
in Table 7-2.  
Prophylaxis Against Risk of Reactivation of Herpes Infection 
Patients may be at an increased risk of infection including reactivation of herpes zoster and 
herpes simplex viruses. Antiviral therapy such as acyclovir, valacyclovir, or other antivirals 
may be initiated as clinically indicated. Other antivirals are also acceptable. 
 
Nausea and/or Vomiting 
Standard anti-emetics including 5-hydroxytryptamine 3 serotonin receptor antagonists are 
recommended for emesis if it occurs once treatment is initiated; prophylactic anti-emetics 
may also be considered at the physician’s discretion. Dexamethasone should not be 
administered as an anti-emetic. Fluid deficit should be corrected before initiation of study 
drug and during treatment. 
Diarrhea 
Prophylactic antidiarrheals will not be used in this protocol. However, diarrhea should be 
managed according to clinical practice, including the administration of antidiarrheals once 
infectious causes are excluded. Fluid intake should be maintained to avoid dehydration. 
Fluid deficit should be corrected before initiation of treatment and during treatment. 
Erythematous Rash With or Without Pruritus 
As with bortezomib, rash with or without pruritus has been reported with IXAZOMIB, 
primarily at the higher doses tested and when given with agents where rash is an overlapping 
toxicity. The rash may range from limited erythematous areas, macular and/or small papular 


57 
 
bumps that may or may not be pruritic over a few areas of the body, to a more generalized 
eruption that is predominately on the trunk or extremities. Rash has been most commonly 
characterized as maculopapular or macular. To date, when it does occur, rash is most 
commonly reported within the first 3 cycles of therapy. The rash is often transient, self-
limiting, and is typically Grade 1 to 2 in severity.  
Symptomatic measures such as antihistamines or corticosteroids (oral or topical) have been 
successfully used to manage rash and have been used prophylactically in subsequent cycles. 
The use of a topical, IV, or oral steroid (eg, prednisone ≤ 10 mg per day or equivalent) is 
permitted. Management of a Grade 3 rash may require intravenous antihistamines or 
corticosteroids. Administration of IXAZOMIB should be modified per protocol (see Table 
7.1).  
In line with clinical practice, dermatology consult and biopsy of Grade 3 or higher rash or 
any SAE involving rash is recommended. Prophylactic measures should also be considered 
if a patient has previously developed a rash (eg, using a thick, alcohol-free emollient cream 
on dry areas of the body or oral or topical antihistamines). A rare risk is Stevens-Johnson 
Syndrome, a severe and potentially life-threatening rash with skin peeling and mouth sores, 
which should be managed symptomatically according to standard medical practice. Punch 
biopsies for histopathological analysis are encouraged at the discretion of the investigator. 
Thrombocytopenia 
Blood counts should be monitored regularly as outlined in the protocol with additional 
testing obtained according to standard clinical practice. Thrombocytopenia may be severe 
but has been manageable with platelet transfusions according to standard clinical practice. 
Ixazomib and bendamustine administration should be modified as noted as per dose 
modification recommendations in the protocol when thrombocytopenia occurs (see Table 7-
1). Therapy can be reinitiated at a reduced level upon recovery of platelet counts. A rare risk 
is thrombotic thrombocytopenic purpura (TTP), a rare blood disorder where blood clots 
form in small blood vessels throughout the body characterized by thrombocytopenia, 
petechiae, fever, or possibly more serious signs and symptoms. TTP should be managed 
symptomatically according to standard medical practice. 
 
Neutropenia 
Blood counts should be monitored regularly as outlined in the protocol with additional 
testing obtained according to standard clinical practice. Neutropenia may be severe but has 


58 
 
been manageable. Growth factor support is not required but may be considered according to 
standard clinical practice. Ixazomib and bendamustine administration should be modified as 
noted as per dose modification recommendations in the protocol when neutropenia occurs 
(see Table 7-1). Therapy can be reinitiated at a reduced level upon recovery of ANCs. 
Fluid Deficit 
Dehydration should be avoided since IXAZOMIB may cause vomiting, diarrhea, and 
dehydration. Acute renal failure has been reported in patients treated with IXAZOMIB, 
commonly in the setting of the previously noted gastrointestinal toxicities and dehydration. 
Fluid deficit should be corrected before initiation of study drug and as needed during 
treatment to avoid dehydration. 
Hypotension 
Symptomatic hypotension and orthostatic hypotension with or without syncope have been 
reported with IXAZOMIB. Blood pressure should be closely monitored while the patient is 
on study treatment and fluid deficit should be corrected as needed, especially in the setting 
of concomitant symptoms such as nausea, vomiting, diarrhea, or anorexia. Patients taking 
medications and/or diuretics to manage their blood pressure (for either hypo- or 
hypertension) should be managed according to standard clinical practice, including 
considerations for dose adjustments of their concomitant medications during the course of 
the trial. Fluid deficit should be corrected before initiation of study drug and as needed 
during treatment to avoid dehydration. 
Posterior Reversible Encephalopathy Syndrome 
One case of posterior reversible encephalopathy syndrome, which ultimately resolved, has 
been reported with IXAZOMIB. This condition is characterized by headache, seizures and 
visual loss, as well as abrupt increase in blood pressure. Diagnosis may be confirmed by 
magnetic resonance imaging (MRI). If the syndrome is diagnosed or suspected, symptom-
directed treatment should be maintained until the condition is reversed by control of 
hypertension or other instigating factors. Further Ixazomib is contraindicated. 
Transverse Myelitis 
Transverse myelitis has also been reported with IXAZOMIB. It is not known if 
IXAZOMIB causes transverse myelitis; however, because it happened to a patient receiving 
IXAZOMIB, the possibility that IXAZOMIB may have contributed to transverse myelitis 
cannot be excluded. 


59 
 
Progressive Multifocal Leukoencephalopathy (PML) 
One fatal case of progressive multifocal leukoencephalopathy (PML) has been reported with 
MLN9708 in an oncology patient who had previously received a medication associated with 
PML.  PML is a rare, serious infection of the brain that is caused by a virus.  Persons with a 
weakened immune system may develop PML. PML can result in death or severe disability.  
It is not known whether MLN9708 may have contributed to the development PML in this 
patient. 
Infusion Reactions (Bendamustine) 
Infusion reactions to Bendamsutine have occurred commonly in clinical trials. Symptoms 
include fever, chills, pruritus and rash. In rare instances severe anaphylactic and 
anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of 
therapy. Monitor clinically and discontinue drug for severe reactions. Patients who 
experience Grade 3 or worse allergic-type reactions should not be rechallenged. Consider 
measures to prevent severe reactions, including antihistamines, antipyretics and 
corticosteroids in subsequent cycles in patients who have experienced Grade 1 or 2 infusion 
reactions. Discontinue bendamustine for patients with Grade 4 infusion reactions. Consider 
discontinuation for Grade 3 infusions reactions as clinically appropriate considering 
individual benefits, risks, and supportive care. 
Tumor Lysis Syndrome (Bendamustine) 
Tumor lysis syndrome associated with bendamustine treatment has occurred in patients in 
clinical trials and in postmarketing reports. The onset tends to be within the first treatment 
cycle of bendamustine and, without intervention, may lead to acute renal failure and death. 
Preventive measures include vigorous hydration and close monitoring of blood chemistry, 
particularly potassium and uric acid levels. Allopurinol should be used during the beginning 
of bendamustine therapy in those at high risk for tumor lysis. However, there may be an 
increased risk of severe skin toxicity when bendamustine and allopurinol are administered 
concomitantly. 
7.8 Preparation, Reconstitution, and Dispensing 
Ixazomib is an anticancer drug and as with other potentially toxic compounds caution should 
be exercised when handling IXAZOMIB capsules. 


60 
 
7.9 Packaging and Labeling 
The study drug IXAZOMIB capsules will be provided by Millennium. The study drug will 
be labeled and handled as open-label material, and packaging labels will fulfill all 
requirements specified by governing regulations.  
The capsules are individually packaged using cold-form foil-foil blisters that are in a child-
resistant carton. There are 3 capsules in each wallet/carton.  
7.10  
Storage, Handling, and Accountability 
Ixazomib: 
Upon receipt at the investigative site, IXAZOMIB should remain in the blister and carton 
provided until use or until drug is dispensed. The container should be stored at the 
investigative site refrigerated (36°F to 46°F, 2°C to 8°C). Ensure that the drug is used before 
the retest expiry date provided by Millennium. Expiry extensions will be communicated 
accordingly with updated documentation to support the extended shelf life. 
In countries where local regulations permit, IXAZOMIB capsules dispensed to the patient 
for take-home dosing should remain in the blister packaging and refrigerated as noted above 
until the point of use. The investigative site is responsible for providing the medication to 
the patient in the correct daily dose configurations. Comprehensive instructions should be 
provided to the patient in order to ensure compliance with dosing procedures. Patients who 
are receiving take-home medication should be given only 1 cycle of medication at a time. 
Patients should be instructed to store the medication refrigerated (36°F to 46°F, 2°C to 8°C) 
for the duration of each cycle. Patients should be instructed to return their empty blister 
packs to the investigative site, rather than discarding them. Reconciliation will occur 
accordingly when the patient returns for their next cycle of take-home medication. Any 
extreme in temperature should be reported as an excursion and should be dealt with on a 
case-by-case basis. 
Because IXAZOMIB is an investigational agent, it should be handled with due care. 
Patients should be instructed not to chew, break, or open capsules. In case of contact with 
broken capsules, raising dust should be avoided during the clean-up operation. The product 
may be harmful by inhalation, ingestion, or skin absorption. Gloves and protective clothing 
should be worn during cleanup and return of broken capsules and powder to minimize skin 
contact. 


61 
 
The area should be ventilated and the site washed with soap and water after material pick-up 
is complete. The material should be disposed of as hazardous medical waste in compliance 
with federal, state, and local regulations. 
In case of contact with the powder (eg, from a broken capsule), skin should be washed 
immediately with soap and copious amounts of water for at least 15 minutes. In case of 
contact with the eyes, copious amounts of water should be used to flush the eyes for at least 
15 minutes. Medical personnel should be notified. Patients are to be instructed on proper 
storage, accountability, and administration of IXAZOMIB, including that IXAZOMIB is to 
be taken as intact capsules. 
Bendamustine: 
Bendamustine vials should be stored at room temperature (20−25°C [68−77°F]) and 
protected from light. Bendamustine is stable for 30 months when stored at normal room 
temperature conditions, 15°C to 30°C (59−86°F). Bendamustine is a cytotoxic anticancer 
agent and should be handled according to the recommended procedures described in the 
current edition of the American Society of Health-System Pharmacists Technical Assistance 
Bulletin on Handling Cytotoxic and Hazardous Drugs. Procedures described in each 
institution’s pharmacy or hospital standard operating procedure manual should be followed 
when handling cytotoxic drugs. 
Dexathemasone:  
Dexamethasone should be stored according to commercial labeling guidelines. 
7.11      Study Compliance 
Study drug will be administered or dispensed only to eligible patients under the supervision 
of the investigator or identified sub-investigator(s). The appropriate study personnel will 
maintain records of study drug receipt and dispensing. 
 
7.12   
Termination of Treatment and/or Study Participation 
Patients will be informed that they have the right to withdraw from the study at any time for 
any reason, without prejudice to their medical care. The patients will be allowed to complete 
4 cycles of treatment only (or 8 cycles if any evidence of clinical benefit, SD or better). The 


62 
 
investigator also has the right to withdraw patients from the study for any of the following 
reasons: 
 Adverse event 
 Protocol violation 
 Lost to follow-up 
 Progressive disease 
 Study terminated  
 Other 
  
At the time of withdrawal, all study procedures outlined for the End of Study visit should be 
completed. The primary reason for patient’s withdrawal from the study should be recorded 
in the source documents and CRF. 
8.  STUDY PROCEDURES: 
8.1  Study procedures: 
The Study Flow Chart in Schedule of events summarizes the study procedures to be 
performed at each required study visit. Individual study procedures are described in detail 
below. It may be necessary to perform these procedures at unscheduled time points if 
deemed clinically necessary by the investigators. 
8.1.1 Administrative procedures: 
8.1.1.1 Informed consent: 
The investigator must obtain documented informed consent from each potential subject prior 
to participating in clinical trial. 
8.1.1.2 Inclusion/Exclusion criteria: 
The inclusion and exclusion criteria will be during screening (up to 21 days before the first 
dose of study drug). Subjects must continue to meet all eligibility criteria on Day 1 of cycle 
1. 


63 
 
8.1.1.3 Demographics: 
Subject demographics will be documented during screening and at minimum, will include 
subject birth date,race and sex. 
8.1.1.4 Medical History: 
A medical history will be obtained by the investigator or qualified designee. Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator. Details regarding the disease 
(multiple myeloma), for which the subject has enrolled in this study will be recorded 
separately and not listed as medical history. 
8.1.1.5  Medication history: 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 30 days before the enrollment. Treatment for the disease (multiple myeloma) for 
which the subject has enrolled in this study will be recorded separately and not listed as a 
prior medication. The investigator or qualified designee will record medication, if any, taken 
by the subject during the trial. All medications related to reportable SAEs and ECIs should 
be recorded as defined in Section 10. 
8.1.1.6  Disease (Multiple Myeloma) details and treatments 
1. Disease Details 
The investigator or qualified designee will obtain prior and current details regarding 
multiple myeloma status. See Appendices for Multiple Myeloma response criteria.  
2.Prior Treatment Details 
The investigator or qualified designee will review all prior multiple myeloma treatments 
including systemic treatments, radiation and surgeries. 
8.1.1.7 Study compliance 
Subjects will be followed for compliance to allowed concomitant medications and other 
activity restriction according to section 


64 
 
8.1.2 Clinical Procedures/Assessments 
8.1.2.1 Adverse event monitoring(AE) monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs and more frequently if clinically indicated. 
Adverse events will be graded and recorded throughout the study and during the follow-up 
period according to NCI CTCAE Version 4.0. Toxicities will be characterized in terms 
regarding seriousness, causality, toxicity grading, and action taken with regard to trial 
treatment. 
8.1.2.2 Physical examination 
The investigator or qualified designee will perform a complete physical exam during the 
screening and other required study visits. Clinically significant abnormal findings should be 
recorded as medical history. 
8.1.2.3 Vital signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of MLN 9708 and bendamustine and at treatment 
discontinuation. Vital signs should include temperature, pulse, respiratory rate, weight and 
blood pressure. 
8.1.2.4 Eastern Co-operative Oncology group(ECOG) group performance scale 
The investigator or qualified designee will assess ECOG status (see Appendices) at 
screening, prior to the administration of each dose of MLN9708 and bendamustine, 
discontinuation of both drugs and post study visits as specified in the Schedule of events. 
8.1.2.5 Multiple myeloma assessment 
Multiple myeloma assessment includes peripheral blood and urine quantification of 
monoclonal protein including serum protein electrophoresis (SPEP), serum immunofixation 
(IFIX), serum free light chain levels, urine protein electrophoresis (UPEP) and 24-hour urine 
Bence-Jones protein quantification, and bone marrow examination. These will be performed 
as specified in the schedule of events. A skeletal bone survey may be completed as clinically 
indicated. 
 


65 
 
8.1.3 Other procedures: 
Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to study completion, all applicable activities 
scheduled for the final study visit should be performed at the time of discontinuation. Any 
adverse events which are present at the time of discontinuation/ withdrawal should be 
followed in accordance with the safety requirements outlined in Section 10.- Assessing and 
Recording Adverse Events. Subjects who complete four cycles of MLN9708 and 
bendamustine will be considered having completed the study treatment. 
After discontinuing treatment, these subjects, if possible, should return to the site for a 
Safety Follow-up Visit (8.1.4.5) and then proceed to the Follow-Up Period of the study 
(described in Section 8.1.4.6). Subject will be replaced if he/she drops out in the Phase I 
portion of study prior to completing the dosing for DLT. 
8.1.4 Study definitions 
8.1.4.1 Screening 
A subject will be considered to be in the “Screening” period from the time he/she signs 
consent until the date the subject is determined as either “eligible” or “ineligible” (screen 
failure) by PI or a Co-I. Patients may be consented to this study based on disease eligibility 
and other criteria at the time of consent, but later removed from the study prior to initiation 
of MLN9708 and bendamustine if the change of disease status makes the subject 
“ineligible”. In the event that this occurs, the subject will be replaced when the eligibility is 
again checked on day 1 cycle 1. 
8.1.4.2 Enrolled 
A subject will be considered to be “Enrolled” onto the study once they have signed consent 
AND have successfully met all screening criteria, as documented by the inclusion/exclusion 
document, AND the eligibility criteria has been reviewed and accepted by the PI or a co-I. 
The date of enrollment will be documented as the date that the PI or a co-I has reviewed and 
approved the subject’s eligibility. 


66 
 
8.1.4.3 Treatment Period 
The “Treatment Period” is defined as the first day through the last day of treatment with 
IXAZOMIB (MLN9708) and bendamsutine from first through the fourth cycle (or up to 4 
more cycles in responders).  
The assessment and reporting period for adverse events (AE) related to the IXAZOMIB 
(MLN9708) and bendamsutine will start from the first dose of each drug administration until 
30 days after the last dose administration. 
8.1.4.4 On Study 
The “On Study period” starts from the day that a subject signs the protocol consent 
document and subsequently meets the protocol eligibility criteria (“Enrolled”), receives 
IXAZOMIB (MLN 9708) and bendamsutine treatment (8 cycles) and ends 30 days after the 
last dose of both drugs or prior to this period if one of the following event occurs earlier: 
1. Death 
2. Lost to follow-up 
3. Withdrawal of consent  
4. Entry on to a competing trial 
5. Multiple myeloma progression/relapse and its treatment or development of new 
malignancy and its treatment 
6. Unacceptable or dose limiting toxicity or complication 
Thirty days after the last dose of both drugs, the patient will be considered “off treatment.” 
But they will be followed for the primary and secondary endpoints off treatment until 2 
years as mentioned in “Follow Up Period”. 
8.1.4.5 Post treatment safety follow up visits 
The “follow-up period” is defined as the first day a subject is no longer receiving 
IXAZOMIB (MLN9708) and bendamustine until three years after this date. 
The mandatory “end-of-treatment safety follow-up visit” will be performed approximately 
30 days after the last dose of IXAZOMIB (MLN9708) and bendamustine or before the 


67 
 
initiation of a new anti-MM treatment, whichever comes first. All AEs that occur prior to the 
safety follow-up visit should be recorded.  
Subjects with an AE of grade >1 will be followed until the resolution of the AE to grade 0-1 
or until the beginning of a new anti-MM therapy, whichever occurs first.  
SAEs that occur within 90 days of the end of treatment or before initiation of a new anti-
MM treatment should also be followed and recorded. 
8.1.4.6 Survival follow up 
After the “end-of-treatment safety evaluation visit,” subjects will be followed for two years.  
Subjects who have stopped therapy for reasons other than MM relapse/progression will be 
followed every eight weeks (+/- 2 weeks) for directed follow-up visits for one year or until 
MM relapse/progression.  Subjects will be further followed every 12 weeks (+/- 2 weeks) for 
the second year or until MM relapse/progression. Once a subject experiences confirmed MM 
relapse/progression or starts a new anti-MM therapy, the subject moves into the survival 
follow-up phase and should be contacted (by site visit or telephone) every 12 weeks to 
assess for survival status until death, withdrawal of consent, or the end of the study, 
whichever occurs first. 
In addition, new primary malignancies that occur during the follow-up period must be 
reported, regardless of causality to study regimen, for a minimum of three years after the last 
dose. At the end of year three, study staff will review patient medical records or will contact 
the patient via telephone to obtain this information regarding possible new primary 
malignancies. 
9.  STATISTICAL AND QUANTITATIVE ANALYSES 
9.1    Statistical Methods 
The section describes the statistical methods to be used to analyze the safety and efficacy as 
described above in the objectives. These methods may be revised and updated due to reasons 
such as regulatory requirements or need for further clarifications. The final analysis plan 
will be documented in a formal statistical analysis plan (SAP) that must be finalized before 
the database lock. The SAP will include how the variables will be derived, how missing data 
will be handled and how censoring procedures will be applied for time to event related 
variables as well as the details on the statistical methods to be used for safety and efficacy 
analysis. The final clinical study report will discuss deviations from the SAP, if any. 


68 
 
9.2 General considerations 
This Phase I/II study is designed to first identify doses of IXAZOMIB (MLN9708) and 
bendamustine when delivered together in 28 day cycles with an acceptable adverse event 
profile and then to assess the efficacy of the combination in patients with relapsed/refractory 
multiple myeloma. Responders (stable disease or more), will continue to recieve up to 8 
cycles total in the absence of further progressive disease. 
9.3 Determination of sample size 
This trial will enroll up to 28 patients in total. The actual number of dose cohorts explored 
will depend upon the safety profile. In the Phase II portion of the study about 19 patients 
will be treated to look for the response rate. 
Simon’s 2-stage design allows for early termination of enrollment when there is evidence 
that a drug or drug combination’s anti-tumor activity is too low. The trial is conducted in 
two stages with an option to stop the trial and not recommend the agent/combination for 
further development after the first stage. For specified null and alternative hypotheses, 
significanc3e (α) level and power (1-β) to detect the alternative hypothesis, a Simon 2-stage 
design minimizes the expected total sample size when the true response is the null 
hypothesis response rate. 
A Simon 2-stage design for a null response rate of 20%, an alternative response rate of 40%, 
a significance level less than 15% and power of at least 80%, a Simon 2-stage design is:    
Enroll 14 patients (including those treated at the MTD in Phase I) and continue 
enrollment only if the observed response rate is at least 28.6% (4/14); 
If enrollment continues, treat an additional 5 patients (19 in total, including those 
treated at the MTD in Phase 1) and consider the combination worthy of further 
development only if at least 6/19 patients (31.58%) achieve a response. 
If the true response rate is 20%, the combination would be declared worthy of further 
development only 14.7% of the time. If the true response rate is 40%, the combination 
would be declared worthy of further development 80.7% of the time. 
These rules mean that the study could be terminated for futility in Phase 2 after 14 patients 
have been treated at recommended Phase 2 dose (including 6 patients in Phase 1 and 8 in 
Phase 2), if no objective partial responses are observed.  


69 
 
DSMC will have authority to stop study for any unexpected adverse events during the entire 
course of the study. During the phase 2 portion of the study, in the event of development of 
Grade 3-5 non-hematological toxicity in 6 or more (out of 19) patients, the study will be 
suspended. The DSMC will be asked to review the Grade 3-5 events and their attribution to 
trial intervention and make a final determination of safety. This would suspend the study 
16% of the time when the true rate of Grade 3-5 non-hematological toxicity was 20% but 
92% of the time if the true rate was 45%. 
A secondary assessment of response will be made excluding those patients who withdraw 
from protocol therapy without progression from the response assessment. 
9.4 Statistical analysis 
All statistical analysis will be performed using SAS 9.2 or higher. 
9.4.1 Demographics and Baseline characteristics 
Demographics and baseline characteristics will be summarized using descriptive statistics 
for continuous variables, and frequencies and percentages for categorical variables. 
9.4.2 Safety analysis 
The safety analysis will include all patients who received any study medication. The safety 
end points will include: 
 Incidence of DLTs 
 Incidence of AE and AEs considered to be drug related 
 Incidence of grade 3 and grade 4 AEs 
 Incidence of SAEs 
 Laboratory values 
The safety analysis will be listed and/or summarized by dose cohort. No inferential statistics 
will be performed.  
All patients who received at least one dose bendamustine and IXAZOMIB (MLN9708) will 
be included in the safety analysis. 


70 
 
The analysis of safety will be based on the frequency of adverse events and their severity for 
patients in each portion who received at least one dose of study treatment. Worst toxicity 
grades per patient will be tabulated for select adverse events and laboratory measurements 
by using NCI CTCAE criteria v4.0. 
9.4.3 Efficacy analysis 
Two populations will be used in the efficacy analysis, Intent to treat (IIT) and per protocol 
(PP) populations. The IIT population will include all safety population who provide efficacy 
assessment, and PP population will include all IIT population without major protocol 
violations. 
The efficacy end points will include: 
 Overall response rate(ORR) 
 Duration of response 
These variables will be analyzed /summarized based on the IIT population as well as PP 
population as appropriate. The percentages of CR, CR+PR, CR+PR+SD will be presented, 
as will the median duration of response. The 95% confidence intervals of these percentages 
will also be presented. 
Additional analysis will be performed like  
Overall survival (OS) 
Progression free survival (PFS) 
The primary goal of the Phase II portion of the study is to assess whether the combination 
identified in Phase I has sufficient anti-tumor activity to warrant further evaluation of the 
combination. The primary endpoint will be response assessed after 4 cycles of treatment, 
with patients experiencing progressive disease prior to the completion of 4 cycles classified 
as non-responders. For the primary assessment of response, any subject who withdraws from 
protocol treatment prior to completion of 4 cycles of treatment without progression would 
also be classified as a non-responder. 
The 4-cycle response rate (at least partial response) for patients with relapsed/refractory 
multiple myeloma is about 20%. A true 4-cycle response rate of 40% for the combination of 
IXAZOMIB (MLN9708) and bendamustine would be considered interesting and worthy of 


71 
 
further study. A Simon 2-stage design (see Simon R. Optimal two-stage designs for Phase II 
clinical trials. Controlled Clinical trials. 10:1-10, 1989) is proposed for the Phase II portion 
of this study.  
10.    ADVERSE EVENTS   
10.1    
Definitions 
10.1.1       Adverse Event Definition 
Adverse event (AE) means any untoward medical occurrence in a patient or subject 
administered a pharmaceutical product; the untoward medical occurrence does not 
necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product whether 
or not it is related to the medicinal product. This includes any newly occurring event, or a 
previous condition that has increased in severity or frequency since the administration of 
study drug. 
An abnormal laboratory value less than grade 2 lab abnormality will not be assessed as an 
AE unless that value leads to discontinuation or delay in treatment, dose modification, 
therapeutic intervention, or is considered by the investigator to be a clinically significant 
change from baseline.  
10.1.2    Serious Adverse Event Definition 
Serious AE (SAE) means any untoward medical occurrence that at any dose: 
 Results in death. 
 Is life-threatening (refers to an AE in which the patient was at risk of death at the 
time of the event. It does not refer to an event which hypothetically might have 
caused death if it were more severe). 
 Requires inpatient hospitalization or prolongation of an existing hospitalization 
(see clarification in the paragraph below on planned hospitalizations). 
 as a substantial disruption of a person’s ability to conduct normal life functions). 
 Is a congenital anomaly/birth defect. 


72 
 
 Is a medically important event. This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered 
serious when, based on appropriate medical judgment, may jeopardize the patient, 
require medical or surgical intervention to prevent 1 of the outcomes listed above, or 
involves suspected transmission via a medicinal product of an infectious agent.  
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse; any organism, virus, or infectious particle (eg, prion protein transmitting 
Transmissible Spongiform Encephalopathy), pathogenic or nonpathogenic, is 
considered an infectious agent.  
Clarification should be made between a serious AE (SAE) and an AE that is considered 
severe in intensity (Grade 3 or 4), because the terms serious and severe are NOT 
synonymous. The general term severe is often used to describe the intensity (severity) of a 
specific event; the event itself, however, may be of relatively minor medical significance 
(such as a Grade 3 headache). This is NOT the same as serious, which is based on 
patient/event outcome or action criteria described above, and is usually associated with 
events that pose a threat to a patient’s life or ability to function. A severe AE (Grade 3 or 4) 
does not necessarily need to be considered serious. For example, a white blood cell count of 
1000/mm3 to less than 2000 is considered Grade 3 (severe) but may not be considered 
serious. Seriousness (not intensity) serves as a guide for defining regulatory reporting 
obligations. 
10.2    Procedures for Reporting Serious Adverse Events 
AEs may be spontaneously reported by the patient and/or in response to an open question 
from study personnel or revealed by observation, physical examination, or other diagnostic 
procedures. Any clinically relevant deterioration in laboratory assessments or other clinical 
finding is considered an AE. When possible, signs and symptoms indicating a common 
underlying pathology should be noted as one comprehensive event. For serious AEs, the 
investigator must determine both the intensity of the event and the relationship of the event 
to study drug administration.  
AEs which are serious must be reported to Millennium Pharmacovigilance (or designee) 
from the first dose of study drug through 30 days after administration of the last dose of 
IXAZOMIB. Any SAE that occurs at any time after completion of IXAZOMIB treatment 
or after the designated follow-up period that the sponsor-investigator and/or sub-investigator 


73 
 
considers to be related to any study drug must be reported to Millennium Pharmacovigilance 
(or designee). In addition, new primary malignancies that occur during the follow-up periods 
must be reported, regardless of causality to study regimen, for a minimum of three years 
after the last dose of the investigational product, starting from the first dose of study drug. 
All new cases of primary malignancy must be reported to Millennium Pharmacovigilance 
(or designee).   
Planned hospital admissions or surgical procedures for an illness or disease that existed 
before the patient was enrolled in the trial are not to be considered AEs unless the condition 
deteriorated in an unexpected manner during the trial (e.g., surgery was performed earlier or 
later than planned). All SAEs should be monitored until they are resolved or are clearly 
determined to be due to a patient’s stable or chronic condition or intercurrent illness(es). 
Since this is an investigator-initiated study, the principal investigator Parameswaran Hari 
also referred to as the sponsor-investigator, is responsible for reporting serious adverse 
events (SAEs) to any regulatory agency and to the sponsor- investigator’s EC or IRB.   
Regardless of expectedness or causality, all SAEs (including serious pretreatment events) 
must also be reported in English to Millennium Pharmacovigilance (or designee): 
Fatal and Life Threatening SAEs within 24 hours of the sponsor-investigator’s 
observation or awareness of the event 
 
All other serious (non-fatal/non life threatening) events within 4 calendar days of 
the sponsor-investigator’s observation or awareness of the event 
 
See below for contact information for the reporting of SAEs to Millennium 
Pharmacovigilance.  
The sponsor-investigator must fax or email the SAE Form per the timelines above. A sample 
of an SAE Form will be provided.  
The SAE report must include at minimum: 
 Event term(s) 
 Serious criteria 
 Intensity of the event(s): Sponsor-investigator’s or sub-investigator’s 
determination. Intensity for each SAE, including any lab abnormalities, will be 
determined by using the NCI CTCAE version specified in the protocol, as a 


74 
 
guideline, whenever possible. The criteria are available online at 
http://ctep.cancer.gov/reporting/ctc.html. 
 Causality of the event(s): Sponsor-investigator’s or sub-investigator’s 
determination of the relationship of the event(s) to study drug administration.  
Follow-up information on the SAE may be requested by Millennium.  
Intensity for each SAE, including any lab abnormalities, will be determined by using the 
NCI CTCAE version used at your institution, as a guideline, whenever possible. The criteria 
are available online at http://ctep.cancer.gov/reporting/ctc.html. 
In the event that this is a multisite study, the sponsor-investigator is responsible to ensure 
that the SAE reports are sent to Millennium Pharmacovigilance (or designee) from all sites 
participating in the study. Sub-investigators must report all SAEs to the sponsor-investigator 
so that the sponsor-investigator can meet his/her foregoing reporting obligations to the 
required regulatory agencies and to Millennium Pharmacovigilance, unless otherwise agreed 
between the sponsor-investigator and sub-investigator(s).  
Relationship to all study drugs for each SAE will be determined by the investigator or sub-
investigator by responding yes or no to the question: Is there a reasonable possibility that the 
AE is associated with the study drug(s)? 
Sponsor-investigator must also provide Millennium Pharmacovigilance with a copy of all 
communications with applicable regulatory authorities related to the study product(s), as 
soon as possible but no later than 4 calendar days of such communication. 
 
 
SAE and Pregnancy Reporting Contact Information 
 
Fax Number: 1-800-963-6290 
Email: TakedaOncoCases@cognizant.com 
Suggested Reporting Form:   
• 
SAE Report Form (provided by Millennium) 
• 
US FDA MedWatch 3500A:  
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm 
• 
Any other form deemed appropriate by the sponsor-investigator 


75 
 
10.3    Procedures for Reporting Drug Exposure During Pregnancy and Birth 
Events 
If a woman becomes pregnant or suspects that she is pregnant while participating in this 
study or within 90 days after the last dose, she must inform the investigator immediately and 
permanently discontinue study drug. The sponsor-investigator must immediately fax a 
completed Pregnancy Form to the Millennium Department of Pharmacovigilance or 
designee. The pregnancy must be followed for the final pregnancy outcome. 
If a female partner of a male patient becomes pregnant during the male patient’s 
participation in this study, the sponsor-investigator must also immediately fax a completed 
Pregnancy Form to the Millennium Department of Pharmacovigilance or designee. Every 
effort should be made to follow the pregnancy for the final pregnancy outcome. 
Suggested Pregnancy Reporting Form: 
 Pregnancy Report Form (provided by Millennium)   
11.    ADMINISTRATIVE REQUIREMENTS  
11.1    
Product Complaints   
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product. Individuals 
who identify a potential product complaint situation should immediately contact MedComm 
Solutions (see below) and report the event. Whenever possible, the associated product 
should be maintained in accordance with the label instructions pending further guidance 
from a TAKEDA Quality representative. 
For Product Complaints, 
 
Phone: 1‐877‐TAKEDA7 (1‐877‐825‐3327) 
 
E‐mail: medicalinformation@tpna.com 
 
FAX: 1‐800‐247‐8860 
 
Hours: Mon‐Fri, 8 a.m. – 6 p.m. ET 
 
Product complaints in and of themselves are not AEs. If a product complaint results in an 
SAE, an SAE form should be completed and sent to Millennium Pharmacovigilance 
 
11.2 Data safety monitoring:  
This study will be reviewed by the Medical College of Wisconsin Cancer Center Data 
Safety Monitoring Committee (MCW CC DSMC). The DSMC reviews the research 


76 
 
protocol, informed consent documents and plans for safety and data monitoring. The DSMC 
will review interim data to detect evidence of efficacy or adverse effects to determine if the 
trial should continue as originally designed, should be changed or should be stopped based 
on the data. A copy of the MCW CC Data and Safety Monitoring Plan is attached to the 
protocol and membership roster will be maintained in the study research file and updated as 
membership changes. The committee will review reports from the study PI twice annually 
(or more frequently if needed) and provide recommendations on trial continuation, 
suspension or termination as necessary. Since this study is performed under an FDA IND 
application, the principal investigator will submit individual adverse event reports and IND 
safety reports to the FDA per FDA regulations CFR 21 Part 312. 
As per the Data Safety Monitoring Plan, the DSMC will: 
 review interim analysis, if applicable, and determine specific data to be analyzed 
 evaluate end point/stop point rules 
 review protocol violations and deviations to assess adequacy of study 
 enrollment 
- 
followed eligibility criteria 
- 
enrollment numbers 
- 
visit compliance 
- 
screening failure information 
 review IND/IDE information 
 discuss investigator or key personnel changes 
 evaluate the aggregate analysis of adverse events/serious adverse events.  
DSMC Meeting Outcome - The major outcomes following data review include: 
 continuing the trial unchanged 
 modify the protocols and/or consent form (It may be unethical to continue giving a 
placebo after a new treatment has been proven to be effective or to continue a new 
treatment when there is no chance the trial will be positive.) 
 terminate the trial 
A summary of the MCW CC DSMC responsibilities are as follows: • Review the clinical 
trial for data integrity and safety  


77 
 
• Review all unexpected grade 3, and all grade 4, and 5 adverse events, as well as any others 
requiring expedited reporting as defined in this protocol. (Grades 4 & 5 events must be 
reported to the DSMC within 5 calendar days of study staff’s knowledge.) Review all DSM 
reports  
• Submit a summary of any recommendations related to study conduct  
• Terminate the study if deemed unsafe for patients  
Any available DSMC letters will be submitted to the IRB of record as required. 
11.3 Clinical trials management system 
Ongoing Study Management: 
The study will use the OnCore CTMS for collection and management of data from the 
Participating Institutions. 
 Electronic Case Report Forms and Source documents will be entered and uploaded in the 
OnCore CTMS. Source Documents will include all documents that verify the data collected 
for eCRF’s, AE’s and SAE’s. (this is only if needed – we will keep a shadow chart here, so 
the language about source documents can be deleted). 
  
Ongoing Communication with Participating Institution Research Staff 
The study staff will receive OnCore CTMS training from the MCW OnCore CTMS 
Administrator. 
11.4 Monitoring 
The Cancer Center Clinical Trials Office (CCCTO) is committed to a risk-based and 
objective-based approach to Quality Assurance reviews to maximize the efficiency and 
merit of trial oversight. All studies will have the initial Internal Quality Assurance (IQA) 
Review within the first 3 months of the first subject enrolled on trial. Trials are categorized 
as low risk, intermediate risk, or high risk at the discretion of the CCCTO Quality Assurance 
staff. This study has been categorized as High Risk by the MCW Cancer Center Quality 
Assurance Staff. High Risk studies will be reviewed as follows: 
  
•  The study will be reviewed biannually by the MCW Cancer Center Quality Assurance 
Staff. 
•  30% of subject files will be selected randomly for review (max 10 subjects at each 


78 
 
monitoring timepoint). 
•   Consent, eligibility, adherence to the treatment plan and objective based data will be 
reviewed for those files selected 
•   1 file will be selected randomly for a comprehensive review at each monitoring timepoint. 
 
A letter/report will be provided to the study staff and the DSMC after each IQA review. 
Necessary corrective action or training will be provided to the staff as needed throughout 
and following each IQA review. Directed audits may be requested at any time by the 
CCCTO QA Staff, DSMC, Research Manager, IRB, study staff member, or administrative 
staff. 
 
 


79 
 
12.    REFERENCES    
1. Kyle RA, Rajkumar SV. Multiple myeloma. N Engl J Med. 2004;351(18):1860–73. 
2. Lacy MQ, Gertz MA, Dispenzieri A, et al. Long-term results of response to therapy, time 
to progression, and survival with lenalidomide plus dexamethasone in newly diagnosed 
myeloma. Mayo Clin Proc. 2007;82(10):1179–84. 
3. Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone 
combination therapy in patients with newly diagnosed multiple myeloma. Blood. 
2010;116(5):679–86. 
4. AndAnderson KC. The role of immunomodulatory drugs in multiple myeloma. Semin 
Hematol. 2003;40(4 Suppl 4):23–32. 
5. Jakubowiak AJ, Dytfeld D, Griffith KA, et al. A phase 1/2 study of carfilzomib in 
combination with lenalidomide and low-dose dexamethasone as a frontline treatment for 
multiple myeloma. Blood. 2012;120(9):1801–9. 
6. Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose 
dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for 
newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet 
Oncol. 2010;11(1):29–37. 
7. Brenner H, Gondos A, Pulte D. Recent major improvement in long-term survival of 
younger patients with multiple myeloma. Blood. 2008;111(5):2521–6. 
8. Dimopoulos MA, Chen C, Spencer A, et al. Long-term follow-up on overall survival from 
the MM-009 and MM-010 phase III trials of lenalidomide plus dexamethasone in patients 
with relapsed or refractory multiple myeloma. Leukemia. 2009;23(11):2147–52. 
9. Gaul L, Mandl-weber S, Baumann P, Emmerich B, Schmidmaier R. Bendamustine 
induces G2 cell cycle arrest and apoptosis in myeloma cells: the role of ATM-Chk2-Cdc25A 
and ATM-p53-p21-pathways. J Cancer Res Clin Oncol. 2008;134(2):245–53. 
10. Pönisch W, Mitrou PS, Merkle K, et al. Treatment of bendamustine and prednisone in 
patients with newly diagnosed multiple myeloma results in superior complete response rate, 
prolonged time to treatment failure and improved quality of life compared to treatment with 
melphalan and prednisone--a randomized phase III study of the East German Study Group 
of Hematology and Oncology (OSHO). J Cancer Res Clin Oncol. 2006;132(4):205–12. 
11. Knop S, Straka C, Haen M, Schwedes R, Hebart H, Einsele H. The efficacy and toxicity 
of bendamustine in recurrent multiple myeloma after high-dose chemotherapy. 
Haematologica. 2005;90(9):1287–8. 
12. Pönisch W, Rozanski M, Goldschmidt H, et al. Combined bendamustine, prednisolone 
and thalidomide for refractory or relapsed multiple myeloma after autologous stem-cell 


80 
 
transplantation or conventional chemotherapy: results of a Phase I clinical trial. Br J 
Haematol. 2008;143(2):191–200. 
13. Lentzsch S, O'Sullivan A, Kennedy RC, et al. Combination of bendamustine, 
lenalidomide, and dexamethasone (BLD) in patients with relapsed or refractory multiple 
myeloma is feasible and highly effective: results of phase 1/2 open-label, dose escalation 
study. Blood. 2012;119(20):4608–13. 
14. Pönisch W, Moll B, Bourgeois M, et al. Bendamustine and prednisone in combination 
with bortezomib (BPV) in the treatment of patients with relapsed or refractory multiple 
myeloma and light chain-induced renal failure. J Cancer Res Clin Oncol. 
2013;139(11):1937–46. 
15. Ludwig H, Kasparu H, Leitgeb C, et al. Bendamustine-bortezomib-dexamethasone is an 
active and well-tolerated regimen in patients with relapsed or refractory multiple myeloma. 
Blood. 2014;123(7):985–91. 
16. Gupta N., et al., Clinical pharmacokinetics of intravenous and oral MLN9708, an 
investigational proteasome inhibitor: An analysis of data from four phase 1 monotherapy 
studies. in 52nd ASH Annual Meeting and Exposition, 2010. 116(21): P. abstr 1813. 
17. Gupta N, Saleh M., Venkatakrishnan K. Flat-dosing versus BSA-based dosing for 
MLN9708, an investigational proteasome inhibitor: Population pharmacokinetic (PK) 
analysis of pooled data from 4 phase-1 studies in 53rd ASH Annual Meeting and Exposition. 
2011. San Diego, CA; p. abstr 1433.  
18. Chow LQ, et al. MLN9708, an investigational proteasome inhibitor, in patients with 
solid tumors; updated phase 1 results in head and neck symposium. 2012. Phoenix, AZ.  
19. Assouline S, et al. Once-weekly MLN9708, an investigational proteasome inhibitor, in 
patients with relapsed/refractory lymphoma: Results of a phase 1 dose-escalation study in 
17th EHA Annual Congress. 2012. Amsterdam, The Netherlands.  
20. Lonial S, et al. Phase I study of twice-weekly dosing of the investigational oral 
proteasome inhibitor MLN9708 in patients (pts) with relapsed and/or refractory multiple 
myeloma (MM) in ASCO annual meeting. 2012. Chicago, IL.  
21. Kumar S, et al. Weekly dosing of the investigational oral proteasome inhibitor 
MLN9708 in patients with relapsed and/or refractory multiple myeloma: Results from a 
phase 1 dose- escalation study in 53rd ASH Annual Meeting and Exposition; 2011 10–13 
dec; San Diego, CA; p. abstr 816. 
22. Merlini Gea. MLN9708, a novel, investigational oral proteasome inhibitor, in patients 
with relapsed or refractory light-chain amyloidosis (AL): Results of a phase 1 study in 54th 
ASH Annual Meeting and Exposition. 2012. Atlanta, GA. 
23. Kumar Sea. A phase 1/2 study of weekly MLN9708, an investigational oral proteasome 
inhibitor, in combination with lenalidomide and dexamethasone in patients with previously 


81 
 
untreated multiple myeloma (MM) in 54th ASH Annual Meeting and Exposition. 2012. 
Atlanta, GA. 
24. Richardson PG, et al. MLN9708, an investigational proteasome inhibitor, in combination 
with lenalidomide and dexamethasone in previously untreated multiple myeloma patients 
(pts):  evaluation of weekly and twice-weekly dosing in 17th EHA Annual Congress. 2012. 
Amsterdam, The Netherlands. 
25. San Miguel J, et al. Oral MLN9708, an an investigational proteasome inhibitor, in 
combination with melphalan and prednisone in patients with previously untreated multiple 
myeloma: A phase 1 study in 17th EHA Annual Congress. 2012. Amsterdam, The 
Netherlands. 
26. Richardson P, Baz R, Wang L, Jakubowiak A, Berg D, Liu G, et al.  
Investigational agent MLN9708, an oral proteasome inhibitor, in patients (pts) with relapsed 
and/or refractory multiple myeloma (MM): Results from the expansion cohorts of a phase 1 
dose-escalation study in: 53rd ASH Annual Meeting and Exposition; 2011 10–13 Dec; San 
Diego, CA; p. abstr 301. 
27. Lonial S, Baz R, Wang M, Talpaz M, Liu G, Berg D, et al. Phase I study of twice 
weekly dosing of the investigational oral proteasome inhibitor MLN9708 in patients (pts) 
with relapsed and/or refractory multiple myeloma (MM). J Clin Oncol (ASCO meeting 
abstracts) 2012;30(15 suppl):Abstr 8017. 
28. Kumar S, Bensinger W, Reeder C, Zimmerman T, Berenson J, Berg D, et al.  
Weekly dosing of the investigational oral proteasome inhibitor MLN9708 in patients with 
relapsed and/or refractory multiple myeloma: Results from a phase 1 dose- escalation study 
in: 53rd ASH annual meeting and exposition; 2011 10–13 dec; San Diego, CA; p. abstr 816. 
29. Kumar S, Bensinger W, Reeder C, Zimmerman T, Berenson J, Liu G, et al.  
Weekly dosing of the investigational oral proteasome inhibitor MLN9708 in patients (pts) 
with relapsed/refractory multiple myeloma (MM): A phase I study. J Clin Oncol (ASCO 
meeting abstracts) 2012:Abstract 8034. 
30. Kumar S, Niesvizky R, Berdeja J, Bensinger W, Zimmerman T, Berenson J, et al.  
Safety and pharmacokinetics of weekly MLN9708, an investigational oral proteasome 
inhibitor, alone and in combination. Clinical Lymphoma Myeloma and Leukemia 
2013;13(supplement 1):S154; abstr P–230.  
31. Rodon P, Hulin C, Pegourie B, et al. Phase II study of bendamustine, bortezomib and 
dexamethasone as second-line treatment for elderly patients with multiple myeloma: the 
Intergroupe Francophone du Myelome 2009-01 trial. Haematologica. 2015;100(2):e56–9. 
32. Offidani M, Corvatta L, Maracci L, et al. Efficacy and tolerability of bendamustine, 
bortezomib and dexamethasone in patients with relapsed-refractory multiple myeloma: a 
phase II study. Blood Cancer J. 2013;3:e162. 
 
 


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13.  APPENDICES 
13.1    
Eastern Cooperative Oncology Group (ECOG) Scale for Performance 
Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all predisease performance without restriction 
1 
Symptoms but ambulatory. Restricted in physically strenuous activity, but ambulatory and 
able to carry out work of a light or sedentary nature (eg, light housework, office work) 
2 
In bed < 50% of the time. Ambulatory and capable of all self-care, but unable to carry out 
any work activities. Up and about more than 50% of waking hours. 
3 
In bed > 50% of the time. Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to 
bed or chair 
5 
Dead 
Source:  Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5 (6):649-55.  
 
 
 


83 
 
13.2   
Cockcroft-Gault Equation 
For males: 
Creatinine Clearance = (140-age[years]  weight [kg]) 
OR 
(140–age[years]  weight [kg]) 
72  (serum creatinine[mg/dL])  
0.81  (serum creatinine[mol/L]) 
 
For females: 
Creatinine Clearance = 0.85 (140-age[years]  weight [kg]) OR 0.85 (140-age[years]  weight [kg]) 
72  (serum creatinine[mg/dL])  
0.81  (serum creatinine[mol/L]) 
 
Source:  Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16(1):31-41. 
 
 
 


84 
 
13.3      Response criteria in Multiple myeloma 
 
CR: Negative immunofixation of serum and urine, disappearance of any soft tissue 
plasmacytomas, and < 5% plasma cells in bone marrow; in patients for whom only 
measurable disease is by serum FLC level, normal FLC ratio of 0.26 to 1.65 in addition to 
CR criteria is required; two consecutive assessments are needed. 
 
 
sCR: CR as defined plus normal FLC ratio and absence of clonal plasma cells by 
immunohistochemistry or two- to four-color flowcytometry; two consecutive assessments of 
laboratory parameters are needed. 
 
vGPR: Serum and urine M component detectable by immunofixation but not on 
electrophoresis or ≥ 90% reduction in serum M component plus urine M component <100 
mg/24 h; in patients for whom only measurable disease is by serum FLC level, > 90% 
decrease in difference between involved and uninvolved FLC levels, in addition to VGPR 
criteria, is required; two consecutive assessments are needed. 
 
PR: ≥ 50% reduction of serum M protein and reduction in 24-hour urinary M protein by ≥ 
90% or to < 200 mg/24 h. If serum and urine M protein are not measurable, ≥50% decrease 
in difference between involved and uninvolved FLC levels is required in place of M protein 
criteria. If serum and urine M protein and serum FLC assay are not measurable, ≥ 50% 
reduction in bone marrow plasma cells is required in place of M protein, provided baseline 
percentage was ≥30%. In addition, if present at baseline, ≥50% reduction in size of soft 
tissue plasmacytomas is required. Two consecutive assessments are needed; no known 
evidence of progressive or new bone lesions if radiographic studies. 
 
 
SD: Not meeting criteria for CR, VGPR, PR, or PD; no known evidence of progressive or 
new bone lesions if radiographic studies were performed. 
 
PD: Increase of 25% from lowest response value in any of following: Serum M component 
with absolute increase ≥ 0.5 g/dL; serum M component increases ≥1 g/dL are sufficient to 
define relapse if starting M component is  ≥ 5 g/dL and/or; Urine M component (absolute 
increase must be ≥200 mg/24 h) and/or; Only in patients without measurable serum and 
urine M protein levels: difference between involved and uninvolved FLC levels (absolute 
increase must be > 10 mg/dL);Only in patients without measurable serum and urine M 
protein levels and without measurable disease by FLC level, bone marrow plasma cell 
percentage (absolute percentage must be ≥ 10%) .Development of new or definite increase 
in size of existing bone lesions or soft tissue plasmacytomas. Development of hypercalcemia 
that can be attributed solely to plasma cell proliferative disorder. Two consecutive 
assessments before new therapy are needed. 
 
Source: Paulmbo et al. Journal Of Clinical Oncology 2014; 32:587-600 for International 
Myeloma Working group. 


85 
 
13.4 Enrollment Worksheet 
PI: Parameswaran Hari  
Protocol#24991 
Phase I/II Study Of Bendamustine And Ixazomib (MLN9708) Plus Dexamethasone In 
Relapsed/Refractory Multiple Myeloma 
Enrollment Worksheet 
Subject Name:    
Subjects DOB:  
Subjects MR#: 
Subjects ID #: 
Bendamustine:  _____mg/m2-  Days 1,2 every 28 days 
MLN9708: 4mg- Days 1,8,15 every 28 days 
Dexamethasone: 40mg Days 1,8,15 every 28 days 
Please email a copy of the signed patients consent (signature page) with this enrollment 
form to IDS when patient has been enrolled in study. 
_________________________________________ 
Name of Principal Investigator or Authorized Representative (please print) 
_________________________________________ 
Signature of Principal Investigator or Authorized Representative 
_______________Date