Clinical trial NCT02119468
Conditions: Refractory Plasma Cell Myeloma Recurrent Plasma Cell Myeloma
Sponsor: City of Hope Medical Center
Start date: 2014-06-30; Completion date: 2022-12-01
Enrollment: 32 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase I/II trial studies the side effects and best dose of ixazomib and to see how well it works when given together with pomalidomide and dexamethasone in treating patients with relapsed or relapsed/refractory multiple myeloma. Ixazomib may stop the growth of cancer by interfering with proteasomes (the protein breakdown mechanism in the cells). Pomalidomide and dexamethasone can modify and regulate the immune system and may stop cancer cells from growing. Giving ixazomib with pomalidomide and dexamethasone may be an effective treatment for relapsed or relapsed/refractory multiple myeloma.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the recommended phase II dose (RP2D) of MLN9708 (ixazomib), when given in combination with pomalidomide and dexamethasone, in patients with relapsed or relapsed/refractory multiple myeloma. (Phase I) II. To estimate the response rate and to evaluate the antitumor activity of the three drug combination: MLN9708 (at the RP2D), pomalidomide and dexamethasone, in patients with relapsed or relapsed/refractory multiple myeloma. (Phase II)

SECONDARY OBJECTIVES:

I. To evaluate the safety of MLN9708 at each dose level when given as part of a three drug combination by assessing the following: type, frequency, severity, attribution, time course and duration of adverse events; and clinical laboratory tests at various points in the study. (Phase I) II. To characterize and evaluate toxicities, including type, frequency, severity, attribution, time course and duration, at the RP2D, for the three drug combination. (Phase II) III. To obtain estimates of response duration, depth of response, clinical benefit response, and survival (overall and progression-free), at the RP2D, for the three drug combination. (Phase II)

OUTLINE: This is a phase I, dose-escalation study of ixazomib followed by a phase II study.

Patients receive ixazomib orally (PO) on days 1, 8, and 15; dexamethasone PO on days 1, 8, 15, and 22; and pomalidomide PO on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years.

Arms: arm 1: Patients receive 3mg ixazomib citrate (MLN9708) orally on days 1, 8, and 15; dexamethasone orally on days 1, 8, 15, and 22; and pomalidomide orally on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive 4mg ixazomib citrate (MLN9708) orally on days 1, 8, and 15; dexamethasone orally on days 1, 8, 15, and 22; and pomalidomide orally on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: ixazomib citrate intervention 2: dexamethasone intervention 3: pomalidomide
Intervention descriptions: intervention 1: Given orally intervention 2: Given orally intervention 3: Given orally

Protocol documents:
Prot_SAP_000.pdf: 
 
 TITLE: Phase I/II Trial of MLN9708 plus Pomalidomide and Dexamethasone for Relapsed or 
Relapsed Refractory Multiple Myeloma 
 
NCT02119468 
 
Document Date: 03/07/2017 
 
 


 
IRB #12267 
 
03/07/2017 
Version: 07 
CITY OF HOPE MEDICAL CENTER 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
 
DEPARTMENT OF HEMATOLOGY AND HEMATOPOIETIC CELL TRANSPLANTATION          
 
 
TITLE:   Phase I/II Trial of MLN9708 plus Pomalidomide and Dexamethasone for Relapsed or 
Relapsed Refractory Multiple Myeloma 
 
CITY OF HOPE PROTOCOL NUMBER/VERSION:  
IRB # 12267    
 
VERSION: 07 
 
 
DATE(S)/ OF AMENDMENT(S)/REVISION(S): 
 
 
COH Initial Protocol Dated 11/01/2013  
 
 
 
 
 
Version: 00 
COH Amendment 01 Protocol Dated 05/12/2014 
 
 
 
 
Version: 01 
COH Amendment 02 Protocol Dated 03/23/2015 
 
 
 
 
Version: 02 
COH Amendment 03 personnel update Dated 12/16/2015  
 
 
Version: 03 
COH Amendment 04 Protocol Dated 12/17/2015 
 
 
 
 
Version: 04 
COH Amendment 05 Protocol Dated 08/01/2016 
 
 
 
 
Version: 05 
COH Amendment 06 at Continuation Title Page Dated 11/09/2016  
 
Version: 06 
COH Amendment 07 Protocol Dated 03/07/2017 
 
 
 
 
Version: 07 
 
 
 
DISEASE SITE: 
Multiple Myeloma 
STAGE (If applicable):  
 
 
 
 
 
MODALITY(IES): 
 
 
 
 
 
TYPE (e.g., Pilot, Phase I, etc.):  
 
 
Phase I/II 
 
 
PRINCIPAL INVESTIGATOR: 
 
 
Amrita Krishnan, M.D. 
Designs, responsible for study conduct 
and data analysis  
 
COLLABORATING INVESTIGATOR(S): 
 
Joycelynne M. Palmer, Ph.D (Biostatistics) 
 
 
PARTICIPATING CLINICIANS:  
 
 
Haris Ali, M.D., Ahmed Aribi, M.D.,  Elizabeth Budde, M.D., Robert 
Chen, 
M.D., 
Stephen 
Forman, 
M.D., 
Myo 
Htut, 
M.D., 
Chatchada,Karanes, M.D., Samer Khaled, M.D., Auayporn 
Nademanee, M.D., Nitya Nathwani, M.D., Ryotaro Nakamura, M.D., 
Margaret O’Donnell, M.D., Pablo Parker, M.D., Leslie Popplewell, 
M.D., Michael Rosenzweig, M.D., Tanya Siddiqi, M.D., David 
Snyder, M.D., Anthony Stein, M.D., Eileen Smith, M.D., Amandeep 
Salhotra, M.D. Ji-Lian Cai, M.D., Leonard Farol, M.D., Ricardo 
Spielberger, M.D., George Somlo, M.D., Alex Herrera, M.D., 
Matthew Mei, M.D., Haris Ali, M.D., Jasmine Zain, M.D., Ibrahim 
Aldoss, M.D., Monzr Al Malki M.D., 
 


  
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CLINICAL STUDY PROTOCOL  
MMRC-051 
 
COH IRB # 12267 
 
 
Title:  
Phase I/II trial of MLN9708 plus Pomalidomide and 
Dexamethasone for Relapsed or Relapsed Refractory  
 
Multiple Myeloma 
 
 
Phase: 
 Phase I/II 
 
Protocol Version: 
Version 6.0 
03/03/2017 
 
Study Sponsor: 
City of Hope National Medical Center  
Investigator Initiated Trial 
 
Principal Investigator: 
 
Amrita Krishnan, MD  
 
Lead Principal Investigator 
 
City of Hope 
 
Collaborating Investigators: 
Prashant Kapoor, MD  
 
Mayo Clinic – Rochester 
 
 
Joseph Mikhael, MD 
 
Mayo Clinic - Arizona 
 
Ajay Nooka, MD, MPH 
Winship Cancer Institute of Emory University School of 
Medicine   
 
Jesus G. Berdeja, MD 
Sarah Cannon Research Institute Center 
 
Study Statistician 
Joycelynne M. Palmer, PhD 
 
City of Hope 
 
 
This is an investigator-initiated study.  The lead principal investigator, Amrita Krishnan, MD 
(who may also be referred to as the sponsor-investigator), is conducting the study and City of 
Hope National Medical Center, and is acting as the study sponsor.  Therefore, the legal/ethical 
obligations of the lead principal investigator include both those of a sponsor and those of an 
investigator. 
 
 


  
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Phase I/II trial of MLN9708 plus Pomalidomide and Dexamethasone  
for Relapsed or Relapsed Refractory Multiple Myeloma 
 
 
 
Protocol Acceptance Form – Amendment6.0 Protocol Dated  03-Mar-2017 
 
 
 
 
 
 
 
I have read this protocol and agree to conduct the study as outlined herein, in accordance with 
Good Clinical Practices (GCPs) and the Declaration of Helsinki, and complying with the 
obligations and requirements of clinical Investigators and all other requirements listed in 21 
CRF part 312. 
 
 
 
 
 
 
 
 
 
 
_______________________________________ 
_____________________________ 
Principal Investigator Signature 
 
 
Date 
 
 
________________________________________ ______________________________ 
Print Principal Investigator Name and Title  
Date 
 
 


  
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PROTOCOL SUMMARY  
 
Protocol Title: 
Phase I/II trial of MLN9708 plus Pomalidomide and Dexamethasone for Relapsed or 
Relapsed Refractory Multiple Myeloma   
Brief Protocol Title for the Lay Public (if applicable): 
Phase I/II trial of MLN9708 plus Pomalidomide and Dexamethasone for Relapsed or 
Relapsed Refractory Multiple Myeloma 
Study Phase: 
Phase I/II 
Participating Sites: 
▪ City of Hope  
▪ Mayo Clinic: Rochester and Arizona   
▪ Winship Cancer Institute of Emory University School of Medicine 
▪ Sarah Cannon Research Institute Center  
Rationale for this Study: 
Novel drugs are needed for the treatment of relapsed or relapsed refractory multiple myeloma.  
The combination of  proteasome inhibitor (PI) and immunomodulating (IMiD) agents has 
produced significant responses. Many patients are exposed to these classes of drugs earlier in 
the course of therapy, for patients who relapse after agents such as the PI bortezomib and the 
IMiD lenalidomide, newer agents are now available or in development including 
pomalidomide and MLN9708.  Pomalidomide is an IMiD that is active even in patients who 
are refractory to other IMiDS such as lenalidomide. MLN9708 is a PI that has shown activity 
in patients refractory to bortezomib. MLN9708 has shown activity in Phase I/II trials and 
pomalidomide and dexamethasone have shown activity in Phase I/II and III trials. Hence 
combining the two agents and including dexamethasone for synergy could potentially induce 
responses in this refractory patient population. 
Objectives: 
Phase I: 
Primary: 
1) To determine the recommended phase II dose (RP2D) of MLN9708 when given in 
combination with pomalidomide and dexamethasone, in patients with relapsed or 
relapsed/refractory multiple myeloma. 
Secondary: 
2) To evaluate the safety of MLN9708 at each dose level when given as part of a three drug 
combination by assessing the following: 
 
- type, frequency, severity, attribution, time course and duration of adverse events 
 
- clinical laboratory tests at various points in the study 
 
 


  
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Phase II: 
Primary: 
1. To estimate the response rate and to evaluate the antitumor activity of the three drug 
combination: MLN9708 (at the RP2D), pomalidomide and dexamethasone, in patients with 
relapsed or relapsed/refractory multiple myeloma. 
Secondary: 
At the RP2D, for the three drug combination: 
2. To characterize and evaluate toxicities, including type, frequency, severity, attribution, time 
course and duration. 
3. To obtain estimates of response duration, depth of response, clinical benefit response, and 
survival (overall and progression-free). 
Study Design: 
This study will be conducted as a multicenter phase I/II trial.  
 
The phase I portion will follow a standard 3+3 dose escalation design, to evaluate  toxicities 
associated with MLN9708 when given in combination with pomalidomide and 
dexamethasone. Two doses of MLN9708, 3mg and 4 mg, will be tested in up to three possible 
dose levels:   
Schedule: Each cycle is 28 days  
Dose Level 
Pomalidomide  
MLN9708 
Dexamethasone* 
-1 
3mg daily on days 1-21 
3 mg on days 1, 8 and 15 
40 mg on days 1, 8, 15 and 22 
1 
4 mg daily on days 1 - 21 
3 mg on days 1, 8 and 15 
40 mg on days 1, 8, 15 and 22 
2 
4 mg daily on days 1 - 21 
4 mg on days 1, 8 and 15 
40 mg on days 1, 8, 15 and 22 
*: Patients >75 years, at the time of trial registration, will receive a dexamethasone starting 
dose of 20mg on the same set schedule. 
 
The RP2D identified in the phase I portion of the study will be brought forward for activity 
evaluation. 
 
The phase II portion of this study will implement a Gehan two-stage design to estimate the 
response rate and to evaluate the activity of MLN9708 when given in combination with 
pomalidomide and dexamethasone (Gehan, 1961). 
Endpoints: 
Phase I: 
The primary endpoint is toxicity. Toxicity will be graded according to the NCI-Common 


  
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Terminology Criteria for Adverse Events version 4.03. Dose limiting toxicity (DLT) is 
defined in section 7.3 of the protocol. 
Phase II: 
The primary endpoint is response rate (sCR/CR/VGPR and PR) and is based on the 
International Myeloma Working Group (IMWG) criteria.  
Sample Size: 
Phase I: 
The phase I study will follow a 3+3 design, to evaluate toxicities associated with MLN9708 
when given in combination with pomalidomide and dexamethasone. Two doses of MLN9708 
(3 mg and 4 mg) will be tested in up to three possible dose levels. In the phase I portion of this 
study, the total sample size will depend on the number of dose levels evaluated to determine 
the RP2D. While the phase I study is expected to enroll and treat 9 patients (3 patients at dose 
level 1, and another 6 at dose level 2-assuming the 4mg dose is well tolerated), a maximum of 
18 patients could be treated (6 patients treated at each dose level. 
 
Phase II: 
The phase II portion of the study is expected to enroll a minimum of 9 and a maximum of 25 
patients. The six patients treated at the RP2D in the phase I portion of the study will count 
toward the 25 patients required; given this, we expect to enroll only 19 new patients during 
the phase II trial portion. The sample size is based on the desire to achieve a (promising) 
target response rate of >30%.   
Estimated Duration of the Study 
Accrual, for both phases, is expected to be completed in 26 months; with approximately 2 
patients enrolled each month. Patients will be treated in 28-day treatment cycles until disease 
relapse, progression or unacceptable toxicity, withdrawal of consent, or protocol specified 
parameters to stop treatment. Patients who discontinue study treatment for reasons other than 
disease relapse/progression will continue to have disease assessments per International 
Myeloma Working Group (IMWG) criteria until relapse or progression, initiation of new 
anticancer treatment, or death whichever occurs first. Patients will be followed to collect 
further anticancer treatment and survival information until death, loss to follow-up, 
withdrawal of consent, study termination or up to 24 months post treatment. 
Summary of Patient Eligibility Criteria: 
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 informed 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. Females of childbearing potential (FCBP) must have a negative serum or urine 
pregnancy test with a sensitivity of at least 25 mIU/mL within 10 – 14 days prior to 
and again within 24 hours of starting pomalidomide and must either commit to 
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of birth control, one highly effective method and one additional effective method at the 
same time, at least 28 days before she starts taking pomalidomide through 90 days 
after the last dose of study drug.  FCBP must also agree to ongoing pregnancy testing.  
Men must agree to use a latex condom during sexual contact with a FCBP even if they 
have had a vasectomy from the time of signing the informed consent form through 90 
days after the last dose of study drug.   
4. All patients must be registered in and must comply with all requirements of the 
POMALYST REMS™ program.   
5. Patients must have a diagnosis of relapsed or relapsed and refractory Multiple 
Myeloma with a minimum of one prior regimen and a maximum of 5 prior regimens.  
6. Patients must have had therapy with a proteasome inhibitor and lenalidomide and be 
refractory to lenalidomide according to the IMWG definition of refractory disease 
(progressive disease on or within 60 days of stopping lenalidomide). 
7. Patients must have measurable disease defined as one of the following: 
 Serum M protein ≥ 0.5 g/dL 
 Urine M protein ≥ 200 mg/24 hours 
 Serum free light chain ≥ 10 mg/dL provided the FLC ratio is abnormal. 
8. Eastern Cooperative Oncology Group (ECOG) performance status and/or other 
performance status 0, 1, or  2. 
9. Patients must meet the following clinical laboratory criteria: 
 Absolute neutrophil count (ANC)  1,000/mm3  
 Platelet count > 75,000/µL for patients in whom < 50% of bone marrow nucleated 
cells are plasma cells; or a platelet count > 50,000/µL for patients in whom > 50% 
of bone marrow nucleated cells are plasma cells. Platelet transfusions are not 
allowed within 3 days of last platelet assessment to confirm eligibility. 
 Total bilirubin  1.5  the institutional upper limit of normal range (IULN). 
 Alanine 
aminotransferase 
(ALT) 
and 
aspartate 
aminotransferase 
(AST)  3  IULN (institutional upper limit of normal range) 
 Calculated creatinine clearance  45 mL/min (Appendix15.2) 
 
Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study: 
1. Female patients who are pregnant or breastfeeding 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. 
3. Prior treatment with a multidrug regimen containing pomalidomide except the 2 drug 
combination of pomalidomide and dexamethasone. 
4. Major surgery within 14 days before enrollment. 
5. Radiotherapy within 14 days before enrollment. If the involved field is small, 7 days 
will be considered a sufficient interval between treatment and administration of the 
MLN9708. 
6. Central nervous system involvement. 
7. Infection requiring systemic antibiotic therapy or other serious infection within 
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8. 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. 
9. Systemic treatment, within 14 days before the first dose of MLN9708, 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. 
10. Unable or unwilling to undergo antithrombotic prophylaxis. 
11. Ongoing or active systemic infection, active hepatitis B or C virus infection, or known 
human immunodeficiency virus (HIV) positive. 
12. Any serious medical or psychiatric illness that could, in the investigator’s opinion, 
potentially interfere with the completion of treatment according to this protocol. 
13. Known allergy to any of the study medications, their analogues, or excipients in the 
various formulations of any agent. 
14. Known GI disease or GI procedure that could interfere with the oral absorption or 
tolerance of MLN9708 or pomalidomide including difficulty swallowing. 
15. Diagnosed or treated for another malignancy within 2 years before study enrollment or 
previously diagnosed with another malignancy with evidence of residual disease.  
Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not 
excluded if they have undergone complete resection. 
16. Patient has > Grade 2 peripheral neuropathy  on clinical examination during the 
screening period. 
17. Participation in other clinical trials, including those with other investigational agents 
not included in this trial, within 21days of the start of this trial and throughout the 
duration of this trial (for all other standard therapies, no treatment within 14 days of 
the start of this trial). 
18. Patients who are pomalidomide refractory, defined as patients who progress on or 
within 60 days of pomalidomide when given as a single agent or with dexamethasone. 
Investigational Product Dosage and Administration: 
MLN9708: 3mg or 4 mg oral; Pomalidomide: 3mg or 4mg oral; Dexamethasone: 40 mg oral 
(Note: Patients >75 years, at the time of trial registration, will receive a Dexamethasone dose 
of 20 mg on the same set schedule.) 
 
Clinical Observations and Tests to be Performed: 
Standard myeloma restaging studies (SPEP, UPEP, Bone Marrow Biopsy, Serum and Urine 
Immunofixation, Serum free lites, when applicable).  Refer to the Table of Assessments for 
complete details.  
Statistical Considerations: 
Phase I: 
The primary objective of the phase I study is to determine the recommended phase II dose 
(RP2D) of MLN9708 when given in combination with pomalidomide and dexamethasone, in 
patients with relapsed or relapsed/refractory multiple myeloma. 
 


  
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The phase I study will follow a 3+3 design for enrollment with dose escalation, or expansion 
of a cohort on the basis of the occurrence of dose limiting toxicities (DLTs) during cycle 1. 
Two doses of MLN9708 will be tested in up to three possible dose levels (dose level -1 and 
dose level 1: 3mg / dose level 2: 4 mg, administered on days 1, 8 and 15 of a 28 day cycle). 
The highest dose level that produces ≤1/6 DLTs in cycle 1 will be the maximum tolerated 
dose (MTD). The RP2D of MLN9708 and pomalidomide will generally be the MTD, but it 
may be less than the MTD  based on a review of available data/cumulative toxicities from 
phase I.  
 
Analysis: Observed toxicities will be summarized in terms of type (organ affected or 
laboratory determination), severity, time of onset, duration, probable association with the 
study regimen and reversibility or outcome. Baseline information (e.g. the extent of prior 
therapy) and demographic information will be presented as well to describe the patients 
treated in this study. 
 
Phase II: 
The  primary objective is to estimate the response rate and to evaluate the antitumor activity of 
the three drug combination: MLN9708 (at the RP2D), pomalidomide, and dexamethasone, in 
patients with relapsed or relapsed/refractory multiple myeloma. The primary endpoint is a 
confirmed tumor response of sCR/CR/VGPR or PR and is based on IMWG Criteria. A single 
cycle of treatment will be given in a 28 day cycle. Each patient’s disease status will be 
evaluated at baseline. Response will be assessed at the end of each cycle/just prior to the start 
of each cycle and is based on the IMWG criteria.  
 
Statistics/Sample Size and Accrual: The phase II portion of this study will implement a 
Gehan two-stage design to estimate the response rate and to evaluate the activity of MLN9708 
when given in combination with pomalidomide and dexamethasone (Gehan 1961). The phase 
II portion of the study is expected to enroll a minimum of 9 and a maximum of 25 patients. 
The six patients treated at the RP2D in the phase I portion of the study will count toward the 
25 patients required; given this, we expect to enroll only 19 new patients on the phase II trial. 
The sample size is based on the desire to estimate the response rate with at most 10% standard 
error, and early stopping if the combination is unexpectedly ineffective.  
  
At stage 1, 9 patients will be entered on the study. If 0 responses are seen in the first 9 patients 
treated, the study will be terminated and the true regimen response will be declared ≤30%. If 
at least 1 patient responds, the trial will continue to the second stage. Because patients treated 
during the phase I portion of the trial at the dose selected for the phase II trial will be counted 
(n=6), only 3 additional patients will be enrolled at stage 1. Under this design if the study 
regimen is >30% effective, there would be ~95.6% chance of at least one success. 
 
At stage 2, 16 additional patients will be entered. This accrual provides for estimation of the 
response rate with no more than 10% standard error.  
 
Analysis: The overall response rate will be calculated as the percent of evaluable patients that 
have confirmed sCR/CR/VGPR or PR; the clinical benefit response rate will be calculated as 
the percent of evaluable patients that have confirmed sCR/CR/VGPR/PR/ MR or SD; exact 


  
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95% confidence intervals will be calculated for these estimates. Response rates will also be 
evaluated based on number and type of prior therapy(ies). Time to response, duration of 
response, and survival will be estimated using the product-limit method of Kaplan and Meier. 
 
Sponsor 
Investigator Initiated Trial - City of Hope  
Case Report Forms 
This trial will utilize the Medidata RAVE® Electronic Data Capture system.     


  
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SCHEDULE OF EVENTS   
PROCEDURES 
Screen 
Cycle 1 
Each cycle is 28 days 
Cycle 2+* 
Each cycle is 28 days 
End of 
Treatment  
Post 
Study 
Follow 
Up 
-21d to 
-1d 
Day 
1 
Day 
8 
Day 
15 
Day 
22 
Day 
1 
Day 
8 
Day 
15* 
Day 
22 
 
 
Window 
 
± 1 
 
± 1 
 
± 1 
 
± 1 
 
± 1 
 
± 1 
 
± 1 
 
± 1 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Medical History, Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X11 
PE, Height1, Weight, ECOG 
X 
 
 
 
 
X 
 
 
 
X 
 
Toxicity Evaluation  
 
X 
 
 
 
X 
 
 
 
X 
 
Vital Signs  (HR, Temp, BP)  
X 
X 
 
 
 
X 
 
 
 
X 
 
12-lead ECG3 
X3 
 
 
 
 
 
 
 
 
X 
 
Education and counseling 
guidance document4 
X 
 
 
 
 
X 
 
 
 
X 
 
CBC5 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
Serum Chemistry5 
X 
 
 
X 
 
X 
 
 
 
X 
 
Neurological exam6  
X 
 
 
 
 
X 
 
 
 
X 
 
PT/PTT12 
X 
 
 
 
 
 
 
 
 
X 
 
Pregnancy test [FCBP] 2  
X 
X 
X 
X 
X 
X 
 
X2 
 
X2 
 
Extramedullary disease7 
X 
 
 
 
 
X 
 
 
 
X 
 
Skeletal Survey 8 
X 
 
 
 
 
 
 
 
 
 
 
Bone Marrow Aspiration/Biopsy9 
X 
 
 
 
 
X 
 
 
 
 
 
Myeloma-specific lab tests10 
X 
 
 
 
 
X 
 
 
 
X 
 
MLN9708 Administration 
 
X 
X 
X 
 
X 
X 
X 
 
 
 
Dexamethasone 
 
X 
X 
X 
X 
X13 
X13 
X13 
X13 
 
 
Pomalidomide Administration 
 
Days 1 - 21 
Days 1 – 21 
 
 


  
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PROCEDURES 
Screen 
Cycle 1 
Each cycle is 28 days 
Cycle 2+* 
Each cycle is 28 days 
End of 
Treatment  
Post 
Study 
Follow 
Up 
-21d to 
-1d 
Day 
1 
Day 
8 
Day 
15 
Day 
22 
Day 
1 
Day 
8 
Day 
15* 
Day 
22 
 
 
Follow for PD and survival 
 
 
 
 
X11 
 
1)  Measured at screening only.  
2)  FCBP - A female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) 
has not been naturally postmenopausal for at least 24 consecutive months. Pregnancy tests for FCBP must be performed within 10 to 14 days and 
again within 24 hours of initiation of therapy. Repeat pregnancy test every week for the first 4 weeks and then every 28 days while on therapy and 
during interruptions in therapy and 28 days following discontinuation of pomalidomide.  Women with irregular menstruation must have pregnancy 
testing every 14 days while on therapy and during interruptions and 14 and 28 days after discontinuation of Pomalidomide.  For Cycle 2 and forward, 
the D15 pregnancy test (if required) can be done locally and results faxed to the main institution. 
3)  ECG (12-Lead) should be performed and read locally.     
4)  All patients must be counseled about pregnancy precautions, risks of fetal exposure and other risks. All patients enrolled into this trial, must be 
registered in and must comply with all requirements of the POMALYST REMS™ program.   
5)  CBC to be performed and reviewed by clinician within 24 hours of day of dosing (first day of each cycle).  Alternately, a STAT CBC may be drawn on 
day of dosing, however should be reviewed prior to administration of investigational product(s). Serum Chemistry to be performed and reviewed by 
the investigator within 24 hours of day of dosing (first day of each cycle).  Alternately, a STAT CMP may be drawn on day of dosing however should 
be reviewed by the investigator prior to administration of investigational product(s).  Chemistry includes: glucose, calcium, albumin, total protein, 
sodium, potassium, BUN, creatinine, ALP, ALT, AST, bilirubin and uric acid (uric acid to be drawn at screening and then as needed based on tumor 
lysis syndrome risk).  Weight and serum creatinine will be used to calculate creatinine clearance by Cockroft-Gault equation (see appendix 15.2).   
6)  Neurological assessment required at screening and Day 1 of Cycle 2+. 
7)    Extramedullary Disease: prior to study (28 days), testing required only if extramedullary disease is present, every 12 weeks (if present at screening) 
or upon clinical suspicion of progressive disease (if present at screening).  This may include CT scan of the abdomen/pelvis, CT or x-ray of the chest, 
ultrasound of the liver/spleen or abdomen.      
8) 
Skeletal survey (including skull, all long bones, pelvis and chest) with tumor measurements (measurements required if plasmacytomas are present).  
Also required if previous survey >28 days from study entry and at any time when clinically indicated. 
9)  A bone marrow aspiration and biopsy is required at screening; Repeat bone marrow biopsy/aspirate as appropriate to confirm achievement of 
response (aspirate only—biopsy not required).   
10)  Myeloma lab tests: B2Microglobulin (collected at screening only); serum immunoelectrophoresis, immunoglobulin assay, M band quantitation by 
immunofixation, free light chain and 24 hour urine collection for Bence Jones protein to be performed at baseline prior to study, prior to each cycle (to 
confirm  complete response and in patients with urine only measurable disease) thereafter and at time of end of treatment  (if last tests were > 3 
weeks).  
11) End of study follow-up to be completed every three months for two years to include second primary malignancies, new therapies for the treatment of 
MM only (not all concomitant medication) and survival. 
12)  Due to the risk of blood clots while on Pomalidomide, if patient is started on warfarin, routine monitoring of INR should occur (as per your 
institutuional guidelines).   
13)  After the patient has been on Dexamethasone over one year, the patient can discontinue Dexamethasone at their next scheduled visit.     
 


  
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*Additional tests to be performed at the beginning of each cycle and at any reasonable time point during treatment if indicated for monitoring of drug 
profile/safety or, for disease/health status at the discretion of the clinical investigator.  Starting with Cycle 2 and forward, the patient is not required to 
come to the main hospital/institution for a Day 15 visit.  The patient can be seen locally by their physician at their discretion.


  
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TABLE OF CONTENTS 
PROTOCOL SUMMARY ........................................................................................................3 
SCHEDULE OF EVENTS .....................................................................................................10 
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS ............................................16 
1. BACKGROUND AND STUDY RATIONALE ................................................................19 
1.1 Multiple Myeloma Background ....................................................................................19 
1.2 MLN9708 .....................................................................................................................20 
1.2.1 Preclinical Experience ...........................................................................................20 
1.2.2 Clinical Experience ................................................................................................20 
1.2.3 Pharmacokinetics and Drug Metabolism ...............................................................20 
1.2.4 Clinical Trial Experience Using the Oral Formulation of MLN9708 ...................21 
1.2.5 Overview of the Oral Formulation of MLN9708 ..................................................23 
1.2.6 MLN9708 in Relapsed and/or Refractory Multiple Myeloma ..............................25 
1.2.7 MLM9708 in Newly Diagnosed Multiple Myeloma (NDMM) ............................29 
1.3 Pomalidomide ...............................................................................................................30 
1.3.1 Mechanism of Action.............................................................................................31 
1.3.2 Pharmakokinetics ...................................................................................................31 
1.3.3 Non-clinical Toxicology ........................................................................................32 
1.3.4 Clinical Studies ......................................................................................................33 
1.4 Study Rationale .............................................................................................................34 
1.5 Potential Risks and Benefits .........................................................................................35 
2. STUDY OBJECTIVES ......................................................................................................35 
2.1 Study Objectives (Phase I) ...........................................................................................35 
2.1.1 Primary: .................................................................................................................35 
2.1.2 Secondary: .............................................................................................................36 
2.2 Study Objectives (Phase II) ..........................................................................................36 
2.2.1 Primary: .................................................................................................................36 
2.2.2 Secondary: .............................................................................................................36 
3. STUDY ENDPOINTS ........................................................................................................36 
3.1 Primary Endpoints ........................................................................................................36 
4. STUDY DESIGN ...............................................................................................................38 
4.1 Overview of Study Design ...........................................................................................38 
4.1.1 Phase I: ...................................................................................................................38 
4.1.2 Phase II ..................................................................................................................38 
4.2 Number of Patients .......................................................................................................38 
4.3 Duration of Study .........................................................................................................38 
5. STUDY POPULATION .....................................................................................................39 
5.1 Inclusion Criteria ..........................................................................................................39 
5.2 Exclusion Criteria .........................................................................................................40 
6. PATIENT ENROLLMENT ................................................................................................42 
7. STUDY TREATMENT ......................................................................................................43 
7.1 Dose and Schedule ........................................................................................................43 
7.2 Dose Levels to be Tested ..............................................................................................43 
7.3 Dose Limiting Toxicity ................................................................................................43 
7.4 Dose Escalation/Expansion ..........................................................................................44 


  
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7.5 Recommended Phase II Dose (RP2D) ..........................................................................45 
7.6 Study Drug Administration ..........................................................................................45 
7.6.1 MLN9708 Administration .....................................................................................45 
7.6.2 Pomalidomide Administration ...............................................................................46 
7.6.3 Dexamethasone Administration .............................................................................46 
7.6.4 Growth factor Administration ................................................................................47 
7.7 Dose-Modification Guidelines .....................................................................................47 
7.8 Dose Reduction Steps ...................................................................................................48 
7.8.1 Dose Reduction Steps for Pomalidomide ..............................................................48 
7.8.2 Dose Reduction Steps for MLN9708.....................................................................48 
7.8.3 Dose Reduction Steps for Dexamethasone ............................................................48 
7.9 Dose Modification Guidelines for Treatment Related Toxicity ...................................49 
7.9.1 Dose Modification for MLN9708 and Pomalidmide During a Cycle of Therapy.49 
7.9.2 Dexamethasone Dose Modification Guidelines ....................................................52 
7.10 Criteria for Beginning or Delaying a Subsequent Treatment Cycle ...........................53 
7.11 Concomitant Medications ...........................................................................................53 
7.11.1 Excluded Concomitant Medications and Procedures ..........................................53 
7.11.2 Permitted/Recommended Concomitant Medications and Procedures .................54 
7.11.3 Required/Recommended Concomitant Therapy ..................................................55 
7.11.4 Pregnancy.............................................................................................................56 
7.12 Management of Clinical Events .................................................................................57 
8. STUDY DRUG ...................................................................................................................60 
8.1 Packaging and Labeling ................................................................................................60 
8.1.1 MLN9708...............................................................................................................60 
8.1.2 Pomalidomide ........................................................................................................60 
8.2 Storage, Handling, and Accountability .........................................................................61 
8.2.1 MLN9708...............................................................................................................61 
8.2.2 Pomalidomide ........................................................................................................62 
9. STUDY COMPLIANCE ....................................................................................................63 
9.1 Treatment Assignment ..................................................................................................63 
9.2 Termination of Treatment and/or Study Participation ..................................................63 
10. STATISTICAL AND QUANTITATIVE ANALYSES ...................................................64 
10.1 Statistical Methods .....................................................................................................64 
10.1.1 Determination of Sample Size .............................................................................64 
10.1.2 Populations for Analysis ......................................................................................65 
10.1.3 Demographic and Baseline Characteristics .........................................................65 
10.1.4 Efficacy Analysis .................................................................................................65 
10.1.5 Safety Analysis ....................................................................................................66 
11. ADVERSE EVENTS.................................... ERROR! BOOKMARK NOT DEFINED. 
11.1 Definition of Risk Level .............................................................................................67 
11.2 Monitoring and Personnel Responsible for Monitoring .............................................67 
11.3 Definitions ..................................................................................................................68 
11.3.1 Pretreatment Event Definition .............................................................................68 
11.3.2 Adverse Event Definition ....................................................................................68 
11.3.3 Unexpected Adverse Event [21 CFR 312.32 (a)] ................................................69 
11.3.4 Expected Adverse Event ......................................................................................69 


  
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11.2     REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED 
PROBLEMS ...............................................................................................................71 
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events ................78 
12. ADMINISTRATIVE REQUIREMENTS ........................................................................79 
12.1 Good Clinical Practice ................................................................................................79 
12.2 Ethical Considerations ................................................................................................80 
12.3 Patient Information and Informed Consent ................................................................80 
12.4 Patient Confidentiality ................................................................................................81 
12.5 Investigator Compliance .............................................................................................81 
12.6 Study Documentation and Archives ...........................................................................82 
12.6.1 Source Documents ...............................................................................................82 
12.6.2 Case Report Form Completion ............................................................................82 
12.7 Archival of Records ....................................................................................................83 
12.8 Study Monitoring and Data Collection .......................................................................83 
12.9 Investigator and Site Responsibility for Drug Accountability ...................................84 
12.10 MLN9708 Product Complaints ................................................................................84 
12.11 Closure of the Study .................................................................................................85 
12.12 Record Retention ......................................................................................................85 
13. USE OF INFORMATION ................................................................................................85 
14. REFERENCES .................................................................................................................86 
15. APPENDICES ..................................................................................................................89 
15.1 Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status ..........89 
15.2 Cockcroft-Gault Equation ...........................................................................................90 
15.3 Notification of Unanticipated Problem/Serious Adverse Event/Pregnancy ...............91 
Unanticipated Problem/Serious Adverse Event/Pregnancy Information……………..91 
    15.3.1 Millennium Pregnancy Reporting Form ..................................................................92 
15.4 International Myeloma Working Group Response Criteria27 .....................................95 
15.5 CITY OF HOPE DATA COORDINATING CENTER PLAN………....................96 
 
 


  
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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS 
Abbreviation 
Term  
AE 
AESI 
AL 
adverse event 
adverse event of special interest 
amyloidosis 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration versus time curve 
AUCτ 
area under the plasma concentration versus time curve from zero to next dose 
BCRP 
breast cancer resistance protein 
hCG
beta-human chorionic gonadotropin 
BMA 
bone marrow aspirate 
BMB 
bone marrow biopsy 
BSA 
body surface area 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CHF 
congestive heart failure 
CL 
clearance 
Cmax 
single-dose maximum (peak) concentration   
CO2 
carbon dioxide 
CR 
complete remission   
CRA 
Clinical Research Associate 
CRP 
C-reactive protein 
CT 
computed tomography 
CV 
 cardiovascular  
CYP 
cytochrome P450 
DCC 
DLT 
data coordinating center 
dose-limiting toxicity 
DNA 
DSMC 
deoxyribonucleic acid 
data safety monitoring committee 
ECG 
electrocardiogram 


  
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Abbreviation 
Term  
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOS 
End of Study (visit) 
EOT 
End of Treatment (visit) 
FCBP 
female of child bearing potential 
FDA 
United States Food and Drug Administration 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony stimulating factor 
GGT 
gamma glutamyl transferase 
Hb 
hemoglobin 
Hct 
hematocrit 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
IC50 
concentration producing 50% inhibition 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
IMiDS 
independent ethics committee 
immunomodulatory agents  
IMWG 
International Myeloma Working Group 
IRB 
Institutional Review Board 
IV 
intravenous; intravenously 
KPS 
Karnofsky Performance Status 
LDH 
lactate dehydrogenase 
LFT 
liver function test(s) 
MedDRA 
Medical Dictionary for Regulatory Activities 
Millennium 
MM 
Millennium Pharmaceuticals, Inc., and its affiliates 
multiple myeloma  
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NDMM 
newly diagnosed multiple myeloma 
NCI 
National Cancer Institute 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NK 
Natural killer cells 
NYHA 
New York Heart Association 


  
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Abbreviation 
Term  
OS 
overall survival 
PBMC 
peripheral blood mononuclear cell 
PD 
progressive disease 
PFS 
progression free survival 
Pgp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
PO 
per os; by mouth (orally) 
PR 
PMT 
partial remission  
Protocol Monitoring Team 
RBC 
red blood cell 
RP2D 
recommended phase 2 dose 
RRMM 
relapsed refractory multiple myeloma 
SAE 
serious adverse event 
SD 
stable disease 
Tmax 
single-dose time to reach maximum (peak) concentration 
TEAE 
treatment emergent adverse event 
TTP 
time to prgression 
TW 
twice weekly 
ULN 
upper limit of the normal range 
US 
United States 
Vd 
volume of distribution in the terminal phase 
VGPG 
very good partial response 
W 
weekly 
WBC 
white blood cell 
WHO 
World Health Organization 
 


  
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1.    
BACKGROUND AND STUDY RATIONALE 
1.1    Multiple Myeloma Background 
Multiple myeloma (MM) is an incurable malignancy that is the second most common 
hematological malignancy. There are approximately 20,000 new cases per year and 10,000 
deaths per year from MM in the United States. 1  Treatment options for relapsed MM include 
the following: 
Bortezomib; A drug in the class of proteasome inhibitors, it was approved as monotherapy for 
relapsed MM.2   Given the efficacy and tolerability of the drug it is often used in combination 
with agents such as alkylators ( cyclophosphamide), immunomodulatory agents (IMiDS), or 
liposomal doxorubicin either in the upfront setting or relapsed setting. 3 
Carfilzomib: Also a proteasome inhibitor, was approved in 2012 for patients who had prior 
therapy with bortezomib and an IMID and were progressing on or refractory to their most recent 
therapy. It has less peripheral neuropathy than bortezomib and has shown responses in 
bortezomib refractory patients.4  However, there are concerns with potential cardiac, pulmonary 
and renal side effects. Also the administration schedule of consecutive days of intravenous 
dosing make it a more cumbersome regimen for patients.  
Lenalidomide/Thalidomide: Drugs in the class known as immunomodulatory agents. 
Lenalidomide in conjunction with dexamethasone is approved for relapsed myeloma. 5 
Thalidomide is also approved for myeloma therapy but in the United States, lenalidomide is 
used preferentially due to its more favorable side effect profile. Similar to the practice with 
bortezomib both drugs are now commonly used in the upfront induction setting for therapy of 
myeloma in conjunction with dexamethasone for synergy. 6 
Unfortunately even with the advent of these active novel agents and improved response rates of 
combination therapy, all patients with myeloma ultimately relapse.  However, patients are living 
longer and hence, the goals of MM therapy are not only efficacy but also favorable toxicity 
profiles.7  In addition as these novel agents are being used earlier in the course of myeloma 
therapy, when patients do relapse, their disease is often refractory to the approved agents. 
Survival for this group of patients, especially those refractory to bortezomib and lenalidomide, 
the so called double refractory group is especially poor. 8 


  
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Hence new therapies for patients with relapsed disease are needed. In addition, oral therapies 
have the advantage of ease of administration and the potential for longer term use.  
1.2         MLN9708  
1.2.1    Preclinical Experience 
Please refer to the current MLN9708 Investigator’s Brochure (IB) and Safety Management 
Attachment (SMA). 
1.2.2    
Clinical Experience 
As of 30 April 2012, 382 patients have been treated with MLN9708 across 9 enrolling, sponsor-
led phase 1 or phase 1/2 studies evaluating both twice-weekly and weekly dosing schedules.  
MLN9708 is available as an intravenous and oral formulation. Regardless of the route of 
administration in the twice-weekly dosing schedule, MLN9708 is given on Days 1, 4, 8, and 11 
of a 21-day cycle; in the weekly dosing schedule, the drug is given on Days 1, 8, and 15 of a 28-
day cycle. To date, the development of oral MLN9708 has focused on multiple myeloma 
[relapsed and/or refractory and newly diagnosed] and a different yet related plasma cell 
dyscrasia, systemic light chain (AL) amyloidosis. A clinical pharmacology study looking at 
drug-drug interactions, the effect of food, and bioavailability also uses the oral formulation. 
Details of these trials can be found in ClinicalTrials.gov and the MLN9708 IB.   
1.2.3   Pharmacokinetics and Drug Metabolism 
Clinical IV and PO pharmacokinetic (PK) data show that MLN9708 (measured as the 
biologically active boronic acid form of MLN9708 [MLN2238]) has multi-exponential 
disposition with a rapid initial phase that is largely over by 4 hours.  Oral MLN9708 is rapidly 
absorbed with a median time to first maximum plasma concentration (Tmax) of approximately 
0.5 to 2.0 hours and terminal t1/2 after multiple dosing of approximately 5 to 7 days.9  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.10  Based on these data, a 
recommendation was made for fixed dosing in clinical trials.  An absolute bioavailability of 
67% was determined for MLN9708 using the population PK analysis.  See the IB for 
information on the PK for IV doses of MLN9708. 
Metabolism appears to be the major route of elimination for MLN9708, with negligible urinary 
excretion of the parent drug (< 3% of dose).  In vitro studies of liver microsomes show that 


  
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MLN9708 is metabolized by multiple cytochrome P450 enzymes (CYPs) and non-CYP 
enzymes/proteins.  The rank order of relative biotransformation activity of the 5 major human 
CYP isozymes is 3A4 (34.2%) > 1A2 (30.7%) > 2D6 (14.7%) > 2C9 (12.1%) > 2C19 (< 1%).  
MLN9708 is not an inhibitor of CYPs 1A2, 2C9, 2C19, 2D6, or 3A4, nor is it a time-dependent 
inhibitor of CYP3A4/5.  The potential for MLN9708 treatment to produce 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 because of the potential for first-pass metabolism when 
MLN9708 is administered via the PO route and because of the moderate contribution of 
CYP3A4- and CYP1A2-mediated metabolism of MLN9708 in human liver microsomes.  
MLN9708 may be a weak substrate of P-glycoprotein (P-gp), breast cancer resistance protein 
(BCRP), and multidrug resistance associated protein (MRP2) efflux pump transporters.  
MLN9708 is not an inhibitor of P-gp, BCRP, and MRP2.  The potential for DDIs with 
substrates or inhibitors of P-gp, BCRP, and MRP2 is, therefore, inferred to be low. 
1.2.4    
Clinical Trial Experience Using the Oral Formulation of MLN9708 
In the 7 studies actively enrolling patients to investigate oral MLN9708 in patients with 
differing malignancies (multiple myeloma, AL amyloidosis, nonhematologic cancers, and 
lymphoma), a total of 242 patients have been treated as of 30 April 2012. These patients have 
been treated with different doses of MLN9708, either as a single agent treatment or in 
combination with currently clinically available treatments. Information regarding the ongoing 
studies, patient populations, and doses investigated are included in Table 1-1. 


  
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Table 1-1   
Ongoing Studies of Oral MLN9708 
Trial/ 
Population 
Description 
Doses Investigated 
C16003 
RRMM 
N = 58 
PO, twice weekly (TW), single agent 
0.24-2.23 mg/m2, TW 
MTD:  2.0 mg/m2 
DLT:  rash, thrombocytopenia 
C16004 
RRMM 
N = 52 
PO, weekly (W), single agent 
0.24-3.95 mg/m2, W 
MTD:  2.97 mg/m2 
DLT:  rash, nausea, vomiting, diarrhea 
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 
RP2D*:  4.0 mg fixed (switched to fixed dosing in 
phase 2, relevant to 2.23 mg/m2) 
C16006 
NDMM 
N = 28 
PO, TW (Arm A- 42 day cycle) and W 
(Arm B- 28 day cycle), combination 
with melphalan and prednisone 
Arm A*:  3-3.7 mg, fixed dose, TW 
DLT: rash, thrombocytopenia, subileus 
Arm B*:  5.5 mg, fixed dose, W 
DLT: Esophageal ulcer 
C16007 
RR-AL 
N = 6 
PO, W, single agent 
4-5.5 mg, fixed dose*, W 
MTD: 4 mg 
DLT: thrombocytopenia, dirrhea, dyspnea, acute 
rise in creatinine, cardiac arrest 
 
C16008 
NDMM 
N=11 
PO, TW, combination with LenDex 21 
day cycle 
3.0-3.7 mg fixed dose* W 
MTD: 4 mg 
DLT: 
C16009 
Solid 
tumors, 
Lymphomas 
N = 22 
PO, W, single agent 
5.5 mg fixed dose* W 
C16010 
RRMM 
N = 1 
PO, W, combination with LenDex 
4.0 mg fixed dose* W 
TB-
MC010034 
RRMM 
N = 5 
PO, W, single agent in 1s part of study 
then in combination with LenDex in 2nd 
part 
3.0 mg fixed dose* W 
DLT: thrombocytopenia, nausea, hypertension, 
diarrhea 
Abbreviations:  RRAL = Relapsed or refractory Primary systemic light chain (AL) amyloidosis; BSA = body 
surface area ; DLT = dose-limiting toxicity; IV = intravenuously; LenDex = lenalidomide plus 
dexamethasone; MTD = maximum tolerated dose; NDMM = newly diagnosed multiple myeloma; PO = 
orally; RRMM = relapsed and/or refractory multiple myeloma; RPh2D = recommended phase 2 dose 
* Approximate body surface area (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. 


  
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1.2.5     Overview of the Oral Formulation of MLN9708 
The emerging safety profile indicates that oral MLN9708 is generally well tolerated with 
predominant toxicities largely reversible, able to be monitored by routine clinical examinations 
and manageable by dose reductions, discontinuation, or standard supportive care. From 
experience from phase 1 through 2 studies the major toxicities can be managed to allow repeat 
treatment cycles over periods extending beyond 24 months.  
In the 4 ongoing studies (C16003, C16004, C16007, and C16009) investigating single-agent 
oral MLN9708 in patients with differing malignancies (multiple myeloma, AL amyloidosis, 
nonhematologic cancers, and lymphoma), a total of 146 patients have been treated as of 30 April 
2012. These patients have been treated with different doses of MLN9708 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 MLN9708 Studies (C16003, C16004, C16007, and C16009) 
is shown in Table 1-2. 
Table 1-2 
Summary of Most Common (At Least 10% of Total) All Grade Treatment-
Emergent Adverse Events (Oral MLN9708 Single-Agent [C16003/4/7/9] 
Safety Population) 
Primary System Organ Class  
Preferred Term and Incidence 
N=146 
n (%) 
Subjects with at Least One Adverse Event 135 (92) 
 
Gastrointestinal disorders 102 (70) 
Nausea 68 (47); Diarrhoea 55 (38); Vomiting 51 (35); 
Abdominal pain 21 (14); Constipation 21 (14) 
General disorders and administration site conditions 98 
(67) 
Fatigue 71 (49); Pyrexia 31 (21); Oedema peripheral 15 
(10) 
Blood and lymphatic system disorders 77 (53) 
Thrombocytopenia 60 (41); Anaemia 30 (21); 
Neutropenia 23 (16); Leukopenia 15 (10) 
Nervous system disorders 63 (43) 
Headache 20 (14); Dizziness 18 (12) 
Metabolism and nutrition disorders 60 (41) 
Decreased appetite 39 (27) Dehydration 21 (14) 
Respiratory, thoracic and mediastinal disorders 60 (41) 
Cough 22 (15); Dyspnoea 21 (14) 
Skin and subcutaneous tissue disorders 60 (41) 
Rash macular 17 (12) 
Musculoskeletal and connective tissue disorders 56 
(38) 
Arthralgia 20 (14); Back pain 17 (12) 
Infections and infestations 54 (37) 
Upper respiratory tract infection 21 (14) 
Source: MLN9708 Investigator’s Brochure Edition 6 
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, any event that is considered drug-related regardless of the 
start date of the event, or any event that is present at baseline but worsens in intensity or is subsequently 
considered by the investigator to be drug-related.  


  
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Subject Incidence: A subject counts once for each preferred term. Percentages use the number of treated subjects as 
the denominator 
 
In the 3 studies actively enrolling patients to investigate oral MLN9708 in combination with 
standard combination regimens in patients with newly diagnosed multiple myeloma, a total of 
96 patients have been treated as of 30 April 2012. These patients have been treated with 
different doses of MLN9708 in combination with lenalidomide and dexamethasone in 2 trials 
(C16005 and C16008) and with melphalan and prednisone in 1 trial (C16006). The most 
frequent (at least 10%) adverse events occurring in the pooled safety population from Studies 
C16005, C16006, and C16008 is shown in Table 1-3. In combinations trials, related is defined 
as possibly related to any drug in the combination regimen, not just specifically related to 
MLN9708. 
 
Table 1-3 
Summary of Most Common (At Least 10% of Total) Treatment- Emergent 
Adverse Events (Oral MLN9708 Combination Agent [C16005/6/8] Safety 
Population) 
 
Primary System Organ Class  
Preferred Term and Incidence 
N= 96 
n (%) 
Subjects with at Least One Adverse Event 135 (92) 
 
 
Gastrointestinal disorders 70 (73) 
Nausea 32 (33); Constipation 29 (30); Vomiting 
25 (26) 
Diarrhoea 22 (23) 
General disorders and administration site 
conditions 64 (67) 
Fatigue 37 (39); Oedema peripheral 20 (21); 
Pyrexia 19 (20) 
Skin and subcutaneous tissue disorders 57 
(59) 
Rash 13 (14) 
Nervous system disorders 46 (48) 
Neuropathy peripheral 13 (14); Dysgeusia 12 
(13) 
Dizziness 11 (11) 
Musculoskeletal and connective tissue 
disorders 45 (47) 
Back pain 18 (19); Muscle spasms 10 (10) 
Blood and lymphatic system disorders 42 (44) 
Thrombocytopenia 28 (29); Anaemia 22 (23);  
Neutropenia 19 (20) 
Infections and infestations 40 (42) 
Upper respiratory tract infection 17 (18);  
Metabolism and nutrition disorders 38 (40) 
Decreased appetite 11 (11) 
Respiratory, thoracic and mediastinal 
disorders 34 (35) 
Dyspnoea 13 (14); Cough 11 (11) 
Psychiatric disorders 23 (24) 
Insomnia 15 (16) 
Source: MLN9708 Investigator’s Brochure Edition 6. 
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, any event that is considered drug-related regardless of the 
start date of the event, or any event that is present at baseline but worsens in intensity or is subsequently 
considered by the investigator to be drug-related. 


  
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Subject Incidence: A subject counts once for each preferred term. Percentages use the number of treated subjects as 
the denominator. 
 
 
 
 
The clinical experience with MLN9708 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 MLN9708, when combined with established therapies, and across the malignancies 
studied (advanced solid tumors 11, non-Hodgkin’s disease, Hodgkin’s disease 12, relapsed and/or 
refractory multiple myeloma [RRMM;13,14], relapsed or refractory systemic light chain 
amyloidosis [RRAL; 15], and newly diagnosed multiple myeloma [NDMM;16,17,18]) to date. 
 
Though additional data are needed to characterize the clinical benefit of this drug, the emerging 
data supports the ongoing development of MLN9708. 
 
Of particular relevance to this study (C16011) is the clinical experience from Studies C16004 
and C16007 in which single-agent MLN9708 is administered weekly in patients with RRMM or 
RRAL, respectively.  
 
1.2.6    
MLN9708 in Relapsed and/or Refractory Multiple Myeloma 
Study C16004 is an open-label, dose-escalation, phase 1 study of MLN9708 administered 
weekly on Days 1, 8, and 15 of a 28-day cycle in adult patients with RRMM. Patients with MM 
enrolled in the dose-escalation component of the study have relapsed following at least 2 lines  
of therapy, which must have included bortezomib, thalidomide (or lenalidomide), and 
corticosteroids. The dose-escalation phase of the trial has completed. In this study, 2 of 3 
patients experienced protocol-defined DLTs (Grade 3 rash and Grade 3 nausea, vomiting, and 
diarrhea) at a dose of 3.95 mg/m2. As per protocol, subsequent patients were treated at 1 dose 
level below (2.97mg/m2) where 1 of 6 patients experienced a DLT (Grade 3 nausea, vomiting, 
and diarrhea). The MTD of weekly oral MLN9708 was determined to be 2.97 mg/m2. 
Once the MTD was established, cohorts of patients representing the heterogeneous patient 
population currently seen in clinical practice were enrolled in order to further evaluate the 
safety, tolerability, efficacy, PK, and pharmacodynamics of oral MLN9708. The MTD 
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1. Relapsed and Refractory expansion cohort [refractory is defined as disease progression while 
on therapy or within 60 days after the last dose of therapy]; 
2. Carfilzomib expansion cohort 
3. Proteasome Inhibitor-Naïve expansion cohort 
4. Velcade-Relapsed expansion cohort 
Final study results are not available for this ongoing trial, but preliminary data suggest 
MLN9708 has antitumor activity in heavily pretreated MM patients, with durable 
responses/disease control, and is generally well tolerated.19,20 
As of the 30 April 2012 data cut, these patients are considered heavily pretreated as evidenced 
by a median number of 4 (range 1–13) prior lines of therapy, with 66% refractory to the last line 
of therapy. Patients have received a median of 2 cycles of therapy (range, 1- 11). Five patients 
have achieved objective response: 1 patient achieved a VGPR and 4 patients achieved a PR. 
Additionally, 15 patients achieved durable disease stabilization for up to 9.5 months. At data 
cut-off, 15 patients remain on treatment; discontinuation of treatment was primarily due to 
progressive disease (69%). 
 
A summary of the safety profile of patients treated in Study C16004 is outlined in Table 1-4. 
Overall, 92% of patients experienced a TEAE of any grade and of any cause. Peripheral 
neuropathy was limited to Grade 1/ 2 in 6 patients, with 3 patients reporting baseline Grade 1 
PN at study entry. 
 
Table 1-4    
Study C16004, Oral MLN9708, Single Agent, Given Weekly:  Most 
Common TEAEs as of 30 April 12 (N= 52) 
Most Common (> 20%) Any Grade and Irrespective 
of Cause 
Thrombocytopenia (54%) 
Fatigue (48%) 
Nausea (44%), diarrhea (44%) 
Vomiting (37%) 
Decreased appetite (33%) 
Rash* (31%) 
Anemia (25%) 
Neutropenia (23%) 
Drug-Related Grade  3 in > 5% of patients 
 
Thrombocytopenia (38%) 
Diarrhea and neutropenia 17% (each), fatigue and 
lymphopenia 10% (each), nausea and decreased 
appetite 8% (each) and vomiting 6% 


  
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Source: MLN9708 Investigator’s Brochure Edition 6 
* Rash includes preferred terms of rash macular, rash, maculo-papular, rash morbilliform, rash pruritic, 
pruritus,, rash erythematous, exfoliative rash, and rash popular 
 
 
Dose reductions required were due to AEs that included rash, neutropenia, thrombocytopenia, 
diarrhea, nausea, vomiting, dehydration, hypotension, increase in serum creatinine, abdominal 
pain, ileus, fatigue, and pneumonia. The AEs reported for the 5 patients who were required to 
discontinue treatment included Grade 2 MLN9708-related nausea/vomiting in 1 patient treated 
above the MTD, Grade 3 MLN9708-related diarrhea in a second patient, related Grade 3 
thrombocytopenia, related Grade 2 dyspnea, and notrelated Grade 4 elevation in creatinine (1 
patient each). There were no on-study deaths.  
Study C16007 is evaluating single agent weekly , Day 1, 8, and 15 of a 28-day cycle, oral 
dosing in patients with RRAL after at least 1 prior therapy. The objectives of this study are to 
determine the safety, tolerability, and MTD, as well as to determine hematologic and organ 
response rates in this patient population. The starting dose level was selected from Study 
C16004 as previously described. In Study C16007 the dose was switched from the BSA-based 
dosing to the fixed dose, thereby the 4.0 mg fixed starting dose in Study C16007 corresponds to 
the 2.23 mg/m2 dose (one dose level below MTD) from Study C16004. This study is currently 
enrolling patients in the dose-expansion portion of the trial. 
As of 30 April 2012, 14 patients have been treated in this study. At the first dose level of 4.0 
mg, 1 of 6 patients experienced a protocol-defined DLT (that is, thrombocytopenia that lasted 
more than 2 weeks, which met the definition of a DLT due to the delay in starting Cycle 2). As 
per protocol, the dose was escalated to 5.5 mg for the next cohort of patients where 2 of 5 
patients experienced a DLT (Grade 3 diarrhea, n=1; and Grade 2 dyspnea, Grade 2 acute rise in 
serum creatinine, and Grade 4 cardiac arrest, n=1). The latter patient did not appear to have 
cardiac AL amyloidosis by echocardiogram on study entry, but did have substantial renal 
involvement. After the occurrence of this DLT, diagnoses included cardiac involvement and 
CHF. The MTD of weekly oral MLN9708 was determined to be 4.0 mg. Following the 
establishment of the MTD, patients are currently being enrolled in to 1 of 2 cohorts: proteasome 
inhibitor naïve or proteasome inhibitor exposed.21 
As of the 30 April 2012 data cut, the patients enrolled in the study are considered heavily 
pretreated, as evidenced by a median number of 3 prior lines of therapy (range 1–7), with 38% 


  
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and 46% of patients having been previously treated with bortezomib and lenalidomide, 
respectively. To be eligible for the study, patients must have amyloid involvement of the heart, 
kidney, or both; at the data cut the organ involvement distribution was 6, 4, and 4 patients, 
respectively. Patients have received a median of 2.5 cycles of therapy (range, 1-12). Eight 
patients remain on treatment. Early signs of activity have been reported. There were 11 patients 
who have received at least 1 cycle of therapy with completed response assessments (9 in the 4.0 
mg [MTD] cohort and 2 in the 5.5 mg cohort). The overall hematologic response rate at MTD is 
56% (5 patients achieved a hematologic response [4 VGPR and 1 PR]; 3 patients showed no 
change, and 1 patient had an early progression.  
A summary of the safety profile of patients treated in Study C16007 is outlined in Table 1-5. 
Overall, 86% of patients experienced a TEAE of any grade and of any cause. 
Table 1-5    
Study C16007, Oral MLN9708, Single Agent Given Weekly  Most 
Common TEAEs as of 30April 12 (N = 14) 
Most Common (> 20%) 
Any Grade and Irrespective of Cause 
Nausea (50%) 
Fatigue (36%) 
Thrombocytopenia (29%) 
Diarrhea (29%) 
Decreased Appetite (21%) 
Peripheral Edema (21%) 
Dyspnea (21%) 
Abdominal pain (21%) 
Drug-Related Grade  3 in more than 3 Patients  
Thrombocytopenia 5 patients, rash 3 patients, 
dehydration 2 patients, fatigue 2 patients 
 
Source: MLN9708 Investigator’s Brochure Edition 6 
One patient discontinued study drug administration due to a TEAE (patient with DLT of acute 
rise in serum creatinine, dyspnea, and cardiac arrest treated at 5.5 mg, as noted above). No death 
has been reported. 
The potential risks reported with MLN9708 use, pooled from all studies using the oral 
formulations, were anticipated based on preclinical data and previous experience with 
VELCADE and are noted in the MLN9708 IB, SMA, and ICF documents. Regardless of 
whether MLN9708 is administered on the once weekly or twice weekly dosing schedule, there 
is consistency among the type of TEAEs reported, despite some differences in the frequency and 
severity of the reported events. While the predominant potential toxicities may be severe in 
some cases, they are largely reversible, and can be managed by routine clinical monitoring and 


  
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standard medical interventions, which may include dose reductions and supportive care.  Please 
refer to the MLN9708 IB and SMA for further information. 
1.2.7    
MLM9708 in Newly Diagnosed Multiple Myeloma (NDMM) 
In Study C16005, MLN9708 is given weekly (Days 1, 8, and 15), in combination with 
lenalidomide (Days 1-21), and dexamethasone (Days 1, 8, 15, and 22) in a 28-day cycle.  
Enrollment to this study is closed.   
Clinical data as of 30 April 2012 is available.  The MTD in Study C16005 was determined to be 
2.97 mg/m2 given weekly in a 28-day cycle with LenDex.  The DLTs were urticarial rash, 
dizziness, nausea, orthostatic hypotension, vomiting, diarrhoea, and syncope.  The 
recommended phase 2 dose (RP2D) estimation was established following evaluation of the 
available data from the phase 1 portion of the trial which included, but was not limited to, 
analyses of efficacy results and adverse events (Grade 3/4 AEs, SAEs, all grades peripheral 
neuropathy, and treatment discontinuation).  Given that the dose of MLN9708 at 2.97 mg/m2 
compromised the maximal dosing of lenalidomide and that the dose of 2.23 mg/m2 is very 
tolerable and clinically active, Millennium designated 2.23 mg/m2 as the RP2D after evaluation 
of the data and discussion with investigators.  The RP2D of 2.23 mg/m2 has been translated into 
a fixed dose of 4.0 mg based on the results from the population PK analysis.  Enrollment in 
this study has been completed; final study results are not available, but preliminary data 
suggests oral MLN9708 given weekly plus lenalidomide and dexamethasone in a 28-day cycle 
appears well tolerated with manageable toxicity and encouraging antitumor activity.   
In Study C16005, 15 of 15 (100%) patients in the dose escalation portion of the study 
experienced at least 1 TEAE irrespective of grade or causality.  At the MTD across all dose 
expansion cohorts 49 of 53 patients (including 3 patients from the dose escalation cohort [92%]) 
reported at least 1 TEAE irrespective of grade or causality.  In the MTD cohorts, fatigue was the 
most common AE reported (38%).  Other common AEs reported include nausea (32%), 
constipation (30%), upper respiratory infection (23%), and peripheral oedema (21%).  Skin 
toxicity, primarily erythematous rash, occurred in 62% of patients (of note, rash is an 
overlapping toxicity with MLN9708 and lenalidomide).  Peripheral neuropathy was reported in 
13% of patients; Grade 3 in 1 patient.   
A summary of the overall safety profile of patients treated in Study C16005 is outlined in Table 
1-6.  Overall, 100% of 65 patients experienced at least one TEAE of any grade and of any cause.   
Table 1-6    
Study C16005:  Oral MLN9708 Given Weekly in Combination With 
Lenalidomide and Dexamethasone, Most Common TEAEs as of 30 
April 2012 
Most Common (> 20%) Any Grade and Irrespective of 
Fatigue (37%) 


  
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Cause 
Nausea (34%) 
Constipation (31%) 
Vomiting (28%) 
Diarrhoea (26%) 
Thrombocytopenia (23%) 
Upper respiratory tract infection (22%) 
Anaemia and oedema peripheral ( 20% each) 
Drug-Relateda Grade  3 in  2 Patients  
Nausea, vomiting (n=3 each)  
Thrombocytopenia, lymphopenia, rash pruritic (n=2 each ) 
 
Source: MLN9708 Investigator’s Brochure Edition 6. 
a 
Related means to ANY drug in the study drug combination. 
 
The most common drug-related SAEs reported in Study C16005 as of 30 April 2012 include 
pneumonia, infection, diverticulitis, localised infection, gastrointestinal haemorrhage, 
respiratory syncytial virus (RSV) pneumonia faecaloma, pyrexia, pneumonia respiratory 
syncytial viral, non-cardiac chest pain, peripheral oedma, asthenia, hyponatraemia vomiting, 
diarrhoea, nausea, chest pain, dehydration, anemia, dizziness, peripheral sensory neuropathy, 
orthostatic hypotension, embolism, muscular weakness, acute renal failure, blood creatinine 
increased, maculopapular rash, atrial fibrillation, syncope, hypotension, and deep vein 
thrombosis, and back pain.   
As of the clinical data cutoff, 4 patients have discontinued treatment due to TEAEs including 
gastrointestinal haemorrhage, angioedema, syncope, and RSV pneumonia. 
One death was reported for a patient with RSV pneumonia; the event was deemed by the 
investigator to be related to treatment with MLN9708.   
1.2.7.1  
Clinical Trial Experience Using the Intravenous Formulation of MLN9708 
See the IB for descriptions of the 2 ongoing studies investigating IV MLN9708 in advanced 
solid tumors and advanced lymphoma (Studies C16001 and C16002, respectively). 
1.3 
Pomalidomide 
Pomalidomide is a thalidomide analogue indicated for patients with multiple myeloma who 
have received at least two prior therapies including lenalidomide and bortezomib and have 
demonstrated disease progression on or within 60 days of completion of the last therapy. 
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POMALYST is an immunomodulatory antineoplastic agent. The chemical name is (RS)-4-
Amino-2-(2,6-dioxo-piperidin-3-yl)-isoindoline-1,3-dione and it has the following chemical 
structure: 
 
 
POMALYST is available in 1 mg, 2 mg, 3 mg and 4 mg capsules for oral administration. Each 
capsule contains pomalidomide as the active ingredient and the following inactive ingredients: 
mannitol, pregelatinized starch and sodium stearyl fumarate. The 1 mg capsule shell contains 
gelatin, titanium dioxide, FD&C blue 2, yellow iron oxide, white ink and black ink. The 2 mg 
capsule shell contains gelatin, titanium dioxide, FD&C blue 2, yellow iron oxide, FD&C red 3 
and white ink. The 3 mg capsule shell contains gelatin, titanium dioxide, FD&C blue 2, yellow 
iron oxide and white ink. The 4 mg capsule shell contains gelatin, titanium dioxide, FD&C blue 
1, FD&C blue 2 and white ink. 
1.3.1      Mechanism of Action 
Pomalidomide, an analogue of thalidomide, is an immunomodulatory agent with antineoplastic 
activity. In in vitro cellular assays, pomalidomide inhibited proliferation and induced apoptosis 
of hematopoietic tumor cells. Additionally, pomalidomide inhibited the proliferation of 
lenalidomide-resistant multiple myeloma cell lines and synergized with dexamethasone in both 
lenalidomide-sensitive and lenalidomide-resistant cell lines to induce tumor cell apoptosis. 
Pomalidomide enhanced T cell- and natural killer (NK) cell-mediated immunity and inhibited 
production of pro-inflammatory cytokines (e.g., TNF-α and IL-6) by monocytes. Pomalidomide 
demonstrated anti-angiogenic activity in a mouse tumor model and in the in vitro umbilical cord 
model. 
1.3.2    Pharmakokinetics 
Absorption 
Following administration of single oral doses of POMALYST, the Cmax for pomalidomide 
occurs at 2 and 3 hours post dose. The systemic exposure (AUC) of pomalidomide increases in 


  
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an approximately dose proportional manner. In patients with multiple myeloma who received 
POMALYST 4 mg daily alone or in combination with dexamethasone, pomalidomide steady- 
state drug exposure was characterized by AUC(Τ) of 400 ng.hr/ mL and maximum plasma 
concentration (Cmax) of 75 ng/mL. Following multiple doses, pomalidomide has an 
accumulation ratio of 27 to 31 %. 
Distribution 
Pomalidomide has a mean apparent volume of distribution (Vd/F) between 62 and 138 L at 
steady state. Pomalidomide is distributed in semen of healthy subjects at a concentration of 
approximately 67% of plasma level at 4 hours post-dose (~Tmax) after 4 days of once daily 
dosing at 2 mg. Human plasma protein binding ranges from 12% to 44% and is not 
concentration dependent. 
Metabolism 
Pomalidomide is primarily metabolized in the liver by CYP1A2 and CYP3A4. In vitro, 
CYP1A2 and CYP3A4 were identified as the primary enzymes involved in the CYP-mediated 
hydroxylation of pomalidomide, with additional minor contributions from CYP2C19 and 
CYP2D6. 
Elimination 
Pomalidomide is eliminated with a median plasma half-life of approximately 9.5 hours in 
healthy subjects and approximately 7.5 hours in patients with multiple myeloma. Pomalidomide 
has a mean total body clearance (CL/ F) of 7-10 L/ hr. 
Following a single oral administration of [14C]-pomalidomide (2 mg) to healthy subjects, 
approximately 73% and 15% of the radioactive dose was eliminated in urine and feces, 
respectively, with approximately 2% and 8% of the radiolabeled dose eliminated unchanged as 
pomalidomide in urine and feces. 
1.3.3   Non-clinical Toxicology 
Carcinogenesis, Mutagenesis, Impairment of Fertility  
Studies examining the carcinogenic potential of pomalidomide have not been conducted. One of 
twelve monkeys dosed with 1 mg/kg of pomalidomide (an exposure approximately 15-fold of 


  
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the exposure in patients at the recommended dose of 4 mg/per day) developed acute myeloid 
leukemia in a 9-month repeat-dose toxicology study. 
Pomalidomide was not mutagenic or clastogenic in a battery of tests, including the bacteria 
reverse mutation assay (Ames test), the in vitro assay using human peripheral blood 
lymphocytes and the micronucleus test in orally treated rats administered doses up to 2000 
mg/kg/day. 
In a fertility and early embryonic development study in rats, drug-treated males were mated with 
untreated or treated females. Pomalidomide was administered to males and females at doses of 
25 to 1000 mg/kg/day. When treated males were mated with treated females, there was an 
increase in post-implantation loss and a decrease in mean number of viable embryos at all dose 
levels. There were no other effects on reproductive functions or the number of pregnancies. The 
lowest dose tested in animals resulted in an exposure (AUC) approximately 100-fold of 
theexposure in patients at the recommended dose of 4 mg/day. When treated males on this study 
were mated with untreated females, all uterine parameters were comparable to the controls. 
Based on these results, the observed effects were attributed to the treatment of females. 
Pomalidomide does not inhibit or induce CYP450 enzymes or any of the transporters in vitro. 
1.3.4   Clinical Studies 
Multiple Myeloma 
The trial that led to the recent approval of pomalidimide was a Phase 2, multicenter, randomized 
open label study in patients with relapsed multiple myeloma who were refractory to their last 
myeloma therapy and had received lenalidomide and bortezomib. Patients were considered 
relapsed if they had achieved at least stable disease for at least one cycle of treatment to at least 
one prior regimen and then developed progressive disease. Patients were considered refractory if 
they experienced disease progression on or within 60 days of their last therapy. A total of 221 
patients were randomized to receive pomalidomide alone or pomalidomide with Low dose Dex. 
In Trial 1, the safety and efficacy of pomalidomide 4 mg, once daily for 21 of 28 days, until 
disease progression, were evaluated alone and in combination with Low dose Dex (40 mg per 
day given only on Days 1, 8, 15 and 22 of each 28-day cycle for patients 75 years or younger, or 
20mg per day given only on Days 1, 8, 15 and 22 of each 28-day cycle for patients greater than 
75 years of age). Patients in the pomalidomide alone arm were allowed to add Low dose Dex 
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Most common adverse reactions (≥30%) included fatigue and asthenia, neutropenia, anemia, 
constipation, nausea, diarrhea, dyspnea, upper- respiratory tract infections, back pain and 
pyrexia (6.1). 
A recent phase III randomized trial comparing pomalidomide plus dexamethasone, to high-dose 
dexamethasone alone in patients with relapse and refractory MM, demonstrated higher response 
rates, PFS and OS in the pomalidomide arm. Ten percent (10%) of patients treated on the 
dexamethasone alone arm achieved an objective response and 31% of the patients on the 
combination arm with pomalidomide and low-dose dexamethasone achieved a response; odds 
ratio [OR] 4·22 [2·35 –7·58] p<0·0001 . 26 The treatment regimens most commonly used in 
Europe are very different from those used in the United States, as patient access to many of the 
novel agents is more limited in Europe. None of the patients enrolled/treated in that trial had 
been previously treated with carfilzomib or pomalidomide. For this trial, where MLN9708 will 
be added to pomalidomide and dexamethasone, patients with prior exposure to either of these 
agents would not be excluded. As many patients (>50%) are likely to have been previously 
treated with one or both of these agents we consider a response rate of 30% sufficient efficacy to 
justify further development. 
1.4      Study Rationale 
Pomalidomide is the newest immunomodulatory drug that is chemically a combination of 
thalidomide and lenalidomide. It has been studied in phase I-III trials for patients with relapsed 
myeloma.  It has shown activity even in lenalidomide refractory patients and phase III trials 
have demonstrated superior overall and progression free survival (OS/PFS) compared to high 
dose dexamethasone.  22,23 
MLN9708 is a next generation small molecule 20-s proteasome inhibitor generated with the aim 
of improving the efficacy seen with bortezomib in MM but further improvement in drug 
administration. It has shown activity in the relapsed and relapsed/refractory MM setting 
including bortezomib refractory patients. 24 Therefore given the synergy seen with IMIDS and 
proteasome inhibitors as well as the activity of both compounds in relapsed MM, this becomes 
an attractive combination for study in the relapsed/relapsed refractory setting. 
Dosing Justification 
As mentioned above, the standard FDA approved dose of pomalidomide is 4mg days 1-21. 
Maximum response is seen when it is combined with dexamethasone. Because of an impetus in 
myeloma therapy to be relatively steroid sparing, the generally accepted dose of dexamethasone 


  
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is a “ Low dose” weekly dosing of 40mg. Data generated from the MLN9708 plus lenalidomide 
and dexamethasone trial confirmed the tolerability of this new proteasome inhibitor with an 
IMID. The RP2D of MLN9708 is 4mg d1,8,15.  However, the potential for overlapping 
hematologic toxicity especially in a more advanced disease population with pomalidomide 
(which tends to be more myelosuppressive than lenalidomide) in conjunction with MLN9708 
led to the choice of an initial dose of 3mg for MLN9708. Because of the synergy between 
IMIDS and proteasome inhibitors we would still expect to see activity at this dose. 
1.5 
Potential Risks and Benefits 
Please refer to the current MLN9708 Investigator’s Brochure (IB) and the Package Insert for 
pomalidomide. 
MLN9708 is a modified dipeptide boronic acid proteasome inhibitor similar to VELCADE, 
which has a known safety profile [VELCADE PI].  The most frequent AEs reported to date in 
the ongoing MLN9708 phase 1 studies were anticipated based on preclinical data and previous 
experience with VELCADE, and are noted in the IB, and the informed consent documents. 
However, it is possible that MLN9708 will have toxicities that were not previously observed in 
or predicted from such sources. Patients will be monitored closely for anticipated toxicities.  
The toxicity profile of MLN9708 and pomalidomide in combination with dexamethasone is 
unknown and will be evaluated in this trial. 
MLN9708 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 11,12,13,14,16,17,18. 
This study will be conducted in compliance with the protocol, good clinical practice (GCP), 
applicable regulatory requirements, and International Conference on Harmonisation (ICH) 
guidelines.  
2.    
STUDY OBJECTIVES 
2.1    Study Objectives (Phase I) 
2.1.1     Primary: 
1. To determine the recommended phase II dose (RP2D) of MLN9708, when given in 
combination with pomalidomide and dexamethasone, in patients with relapsed or 
relapsed/refractory multiple myeloma. 


  
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2.1.2     Secondary: 
2. To evaluate the safety of MLN9708 at each dose level when given as part of a three drug 
combination by assessing the following: 
 
- type, frequency, severity, attribution, time course and duration of adverse events 
 
- clinical laboratory tests at various points in the study 
2.2    Study Objectives (Phase II) 
2.2.1    Primary: 
1. To estimate the response rate and to evaluate the antitumor activity of the three drug 
combination: MLN9708 (at the RP2D), pomalidomide and dexamethasone, in patients with 
relapsed or relapsed/refractory multiple myeloma.  
2.2.2    Secondary: 
At the RP2D, for the three drug combination: 
2. To characterize and evaluate toxicities, including type, frequency, severity, attribution, time 
course and duration. 
3. To obtain estimates of response duration, depth of response, clinical benefit response, and 
survival (overall and progression-free). 
3.    
STUDY ENDPOINTS 
3.1    Primary Endpoints  
Phase I: 
The primary endpoint is toxicity. Toxicity will be graded according to the NCI-Common 
Terminology Criteria for Adverse Events version 4.03.  A DLT will be defined as any of the 
following toxicities that are at least possibly related to either Pomalidomide or MLN9708 and 
occur during cycle 1:  
 Grade 4 neutropenia  
 Grade 3 neutropenia with fevers > 38.5°C 
 Grade 4 thrombocytopenia  
 Grade 3 thrombocytopenia with bleeding 


  
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 Grade 3 or higher non-hematological toxicity will be considered dose limiting, with the 
following exceptions: diarrhea, fatigue, nausea or vomiting will only be considered dose 
limiting if, after 48 hours it has not recovered to <Grade 3 (despite maximal medical 
therapy), allergic reaction/hypersensitivity, or electrolyte/metabolic toxicity unable to be 
corrected to <Grade 1 or baseline within 48 hours will be considered dose limiting. 
 Delay in starting cycle 2 on the scheduled day 1 for > 7 days due to treatment related 
toxicity 
 Any dose modification or delay during cycle 1, except modifications/delays done in 
response to hypo- hyperthyroidism <=Grade 2, herpes zoster infection, all considered 
idiopathic or intrinsic to the underlying myeloma. 
 
Phase II: 
The primary activity endpoint is response rate (confirmed sCR/CR/VGPR or PR), based on the 
International Myeloma Working Group (IMWG) criteria, calculated as the number of 
responders divided by the number of evaluable patients. Confirmation of sCR/CR/VGPR or PR 
assessed by IMWG criteria. 
Secondary activity endpoints for this study are as follows: 
 Duration of response, defined as the time interval from the date of first documented 
response (sCR/CR/VGPR or PR) to documented disease relapse, progression or death 
whichever occurs first. 
 Clinical benefit response, based on the International Myeloma Working Group (IMWG) 
criteria, calculated as the number of responders plus those with a minimal response 
(MR) or stable disease (SD) divided by the number of evaluable patients. Confirmation 
of sCR/CR/VGPR/PR/MR or SD assessed by IMWG criteria. 
 Overall survival, defined as the time interval from date of first dose of study drug to date 
of death from any cause. 
 Progression-free survival, defined as the time interval from date of first dose of study 
drug to first documented disease relapse, progression or death from any cause, 
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4.    
STUDY DESIGN  
4.1    Overview of Study Design 
4.1.1    Phase I: 
The phase I portion of the study is based on a 3 + 3 dose escalation design, to evaluate toxicities 
associated with MLN9708 when given in combination with pomalidomide and dexamethasone. 
Two doses of MLN9708 (dose level -1 and dose level 1: 3mg; dose level 2: 4mg) will be tested 
in up to three possible dose levels. Based on previous combination trials of MLN9708, the 4mg 
dose of MLN9708 is expected to be well tolerated. Given that this is the first study to combine 
MLN9708, with dexamethasone and pomalidomide, patients will initially be treated at a 3mg 
dose. The maximum tolerated dose (MTD) will be established by evaluating dose limiting 
toxicity (DLT) during cycle 1. The recommended phase II dose (RP2D) of MLN9708 and 
pomalidomide will generally be the MTD, but it may be less than the MTD  based on a review 
of available data/cumulative toxicities from phase I. Patients will be treated with oral MLN9708  
on days 1, 8, and 15 of each 28 day cycle and with Dexamethasone on days 1, 8, 15 and 22 of 
each 28 day cycle.  Pomalidomide will be given on days 1-21 of each 28 day cycle. The dose of 
MLN9708 and Pomalidomide administered will depend on the dose level assignment; the dose 
of dexamethasone will be fixed (Patients >75 years, at the time of trial registration, will receive 
a Dexamethasone starting dose of 20 mg on the same set schedule). 
 
    Phase II  
Patients who enroll during the phase II portion of the trial will  be treated at the same dose and 
schedule of MLN9708, pomalidomide and dexamethasone determined safe during the phase I 
study (the RP2D). 
4.2    Number of Patients 
The phase I study is expected to enroll and treat 9 patients; 3 patients at dose level 1, and 
another 6 treated at dose level 2 -assuming the 4mg dose of MLN9708 is well tolerated. The 
phase II portion of the trial is expected to enroll a minimum of 9 and a maximum of 25 patients. 
The six patients treated at the RP2D in the phase I portion of the study will count toward the 25 
patients required; given this, we expect to enroll only 19 new patients on the phase II trial. 
4.3    Duration of Study 
Accrual, for both phases, is expected to be completed in 26 months; with approximately 2 
patients enrolled each month. Patients will be treated in 28-day treatment cycles until disease 
relapse, progression or unacceptable toxicity, withdrawal of consent, or protocol specified 
parameters to stop treatment. Patients who discontinue study treatment for reasons other than 
disease relapse/progression will continue to have disease assessments per International 
Myeloma Working Group (IMWG) criteria until relapse or progression, initiation of new 


  
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anticancer treatment, or death whichever occurs first.  Patients will be followed to collect further 
anticancer treatment and survival information until death, loss to follow-up, withdrawal of 
consent, study termination or up to 24 months post treatment. 
5.    
STUDY POPULATION 
5.1    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 informed 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. Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy 
test with a sensitivity of at least 25 mIU/mL within 10 – 14 days prior to and again within 
24 hours of starting pomalidomide or MLN9708 and must either commit to continued 
abstinence from heterosexual intercourse or begin TWO acceptable methods of birth 
control, one highly effective method and one additional effective method AT THE SAME 
TIME, at least 28 days before she starts taking pomalidomide or MLN9708 through 90 
days after the last dose of study drug.  FCBP must also agree to ongoing pregnancy 
testing.  Men must agree to use a latex condom during sexual contact with a FCBP even if 
they have had a vasectomy from the time of signing the informed consent form through 90 
days after the last dose of study drug.  All patients must be counseled at a minimum of 
every 28 days about pregnancy precautions and risks of fetal exposure.  
4. All patients enrolled into this trial, must be registered in and must comply with all 
requirements of the POMALYST REMS™ program.  
5. Patients must have a diagnosis of relapsed or relapsed and refractory Multiple Myeloma 
with a minimum of one prior regimen and a maximum of 5 prior regimens.  
6. Patients must have had therapy with a proteasome inhibitor and lenalidomide and be 
refractory to lenalidomide according to the IMWG definition of refractory disease 
(progressive disease on or within 60 days of stopping lenalidomide). 
7. Patients must have measurable disease defined as one of the following: 


  
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a. Serum M protein ≥ 0.5 g/dL 
b. Urine M protein ≥ 200 mg/24 hours 
c. Serum free light chain ≥ 10 mg/dL provided the FLC ratio is abnormal. 
8. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2. 
9. Patients must meet the following clinical laboratory criteria: 
 Absolute neutrophil count (ANC)  1,000/mm3  
 Platelet count > 75,000/µL for patients in whom < 50% of bone marrow nucleated 
cells are plasma cells; or a platelet count > 50,000/µL for patients in whom > 50% of 
bone marrow nucleated cells are plasma cells. Platelet transfusions are not allowed 
within 3 days of last platelet assessment to confirm eligibility.     
 Total bilirubin  1.5  the institutional upper limit of the normal range (IULN). 
 Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)  3  IULN. 
 Calculated creatinine clearance  45mL/min (see Appendix 15.2). 
5.2    Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study: 
1. Female patients who are pregnant or breastfeeding 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. 
3. Prior therapy with a combination regimen containing pomalidomide except the 2 
drug combination of pomalidomide and dexamethasone.  
4. Major surgery within 14 days before enrollment. 
5. Radiotherapy within 14 days before enrollment. If the involved field is small, 7 days 
will be considered a sufficient interval between treatment and administration of the 
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6. Central nervous system involvement. 
7. Infection requiring systemic antibiotic therapy or other serious infection within 
14 days before study enrollment. 
8. 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. 
9. Systemic treatment, within 14 days before the first dose of MLN9708, 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. 
10. Unable or unwilling to undergo antithrombotic prophylaxis. 
11. Ongoing or active systemic infection, active hepatitis B or C virus infection, or 
known human immunodeficiency virus (HIV) positive. 
12. Any serious medical or psychiatric illness that could, in the investigator’s opinion, 
potentially interfere with the completion of treatment according to this protocol. 
13. Known allergy to any of the study medications, their analogues, or excipients in the 
various formulations of any agent. 
14. Known GI disease or GI procedure that could interfere with the oral absorption or 
tolerance of MLN9708 or pomalidomide including difficulty swallowing. 
15. Diagnosed or treated for another malignancy within 2 years before study enrollment 
or previously diagnosed with another malignancy with evidence of residual disease.  
Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not 
excluded if they have undergone complete resection. 
16. Patient has > Grade 2 peripheral neuropathy on clinical examination during the 
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17. Participation in other clinical trials, including those with other investigational agents 
not included in this trial, within 21days of the start of this trial and throughout the 
duration of this trial (for all other standard therapies, no treatment within 14 days of 
the start of this trial). 
18. Patients who are pomalidomide refractory, defined as patients who progress on or 
within 60 days of pomalidomide when given as a single agent or with 
dexamethasone. 
6.    
  PATIENT ENROLLMENT 
Phase I Dose Escalation Portion – Prior to discussing protocol entry with the patient, contact 
the City of Hope Data Coordinating Center to ensure that a treatment slot on the protocol is 
available. 
 
Phase I and II Patient Enrollment  
The screening period for a particular patient commences when the patient signs the informed 
consent.  Consent must be signed before any study-specific tests may be performed. After a 
patient has been screened and has successfully fulfilled all eligibility criteria, the site 
representative will email the inclusion/exclusion checklist and all other required source 
documentation to the City of Hope Data Coordinating Center.  In order to ensure 
privacy/security, please ensure that you type #secure# in the subject line of all correspondence 
related to the trial/patient: 
Lupe Duarte, CCRC 
Multiple Myeloma Project Manager 
Phone:  626-256-4673 x 63968 
Fax:  626 301-8422 
Email: dcc@coh.org 
 
A unique patient number will be assigned at that time that will be used to identify the patient 
throughout the clinical study and must be used on all study documentation related to that 
patient.  Patients will be assigned to a dose level at enrollment.  Prior to accepting the 
registration, the COH DCC staff member will verify the following: 
 


  
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1. IRB approval at the registering institution 
2. Patient eligibility 
3. Existence of a signed consent form 
4. Existence of a signed authorization for use and disclosure of protected health 
information (if applicable). 
Treatment cannot begin prior to registration and must begin < 7 days after registration.  
Pretreatment tests/procedures must be completed within the guidelines specified on the test 
schedule.  
7.  STUDY TREATMENT 
7.1   Dose and Schedule 
The phase I study will follow a standard 3 + 3 dose escalation design, to evaluate toxicities 
associated with MLN9708 when given in combination with pomalidomide and dexamethasone. 
Two doses of MLN9708 (3 mg and 4 mg) will be tested in up to three possible dose levels.  
7.2   Dose Levels to be Tested 
Schedule: Each cycle is 28 days  
Dose Level 
Pomalidomide  
MLN9708 
Dexamethasone* 
-1 
3mg daily on days 1-21 
3 mg on days 1, 8 and 15 
40 mg on days 1, 8, 15 and 22 
1 
4 mg daily on days 1 - 21 
3 mg on days 1, 8 and 15 
40 mg on days 1, 8, 15 and 22 
2 
4 mg daily on days 1 - 21 
4 mg on days 1, 8 and 15 
40 mg on days 1, 8, 15 and 22 
*: Patients >75 years, at the time of trial registration, will receive a Dexamethasone dose of 20 
mg on the same set schedule. 
 
7.3  Dose Limiting Toxicity/Unacceptable Toxicity 
Dose Limiting Toxicity (DLT) is defined as any of the following toxicities that are at least 
possibly related to either Pomalidomide or MLN9708 that occur during cycle 1. Toxicity will be 
graded according to the NCI-Common Terminology Criteria for Adverse Events, Version 4.03. 


  
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Note: The Phase II portion of the study will use the same definition to define unacceptable 
toxicity. 
For the purposes of this study, DLT will be defined as: 
 Grade 4 neutropenia  
 Grade 3 neutropenia with fevers > 38.5°C 
 Grade 4 thrombocytopenia  
 Grade 3 thrombocytopenia with bleeding 
 Grade 3 or higher non-hematological toxicity will be considered dose limiting with the 
following exceptions: diarrhea, fatigue, nausea or vomiting will only be considered dose 
limiting if, after 48 hours it has not recovered to <Grade 3 (despite maximal medical 
therapy), allergic reaction/hypersensitivity, or electrolyte/metabolic toxicity unable to be 
corrected to <Grade 1 or baseline within 48 hours will be considered dose limiting.  
 Delay in starting cycle 2 on the scheduled day 1 for > 7 days due to treatment related 
toxicity 
 Any dose modification or delay of MLN9708 or Pomalidomide during cycle 1, except 
modifications/delays done in response to hypo- hyperthyroidism <=Grade 2, herpes 
zoster infection, all considered idiopathic or intrinsic to the underlying myeloma.  
 
7.4    Dose Escalation/Expansion 
DLT incidence will be based on toxicity events encountered during the first cycle of treatment 
with the combination of MLN9708, pomalidomide and dexamethasone. 
Dose de-escalation, escalation or cohort expansion will only take place after 3 patients are fully 
assessed using the Common Terminology Criteria for Adverse Events (CTCAE) of the National 
Cancer Institute (NCI) version 4.03 following the completion of cycle 1.  
Dose escalation will occur according to the following rules: 
 If zero out of 3 evaluable patients has a DLT in cycle 1 then the next dose level of 
combination therapy will be tested. 
 If 1 out of 3 evaluable patients has a DLT in cycle 1, three additional patients will be 
assessed at the same dose level of combination therapy. 
 If 2 out of 3 patients have a DLT in cycle 1, dose escalation will cease and the next 
lower dose level of combination therapy will be expanded. Note: If 2 of 3 experience 
DLT on dose level -1, the trial will be stopped. 
 If 1 out of 6 evaluable patients has a DLT in cycle 1, then dose escalation to the next 
dose level of combination therapy will continue.  


  
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 If 2 or more out of 6 patients have a DLT in cycle 1, dose escalation will cease and the 
next lower dose level of combination therapy will be expanded. Note: If 2 of 6 
experience DLT on dose level -1 the trial will be stopped. 
The highest dose level that produces ≤1/6 DLTs in cycle 1 will be the maximum tolerated dose 
(MTD). 
Note:  Patients may continue therapy unless there is unacceptable toxicity, disease progression 
or withdrawl of consent.   
7.5   Recommended Phase II Dose (RP2D) 
The MTD will be based on the assessment of DLT during cycle 1 (see section 7.4). The MTD 
will be defined as the highest dose at which ≤ 1/6  patients in a cohort experience DLT. The 
recommended phase II dose (RP2D) of MLN9708 and pomalidomide will generally be the 
MTD, but it may be less than the MTD  based on a review of available data/cumulative 
toxicities from phase I.   
7.6    Study Drug 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 study drug should be modified as 
needed to accommodate patient tolerance to treatment; this may include symptomatic treatment, 
dose interruptions, and adjustments of dose. 
7.6.1   MLN9708 Administration 
Patients should be instructed to swallow MLN9708 capsules whole, with water, and not to 
break, chew, or open the capsules.  MLN9708 should be taken on an empty stomach (no food or 
drink) at least 1 hour before or 2 hours after a meal.  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. 


  
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7.6.2    Pomalidomide Administration 
Pomalidomide capsules should be swallowed whole, and should not be broken, chewed or 
opened.  Pomalidomide should be taken without food, at least 2 hours before or 2 hours after a 
meal.  Pomalidomide capsules may be taken with water.  
If a dose of pomalidomide is missed, it should be taken as soon as possible on the same day.  If 
it is missed for the entire day, it should not be made up, rather it should be taken at the next 
scheduled time point. Similarly, 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. 
Patients who take more than the prescribed dose of pomalidomide should be instructed to seek 
emergency medical care if needed and contact study staff immediately.   
Pomalidomide (POMALYST®) will be provided to research patients for the duration of their 
participation in this trial at no charge to them or their insurance providers.  Pomalidomide will 
be provided in accordance with the Celgene Corporation’s POMALYST REMS™  program.  
Per the standard   POMALYST REMS™ program requirements, all physicians who prescribe 
pomalidomide for research patients enrolled into this trial, and all research patients enrolled into 
this trial, must be registered in and must comply with all requirements of the POMALYST 
REMS™ program.   
Drug will be shipped on a per patient basis by the contract pharmacy to the clinic site for IND 
studies.  Only enough pomalidomide for one cycle of therapy will be supplied to the patient 
each cycle.  This is in accordance with the POMALYST REMS™ program. 
Special Handling Instructions 
Female caregivers of childbearing potential should not handle or administer pomalidomide 
unless they are wearing gloves. 
7.6.3    Dexamethasone Administration 
Dexamethsone is commercially available and commercial supplies will be used for this study. 
Oral dexamethasone will be given on an outpatient basis. Missed doses of dexamethasone will 
not be made up.  Similarly, 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. Procedures for dose 
reductions and delays are summarized in Section 7.9.2. 


  
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7.6.4  Growth Factor Administration 
For the Phase I portion of the study, growth factors, granulocyte colony stimulating factor [G-
CSF], may be given prophylactically for at least two days on days 21 – 26 during or beyond 
cycle 2. For the Phase II portion of the study, G-CSF may be given prophylactically for at least 
two days on days 21-26 during or beyond cycle 1. It will be administered subcutaneously at a 
dose of 5ug/kg or per institutional standard practice dosing either daily or every other day for a 
minimum of two doses.  If patients experience neutropenia or dosing delays, we would 
recommend consideration of growth factor in subsequent cycles. 
7.7    Dose Modification Guidelines  
Patients will be evaluated for adverse events at each visit with the NCI Common Toxicity 
Criteria, Version 4.03 used as a guide for the grading of severity.   
As defined in section 7.3, during the phase I portion of the study, any toxicity related dose 
modification 
or 
delay 
of 
MLN9708 
or 
Pomalidomide 
during 
cycle 
1 
except 
modifications/delays done in response to hypo- hyperthyroidism <=Grade 2, herpes zoster 
infection, all considered idiopathic or intrinsic to the underlying myeloma is a DLT.  No dose 
escalations are permitted in any given patient once a dose level has been assigned.  While 
patients experiencing DLT during Cycle 1 may continue on therapy, if toxicity can be managed 
according to the dose modification guidelines outlined below,  the DLT event will contribute to 
the assessment of MTD for that given cohort. Patients will be considered evaluable for toxicity 
if they receive any study drug. Patients will be considered evaluable for dose limiting toxicity if 
they receive at least 75% of both Pomalidomide and MLN9708 and are followed for the full 28 
days during cycle 1  or experience a DLT. For the phase II portion, as part of the primary 
analysis, patients will be considered evaluable for response if they are eligible, have baseline 
disease assessments, and receive any protocol treatment. As part of a secondary analysis, 
patients will be considered evaluable for response if they have baseline disease assessments, 
receive at least 75% of both Pomalidomide and MLN9708 during the first cycle of therapy and 
have had their disease re-evaluated.    
Dose modifications may be performed in all subsequent cycles of treatment regardless of which 
phase of study the patient  is enrolled on.  If toxicities cannot be managed by dose modification 
or the patient cannot tolerate the lowest dose of study drug, the patient is to be discontinued 
from study treatment.  However, patients that have achieved a plateau of response to study 


  
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therapy will continue to adhere to the schedule of assessments followed during the treatment 
phase of the study even though study drug has been discontinued.  
7.8    Dose Reduction Steps  
7.8.1   Dose Reduction Steps for Pomalidomide 
Pomalidomide Dose Reduction Steps 
 
Starting Dose 
 
Daily on Days 1 – 21 every 28 days 
4.0 mg  
3.0 mg 
2.0 mg 
1.0 mg 
3.0 mg  
2.0 mg 
1.0 mg 
- 
2.0 mg  
1.0 mg 
- 
- 
1.0 mg 
- 
- 
- 
7.8.2    Dose Reduction Steps for MLN9708 
MLN9708 Dose Reduction Steps 
 
Starting Dose 
 
Daily on Days 1, 8 and 15 every 28 days 
4.0 mg  
3.0 mg 
2.3 mg 
1.5 mg 
 
3.0 mg  
2.3 mg 
1.5 mg 
- 
 
7.8.3    Dose Reduction Steps for Dexamethasone 
Dexamethasone Dose Reduction Steps** 
 
Starting Dose 
 
Days 1, 8, 15 and 22 every 28 days 
40 mg  
20 mg 
12 mg 
20 mg*  
12 mg 
6 mg 
12 mg  
- 
- 
*: Patients >75 years, at the time of trial registration, will receive a dexamethasone starting dose 
of 20 mg on the same set schedule.  
**: After the patient has been on Dexamethasone over one year, the patient can discontinue 
Dexamethasone at their next scheduled visit.     
 


  
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 Dexamethasone may be permanently discontinued for toxicity at the discretion of the 
investigator but the patient can remain on study therapy with pomalidomide and MLN9708 
if tolerated.  
 After the patient has been on Dexamethasone over one year, the patient can discontinue 
Dexamethasone at their next scheduled visit.     
7.9   Dose Modification Guidelines for Treatment Related Toxicity 
For recommended comcomitant therapy to reduce the risk/severity of potential adverse events 
refer to Section 7.11.  For recommendations on management of adverse events refer to section 
7.12.   In addition, the table below provides guidelines for dose modification based on toxicity.  
Dose modifications different from those recommended may be made in consultation with the 
Lead Principal Investigator based on investigators assessment of toxicity attribution and 
management of individual patients.  
7.9.1   Dose Modification for MLN9708 and Pomalidmide During a Cycle of 
Therapy 
Treatment modifications due to MLN9708 and Pomaliomide related AEs during a cycle of 
therapy are outlined  below. 
CTCAE Category 
AGENTS 
Toxicity During a Cycle 
Hematologic Toxicity during a cycle of therapy 
 
 
> Grade 3 neutropenia 
associated with fever 
(temperature > 38.5C) or 
Grade 4 neutropenia 
 
 
 
 
 
 
 
Pomalidomide 
 
Hold dose. Follow CBC weekly. Use of G-CSF is 
allowed 
and 
recommended. 
If 
neutropenia 
resolved to < grade 2 within the cycle, resume 
pomalidomide and continue through the scheduled 
end of the cycle.  If not resolved to ≤ grade 2, 
omit for remainder of cycle and reduce the dose of 
pomalidomide by one dose level at the start of the 
next cycle.  Omitted doses are not made up. 
Granulocyte colony stimulating factor [G-CSF], 
may be used prophylactically on days 21 – 26. 
Section7.6.4   


  
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MLN9708 
 
Hold dose. Follow CBC weekly. If neutropenia 
resolves to ≤ grade 2 resume treatment on 
schedule day of cycle. However, if the Day 8 or 
15 dose is held, that dose should be omitted and 
treatment should continue with next scheduled 
dose (i.e., if Day 8 is skipped, the next dosing day 
is Day 15) resume MLN9708 at same dose. If 
neutropenia dose not resolve to ≤ Grade 2 during 
the cycle and any 2 doses were held due to 
toxicity then reduce the MLN9708 dose by one 
level at the start of the next cycle. 
Granulocyte colony stimulating factor [G-CSF],) 
may be used prophylactically on days 21 – 26.   
Platelet count < 
25,000/mm3 or G3 
thrombocytopenia with 
bleeding 
 
 
 
 
 
Pomalidomide 
 
Hold dose. Follow CBC weekly. Use of platelet 
transfusions is allowed to proceed with dosing. If 
thrombocytopenia resolved to < grade 2 within the 
cycle, 
resume 
pomalidomide 
and 
continue 
through the scheduled end of the cycle.  If not 
resolved to ≤ grade 2, omit for remainder of cycle 
and reduce the dose of pomalidomide by one dose 
level at the start of the next cycle.  Omitted doses 
are not made up. 
MLN9708 
Hold 
dose. 
Follow 
CBC 
weekly. 
If 
thrombocytopenia resolves to ≤ grade 2 resume 
treatment on schedule day of cycle. However, if 
the Day 8 or 15 dose is held, that dose should be 
omitted and treatment should continue with next 
scheduled dose (i.e., if Day 8 is skipped, the next 
dosing day is Day 15) resume MLN9708 at same 
dose. If thrombocytopenia dose not resolve to ≤ 
Grade 2 during the cycle and any 2 doses were 
held due to toxicity  then reduce the MLN9708 
dose by one level at the start of the next cycle. 
For recurrent episodes of hematologic toxicity, MLN9708 and/ or pomalidomide may be dose 
reduced together or independently at the investigaotrs discretion to manage toxicity.  
Non-Hematologic toxicity during a cycle of therapy 
RASH 
 
Grade 2 or 3 
 
 
Pomalidomide 
Hold pomalidomide and MLN9708. Follow 
weekly. 
Implement supportive therapy (see section 7.11.2) 


  
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MLN9708 
If the toxicity resolves to < grade 1, restart 
MLN9708 and pomalidomide and continue 
through the scheduled end of the cycle.  
Otherwise, omit for remainder of cycle and reduce 
the dose of pomalidomide by one dose level at the 
start of the next cycle.  Omitted doses are not 
made up. 
For 
subsequent 
occurances, 
alternate 
dose 
reductions with MLN9708 and pomalidomide. 
Non-blistering rash 
Grade 4 
Discontinue pomalidomide and MLN9708. 
Withdraw participant from the study. 
Desquamating 
(blistering) rash-any 
Grade or Erythema 
multiforme > Grade 3 
 
Pomalidomide/ 
MLN9708 
Discontinue treatment. Withdraw participant from 
study.   
Hyperthyroidism or 
Hypothyroidism 
 
Pomalidomide 
Omit pomalidomide for remainder of cycle, 
evaluate etiology, and initiate appropriate therapy.  
Restart pomalidomide at investigator’s discretion.  
For toxicity attributable to pomalidomide, reduce 
the dose by one dose level. 
Neuropathy 
Grade 2 peripheral 
neuropathy with pain or 
Grade 3 
 
 
 
 
 
 
 
 
 
Grade 4 
 
 
Pomalidomide 
MLN9708 
Hold MLN9708.  Follow weekly. If the toxicity 
resolves to ≤ grade 1(or baseline), restart 
MLN9708 at next lower dose level and continue 
through the scheduled end of the cycle.  
Otherwise, omit for remainder of cycle and reduce 
the dose of MLN9708  one dose level at the start 
of the next cycle.  Omitted doses are not made up. 
For recurrent Grade 2 peripheral neuropathy with 
pain or grade 3 neuropathy, hold treatment. If the 
toxicity resolves to ≤ grade 1(or baseline), reduce 
pomalidomide and /or MLN9708 at investigators 
discretion.  
 
Discontinue teatment.  Withdraw participant from 
study. 
Herpes Zoster 
reactivation any grade 
Pomalidomide 
MLN9708 
Hold MLN9708 and pomalidomide until lesions 
are dry.  Initiate antiviral therapy (maintain dose 
level). 
Venous 
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Thrombosis/Embolism > 
Grade 3 
MLN9708 
appropriate; restart at investigator’s discretion 
(maintain dose level). 
Other Pomalidomide or 
MLN9708 related non-
hematologic toxicity 
Grade > 3 
 
 
Grade 4 related non-
hematologic toxicity 
Pomalidomide 
MLN9708 
Determine attribution of toxicity and hold both 
pomalidomide and MLN9708.    Follow at least 
weekly.  If toxicity resolves to < grade 1 or 
baseline, resume therapy with one level dose 
reduction. 
 
Consider permanent discontinuation of therapy.  
Exceptions may be made following discussion 
with the Lead Principal Investigator for patients 
that are experiencing clinical benefit. 
Once MLN9708 or pomalidomide is reduced for any toxicity, the dose may not be re-
escalated. 
7.9.2   Dexamethasone Dose Modification Guidelines* 
Body System 
Symptom 
Recommended Action 
Gastrointestinal 
Dyspepsia, gastric or duodenal 
ulcer, gastritis Grade 1–2  
(requiring medical management) 
Treat with H2 blockers, sucralfate, 
or omeprazole. If symptoms persist 
despite above measures, decrease 
dexamethasone dose by 1 dose level. 
Gastrointestinal 
> Grade 3  
(requiring hospitalization or 
surgery) 
Hold dexamethasone until symptoms 
adequately controlled. Restart and 
decrease one dose level of current 
dose along with concurrent therapy 
with H2 blockers, sucralfate, or 
omeprazole. If symptoms persist 
despite above measures, discontinue 
dexamethasone and do not resume. 
Gastrointestinal 
Acute pancreatitis 
Discontinue dexamethasone and do 
not resume 
Cardiovascular 
Edema 
>Grade 3 (limiting function and 
unresponsive to therapy or 
anasarca) 
Diuretics as needed, and decrease 
dexamethasone dose by 1 dose level; 
if edema persists despite above 
measures, decrease dose another 
dose level. Discontinue 
dexamethasone and do not resume if 
symptoms persist despite second 
reduction. 
Neurology 
Confusion or Mood alteration  
> Grade 2 (interfering with 
Hold dexamethasone until symptoms 
resolve. Restart with one dose level 


  
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function +/- interfering with 
activities of daily living) 
reduction. If symptoms persist 
despite above measures, discontinue 
dexamethasone and do not resume. 
Musculoskeletal 
Muscle weakness  
> Grade 2 (symptomatic and 
interfering with function +/- 
interfering with activities of 
daily living) 
Decrease dexamethasone dose by 
one dose level. If weakness persists 
despite above measures, decrease 
dose by one dose level. Discontinue 
dexamethasone and do not resume if 
symptoms persist. 
Metabolic 
Hyperglycemia > Grade 3 or 
higher 
Treatment with insulin or oral 
hypoglycemics as needed. If 
uncontrolled despite above 
measures, decrease dose by one dose 
level until levels are satisfactory. 
7.10    Criteria for Beginning or Delaying a Subsequent Treatment Cycle 
For a new cycle of treatment to begin, the patient must meet the following criteria: 
• 
ANC must be ≥ 1,000/mm3. 
• 
Platelet count must be ≥ 75,000/mm3 or  > =50,000/mm3 for patients with baseline 
platelets ≥50,000/mm3 but <75,000/mm3. 
• 
All other nonhematologic toxicity (except for alopecia) must have resolved to ≤ Grade 1 
or to the patient’s baseline condition 
If the patient fails to meet the above-cited criteria for initiation of the next cycle of treatment, 
dosing should be delayed for 1 week. At the end of that time, the patient should be re-evaluated 
to determine whether the criteria have been met. If the patient continues to fail to meet the 
above-cited criteria, delay therapy and continue to re evaluate. The maximum delay before 
treatment should be discontinued will be 3 weeks or at the discretion of the Principal 
Investigator. 
7.11    
Concomitant Medications 
7.11.1 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 
during this study.  A drug/drug interaction (DDI) with a strong inhibitor would increase 
MLN2238 (metabolite of MLN9708) exposure. 


  
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 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 to use.  A DDI with a strong 
inducer would decrease MLN2238 (metabolite of MLN9708) exposure. 
 Strong CYP3A inducers:  rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, and 
phenobarbital 
Please refer to a complete listing of prohibited medications, strong CYP3A and CYP1A2 
inhibitors 
that 
can 
be 
found 
via 
the 
following 
link:  
http://medicine.iupui.edu/clinpharm/ddis/main-table/. 
The dietary supplements St John’s wort and Ginkgo biloba are not permitted. 
The following procedures are prohibited during the study: 
 Any antineoplastic treatment with activity against MM except for drugs in this treatment 
regimen. 
 Radiation therapy (the requirement for local radiation therapy generally indicates disease 
progression). 
 Platelet transfusions to help patients meet eligibility criteria are not allowed within 
3 days before study drug dosing. 
 Adjuvant hormone therapy for breast or prostate cancer. 
7.11.2    
Permitted/Recommended 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 and is strongly recommended.  


  
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 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. 
Intravenous fluids should be given to prevent volume depletion. 
 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. 
 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.  
 Fluid deficits should be corrected before and throughout treatment. 
7.11.3  Required/Recommended Concomitant Therapy 
 Pomalidomide increases the risk of thromboembolism. Anti-coagulation prophylaxis is 
required after an assessment of each patient’s underlying risk factors, unless there is an 
excess risk of bleeding. 
 Antiviral therapy such as acyclovir is recommended for herpes prophylaxis.   
 For the Phase I portion of the study, growth factors, granulocyte colony stimulating 
factor [G-CSF], may be given prophylactically for at least two days on days 21 – 26 
during or beyond cycle 2. For the Phase II portion of the study, G-CSF may be given 
prophylactically for at least two days on days 21-26 during or beyond cycle 1. It will be 
administered subcutaneously at a dose of 5ug/kg or per institutional standard practice 
dosing either daily or every other day for a minimum of two doses.  If patients 
experience neutropenia or dosing delays, we would recommend consideration of growth 
factor in subsequent cycles. 
 Allopurinol is recommended for patients with high tumor burden due to the possibility of 
tumor lysis syndrome. 


  
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7.11.4   Pregnancy 
It is not known what effects MLN9708 has on human pregnancy or development of the embryo 
or fetus.  Pomalidomide can cause fetal harm when administered during pregnancy. Therefore, 
female patients participating in this study should avoid becoming pregnant, and male patients 
should avoid impregnating a female partner.  Females of child bearing potential* and male 
patients should use effective methods of contraception through defined periods during and after 
study treatment as specified below. 
A female of child bearing potential is any sexually mature female who: 
1) has not undergone a hysterectomy or bilateral oophorectomy; or 
2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had 
menses at any time in the preceding 24 consecutive months). 
7.11.4.1   Females  
Females of reproductive potential must commit either to abstain continuously from heterosexual 
sexual intercourse or to use two methods of reliable birth control simultaneously (one highly 
effective form of contraception – tubal ligation, IUD, hormonal (birth control pills, injections, 
hormonal patches, vaginal rings or implants) or partner’s vasectomy and one additional effective 
contraceptive method – male latex or synthetic condom, diaphragm or cervical cap. 
Contraception must begin 4 weeks prior to initiating treatment, during therapy, during dose 
interruptions and continuing for 4 weeks following discontinuation of pomalidomide or 90 days 
following discontinuation of MLN9708. Reliable contraception is indicated even where there 
has been a history of infertility, unless due to hysterectomy. Females of reproductive potential 
should be referred to a qualified provider of contraceptive methods, if needed.  
Females of reproductive potential must have 2 negative pregnancy tests before initiating 
therapy. The first test should be performed within 10-14 days, and the second test within 24 
hours prior to prescribing pomalidmide and MLN9708. Once treatment has started and during 
dose interruptions, pregnancy testing for females of reproductive potential should occur weekly 
during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in 
females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing 
should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient 
misses her period or if there is any abnormality in her menstrual bleeding.  Treatment with 
pomalidomide and MLN9708 must be discontinued during this evaluation. All study 


  
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participants must be registered into the mandatory POMALYST REMS™ program, and be 
willing and able to comply with the requirements of the POMALYST REMS™ program. 
7.11.4.2   Males  
Pomalidomide is present in the semen of males who take pomalidomide. The effects of 
MLN9708 are unknown. Therefore, males must always use a latex or synthetic condom during 
any sexual contact with females of reproductive potential while taking pomalidomide or 
MLN9708 and for up to 28 days after discontinuing pomalidomide or 90 days after 
discomtinuation of MLN9708, even if they have undergone a successful vasectomy. Male 
patients taking pomalidmide or MLN9708 must not donate sperm. All study participants must 
be registered into the mandatory POMALYST REMS™ program, and be willing and able to 
comply with the requirements of the POMALYST REMS™ program. 
7.12  
 Management of Clinical Events 
Adverse drug reactions such as thrombocytopenia, diarrhea, fatigue, nausea, vomiting, and rash 
have been associated with MLN9708 treatment. Management guidelines regarding these events 
are outlined below. Further details of management of MLN9708 AEs are described  the 
MLN9708 IB. 
Prophylaxis Against Risk of Infection 
If lymphopenia is noted, patients may be at an increased risk of infection.  In particular, 
lymphopenia can be associated with reactivation of herpes zoster and herpes simplex viruses.  
Antiviral therapy such as acyclovir or valacyclovir may be initiated as clinically indicated.  
Other antivirals are also acceptable. 
Nausea and/or Vomiting 
Standard anti-emetics, including 5-HT3 antagonists, are recommended for emesis occurring 
upon treatment initiation; prophylactic anti-emetics may also be considered.  Dexamethasone 
should not be administered as an anti-emetic.  Fluid deficits should be corrected before initiation 
of study drug and during treatment. 
Diarrhea 
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 deficits should be corrected before initiation of treatment and during 
treatment. Prophylactic antidiarrheals are not generally recommended. 


  
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Erythematous Rash With or Without Pruritus 
As with VELCADE, rash with or without pruritus has been reported with MLN9708, primarily 
at the higher doses tested. The rash may range from some erythematous areas, macular and/or 
small papular bumps that may or may not be pruritic over a few areas of the body or more 
generalized, has been transient and has resolved either spontaneously or with standard 
symptomatic measures such as oral or topical steroids and/or antihistamines. Prophylactic 
measures should also be considered if a patient develops a rash (eg, using a thick, alcohol-free 
emollient cream on dry areas of the body).  In the case of rash, the use of a topical or oral steroid 
(eg, prednisone ≤ 10 mg per day or equivalent) is permitted.  A rare risk is Stevens-Johnson 
Syndrome, a severe, life-threatening or deadly rash with skin peeling and mouth sores, which 
should be managed symptomatically according to standard medical practice.  
Thrombocytopenia 
Thrombocytopenia has been reported to date primarily at the higher doses tested.  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. Thrombocytopenia 
nadirs commonly recover without intervention by the beginning of the next scheduled cycle. 
MLN9708 administration should be modified as noted as per dose modification 
recommendations when thrombocytopenia occurs.  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 
Neutropenia has been reported with MLN9708 and pomalidomide.  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 been manageable with G-CSF 
Neutropenic nadirs commonly recover without intervention by the beginning of the next 
scheduled cycle or with a short delay in treatment.  MLN9708 administration should be 
modified when neutropenia occurs, as noted in the dose modification recommendations. Given 
that MLN9708 will be administered in combination with pomalidomide, with overlapping 
toxicity of neutropenia,  G-CSF will be used prophylactically in this protocol. 


  
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Fluid Deficits 
Dehydration should be avoided because MLN9708 may cause vomiting, diarrhea, and 
dehydration.  Acute renal failure has been reported with MLN9708.  Fluid deficits should be 
corrected before initiation of study drug and during treatment and as needed during therapy.   
Nonsteroidal anti-inflammatory drugs (NSAIDs) induced prevalence of nephrotoxicity is 
relatively low; however, given the wide use of these agents many persons are at risk, including 
for example, patients with cardio-renal disease, dehydration, and the aging kidney. NSAIDs 
should be avoided with impaired renal function given reported NSAID-induced renal failure in 
patients with decreased renal function. Until further information is available, intake of NSAIDs 
while on this protocol should be avoided. 
Hypotension 
Symptomatic hypotension and orthostatic hypotension have been reported with MLN9708. 
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.  
Posterior Reversible Encephalopathy Syndrome  
One case of posterior reversible encephalopathy syndrome (PRES) has been reported with 
MLN9708.  While this case ultimately resolved, PRES has also been reported rarely with 
another proteasome inhibitor, Velcade.  PRES is characterized by headache, seizures and visual 
loss, as well as abrupt increase in blood pressure.  Prompt diagnosis and initiation of 
antihypertensive and anticonvulsant therapy are important to prevent irreversible end-organ 
damage. 
Anticoagulation Consideration   
Pomalidomide increases the risk of thrombotic events in patients who are at high risk or with a 
history a thrombosis, in particular when combined with other drugs known to cause thrombosis.  


  
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Consideration should be given to the requirement of aspirin (81 or 325 mg) or some other form 
of prophylaxis as deemed appropriate. Low molecular weight heparin may be utilized in patients 
that are intolerant to ASA. Coumadin should be used with caution and close monitoring of INR. 
8.  
STUDY DRUG  
8.1  Packaging and Labeling 
8.1.1   MLN9708 
The study drug MLN9708 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.   
MLN9708 capsules should be stored unopened at 2°C to 8°C (36°F-46°F).  The capsules are 
individually packaged in cold form foil-foil blisters in a child-resistant package.  The 0.5-, 2.3-, 
3.0-, and 4.0 mg capsules are supplied as a 1 x 3 blister card in a child-resistant cardboard 
wallet.  
8.1.2   Pomalidomide 
Pomalidomide capsules will be provided by Celgene Corporation as 1.0, 2.0, 3.0 and 4.0 mg 
capsules for oral administration.   
Pomalidomide (POMALYST®) will be provided to research patients for the duration of their 
participation in this trial at no charge to them or their insurance providers.  Pomalidomide will 
be provided in accordance with the  Celgene Corporation’s POMALYST REMS™  program.  
Per the standard   POMALYST REMS™ program requirements, all physicians who prescribe 
pomalidomide for research patients enrolled into this trial, and all research patients enrolled into 
this trial, must be registered in and must comply with all requirements of the POMALYST 
REMS™ program.   
Drug will be shipped on a per patient basis by the contract pharmacy to the clinic site for IND 
studies. Only enough pomalidomide for one cycle of therapy will be supplied to the patient each 
cycle.  This is in accordance with the POMALYST REMS™ program. 
Pomalidomide investigational supplies are dispensed to the patients in individual bottles of 
capsules.  Each bottle will identify the contents as study medication.  In addition, the label will 
bear Celgene’s name, quantity contained and the standard caution statement as follows:  
Caution: New drug - Limited by Federal law to investigational use. Pomalidomide should not be 


  
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handled by FCBP unless wearing gloves.  All bottles will contain the following warning label:  
“WARNING: POTENTIAL FOR HUMAN BIRTH DEFECTS.” 
The study drug label must be clearly visible.  Additional labels must not cover the Celgene 
label. 
8.2  Storage, Handling, and Accountability 
MLN9708 and pomalidomide are anticancer drugs and as with other potentially toxic 
compounds caution should be exercised when handling MLN9708 and pomalidomide capsules. 
8.2.1   MLN9708 
Upon receipt at the investigative site, MLN9708 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, MLN9708 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 MLN9708 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. 


  
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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 MLN9708, including that MLN9708 is to be taken as 
intact capsules. 
Investigational MLN9708 (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. 
8.2.2   Pomalidomide 
Care should be exercised in handling of pomalidomide. Pomalidomide capsules should not be 
opened or crushed. If powder from pomalidomide contacts the skin, wash the skin immediately 
and thoroughly with soap and water. If  pomalidomide contacts the mucous membranes, flush 
thoroughly with water.  
 
The Investigator or designee is responsible for taking an inventory of each shipment of 
pomalidomide received, and comparing it with the accompanying study drug accountability 
form.  The Investigator or designee will verify the accuracy of the information on the form, sign 
and date it, retain a copy in the study file, and return a copy to Celgene or its representative.   
 
Storage 
At the study site, all pomalidomide will be stored in a locked, safe area to prevent unauthorized 
access. The study drug should be stored at room temperature away from direct sunlight and 
protected from excessive heat and cold. 
 
Unused study drug supplies 
Celgene will instruct the Investigator or designee on the return or destruction of unused 
pomalidomide.  If any pomalidomide is lost or damaged, its disposition should be documented 
in the source documents.  Pomalidomide supplies will be retained at the clinical site pending 
instructions for disposition by Celgene.  Patients will be instructed to return empty bottles or 
unused capsules.   
 
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each cycle. 
 
9.      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. 
9.1   Treatment Assignment  
Patients will be assigned at the time of enrollment (per section 6.0) to a given dose level during 
the phase I portion of the study or to the recommended phase II dose as determined during the 
phase I portion of the study.  
9.2   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 investigator also has the right to withdraw 
patients from the study for any of the following reasons: 
 Adverse event 
 Lack of Protocol adherence 
 Lost to follow-up 
 Progressive disease 
 Study termination  
At the time of withdrawal, all study procedures outlined for the End of Treatment  visit should 
be completed. The primary reason for patient’s withdrawal from the study will be recorded in 
the source documents and CRF. 
The Lead Principal Investigator or designee must be notified within 24 hours if a patient is 
withdrawn from the study by the Data Coordinating Center or designee. 
If the reason for withdrawal is the occurrence of an AE, the Investigator will follow the patient  
until such events resolve, stabilize, and according to the Investigator’s judgment, there is no 
need of further follow up.   


  
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10.    STATISTICAL AND QUANTITATIVE ANALYSES 
10.1    
Statistical Methods 
10.1.1     
Determination of Sample Size 
Phase I: The phase I study will follow a 3+3 design, to evaluate toxicities associated with 
MLN9708 when given in combination with pomalidomide and dexamethasone. Two doses of 
MLN9708 (dose level -1 and dose level 1: 3 mg; dose level 2: 4 mg) will be tested in up to three 
possible dose levels; there will be no dose reductions below the 3mg dose of MLN9708. In the 
phase I portion of this study, the total sample size will depend on the number of dose levels 
evaluated to determine the maximum tolerated dose (MTD). While the phase I study is expected 
to enroll and treat 9 patients (3 patients treated on dose level 1 and 6 additional patients treated 
at dose level 2 -assuming the 4mg dose is well tolerated), a maximum of 18 patients could be 
treated (6 patients per dose level). The highest dose level that produces ≤1/6 DLTs in cycle 1 
will be the MTD. (See section 7.4  for dose expansion/escalation rules.) The recommended 
phase II dose (RP2D) of MLN9708 and pomalidomide will generally be the MTD, but it may be 
less than the MTD  based on a review of available data/cumulative toxicities from phase I. 
Phase II: For this trial, where MLN9708 will be added to pomalidomide and dexamethasone, 
patients with prior exposure to either of these agents would not be excluded, unlike the patients 
treated on the randomized phase III study of comparing pomalidomide plus dexamethasone, to 
high-dose dexamethasone alone. As many patients (>50%) are likely to have been previously 
treated with one or both of these agents we consider a response rate of 30% sufficient efficacy to 
justify further development.26 In addition, the estimation of response in this refractory/high-risk 
population is of equal importance. Given this, the phase II portion of the trial, will use a Gehan 
two stage design (Gehan, 1961). The phase II trial is expected to enroll a minimum of 9 and a 
maximum of 25 patients. The six patients treated at the RP2D in the phase I portion of the study 
will count toward the 25 patients required. Given this, we expect to enroll only 19 new patients 
on the phase II trial. The sample size is based on the desire to estimate the response rate with at 
most 10% standard error, and early stopping if the combination is unexpectedly ineffective. The 
primary endpoint is confirmed tumor response (sCR/CR/VGPR or PR).  
At stage 1, 9 patients will be entered on the study. If 0 responses are seen in the first 9 patients 
treated, the study will be terminated and the true regimen response will be declared ≤30%. If at 
least 1 patient responds, the trial will continue to the second stage. Because patients treated 
during the phase I portion of the trial at the dose selected for the phase II trial will be counted 


  
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(n=6), only 3 additional patients will be enrolled at stage 1. Under this design if the study 
regimen is >30% effective, there would be ~95.6% chance of at least one success. At stage 2, 16 
additional patients will be entered. This accrual provides for estimation of the response rate with 
no more than 10% standard error.   
10.1.2       
Populations for Analysis 
Phase I (Evaluable for Toxicity): Patients will be considered evaluable for toxicity if they 
receive any study drug. Patients will be considered evaluable for dose limiting toxicity if they 
receive at least 75% of both Pomalidomide and MLN9708 and are followed for the full 28 days 
during cycle 1  or experience a DLT.  All patients who are not evaluable for dose limiting 
toxicity will be replaced. 
Phase II (Evaluable for Toxicity): Patients will be considered evaluable for toxicity if they 
receive any study drug.  Patients in Phase II will not be replaced based on toxicity.  
Phase I and II (Evaluable for Response): For the phase II portion, as part of the primary 
analysis, patients will be considered evaluable for response if they are eligible, have baseline 
disease assessments, and receive any protocol treatment. As part of a secondary analysis, 
patients will be considered evaluable for response if they have baseline disease assessments, 
receive at least 75% of both Pomalidomide and MLN9708 during the first cycle of therapy and 
have had their disease re-evaluated. Patients will have their response classified according to the 
IMWG response criteria. All patients in phase II and those treated at the RP2D in phase I, who 
are not evaluable for response will be replaced. 
10.1.3    
Demographic and Baseline Characteristics 
Patient demographic and baseline characteristics, including age, gender, medical history, and 
prior therapy, will be summarized using descriptive statistics. For continuous variables, 
descriptive statistics (number [n], mean, standard deviation, standard error, median (range) will 
be provided. For categorical variables, patient counts and percentages will be provided.  
10.1.4          Efficacy Analysis 
A primary activity endpoint is not defined for the Phase I study. The primary activity endpoint 
for the Phase II study is response rate. Response rates (overall, clinical benefit) and depth of 
response will be calculated as the percent of evaluable patients that have confirmed 
sCR/CR/VGPR or PR (overall) or sCR/CR/VGPR/PR/MR or SD (clinical benefit), exact 95% 
confidence intervals will be calculated for these estimates. Response rates will also be evaluated 


  
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based on number and type of prior therapy(ies). Response defined as per modified IMWG 
criteria. Time to response, duration of response, and survival (overall and progression-free) will 
be estimated using the product-limit method of Kaplan and Meier.  
10.1.5    
Safety Analysis and Stopping Rules for Excessive Toxicity 
Toxicity information recorded will include the type, severity, and the probable association with 
the study regimen. Tables will be constructed to summarize the observed incidence by severity 
and type of toxicity. 
The following table will be consulted as relevant toxicities are encountered. The early stopping 
rule for safety/toxicity will be assessed for each patient after cycle 1. The expected rate of 
unacceptable toxicity should not be ≥33%. Note: Unacceptable toxicity is defined in section 7.3 
of the protocol. See the table below for detailed early stopping rules. These rules are in addition 
to the quarterly review of all toxicities submitted to the COH DSMC. Patients with ongoing 
toxicity (cycle 1 toxicity persisting beyond day +28) will be followed until resolution or 
stability.  If more than the specified number of patients has significant treatment related 
toxicities, patient accrual will be halted and a full review of the data by the Data Safety 
Monitoring Committee (DSMC) will be mandated. Patient accrual will not resume until 
approved by the DSMC to do so. 
# of patients 
treated at 
phase II dose 
# of patients 
with 
unacceptable 
toxicity to halt 
enrollment1 
Given the following toxicity rates, 
cumulative probability of early 
stopping: 
15% 
33% 
45% 
6 
2 
0.22 
0.64 
0.84 
12 
4 
0.24 
0.73 
0.92 
18 
6 
0.25 
0.78 
0.95 
1: For each unacceptable toxicity, halt enrollment and evaluate if 
the cumulative # of patients reaches or exceeds the specified limits. 
We recognize that these stopping rules represent the overall stoping rules including the patient 
evaluated on a given dose during the Phase I portion. As such, these rules represent the stopping 
probabilities of a dose with the above toxicity rates, including stopping during the phase I dose 
finding portion. Once the MTD has been selected, and additional patients are accrued 
(presumably at the MTD), the probability of early stopping is less (e.g. 26% of chance of early 
stopping at 12 patients if the true probability of unacceptable toxicity is 33%, and a 44% chance 


  
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of early stopping at 18 patients in that scenario). This represents the probability of early 
stopping conditional on passing the criteria for MTD selection (0 or 1 out of 6). 
11.    DATA AND SAFETY MONITORING   
11.1    
Definition of Risk Level 
This is a Risk Level 4 study, as defined in the “City of Hope Data and Safety Monitoring Plan”, 
http://www.coh.org/dsmc/Pages/forms-and-procedures.aspx. City of Hope is sponsor of this 
IND. 
11.2  Monitoring and Personnel Responsible for Monitoring 
The Protocol Monitoring Team (PMT) consisting of the PI, Collaborating Investigator, 
CRC/protocol nurse, statistician and COH Data Coordinating Center staff is responsible for 
monitoring the data and safety of this study, including implementation of the stopping rules for 
safety and efficacy.   
 
Beginning with the enrollment of the first patient, the PMT will meet weekly or bi-weekly via 
teleconference for patient and protocol management issues.   
 
This study will utilize the Phase I tracking log to monitor data and safety for dose escalation, 
recording doses administered, and resultant adverse events.  The tracking log will contain dose 
levels administered, DLT-defining adverse events, and documentation that the data from a dose 
level is complete before dose escalation.  Those data and safety elements will be reported to the 
COH DSMC as applicable within the PMT report, which will be submitted quarterly from the 
anniversary date of activation, as noted in Table 1 below.  
 
 Table 1:  City of Hope PMT Reporting Timelines for the DSMC 
 
Risk Level 
Phase 
Standard Reporting 
Requirement 
RL 1, RL2, and Compassionate 
Use Studies 
No reports required 
3 
I 
Every 3 months from 
activation date, as 
indicated in MIDAS 


  
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3 
Pilot, 
Feasibility, 
II-IV 
Every 6 months from 
activation date, as 
indicated in MIDAS 
4 
Pilot, 
Feasibility, 
I-IV 
Every 3 months from 
activation date, as 
indicated in MIDAS 
 
During periods of active protocol enrollment, quarterly reports of all protocol activity will be 
submitted to the DSMC and will include:  
1) The number of patients screened, enrolled and treated. 
2) Cohort status updates. 
3) List of AEs (including SAEs/UPs). 
4) Protocol deviations. 
 
Annual continuation reports will be made to the IRB, Cancer Protocol Review and Monitoring 
Committee (CPRMC) at COH and to the Food and Drug Administration (FDA).  These reports 
will be made available to participating institutions (as requested). 
11.3  Definitions 
11.3.1    
Pretreatment Event Definition 
A pretreatment event is any untoward medical occurrence in a patient or subject who has signed 
informed consent to participate in a study but before administration of any study medication; it 
does not necessarily have to have a causal relationship with study participation.  For serious pre-
treatment events, the investigator must determine both the intensity of the event and the 
relationship of the event to the study procedures. 
11.3.2       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 


  
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increased in severity or frequency since the administration of study drug.  When possible, signs 
and symptoms indicating a common underlying pathology should be noted as one 
comprehensive event. 
An abnormal laboratory value 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.   
11.3.3       Unexpected Adverse Event [21 CFR 312.32 (a)] 
An AE is unexpected if it is not listed in the investigator’s brochure and/or package insert; is not 
listed at the specificity or severity that has been observed; is not consistent with the risk 
information described in the protocol and/or consent; is not an expected natural progression of 
any underlying disease, disorder, condition, or predisposed risk factor of the research participant 
experiencing the AE. 
11.3.4       Expected Adverse Event 
Any event that does not meet the criteria for an unexpected event OR is an expected natural 
progression of any underlying disease, disorder, condition, or predisposed risk factor of the 
research participant experiencing the AE. 
 
         11.3.5    Serious Adverse Event (SAE) [21 CFR 312.32] is defined as any expected or 
unexpected AE that, at any dose,  results in any of the following outcomes: 
 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 (except scheduled hospitalizations for non-acute, unrelated 
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 Results in persistent or significant disability or incapacity (Disability is 
defined as a substantial disruption of a person’s ability to conduct normal life 
functions).   
 Is a congenital anomaly/birth defect. 
 Secondary malignancy, or 
 Any other AE that, based upon appropriate medical judgment, may 
jeopardize the subject’s health and may require medical or surgical 
intervention to prevent one of the outcomes listed above (examples of such 
events include allergic bronchospasm requiring intensive treatment in the 
emergency room or at home, blood dyscrasisas of convulsions that do not result 
in inpatient hospitalization, or the development of drug dependency or drug 
abuse). 
11.3.6      Unanticipated problem – Any incident, experience or outcome that meets all 
three of the following criteria: 
1. Unexpected (in term nature, severity, or frequency) given the following: a) the 
research procedures described in the protocol-related documents such as the IRB 
approved research protocol, informed consent document or Investigator Brochure 
(IB); and b) the characteristics of the subject population being studied; AND 
2. Related or possibly related to participation in the research (possibly related means 
there is a reasonable possibility that the incident, experience, or outcomes may 
have been caused by the drugs, devices or procedures involved in the research); 
AND 
3. Suggests that the research places subjects or others at greater risk of harm 
(including physical, psychological, economic, or social harm) than previously 
known or recognized. 
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 


  
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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. 
AEs which are serious must be reported to Celgene and Millennium Pharmacovigilance (or 
designee) from the date the participant signs Informed Consent through 30 days after 
administration of the last dost of pomalidomide or MLN9708. Any SAE that occurs at any time 
after completion of MLN9708/pomalidmide treatment or after the designated follow-up period 
that the sponsor-investigator and/or sub-investigator considers to be related to any study drug 
must be reported to Millennium/Celgene 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/Celgene 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). Each 
Investigator is also responsible for reviewing their institutional guidelines and reporting locally 
based on those guidelines (i.e., unanticipated problems). 
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)? 
 
11.2  Reporting of Unanticipated Problems and Adverse Events  
Unanticipated Problems: Most unanticipated problems must be reported to the COH 
DSMC and IRB within 5 calendar days according to definitions and guidelines at 
http://www.coh.org/hrpp/Pages/hrpp-policies.aspx.  Any unanticipated problem that 
occurs during the study conduct will be reported to the DSMC and IRB by submitting 


  
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electronically in iRIS (http://iris.coh.org).  Participating institutions will submit to the 
COH Data Coordinating Center. 
 
Serious Adverse Events - All SAEs occurring during this study, whether observed by 
the physician, nurse, or reported by the patient, will be reported according to 
definitions and guidelines at http://www.coh.org/hrpp/Pages/hrpp-policies.aspx and 
Table 2 below.  Those SAEs that require expedited reporting will be submitted 
electronically in iRIS (http://iris.coh.org/).   
 
Adverse Events - Adverse events will be monitored by the PMT.  Adverse events that 
do not meet the criteria of serious OR are not unanticipated problems will be reported 
only in the continuation reports and PMT reports (see Table 2 below). 
 
Table 2:  City of Hope Adverse Event and Unanticipated Problem Reporting Timelines for 
the DSMC and IRB 
 
Required Reporting Timelines to DSMC for AE/SAEs 
Investigator Initiated Studies  
 
 
 
Required Reporting Timeframe to DSMC 
Attribution 
UNEXPECTED 
EXPECTED 
  
Death while on active treatment or within 30 days of 
last day of treatment 
Possibly, Probably, 
Definitely 
5 calendar days 
Unlikely, Unrelated 
  
Death after 30 days of last active treatment/therapy 
Possibly, Probably, 
Definitely 
5 calendar days 
No reporting required 
Unlikely, Unrelated 
No reporting required 
No reporting required 
  
Grades 3 and 4 AND meeting the definition of 
"serious" 
Possibly, Probably, 
Definitely 
5 calendar days 
10 calendar days 
Unlikely, Unrelated 
5 calendar days 
10 calendar days 
  
Grades 1 and 2 AND resulting in "hospitalization" 
Possibly, Probably, 
Definitely 
5 calendar days 
10 calendar days 
Unlikely, Unrelated 
10 calendar days 
10 calendar days 
 
 
 
An event determined by the IRB of record to be an Unanticipated Problem (UP) will be 
communicated to the Investigator and COH DSMC through the COH IRB Operations 
Director. The DSMC will review the case and make a determination as to whether the 


  
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study will be suspended, terminated, amended, or allowed to continue without 
amendment. 
 
Required Reporting Timeframe to IRB of Record 
Attribution 
UNEXPECTED 
EXPECTED 
 
Death  
Possibly, Probably, 
Definitely 
5 calendar days 
Annual 
Unlikely, Unrelated 
Annual 
Annual 
 
Grades 3 and 4 AND meeting the definition of a UP 
Possibly, Probably, 
Definitely 
5 calendar days 
Annual 
Unlikely, Unrelated 
Annual  
Annual 
 
Grade 1 and 2 AND meeting the definition of a 
UP   
Possibly, Probably, 
Definitely 
5 calendar days 
Annual 
Unlikely, Unrelated 
Annual 
Annual 
The Sponsor-Investigator and the COH Data Coordinating Center must be notified by phone, 
fax or of the occurrence of any SAE or Unanticipated Problem within 24 hours of the 
investigator, designee, or site personnel’s knowledge of the event.  To report an SAE/UP, the 
site representative must complete the Notification of Unanticipated Problem/Serious Adverse 
Event/Pregnancy Form (attached as an Appendix 15.3) and MEDWATCH 3500A form , then 
fax or scan/email the forms  (as noted below) using secure email (#secure# in subject line of 
email): 
City of Hope Data Coordinating Center 
Fax Number:  626 301-8422 
COH DCC email:  dcc@coh.org (always use #secure# in subject line) 
Telephone reports must be followed by a written report within 24 hours.  Follow-up reports 
must be submitted in a timely fasion as additional information becomes available. 
The Investigator is responsible for notifying the Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC) in accordance with local institutional regulations, of all 
SAEs.  The Sponsor-Investigator, the City of Hope Data Coordinating Center and/or 


  
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Millennium/Celgene may request additional source documentation pertaining to the SAE.  If a 
patient is permanently withdrwawn from the study because of a SAE, this information must be 
included in the initial or follow-up SAE report as well as the Study Discontinuation case report 
form. 
The investigator is responsible for reporting serious adverse events that occur from the signing 
of the study specific consent through the duration of the post-therapy adverse event collection 
period to the City of Hope Data Coordinating Center (see section above for submission 
guidelines), as indicated when using MLN9708 and Pomalidomide within 24 hours of becoming 
aware of the SAE.  Notification can be made via phone or telefacsimile using the MEDWATCH 
3500A form.  The Sponsor-Investigator, through the COH DCC, will report to Millennium and 
Celgene within 24 hours. 
SAE and Pregnancy Reporting Contact Information - Millennium 
 
Millennium Pharmacovigilance Designee, PPDI, PVG: 
 
The COH DCC will fax the MEDWATCH 3500A form (Millennium Pregnancy Form attached 
as Appendix 15.4.4 when reporting pregnancy)  within 24 hours to:    
 
Cognizant 
 
 Contact Information: 
 
Fax Number:  1-800-963-6290 
 
Email:  TakedaOncoCases@cognizant.com 
 
 
SAE and Pregnancy Reporting Contact Information – Celgene 
The Sponsor-Investigator through the COH DCC will inform Celgene in writing using the 
MEDWATCH 3500A of any SAE within 24 hours of being aware of the event.  The written 
report must be completed and supplied to Celgene by facsimile within 24 hours/1 business day.  
The initial report must be as complete as possible, including an assessment of the causal 
relationship between the event and the investigational product(s), if available.  Information not 
available at the time of the initial report (e.g., an end date for the adverse event or laboratory 
values received after the report) must be documented on a follow-up report.  A final report to 
document resolution of the SAE is required.  The Celgene tracking number (PO-MM-PI-0062) 
and the institutional protocol number should be included on SAE reports (or on the fax cover 
letter) sent to Celgene.  A copy of the fax transmission confirmation of the SAE report to 


  
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Celgene should be attached to the SAE and retained with the patient records. 
 
Celgene Drug Safety Contact Information: 
Celgene Corporation 
Global Drug Safety and Risk Management 
Connell Corporate Park 
300 Connell Dr.  Suite 6000 
Berkeley Heights, NJ 07922 
Fax:  (908) 673-9115/Email:  drugsafety@celgene.com 
 
ADDITIONAL REPORTING REQUIREMENTS  
Serious Adverse Events meeting the requirements for expedited reporting to the FDA, as 
defined in 21 CFR 312.32, will be reported as an IND safety report using the MedWatch Form 
FDA 3500Afor Mandatory Reporting which can be found at:  
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm 
 
The City of Hope Data Coordinating Center will work with participating institutions to obtain 
the required serious adverse event report forms including any follow up information.   
 
The IND is held by COH, and the Sponsor-Investigator or designee, including the City of Hope 
Data Coordinating Center will be responsible for contacting the Office of IND Development 
and Regulatory Affairs (OIDRA) at COH to ensure prompt reporting of safety reports to the 
FDA.  OIDRA will assist the PI and COH DCC with the preparation of the report and submit 
the report to the FDA in accordance with the following: 
 
any unexpected fatal or life threatening adverse experience associated with use of the 
drug must be reported to the FDA no later than 7 calendar days after initial receipt of the 
information [21 CFR 312.32(c)(2)]; 
 
any adverse experience associated with use of the drug that is both serious and 
unexpected must be submitted no later than 15 calendar days after initial receipt of the 
information [21 CFR 312.32(c)(1)] 
 
any follow-up information to a study report shall be reported as soon as the relevant 
information becomes available. [21 CFR 312.32(d)(3)] 


  
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Sponsor-investigator or designee must also provide Millennium/Celgene Pharmacovigilance 
with a copy of all communications with applicable regulatory authorities related to the study or 
study drug(s), including, but not limited to, telephone conversation logs within 24 hours of such 
communication. 
Adverse Events of Special Interest (AESIs) are a subset of AEs that are to be reported to 
Millennium on a quarterly basis by the sponsor-investigator. These adverse events will be 
captured using Medidata RAVE, the electronic data capture system used for data collection for 
this trial as part of routine data collection.  A report will be generated and submitted to 
Millennium on a quarterly basis by the City of Hope Data Coordinating Center.  Millennium 
will provide the current list of AESIs and updates to the list will be distributed to the sponsor-
investigator as appropriate. 
The highest grade of non-Serious Adverse Events of Special Interest (AESIs) observed in 
patients will be reported.  AESIs are defined as: 
1. Neuropathy 
o Neuropathy peripheral 
o Peripheral sensory neuropathy 
o Polyneuropathy 
o Paraesthesia 
o Hyperaesthesia 
o Burning sensation 
o Oral pain 
o Paraesthesia oral 
o Muscle spasms  
o Muscular weakness 
2. Hematologic Toxicities 
3. Rash 
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o Rash macular 
o Rash maculo-papular 
o Rash generalized 
o Rash pruritic 
o Pruritus 
o Rash erythematous 
o Erythema 
o Rash popular 
o Skin exfoliation 
o Exfoliative rash 
4. Respiratory Complaints 
o Pneumonia  
o Pneumonitis 
5. Renal toxicity 
o Blood creatinine increased 
o Blood creatinine abnormal 
o Blood urea decreased 
o Renal failure acute 
o Renal failure 
o Renal impairment 
6. Hypotension 
o Orthostatic hypotension 
o Presyncope 
o Syncope 
7. New Primary Malignancy 
o For all myeloma studies, new primary malignancies must be reported for at least 
two years from the Clinical Trial patient’s first dose of MLN9708. 


  
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Procedures for Reporting Drug Exposure During Pregnancy and Birth Events 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) of a female patient occurring while the patient is on MLN9708 or pomalidomide, 
or within 90 days of the patient’s last dose of therapy), are considered immediately reportable 
events. MLN9708 and pomalidomide are to be discontinued immediately. The pregnancy, 
suspected pregnancy, or positive pregnancy test must be reported. The investigator must notify 
the sponsor-investigator and the COH DCC immediately by phone and by completing and 
faxing the Notification of Unanticipated Problem/Serious Adverse Event/Pregnancy Form 
(attached as an Appendix 15.3).  The sponsor-investigator through the COH DCC will be 
responsible for notifying Millennnium Pharmacovigilence(through Millennium Pregnancy Form 
attached as Appendix 15.4.4)//Celgene Drug Safety.   
 
The female patient should be referred to an obstetrician-gynecologist, preferably one 
experienced in reproductive toxicity for further evaluation and counseling. 
 
The Investigator will follow the female patient until completion of the pregnancy, and must 
notify the sponsor-investigator and the COH DCC immediately phone and by completing by 
completing and faxing the Notification of Unanticipated Problem/Serious Adverse 
Event/Pregnancy Form (attached as an Appendix 15.3).  The sponsor-investigator through the 
COH DCC will be responsible for notifying Millennnium Pharmacovigilence(through 
Millennium Pregnancy Form attached as Appendix 15.4.4)//Celgene Drug Safety immediately 
about the outcome of the pregnancy (either normal or abnormal outcome) using the Pregnancy 
Follow-up Report Form, or approved equivalent form.  
If the outcome of the pregnancy was abnormal (e.g., spontaneous or therapeutic abortion), the 
Investigator should report the abnormal outcome as an AE. If the abnormal outcome meets any 
of the serious criteria, it must be reported as an SAE. The investigator must notify the sponsor-
investigator and the COH DCC immediately phone and by completing by completing and faxing 
the Notification of Unanticipated Problem/Serious Adverse Event/Pregnancy Form (attached as 
an Appendix 15.3).  The sponsor-investigator through the COH DCC will be responsible for 


  
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notifying Millennnium Pharmacovigilence(through Millennium Pregnancy Form attached as 
Appendix 15.4.4)//Celgene Drug Safety within 24 hours of the Investigator’s knowledge of the 
event.  
 
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death after 28 days that the Investigator suspects is 
related to the in utero exposure to MLN9708 and pomalidomide should also be reported. The 
investigator must notify the sponsor-investigator and the COH DCC immediately phone and by 
completing by completing and faxing the Notification of Unanticipated Problem/Serious 
Adverse Event/Pregnancy Form (attached as an Appendix 15.3).  The sponsor-investigator 
through 
the 
COH 
DCC 
will 
be 
responsible 
for 
notifying 
Millennnium 
Pharmacovigilence(through 
Millennium 
Pregnancy 
Form 
attached 
as 
Appendix 
15.4.4)//Celgene Drug Safety within 24 hours of the Investigator’s knowledge of the event.  
 
Male Patients 
If a female partner of a male patient taking MLN9708 or pomalidomide becomes pregnant, the 
male patient should notify the Investigator immediately, and the pregnant female partner should 
be advised to call their healthcare provider immediately. 
12.    ADMINISTRATIVE REQUIREMENTS 
12.1    
Good Clinical Practice 
The study will be conducted in accordance with the International Conference on Harmonisation 
(ICH) for Good Clinical Practice (GCP) and the appropriate regulatory requirement(s).  The 
investigator will be thoroughly familiar with the appropriate use of the study drug as described 
in the protocol and Investigator’s Brochure.  Essential clinical documents will be maintained to 
demonstrate the validity of the study and the integrity of the data collected.  Master files should 
be established at the beginning of the study, maintained for the duration of the study and 
retained according to the appropriate regulations.   


  
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12.2    
Ethical Considerations 
The study will be conducted in accordance with applicable regulatory requirement(s) and will 
adhere to GCP standards.  The IRB will review all appropriate study documentation in order to 
safeguard the rights, safety and well-being of the patients.  The study will be conducted only at 
sites where IRB approval has been obtained.  The protocol, Investigator’s Brochure, informed 
consent form, advertisements (if applicable), written information given to the patients (including 
diary cards), safety updates, annual progress reports, and any revisions to these documents will 
be provided to the IRB by the investigator.  Millennium/Celgene requests that informed consent 
documents be reviewed by Millennium/Celgene or designee prior to IRB submission.   
This study must have the approval of a properly constituted IRB or IEC.  Before the 
investigational drug is shipped to the Site Investigator, the Site Investigator or designee will 
provide the COH DCC with a copy of the IRB/IEC approval letter stating that the study protocol 
and any subsequent amendments and informed consent form have been reviewed and approved. 
The COH DCC will be responsible for obtaining annual IRB/IEC reapproval throughout the 
duration of the study.  Copies of the Investigator’s annual report to the IRB/IEC and copies of 
the IRB/IEC continuance of approval must be submitted to the COH DCC.   
The Site Investigator is also responsible for notifying their IRB/IEC of any significant adverse 
events that are serious, unanticipated and/or unexpected. 
The COH DCC will provide study sites with any investigational new drug (IND) safety reports 
generated, changes to the Investigator’s Brochure IB, and any safety updates.  The Site 
Investigator is responsible for immediately notifying their IRB/IEC of any such updates. 
The Lead Principal Investigator along with the COH DCC will initiate in writing any 
substantive changes to this protocol as a protocol amendment.  The amendment will be 
submitted to the IRB/IEC, together with a revised informed consent, if applicable.  Written 
documentation of IRB/IEC approval must be received before the amendment is implemented.  
Upon completion of the trial, the Site Investigator must provide the IRB/IEC with a summary of 
the trial’s outcome. 
12.3    
Patient Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from either 
the patient or his/her guardian or legal representative before study participation.  The method of 
obtaining and documenting the informed consent and the contents of the consent must comply 
with the ICH-GCP and all applicable regulatory requirements. 


  
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The City of Hope Data Coordinating Center will provide the Site Investigator with a sample 
consent form.  Local and/or institutional requirements may require disclosure of additional 
information in the informed consent.  Any changes to the consent form must be submitted to the 
COH DCC for approval, prior to submission to the IRB/IEC.  The IRB/IEC will review the 
consenf form for approval.  A copy of the approved form must be submitted to the COH DCC 
prior to initiation of the study. 
Before implementing any study procedure, informed consent shall be documented by the use of 
a written consent form approved by the IRB/IEC and signed and dated by the patient or the 
patient’s legally authorized representative at the time of consent.  A copy of the signed informed 
consent will be given to the patient or patient’s legally authorized representative.  The original 
signed consent must be maintained by the Site Investigator and available for inspection by the 
COH DCC, its designated representatives, or regulatory authority at any time. 
12.4    
Patient Confidentiality 
In order to maintain patient privacy, all data capture records, drug accountability records, study 
reports and communications will identify the patient by initials and the assigned patient number.  
If requested, the investigator will grant monitor(s) and auditor(s) from City of Hope, 
Millennium/Celgene or its designees and regulatory authority (ies) access to the patient’s 
original medical records for verification of data gathered on the data capture records and to audit 
the data collection process.  The patient’s confidentiality will be maintained and will not be 
made publicly available to the extent permitted by the applicable laws and regulations. 
The investigator/institution will permit direct access to source data and documents by the COH 
DCC staff, its designees, the FDA, and other applicable regulatory authorities.  The access may 
consist of trial-related monitoring, including remote monitoring, audits, IRB/IEC reviews, and 
FDA/regulatory authority inspections. 
Release of research results should preserve the privacy of medical information and must be 
carried out in accordance with Department of Health and Human Services Standards for Privacy 
of Individually Identifiable Health Information, 45 CFR 164.508. 
12.5    
Investigator Compliance 
The investigator will conduct the study in compliance with the protocol given 
approval/favorable opinion by the IRB and the appropriate regulatory authority(ies).  Changes to 
the protocol will require approval from Millennium/Celgene and written IRB approval/favorable 
opinion from City of Hope (as the sponsor) prior to implementation, except when the 


  
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modification is needed to eliminate an immediate hazard(s) to patients.  The IRB may provide, 
if applicable regulatory authority(ies) permit, expedited review and approval/favorable opinion 
for minor change(s) in ongoing studies that have the approval /favorable opinion of the IRB.  
The investigator will submit all protocol modifications to Millennium/Celgene and the 
regulatory authority(ies) in accordance with the governing regulations.  
Any departures from the protocol must be fully documented in the source documents.  
12.6     Study Documentation and Archives 
12.6.1 Source Documents 
Source documents are original documents, data, and records (e.g., medical records, data 
collection forms, pharmacy dispensing records, recorded data from automated instruments, 
laboratory data) that are relevant to the clinical trial.  The Site Investigator or their designee will 
prepare and maintain adequate and accurate source documents.  These documents are designed 
to record all observations and other pertinent data for each patient enrolled in this clinical trial.  
Source documents must be adequate to reconstruct all data transcribed onto the case report 
forms. 
12.6.2  Case Report Form Completion 
All data will be collecting using COH data collection forms via an electronic data capture 
system, Medidata RAVE.  All case report forms must be completed by designated study 
personnel.  The completed case report forms must be reviewed, signed and dated by the Site 
Investigator or designee in a timely fashion. 
All data will be submitted as follows: 
 Eligibilty Checklist:  the participating institutions at the registering site will 
have completed and faxed this form at the time of registration. 
 On-Study/Baseline Forms:  completed on-study forms are due within two 
weeks of registration. 
 Treatment Forms (Cycle Forms):  completed forms are due within 2 weeks of 
completion of a cycle (unless needed sooner for DLT assessment during Phase I).  
The City of Hope Data Coordinating center will communicate with site staff if 
forms are needed sooner. 


  
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 Adverse Event Collection:  completed adverse events are due within two weeks 
of a cycle (unless needed sooner for DLT assessment during Phase I).  The City 
of Hope Data Cooridnating center will communicate with site staff if forms are 
needed sooner. 
 Response/Off Treatment/Off Study/Follow-Up:  forms will be completed each 
time a patient is evaluated for response, comes off treatment, new follow-up 
information is obtained or comes off study.   
12.7    
Archival of Records 
According to 21 CFR 312.62I, the Site Investigators shall retain records required to be 
maintained under this part for a period of 2 years following the date a marketing application is 
approved for the drug for the indication for which it is being investigated.  If no application is to 
be filed or if the application is not approved for such indication, the Site Investigator shall retain 
these records until 2 years after the investigation is discontinued and the FDA or applicable 
regulatory authorities are notified. 
The Site Investigator must retain protocols, amendments, IRB/IEC approvals, copies of the 
Form FDA1572, signed and dated consent forms, medical records, case report forms, drug 
accountability records, all correspondence, and any other documents pertaining to the conduct 
of the study. 
12.8  Study Monitoring and Data Collection  
Following initiation of the study site, remote monitoring will be completed by the COH DCC.  
The Site Investigator will allocate sufficient time for the designated site staff to submit source 
documentation as required to complete remote monitoring. 
The purpose of trial monitoring is to verify the following: 
 The rights and well-being of human subjects are protected. 
 The reported data are accurate , complete, and verificable from source documents. 
 The conduct of the trial is in compliance with the currently approved protocol, 
amendment(s), ICH GCP, FDA CFR, and any other applicable regulatory requirements. 
The COH DCC will submit a prepare a written report after each remote monitoring timepoint or 
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remotely and significant findings, deviations and deficiencies, conclusions, actions taken or to 
be taken to ensure site compliance.  
City of Hope’s Data Coordinating Center, regulatory authorities, the IRB and/or 
Millennium/Celgene may request access to all source documents, data capture records, and 
other study documentation for on-site audit, inspection and remote monitoring.  Direct access to 
these documents must be guaranteed by the investigator, who must provide support at all times 
for these activities. 
12.9    
Investigator and Site Responsibility for Drug Accountability 
Accountability for the study drug at all study sites is the responsibility of the principal 
investigator.  The investigator will ensure that the drug is used only in accordance with this 
protocol.  Drug accountability records for each respective drug/company, MLN9708 for 
Millennium and pomalidomide for Celgene indicating the drug’s delivery date to the site, 
inventory at the site, use by each patient, and amount returned to Millennium/Celgene or a 
designee or disposal of the drug (if applicable and if approved by Millennium/Celgene) will be 
maintained by the clinical site.  Accountability records will include dates, quantities, lot 
numbers, expiration dates (if applicable), and patient numbers.  Accountability records will need 
to be submitted to the COH DCC as requested. 
12.10    MLN9708 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 
Millennium Quality representative. 
For Product Complaints, 
call MedComm Solutions at 
877-674-3784 (877 MPI DRUG)  
(US and International) 
 
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. 


  
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12.11    Closure of the Study 
This study may be prematurely terminated, if in the opinion of the investigator or 
Millennium/Celgene, there is sufficient reasonable cause.  Written notification documenting the 
reason for study termination will be provided to the investigator or Millennium/Celgene by the 
terminating party.   
Circumstances that may warrant termination include, but are not limited to: 
 Determination of unexpected, significant, or unacceptable risk to patients 
 Failure to enter patients at an acceptable rate 
 Insufficient adherence to protocol requirements 
 Insufficient, incomplete and/or unevaluable data 
 Determination of efficacy based on interim analysis 
 Plans to modify, suspend or discontinue the development of the drug 
12.12    Record Retention 
The investigator will maintain all study records according to the ICH-GCP and applicable 
regulatory requirement(s).   
13.    USE OF INFORMATION 
All information regarding MLN9708 supplied by Millennium and pomalidomide by Celgene to 
the investigator is privileged and confidential information.  The investigator agrees to use this 
information to accomplish the study and will not use it for other purposes without consent from 
Millennium/Celgene.  It is understood that there is an obligation to provide Millennium/Celgene 
with complete data obtained during the study.  The information obtained from the clinical study 
will be used toward the development of MLN9708 and may be disclosed to regulatory 
authority(ies), other investigators, corporate partners, or consultants as required. 
Upon completion of the clinical study and evaluation of results by Millennium/Celgene, the 
hospital or institution and/or investigator may publish or disclose the clinical trial results 
pursuant to the terms contained in the applicable Clinical Trial Agreement.    
 


  
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14.    REFERENCES    
1. Jemal A, Siegel R, XU J et al., Cancer Statistics 2010 Cancer J Clin 60;277-300 
2. Richardson PG, Sonneveld P, Schuster MW et al., Bortezomib or high dose 
dexamethasone for relapsed multiple myeloma. N Eng J Med 2005 ;352(24) 2487-98 
3. Kumar S, Flinn I, Richardson P et al, Novel three drug and four drug combination 
regimens of Bortezomib, Dexamethasone, Cyclophosphamide and Lenalidomide for 
previously untreated MM: Results from the Multi Center Randomized Phase 2 Evolution 
Study. Blood 2010;116(21):abstr621 
4. Vij R, Siegel D, Kaufman J et al, Results of an ongoing open label phase II study of 
carfilzomib in patients with relapsed and or refractory MM. J Clin Oncol 28:15s,2010 
5. Dimopoulos , Spencer A, Attal M et al., Lenalidomide plus dexamethasone for relapsed 
or refractory myeloma. N Engl J Med. 2007.357:2123-32 
6. Rajkumar S, Jacobus S, Callander N et al., Lenalidomide plus low dose dexamethasone 
as initial therapy for newly diagnosed MM: an open label randomized controlled trial. 
Lancet Oncology 2010;11:29-37 
7. Kumar S, Rajkumar SV, Dispenzieri A et al., Improved survival in MM and the impact 
of novel therapies. Blood 2008;1115) 2516-20 
8. Kumar S, Lee JH, Lahuerta J et al. on behalf of the international myeloma working 
group. Risk of Progression and survival in multiple myeloma relapsing after therapy 
with IMIDS and bortezomib: A multicenter international myeloma working group study. 
Leukemia 2011:1 
9. 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. Blood (ASH Annual Meeting Abstracts), 2010. 116(21): p. abstr 
1813. 
10. Gupta, N., M. Saleh, and K. Venkatakrishnan. 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. 
11. Chow, L.Q., et al. MLN9708, an investigational proteasome inhibitor, in patients with 
solid tumors; Updated phase 1 results in Head and Neck Symposium. 2012. Phoenix, AZ 
12. 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. 
13. 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, Illinois. 
14. Kumar, S., et al. Oral weekly MLN9708, an investigational proteasome inhibitor, in 
combination with lenalidomide and dexamethasone in patients (pts) with previously 


  
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untreated multiple myeloma (MM): A phase I/II study in ASCO Annual Meeting. 2012. 
Chicago, Illinois. 
15. Merlini, G., et al. 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, Georgia. 
16. Kumar, S. et al. A Phase 1/2 Study of Weekly MLN9708, an Investigational Oral 
Proteasome Inhibitor, in Combination with Lenalidomide and Dexamethasone in 
Patients with Previously Untreated Multiple Myeloma (MM) in 54th ASH Annual 
Meeting and Exposition. 2012. Atlanta, Georgia. 
17. Richardson, P.G., 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. 
18. 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. 
19. 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. 
San Diego, CA 
20. Kumar S., et al. Weekly dosing of the investigational oral proteasome inhibitor 
MLN9708 in patients (pts) with relapsed/refractory multiple myeloma (MM): A phase I 
study in ASCO Annual Meeting. 2012. Chicago, Illinois. 
21. Sanchorawala V., et al. Poster Presentation: Phase 1 study of MLN9708, a novel, 
investigational oral proteasome inhibitor, in patients with relapsed or refractory light-
chain amyloidosis. XIII International Symposium on Amyloidosis, Groningen, The 
Netherlands 2012. 
22. Lacy M, Hayman S, Gertz M, et al., Pomalidomide plus low dose dexamethasone as 
therapy for relapsed multiple myeloma. J Clin Oncol 2009;27:5008-14 
23. Lacy MQ, Hayman S,Gertz MA, Pomalidomide plus low dose dexamethasone is active 
and well tolerated in lenalidomide refractory multiple myeloma. Leukemia. 2010;:1934-
39 
24. Richardson P, Baz R, Wang L et al., Investigational Agent MLN9708 an oral 
proteasome inhibitor in patients with relapsed and or refractory MM: Results from the 
Expansion Cohorts of a Phase I Dose Escalation Study. Blood 2011 118:abstr301 
25.  Rajkumar S.V., Harousseau J.L., Durie B., et al., Consensus recommendations for the 
uniform reporting of clinical trials: report of the International Myeloma Workshop 
Consensus Panel Blood. 2011 117: 4691-4695. 


  
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26. Jesus San Miguel, Katja Weisel, Philippe Moreau et al., Pomalidomide plus low-dose 
dexamethasone versus high-dose dexamethasone alone for patients with relapsed and 
refractory multiple myeloma (MM-003): a randomised open-label phase 3 trial. Lancet 
Oncol 2013; 14:1055-66.  
27. Gehan EA. The determination of the number of patients required in a preliminary and a 
follow-up trial of a new chemotherapeutic agent. J Chronic Dis. 1961 Apr;13:346–353.  
 
 
 


  
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15.    APPENDICES 
15.1    
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.  
 
 
 


  
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15.2   
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. 
 


  
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15.3   NOTIFICATION OF UNANTICIPATED PROBLEM/SERIOUS ADVERSE 
EVENT/PREGNANCY 
City of Hope Data Coordinating Center 
Department of Clinical Research Information Support 
 
NOTIFICATION OF UNANTICIPATED PROBLEM/SERIOUS ADVERSE EVENT/PREGNANCY 
For Use by Participating Institutions Only 
 
THIS FORM ALONG WITH A COPY OF THE MEDWATCH 3500A FORM MUST BE SUBMITTED TO THE DATA 
COORDINATING CENTER AT CITY OF HOPE WITHIN 24 HOURS OF KNOWLEDGE OF ONSET OF SERIOUS ADVERSE 
EVENT, UNANCTICIPATED PROBLEM OR KNOWLEDGE OF PREGNANCY (MEETING REPORTING CRITERIA DESCRIBED 
IN PROTOCOL).  SCAN/EMAIL DOCUMENT TO DCC@COH.ORG (PLEASE USE #SECURE# IN SUBJECT LINE OF ANY 
CORRESPONDENCE) 
COH IRB #12267 - Participating Site IRB # ___________ 
 
Phase I/II trial of MLN9708 plus Pomalidomide and Dexamethasone for Relapsed or 
Relapsed Refractory Multiple Myeloma 
Participating/Treating Institution:  ________________________________________________________ 
 
Reporter:  ______________________________________Phone #:________________________________ 
 
Email:   ________________________________ 
 
PATIENT INFORMATION Pt Study ID:  _____________________________ 
UNANTICIPATED PROBLEM/SERIOUS ADVERSE EVENT/PREGNANCY INFORMATION 
 
Serious Adverse Event/Unanticipated Problem:  _______________________________________________ 
 
Grade:  _______________ 
Was this a dose limiting toxicity?   ________________________________ 
 
Attribution to MLN9708 (Unrelated, Unlikely, Possible, Probable, or Definite):  ______________________ 
 
Attribution to Pomalidome (Unrelated, Unlikely, Possible, Probable, or Definite):  _____________________ 
 
Start Date of SAE/UP: ____/____/____  
 
REPORTING INFORMATION 
Has the event been reported to the following? 
 
Via Fax to Data Coordinating Center (COH)  
 
__ No    __ Yes   Date: __ __ / __ __  / __ __ 
  Phone:  626-256-4673x63968/Email:  dcc@coh.org (use #secure# in subject line)  
 
Participating Site Institutional IRB?  
 
 
__ No    __ Yes   Date: __ __ / __ __  / __ __ 
 
SCAN/EMAIL THIS FORM AND THE MEDWATCH 3500A FORM OR PREGNANCY 
FORM TO DCC@COH.ORG (USE #SECURE# IN SUBJECT LINE) 


  
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15.3.1  Millennium Pregnancy Reporting Form 
 
 


  
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15.4      International Myeloma Working Group Response Criteria27 
Response1 
IMWG criteria 
sCR 
CR as defined below plus:  
 
normal FLC ratio and  
 
absence of clonal cells in bone marrow by immunohistochemistry or 2 – 4 color 
flow cytometry 
CR 
 
Negative immunofixation on the serum and urine and  
 
disappearance of any soft tissue plasmacytomas and  
 
< 5% plasma cells in bone marrow.   
 
In patients with only FLC disease, a normal FLC ratio of 0.26–1.65 is required.  
VGPR 
 
Serum and urine M-protein detectable by immunofixation but not on 
electrophoresis or 
 
> 90% reduction in serum M-protein plus urine M-protein level < 100 mg/24 h.   
 
In patients with only FLC disease, >90% decrease in the difference between 
involved and uninvolved FLC levels is required. 
PR 
 
50% reduction of serum M-protein and reduction in 24 hours urinary M-protein 
by >90% or to < 200 mg/24 h 
 
If the serum and urine M-protein are unmeasurable,3 a > 50% decrease in the 
difference between involved and uninvolved FLC levels is required in place of 
the M-protein criteria 
 
If serum and urine M-protein are not measurable, and serum free light assay is 
also not measureable, > 50% reduction in plasma cells is required in place of M-
protein, provided baseline bone marrow plasma cell percentage was > 30% 
 
In addition to the above listed criteria, if present at baseline, a > 50% reduction 
in the size of soft tissue plasmacytomas is also required 
Stable Disease 
 
Not meeting criteria for CR, VGPR, PR or progressive disease 
MR 
 
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1. 
Adapted from Durie BGM, et al. Leukemia 2006; 20: 1467-1473;  
All response categories (CR, sCR, VGPR, and PD) require two consecutive assessments made at anytime 
before the institution of any new therapy; complete response and PR and SD categories also require no 
known evidence of progressive or new bone lesions if radiographic studies were performed.  VGPR and 
CR categories require serum and urine studies regardless of whether disease at baseline was measurable 
in serum, urine both or either.  Radiographic studies are not required to satisfy these response 
requirements. Bone marrow assessments need not be confirmed.  For progressive disease, serum M-
component increases of ≥ I gm/dl are sufficient to define response if starting M-component is ≥ 5 g/dl.     
 
IMWG clarification for coding PD:  Clarified that Bone marrow criteria for PD are to be used only in 
patients without measurable disease by M protein and by FLC levels.  Clarified that 25% increase refers 
to M protein, FLC, and bone marrow results and does not refer to bone lesions, soft tissue plasmacytomas 
or hypercalcemia.  Note the lowest response value does not need to be a confirmed value. 
 
 
protein by 50 to 89% which still exceeds 200 mg per 24 hr 
 
In addition to the above criteria, if present at baseline, 25-49% reduction in the 
size of soft tissue plasmacytomas is also required 
 
No increase in size or number of lytic bone lesions (development of 
compression fracture does not exclude response) 
Progressive 
disease 
Increase of > 25% from lowest response value in any one of the following: 
 
Serum M-component (the absolute increase must be > 0.5 g/dL) and/or  
 
Urine M-component (the absolute increase must be > 200 mg/24h) and/or  
 
Only in patients without measurable serum and urine M-protein, the difference 
between involved and uninvolved FLC levels. The absolute increase must be > 10 
mg/dL 
 
Only in patients without measurable serum and urine M-protein and without 
measurable disease by  FLC levels, bone marrow plasma cell percentage (absolute % 
must be ≥ 10%)  
 
Definite development of new bone lesions or soft tissue plasmacytomas or definite 
increase in the size of existing bone lesions or soft tissue plasmacytomas 
 
Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL ) that can be 
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Appendix 15.5:  City of Hope Data Coordinating Center Plan 
 
 
City of Hope 
Data Coordinating Center 
 
City of Hope has been designated to oversee this trial as the Data Coordinating Center. 
 
This document will serve as guidance as to the responsibilities of the Data Coordinating Center, 
as well as those of the participating sites. 
 


  
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City of Hope Data Coordinating Center Responsibilities 
There are multiple responsibilities associated with serving in the capacity of a data coordinating 
center.  The City of Hope Data Coordinating Center within the Division of Clinical Research 
Information Support (CRIS) has adequate resources and expertise to carry out these 
responsibilities: 
 
1. Assist with the design and development of the initial protocol, subsequent amendments 
and template informed consent documents for use at each participating institution (as 
applicable).   
2. Selecting appropriately qualified participating sites/principal investigators (as applicable). 
3. Ascertaining each protocol is reviewed and approved by the IRB at the participating site 
prior to enrollment of subjects at that site. 
4. Ensuring, if the study is federally funded, that each collaborating institution holds an 
applicable OHRP-approved Federal Wide Assurance (FWA).   
5. Collecting and maintaining critical documents for the Trial Master File from participating 
investigators, e.g. resume/CV, medical license, certification of completion of training (as 
applicable), laboratory certifications and laboratory norms, financial disclosure forms, 
etc.  Maintaining the file throughout the course of the trial. 
6. Distribution of Regulatory Document Binder template to participating sites.  A 
standardized regulatory document template will be sent out to the sites that includes filing 
of all essential documents for the trial.  A standard table of contents and tabbed dividers 
will be provided to the participating site prior to the protocol initiation meeting.   
7. Storing and/or managing data and data and safety monitoring. 
8. Protecting the confidentiality of data received from participating sites in accordance with 
HIPAA.   
9. Ensuring informed consent is obtained and documented from each subject in compliance 
with US regulations. 
10. Maintaining documentation of all participating site IRB approvals for the protocol 
(including all subsequent amendments).  Ensuring that participating sites are using the 
correct version of the protocol and consent document.  
11. Assuring that all relevant IRB correspondence (continuing review and amendments) and 
study status changes are communicated to all participating sites in a timely basis. 
12. Providing study specific training to the research personnel at the participating site, both at 
trial initiation and throughout the course of the trial (re-training as needed).  Training will 
include but not be limited to:  protocol background, inclusion/exclusion, registration 
procedures, treatment schema, dose modification guidelines, AE/SAE/UP reporting 
guidelines, investigator/staff responsibilities, subsequent amendment changes, etc.  The 
training will be documented and will be continuous throughout the course of the trial.  
13. Developing and providing protocol specific case report forms for each participating site 
(paper and/or EDC).  Training of staff on case report forms at study initiation.  Continued 
training of participating site staff if any new changes occur to case report forms during 
length of study. 
14. Centrally registering/randomizing subjects and tracking subject enrollment for all 
subjects. 
15. Tracking, reporting and maintaining documentation of all serious adverse events and 


  
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unanticipated problems and dissemination of the information to participating sites for 
submission to their local committees (as applicable). 
16. Providing periodic updates to study sponsor and participating sites on subject enrollment, 
general study progress, and relevant scientific advances either via email distribution or 
via teleconferences. 
17. Preparation and coordination of teleconferences on an as needed basis (may be weekly, 
bi-weekly, monthly or quarterly). 
18. Primary liaison for participating sites with continuous and frequent communication via 
email and/or teleconference to ensure protocol is running smoothly, questions have been 
answered and documenting any issues.  Addressing issues with study sponsor 
immediately. 
19. Documenting receipt, shipment and storage of study specimens, drugs and/or devices (if 
applicable). 
20. Conducting continuous quality assurance checks of database, as well as protocol 
adherence on periodic basis (remote). 
21. Monitoring, on a periodic basis, either onsite or remotely of the participating sites to 
assess research study progress and compliance with the IRB approved protocol.   
22. Securing compliance at participating sites that are not adhering to the current version of 
the research protocol and/or good clinical research practices.  
23. Terminating the involvement, if necessary, of non-compliant investigators and reporting 
such action to the IRB.  
 
Responsibilities of the Participating Site Principal Investigators 
 
1. Signs Form FDA 1572 to acknowledge responsibilities as defined by the regulations.  
2. Provides the Data Coordinating Center and/or sponsor with required information that 
either attest to the absence of financial interests or arrangements as described in the Code 
of Federal Regulations (21. CFR 54.4) and reported on form FDA 3454 that is completed 
by the sponsor or provides the sponsor a complete and accurate disclosure of financial 
interests and arrangements as described in the regulations (21. CFR 54.4) and reported on 
form FDA 3455 that is completed by the sponsor.  
3. Supervises members of the research team that are qualified by their education and 
training to accept these responsibilities for study related activities not directly performed 
by the PI.  
4. Ensures the safety and welfare of study subjects by being knowledgeable about ongoing 
study protocols and investigator articles.  
5. Participates as appropriate in the hiring and training of individuals recruited as members 
of the research team.  
6. Ensures that specific sponsor requirements of the PI are fulfilled as requested.  
7. Meets with the data coordinating center’s and/or sponsors’ representative as appropriate 
to discuss planned and ongoing studies.  Participates in regularly scheduled 
teleconferences to discuss site specific information, including but not limited to:  patient 
status, data collection, adverse event reporting, etc. 
8. Ensures the participating site completes required data collection in a timely fashion 
and/or as spelled out in protocol. 
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findings (if applicable). 
 
Each participating sites individual investigator must adhere to the following requirements in 
order to participate in the conduct of clinical trials with City of Hope:    
 
 To review the Belmont report, Ethical principles and Guidelines for the Protection of 
Human Subjects of Research, the U.S. Department of Health and Human Services 
(DHHS) and FDA regulations for the protection of human subjects at 45 CFR 46, 21 
CFR50, 56, 312 and 812; the COH Federal Wide Assurance; and, the COH institutional 
policies and procedures for the protection of human subjects, located at the COH IRB 
website through the COH Intranet (a copy will be distributed to participating sites). 
 To understand and accept the responsibility to comply with the standards and 
requirements stipulated in the above documents and in the study protocol and to protect 
the rights and welfare of human subjects involved in research.  
 To comply with all other applicable federal, international, state and local laws, 
regulations, and policies that may provide additional protection for human subjects 
participating in research.  
 To abide by all determinations of the COH IRB and to accept the final authority and 
decisions of the COH IRB, including but not limited to directives to terminate 
participation in designated research activities.  
 To complete any educational training required by the COH (including by the Data 
Coordinating Center) and/or the COH IRB prior to initiating research.  
 To report promptly to the COH DCC any proposed changes in the research.  These must 
be reviewed and approved by the COH IRB. 
 To NOT initiate changes in the research without prior COH IRB review and approval, 
except where necessary to eliminate apparent immediate hazards to subjects. 
 To report promptly to the COH PI any serious adverse events and/or unanticipated 
problems involving risks to subject or other as defined in the protocol and in accordance 
with COH policies and procedures. 
 To obtain, document and maintain records of informed consent for each subject (when 
responsible for enrolling subjects) or each subject’s legally authorized representative as 
required under DHHS and FDA regulations (or any other national procedural standards) 
as stipulated by the COH IRB. 
 To acknowledge and agree to cooperate in the COH IRB’s responsibility for initial and 
continuing reviews, record keeping and for internal and external research regulatory 
reporting requirements.  
 To provide all information requested by the COH IRB in a timely fashion.  
 To comply with all applicable FA regulations and fulfill all investigator responsibilities, 
including those described at 21 CFR 312 (IND regulations) and 812 (IDE regulations) 
when conducting research involving FDA regulated. 
 To NOT enroll patients in research prior to review and approval by the COH IRB of the 
protocol and then subsequent review/approval at the participating site. 
 To acknowledge that he/she is primarily responsible for safeguarding the rights and 
welfare of each research subject and that the subject’s rights and welfare must take 
precedence over the goals and requirements of the research.  
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of the participating site, investigators and other research staff personnel.    
 To agree to communicate with the COH/PI in a timely manner.  
 To agree that COH Data Coordinating Center staff will train current and/or new 
research personnel in protocol management and data collections.  
 To agree to on-site and/or remote monitoring of all relevant data by COH Data 
Coordinating Center staff to assure compliance with protocol requirements and quality of 
the data.  This will entail submission of all source documentation as requested by the 
COH DCC. 
 To agree to remote review of source documentation as requested by the COH DCC staff. 
 To participate in weekly teleconference calls (if applicable), to attend a quarterly group 
meeting (if applicable) and to attend an annual group meeting (if applicable), put together 
by the COH DCC. 
 To submit all required data according to the protocol data submission schedule in a 
timely manner. 
 To notify immediately the COH Data Coordinating Center upon notification of any 
external audit. 


  
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Responsibilities of the Participating Site Study Coordinator, Clinical Research Associate 
and/or Data Manager  
 
1. Responsible for the sound conduct of the clinical trial, including but not limited to 
recruitment, screening, enrollment, treatment and follow-up of eligible subjects 
according to protocol requirements (e.g., subject follow-up, case report form completion 
in a timely fashion and reporting of adverse events, unanticipated problems).  
2. Responsible for the maintenance of accurate and complete documentation including 
signed informed consent forms, source documentation, subject logs and study-related 
communications.   
3. Responsible for the organizational management of all aspects of the trial including but 
not limited to overseeing timeliness in completing case report forms, reporting serious 
adverse events, managing caseload and managing study files.  
4. Communicates all protocol-related issues/problems to the appropriate team members, 
including but not limited to questions regarding the conduct of the clinical trial, concern 
regarding possible Serious Adverse Events/Adverse Events/Unanticipated Problems 
(SAE/AE/UP) or subject compliance.  
5. Develops organizational aids and checklists to facilitate patient recruitment and 
enrollment as well as the collection of complete and accurate study data.  
6. Enrolls subjects in studies and manages their participation according to ethical, 
regulatory and protocol-specific requirements. 
7. Tracks study enrollment. 
8. Maintains study files for each study subject.  
9. Maintains confidentiality of study subject’s identity.  
10. Participates in quality assurance activities (onsite and/or remote monitoring visits 
(including submission of de-identified source documents for remote monitoring), 
internal audits, sponsor audits, FDA audits.  
 
Responsibilities of the Participating Site Regulatory Office and/or Designee 
 
1. Responsible for protocol submission – initial protocol, informed consent and subsequent 
amendments. 
2. Responsible for communication to the City of Hope Data Coordinating Center any 
questions related to the regulatory document submission process at their participating 
site. 
3. Maintains the regulatory documentation and regulatory files for each applicable research 
project at the participating site.   
4. Maintains the Regulatory Document Binder distributed by City of Hope’s Data 
Coordinating Center locally.  Ensures all documentation is up to date and filed in a timely 
fashion. 
5. Submits institutional review board approvals for initial protocol submission as well as 
subsequent amendments to the City of Hope Data Coordinating Center.   
6. If applicable, submits serious adverse events and/or unanticipated problems to their local 
regulatory committees, and sends appropriate copies to the Data Coordinating Center as 
spelled out in the protocol. 
 


  
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Required Documents to be Sent by Participating Site to the City of Hope Data 
Coordinating Center Prior to Site Activation 
 
1. Participating site’s Investigational Review Board (IRB) approval letter for initial protocol 
and consent form. All correspondence between the IRB and study site will be maintained 
at the study site in the regulatory binder. 
2. Completed FDA1572 that includes all investigators who will participate in the clinical 
trial along with current signed and dated CV, copy of medical license for each 
investigator and Human Subjects Research and HIPAA training records and 
certifications. 
a. FDA1572 will be updated if changes/additions occur and a copy is to be sent to 
the Data Coordinating Center. 
3. Financial Disclosure (FDA3455) 
4. Delegation of Authority Form  
a. The delegation of authority form will be completed for all study personnel which 
will include the name, signature, and initials of all personnel signing Case Report 
Forms (CRFs), whether paper or in EDC. 
5. Laboratory Certification 
a. The participating site will submit to the Data Coordinating Center all laboratory 
certifications from their institution as well as a copy of the normal ranges.  A copy 
of the laboratory director’s CV and medical license will also be submitted and 
kept on file. 
6. Local IRB membership list 
7. The Data Coordinating Center will complete a trial initiation checklist indicating all 
requirements for the study (including training of participating site) and the regulatory 
binder have been met prior to initiation/activation of the study at the participating site.  A 
template for what is to be filed will be sent to each participating site.  The site will 
maintain documents and send copies to the COH DCC. 
 
Training: 
 
COH Data Coordinating Center staff will be responsible for training research personnel at 
every participating site.    
 
The COH Data Coordinating Center will also provide participating sites with a complete study 
roster that includes who to contact for any questions.  This roster will be updated (as needed) 
throughout the course of the trial and distributed to sites. 
 
Training will be conducted either on-site and/or at City of Hope or via teleconference.  The 
following training will be completed at different time-points and/or as needed:   
 
 Initial training of current research personnel during site initiation visit (via 
teleconference) on protocol management and data collection; 
 Interim training on data collection on new case report forms as specified per 
protocol.    
 Subsequent training of any new staff at participating sites. 


  
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Training components will include, but are not limited to protocol management, screening 
procedures, inclusion/exclusion criteria, randomization, study calendar, study procedures, 
investigational product, treatment plan, AE monitoring, dose modification, guidelines of SAE 
reporting, 
data 
submission 
schedule, 
eligibility 
checklist, 
informed 
consent 
process/documentation of informed consent (when applicable), and data collection training on all 
CRFs as required per protocol.   This may include training on GCP guidelines to ensure 
compliance with all applicable rules and regulations.  Training will also include review of all 
items needed in regulatory binder. 
 
Data Collection Instruments: 
 
1. Data for this trial will be collected using Medidata RAVE, City of Hope’s electronic 
capture system. 
2. Medidata RAVE is a web based, password protected system.  It is fully compliant with 
global regulatory requirements, including 21CRF Part 11 compliant. 
3. Participating staff will be required to complete an Account Activation Form (AAF) to 
obtain access to the Medidata RAVE system once IRB approval documentation is 
received. 
4. Participating site staff will obtain log in information once they fax in the required AAF. 
5. Once their AAF is received, the participating site staff will receive their individual login 
information. 
6. The participating site staff (whether Principal Investigator or the staff collecting data at 
site) are required to take an eLearning Module within Medidata RAVE in order to obtain 
full access. 
7. The participating site staff will receive training via teleconference by COH DCC staff to 
review eCRFs that are specific to this protocol.  Continuous training will be offered to 
participating sites if any amendments affect changes to the eCRFs during the course of 
the trial. 
8. The eCRFs within Medidata RAVE for this trial will have detailed instructions in the 
form of Help Text that provide instructions for completing each required field on each 
form. 
9. Participating sites will be required to complete data collection within Medidata RAVE in 
a timely manner.  Data will be expected to be completed within 2 weeks of each subject 
visit (or as per the study protocol – if needed sooner).   
a. The Data Coordinating Center will run monthly data expectation reports that will 
list any outstanding and overdue data. 
b. The Data Coordinating Center will send via email to the participating site a report 
monthly on any missing and/or overdue data forms.  The participating site will be 
required to complete the missing and/or overdue data forms within 1 week of 
receipt of the report. 
c. If the data is not completed, the Data Coordinating Center will reach out to the 
participating site’s Principal Investigator and site staff to ensure prompt 
completion of data.   
d. If any issues continue, the Data Coordinating Center will communicate with the 
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105 
issues. 
10. Query reports will be generated on a monthly basis by the Data Coordinating Center. 
a. The Data Coordinating Center will send via email to the participating site a report 
monthly on any outstanding queries.  The participating site will be required to 
complete the queries within 2 weeks of receipt of the report. 
b. If the queries have not been resolved in a timely manner, the Data Coordinating 
Center will reach out to the participating site’s Principal Investigator and site staff 
to ensure prompt resolution of the queries and/or to discuss an extension on the 
due date. 
c. If the queries have not been completed in a timely manner, after discussion with 
the participating site’s Principal Investigator and site staff, the Data Coordinating 
center will communicate with the sponsor with the hope of resolving any issues. 
 
General Instructions for Completing Case Report Forms: 
 
1. All data recorded on case report forms must be verifiable in the source documents 
maintained at the participating site.  Source documents refer to all notes and reports 
contained in the subject’s medical record. 
2. When completing the initial eligibility checklist, participating sites are asked to print and 
use black ink. 
3. The subject must not be identified by name on any study document.  If a form such as a 
radiographic report or lab report is submitted, the subject’s name must be obliterated and 
replaced with the subject’s initials and registration number. 
4. All dates must be verifiable by source documents.   
 
Data Transmission:  
 
1. Registration documents including eligibility checklist, demographics and corresponding 
source documentation will be sent to the Data Coordinating Center via fax or via City of 
Hope’s Secure Mail system in order to ensure proper registration/randomization of each 
subject.  As this information may contain identifiers (patient name, medical record 
number, date of birth, sex, race, ethnicity, zip code as required for internal registration), it 
is imperative that participating sites either fax this data OR use the Secure Mail route by 
typing #secure# in the email subject line.  All participating sites will be sent out the City 
of Hope Secure Mail guide. 
2. All subjects will be granted a protocol specific number (i.e., COH-001, CED-001) that 
will be assigned by the COH Data Coordinating Center. 
3. Subsequent data collection then will take place via the web-based Medidata RAVE 
system.  Participating sites will need to ensure they have the capability and access to a 
computer and the internet in order to complete data collection. 
4. The Data Coordinating Center will at times need to contact the participating site to obtain 
information but will always refer to the protocol specific patient number. 
 
Data Analysis:  
 
Joycelynne M. Palmer, PhD, is responsible for data analysis. Details regarding the study design 


  
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106 
and planned analyses can be found in section 10.0 of the protocol document. 
 
Quality Assurance and Monitoring 
 
1. The COH Data Coordinating staff will monitor each protocol conducted at participating 
sites to verify that the rights and well-being of human subjects are protected, the 
reported trial data are accurate, complete and verifiable from source documents, and 
that the conduct of the trial is in compliance with the currently approved 
protocol/amendment(s) with the GCP and with applicable regulatory requirements.  The 
COH Data Coordinating Center will determine the appropriate extent and nature of the 
monitoring based on considerations such as study objective, purpose, design, 
complexity, blinding, size and endpoints of the trial.  A trial may require onsite 
monitoring at the participating site or may be subject to remote monitoring.  Remote 
monitoring will involve the participating site submitting de-identified source 
documentation to the COH Data Coordinating Center.  Monitoring of that data will be 
done at COH by assuring the data captured onto CRFs is the same as the source 
documentation submitted.   
2. Each IRB approved protocol will undergo monitoring evaluations by the COH Data 
Coordinating Center staff at varying time points as determined by the Division of 
Clinical Research Information Support.  A trial may require onsite monitoring at the 
participating site or may be subject to remote monitoring.  Remote monitoring will 
involve the participating site submitting de-identified source documentation to the COH 
Data Coordinating Center.  Monitoring of that data will be done at COH by assuring the 
data captured onto CRFs is the same as the source documentation submitted.  
3. In addition, COH research personnel from the Office of Clinical Research Auditing & 
Monitoring may audit protocol compliance at participating sites at intervals decided by 
the coordinating center and their office.  Auditing is dependent upon the protocol’s phase, 
accrual rate, IND status, and results of previous evaluations.   
4. Participating sites will be informed of intended monitoring evaluations in a timely 
manner prior to the proposed visit and/or request for remote monitoring.  When informed 
of an impending monitoring evaluation (either onsite or remotely) by COH staff, the 
participating site is required to prepare for the visit by including but not limited to:  1) 
providing adequate, private space for COH staff to conduct the evaluation, 2) having a 
contact person available for periodic questions, 3) providing the medical record or 
applicable documentation for each subject monitored on the day of the visit, 4) providing 
an organized collection of regulatory documents pertaining to the study,  5) flagging all 
source documents pertinent to data collections; and/or 6) de-identifying and submitting to 
the Data Coordinating Center all source documentation for subjects.  Following any 
evaluation, an estimate of the next monitoring visit (whether onsite or remote) will be 
given to the participating site staff.   
5. The DCC will compare the subject’s records and other supporting documents with the 
data entered on the CRFs (paper or electronic).     
6. The DCC will ensure: 
 
a. That the information recorded is complete and accurate. 


  
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107 
b. That there are no omissions of specific data elements such as the administration to 
any subject of concomitant test articles or the development of an intercurrent 
illness. 
c. Missing visits and examinations are noted in the records. 
d. Subjects failing to complete the study and the reason for each failure are noted. 
e. There is an original fully executed informed consent document in the subject 
record. 
f. That study subjects initial (and subsequently thereafter, if applicable) met 
protocol mandated eligibility criteria for study participation. 
g. That proper procedures were followed in obtaining informed consent from study 
subjects, as dictated by local regulatory guidelines (and may be subject to 
differences internationally). 
h. That source data/documents and other trial records are accurate, complete, up-to-
date and maintained. 
i. That the participating site investigator provides all the required reports, 
notification, applications and submissions. 
j. That these documents are accurate, completely, timely, legible and dated. 
 
7. The Data Coordinating center will specifically verify that: 
 
a. The data required by the protocol are reported accurately on the CRF and are 
consistent with the source data/documents. 
b. Any dose and/or therapy modifications are well documented for each of the trial 
subjects. 
c. Adverse events, serious adverse events, concomitant medications and inter-
current illnesses are reported in the CRFs in accordance with the protocol. 
d. That study procedures were performed in adherence to the protocol document and 
that deviations from written procedures were discovered and properly reported to 
the IRB. 
 
8. The findings from the visit (whether on-site or remote) will be presented to the 
participating site in the form of a detailed, written report.  This report will include a 
summary of what was reviewed and any findings concerning significant deficiencies and 
actions recommended for compliance.  The report will be provided to appropriate 
participating site staff within 21 days of the evaluation completion.  The participating site 
staff is required to provide a written response to the findings with the corrective plan of 
actions within 14 days upon receipt of the report (if corrective action is suggested). 
 
Adverse Event/Serious Adverse Event/Unanticipated Problem Reporting 
 
1. The Data Coordinating Center will be responsible for tracking, reporting and maintaining 
documentation of all serious adverse events and unanticipated problems and 
dissemination of the information to participating sites. 
2. The Data Coordinating Center will be responsible for reporting of adverse event data to 
the study sponsor (as required). 
3. The participating sites are responsible for reporting all adverse events as required in 


  
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108 
Section 11.0 of the protocol, as well as to report per their local institutional guidelines. 
4. The Data Coordinating Center will be responsible for distributing DSMC 
findings/updates/reviews to the participating sites for submission as per their local 
guidelines (if applicable). 
 


 
IRB #12267 
 
03/07/2017 
Version: 07 
CITY OF HOPE MEDICAL CENTER 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
 
DEPARTMENT OF HEMATOLOGY AND HEMATOPOIETIC CELL TRANSPLANTATION          
 
 
TITLE:   Phase I/II Trial of MLN9708 plus Pomalidomide and Dexamethasone for Relapsed or 
Relapsed Refractory Multiple Myeloma 
 
CITY OF HOPE PROTOCOL NUMBER/VERSION:  
IRB # 12267    
 
VERSION: 07 
 
 
DATE(S)/ OF AMENDMENT(S)/REVISION(S): 
 
 
COH Initial Protocol Dated 11/01/2013  
 
 
 
 
 
Version: 00 
COH Amendment 01 Protocol Dated 05/12/2014 
 
 
 
 
Version: 01 
COH Amendment 02 Protocol Dated 03/23/2015 
 
 
 
 
Version: 02 
COH Amendment 03 personnel update Dated 12/16/2015  
 
 
Version: 03 
COH Amendment 04 Protocol Dated 12/17/2015 
 
 
 
 
Version: 04 
COH Amendment 05 Protocol Dated 08/01/2016 
 
 
 
 
Version: 05 
COH Amendment 06 at Continuation Title Page Dated 11/09/2016  
 
Version: 06 
COH Amendment 07 Protocol Dated 03/07/2017 
 
 
 
 
Version: 07 
 
 
 
DISEASE SITE: 
Multiple Myeloma 
STAGE (If applicable):  
 
 
 
 
 
MODALITY(IES): 
 
 
 
 
 
TYPE (e.g., Pilot, Phase I, etc.):  
 
 
Phase I/II 
 
 
PRINCIPAL INVESTIGATOR: 
 
 
Amrita Krishnan, M.D. 
Designs, responsible for study conduct 
and data analysis  
 
COLLABORATING INVESTIGATOR(S): 
 
Joycelynne M. Palmer, Ph.D (Biostatistics) 
 
 
PARTICIPATING CLINICIANS:  
 
 
Haris Ali, M.D., Ahmed Aribi, M.D.,  Elizabeth Budde, M.D., Robert 
Chen, 
M.D., 
Stephen 
Forman, 
M.D., 
Myo 
Htut, 
M.D., 
Chatchada,Karanes, M.D., Samer Khaled, M.D., Auayporn 
Nademanee, M.D., Nitya Nathwani, M.D., Ryotaro Nakamura, M.D., 
Margaret O’Donnell, M.D., Pablo Parker, M.D., Leslie Popplewell, 
M.D., Michael Rosenzweig, M.D., Tanya Siddiqi, M.D., David 
Snyder, M.D., Anthony Stein, M.D., Eileen Smith, M.D., Amandeep 
Salhotra, M.D. Ji-Lian Cai, M.D., Leonard Farol, M.D., Ricardo 
Spielberger, M.D., George Somlo, M.D., Alex Herrera, M.D., 
Matthew Mei, M.D., Haris Ali, M.D., Jasmine Zain, M.D., Ibrahim 
Aldoss, M.D., Monzr Al Malki M.D., 
 


  
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CLINICAL STUDY PROTOCOL  
MMRC-051 
 
COH IRB # 12267 
 
 
Title:  
Phase I/II trial of MLN9708 plus Pomalidomide and 
Dexamethasone for Relapsed or Relapsed Refractory  
 
Multiple Myeloma 
 
 
Phase: 
 Phase I/II 
 
Protocol Version: 
Version 6.0 
03/03/2017 
 
Study Sponsor: 
City of Hope National Medical Center  
Investigator Initiated Trial 
 
Principal Investigator: 
 
Amrita Krishnan, MD  
 
Lead Principal Investigator 
 
City of Hope 
 
Collaborating Investigators: 
Prashant Kapoor, MD  
 
Mayo Clinic – Rochester 
 
 
Joseph Mikhael, MD 
 
Mayo Clinic - Arizona 
 
Ajay Nooka, MD, MPH 
Winship Cancer Institute of Emory University School of 
Medicine   
 
Jesus G. Berdeja, MD 
Sarah Cannon Research Institute Center 
 
Study Statistician 
Joycelynne M. Palmer, PhD 
 
City of Hope 
 
 
This is an investigator-initiated study.  The lead principal investigator, Amrita Krishnan, MD 
(who may also be referred to as the sponsor-investigator), is conducting the study and City of 
Hope National Medical Center, and is acting as the study sponsor.  Therefore, the legal/ethical 
obligations of the lead principal investigator include both those of a sponsor and those of an 
investigator. 
 
 


  
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Phase I/II trial of MLN9708 plus Pomalidomide and Dexamethasone  
for Relapsed or Relapsed Refractory Multiple Myeloma 
 
 
 
Protocol Acceptance Form – Amendment6.0 Protocol Dated  03-Mar-2017 
 
 
 
 
 
 
 
I have read this protocol and agree to conduct the study as outlined herein, in accordance with 
Good Clinical Practices (GCPs) and the Declaration of Helsinki, and complying with the 
obligations and requirements of clinical Investigators and all other requirements listed in 21 
CRF part 312. 
 
 
 
 
 
 
 
 
 
 
_______________________________________ 
_____________________________ 
Principal Investigator Signature 
 
 
Date 
 
 
________________________________________ ______________________________ 
Print Principal Investigator Name and Title  
Date 
 
 


  
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PROTOCOL SUMMARY  
 
Protocol Title: 
Phase I/II trial of MLN9708 plus Pomalidomide and Dexamethasone for Relapsed or 
Relapsed Refractory Multiple Myeloma   
Brief Protocol Title for the Lay Public (if applicable): 
Phase I/II trial of MLN9708 plus Pomalidomide and Dexamethasone for Relapsed or 
Relapsed Refractory Multiple Myeloma 
Study Phase: 
Phase I/II 
Participating Sites: 
▪ City of Hope  
▪ Mayo Clinic: Rochester and Arizona   
▪ Winship Cancer Institute of Emory University School of Medicine 
▪ Sarah Cannon Research Institute Center  
Rationale for this Study: 
Novel drugs are needed for the treatment of relapsed or relapsed refractory multiple myeloma.  
The combination of  proteasome inhibitor (PI) and immunomodulating (IMiD) agents has 
produced significant responses. Many patients are exposed to these classes of drugs earlier in 
the course of therapy, for patients who relapse after agents such as the PI bortezomib and the 
IMiD lenalidomide, newer agents are now available or in development including 
pomalidomide and MLN9708.  Pomalidomide is an IMiD that is active even in patients who 
are refractory to other IMiDS such as lenalidomide. MLN9708 is a PI that has shown activity 
in patients refractory to bortezomib. MLN9708 has shown activity in Phase I/II trials and 
pomalidomide and dexamethasone have shown activity in Phase I/II and III trials. Hence 
combining the two agents and including dexamethasone for synergy could potentially induce 
responses in this refractory patient population. 
Objectives: 
Phase I: 
Primary: 
1) To determine the recommended phase II dose (RP2D) of MLN9708 when given in 
combination with pomalidomide and dexamethasone, in patients with relapsed or 
relapsed/refractory multiple myeloma. 
Secondary: 
2) To evaluate the safety of MLN9708 at each dose level when given as part of a three drug 
combination by assessing the following: 
 
- type, frequency, severity, attribution, time course and duration of adverse events 
 
- clinical laboratory tests at various points in the study 
 
 


  
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Phase II: 
Primary: 
1. To estimate the response rate and to evaluate the antitumor activity of the three drug 
combination: MLN9708 (at the RP2D), pomalidomide and dexamethasone, in patients with 
relapsed or relapsed/refractory multiple myeloma. 
Secondary: 
At the RP2D, for the three drug combination: 
2. To characterize and evaluate toxicities, including type, frequency, severity, attribution, time 
course and duration. 
3. To obtain estimates of response duration, depth of response, clinical benefit response, and 
survival (overall and progression-free). 
Study Design: 
This study will be conducted as a multicenter phase I/II trial.  
 
The phase I portion will follow a standard 3+3 dose escalation design, to evaluate  toxicities 
associated with MLN9708 when given in combination with pomalidomide and 
dexamethasone. Two doses of MLN9708, 3mg and 4 mg, will be tested in up to three possible 
dose levels:   
Schedule: Each cycle is 28 days  
Dose Level 
Pomalidomide  
MLN9708 
Dexamethasone* 
-1 
3mg daily on days 1-21 
3 mg on days 1, 8 and 15 
40 mg on days 1, 8, 15 and 22 
1 
4 mg daily on days 1 - 21 
3 mg on days 1, 8 and 15 
40 mg on days 1, 8, 15 and 22 
2 
4 mg daily on days 1 - 21 
4 mg on days 1, 8 and 15 
40 mg on days 1, 8, 15 and 22 
*: Patients >75 years, at the time of trial registration, will receive a dexamethasone starting 
dose of 20mg on the same set schedule. 
 
The RP2D identified in the phase I portion of the study will be brought forward for activity 
evaluation. 
 
The phase II portion of this study will implement a Gehan two-stage design to estimate the 
response rate and to evaluate the activity of MLN9708 when given in combination with 
pomalidomide and dexamethasone (Gehan, 1961). 
Endpoints: 
Phase I: 
The primary endpoint is toxicity. Toxicity will be graded according to the NCI-Common 


  
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Terminology Criteria for Adverse Events version 4.03. Dose limiting toxicity (DLT) is 
defined in section 7.3 of the protocol. 
Phase II: 
The primary endpoint is response rate (sCR/CR/VGPR and PR) and is based on the 
International Myeloma Working Group (IMWG) criteria.  
Sample Size: 
Phase I: 
The phase I study will follow a 3+3 design, to evaluate toxicities associated with MLN9708 
when given in combination with pomalidomide and dexamethasone. Two doses of MLN9708 
(3 mg and 4 mg) will be tested in up to three possible dose levels. In the phase I portion of this 
study, the total sample size will depend on the number of dose levels evaluated to determine 
the RP2D. While the phase I study is expected to enroll and treat 9 patients (3 patients at dose 
level 1, and another 6 at dose level 2-assuming the 4mg dose is well tolerated), a maximum of 
18 patients could be treated (6 patients treated at each dose level. 
 
Phase II: 
The phase II portion of the study is expected to enroll a minimum of 9 and a maximum of 25 
patients. The six patients treated at the RP2D in the phase I portion of the study will count 
toward the 25 patients required; given this, we expect to enroll only 19 new patients during 
the phase II trial portion. The sample size is based on the desire to achieve a (promising) 
target response rate of >30%.   
Estimated Duration of the Study 
Accrual, for both phases, is expected to be completed in 26 months; with approximately 2 
patients enrolled each month. Patients will be treated in 28-day treatment cycles until disease 
relapse, progression or unacceptable toxicity, withdrawal of consent, or protocol specified 
parameters to stop treatment. Patients who discontinue study treatment for reasons other than 
disease relapse/progression will continue to have disease assessments per International 
Myeloma Working Group (IMWG) criteria until relapse or progression, initiation of new 
anticancer treatment, or death whichever occurs first. Patients will be followed to collect 
further anticancer treatment and survival information until death, loss to follow-up, 
withdrawal of consent, study termination or up to 24 months post treatment. 
Summary of Patient Eligibility Criteria: 
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 informed 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. Females of childbearing potential (FCBP) must have a negative serum or urine 
pregnancy test with a sensitivity of at least 25 mIU/mL within 10 – 14 days prior to 
and again within 24 hours of starting pomalidomide and must either commit to 
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of birth control, one highly effective method and one additional effective method at the 
same time, at least 28 days before she starts taking pomalidomide through 90 days 
after the last dose of study drug.  FCBP must also agree to ongoing pregnancy testing.  
Men must agree to use a latex condom during sexual contact with a FCBP even if they 
have had a vasectomy from the time of signing the informed consent form through 90 
days after the last dose of study drug.   
4. All patients must be registered in and must comply with all requirements of the 
POMALYST REMS™ program.   
5. Patients must have a diagnosis of relapsed or relapsed and refractory Multiple 
Myeloma with a minimum of one prior regimen and a maximum of 5 prior regimens.  
6. Patients must have had therapy with a proteasome inhibitor and lenalidomide and be 
refractory to lenalidomide according to the IMWG definition of refractory disease 
(progressive disease on or within 60 days of stopping lenalidomide). 
7. Patients must have measurable disease defined as one of the following: 
 Serum M protein ≥ 0.5 g/dL 
 Urine M protein ≥ 200 mg/24 hours 
 Serum free light chain ≥ 10 mg/dL provided the FLC ratio is abnormal. 
8. Eastern Cooperative Oncology Group (ECOG) performance status and/or other 
performance status 0, 1, or  2. 
9. Patients must meet the following clinical laboratory criteria: 
 Absolute neutrophil count (ANC)  1,000/mm3  
 Platelet count > 75,000/µL for patients in whom < 50% of bone marrow nucleated 
cells are plasma cells; or a platelet count > 50,000/µL for patients in whom > 50% 
of bone marrow nucleated cells are plasma cells. Platelet transfusions are not 
allowed within 3 days of last platelet assessment to confirm eligibility. 
 Total bilirubin  1.5  the institutional upper limit of normal range (IULN). 
 Alanine 
aminotransferase 
(ALT) 
and 
aspartate 
aminotransferase 
(AST)  3  IULN (institutional upper limit of normal range) 
 Calculated creatinine clearance  45 mL/min (Appendix15.2) 
 
Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study: 
1. Female patients who are pregnant or breastfeeding 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. 
3. Prior treatment with a multidrug regimen containing pomalidomide except the 2 drug 
combination of pomalidomide and dexamethasone. 
4. Major surgery within 14 days before enrollment. 
5. Radiotherapy within 14 days before enrollment. If the involved field is small, 7 days 
will be considered a sufficient interval between treatment and administration of the 
MLN9708. 
6. Central nervous system involvement. 
7. Infection requiring systemic antibiotic therapy or other serious infection within 
14 days before study enrollment. 


  
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8. 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. 
9. Systemic treatment, within 14 days before the first dose of MLN9708, 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. 
10. Unable or unwilling to undergo antithrombotic prophylaxis. 
11. Ongoing or active systemic infection, active hepatitis B or C virus infection, or known 
human immunodeficiency virus (HIV) positive. 
12. Any serious medical or psychiatric illness that could, in the investigator’s opinion, 
potentially interfere with the completion of treatment according to this protocol. 
13. Known allergy to any of the study medications, their analogues, or excipients in the 
various formulations of any agent. 
14. Known GI disease or GI procedure that could interfere with the oral absorption or 
tolerance of MLN9708 or pomalidomide including difficulty swallowing. 
15. Diagnosed or treated for another malignancy within 2 years before study enrollment or 
previously diagnosed with another malignancy with evidence of residual disease.  
Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not 
excluded if they have undergone complete resection. 
16. Patient has > Grade 2 peripheral neuropathy  on clinical examination during the 
screening period. 
17. Participation in other clinical trials, including those with other investigational agents 
not included in this trial, within 21days of the start of this trial and throughout the 
duration of this trial (for all other standard therapies, no treatment within 14 days of 
the start of this trial). 
18. Patients who are pomalidomide refractory, defined as patients who progress on or 
within 60 days of pomalidomide when given as a single agent or with dexamethasone. 
Investigational Product Dosage and Administration: 
MLN9708: 3mg or 4 mg oral; Pomalidomide: 3mg or 4mg oral; Dexamethasone: 40 mg oral 
(Note: Patients >75 years, at the time of trial registration, will receive a Dexamethasone dose 
of 20 mg on the same set schedule.) 
 
Clinical Observations and Tests to be Performed: 
Standard myeloma restaging studies (SPEP, UPEP, Bone Marrow Biopsy, Serum and Urine 
Immunofixation, Serum free lites, when applicable).  Refer to the Table of Assessments for 
complete details.  
Statistical Considerations: 
Phase I: 
The primary objective of the phase I study is to determine the recommended phase II dose 
(RP2D) of MLN9708 when given in combination with pomalidomide and dexamethasone, in 
patients with relapsed or relapsed/refractory multiple myeloma. 
 


  
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The phase I study will follow a 3+3 design for enrollment with dose escalation, or expansion 
of a cohort on the basis of the occurrence of dose limiting toxicities (DLTs) during cycle 1. 
Two doses of MLN9708 will be tested in up to three possible dose levels (dose level -1 and 
dose level 1: 3mg / dose level 2: 4 mg, administered on days 1, 8 and 15 of a 28 day cycle). 
The highest dose level that produces ≤1/6 DLTs in cycle 1 will be the maximum tolerated 
dose (MTD). The RP2D of MLN9708 and pomalidomide will generally be the MTD, but it 
may be less than the MTD  based on a review of available data/cumulative toxicities from 
phase I.  
 
Analysis: Observed toxicities will be summarized in terms of type (organ affected or 
laboratory determination), severity, time of onset, duration, probable association with the 
study regimen and reversibility or outcome. Baseline information (e.g. the extent of prior 
therapy) and demographic information will be presented as well to describe the patients 
treated in this study. 
 
Phase II: 
The  primary objective is to estimate the response rate and to evaluate the antitumor activity of 
the three drug combination: MLN9708 (at the RP2D), pomalidomide, and dexamethasone, in 
patients with relapsed or relapsed/refractory multiple myeloma. The primary endpoint is a 
confirmed tumor response of sCR/CR/VGPR or PR and is based on IMWG Criteria. A single 
cycle of treatment will be given in a 28 day cycle. Each patient’s disease status will be 
evaluated at baseline. Response will be assessed at the end of each cycle/just prior to the start 
of each cycle and is based on the IMWG criteria.  
 
Statistics/Sample Size and Accrual: The phase II portion of this study will implement a 
Gehan two-stage design to estimate the response rate and to evaluate the activity of MLN9708 
when given in combination with pomalidomide and dexamethasone (Gehan 1961). The phase 
II portion of the study is expected to enroll a minimum of 9 and a maximum of 25 patients. 
The six patients treated at the RP2D in the phase I portion of the study will count toward the 
25 patients required; given this, we expect to enroll only 19 new patients on the phase II trial. 
The sample size is based on the desire to estimate the response rate with at most 10% standard 
error, and early stopping if the combination is unexpectedly ineffective.  
  
At stage 1, 9 patients will be entered on the study. If 0 responses are seen in the first 9 patients 
treated, the study will be terminated and the true regimen response will be declared ≤30%. If 
at least 1 patient responds, the trial will continue to the second stage. Because patients treated 
during the phase I portion of the trial at the dose selected for the phase II trial will be counted 
(n=6), only 3 additional patients will be enrolled at stage 1. Under this design if the study 
regimen is >30% effective, there would be ~95.6% chance of at least one success. 
 
At stage 2, 16 additional patients will be entered. This accrual provides for estimation of the 
response rate with no more than 10% standard error.  
 
Analysis: The overall response rate will be calculated as the percent of evaluable patients that 
have confirmed sCR/CR/VGPR or PR; the clinical benefit response rate will be calculated as 
the percent of evaluable patients that have confirmed sCR/CR/VGPR/PR/ MR or SD; exact 


  
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95% confidence intervals will be calculated for these estimates. Response rates will also be 
evaluated based on number and type of prior therapy(ies). Time to response, duration of 
response, and survival will be estimated using the product-limit method of Kaplan and Meier. 
 
Sponsor 
Investigator Initiated Trial - City of Hope  
Case Report Forms 
This trial will utilize the Medidata RAVE® Electronic Data Capture system.     


  
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SCHEDULE OF EVENTS   
PROCEDURES 
Screen 
Cycle 1 
Each cycle is 28 days 
Cycle 2+* 
Each cycle is 28 days 
End of 
Treatment  
Post 
Study 
Follow 
Up 
-21d to 
-1d 
Day 
1 
Day 
8 
Day 
15 
Day 
22 
Day 
1 
Day 
8 
Day 
15* 
Day 
22 
 
 
Window 
 
± 1 
 
± 1 
 
± 1 
 
± 1 
 
± 1 
 
± 1 
 
± 1 
 
± 1 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Medical History, Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X11 
PE, Height1, Weight, ECOG 
X 
 
 
 
 
X 
 
 
 
X 
 
Toxicity Evaluation  
 
X 
 
 
 
X 
 
 
 
X 
 
Vital Signs  (HR, Temp, BP)  
X 
X 
 
 
 
X 
 
 
 
X 
 
12-lead ECG3 
X3 
 
 
 
 
 
 
 
 
X 
 
Education and counseling 
guidance document4 
X 
 
 
 
 
X 
 
 
 
X 
 
CBC5 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
Serum Chemistry5 
X 
 
 
X 
 
X 
 
 
 
X 
 
Neurological exam6  
X 
 
 
 
 
X 
 
 
 
X 
 
PT/PTT12 
X 
 
 
 
 
 
 
 
 
X 
 
Pregnancy test [FCBP] 2  
X 
X 
X 
X 
X 
X 
 
X2 
 
X2 
 
Extramedullary disease7 
X 
 
 
 
 
X 
 
 
 
X 
 
Skeletal Survey 8 
X 
 
 
 
 
 
 
 
 
 
 
Bone Marrow Aspiration/Biopsy9 
X 
 
 
 
 
X 
 
 
 
 
 
Myeloma-specific lab tests10 
X 
 
 
 
 
X 
 
 
 
X 
 
MLN9708 Administration 
 
X 
X 
X 
 
X 
X 
X 
 
 
 
Dexamethasone 
 
X 
X 
X 
X 
X13 
X13 
X13 
X13 
 
 
Pomalidomide Administration 
 
Days 1 - 21 
Days 1 – 21 
 
 


  
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PROCEDURES 
Screen 
Cycle 1 
Each cycle is 28 days 
Cycle 2+* 
Each cycle is 28 days 
End of 
Treatment  
Post 
Study 
Follow 
Up 
-21d to 
-1d 
Day 
1 
Day 
8 
Day 
15 
Day 
22 
Day 
1 
Day 
8 
Day 
15* 
Day 
22 
 
 
Follow for PD and survival 
 
 
 
 
X11 
 
1)  Measured at screening only.  
2)  FCBP - A female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) 
has not been naturally postmenopausal for at least 24 consecutive months. Pregnancy tests for FCBP must be performed within 10 to 14 days and 
again within 24 hours of initiation of therapy. Repeat pregnancy test every week for the first 4 weeks and then every 28 days while on therapy and 
during interruptions in therapy and 28 days following discontinuation of pomalidomide.  Women with irregular menstruation must have pregnancy 
testing every 14 days while on therapy and during interruptions and 14 and 28 days after discontinuation of Pomalidomide.  For Cycle 2 and forward, 
the D15 pregnancy test (if required) can be done locally and results faxed to the main institution. 
3)  ECG (12-Lead) should be performed and read locally.     
4)  All patients must be counseled about pregnancy precautions, risks of fetal exposure and other risks. All patients enrolled into this trial, must be 
registered in and must comply with all requirements of the POMALYST REMS™ program.   
5)  CBC to be performed and reviewed by clinician within 24 hours of day of dosing (first day of each cycle).  Alternately, a STAT CBC may be drawn on 
day of dosing, however should be reviewed prior to administration of investigational product(s). Serum Chemistry to be performed and reviewed by 
the investigator within 24 hours of day of dosing (first day of each cycle).  Alternately, a STAT CMP may be drawn on day of dosing however should 
be reviewed by the investigator prior to administration of investigational product(s).  Chemistry includes: glucose, calcium, albumin, total protein, 
sodium, potassium, BUN, creatinine, ALP, ALT, AST, bilirubin and uric acid (uric acid to be drawn at screening and then as needed based on tumor 
lysis syndrome risk).  Weight and serum creatinine will be used to calculate creatinine clearance by Cockroft-Gault equation (see appendix 15.2).   
6)  Neurological assessment required at screening and Day 1 of Cycle 2+. 
7)    Extramedullary Disease: prior to study (28 days), testing required only if extramedullary disease is present, every 12 weeks (if present at screening) 
or upon clinical suspicion of progressive disease (if present at screening).  This may include CT scan of the abdomen/pelvis, CT or x-ray of the chest, 
ultrasound of the liver/spleen or abdomen.      
8) 
Skeletal survey (including skull, all long bones, pelvis and chest) with tumor measurements (measurements required if plasmacytomas are present).  
Also required if previous survey >28 days from study entry and at any time when clinically indicated. 
9)  A bone marrow aspiration and biopsy is required at screening; Repeat bone marrow biopsy/aspirate as appropriate to confirm achievement of 
response (aspirate only—biopsy not required).   
10)  Myeloma lab tests: B2Microglobulin (collected at screening only); serum immunoelectrophoresis, immunoglobulin assay, M band quantitation by 
immunofixation, free light chain and 24 hour urine collection for Bence Jones protein to be performed at baseline prior to study, prior to each cycle (to 
confirm  complete response and in patients with urine only measurable disease) thereafter and at time of end of treatment  (if last tests were > 3 
weeks).  
11) End of study follow-up to be completed every three months for two years to include second primary malignancies, new therapies for the treatment of 
MM only (not all concomitant medication) and survival. 
12)  Due to the risk of blood clots while on Pomalidomide, if patient is started on warfarin, routine monitoring of INR should occur (as per your 
institutuional guidelines).   
13)  After the patient has been on Dexamethasone over one year, the patient can discontinue Dexamethasone at their next scheduled visit.     
 


  
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*Additional tests to be performed at the beginning of each cycle and at any reasonable time point during treatment if indicated for monitoring of drug 
profile/safety or, for disease/health status at the discretion of the clinical investigator.  Starting with Cycle 2 and forward, the patient is not required to 
come to the main hospital/institution for a Day 15 visit.  The patient can be seen locally by their physician at their discretion.


  
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TABLE OF CONTENTS 
PROTOCOL SUMMARY ........................................................................................................3 
SCHEDULE OF EVENTS .....................................................................................................10 
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS ............................................16 
1. BACKGROUND AND STUDY RATIONALE ................................................................19 
1.1 Multiple Myeloma Background ....................................................................................19 
1.2 MLN9708 .....................................................................................................................20 
1.2.1 Preclinical Experience ...........................................................................................20 
1.2.2 Clinical Experience ................................................................................................20 
1.2.3 Pharmacokinetics and Drug Metabolism ...............................................................20 
1.2.4 Clinical Trial Experience Using the Oral Formulation of MLN9708 ...................21 
1.2.5 Overview of the Oral Formulation of MLN9708 ..................................................23 
1.2.6 MLN9708 in Relapsed and/or Refractory Multiple Myeloma ..............................25 
1.2.7 MLM9708 in Newly Diagnosed Multiple Myeloma (NDMM) ............................29 
1.3 Pomalidomide ...............................................................................................................30 
1.3.1 Mechanism of Action.............................................................................................31 
1.3.2 Pharmakokinetics ...................................................................................................31 
1.3.3 Non-clinical Toxicology ........................................................................................32 
1.3.4 Clinical Studies ......................................................................................................33 
1.4 Study Rationale .............................................................................................................34 
1.5 Potential Risks and Benefits .........................................................................................35 
2. STUDY OBJECTIVES ......................................................................................................35 
2.1 Study Objectives (Phase I) ...........................................................................................35 
2.1.1 Primary: .................................................................................................................35 
2.1.2 Secondary: .............................................................................................................36 
2.2 Study Objectives (Phase II) ..........................................................................................36 
2.2.1 Primary: .................................................................................................................36 
2.2.2 Secondary: .............................................................................................................36 
3. STUDY ENDPOINTS ........................................................................................................36 
3.1 Primary Endpoints ........................................................................................................36 
4. STUDY DESIGN ...............................................................................................................38 
4.1 Overview of Study Design ...........................................................................................38 
4.1.1 Phase I: ...................................................................................................................38 
4.1.2 Phase II ..................................................................................................................38 
4.2 Number of Patients .......................................................................................................38 
4.3 Duration of Study .........................................................................................................38 
5. STUDY POPULATION .....................................................................................................39 
5.1 Inclusion Criteria ..........................................................................................................39 
5.2 Exclusion Criteria .........................................................................................................40 
6. PATIENT ENROLLMENT ................................................................................................42 
7. STUDY TREATMENT ......................................................................................................43 
7.1 Dose and Schedule ........................................................................................................43 
7.2 Dose Levels to be Tested ..............................................................................................43 
7.3 Dose Limiting Toxicity ................................................................................................43 
7.4 Dose Escalation/Expansion ..........................................................................................44 


  
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7.5 Recommended Phase II Dose (RP2D) ..........................................................................45 
7.6 Study Drug Administration ..........................................................................................45 
7.6.1 MLN9708 Administration .....................................................................................45 
7.6.2 Pomalidomide Administration ...............................................................................46 
7.6.3 Dexamethasone Administration .............................................................................46 
7.6.4 Growth factor Administration ................................................................................47 
7.7 Dose-Modification Guidelines .....................................................................................47 
7.8 Dose Reduction Steps ...................................................................................................48 
7.8.1 Dose Reduction Steps for Pomalidomide ..............................................................48 
7.8.2 Dose Reduction Steps for MLN9708.....................................................................48 
7.8.3 Dose Reduction Steps for Dexamethasone ............................................................48 
7.9 Dose Modification Guidelines for Treatment Related Toxicity ...................................49 
7.9.1 Dose Modification for MLN9708 and Pomalidmide During a Cycle of Therapy.49 
7.9.2 Dexamethasone Dose Modification Guidelines ....................................................52 
7.10 Criteria for Beginning or Delaying a Subsequent Treatment Cycle ...........................53 
7.11 Concomitant Medications ...........................................................................................53 
7.11.1 Excluded Concomitant Medications and Procedures ..........................................53 
7.11.2 Permitted/Recommended Concomitant Medications and Procedures .................54 
7.11.3 Required/Recommended Concomitant Therapy ..................................................55 
7.11.4 Pregnancy.............................................................................................................56 
7.12 Management of Clinical Events .................................................................................57 
8. STUDY DRUG ...................................................................................................................60 
8.1 Packaging and Labeling ................................................................................................60 
8.1.1 MLN9708...............................................................................................................60 
8.1.2 Pomalidomide ........................................................................................................60 
8.2 Storage, Handling, and Accountability .........................................................................61 
8.2.1 MLN9708...............................................................................................................61 
8.2.2 Pomalidomide ........................................................................................................62 
9. STUDY COMPLIANCE ....................................................................................................63 
9.1 Treatment Assignment ..................................................................................................63 
9.2 Termination of Treatment and/or Study Participation ..................................................63 
10. STATISTICAL AND QUANTITATIVE ANALYSES ...................................................64 
10.1 Statistical Methods .....................................................................................................64 
10.1.1 Determination of Sample Size .............................................................................64 
10.1.2 Populations for Analysis ......................................................................................65 
10.1.3 Demographic and Baseline Characteristics .........................................................65 
10.1.4 Efficacy Analysis .................................................................................................65 
10.1.5 Safety Analysis ....................................................................................................66 
11. ADVERSE EVENTS.................................... ERROR! BOOKMARK NOT DEFINED. 
11.1 Definition of Risk Level .............................................................................................67 
11.2 Monitoring and Personnel Responsible for Monitoring .............................................67 
11.3 Definitions ..................................................................................................................68 
11.3.1 Pretreatment Event Definition .............................................................................68 
11.3.2 Adverse Event Definition ....................................................................................68 
11.3.3 Unexpected Adverse Event [21 CFR 312.32 (a)] ................................................69 
11.3.4 Expected Adverse Event ......................................................................................69 


  
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11.2     REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED 
PROBLEMS ...............................................................................................................71 
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events ................78 
12. ADMINISTRATIVE REQUIREMENTS ........................................................................79 
12.1 Good Clinical Practice ................................................................................................79 
12.2 Ethical Considerations ................................................................................................80 
12.3 Patient Information and Informed Consent ................................................................80 
12.4 Patient Confidentiality ................................................................................................81 
12.5 Investigator Compliance .............................................................................................81 
12.6 Study Documentation and Archives ...........................................................................82 
12.6.1 Source Documents ...............................................................................................82 
12.6.2 Case Report Form Completion ............................................................................82 
12.7 Archival of Records ....................................................................................................83 
12.8 Study Monitoring and Data Collection .......................................................................83 
12.9 Investigator and Site Responsibility for Drug Accountability ...................................84 
12.10 MLN9708 Product Complaints ................................................................................84 
12.11 Closure of the Study .................................................................................................85 
12.12 Record Retention ......................................................................................................85 
13. USE OF INFORMATION ................................................................................................85 
14. REFERENCES .................................................................................................................86 
15. APPENDICES ..................................................................................................................89 
15.1 Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status ..........89 
15.2 Cockcroft-Gault Equation ...........................................................................................90 
15.3 Notification of Unanticipated Problem/Serious Adverse Event/Pregnancy ...............91 
Unanticipated Problem/Serious Adverse Event/Pregnancy Information……………..91 
    15.3.1 Millennium Pregnancy Reporting Form ..................................................................92 
15.4 International Myeloma Working Group Response Criteria27 .....................................95 
15.5 CITY OF HOPE DATA COORDINATING CENTER PLAN………....................96 
 
 


  
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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS 
Abbreviation 
Term  
AE 
AESI 
AL 
adverse event 
adverse event of special interest 
amyloidosis 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration versus time curve 
AUCτ 
area under the plasma concentration versus time curve from zero to next dose 
BCRP 
breast cancer resistance protein 
hCG
beta-human chorionic gonadotropin 
BMA 
bone marrow aspirate 
BMB 
bone marrow biopsy 
BSA 
body surface area 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CHF 
congestive heart failure 
CL 
clearance 
Cmax 
single-dose maximum (peak) concentration   
CO2 
carbon dioxide 
CR 
complete remission   
CRA 
Clinical Research Associate 
CRP 
C-reactive protein 
CT 
computed tomography 
CV 
 cardiovascular  
CYP 
cytochrome P450 
DCC 
DLT 
data coordinating center 
dose-limiting toxicity 
DNA 
DSMC 
deoxyribonucleic acid 
data safety monitoring committee 
ECG 
electrocardiogram 


  
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Abbreviation 
Term  
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOS 
End of Study (visit) 
EOT 
End of Treatment (visit) 
FCBP 
female of child bearing potential 
FDA 
United States Food and Drug Administration 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony stimulating factor 
GGT 
gamma glutamyl transferase 
Hb 
hemoglobin 
Hct 
hematocrit 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
IC50 
concentration producing 50% inhibition 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
IMiDS 
independent ethics committee 
immunomodulatory agents  
IMWG 
International Myeloma Working Group 
IRB 
Institutional Review Board 
IV 
intravenous; intravenously 
KPS 
Karnofsky Performance Status 
LDH 
lactate dehydrogenase 
LFT 
liver function test(s) 
MedDRA 
Medical Dictionary for Regulatory Activities 
Millennium 
MM 
Millennium Pharmaceuticals, Inc., and its affiliates 
multiple myeloma  
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NDMM 
newly diagnosed multiple myeloma 
NCI 
National Cancer Institute 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NK 
Natural killer cells 
NYHA 
New York Heart Association 


  
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Abbreviation 
Term  
OS 
overall survival 
PBMC 
peripheral blood mononuclear cell 
PD 
progressive disease 
PFS 
progression free survival 
Pgp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
PO 
per os; by mouth (orally) 
PR 
PMT 
partial remission  
Protocol Monitoring Team 
RBC 
red blood cell 
RP2D 
recommended phase 2 dose 
RRMM 
relapsed refractory multiple myeloma 
SAE 
serious adverse event 
SD 
stable disease 
Tmax 
single-dose time to reach maximum (peak) concentration 
TEAE 
treatment emergent adverse event 
TTP 
time to prgression 
TW 
twice weekly 
ULN 
upper limit of the normal range 
US 
United States 
Vd 
volume of distribution in the terminal phase 
VGPG 
very good partial response 
W 
weekly 
WBC 
white blood cell 
WHO 
World Health Organization 
 


  
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1.    
BACKGROUND AND STUDY RATIONALE 
1.1    Multiple Myeloma Background 
Multiple myeloma (MM) is an incurable malignancy that is the second most common 
hematological malignancy. There are approximately 20,000 new cases per year and 10,000 
deaths per year from MM in the United States. 1  Treatment options for relapsed MM include 
the following: 
Bortezomib; A drug in the class of proteasome inhibitors, it was approved as monotherapy for 
relapsed MM.2   Given the efficacy and tolerability of the drug it is often used in combination 
with agents such as alkylators ( cyclophosphamide), immunomodulatory agents (IMiDS), or 
liposomal doxorubicin either in the upfront setting or relapsed setting. 3 
Carfilzomib: Also a proteasome inhibitor, was approved in 2012 for patients who had prior 
therapy with bortezomib and an IMID and were progressing on or refractory to their most recent 
therapy. It has less peripheral neuropathy than bortezomib and has shown responses in 
bortezomib refractory patients.4  However, there are concerns with potential cardiac, pulmonary 
and renal side effects. Also the administration schedule of consecutive days of intravenous 
dosing make it a more cumbersome regimen for patients.  
Lenalidomide/Thalidomide: Drugs in the class known as immunomodulatory agents. 
Lenalidomide in conjunction with dexamethasone is approved for relapsed myeloma. 5 
Thalidomide is also approved for myeloma therapy but in the United States, lenalidomide is 
used preferentially due to its more favorable side effect profile. Similar to the practice with 
bortezomib both drugs are now commonly used in the upfront induction setting for therapy of 
myeloma in conjunction with dexamethasone for synergy. 6 
Unfortunately even with the advent of these active novel agents and improved response rates of 
combination therapy, all patients with myeloma ultimately relapse.  However, patients are living 
longer and hence, the goals of MM therapy are not only efficacy but also favorable toxicity 
profiles.7  In addition as these novel agents are being used earlier in the course of myeloma 
therapy, when patients do relapse, their disease is often refractory to the approved agents. 
Survival for this group of patients, especially those refractory to bortezomib and lenalidomide, 
the so called double refractory group is especially poor. 8 


  
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Hence new therapies for patients with relapsed disease are needed. In addition, oral therapies 
have the advantage of ease of administration and the potential for longer term use.  
1.2         MLN9708  
1.2.1    Preclinical Experience 
Please refer to the current MLN9708 Investigator’s Brochure (IB) and Safety Management 
Attachment (SMA). 
1.2.2    
Clinical Experience 
As of 30 April 2012, 382 patients have been treated with MLN9708 across 9 enrolling, sponsor-
led phase 1 or phase 1/2 studies evaluating both twice-weekly and weekly dosing schedules.  
MLN9708 is available as an intravenous and oral formulation. Regardless of the route of 
administration in the twice-weekly dosing schedule, MLN9708 is given on Days 1, 4, 8, and 11 
of a 21-day cycle; in the weekly dosing schedule, the drug is given on Days 1, 8, and 15 of a 28-
day cycle. To date, the development of oral MLN9708 has focused on multiple myeloma 
[relapsed and/or refractory and newly diagnosed] and a different yet related plasma cell 
dyscrasia, systemic light chain (AL) amyloidosis. A clinical pharmacology study looking at 
drug-drug interactions, the effect of food, and bioavailability also uses the oral formulation. 
Details of these trials can be found in ClinicalTrials.gov and the MLN9708 IB.   
1.2.3   Pharmacokinetics and Drug Metabolism 
Clinical IV and PO pharmacokinetic (PK) data show that MLN9708 (measured as the 
biologically active boronic acid form of MLN9708 [MLN2238]) has multi-exponential 
disposition with a rapid initial phase that is largely over by 4 hours.  Oral MLN9708 is rapidly 
absorbed with a median time to first maximum plasma concentration (Tmax) of approximately 
0.5 to 2.0 hours and terminal t1/2 after multiple dosing of approximately 5 to 7 days.9  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.10  Based on these data, a 
recommendation was made for fixed dosing in clinical trials.  An absolute bioavailability of 
67% was determined for MLN9708 using the population PK analysis.  See the IB for 
information on the PK for IV doses of MLN9708. 
Metabolism appears to be the major route of elimination for MLN9708, with negligible urinary 
excretion of the parent drug (< 3% of dose).  In vitro studies of liver microsomes show that 


  
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MLN9708 is metabolized by multiple cytochrome P450 enzymes (CYPs) and non-CYP 
enzymes/proteins.  The rank order of relative biotransformation activity of the 5 major human 
CYP isozymes is 3A4 (34.2%) > 1A2 (30.7%) > 2D6 (14.7%) > 2C9 (12.1%) > 2C19 (< 1%).  
MLN9708 is not an inhibitor of CYPs 1A2, 2C9, 2C19, 2D6, or 3A4, nor is it a time-dependent 
inhibitor of CYP3A4/5.  The potential for MLN9708 treatment to produce 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 because of the potential for first-pass metabolism when 
MLN9708 is administered via the PO route and because of the moderate contribution of 
CYP3A4- and CYP1A2-mediated metabolism of MLN9708 in human liver microsomes.  
MLN9708 may be a weak substrate of P-glycoprotein (P-gp), breast cancer resistance protein 
(BCRP), and multidrug resistance associated protein (MRP2) efflux pump transporters.  
MLN9708 is not an inhibitor of P-gp, BCRP, and MRP2.  The potential for DDIs with 
substrates or inhibitors of P-gp, BCRP, and MRP2 is, therefore, inferred to be low. 
1.2.4    
Clinical Trial Experience Using the Oral Formulation of MLN9708 
In the 7 studies actively enrolling patients to investigate oral MLN9708 in patients with 
differing malignancies (multiple myeloma, AL amyloidosis, nonhematologic cancers, and 
lymphoma), a total of 242 patients have been treated as of 30 April 2012. These patients have 
been treated with different doses of MLN9708, either as a single agent treatment or in 
combination with currently clinically available treatments. Information regarding the ongoing 
studies, patient populations, and doses investigated are included in Table 1-1. 


  
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Table 1-1   
Ongoing Studies of Oral MLN9708 
Trial/ 
Population 
Description 
Doses Investigated 
C16003 
RRMM 
N = 58 
PO, twice weekly (TW), single agent 
0.24-2.23 mg/m2, TW 
MTD:  2.0 mg/m2 
DLT:  rash, thrombocytopenia 
C16004 
RRMM 
N = 52 
PO, weekly (W), single agent 
0.24-3.95 mg/m2, W 
MTD:  2.97 mg/m2 
DLT:  rash, nausea, vomiting, diarrhea 
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 
RP2D*:  4.0 mg fixed (switched to fixed dosing in 
phase 2, relevant to 2.23 mg/m2) 
C16006 
NDMM 
N = 28 
PO, TW (Arm A- 42 day cycle) and W 
(Arm B- 28 day cycle), combination 
with melphalan and prednisone 
Arm A*:  3-3.7 mg, fixed dose, TW 
DLT: rash, thrombocytopenia, subileus 
Arm B*:  5.5 mg, fixed dose, W 
DLT: Esophageal ulcer 
C16007 
RR-AL 
N = 6 
PO, W, single agent 
4-5.5 mg, fixed dose*, W 
MTD: 4 mg 
DLT: thrombocytopenia, dirrhea, dyspnea, acute 
rise in creatinine, cardiac arrest 
 
C16008 
NDMM 
N=11 
PO, TW, combination with LenDex 21 
day cycle 
3.0-3.7 mg fixed dose* W 
MTD: 4 mg 
DLT: 
C16009 
Solid 
tumors, 
Lymphomas 
N = 22 
PO, W, single agent 
5.5 mg fixed dose* W 
C16010 
RRMM 
N = 1 
PO, W, combination with LenDex 
4.0 mg fixed dose* W 
TB-
MC010034 
RRMM 
N = 5 
PO, W, single agent in 1s part of study 
then in combination with LenDex in 2nd 
part 
3.0 mg fixed dose* W 
DLT: thrombocytopenia, nausea, hypertension, 
diarrhea 
Abbreviations:  RRAL = Relapsed or refractory Primary systemic light chain (AL) amyloidosis; BSA = body 
surface area ; DLT = dose-limiting toxicity; IV = intravenuously; LenDex = lenalidomide plus 
dexamethasone; MTD = maximum tolerated dose; NDMM = newly diagnosed multiple myeloma; PO = 
orally; RRMM = relapsed and/or refractory multiple myeloma; RPh2D = recommended phase 2 dose 
* Approximate body surface area (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. 


  
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1.2.5     Overview of the Oral Formulation of MLN9708 
The emerging safety profile indicates that oral MLN9708 is generally well tolerated with 
predominant toxicities largely reversible, able to be monitored by routine clinical examinations 
and manageable by dose reductions, discontinuation, or standard supportive care. From 
experience from phase 1 through 2 studies the major toxicities can be managed to allow repeat 
treatment cycles over periods extending beyond 24 months.  
In the 4 ongoing studies (C16003, C16004, C16007, and C16009) investigating single-agent 
oral MLN9708 in patients with differing malignancies (multiple myeloma, AL amyloidosis, 
nonhematologic cancers, and lymphoma), a total of 146 patients have been treated as of 30 April 
2012. These patients have been treated with different doses of MLN9708 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 MLN9708 Studies (C16003, C16004, C16007, and C16009) 
is shown in Table 1-2. 
Table 1-2 
Summary of Most Common (At Least 10% of Total) All Grade Treatment-
Emergent Adverse Events (Oral MLN9708 Single-Agent [C16003/4/7/9] 
Safety Population) 
Primary System Organ Class  
Preferred Term and Incidence 
N=146 
n (%) 
Subjects with at Least One Adverse Event 135 (92) 
 
Gastrointestinal disorders 102 (70) 
Nausea 68 (47); Diarrhoea 55 (38); Vomiting 51 (35); 
Abdominal pain 21 (14); Constipation 21 (14) 
General disorders and administration site conditions 98 
(67) 
Fatigue 71 (49); Pyrexia 31 (21); Oedema peripheral 15 
(10) 
Blood and lymphatic system disorders 77 (53) 
Thrombocytopenia 60 (41); Anaemia 30 (21); 
Neutropenia 23 (16); Leukopenia 15 (10) 
Nervous system disorders 63 (43) 
Headache 20 (14); Dizziness 18 (12) 
Metabolism and nutrition disorders 60 (41) 
Decreased appetite 39 (27) Dehydration 21 (14) 
Respiratory, thoracic and mediastinal disorders 60 (41) 
Cough 22 (15); Dyspnoea 21 (14) 
Skin and subcutaneous tissue disorders 60 (41) 
Rash macular 17 (12) 
Musculoskeletal and connective tissue disorders 56 
(38) 
Arthralgia 20 (14); Back pain 17 (12) 
Infections and infestations 54 (37) 
Upper respiratory tract infection 21 (14) 
Source: MLN9708 Investigator’s Brochure Edition 6 
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, any event that is considered drug-related regardless of the 
start date of the event, or any event that is present at baseline but worsens in intensity or is subsequently 
considered by the investigator to be drug-related.  


  
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Subject Incidence: A subject counts once for each preferred term. Percentages use the number of treated subjects as 
the denominator 
 
In the 3 studies actively enrolling patients to investigate oral MLN9708 in combination with 
standard combination regimens in patients with newly diagnosed multiple myeloma, a total of 
96 patients have been treated as of 30 April 2012. These patients have been treated with 
different doses of MLN9708 in combination with lenalidomide and dexamethasone in 2 trials 
(C16005 and C16008) and with melphalan and prednisone in 1 trial (C16006). The most 
frequent (at least 10%) adverse events occurring in the pooled safety population from Studies 
C16005, C16006, and C16008 is shown in Table 1-3. In combinations trials, related is defined 
as possibly related to any drug in the combination regimen, not just specifically related to 
MLN9708. 
 
Table 1-3 
Summary of Most Common (At Least 10% of Total) Treatment- Emergent 
Adverse Events (Oral MLN9708 Combination Agent [C16005/6/8] Safety 
Population) 
 
Primary System Organ Class  
Preferred Term and Incidence 
N= 96 
n (%) 
Subjects with at Least One Adverse Event 135 (92) 
 
 
Gastrointestinal disorders 70 (73) 
Nausea 32 (33); Constipation 29 (30); Vomiting 
25 (26) 
Diarrhoea 22 (23) 
General disorders and administration site 
conditions 64 (67) 
Fatigue 37 (39); Oedema peripheral 20 (21); 
Pyrexia 19 (20) 
Skin and subcutaneous tissue disorders 57 
(59) 
Rash 13 (14) 
Nervous system disorders 46 (48) 
Neuropathy peripheral 13 (14); Dysgeusia 12 
(13) 
Dizziness 11 (11) 
Musculoskeletal and connective tissue 
disorders 45 (47) 
Back pain 18 (19); Muscle spasms 10 (10) 
Blood and lymphatic system disorders 42 (44) 
Thrombocytopenia 28 (29); Anaemia 22 (23);  
Neutropenia 19 (20) 
Infections and infestations 40 (42) 
Upper respiratory tract infection 17 (18);  
Metabolism and nutrition disorders 38 (40) 
Decreased appetite 11 (11) 
Respiratory, thoracic and mediastinal 
disorders 34 (35) 
Dyspnoea 13 (14); Cough 11 (11) 
Psychiatric disorders 23 (24) 
Insomnia 15 (16) 
Source: MLN9708 Investigator’s Brochure Edition 6. 
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, any event that is considered drug-related regardless of the 
start date of the event, or any event that is present at baseline but worsens in intensity or is subsequently 
considered by the investigator to be drug-related. 


  
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Subject Incidence: A subject counts once for each preferred term. Percentages use the number of treated subjects as 
the denominator. 
 
 
 
 
The clinical experience with MLN9708 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 MLN9708, when combined with established therapies, and across the malignancies 
studied (advanced solid tumors 11, non-Hodgkin’s disease, Hodgkin’s disease 12, relapsed and/or 
refractory multiple myeloma [RRMM;13,14], relapsed or refractory systemic light chain 
amyloidosis [RRAL; 15], and newly diagnosed multiple myeloma [NDMM;16,17,18]) to date. 
 
Though additional data are needed to characterize the clinical benefit of this drug, the emerging 
data supports the ongoing development of MLN9708. 
 
Of particular relevance to this study (C16011) is the clinical experience from Studies C16004 
and C16007 in which single-agent MLN9708 is administered weekly in patients with RRMM or 
RRAL, respectively.  
 
1.2.6    
MLN9708 in Relapsed and/or Refractory Multiple Myeloma 
Study C16004 is an open-label, dose-escalation, phase 1 study of MLN9708 administered 
weekly on Days 1, 8, and 15 of a 28-day cycle in adult patients with RRMM. Patients with MM 
enrolled in the dose-escalation component of the study have relapsed following at least 2 lines  
of therapy, which must have included bortezomib, thalidomide (or lenalidomide), and 
corticosteroids. The dose-escalation phase of the trial has completed. In this study, 2 of 3 
patients experienced protocol-defined DLTs (Grade 3 rash and Grade 3 nausea, vomiting, and 
diarrhea) at a dose of 3.95 mg/m2. As per protocol, subsequent patients were treated at 1 dose 
level below (2.97mg/m2) where 1 of 6 patients experienced a DLT (Grade 3 nausea, vomiting, 
and diarrhea). The MTD of weekly oral MLN9708 was determined to be 2.97 mg/m2. 
Once the MTD was established, cohorts of patients representing the heterogeneous patient 
population currently seen in clinical practice were enrolled in order to further evaluate the 
safety, tolerability, efficacy, PK, and pharmacodynamics of oral MLN9708. The MTD 
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1. Relapsed and Refractory expansion cohort [refractory is defined as disease progression while 
on therapy or within 60 days after the last dose of therapy]; 
2. Carfilzomib expansion cohort 
3. Proteasome Inhibitor-Naïve expansion cohort 
4. Velcade-Relapsed expansion cohort 
Final study results are not available for this ongoing trial, but preliminary data suggest 
MLN9708 has antitumor activity in heavily pretreated MM patients, with durable 
responses/disease control, and is generally well tolerated.19,20 
As of the 30 April 2012 data cut, these patients are considered heavily pretreated as evidenced 
by a median number of 4 (range 1–13) prior lines of therapy, with 66% refractory to the last line 
of therapy. Patients have received a median of 2 cycles of therapy (range, 1- 11). Five patients 
have achieved objective response: 1 patient achieved a VGPR and 4 patients achieved a PR. 
Additionally, 15 patients achieved durable disease stabilization for up to 9.5 months. At data 
cut-off, 15 patients remain on treatment; discontinuation of treatment was primarily due to 
progressive disease (69%). 
 
A summary of the safety profile of patients treated in Study C16004 is outlined in Table 1-4. 
Overall, 92% of patients experienced a TEAE of any grade and of any cause. Peripheral 
neuropathy was limited to Grade 1/ 2 in 6 patients, with 3 patients reporting baseline Grade 1 
PN at study entry. 
 
Table 1-4    
Study C16004, Oral MLN9708, Single Agent, Given Weekly:  Most 
Common TEAEs as of 30 April 12 (N= 52) 
Most Common (> 20%) Any Grade and Irrespective 
of Cause 
Thrombocytopenia (54%) 
Fatigue (48%) 
Nausea (44%), diarrhea (44%) 
Vomiting (37%) 
Decreased appetite (33%) 
Rash* (31%) 
Anemia (25%) 
Neutropenia (23%) 
Drug-Related Grade  3 in > 5% of patients 
 
Thrombocytopenia (38%) 
Diarrhea and neutropenia 17% (each), fatigue and 
lymphopenia 10% (each), nausea and decreased 
appetite 8% (each) and vomiting 6% 


  
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Source: MLN9708 Investigator’s Brochure Edition 6 
* Rash includes preferred terms of rash macular, rash, maculo-papular, rash morbilliform, rash pruritic, 
pruritus,, rash erythematous, exfoliative rash, and rash popular 
 
 
Dose reductions required were due to AEs that included rash, neutropenia, thrombocytopenia, 
diarrhea, nausea, vomiting, dehydration, hypotension, increase in serum creatinine, abdominal 
pain, ileus, fatigue, and pneumonia. The AEs reported for the 5 patients who were required to 
discontinue treatment included Grade 2 MLN9708-related nausea/vomiting in 1 patient treated 
above the MTD, Grade 3 MLN9708-related diarrhea in a second patient, related Grade 3 
thrombocytopenia, related Grade 2 dyspnea, and notrelated Grade 4 elevation in creatinine (1 
patient each). There were no on-study deaths.  
Study C16007 is evaluating single agent weekly , Day 1, 8, and 15 of a 28-day cycle, oral 
dosing in patients with RRAL after at least 1 prior therapy. The objectives of this study are to 
determine the safety, tolerability, and MTD, as well as to determine hematologic and organ 
response rates in this patient population. The starting dose level was selected from Study 
C16004 as previously described. In Study C16007 the dose was switched from the BSA-based 
dosing to the fixed dose, thereby the 4.0 mg fixed starting dose in Study C16007 corresponds to 
the 2.23 mg/m2 dose (one dose level below MTD) from Study C16004. This study is currently 
enrolling patients in the dose-expansion portion of the trial. 
As of 30 April 2012, 14 patients have been treated in this study. At the first dose level of 4.0 
mg, 1 of 6 patients experienced a protocol-defined DLT (that is, thrombocytopenia that lasted 
more than 2 weeks, which met the definition of a DLT due to the delay in starting Cycle 2). As 
per protocol, the dose was escalated to 5.5 mg for the next cohort of patients where 2 of 5 
patients experienced a DLT (Grade 3 diarrhea, n=1; and Grade 2 dyspnea, Grade 2 acute rise in 
serum creatinine, and Grade 4 cardiac arrest, n=1). The latter patient did not appear to have 
cardiac AL amyloidosis by echocardiogram on study entry, but did have substantial renal 
involvement. After the occurrence of this DLT, diagnoses included cardiac involvement and 
CHF. The MTD of weekly oral MLN9708 was determined to be 4.0 mg. Following the 
establishment of the MTD, patients are currently being enrolled in to 1 of 2 cohorts: proteasome 
inhibitor naïve or proteasome inhibitor exposed.21 
As of the 30 April 2012 data cut, the patients enrolled in the study are considered heavily 
pretreated, as evidenced by a median number of 3 prior lines of therapy (range 1–7), with 38% 


  
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and 46% of patients having been previously treated with bortezomib and lenalidomide, 
respectively. To be eligible for the study, patients must have amyloid involvement of the heart, 
kidney, or both; at the data cut the organ involvement distribution was 6, 4, and 4 patients, 
respectively. Patients have received a median of 2.5 cycles of therapy (range, 1-12). Eight 
patients remain on treatment. Early signs of activity have been reported. There were 11 patients 
who have received at least 1 cycle of therapy with completed response assessments (9 in the 4.0 
mg [MTD] cohort and 2 in the 5.5 mg cohort). The overall hematologic response rate at MTD is 
56% (5 patients achieved a hematologic response [4 VGPR and 1 PR]; 3 patients showed no 
change, and 1 patient had an early progression.  
A summary of the safety profile of patients treated in Study C16007 is outlined in Table 1-5. 
Overall, 86% of patients experienced a TEAE of any grade and of any cause. 
Table 1-5    
Study C16007, Oral MLN9708, Single Agent Given Weekly  Most 
Common TEAEs as of 30April 12 (N = 14) 
Most Common (> 20%) 
Any Grade and Irrespective of Cause 
Nausea (50%) 
Fatigue (36%) 
Thrombocytopenia (29%) 
Diarrhea (29%) 
Decreased Appetite (21%) 
Peripheral Edema (21%) 
Dyspnea (21%) 
Abdominal pain (21%) 
Drug-Related Grade  3 in more than 3 Patients  
Thrombocytopenia 5 patients, rash 3 patients, 
dehydration 2 patients, fatigue 2 patients 
 
Source: MLN9708 Investigator’s Brochure Edition 6 
One patient discontinued study drug administration due to a TEAE (patient with DLT of acute 
rise in serum creatinine, dyspnea, and cardiac arrest treated at 5.5 mg, as noted above). No death 
has been reported. 
The potential risks reported with MLN9708 use, pooled from all studies using the oral 
formulations, were anticipated based on preclinical data and previous experience with 
VELCADE and are noted in the MLN9708 IB, SMA, and ICF documents. Regardless of 
whether MLN9708 is administered on the once weekly or twice weekly dosing schedule, there 
is consistency among the type of TEAEs reported, despite some differences in the frequency and 
severity of the reported events. While the predominant potential toxicities may be severe in 
some cases, they are largely reversible, and can be managed by routine clinical monitoring and 


  
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standard medical interventions, which may include dose reductions and supportive care.  Please 
refer to the MLN9708 IB and SMA for further information. 
1.2.7    
MLM9708 in Newly Diagnosed Multiple Myeloma (NDMM) 
In Study C16005, MLN9708 is given weekly (Days 1, 8, and 15), in combination with 
lenalidomide (Days 1-21), and dexamethasone (Days 1, 8, 15, and 22) in a 28-day cycle.  
Enrollment to this study is closed.   
Clinical data as of 30 April 2012 is available.  The MTD in Study C16005 was determined to be 
2.97 mg/m2 given weekly in a 28-day cycle with LenDex.  The DLTs were urticarial rash, 
dizziness, nausea, orthostatic hypotension, vomiting, diarrhoea, and syncope.  The 
recommended phase 2 dose (RP2D) estimation was established following evaluation of the 
available data from the phase 1 portion of the trial which included, but was not limited to, 
analyses of efficacy results and adverse events (Grade 3/4 AEs, SAEs, all grades peripheral 
neuropathy, and treatment discontinuation).  Given that the dose of MLN9708 at 2.97 mg/m2 
compromised the maximal dosing of lenalidomide and that the dose of 2.23 mg/m2 is very 
tolerable and clinically active, Millennium designated 2.23 mg/m2 as the RP2D after evaluation 
of the data and discussion with investigators.  The RP2D of 2.23 mg/m2 has been translated into 
a fixed dose of 4.0 mg based on the results from the population PK analysis.  Enrollment in 
this study has been completed; final study results are not available, but preliminary data 
suggests oral MLN9708 given weekly plus lenalidomide and dexamethasone in a 28-day cycle 
appears well tolerated with manageable toxicity and encouraging antitumor activity.   
In Study C16005, 15 of 15 (100%) patients in the dose escalation portion of the study 
experienced at least 1 TEAE irrespective of grade or causality.  At the MTD across all dose 
expansion cohorts 49 of 53 patients (including 3 patients from the dose escalation cohort [92%]) 
reported at least 1 TEAE irrespective of grade or causality.  In the MTD cohorts, fatigue was the 
most common AE reported (38%).  Other common AEs reported include nausea (32%), 
constipation (30%), upper respiratory infection (23%), and peripheral oedema (21%).  Skin 
toxicity, primarily erythematous rash, occurred in 62% of patients (of note, rash is an 
overlapping toxicity with MLN9708 and lenalidomide).  Peripheral neuropathy was reported in 
13% of patients; Grade 3 in 1 patient.   
A summary of the overall safety profile of patients treated in Study C16005 is outlined in Table 
1-6.  Overall, 100% of 65 patients experienced at least one TEAE of any grade and of any cause.   
Table 1-6    
Study C16005:  Oral MLN9708 Given Weekly in Combination With 
Lenalidomide and Dexamethasone, Most Common TEAEs as of 30 
April 2012 
Most Common (> 20%) Any Grade and Irrespective of 
Fatigue (37%) 


  
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Cause 
Nausea (34%) 
Constipation (31%) 
Vomiting (28%) 
Diarrhoea (26%) 
Thrombocytopenia (23%) 
Upper respiratory tract infection (22%) 
Anaemia and oedema peripheral ( 20% each) 
Drug-Relateda Grade  3 in  2 Patients  
Nausea, vomiting (n=3 each)  
Thrombocytopenia, lymphopenia, rash pruritic (n=2 each ) 
 
Source: MLN9708 Investigator’s Brochure Edition 6. 
a 
Related means to ANY drug in the study drug combination. 
 
The most common drug-related SAEs reported in Study C16005 as of 30 April 2012 include 
pneumonia, infection, diverticulitis, localised infection, gastrointestinal haemorrhage, 
respiratory syncytial virus (RSV) pneumonia faecaloma, pyrexia, pneumonia respiratory 
syncytial viral, non-cardiac chest pain, peripheral oedma, asthenia, hyponatraemia vomiting, 
diarrhoea, nausea, chest pain, dehydration, anemia, dizziness, peripheral sensory neuropathy, 
orthostatic hypotension, embolism, muscular weakness, acute renal failure, blood creatinine 
increased, maculopapular rash, atrial fibrillation, syncope, hypotension, and deep vein 
thrombosis, and back pain.   
As of the clinical data cutoff, 4 patients have discontinued treatment due to TEAEs including 
gastrointestinal haemorrhage, angioedema, syncope, and RSV pneumonia. 
One death was reported for a patient with RSV pneumonia; the event was deemed by the 
investigator to be related to treatment with MLN9708.   
1.2.7.1  
Clinical Trial Experience Using the Intravenous Formulation of MLN9708 
See the IB for descriptions of the 2 ongoing studies investigating IV MLN9708 in advanced 
solid tumors and advanced lymphoma (Studies C16001 and C16002, respectively). 
1.3 
Pomalidomide 
Pomalidomide is a thalidomide analogue indicated for patients with multiple myeloma who 
have received at least two prior therapies including lenalidomide and bortezomib and have 
demonstrated disease progression on or within 60 days of completion of the last therapy. 
Approval is based on response rate. 


  
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POMALYST is an immunomodulatory antineoplastic agent. The chemical name is (RS)-4-
Amino-2-(2,6-dioxo-piperidin-3-yl)-isoindoline-1,3-dione and it has the following chemical 
structure: 
 
 
POMALYST is available in 1 mg, 2 mg, 3 mg and 4 mg capsules for oral administration. Each 
capsule contains pomalidomide as the active ingredient and the following inactive ingredients: 
mannitol, pregelatinized starch and sodium stearyl fumarate. The 1 mg capsule shell contains 
gelatin, titanium dioxide, FD&C blue 2, yellow iron oxide, white ink and black ink. The 2 mg 
capsule shell contains gelatin, titanium dioxide, FD&C blue 2, yellow iron oxide, FD&C red 3 
and white ink. The 3 mg capsule shell contains gelatin, titanium dioxide, FD&C blue 2, yellow 
iron oxide and white ink. The 4 mg capsule shell contains gelatin, titanium dioxide, FD&C blue 
1, FD&C blue 2 and white ink. 
1.3.1      Mechanism of Action 
Pomalidomide, an analogue of thalidomide, is an immunomodulatory agent with antineoplastic 
activity. In in vitro cellular assays, pomalidomide inhibited proliferation and induced apoptosis 
of hematopoietic tumor cells. Additionally, pomalidomide inhibited the proliferation of 
lenalidomide-resistant multiple myeloma cell lines and synergized with dexamethasone in both 
lenalidomide-sensitive and lenalidomide-resistant cell lines to induce tumor cell apoptosis. 
Pomalidomide enhanced T cell- and natural killer (NK) cell-mediated immunity and inhibited 
production of pro-inflammatory cytokines (e.g., TNF-α and IL-6) by monocytes. Pomalidomide 
demonstrated anti-angiogenic activity in a mouse tumor model and in the in vitro umbilical cord 
model. 
1.3.2    Pharmakokinetics 
Absorption 
Following administration of single oral doses of POMALYST, the Cmax for pomalidomide 
occurs at 2 and 3 hours post dose. The systemic exposure (AUC) of pomalidomide increases in 


  
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an approximately dose proportional manner. In patients with multiple myeloma who received 
POMALYST 4 mg daily alone or in combination with dexamethasone, pomalidomide steady- 
state drug exposure was characterized by AUC(Τ) of 400 ng.hr/ mL and maximum plasma 
concentration (Cmax) of 75 ng/mL. Following multiple doses, pomalidomide has an 
accumulation ratio of 27 to 31 %. 
Distribution 
Pomalidomide has a mean apparent volume of distribution (Vd/F) between 62 and 138 L at 
steady state. Pomalidomide is distributed in semen of healthy subjects at a concentration of 
approximately 67% of plasma level at 4 hours post-dose (~Tmax) after 4 days of once daily 
dosing at 2 mg. Human plasma protein binding ranges from 12% to 44% and is not 
concentration dependent. 
Metabolism 
Pomalidomide is primarily metabolized in the liver by CYP1A2 and CYP3A4. In vitro, 
CYP1A2 and CYP3A4 were identified as the primary enzymes involved in the CYP-mediated 
hydroxylation of pomalidomide, with additional minor contributions from CYP2C19 and 
CYP2D6. 
Elimination 
Pomalidomide is eliminated with a median plasma half-life of approximately 9.5 hours in 
healthy subjects and approximately 7.5 hours in patients with multiple myeloma. Pomalidomide 
has a mean total body clearance (CL/ F) of 7-10 L/ hr. 
Following a single oral administration of [14C]-pomalidomide (2 mg) to healthy subjects, 
approximately 73% and 15% of the radioactive dose was eliminated in urine and feces, 
respectively, with approximately 2% and 8% of the radiolabeled dose eliminated unchanged as 
pomalidomide in urine and feces. 
1.3.3   Non-clinical Toxicology 
Carcinogenesis, Mutagenesis, Impairment of Fertility  
Studies examining the carcinogenic potential of pomalidomide have not been conducted. One of 
twelve monkeys dosed with 1 mg/kg of pomalidomide (an exposure approximately 15-fold of 


  
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the exposure in patients at the recommended dose of 4 mg/per day) developed acute myeloid 
leukemia in a 9-month repeat-dose toxicology study. 
Pomalidomide was not mutagenic or clastogenic in a battery of tests, including the bacteria 
reverse mutation assay (Ames test), the in vitro assay using human peripheral blood 
lymphocytes and the micronucleus test in orally treated rats administered doses up to 2000 
mg/kg/day. 
In a fertility and early embryonic development study in rats, drug-treated males were mated with 
untreated or treated females. Pomalidomide was administered to males and females at doses of 
25 to 1000 mg/kg/day. When treated males were mated with treated females, there was an 
increase in post-implantation loss and a decrease in mean number of viable embryos at all dose 
levels. There were no other effects on reproductive functions or the number of pregnancies. The 
lowest dose tested in animals resulted in an exposure (AUC) approximately 100-fold of 
theexposure in patients at the recommended dose of 4 mg/day. When treated males on this study 
were mated with untreated females, all uterine parameters were comparable to the controls. 
Based on these results, the observed effects were attributed to the treatment of females. 
Pomalidomide does not inhibit or induce CYP450 enzymes or any of the transporters in vitro. 
1.3.4   Clinical Studies 
Multiple Myeloma 
The trial that led to the recent approval of pomalidimide was a Phase 2, multicenter, randomized 
open label study in patients with relapsed multiple myeloma who were refractory to their last 
myeloma therapy and had received lenalidomide and bortezomib. Patients were considered 
relapsed if they had achieved at least stable disease for at least one cycle of treatment to at least 
one prior regimen and then developed progressive disease. Patients were considered refractory if 
they experienced disease progression on or within 60 days of their last therapy. A total of 221 
patients were randomized to receive pomalidomide alone or pomalidomide with Low dose Dex. 
In Trial 1, the safety and efficacy of pomalidomide 4 mg, once daily for 21 of 28 days, until 
disease progression, were evaluated alone and in combination with Low dose Dex (40 mg per 
day given only on Days 1, 8, 15 and 22 of each 28-day cycle for patients 75 years or younger, or 
20mg per day given only on Days 1, 8, 15 and 22 of each 28-day cycle for patients greater than 
75 years of age). Patients in the pomalidomide alone arm were allowed to add Low dose Dex 
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Most common adverse reactions (≥30%) included fatigue and asthenia, neutropenia, anemia, 
constipation, nausea, diarrhea, dyspnea, upper- respiratory tract infections, back pain and 
pyrexia (6.1). 
A recent phase III randomized trial comparing pomalidomide plus dexamethasone, to high-dose 
dexamethasone alone in patients with relapse and refractory MM, demonstrated higher response 
rates, PFS and OS in the pomalidomide arm. Ten percent (10%) of patients treated on the 
dexamethasone alone arm achieved an objective response and 31% of the patients on the 
combination arm with pomalidomide and low-dose dexamethasone achieved a response; odds 
ratio [OR] 4·22 [2·35 –7·58] p<0·0001 . 26 The treatment regimens most commonly used in 
Europe are very different from those used in the United States, as patient access to many of the 
novel agents is more limited in Europe. None of the patients enrolled/treated in that trial had 
been previously treated with carfilzomib or pomalidomide. For this trial, where MLN9708 will 
be added to pomalidomide and dexamethasone, patients with prior exposure to either of these 
agents would not be excluded. As many patients (>50%) are likely to have been previously 
treated with one or both of these agents we consider a response rate of 30% sufficient efficacy to 
justify further development. 
1.4      Study Rationale 
Pomalidomide is the newest immunomodulatory drug that is chemically a combination of 
thalidomide and lenalidomide. It has been studied in phase I-III trials for patients with relapsed 
myeloma.  It has shown activity even in lenalidomide refractory patients and phase III trials 
have demonstrated superior overall and progression free survival (OS/PFS) compared to high 
dose dexamethasone.  22,23 
MLN9708 is a next generation small molecule 20-s proteasome inhibitor generated with the aim 
of improving the efficacy seen with bortezomib in MM but further improvement in drug 
administration. It has shown activity in the relapsed and relapsed/refractory MM setting 
including bortezomib refractory patients. 24 Therefore given the synergy seen with IMIDS and 
proteasome inhibitors as well as the activity of both compounds in relapsed MM, this becomes 
an attractive combination for study in the relapsed/relapsed refractory setting. 
Dosing Justification 
As mentioned above, the standard FDA approved dose of pomalidomide is 4mg days 1-21. 
Maximum response is seen when it is combined with dexamethasone. Because of an impetus in 
myeloma therapy to be relatively steroid sparing, the generally accepted dose of dexamethasone 


  
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is a “ Low dose” weekly dosing of 40mg. Data generated from the MLN9708 plus lenalidomide 
and dexamethasone trial confirmed the tolerability of this new proteasome inhibitor with an 
IMID. The RP2D of MLN9708 is 4mg d1,8,15.  However, the potential for overlapping 
hematologic toxicity especially in a more advanced disease population with pomalidomide 
(which tends to be more myelosuppressive than lenalidomide) in conjunction with MLN9708 
led to the choice of an initial dose of 3mg for MLN9708. Because of the synergy between 
IMIDS and proteasome inhibitors we would still expect to see activity at this dose. 
1.5 
Potential Risks and Benefits 
Please refer to the current MLN9708 Investigator’s Brochure (IB) and the Package Insert for 
pomalidomide. 
MLN9708 is a modified dipeptide boronic acid proteasome inhibitor similar to VELCADE, 
which has a known safety profile [VELCADE PI].  The most frequent AEs reported to date in 
the ongoing MLN9708 phase 1 studies were anticipated based on preclinical data and previous 
experience with VELCADE, and are noted in the IB, and the informed consent documents. 
However, it is possible that MLN9708 will have toxicities that were not previously observed in 
or predicted from such sources. Patients will be monitored closely for anticipated toxicities.  
The toxicity profile of MLN9708 and pomalidomide in combination with dexamethasone is 
unknown and will be evaluated in this trial. 
MLN9708 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 11,12,13,14,16,17,18. 
This study will be conducted in compliance with the protocol, good clinical practice (GCP), 
applicable regulatory requirements, and International Conference on Harmonisation (ICH) 
guidelines.  
2.    
STUDY OBJECTIVES 
2.1    Study Objectives (Phase I) 
2.1.1     Primary: 
1. To determine the recommended phase II dose (RP2D) of MLN9708, when given in 
combination with pomalidomide and dexamethasone, in patients with relapsed or 
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2.1.2     Secondary: 
2. To evaluate the safety of MLN9708 at each dose level when given as part of a three drug 
combination by assessing the following: 
 
- type, frequency, severity, attribution, time course and duration of adverse events 
 
- clinical laboratory tests at various points in the study 
2.2    Study Objectives (Phase II) 
2.2.1    Primary: 
1. To estimate the response rate and to evaluate the antitumor activity of the three drug 
combination: MLN9708 (at the RP2D), pomalidomide and dexamethasone, in patients with 
relapsed or relapsed/refractory multiple myeloma.  
2.2.2    Secondary: 
At the RP2D, for the three drug combination: 
2. To characterize and evaluate toxicities, including type, frequency, severity, attribution, time 
course and duration. 
3. To obtain estimates of response duration, depth of response, clinical benefit response, and 
survival (overall and progression-free). 
3.    
STUDY ENDPOINTS 
3.1    Primary Endpoints  
Phase I: 
The primary endpoint is toxicity. Toxicity will be graded according to the NCI-Common 
Terminology Criteria for Adverse Events version 4.03.  A DLT will be defined as any of the 
following toxicities that are at least possibly related to either Pomalidomide or MLN9708 and 
occur during cycle 1:  
 Grade 4 neutropenia  
 Grade 3 neutropenia with fevers > 38.5°C 
 Grade 4 thrombocytopenia  
 Grade 3 thrombocytopenia with bleeding 


  
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 Grade 3 or higher non-hematological toxicity will be considered dose limiting, with the 
following exceptions: diarrhea, fatigue, nausea or vomiting will only be considered dose 
limiting if, after 48 hours it has not recovered to <Grade 3 (despite maximal medical 
therapy), allergic reaction/hypersensitivity, or electrolyte/metabolic toxicity unable to be 
corrected to <Grade 1 or baseline within 48 hours will be considered dose limiting. 
 Delay in starting cycle 2 on the scheduled day 1 for > 7 days due to treatment related 
toxicity 
 Any dose modification or delay during cycle 1, except modifications/delays done in 
response to hypo- hyperthyroidism <=Grade 2, herpes zoster infection, all considered 
idiopathic or intrinsic to the underlying myeloma. 
 
Phase II: 
The primary activity endpoint is response rate (confirmed sCR/CR/VGPR or PR), based on the 
International Myeloma Working Group (IMWG) criteria, calculated as the number of 
responders divided by the number of evaluable patients. Confirmation of sCR/CR/VGPR or PR 
assessed by IMWG criteria. 
Secondary activity endpoints for this study are as follows: 
 Duration of response, defined as the time interval from the date of first documented 
response (sCR/CR/VGPR or PR) to documented disease relapse, progression or death 
whichever occurs first. 
 Clinical benefit response, based on the International Myeloma Working Group (IMWG) 
criteria, calculated as the number of responders plus those with a minimal response 
(MR) or stable disease (SD) divided by the number of evaluable patients. Confirmation 
of sCR/CR/VGPR/PR/MR or SD assessed by IMWG criteria. 
 Overall survival, defined as the time interval from date of first dose of study drug to date 
of death from any cause. 
 Progression-free survival, defined as the time interval from date of first dose of study 
drug to first documented disease relapse, progression or death from any cause, 
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4.    
STUDY DESIGN  
4.1    Overview of Study Design 
4.1.1    Phase I: 
The phase I portion of the study is based on a 3 + 3 dose escalation design, to evaluate toxicities 
associated with MLN9708 when given in combination with pomalidomide and dexamethasone. 
Two doses of MLN9708 (dose level -1 and dose level 1: 3mg; dose level 2: 4mg) will be tested 
in up to three possible dose levels. Based on previous combination trials of MLN9708, the 4mg 
dose of MLN9708 is expected to be well tolerated. Given that this is the first study to combine 
MLN9708, with dexamethasone and pomalidomide, patients will initially be treated at a 3mg 
dose. The maximum tolerated dose (MTD) will be established by evaluating dose limiting 
toxicity (DLT) during cycle 1. The recommended phase II dose (RP2D) of MLN9708 and 
pomalidomide will generally be the MTD, but it may be less than the MTD  based on a review 
of available data/cumulative toxicities from phase I. Patients will be treated with oral MLN9708  
on days 1, 8, and 15 of each 28 day cycle and with Dexamethasone on days 1, 8, 15 and 22 of 
each 28 day cycle.  Pomalidomide will be given on days 1-21 of each 28 day cycle. The dose of 
MLN9708 and Pomalidomide administered will depend on the dose level assignment; the dose 
of dexamethasone will be fixed (Patients >75 years, at the time of trial registration, will receive 
a Dexamethasone starting dose of 20 mg on the same set schedule). 
 
    Phase II  
Patients who enroll during the phase II portion of the trial will  be treated at the same dose and 
schedule of MLN9708, pomalidomide and dexamethasone determined safe during the phase I 
study (the RP2D). 
4.2    Number of Patients 
The phase I study is expected to enroll and treat 9 patients; 3 patients at dose level 1, and 
another 6 treated at dose level 2 -assuming the 4mg dose of MLN9708 is well tolerated. The 
phase II portion of the trial is expected to enroll a minimum of 9 and a maximum of 25 patients. 
The six patients treated at the RP2D in the phase I portion of the study will count toward the 25 
patients required; given this, we expect to enroll only 19 new patients on the phase II trial. 
4.3    Duration of Study 
Accrual, for both phases, is expected to be completed in 26 months; with approximately 2 
patients enrolled each month. Patients will be treated in 28-day treatment cycles until disease 
relapse, progression or unacceptable toxicity, withdrawal of consent, or protocol specified 
parameters to stop treatment. Patients who discontinue study treatment for reasons other than 
disease relapse/progression will continue to have disease assessments per International 
Myeloma Working Group (IMWG) criteria until relapse or progression, initiation of new 


  
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anticancer treatment, or death whichever occurs first.  Patients will be followed to collect further 
anticancer treatment and survival information until death, loss to follow-up, withdrawal of 
consent, study termination or up to 24 months post treatment. 
5.    
STUDY POPULATION 
5.1    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 informed 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. Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy 
test with a sensitivity of at least 25 mIU/mL within 10 – 14 days prior to and again within 
24 hours of starting pomalidomide or MLN9708 and must either commit to continued 
abstinence from heterosexual intercourse or begin TWO acceptable methods of birth 
control, one highly effective method and one additional effective method AT THE SAME 
TIME, at least 28 days before she starts taking pomalidomide or MLN9708 through 90 
days after the last dose of study drug.  FCBP must also agree to ongoing pregnancy 
testing.  Men must agree to use a latex condom during sexual contact with a FCBP even if 
they have had a vasectomy from the time of signing the informed consent form through 90 
days after the last dose of study drug.  All patients must be counseled at a minimum of 
every 28 days about pregnancy precautions and risks of fetal exposure.  
4. All patients enrolled into this trial, must be registered in and must comply with all 
requirements of the POMALYST REMS™ program.  
5. Patients must have a diagnosis of relapsed or relapsed and refractory Multiple Myeloma 
with a minimum of one prior regimen and a maximum of 5 prior regimens.  
6. Patients must have had therapy with a proteasome inhibitor and lenalidomide and be 
refractory to lenalidomide according to the IMWG definition of refractory disease 
(progressive disease on or within 60 days of stopping lenalidomide). 
7. Patients must have measurable disease defined as one of the following: 


  
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a. Serum M protein ≥ 0.5 g/dL 
b. Urine M protein ≥ 200 mg/24 hours 
c. Serum free light chain ≥ 10 mg/dL provided the FLC ratio is abnormal. 
8. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2. 
9. Patients must meet the following clinical laboratory criteria: 
 Absolute neutrophil count (ANC)  1,000/mm3  
 Platelet count > 75,000/µL for patients in whom < 50% of bone marrow nucleated 
cells are plasma cells; or a platelet count > 50,000/µL for patients in whom > 50% of 
bone marrow nucleated cells are plasma cells. Platelet transfusions are not allowed 
within 3 days of last platelet assessment to confirm eligibility.     
 Total bilirubin  1.5  the institutional upper limit of the normal range (IULN). 
 Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)  3  IULN. 
 Calculated creatinine clearance  45mL/min (see Appendix 15.2). 
5.2    Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study: 
1. Female patients who are pregnant or breastfeeding 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. 
3. Prior therapy with a combination regimen containing pomalidomide except the 2 
drug combination of pomalidomide and dexamethasone.  
4. Major surgery within 14 days before enrollment. 
5. Radiotherapy within 14 days before enrollment. If the involved field is small, 7 days 
will be considered a sufficient interval between treatment and administration of the 
MLN9708. 


  
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6. Central nervous system involvement. 
7. Infection requiring systemic antibiotic therapy or other serious infection within 
14 days before study enrollment. 
8. 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. 
9. Systemic treatment, within 14 days before the first dose of MLN9708, 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. 
10. Unable or unwilling to undergo antithrombotic prophylaxis. 
11. Ongoing or active systemic infection, active hepatitis B or C virus infection, or 
known human immunodeficiency virus (HIV) positive. 
12. Any serious medical or psychiatric illness that could, in the investigator’s opinion, 
potentially interfere with the completion of treatment according to this protocol. 
13. Known allergy to any of the study medications, their analogues, or excipients in the 
various formulations of any agent. 
14. Known GI disease or GI procedure that could interfere with the oral absorption or 
tolerance of MLN9708 or pomalidomide including difficulty swallowing. 
15. Diagnosed or treated for another malignancy within 2 years before study enrollment 
or previously diagnosed with another malignancy with evidence of residual disease.  
Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not 
excluded if they have undergone complete resection. 
16. Patient has > Grade 2 peripheral neuropathy on clinical examination during the 
screening period. 


  
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17. Participation in other clinical trials, including those with other investigational agents 
not included in this trial, within 21days of the start of this trial and throughout the 
duration of this trial (for all other standard therapies, no treatment within 14 days of 
the start of this trial). 
18. Patients who are pomalidomide refractory, defined as patients who progress on or 
within 60 days of pomalidomide when given as a single agent or with 
dexamethasone. 
6.    
  PATIENT ENROLLMENT 
Phase I Dose Escalation Portion – Prior to discussing protocol entry with the patient, contact 
the City of Hope Data Coordinating Center to ensure that a treatment slot on the protocol is 
available. 
 
Phase I and II Patient Enrollment  
The screening period for a particular patient commences when the patient signs the informed 
consent.  Consent must be signed before any study-specific tests may be performed. After a 
patient has been screened and has successfully fulfilled all eligibility criteria, the site 
representative will email the inclusion/exclusion checklist and all other required source 
documentation to the City of Hope Data Coordinating Center.  In order to ensure 
privacy/security, please ensure that you type #secure# in the subject line of all correspondence 
related to the trial/patient: 
Lupe Duarte, CCRC 
Multiple Myeloma Project Manager 
Phone:  626-256-4673 x 63968 
Fax:  626 301-8422 
Email: dcc@coh.org 
 
A unique patient number will be assigned at that time that will be used to identify the patient 
throughout the clinical study and must be used on all study documentation related to that 
patient.  Patients will be assigned to a dose level at enrollment.  Prior to accepting the 
registration, the COH DCC staff member will verify the following: 
 


  
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1. IRB approval at the registering institution 
2. Patient eligibility 
3. Existence of a signed consent form 
4. Existence of a signed authorization for use and disclosure of protected health 
information (if applicable). 
Treatment cannot begin prior to registration and must begin < 7 days after registration.  
Pretreatment tests/procedures must be completed within the guidelines specified on the test 
schedule.  
7.  STUDY TREATMENT 
7.1   Dose and Schedule 
The phase I study will follow a standard 3 + 3 dose escalation design, to evaluate toxicities 
associated with MLN9708 when given in combination with pomalidomide and dexamethasone. 
Two doses of MLN9708 (3 mg and 4 mg) will be tested in up to three possible dose levels.  
7.2   Dose Levels to be Tested 
Schedule: Each cycle is 28 days  
Dose Level 
Pomalidomide  
MLN9708 
Dexamethasone* 
-1 
3mg daily on days 1-21 
3 mg on days 1, 8 and 15 
40 mg on days 1, 8, 15 and 22 
1 
4 mg daily on days 1 - 21 
3 mg on days 1, 8 and 15 
40 mg on days 1, 8, 15 and 22 
2 
4 mg daily on days 1 - 21 
4 mg on days 1, 8 and 15 
40 mg on days 1, 8, 15 and 22 
*: Patients >75 years, at the time of trial registration, will receive a Dexamethasone dose of 20 
mg on the same set schedule. 
 
7.3  Dose Limiting Toxicity/Unacceptable Toxicity 
Dose Limiting Toxicity (DLT) is defined as any of the following toxicities that are at least 
possibly related to either Pomalidomide or MLN9708 that occur during cycle 1. Toxicity will be 
graded according to the NCI-Common Terminology Criteria for Adverse Events, Version 4.03. 


  
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Note: The Phase II portion of the study will use the same definition to define unacceptable 
toxicity. 
For the purposes of this study, DLT will be defined as: 
 Grade 4 neutropenia  
 Grade 3 neutropenia with fevers > 38.5°C 
 Grade 4 thrombocytopenia  
 Grade 3 thrombocytopenia with bleeding 
 Grade 3 or higher non-hematological toxicity will be considered dose limiting with the 
following exceptions: diarrhea, fatigue, nausea or vomiting will only be considered dose 
limiting if, after 48 hours it has not recovered to <Grade 3 (despite maximal medical 
therapy), allergic reaction/hypersensitivity, or electrolyte/metabolic toxicity unable to be 
corrected to <Grade 1 or baseline within 48 hours will be considered dose limiting.  
 Delay in starting cycle 2 on the scheduled day 1 for > 7 days due to treatment related 
toxicity 
 Any dose modification or delay of MLN9708 or Pomalidomide during cycle 1, except 
modifications/delays done in response to hypo- hyperthyroidism <=Grade 2, herpes 
zoster infection, all considered idiopathic or intrinsic to the underlying myeloma.  
 
7.4    Dose Escalation/Expansion 
DLT incidence will be based on toxicity events encountered during the first cycle of treatment 
with the combination of MLN9708, pomalidomide and dexamethasone. 
Dose de-escalation, escalation or cohort expansion will only take place after 3 patients are fully 
assessed using the Common Terminology Criteria for Adverse Events (CTCAE) of the National 
Cancer Institute (NCI) version 4.03 following the completion of cycle 1.  
Dose escalation will occur according to the following rules: 
 If zero out of 3 evaluable patients has a DLT in cycle 1 then the next dose level of 
combination therapy will be tested. 
 If 1 out of 3 evaluable patients has a DLT in cycle 1, three additional patients will be 
assessed at the same dose level of combination therapy. 
 If 2 out of 3 patients have a DLT in cycle 1, dose escalation will cease and the next 
lower dose level of combination therapy will be expanded. Note: If 2 of 3 experience 
DLT on dose level -1, the trial will be stopped. 
 If 1 out of 6 evaluable patients has a DLT in cycle 1, then dose escalation to the next 
dose level of combination therapy will continue.  


  
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 If 2 or more out of 6 patients have a DLT in cycle 1, dose escalation will cease and the 
next lower dose level of combination therapy will be expanded. Note: If 2 of 6 
experience DLT on dose level -1 the trial will be stopped. 
The highest dose level that produces ≤1/6 DLTs in cycle 1 will be the maximum tolerated dose 
(MTD). 
Note:  Patients may continue therapy unless there is unacceptable toxicity, disease progression 
or withdrawl of consent.   
7.5   Recommended Phase II Dose (RP2D) 
The MTD will be based on the assessment of DLT during cycle 1 (see section 7.4). The MTD 
will be defined as the highest dose at which ≤ 1/6  patients in a cohort experience DLT. The 
recommended phase II dose (RP2D) of MLN9708 and pomalidomide will generally be the 
MTD, but it may be less than the MTD  based on a review of available data/cumulative 
toxicities from phase I.   
7.6    Study Drug 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 study drug should be modified as 
needed to accommodate patient tolerance to treatment; this may include symptomatic treatment, 
dose interruptions, and adjustments of dose. 
7.6.1   MLN9708 Administration 
Patients should be instructed to swallow MLN9708 capsules whole, with water, and not to 
break, chew, or open the capsules.  MLN9708 should be taken on an empty stomach (no food or 
drink) at least 1 hour before or 2 hours after a meal.  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. 


  
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7.6.2    Pomalidomide Administration 
Pomalidomide capsules should be swallowed whole, and should not be broken, chewed or 
opened.  Pomalidomide should be taken without food, at least 2 hours before or 2 hours after a 
meal.  Pomalidomide capsules may be taken with water.  
If a dose of pomalidomide is missed, it should be taken as soon as possible on the same day.  If 
it is missed for the entire day, it should not be made up, rather it should be taken at the next 
scheduled time point. Similarly, 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. 
Patients who take more than the prescribed dose of pomalidomide should be instructed to seek 
emergency medical care if needed and contact study staff immediately.   
Pomalidomide (POMALYST®) will be provided to research patients for the duration of their 
participation in this trial at no charge to them or their insurance providers.  Pomalidomide will 
be provided in accordance with the Celgene Corporation’s POMALYST REMS™  program.  
Per the standard   POMALYST REMS™ program requirements, all physicians who prescribe 
pomalidomide for research patients enrolled into this trial, and all research patients enrolled into 
this trial, must be registered in and must comply with all requirements of the POMALYST 
REMS™ program.   
Drug will be shipped on a per patient basis by the contract pharmacy to the clinic site for IND 
studies.  Only enough pomalidomide for one cycle of therapy will be supplied to the patient 
each cycle.  This is in accordance with the POMALYST REMS™ program. 
Special Handling Instructions 
Female caregivers of childbearing potential should not handle or administer pomalidomide 
unless they are wearing gloves. 
7.6.3    Dexamethasone Administration 
Dexamethsone is commercially available and commercial supplies will be used for this study. 
Oral dexamethasone will be given on an outpatient basis. Missed doses of dexamethasone will 
not be made up.  Similarly, 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. Procedures for dose 
reductions and delays are summarized in Section 7.9.2. 


  
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7.6.4  Growth Factor Administration 
For the Phase I portion of the study, growth factors, granulocyte colony stimulating factor [G-
CSF], may be given prophylactically for at least two days on days 21 – 26 during or beyond 
cycle 2. For the Phase II portion of the study, G-CSF may be given prophylactically for at least 
two days on days 21-26 during or beyond cycle 1. It will be administered subcutaneously at a 
dose of 5ug/kg or per institutional standard practice dosing either daily or every other day for a 
minimum of two doses.  If patients experience neutropenia or dosing delays, we would 
recommend consideration of growth factor in subsequent cycles. 
7.7    Dose Modification Guidelines  
Patients will be evaluated for adverse events at each visit with the NCI Common Toxicity 
Criteria, Version 4.03 used as a guide for the grading of severity.   
As defined in section 7.3, during the phase I portion of the study, any toxicity related dose 
modification 
or 
delay 
of 
MLN9708 
or 
Pomalidomide 
during 
cycle 
1 
except 
modifications/delays done in response to hypo- hyperthyroidism <=Grade 2, herpes zoster 
infection, all considered idiopathic or intrinsic to the underlying myeloma is a DLT.  No dose 
escalations are permitted in any given patient once a dose level has been assigned.  While 
patients experiencing DLT during Cycle 1 may continue on therapy, if toxicity can be managed 
according to the dose modification guidelines outlined below,  the DLT event will contribute to 
the assessment of MTD for that given cohort. Patients will be considered evaluable for toxicity 
if they receive any study drug. Patients will be considered evaluable for dose limiting toxicity if 
they receive at least 75% of both Pomalidomide and MLN9708 and are followed for the full 28 
days during cycle 1  or experience a DLT. For the phase II portion, as part of the primary 
analysis, patients will be considered evaluable for response if they are eligible, have baseline 
disease assessments, and receive any protocol treatment. As part of a secondary analysis, 
patients will be considered evaluable for response if they have baseline disease assessments, 
receive at least 75% of both Pomalidomide and MLN9708 during the first cycle of therapy and 
have had their disease re-evaluated.    
Dose modifications may be performed in all subsequent cycles of treatment regardless of which 
phase of study the patient  is enrolled on.  If toxicities cannot be managed by dose modification 
or the patient cannot tolerate the lowest dose of study drug, the patient is to be discontinued 
from study treatment.  However, patients that have achieved a plateau of response to study 


  
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therapy will continue to adhere to the schedule of assessments followed during the treatment 
phase of the study even though study drug has been discontinued.  
7.8    Dose Reduction Steps  
7.8.1   Dose Reduction Steps for Pomalidomide 
Pomalidomide Dose Reduction Steps 
 
Starting Dose 
 
Daily on Days 1 – 21 every 28 days 
4.0 mg  
3.0 mg 
2.0 mg 
1.0 mg 
3.0 mg  
2.0 mg 
1.0 mg 
- 
2.0 mg  
1.0 mg 
- 
- 
1.0 mg 
- 
- 
- 
7.8.2    Dose Reduction Steps for MLN9708 
MLN9708 Dose Reduction Steps 
 
Starting Dose 
 
Daily on Days 1, 8 and 15 every 28 days 
4.0 mg  
3.0 mg 
2.3 mg 
1.5 mg 
 
3.0 mg  
2.3 mg 
1.5 mg 
- 
 
7.8.3    Dose Reduction Steps for Dexamethasone 
Dexamethasone Dose Reduction Steps** 
 
Starting Dose 
 
Days 1, 8, 15 and 22 every 28 days 
40 mg  
20 mg 
12 mg 
20 mg*  
12 mg 
6 mg 
12 mg  
- 
- 
*: Patients >75 years, at the time of trial registration, will receive a dexamethasone starting dose 
of 20 mg on the same set schedule.  
**: After the patient has been on Dexamethasone over one year, the patient can discontinue 
Dexamethasone at their next scheduled visit.     
 


  
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 Dexamethasone may be permanently discontinued for toxicity at the discretion of the 
investigator but the patient can remain on study therapy with pomalidomide and MLN9708 
if tolerated.  
 After the patient has been on Dexamethasone over one year, the patient can discontinue 
Dexamethasone at their next scheduled visit.     
7.9   Dose Modification Guidelines for Treatment Related Toxicity 
For recommended comcomitant therapy to reduce the risk/severity of potential adverse events 
refer to Section 7.11.  For recommendations on management of adverse events refer to section 
7.12.   In addition, the table below provides guidelines for dose modification based on toxicity.  
Dose modifications different from those recommended may be made in consultation with the 
Lead Principal Investigator based on investigators assessment of toxicity attribution and 
management of individual patients.  
7.9.1   Dose Modification for MLN9708 and Pomalidmide During a Cycle of 
Therapy 
Treatment modifications due to MLN9708 and Pomaliomide related AEs during a cycle of 
therapy are outlined  below. 
CTCAE Category 
AGENTS 
Toxicity During a Cycle 
Hematologic Toxicity during a cycle of therapy 
 
 
> Grade 3 neutropenia 
associated with fever 
(temperature > 38.5C) or 
Grade 4 neutropenia 
 
 
 
 
 
 
 
Pomalidomide 
 
Hold dose. Follow CBC weekly. Use of G-CSF is 
allowed 
and 
recommended. 
If 
neutropenia 
resolved to < grade 2 within the cycle, resume 
pomalidomide and continue through the scheduled 
end of the cycle.  If not resolved to ≤ grade 2, 
omit for remainder of cycle and reduce the dose of 
pomalidomide by one dose level at the start of the 
next cycle.  Omitted doses are not made up. 
Granulocyte colony stimulating factor [G-CSF], 
may be used prophylactically on days 21 – 26. 
Section7.6.4   


  
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MLN9708 
 
Hold dose. Follow CBC weekly. If neutropenia 
resolves to ≤ grade 2 resume treatment on 
schedule day of cycle. However, if the Day 8 or 
15 dose is held, that dose should be omitted and 
treatment should continue with next scheduled 
dose (i.e., if Day 8 is skipped, the next dosing day 
is Day 15) resume MLN9708 at same dose. If 
neutropenia dose not resolve to ≤ Grade 2 during 
the cycle and any 2 doses were held due to 
toxicity then reduce the MLN9708 dose by one 
level at the start of the next cycle. 
Granulocyte colony stimulating factor [G-CSF],) 
may be used prophylactically on days 21 – 26.   
Platelet count < 
25,000/mm3 or G3 
thrombocytopenia with 
bleeding 
 
 
 
 
 
Pomalidomide 
 
Hold dose. Follow CBC weekly. Use of platelet 
transfusions is allowed to proceed with dosing. If 
thrombocytopenia resolved to < grade 2 within the 
cycle, 
resume 
pomalidomide 
and 
continue 
through the scheduled end of the cycle.  If not 
resolved to ≤ grade 2, omit for remainder of cycle 
and reduce the dose of pomalidomide by one dose 
level at the start of the next cycle.  Omitted doses 
are not made up. 
MLN9708 
Hold 
dose. 
Follow 
CBC 
weekly. 
If 
thrombocytopenia resolves to ≤ grade 2 resume 
treatment on schedule day of cycle. However, if 
the Day 8 or 15 dose is held, that dose should be 
omitted and treatment should continue with next 
scheduled dose (i.e., if Day 8 is skipped, the next 
dosing day is Day 15) resume MLN9708 at same 
dose. If thrombocytopenia dose not resolve to ≤ 
Grade 2 during the cycle and any 2 doses were 
held due to toxicity  then reduce the MLN9708 
dose by one level at the start of the next cycle. 
For recurrent episodes of hematologic toxicity, MLN9708 and/ or pomalidomide may be dose 
reduced together or independently at the investigaotrs discretion to manage toxicity.  
Non-Hematologic toxicity during a cycle of therapy 
RASH 
 
Grade 2 or 3 
 
 
Pomalidomide 
Hold pomalidomide and MLN9708. Follow 
weekly. 
Implement supportive therapy (see section 7.11.2) 


  
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MLN9708 
If the toxicity resolves to < grade 1, restart 
MLN9708 and pomalidomide and continue 
through the scheduled end of the cycle.  
Otherwise, omit for remainder of cycle and reduce 
the dose of pomalidomide by one dose level at the 
start of the next cycle.  Omitted doses are not 
made up. 
For 
subsequent 
occurances, 
alternate 
dose 
reductions with MLN9708 and pomalidomide. 
Non-blistering rash 
Grade 4 
Discontinue pomalidomide and MLN9708. 
Withdraw participant from the study. 
Desquamating 
(blistering) rash-any 
Grade or Erythema 
multiforme > Grade 3 
 
Pomalidomide/ 
MLN9708 
Discontinue treatment. Withdraw participant from 
study.   
Hyperthyroidism or 
Hypothyroidism 
 
Pomalidomide 
Omit pomalidomide for remainder of cycle, 
evaluate etiology, and initiate appropriate therapy.  
Restart pomalidomide at investigator’s discretion.  
For toxicity attributable to pomalidomide, reduce 
the dose by one dose level. 
Neuropathy 
Grade 2 peripheral 
neuropathy with pain or 
Grade 3 
 
 
 
 
 
 
 
 
 
Grade 4 
 
 
Pomalidomide 
MLN9708 
Hold MLN9708.  Follow weekly. If the toxicity 
resolves to ≤ grade 1(or baseline), restart 
MLN9708 at next lower dose level and continue 
through the scheduled end of the cycle.  
Otherwise, omit for remainder of cycle and reduce 
the dose of MLN9708  one dose level at the start 
of the next cycle.  Omitted doses are not made up. 
For recurrent Grade 2 peripheral neuropathy with 
pain or grade 3 neuropathy, hold treatment. If the 
toxicity resolves to ≤ grade 1(or baseline), reduce 
pomalidomide and /or MLN9708 at investigators 
discretion.  
 
Discontinue teatment.  Withdraw participant from 
study. 
Herpes Zoster 
reactivation any grade 
Pomalidomide 
MLN9708 
Hold MLN9708 and pomalidomide until lesions 
are dry.  Initiate antiviral therapy (maintain dose 
level). 
Venous 
Pomalidomide/ Hold therapy and start full anticoagulation as 


  
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Thrombosis/Embolism > 
Grade 3 
MLN9708 
appropriate; restart at investigator’s discretion 
(maintain dose level). 
Other Pomalidomide or 
MLN9708 related non-
hematologic toxicity 
Grade > 3 
 
 
Grade 4 related non-
hematologic toxicity 
Pomalidomide 
MLN9708 
Determine attribution of toxicity and hold both 
pomalidomide and MLN9708.    Follow at least 
weekly.  If toxicity resolves to < grade 1 or 
baseline, resume therapy with one level dose 
reduction. 
 
Consider permanent discontinuation of therapy.  
Exceptions may be made following discussion 
with the Lead Principal Investigator for patients 
that are experiencing clinical benefit. 
Once MLN9708 or pomalidomide is reduced for any toxicity, the dose may not be re-
escalated. 
7.9.2   Dexamethasone Dose Modification Guidelines* 
Body System 
Symptom 
Recommended Action 
Gastrointestinal 
Dyspepsia, gastric or duodenal 
ulcer, gastritis Grade 1–2  
(requiring medical management) 
Treat with H2 blockers, sucralfate, 
or omeprazole. If symptoms persist 
despite above measures, decrease 
dexamethasone dose by 1 dose level. 
Gastrointestinal 
> Grade 3  
(requiring hospitalization or 
surgery) 
Hold dexamethasone until symptoms 
adequately controlled. Restart and 
decrease one dose level of current 
dose along with concurrent therapy 
with H2 blockers, sucralfate, or 
omeprazole. If symptoms persist 
despite above measures, discontinue 
dexamethasone and do not resume. 
Gastrointestinal 
Acute pancreatitis 
Discontinue dexamethasone and do 
not resume 
Cardiovascular 
Edema 
>Grade 3 (limiting function and 
unresponsive to therapy or 
anasarca) 
Diuretics as needed, and decrease 
dexamethasone dose by 1 dose level; 
if edema persists despite above 
measures, decrease dose another 
dose level. Discontinue 
dexamethasone and do not resume if 
symptoms persist despite second 
reduction. 
Neurology 
Confusion or Mood alteration  
> Grade 2 (interfering with 
Hold dexamethasone until symptoms 
resolve. Restart with one dose level 


  
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function +/- interfering with 
activities of daily living) 
reduction. If symptoms persist 
despite above measures, discontinue 
dexamethasone and do not resume. 
Musculoskeletal 
Muscle weakness  
> Grade 2 (symptomatic and 
interfering with function +/- 
interfering with activities of 
daily living) 
Decrease dexamethasone dose by 
one dose level. If weakness persists 
despite above measures, decrease 
dose by one dose level. Discontinue 
dexamethasone and do not resume if 
symptoms persist. 
Metabolic 
Hyperglycemia > Grade 3 or 
higher 
Treatment with insulin or oral 
hypoglycemics as needed. If 
uncontrolled despite above 
measures, decrease dose by one dose 
level until levels are satisfactory. 
7.10    Criteria for Beginning or Delaying a Subsequent Treatment Cycle 
For a new cycle of treatment to begin, the patient must meet the following criteria: 
• 
ANC must be ≥ 1,000/mm3. 
• 
Platelet count must be ≥ 75,000/mm3 or  > =50,000/mm3 for patients with baseline 
platelets ≥50,000/mm3 but <75,000/mm3. 
• 
All other nonhematologic toxicity (except for alopecia) must have resolved to ≤ Grade 1 
or to the patient’s baseline condition 
If the patient fails to meet the above-cited criteria for initiation of the next cycle of treatment, 
dosing should be delayed for 1 week. At the end of that time, the patient should be re-evaluated 
to determine whether the criteria have been met. If the patient continues to fail to meet the 
above-cited criteria, delay therapy and continue to re evaluate. The maximum delay before 
treatment should be discontinued will be 3 weeks or at the discretion of the Principal 
Investigator. 
7.11    
Concomitant Medications 
7.11.1 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 
during this study.  A drug/drug interaction (DDI) with a strong inhibitor would increase 
MLN2238 (metabolite of MLN9708) exposure. 


  
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 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 to use.  A DDI with a strong 
inducer would decrease MLN2238 (metabolite of MLN9708) exposure. 
 Strong CYP3A inducers:  rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, and 
phenobarbital 
Please refer to a complete listing of prohibited medications, strong CYP3A and CYP1A2 
inhibitors 
that 
can 
be 
found 
via 
the 
following 
link:  
http://medicine.iupui.edu/clinpharm/ddis/main-table/. 
The dietary supplements St John’s wort and Ginkgo biloba are not permitted. 
The following procedures are prohibited during the study: 
 Any antineoplastic treatment with activity against MM except for drugs in this treatment 
regimen. 
 Radiation therapy (the requirement for local radiation therapy generally indicates disease 
progression). 
 Platelet transfusions to help patients meet eligibility criteria are not allowed within 
3 days before study drug dosing. 
 Adjuvant hormone therapy for breast or prostate cancer. 
7.11.2    
Permitted/Recommended 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 and is strongly recommended.  


  
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 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. 
Intravenous fluids should be given to prevent volume depletion. 
 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. 
 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.  
 Fluid deficits should be corrected before and throughout treatment. 
7.11.3  Required/Recommended Concomitant Therapy 
 Pomalidomide increases the risk of thromboembolism. Anti-coagulation prophylaxis is 
required after an assessment of each patient’s underlying risk factors, unless there is an 
excess risk of bleeding. 
 Antiviral therapy such as acyclovir is recommended for herpes prophylaxis.   
 For the Phase I portion of the study, growth factors, granulocyte colony stimulating 
factor [G-CSF], may be given prophylactically for at least two days on days 21 – 26 
during or beyond cycle 2. For the Phase II portion of the study, G-CSF may be given 
prophylactically for at least two days on days 21-26 during or beyond cycle 1. It will be 
administered subcutaneously at a dose of 5ug/kg or per institutional standard practice 
dosing either daily or every other day for a minimum of two doses.  If patients 
experience neutropenia or dosing delays, we would recommend consideration of growth 
factor in subsequent cycles. 
 Allopurinol is recommended for patients with high tumor burden due to the possibility of 
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7.11.4   Pregnancy 
It is not known what effects MLN9708 has on human pregnancy or development of the embryo 
or fetus.  Pomalidomide can cause fetal harm when administered during pregnancy. Therefore, 
female patients participating in this study should avoid becoming pregnant, and male patients 
should avoid impregnating a female partner.  Females of child bearing potential* and male 
patients should use effective methods of contraception through defined periods during and after 
study treatment as specified below. 
A female of child bearing potential is any sexually mature female who: 
1) has not undergone a hysterectomy or bilateral oophorectomy; or 
2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had 
menses at any time in the preceding 24 consecutive months). 
7.11.4.1   Females  
Females of reproductive potential must commit either to abstain continuously from heterosexual 
sexual intercourse or to use two methods of reliable birth control simultaneously (one highly 
effective form of contraception – tubal ligation, IUD, hormonal (birth control pills, injections, 
hormonal patches, vaginal rings or implants) or partner’s vasectomy and one additional effective 
contraceptive method – male latex or synthetic condom, diaphragm or cervical cap. 
Contraception must begin 4 weeks prior to initiating treatment, during therapy, during dose 
interruptions and continuing for 4 weeks following discontinuation of pomalidomide or 90 days 
following discontinuation of MLN9708. Reliable contraception is indicated even where there 
has been a history of infertility, unless due to hysterectomy. Females of reproductive potential 
should be referred to a qualified provider of contraceptive methods, if needed.  
Females of reproductive potential must have 2 negative pregnancy tests before initiating 
therapy. The first test should be performed within 10-14 days, and the second test within 24 
hours prior to prescribing pomalidmide and MLN9708. Once treatment has started and during 
dose interruptions, pregnancy testing for females of reproductive potential should occur weekly 
during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in 
females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing 
should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient 
misses her period or if there is any abnormality in her menstrual bleeding.  Treatment with 
pomalidomide and MLN9708 must be discontinued during this evaluation. All study 


  
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participants must be registered into the mandatory POMALYST REMS™ program, and be 
willing and able to comply with the requirements of the POMALYST REMS™ program. 
7.11.4.2   Males  
Pomalidomide is present in the semen of males who take pomalidomide. The effects of 
MLN9708 are unknown. Therefore, males must always use a latex or synthetic condom during 
any sexual contact with females of reproductive potential while taking pomalidomide or 
MLN9708 and for up to 28 days after discontinuing pomalidomide or 90 days after 
discomtinuation of MLN9708, even if they have undergone a successful vasectomy. Male 
patients taking pomalidmide or MLN9708 must not donate sperm. All study participants must 
be registered into the mandatory POMALYST REMS™ program, and be willing and able to 
comply with the requirements of the POMALYST REMS™ program. 
7.12  
 Management of Clinical Events 
Adverse drug reactions such as thrombocytopenia, diarrhea, fatigue, nausea, vomiting, and rash 
have been associated with MLN9708 treatment. Management guidelines regarding these events 
are outlined below. Further details of management of MLN9708 AEs are described  the 
MLN9708 IB. 
Prophylaxis Against Risk of Infection 
If lymphopenia is noted, patients may be at an increased risk of infection.  In particular, 
lymphopenia can be associated with reactivation of herpes zoster and herpes simplex viruses.  
Antiviral therapy such as acyclovir or valacyclovir may be initiated as clinically indicated.  
Other antivirals are also acceptable. 
Nausea and/or Vomiting 
Standard anti-emetics, including 5-HT3 antagonists, are recommended for emesis occurring 
upon treatment initiation; prophylactic anti-emetics may also be considered.  Dexamethasone 
should not be administered as an anti-emetic.  Fluid deficits should be corrected before initiation 
of study drug and during treatment. 
Diarrhea 
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 deficits should be corrected before initiation of treatment and during 
treatment. Prophylactic antidiarrheals are not generally recommended. 


  
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Erythematous Rash With or Without Pruritus 
As with VELCADE, rash with or without pruritus has been reported with MLN9708, primarily 
at the higher doses tested. The rash may range from some erythematous areas, macular and/or 
small papular bumps that may or may not be pruritic over a few areas of the body or more 
generalized, has been transient and has resolved either spontaneously or with standard 
symptomatic measures such as oral or topical steroids and/or antihistamines. Prophylactic 
measures should also be considered if a patient develops a rash (eg, using a thick, alcohol-free 
emollient cream on dry areas of the body).  In the case of rash, the use of a topical or oral steroid 
(eg, prednisone ≤ 10 mg per day or equivalent) is permitted.  A rare risk is Stevens-Johnson 
Syndrome, a severe, life-threatening or deadly rash with skin peeling and mouth sores, which 
should be managed symptomatically according to standard medical practice.  
Thrombocytopenia 
Thrombocytopenia has been reported to date primarily at the higher doses tested.  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. Thrombocytopenia 
nadirs commonly recover without intervention by the beginning of the next scheduled cycle. 
MLN9708 administration should be modified as noted as per dose modification 
recommendations when thrombocytopenia occurs.  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 
Neutropenia has been reported with MLN9708 and pomalidomide.  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 been manageable with G-CSF 
Neutropenic nadirs commonly recover without intervention by the beginning of the next 
scheduled cycle or with a short delay in treatment.  MLN9708 administration should be 
modified when neutropenia occurs, as noted in the dose modification recommendations. Given 
that MLN9708 will be administered in combination with pomalidomide, with overlapping 
toxicity of neutropenia,  G-CSF will be used prophylactically in this protocol. 


  
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Fluid Deficits 
Dehydration should be avoided because MLN9708 may cause vomiting, diarrhea, and 
dehydration.  Acute renal failure has been reported with MLN9708.  Fluid deficits should be 
corrected before initiation of study drug and during treatment and as needed during therapy.   
Nonsteroidal anti-inflammatory drugs (NSAIDs) induced prevalence of nephrotoxicity is 
relatively low; however, given the wide use of these agents many persons are at risk, including 
for example, patients with cardio-renal disease, dehydration, and the aging kidney. NSAIDs 
should be avoided with impaired renal function given reported NSAID-induced renal failure in 
patients with decreased renal function. Until further information is available, intake of NSAIDs 
while on this protocol should be avoided. 
Hypotension 
Symptomatic hypotension and orthostatic hypotension have been reported with MLN9708. 
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.  
Posterior Reversible Encephalopathy Syndrome  
One case of posterior reversible encephalopathy syndrome (PRES) has been reported with 
MLN9708.  While this case ultimately resolved, PRES has also been reported rarely with 
another proteasome inhibitor, Velcade.  PRES is characterized by headache, seizures and visual 
loss, as well as abrupt increase in blood pressure.  Prompt diagnosis and initiation of 
antihypertensive and anticonvulsant therapy are important to prevent irreversible end-organ 
damage. 
Anticoagulation Consideration   
Pomalidomide increases the risk of thrombotic events in patients who are at high risk or with a 
history a thrombosis, in particular when combined with other drugs known to cause thrombosis.  


  
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Consideration should be given to the requirement of aspirin (81 or 325 mg) or some other form 
of prophylaxis as deemed appropriate. Low molecular weight heparin may be utilized in patients 
that are intolerant to ASA. Coumadin should be used with caution and close monitoring of INR. 
8.  
STUDY DRUG  
8.1  Packaging and Labeling 
8.1.1   MLN9708 
The study drug MLN9708 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.   
MLN9708 capsules should be stored unopened at 2°C to 8°C (36°F-46°F).  The capsules are 
individually packaged in cold form foil-foil blisters in a child-resistant package.  The 0.5-, 2.3-, 
3.0-, and 4.0 mg capsules are supplied as a 1 x 3 blister card in a child-resistant cardboard 
wallet.  
8.1.2   Pomalidomide 
Pomalidomide capsules will be provided by Celgene Corporation as 1.0, 2.0, 3.0 and 4.0 mg 
capsules for oral administration.   
Pomalidomide (POMALYST®) will be provided to research patients for the duration of their 
participation in this trial at no charge to them or their insurance providers.  Pomalidomide will 
be provided in accordance with the  Celgene Corporation’s POMALYST REMS™  program.  
Per the standard   POMALYST REMS™ program requirements, all physicians who prescribe 
pomalidomide for research patients enrolled into this trial, and all research patients enrolled into 
this trial, must be registered in and must comply with all requirements of the POMALYST 
REMS™ program.   
Drug will be shipped on a per patient basis by the contract pharmacy to the clinic site for IND 
studies. Only enough pomalidomide for one cycle of therapy will be supplied to the patient each 
cycle.  This is in accordance with the POMALYST REMS™ program. 
Pomalidomide investigational supplies are dispensed to the patients in individual bottles of 
capsules.  Each bottle will identify the contents as study medication.  In addition, the label will 
bear Celgene’s name, quantity contained and the standard caution statement as follows:  
Caution: New drug - Limited by Federal law to investigational use. Pomalidomide should not be 


  
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handled by FCBP unless wearing gloves.  All bottles will contain the following warning label:  
“WARNING: POTENTIAL FOR HUMAN BIRTH DEFECTS.” 
The study drug label must be clearly visible.  Additional labels must not cover the Celgene 
label. 
8.2  Storage, Handling, and Accountability 
MLN9708 and pomalidomide are anticancer drugs and as with other potentially toxic 
compounds caution should be exercised when handling MLN9708 and pomalidomide capsules. 
8.2.1   MLN9708 
Upon receipt at the investigative site, MLN9708 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, MLN9708 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 MLN9708 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. 


  
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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 MLN9708, including that MLN9708 is to be taken as 
intact capsules. 
Investigational MLN9708 (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. 
8.2.2   Pomalidomide 
Care should be exercised in handling of pomalidomide. Pomalidomide capsules should not be 
opened or crushed. If powder from pomalidomide contacts the skin, wash the skin immediately 
and thoroughly with soap and water. If  pomalidomide contacts the mucous membranes, flush 
thoroughly with water.  
 
The Investigator or designee is responsible for taking an inventory of each shipment of 
pomalidomide received, and comparing it with the accompanying study drug accountability 
form.  The Investigator or designee will verify the accuracy of the information on the form, sign 
and date it, retain a copy in the study file, and return a copy to Celgene or its representative.   
 
Storage 
At the study site, all pomalidomide will be stored in a locked, safe area to prevent unauthorized 
access. The study drug should be stored at room temperature away from direct sunlight and 
protected from excessive heat and cold. 
 
Unused study drug supplies 
Celgene will instruct the Investigator or designee on the return or destruction of unused 
pomalidomide.  If any pomalidomide is lost or damaged, its disposition should be documented 
in the source documents.  Pomalidomide supplies will be retained at the clinical site pending 
instructions for disposition by Celgene.  Patients will be instructed to return empty bottles or 
unused capsules.   
 
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each cycle. 
 
9.      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. 
9.1   Treatment Assignment  
Patients will be assigned at the time of enrollment (per section 6.0) to a given dose level during 
the phase I portion of the study or to the recommended phase II dose as determined during the 
phase I portion of the study.  
9.2   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 investigator also has the right to withdraw 
patients from the study for any of the following reasons: 
 Adverse event 
 Lack of Protocol adherence 
 Lost to follow-up 
 Progressive disease 
 Study termination  
At the time of withdrawal, all study procedures outlined for the End of Treatment  visit should 
be completed. The primary reason for patient’s withdrawal from the study will be recorded in 
the source documents and CRF. 
The Lead Principal Investigator or designee must be notified within 24 hours if a patient is 
withdrawn from the study by the Data Coordinating Center or designee. 
If the reason for withdrawal is the occurrence of an AE, the Investigator will follow the patient  
until such events resolve, stabilize, and according to the Investigator’s judgment, there is no 
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10.    STATISTICAL AND QUANTITATIVE ANALYSES 
10.1    
Statistical Methods 
10.1.1     
Determination of Sample Size 
Phase I: The phase I study will follow a 3+3 design, to evaluate toxicities associated with 
MLN9708 when given in combination with pomalidomide and dexamethasone. Two doses of 
MLN9708 (dose level -1 and dose level 1: 3 mg; dose level 2: 4 mg) will be tested in up to three 
possible dose levels; there will be no dose reductions below the 3mg dose of MLN9708. In the 
phase I portion of this study, the total sample size will depend on the number of dose levels 
evaluated to determine the maximum tolerated dose (MTD). While the phase I study is expected 
to enroll and treat 9 patients (3 patients treated on dose level 1 and 6 additional patients treated 
at dose level 2 -assuming the 4mg dose is well tolerated), a maximum of 18 patients could be 
treated (6 patients per dose level). The highest dose level that produces ≤1/6 DLTs in cycle 1 
will be the MTD. (See section 7.4  for dose expansion/escalation rules.) The recommended 
phase II dose (RP2D) of MLN9708 and pomalidomide will generally be the MTD, but it may be 
less than the MTD  based on a review of available data/cumulative toxicities from phase I. 
Phase II: For this trial, where MLN9708 will be added to pomalidomide and dexamethasone, 
patients with prior exposure to either of these agents would not be excluded, unlike the patients 
treated on the randomized phase III study of comparing pomalidomide plus dexamethasone, to 
high-dose dexamethasone alone. As many patients (>50%) are likely to have been previously 
treated with one or both of these agents we consider a response rate of 30% sufficient efficacy to 
justify further development.26 In addition, the estimation of response in this refractory/high-risk 
population is of equal importance. Given this, the phase II portion of the trial, will use a Gehan 
two stage design (Gehan, 1961). The phase II trial is expected to enroll a minimum of 9 and a 
maximum of 25 patients. The six patients treated at the RP2D in the phase I portion of the study 
will count toward the 25 patients required. Given this, we expect to enroll only 19 new patients 
on the phase II trial. The sample size is based on the desire to estimate the response rate with at 
most 10% standard error, and early stopping if the combination is unexpectedly ineffective. The 
primary endpoint is confirmed tumor response (sCR/CR/VGPR or PR).  
At stage 1, 9 patients will be entered on the study. If 0 responses are seen in the first 9 patients 
treated, the study will be terminated and the true regimen response will be declared ≤30%. If at 
least 1 patient responds, the trial will continue to the second stage. Because patients treated 
during the phase I portion of the trial at the dose selected for the phase II trial will be counted 


  
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(n=6), only 3 additional patients will be enrolled at stage 1. Under this design if the study 
regimen is >30% effective, there would be ~95.6% chance of at least one success. At stage 2, 16 
additional patients will be entered. This accrual provides for estimation of the response rate with 
no more than 10% standard error.   
10.1.2       
Populations for Analysis 
Phase I (Evaluable for Toxicity): Patients will be considered evaluable for toxicity if they 
receive any study drug. Patients will be considered evaluable for dose limiting toxicity if they 
receive at least 75% of both Pomalidomide and MLN9708 and are followed for the full 28 days 
during cycle 1  or experience a DLT.  All patients who are not evaluable for dose limiting 
toxicity will be replaced. 
Phase II (Evaluable for Toxicity): Patients will be considered evaluable for toxicity if they 
receive any study drug.  Patients in Phase II will not be replaced based on toxicity.  
Phase I and II (Evaluable for Response): For the phase II portion, as part of the primary 
analysis, patients will be considered evaluable for response if they are eligible, have baseline 
disease assessments, and receive any protocol treatment. As part of a secondary analysis, 
patients will be considered evaluable for response if they have baseline disease assessments, 
receive at least 75% of both Pomalidomide and MLN9708 during the first cycle of therapy and 
have had their disease re-evaluated. Patients will have their response classified according to the 
IMWG response criteria. All patients in phase II and those treated at the RP2D in phase I, who 
are not evaluable for response will be replaced. 
10.1.3    
Demographic and Baseline Characteristics 
Patient demographic and baseline characteristics, including age, gender, medical history, and 
prior therapy, will be summarized using descriptive statistics. For continuous variables, 
descriptive statistics (number [n], mean, standard deviation, standard error, median (range) will 
be provided. For categorical variables, patient counts and percentages will be provided.  
10.1.4          Efficacy Analysis 
A primary activity endpoint is not defined for the Phase I study. The primary activity endpoint 
for the Phase II study is response rate. Response rates (overall, clinical benefit) and depth of 
response will be calculated as the percent of evaluable patients that have confirmed 
sCR/CR/VGPR or PR (overall) or sCR/CR/VGPR/PR/MR or SD (clinical benefit), exact 95% 
confidence intervals will be calculated for these estimates. Response rates will also be evaluated 


  
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based on number and type of prior therapy(ies). Response defined as per modified IMWG 
criteria. Time to response, duration of response, and survival (overall and progression-free) will 
be estimated using the product-limit method of Kaplan and Meier.  
10.1.5    
Safety Analysis and Stopping Rules for Excessive Toxicity 
Toxicity information recorded will include the type, severity, and the probable association with 
the study regimen. Tables will be constructed to summarize the observed incidence by severity 
and type of toxicity. 
The following table will be consulted as relevant toxicities are encountered. The early stopping 
rule for safety/toxicity will be assessed for each patient after cycle 1. The expected rate of 
unacceptable toxicity should not be ≥33%. Note: Unacceptable toxicity is defined in section 7.3 
of the protocol. See the table below for detailed early stopping rules. These rules are in addition 
to the quarterly review of all toxicities submitted to the COH DSMC. Patients with ongoing 
toxicity (cycle 1 toxicity persisting beyond day +28) will be followed until resolution or 
stability.  If more than the specified number of patients has significant treatment related 
toxicities, patient accrual will be halted and a full review of the data by the Data Safety 
Monitoring Committee (DSMC) will be mandated. Patient accrual will not resume until 
approved by the DSMC to do so. 
# of patients 
treated at 
phase II dose 
# of patients 
with 
unacceptable 
toxicity to halt 
enrollment1 
Given the following toxicity rates, 
cumulative probability of early 
stopping: 
15% 
33% 
45% 
6 
2 
0.22 
0.64 
0.84 
12 
4 
0.24 
0.73 
0.92 
18 
6 
0.25 
0.78 
0.95 
1: For each unacceptable toxicity, halt enrollment and evaluate if 
the cumulative # of patients reaches or exceeds the specified limits. 
We recognize that these stopping rules represent the overall stoping rules including the patient 
evaluated on a given dose during the Phase I portion. As such, these rules represent the stopping 
probabilities of a dose with the above toxicity rates, including stopping during the phase I dose 
finding portion. Once the MTD has been selected, and additional patients are accrued 
(presumably at the MTD), the probability of early stopping is less (e.g. 26% of chance of early 
stopping at 12 patients if the true probability of unacceptable toxicity is 33%, and a 44% chance 


  
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of early stopping at 18 patients in that scenario). This represents the probability of early 
stopping conditional on passing the criteria for MTD selection (0 or 1 out of 6). 
11.    DATA AND SAFETY MONITORING   
11.1    
Definition of Risk Level 
This is a Risk Level 4 study, as defined in the “City of Hope Data and Safety Monitoring Plan”, 
http://www.coh.org/dsmc/Pages/forms-and-procedures.aspx. City of Hope is sponsor of this 
IND. 
11.2  Monitoring and Personnel Responsible for Monitoring 
The Protocol Monitoring Team (PMT) consisting of the PI, Collaborating Investigator, 
CRC/protocol nurse, statistician and COH Data Coordinating Center staff is responsible for 
monitoring the data and safety of this study, including implementation of the stopping rules for 
safety and efficacy.   
 
Beginning with the enrollment of the first patient, the PMT will meet weekly or bi-weekly via 
teleconference for patient and protocol management issues.   
 
This study will utilize the Phase I tracking log to monitor data and safety for dose escalation, 
recording doses administered, and resultant adverse events.  The tracking log will contain dose 
levels administered, DLT-defining adverse events, and documentation that the data from a dose 
level is complete before dose escalation.  Those data and safety elements will be reported to the 
COH DSMC as applicable within the PMT report, which will be submitted quarterly from the 
anniversary date of activation, as noted in Table 1 below.  
 
 Table 1:  City of Hope PMT Reporting Timelines for the DSMC 
 
Risk Level 
Phase 
Standard Reporting 
Requirement 
RL 1, RL2, and Compassionate 
Use Studies 
No reports required 
3 
I 
Every 3 months from 
activation date, as 
indicated in MIDAS 


  
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3 
Pilot, 
Feasibility, 
II-IV 
Every 6 months from 
activation date, as 
indicated in MIDAS 
4 
Pilot, 
Feasibility, 
I-IV 
Every 3 months from 
activation date, as 
indicated in MIDAS 
 
During periods of active protocol enrollment, quarterly reports of all protocol activity will be 
submitted to the DSMC and will include:  
1) The number of patients screened, enrolled and treated. 
2) Cohort status updates. 
3) List of AEs (including SAEs/UPs). 
4) Protocol deviations. 
 
Annual continuation reports will be made to the IRB, Cancer Protocol Review and Monitoring 
Committee (CPRMC) at COH and to the Food and Drug Administration (FDA).  These reports 
will be made available to participating institutions (as requested). 
11.3  Definitions 
11.3.1    
Pretreatment Event Definition 
A pretreatment event is any untoward medical occurrence in a patient or subject who has signed 
informed consent to participate in a study but before administration of any study medication; it 
does not necessarily have to have a causal relationship with study participation.  For serious pre-
treatment events, the investigator must determine both the intensity of the event and the 
relationship of the event to the study procedures. 
11.3.2       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 


  
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increased in severity or frequency since the administration of study drug.  When possible, signs 
and symptoms indicating a common underlying pathology should be noted as one 
comprehensive event. 
An abnormal laboratory value 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.   
11.3.3       Unexpected Adverse Event [21 CFR 312.32 (a)] 
An AE is unexpected if it is not listed in the investigator’s brochure and/or package insert; is not 
listed at the specificity or severity that has been observed; is not consistent with the risk 
information described in the protocol and/or consent; is not an expected natural progression of 
any underlying disease, disorder, condition, or predisposed risk factor of the research participant 
experiencing the AE. 
11.3.4       Expected Adverse Event 
Any event that does not meet the criteria for an unexpected event OR is an expected natural 
progression of any underlying disease, disorder, condition, or predisposed risk factor of the 
research participant experiencing the AE. 
 
         11.3.5    Serious Adverse Event (SAE) [21 CFR 312.32] is defined as any expected or 
unexpected AE that, at any dose,  results in any of the following outcomes: 
 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 (except scheduled hospitalizations for non-acute, unrelated 
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 Results in persistent or significant disability or incapacity (Disability is 
defined as a substantial disruption of a person’s ability to conduct normal life 
functions).   
 Is a congenital anomaly/birth defect. 
 Secondary malignancy, or 
 Any other AE that, based upon appropriate medical judgment, may 
jeopardize the subject’s health and may require medical or surgical 
intervention to prevent one of the outcomes listed above (examples of such 
events include allergic bronchospasm requiring intensive treatment in the 
emergency room or at home, blood dyscrasisas of convulsions that do not result 
in inpatient hospitalization, or the development of drug dependency or drug 
abuse). 
11.3.6      Unanticipated problem – Any incident, experience or outcome that meets all 
three of the following criteria: 
1. Unexpected (in term nature, severity, or frequency) given the following: a) the 
research procedures described in the protocol-related documents such as the IRB 
approved research protocol, informed consent document or Investigator Brochure 
(IB); and b) the characteristics of the subject population being studied; AND 
2. Related or possibly related to participation in the research (possibly related means 
there is a reasonable possibility that the incident, experience, or outcomes may 
have been caused by the drugs, devices or procedures involved in the research); 
AND 
3. Suggests that the research places subjects or others at greater risk of harm 
(including physical, psychological, economic, or social harm) than previously 
known or recognized. 
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 


  
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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. 
AEs which are serious must be reported to Celgene and Millennium Pharmacovigilance (or 
designee) from the date the participant signs Informed Consent through 30 days after 
administration of the last dost of pomalidomide or MLN9708. Any SAE that occurs at any time 
after completion of MLN9708/pomalidmide treatment or after the designated follow-up period 
that the sponsor-investigator and/or sub-investigator considers to be related to any study drug 
must be reported to Millennium/Celgene 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/Celgene 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). Each 
Investigator is also responsible for reviewing their institutional guidelines and reporting locally 
based on those guidelines (i.e., unanticipated problems). 
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)? 
 
11.2  Reporting of Unanticipated Problems and Adverse Events  
Unanticipated Problems: Most unanticipated problems must be reported to the COH 
DSMC and IRB within 5 calendar days according to definitions and guidelines at 
http://www.coh.org/hrpp/Pages/hrpp-policies.aspx.  Any unanticipated problem that 
occurs during the study conduct will be reported to the DSMC and IRB by submitting 


  
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electronically in iRIS (http://iris.coh.org).  Participating institutions will submit to the 
COH Data Coordinating Center. 
 
Serious Adverse Events - All SAEs occurring during this study, whether observed by 
the physician, nurse, or reported by the patient, will be reported according to 
definitions and guidelines at http://www.coh.org/hrpp/Pages/hrpp-policies.aspx and 
Table 2 below.  Those SAEs that require expedited reporting will be submitted 
electronically in iRIS (http://iris.coh.org/).   
 
Adverse Events - Adverse events will be monitored by the PMT.  Adverse events that 
do not meet the criteria of serious OR are not unanticipated problems will be reported 
only in the continuation reports and PMT reports (see Table 2 below). 
 
Table 2:  City of Hope Adverse Event and Unanticipated Problem Reporting Timelines for 
the DSMC and IRB 
 
Required Reporting Timelines to DSMC for AE/SAEs 
Investigator Initiated Studies  
 
 
 
Required Reporting Timeframe to DSMC 
Attribution 
UNEXPECTED 
EXPECTED 
  
Death while on active treatment or within 30 days of 
last day of treatment 
Possibly, Probably, 
Definitely 
5 calendar days 
Unlikely, Unrelated 
  
Death after 30 days of last active treatment/therapy 
Possibly, Probably, 
Definitely 
5 calendar days 
No reporting required 
Unlikely, Unrelated 
No reporting required 
No reporting required 
  
Grades 3 and 4 AND meeting the definition of 
"serious" 
Possibly, Probably, 
Definitely 
5 calendar days 
10 calendar days 
Unlikely, Unrelated 
5 calendar days 
10 calendar days 
  
Grades 1 and 2 AND resulting in "hospitalization" 
Possibly, Probably, 
Definitely 
5 calendar days 
10 calendar days 
Unlikely, Unrelated 
10 calendar days 
10 calendar days 
 
 
 
An event determined by the IRB of record to be an Unanticipated Problem (UP) will be 
communicated to the Investigator and COH DSMC through the COH IRB Operations 
Director. The DSMC will review the case and make a determination as to whether the 


  
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study will be suspended, terminated, amended, or allowed to continue without 
amendment. 
 
Required Reporting Timeframe to IRB of Record 
Attribution 
UNEXPECTED 
EXPECTED 
 
Death  
Possibly, Probably, 
Definitely 
5 calendar days 
Annual 
Unlikely, Unrelated 
Annual 
Annual 
 
Grades 3 and 4 AND meeting the definition of a UP 
Possibly, Probably, 
Definitely 
5 calendar days 
Annual 
Unlikely, Unrelated 
Annual  
Annual 
 
Grade 1 and 2 AND meeting the definition of a 
UP   
Possibly, Probably, 
Definitely 
5 calendar days 
Annual 
Unlikely, Unrelated 
Annual 
Annual 
The Sponsor-Investigator and the COH Data Coordinating Center must be notified by phone, 
fax or of the occurrence of any SAE or Unanticipated Problem within 24 hours of the 
investigator, designee, or site personnel’s knowledge of the event.  To report an SAE/UP, the 
site representative must complete the Notification of Unanticipated Problem/Serious Adverse 
Event/Pregnancy Form (attached as an Appendix 15.3) and MEDWATCH 3500A form , then 
fax or scan/email the forms  (as noted below) using secure email (#secure# in subject line of 
email): 
City of Hope Data Coordinating Center 
Fax Number:  626 301-8422 
COH DCC email:  dcc@coh.org (always use #secure# in subject line) 
Telephone reports must be followed by a written report within 24 hours.  Follow-up reports 
must be submitted in a timely fasion as additional information becomes available. 
The Investigator is responsible for notifying the Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC) in accordance with local institutional regulations, of all 
SAEs.  The Sponsor-Investigator, the City of Hope Data Coordinating Center and/or 


  
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Millennium/Celgene may request additional source documentation pertaining to the SAE.  If a 
patient is permanently withdrwawn from the study because of a SAE, this information must be 
included in the initial or follow-up SAE report as well as the Study Discontinuation case report 
form. 
The investigator is responsible for reporting serious adverse events that occur from the signing 
of the study specific consent through the duration of the post-therapy adverse event collection 
period to the City of Hope Data Coordinating Center (see section above for submission 
guidelines), as indicated when using MLN9708 and Pomalidomide within 24 hours of becoming 
aware of the SAE.  Notification can be made via phone or telefacsimile using the MEDWATCH 
3500A form.  The Sponsor-Investigator, through the COH DCC, will report to Millennium and 
Celgene within 24 hours. 
SAE and Pregnancy Reporting Contact Information - Millennium 
 
Millennium Pharmacovigilance Designee, PPDI, PVG: 
 
The COH DCC will fax the MEDWATCH 3500A form (Millennium Pregnancy Form attached 
as Appendix 15.4.4 when reporting pregnancy)  within 24 hours to:    
 
Cognizant 
 
 Contact Information: 
 
Fax Number:  1-800-963-6290 
 
Email:  TakedaOncoCases@cognizant.com 
 
 
SAE and Pregnancy Reporting Contact Information – Celgene 
The Sponsor-Investigator through the COH DCC will inform Celgene in writing using the 
MEDWATCH 3500A of any SAE within 24 hours of being aware of the event.  The written 
report must be completed and supplied to Celgene by facsimile within 24 hours/1 business day.  
The initial report must be as complete as possible, including an assessment of the causal 
relationship between the event and the investigational product(s), if available.  Information not 
available at the time of the initial report (e.g., an end date for the adverse event or laboratory 
values received after the report) must be documented on a follow-up report.  A final report to 
document resolution of the SAE is required.  The Celgene tracking number (PO-MM-PI-0062) 
and the institutional protocol number should be included on SAE reports (or on the fax cover 
letter) sent to Celgene.  A copy of the fax transmission confirmation of the SAE report to 


  
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Celgene should be attached to the SAE and retained with the patient records. 
 
Celgene Drug Safety Contact Information: 
Celgene Corporation 
Global Drug Safety and Risk Management 
Connell Corporate Park 
300 Connell Dr.  Suite 6000 
Berkeley Heights, NJ 07922 
Fax:  (908) 673-9115/Email:  drugsafety@celgene.com 
 
ADDITIONAL REPORTING REQUIREMENTS  
Serious Adverse Events meeting the requirements for expedited reporting to the FDA, as 
defined in 21 CFR 312.32, will be reported as an IND safety report using the MedWatch Form 
FDA 3500Afor Mandatory Reporting which can be found at:  
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm 
 
The City of Hope Data Coordinating Center will work with participating institutions to obtain 
the required serious adverse event report forms including any follow up information.   
 
The IND is held by COH, and the Sponsor-Investigator or designee, including the City of Hope 
Data Coordinating Center will be responsible for contacting the Office of IND Development 
and Regulatory Affairs (OIDRA) at COH to ensure prompt reporting of safety reports to the 
FDA.  OIDRA will assist the PI and COH DCC with the preparation of the report and submit 
the report to the FDA in accordance with the following: 
 
any unexpected fatal or life threatening adverse experience associated with use of the 
drug must be reported to the FDA no later than 7 calendar days after initial receipt of the 
information [21 CFR 312.32(c)(2)]; 
 
any adverse experience associated with use of the drug that is both serious and 
unexpected must be submitted no later than 15 calendar days after initial receipt of the 
information [21 CFR 312.32(c)(1)] 
 
any follow-up information to a study report shall be reported as soon as the relevant 
information becomes available. [21 CFR 312.32(d)(3)] 


  
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Sponsor-investigator or designee must also provide Millennium/Celgene Pharmacovigilance 
with a copy of all communications with applicable regulatory authorities related to the study or 
study drug(s), including, but not limited to, telephone conversation logs within 24 hours of such 
communication. 
Adverse Events of Special Interest (AESIs) are a subset of AEs that are to be reported to 
Millennium on a quarterly basis by the sponsor-investigator. These adverse events will be 
captured using Medidata RAVE, the electronic data capture system used for data collection for 
this trial as part of routine data collection.  A report will be generated and submitted to 
Millennium on a quarterly basis by the City of Hope Data Coordinating Center.  Millennium 
will provide the current list of AESIs and updates to the list will be distributed to the sponsor-
investigator as appropriate. 
The highest grade of non-Serious Adverse Events of Special Interest (AESIs) observed in 
patients will be reported.  AESIs are defined as: 
1. Neuropathy 
o Neuropathy peripheral 
o Peripheral sensory neuropathy 
o Polyneuropathy 
o Paraesthesia 
o Hyperaesthesia 
o Burning sensation 
o Oral pain 
o Paraesthesia oral 
o Muscle spasms  
o Muscular weakness 
2. Hematologic Toxicities 
3. Rash 
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o Rash macular 
o Rash maculo-papular 
o Rash generalized 
o Rash pruritic 
o Pruritus 
o Rash erythematous 
o Erythema 
o Rash popular 
o Skin exfoliation 
o Exfoliative rash 
4. Respiratory Complaints 
o Pneumonia  
o Pneumonitis 
5. Renal toxicity 
o Blood creatinine increased 
o Blood creatinine abnormal 
o Blood urea decreased 
o Renal failure acute 
o Renal failure 
o Renal impairment 
6. Hypotension 
o Orthostatic hypotension 
o Presyncope 
o Syncope 
7. New Primary Malignancy 
o For all myeloma studies, new primary malignancies must be reported for at least 
two years from the Clinical Trial patient’s first dose of MLN9708. 


  
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Procedures for Reporting Drug Exposure During Pregnancy and Birth Events 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) of a female patient occurring while the patient is on MLN9708 or pomalidomide, 
or within 90 days of the patient’s last dose of therapy), are considered immediately reportable 
events. MLN9708 and pomalidomide are to be discontinued immediately. The pregnancy, 
suspected pregnancy, or positive pregnancy test must be reported. The investigator must notify 
the sponsor-investigator and the COH DCC immediately by phone and by completing and 
faxing the Notification of Unanticipated Problem/Serious Adverse Event/Pregnancy Form 
(attached as an Appendix 15.3).  The sponsor-investigator through the COH DCC will be 
responsible for notifying Millennnium Pharmacovigilence(through Millennium Pregnancy Form 
attached as Appendix 15.4.4)//Celgene Drug Safety.   
 
The female patient should be referred to an obstetrician-gynecologist, preferably one 
experienced in reproductive toxicity for further evaluation and counseling. 
 
The Investigator will follow the female patient until completion of the pregnancy, and must 
notify the sponsor-investigator and the COH DCC immediately phone and by completing by 
completing and faxing the Notification of Unanticipated Problem/Serious Adverse 
Event/Pregnancy Form (attached as an Appendix 15.3).  The sponsor-investigator through the 
COH DCC will be responsible for notifying Millennnium Pharmacovigilence(through 
Millennium Pregnancy Form attached as Appendix 15.4.4)//Celgene Drug Safety immediately 
about the outcome of the pregnancy (either normal or abnormal outcome) using the Pregnancy 
Follow-up Report Form, or approved equivalent form.  
If the outcome of the pregnancy was abnormal (e.g., spontaneous or therapeutic abortion), the 
Investigator should report the abnormal outcome as an AE. If the abnormal outcome meets any 
of the serious criteria, it must be reported as an SAE. The investigator must notify the sponsor-
investigator and the COH DCC immediately phone and by completing by completing and faxing 
the Notification of Unanticipated Problem/Serious Adverse Event/Pregnancy Form (attached as 
an Appendix 15.3).  The sponsor-investigator through the COH DCC will be responsible for 


  
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notifying Millennnium Pharmacovigilence(through Millennium Pregnancy Form attached as 
Appendix 15.4.4)//Celgene Drug Safety within 24 hours of the Investigator’s knowledge of the 
event.  
 
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death after 28 days that the Investigator suspects is 
related to the in utero exposure to MLN9708 and pomalidomide should also be reported. The 
investigator must notify the sponsor-investigator and the COH DCC immediately phone and by 
completing by completing and faxing the Notification of Unanticipated Problem/Serious 
Adverse Event/Pregnancy Form (attached as an Appendix 15.3).  The sponsor-investigator 
through 
the 
COH 
DCC 
will 
be 
responsible 
for 
notifying 
Millennnium 
Pharmacovigilence(through 
Millennium 
Pregnancy 
Form 
attached 
as 
Appendix 
15.4.4)//Celgene Drug Safety within 24 hours of the Investigator’s knowledge of the event.  
 
Male Patients 
If a female partner of a male patient taking MLN9708 or pomalidomide becomes pregnant, the 
male patient should notify the Investigator immediately, and the pregnant female partner should 
be advised to call their healthcare provider immediately. 
12.    ADMINISTRATIVE REQUIREMENTS 
12.1    
Good Clinical Practice 
The study will be conducted in accordance with the International Conference on Harmonisation 
(ICH) for Good Clinical Practice (GCP) and the appropriate regulatory requirement(s).  The 
investigator will be thoroughly familiar with the appropriate use of the study drug as described 
in the protocol and Investigator’s Brochure.  Essential clinical documents will be maintained to 
demonstrate the validity of the study and the integrity of the data collected.  Master files should 
be established at the beginning of the study, maintained for the duration of the study and 
retained according to the appropriate regulations.   


  
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12.2    
Ethical Considerations 
The study will be conducted in accordance with applicable regulatory requirement(s) and will 
adhere to GCP standards.  The IRB will review all appropriate study documentation in order to 
safeguard the rights, safety and well-being of the patients.  The study will be conducted only at 
sites where IRB approval has been obtained.  The protocol, Investigator’s Brochure, informed 
consent form, advertisements (if applicable), written information given to the patients (including 
diary cards), safety updates, annual progress reports, and any revisions to these documents will 
be provided to the IRB by the investigator.  Millennium/Celgene requests that informed consent 
documents be reviewed by Millennium/Celgene or designee prior to IRB submission.   
This study must have the approval of a properly constituted IRB or IEC.  Before the 
investigational drug is shipped to the Site Investigator, the Site Investigator or designee will 
provide the COH DCC with a copy of the IRB/IEC approval letter stating that the study protocol 
and any subsequent amendments and informed consent form have been reviewed and approved. 
The COH DCC will be responsible for obtaining annual IRB/IEC reapproval throughout the 
duration of the study.  Copies of the Investigator’s annual report to the IRB/IEC and copies of 
the IRB/IEC continuance of approval must be submitted to the COH DCC.   
The Site Investigator is also responsible for notifying their IRB/IEC of any significant adverse 
events that are serious, unanticipated and/or unexpected. 
The COH DCC will provide study sites with any investigational new drug (IND) safety reports 
generated, changes to the Investigator’s Brochure IB, and any safety updates.  The Site 
Investigator is responsible for immediately notifying their IRB/IEC of any such updates. 
The Lead Principal Investigator along with the COH DCC will initiate in writing any 
substantive changes to this protocol as a protocol amendment.  The amendment will be 
submitted to the IRB/IEC, together with a revised informed consent, if applicable.  Written 
documentation of IRB/IEC approval must be received before the amendment is implemented.  
Upon completion of the trial, the Site Investigator must provide the IRB/IEC with a summary of 
the trial’s outcome. 
12.3    
Patient Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from either 
the patient or his/her guardian or legal representative before study participation.  The method of 
obtaining and documenting the informed consent and the contents of the consent must comply 
with the ICH-GCP and all applicable regulatory requirements. 


  
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The City of Hope Data Coordinating Center will provide the Site Investigator with a sample 
consent form.  Local and/or institutional requirements may require disclosure of additional 
information in the informed consent.  Any changes to the consent form must be submitted to the 
COH DCC for approval, prior to submission to the IRB/IEC.  The IRB/IEC will review the 
consenf form for approval.  A copy of the approved form must be submitted to the COH DCC 
prior to initiation of the study. 
Before implementing any study procedure, informed consent shall be documented by the use of 
a written consent form approved by the IRB/IEC and signed and dated by the patient or the 
patient’s legally authorized representative at the time of consent.  A copy of the signed informed 
consent will be given to the patient or patient’s legally authorized representative.  The original 
signed consent must be maintained by the Site Investigator and available for inspection by the 
COH DCC, its designated representatives, or regulatory authority at any time. 
12.4    
Patient Confidentiality 
In order to maintain patient privacy, all data capture records, drug accountability records, study 
reports and communications will identify the patient by initials and the assigned patient number.  
If requested, the investigator will grant monitor(s) and auditor(s) from City of Hope, 
Millennium/Celgene or its designees and regulatory authority (ies) access to the patient’s 
original medical records for verification of data gathered on the data capture records and to audit 
the data collection process.  The patient’s confidentiality will be maintained and will not be 
made publicly available to the extent permitted by the applicable laws and regulations. 
The investigator/institution will permit direct access to source data and documents by the COH 
DCC staff, its designees, the FDA, and other applicable regulatory authorities.  The access may 
consist of trial-related monitoring, including remote monitoring, audits, IRB/IEC reviews, and 
FDA/regulatory authority inspections. 
Release of research results should preserve the privacy of medical information and must be 
carried out in accordance with Department of Health and Human Services Standards for Privacy 
of Individually Identifiable Health Information, 45 CFR 164.508. 
12.5    
Investigator Compliance 
The investigator will conduct the study in compliance with the protocol given 
approval/favorable opinion by the IRB and the appropriate regulatory authority(ies).  Changes to 
the protocol will require approval from Millennium/Celgene and written IRB approval/favorable 
opinion from City of Hope (as the sponsor) prior to implementation, except when the 


  
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modification is needed to eliminate an immediate hazard(s) to patients.  The IRB may provide, 
if applicable regulatory authority(ies) permit, expedited review and approval/favorable opinion 
for minor change(s) in ongoing studies that have the approval /favorable opinion of the IRB.  
The investigator will submit all protocol modifications to Millennium/Celgene and the 
regulatory authority(ies) in accordance with the governing regulations.  
Any departures from the protocol must be fully documented in the source documents.  
12.6     Study Documentation and Archives 
12.6.1 Source Documents 
Source documents are original documents, data, and records (e.g., medical records, data 
collection forms, pharmacy dispensing records, recorded data from automated instruments, 
laboratory data) that are relevant to the clinical trial.  The Site Investigator or their designee will 
prepare and maintain adequate and accurate source documents.  These documents are designed 
to record all observations and other pertinent data for each patient enrolled in this clinical trial.  
Source documents must be adequate to reconstruct all data transcribed onto the case report 
forms. 
12.6.2  Case Report Form Completion 
All data will be collecting using COH data collection forms via an electronic data capture 
system, Medidata RAVE.  All case report forms must be completed by designated study 
personnel.  The completed case report forms must be reviewed, signed and dated by the Site 
Investigator or designee in a timely fashion. 
All data will be submitted as follows: 
 Eligibilty Checklist:  the participating institutions at the registering site will 
have completed and faxed this form at the time of registration. 
 On-Study/Baseline Forms:  completed on-study forms are due within two 
weeks of registration. 
 Treatment Forms (Cycle Forms):  completed forms are due within 2 weeks of 
completion of a cycle (unless needed sooner for DLT assessment during Phase I).  
The City of Hope Data Coordinating center will communicate with site staff if 
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 Adverse Event Collection:  completed adverse events are due within two weeks 
of a cycle (unless needed sooner for DLT assessment during Phase I).  The City 
of Hope Data Cooridnating center will communicate with site staff if forms are 
needed sooner. 
 Response/Off Treatment/Off Study/Follow-Up:  forms will be completed each 
time a patient is evaluated for response, comes off treatment, new follow-up 
information is obtained or comes off study.   
12.7    
Archival of Records 
According to 21 CFR 312.62I, the Site Investigators shall retain records required to be 
maintained under this part for a period of 2 years following the date a marketing application is 
approved for the drug for the indication for which it is being investigated.  If no application is to 
be filed or if the application is not approved for such indication, the Site Investigator shall retain 
these records until 2 years after the investigation is discontinued and the FDA or applicable 
regulatory authorities are notified. 
The Site Investigator must retain protocols, amendments, IRB/IEC approvals, copies of the 
Form FDA1572, signed and dated consent forms, medical records, case report forms, drug 
accountability records, all correspondence, and any other documents pertaining to the conduct 
of the study. 
12.8  Study Monitoring and Data Collection  
Following initiation of the study site, remote monitoring will be completed by the COH DCC.  
The Site Investigator will allocate sufficient time for the designated site staff to submit source 
documentation as required to complete remote monitoring. 
The purpose of trial monitoring is to verify the following: 
 The rights and well-being of human subjects are protected. 
 The reported data are accurate , complete, and verificable from source documents. 
 The conduct of the trial is in compliance with the currently approved protocol, 
amendment(s), ICH GCP, FDA CFR, and any other applicable regulatory requirements. 
The COH DCC will submit a prepare a written report after each remote monitoring timepoint or 
trial related communication.  Reports shall include a summary of what the monitor reviewed 


  
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remotely and significant findings, deviations and deficiencies, conclusions, actions taken or to 
be taken to ensure site compliance.  
City of Hope’s Data Coordinating Center, regulatory authorities, the IRB and/or 
Millennium/Celgene may request access to all source documents, data capture records, and 
other study documentation for on-site audit, inspection and remote monitoring.  Direct access to 
these documents must be guaranteed by the investigator, who must provide support at all times 
for these activities. 
12.9    
Investigator and Site Responsibility for Drug Accountability 
Accountability for the study drug at all study sites is the responsibility of the principal 
investigator.  The investigator will ensure that the drug is used only in accordance with this 
protocol.  Drug accountability records for each respective drug/company, MLN9708 for 
Millennium and pomalidomide for Celgene indicating the drug’s delivery date to the site, 
inventory at the site, use by each patient, and amount returned to Millennium/Celgene or a 
designee or disposal of the drug (if applicable and if approved by Millennium/Celgene) will be 
maintained by the clinical site.  Accountability records will include dates, quantities, lot 
numbers, expiration dates (if applicable), and patient numbers.  Accountability records will need 
to be submitted to the COH DCC as requested. 
12.10    MLN9708 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 
Millennium Quality representative. 
For Product Complaints, 
call MedComm Solutions at 
877-674-3784 (877 MPI DRUG)  
(US and International) 
 
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. 


  
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12.11    Closure of the Study 
This study may be prematurely terminated, if in the opinion of the investigator or 
Millennium/Celgene, there is sufficient reasonable cause.  Written notification documenting the 
reason for study termination will be provided to the investigator or Millennium/Celgene by the 
terminating party.   
Circumstances that may warrant termination include, but are not limited to: 
 Determination of unexpected, significant, or unacceptable risk to patients 
 Failure to enter patients at an acceptable rate 
 Insufficient adherence to protocol requirements 
 Insufficient, incomplete and/or unevaluable data 
 Determination of efficacy based on interim analysis 
 Plans to modify, suspend or discontinue the development of the drug 
12.12    Record Retention 
The investigator will maintain all study records according to the ICH-GCP and applicable 
regulatory requirement(s).   
13.    USE OF INFORMATION 
All information regarding MLN9708 supplied by Millennium and pomalidomide by Celgene to 
the investigator is privileged and confidential information.  The investigator agrees to use this 
information to accomplish the study and will not use it for other purposes without consent from 
Millennium/Celgene.  It is understood that there is an obligation to provide Millennium/Celgene 
with complete data obtained during the study.  The information obtained from the clinical study 
will be used toward the development of MLN9708 and may be disclosed to regulatory 
authority(ies), other investigators, corporate partners, or consultants as required. 
Upon completion of the clinical study and evaluation of results by Millennium/Celgene, the 
hospital or institution and/or investigator may publish or disclose the clinical trial results 
pursuant to the terms contained in the applicable Clinical Trial Agreement.    
 


  
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14.    REFERENCES    
1. Jemal A, Siegel R, XU J et al., Cancer Statistics 2010 Cancer J Clin 60;277-300 
2. Richardson PG, Sonneveld P, Schuster MW et al., Bortezomib or high dose 
dexamethasone for relapsed multiple myeloma. N Eng J Med 2005 ;352(24) 2487-98 
3. Kumar S, Flinn I, Richardson P et al, Novel three drug and four drug combination 
regimens of Bortezomib, Dexamethasone, Cyclophosphamide and Lenalidomide for 
previously untreated MM: Results from the Multi Center Randomized Phase 2 Evolution 
Study. Blood 2010;116(21):abstr621 
4. Vij R, Siegel D, Kaufman J et al, Results of an ongoing open label phase II study of 
carfilzomib in patients with relapsed and or refractory MM. J Clin Oncol 28:15s,2010 
5. Dimopoulos , Spencer A, Attal M et al., Lenalidomide plus dexamethasone for relapsed 
or refractory myeloma. N Engl J Med. 2007.357:2123-32 
6. Rajkumar S, Jacobus S, Callander N et al., Lenalidomide plus low dose dexamethasone 
as initial therapy for newly diagnosed MM: an open label randomized controlled trial. 
Lancet Oncology 2010;11:29-37 
7. Kumar S, Rajkumar SV, Dispenzieri A et al., Improved survival in MM and the impact 
of novel therapies. Blood 2008;1115) 2516-20 
8. Kumar S, Lee JH, Lahuerta J et al. on behalf of the international myeloma working 
group. Risk of Progression and survival in multiple myeloma relapsing after therapy 
with IMIDS and bortezomib: A multicenter international myeloma working group study. 
Leukemia 2011:1 
9. 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. Blood (ASH Annual Meeting Abstracts), 2010. 116(21): p. abstr 
1813. 
10. Gupta, N., M. Saleh, and K. Venkatakrishnan. 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. 
11. Chow, L.Q., et al. MLN9708, an investigational proteasome inhibitor, in patients with 
solid tumors; Updated phase 1 results in Head and Neck Symposium. 2012. Phoenix, AZ 
12. 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. 
13. 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, Illinois. 
14. Kumar, S., et al. Oral weekly MLN9708, an investigational proteasome inhibitor, in 
combination with lenalidomide and dexamethasone in patients (pts) with previously 


  
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untreated multiple myeloma (MM): A phase I/II study in ASCO Annual Meeting. 2012. 
Chicago, Illinois. 
15. Merlini, G., et al. 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, Georgia. 
16. Kumar, S. et al. A Phase 1/2 Study of Weekly MLN9708, an Investigational Oral 
Proteasome Inhibitor, in Combination with Lenalidomide and Dexamethasone in 
Patients with Previously Untreated Multiple Myeloma (MM) in 54th ASH Annual 
Meeting and Exposition. 2012. Atlanta, Georgia. 
17. Richardson, P.G., 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. 
18. 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. 
19. 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. 
San Diego, CA 
20. Kumar S., et al. Weekly dosing of the investigational oral proteasome inhibitor 
MLN9708 in patients (pts) with relapsed/refractory multiple myeloma (MM): A phase I 
study in ASCO Annual Meeting. 2012. Chicago, Illinois. 
21. Sanchorawala V., et al. Poster Presentation: Phase 1 study of MLN9708, a novel, 
investigational oral proteasome inhibitor, in patients with relapsed or refractory light-
chain amyloidosis. XIII International Symposium on Amyloidosis, Groningen, The 
Netherlands 2012. 
22. Lacy M, Hayman S, Gertz M, et al., Pomalidomide plus low dose dexamethasone as 
therapy for relapsed multiple myeloma. J Clin Oncol 2009;27:5008-14 
23. Lacy MQ, Hayman S,Gertz MA, Pomalidomide plus low dose dexamethasone is active 
and well tolerated in lenalidomide refractory multiple myeloma. Leukemia. 2010;:1934-
39 
24. Richardson P, Baz R, Wang L et al., Investigational Agent MLN9708 an oral 
proteasome inhibitor in patients with relapsed and or refractory MM: Results from the 
Expansion Cohorts of a Phase I Dose Escalation Study. Blood 2011 118:abstr301 
25.  Rajkumar S.V., Harousseau J.L., Durie B., et al., Consensus recommendations for the 
uniform reporting of clinical trials: report of the International Myeloma Workshop 
Consensus Panel Blood. 2011 117: 4691-4695. 


  
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26. Jesus San Miguel, Katja Weisel, Philippe Moreau et al., Pomalidomide plus low-dose 
dexamethasone versus high-dose dexamethasone alone for patients with relapsed and 
refractory multiple myeloma (MM-003): a randomised open-label phase 3 trial. Lancet 
Oncol 2013; 14:1055-66.  
27. Gehan EA. The determination of the number of patients required in a preliminary and a 
follow-up trial of a new chemotherapeutic agent. J Chronic Dis. 1961 Apr;13:346–353.  
 
 
 


  
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15.    APPENDICES 
15.1    
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.  
 
 
 


  
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15.2   
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. 
 


  
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15.3   NOTIFICATION OF UNANTICIPATED PROBLEM/SERIOUS ADVERSE 
EVENT/PREGNANCY 
City of Hope Data Coordinating Center 
Department of Clinical Research Information Support 
 
NOTIFICATION OF UNANTICIPATED PROBLEM/SERIOUS ADVERSE EVENT/PREGNANCY 
For Use by Participating Institutions Only 
 
THIS FORM ALONG WITH A COPY OF THE MEDWATCH 3500A FORM MUST BE SUBMITTED TO THE DATA 
COORDINATING CENTER AT CITY OF HOPE WITHIN 24 HOURS OF KNOWLEDGE OF ONSET OF SERIOUS ADVERSE 
EVENT, UNANCTICIPATED PROBLEM OR KNOWLEDGE OF PREGNANCY (MEETING REPORTING CRITERIA DESCRIBED 
IN PROTOCOL).  SCAN/EMAIL DOCUMENT TO DCC@COH.ORG (PLEASE USE #SECURE# IN SUBJECT LINE OF ANY 
CORRESPONDENCE) 
COH IRB #12267 - Participating Site IRB # ___________ 
 
Phase I/II trial of MLN9708 plus Pomalidomide and Dexamethasone for Relapsed or 
Relapsed Refractory Multiple Myeloma 
Participating/Treating Institution:  ________________________________________________________ 
 
Reporter:  ______________________________________Phone #:________________________________ 
 
Email:   ________________________________ 
 
PATIENT INFORMATION Pt Study ID:  _____________________________ 
UNANTICIPATED PROBLEM/SERIOUS ADVERSE EVENT/PREGNANCY INFORMATION 
 
Serious Adverse Event/Unanticipated Problem:  _______________________________________________ 
 
Grade:  _______________ 
Was this a dose limiting toxicity?   ________________________________ 
 
Attribution to MLN9708 (Unrelated, Unlikely, Possible, Probable, or Definite):  ______________________ 
 
Attribution to Pomalidome (Unrelated, Unlikely, Possible, Probable, or Definite):  _____________________ 
 
Start Date of SAE/UP: ____/____/____  
 
REPORTING INFORMATION 
Has the event been reported to the following? 
 
Via Fax to Data Coordinating Center (COH)  
 
__ No    __ Yes   Date: __ __ / __ __  / __ __ 
  Phone:  626-256-4673x63968/Email:  dcc@coh.org (use #secure# in subject line)  
 
Participating Site Institutional IRB?  
 
 
__ No    __ Yes   Date: __ __ / __ __  / __ __ 
 
SCAN/EMAIL THIS FORM AND THE MEDWATCH 3500A FORM OR PREGNANCY 
FORM TO DCC@COH.ORG (USE #SECURE# IN SUBJECT LINE) 


  
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15.3.1  Millennium Pregnancy Reporting Form 
 
 


  
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15.4      International Myeloma Working Group Response Criteria27 
Response1 
IMWG criteria 
sCR 
CR as defined below plus:  
 
normal FLC ratio and  
 
absence of clonal cells in bone marrow by immunohistochemistry or 2 – 4 color 
flow cytometry 
CR 
 
Negative immunofixation on the serum and urine and  
 
disappearance of any soft tissue plasmacytomas and  
 
< 5% plasma cells in bone marrow.   
 
In patients with only FLC disease, a normal FLC ratio of 0.26–1.65 is required.  
VGPR 
 
Serum and urine M-protein detectable by immunofixation but not on 
electrophoresis or 
 
> 90% reduction in serum M-protein plus urine M-protein level < 100 mg/24 h.   
 
In patients with only FLC disease, >90% decrease in the difference between 
involved and uninvolved FLC levels is required. 
PR 
 
50% reduction of serum M-protein and reduction in 24 hours urinary M-protein 
by >90% or to < 200 mg/24 h 
 
If the serum and urine M-protein are unmeasurable,3 a > 50% decrease in the 
difference between involved and uninvolved FLC levels is required in place of 
the M-protein criteria 
 
If serum and urine M-protein are not measurable, and serum free light assay is 
also not measureable, > 50% reduction in plasma cells is required in place of M-
protein, provided baseline bone marrow plasma cell percentage was > 30% 
 
In addition to the above listed criteria, if present at baseline, a > 50% reduction 
in the size of soft tissue plasmacytomas is also required 
Stable Disease 
 
Not meeting criteria for CR, VGPR, PR or progressive disease 
MR 
 
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1. 
Adapted from Durie BGM, et al. Leukemia 2006; 20: 1467-1473;  
All response categories (CR, sCR, VGPR, and PD) require two consecutive assessments made at anytime 
before the institution of any new therapy; complete response and PR and SD categories also require no 
known evidence of progressive or new bone lesions if radiographic studies were performed.  VGPR and 
CR categories require serum and urine studies regardless of whether disease at baseline was measurable 
in serum, urine both or either.  Radiographic studies are not required to satisfy these response 
requirements. Bone marrow assessments need not be confirmed.  For progressive disease, serum M-
component increases of ≥ I gm/dl are sufficient to define response if starting M-component is ≥ 5 g/dl.     
 
IMWG clarification for coding PD:  Clarified that Bone marrow criteria for PD are to be used only in 
patients without measurable disease by M protein and by FLC levels.  Clarified that 25% increase refers 
to M protein, FLC, and bone marrow results and does not refer to bone lesions, soft tissue plasmacytomas 
or hypercalcemia.  Note the lowest response value does not need to be a confirmed value. 
 
 
protein by 50 to 89% which still exceeds 200 mg per 24 hr 
 
In addition to the above criteria, if present at baseline, 25-49% reduction in the 
size of soft tissue plasmacytomas is also required 
 
No increase in size or number of lytic bone lesions (development of 
compression fracture does not exclude response) 
Progressive 
disease 
Increase of > 25% from lowest response value in any one of the following: 
 
Serum M-component (the absolute increase must be > 0.5 g/dL) and/or  
 
Urine M-component (the absolute increase must be > 200 mg/24h) and/or  
 
Only in patients without measurable serum and urine M-protein, the difference 
between involved and uninvolved FLC levels. The absolute increase must be > 10 
mg/dL 
 
Only in patients without measurable serum and urine M-protein and without 
measurable disease by  FLC levels, bone marrow plasma cell percentage (absolute % 
must be ≥ 10%)  
 
Definite development of new bone lesions or soft tissue plasmacytomas or definite 
increase in the size of existing bone lesions or soft tissue plasmacytomas 
 
Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL ) that can be 
attributed solely to the plasma cell proliferative disorder 


  
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Appendix 15.5:  City of Hope Data Coordinating Center Plan 
 
 
City of Hope 
Data Coordinating Center 
 
City of Hope has been designated to oversee this trial as the Data Coordinating Center. 
 
This document will serve as guidance as to the responsibilities of the Data Coordinating Center, 
as well as those of the participating sites. 
 


  
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City of Hope Data Coordinating Center Responsibilities 
There are multiple responsibilities associated with serving in the capacity of a data coordinating 
center.  The City of Hope Data Coordinating Center within the Division of Clinical Research 
Information Support (CRIS) has adequate resources and expertise to carry out these 
responsibilities: 
 
1. Assist with the design and development of the initial protocol, subsequent amendments 
and template informed consent documents for use at each participating institution (as 
applicable).   
2. Selecting appropriately qualified participating sites/principal investigators (as applicable). 
3. Ascertaining each protocol is reviewed and approved by the IRB at the participating site 
prior to enrollment of subjects at that site. 
4. Ensuring, if the study is federally funded, that each collaborating institution holds an 
applicable OHRP-approved Federal Wide Assurance (FWA).   
5. Collecting and maintaining critical documents for the Trial Master File from participating 
investigators, e.g. resume/CV, medical license, certification of completion of training (as 
applicable), laboratory certifications and laboratory norms, financial disclosure forms, 
etc.  Maintaining the file throughout the course of the trial. 
6. Distribution of Regulatory Document Binder template to participating sites.  A 
standardized regulatory document template will be sent out to the sites that includes filing 
of all essential documents for the trial.  A standard table of contents and tabbed dividers 
will be provided to the participating site prior to the protocol initiation meeting.   
7. Storing and/or managing data and data and safety monitoring. 
8. Protecting the confidentiality of data received from participating sites in accordance with 
HIPAA.   
9. Ensuring informed consent is obtained and documented from each subject in compliance 
with US regulations. 
10. Maintaining documentation of all participating site IRB approvals for the protocol 
(including all subsequent amendments).  Ensuring that participating sites are using the 
correct version of the protocol and consent document.  
11. Assuring that all relevant IRB correspondence (continuing review and amendments) and 
study status changes are communicated to all participating sites in a timely basis. 
12. Providing study specific training to the research personnel at the participating site, both at 
trial initiation and throughout the course of the trial (re-training as needed).  Training will 
include but not be limited to:  protocol background, inclusion/exclusion, registration 
procedures, treatment schema, dose modification guidelines, AE/SAE/UP reporting 
guidelines, investigator/staff responsibilities, subsequent amendment changes, etc.  The 
training will be documented and will be continuous throughout the course of the trial.  
13. Developing and providing protocol specific case report forms for each participating site 
(paper and/or EDC).  Training of staff on case report forms at study initiation.  Continued 
training of participating site staff if any new changes occur to case report forms during 
length of study. 
14. Centrally registering/randomizing subjects and tracking subject enrollment for all 
subjects. 
15. Tracking, reporting and maintaining documentation of all serious adverse events and 


  
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unanticipated problems and dissemination of the information to participating sites for 
submission to their local committees (as applicable). 
16. Providing periodic updates to study sponsor and participating sites on subject enrollment, 
general study progress, and relevant scientific advances either via email distribution or 
via teleconferences. 
17. Preparation and coordination of teleconferences on an as needed basis (may be weekly, 
bi-weekly, monthly or quarterly). 
18. Primary liaison for participating sites with continuous and frequent communication via 
email and/or teleconference to ensure protocol is running smoothly, questions have been 
answered and documenting any issues.  Addressing issues with study sponsor 
immediately. 
19. Documenting receipt, shipment and storage of study specimens, drugs and/or devices (if 
applicable). 
20. Conducting continuous quality assurance checks of database, as well as protocol 
adherence on periodic basis (remote). 
21. Monitoring, on a periodic basis, either onsite or remotely of the participating sites to 
assess research study progress and compliance with the IRB approved protocol.   
22. Securing compliance at participating sites that are not adhering to the current version of 
the research protocol and/or good clinical research practices.  
23. Terminating the involvement, if necessary, of non-compliant investigators and reporting 
such action to the IRB.  
 
Responsibilities of the Participating Site Principal Investigators 
 
1. Signs Form FDA 1572 to acknowledge responsibilities as defined by the regulations.  
2. Provides the Data Coordinating Center and/or sponsor with required information that 
either attest to the absence of financial interests or arrangements as described in the Code 
of Federal Regulations (21. CFR 54.4) and reported on form FDA 3454 that is completed 
by the sponsor or provides the sponsor a complete and accurate disclosure of financial 
interests and arrangements as described in the regulations (21. CFR 54.4) and reported on 
form FDA 3455 that is completed by the sponsor.  
3. Supervises members of the research team that are qualified by their education and 
training to accept these responsibilities for study related activities not directly performed 
by the PI.  
4. Ensures the safety and welfare of study subjects by being knowledgeable about ongoing 
study protocols and investigator articles.  
5. Participates as appropriate in the hiring and training of individuals recruited as members 
of the research team.  
6. Ensures that specific sponsor requirements of the PI are fulfilled as requested.  
7. Meets with the data coordinating center’s and/or sponsors’ representative as appropriate 
to discuss planned and ongoing studies.  Participates in regularly scheduled 
teleconferences to discuss site specific information, including but not limited to:  patient 
status, data collection, adverse event reporting, etc. 
8. Ensures the participating site completes required data collection in a timely fashion 
and/or as spelled out in protocol. 
9. Meets with auditors (sponsor, FDA, etc.) at the conclusion of their audits to review 


  
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findings (if applicable). 
 
Each participating sites individual investigator must adhere to the following requirements in 
order to participate in the conduct of clinical trials with City of Hope:    
 
 To review the Belmont report, Ethical principles and Guidelines for the Protection of 
Human Subjects of Research, the U.S. Department of Health and Human Services 
(DHHS) and FDA regulations for the protection of human subjects at 45 CFR 46, 21 
CFR50, 56, 312 and 812; the COH Federal Wide Assurance; and, the COH institutional 
policies and procedures for the protection of human subjects, located at the COH IRB 
website through the COH Intranet (a copy will be distributed to participating sites). 
 To understand and accept the responsibility to comply with the standards and 
requirements stipulated in the above documents and in the study protocol and to protect 
the rights and welfare of human subjects involved in research.  
 To comply with all other applicable federal, international, state and local laws, 
regulations, and policies that may provide additional protection for human subjects 
participating in research.  
 To abide by all determinations of the COH IRB and to accept the final authority and 
decisions of the COH IRB, including but not limited to directives to terminate 
participation in designated research activities.  
 To complete any educational training required by the COH (including by the Data 
Coordinating Center) and/or the COH IRB prior to initiating research.  
 To report promptly to the COH DCC any proposed changes in the research.  These must 
be reviewed and approved by the COH IRB. 
 To NOT initiate changes in the research without prior COH IRB review and approval, 
except where necessary to eliminate apparent immediate hazards to subjects. 
 To report promptly to the COH PI any serious adverse events and/or unanticipated 
problems involving risks to subject or other as defined in the protocol and in accordance 
with COH policies and procedures. 
 To obtain, document and maintain records of informed consent for each subject (when 
responsible for enrolling subjects) or each subject’s legally authorized representative as 
required under DHHS and FDA regulations (or any other national procedural standards) 
as stipulated by the COH IRB. 
 To acknowledge and agree to cooperate in the COH IRB’s responsibility for initial and 
continuing reviews, record keeping and for internal and external research regulatory 
reporting requirements.  
 To provide all information requested by the COH IRB in a timely fashion.  
 To comply with all applicable FA regulations and fulfill all investigator responsibilities, 
including those described at 21 CFR 312 (IND regulations) and 812 (IDE regulations) 
when conducting research involving FDA regulated. 
 To NOT enroll patients in research prior to review and approval by the COH IRB of the 
protocol and then subsequent review/approval at the participating site. 
 To acknowledge that he/she is primarily responsible for safeguarding the rights and 
welfare of each research subject and that the subject’s rights and welfare must take 
precedence over the goals and requirements of the research.  
 To inform the COH/PI of important changes taken regarding membership status 


  
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of the participating site, investigators and other research staff personnel.    
 To agree to communicate with the COH/PI in a timely manner.  
 To agree that COH Data Coordinating Center staff will train current and/or new 
research personnel in protocol management and data collections.  
 To agree to on-site and/or remote monitoring of all relevant data by COH Data 
Coordinating Center staff to assure compliance with protocol requirements and quality of 
the data.  This will entail submission of all source documentation as requested by the 
COH DCC. 
 To agree to remote review of source documentation as requested by the COH DCC staff. 
 To participate in weekly teleconference calls (if applicable), to attend a quarterly group 
meeting (if applicable) and to attend an annual group meeting (if applicable), put together 
by the COH DCC. 
 To submit all required data according to the protocol data submission schedule in a 
timely manner. 
 To notify immediately the COH Data Coordinating Center upon notification of any 
external audit. 


  
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Responsibilities of the Participating Site Study Coordinator, Clinical Research Associate 
and/or Data Manager  
 
1. Responsible for the sound conduct of the clinical trial, including but not limited to 
recruitment, screening, enrollment, treatment and follow-up of eligible subjects 
according to protocol requirements (e.g., subject follow-up, case report form completion 
in a timely fashion and reporting of adverse events, unanticipated problems).  
2. Responsible for the maintenance of accurate and complete documentation including 
signed informed consent forms, source documentation, subject logs and study-related 
communications.   
3. Responsible for the organizational management of all aspects of the trial including but 
not limited to overseeing timeliness in completing case report forms, reporting serious 
adverse events, managing caseload and managing study files.  
4. Communicates all protocol-related issues/problems to the appropriate team members, 
including but not limited to questions regarding the conduct of the clinical trial, concern 
regarding possible Serious Adverse Events/Adverse Events/Unanticipated Problems 
(SAE/AE/UP) or subject compliance.  
5. Develops organizational aids and checklists to facilitate patient recruitment and 
enrollment as well as the collection of complete and accurate study data.  
6. Enrolls subjects in studies and manages their participation according to ethical, 
regulatory and protocol-specific requirements. 
7. Tracks study enrollment. 
8. Maintains study files for each study subject.  
9. Maintains confidentiality of study subject’s identity.  
10. Participates in quality assurance activities (onsite and/or remote monitoring visits 
(including submission of de-identified source documents for remote monitoring), 
internal audits, sponsor audits, FDA audits.  
 
Responsibilities of the Participating Site Regulatory Office and/or Designee 
 
1. Responsible for protocol submission – initial protocol, informed consent and subsequent 
amendments. 
2. Responsible for communication to the City of Hope Data Coordinating Center any 
questions related to the regulatory document submission process at their participating 
site. 
3. Maintains the regulatory documentation and regulatory files for each applicable research 
project at the participating site.   
4. Maintains the Regulatory Document Binder distributed by City of Hope’s Data 
Coordinating Center locally.  Ensures all documentation is up to date and filed in a timely 
fashion. 
5. Submits institutional review board approvals for initial protocol submission as well as 
subsequent amendments to the City of Hope Data Coordinating Center.   
6. If applicable, submits serious adverse events and/or unanticipated problems to their local 
regulatory committees, and sends appropriate copies to the Data Coordinating Center as 
spelled out in the protocol. 
 


  
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Required Documents to be Sent by Participating Site to the City of Hope Data 
Coordinating Center Prior to Site Activation 
 
1. Participating site’s Investigational Review Board (IRB) approval letter for initial protocol 
and consent form. All correspondence between the IRB and study site will be maintained 
at the study site in the regulatory binder. 
2. Completed FDA1572 that includes all investigators who will participate in the clinical 
trial along with current signed and dated CV, copy of medical license for each 
investigator and Human Subjects Research and HIPAA training records and 
certifications. 
a. FDA1572 will be updated if changes/additions occur and a copy is to be sent to 
the Data Coordinating Center. 
3. Financial Disclosure (FDA3455) 
4. Delegation of Authority Form  
a. The delegation of authority form will be completed for all study personnel which 
will include the name, signature, and initials of all personnel signing Case Report 
Forms (CRFs), whether paper or in EDC. 
5. Laboratory Certification 
a. The participating site will submit to the Data Coordinating Center all laboratory 
certifications from their institution as well as a copy of the normal ranges.  A copy 
of the laboratory director’s CV and medical license will also be submitted and 
kept on file. 
6. Local IRB membership list 
7. The Data Coordinating Center will complete a trial initiation checklist indicating all 
requirements for the study (including training of participating site) and the regulatory 
binder have been met prior to initiation/activation of the study at the participating site.  A 
template for what is to be filed will be sent to each participating site.  The site will 
maintain documents and send copies to the COH DCC. 
 
Training: 
 
COH Data Coordinating Center staff will be responsible for training research personnel at 
every participating site.    
 
The COH Data Coordinating Center will also provide participating sites with a complete study 
roster that includes who to contact for any questions.  This roster will be updated (as needed) 
throughout the course of the trial and distributed to sites. 
 
Training will be conducted either on-site and/or at City of Hope or via teleconference.  The 
following training will be completed at different time-points and/or as needed:   
 
 Initial training of current research personnel during site initiation visit (via 
teleconference) on protocol management and data collection; 
 Interim training on data collection on new case report forms as specified per 
protocol.    
 Subsequent training of any new staff at participating sites. 


  
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Training components will include, but are not limited to protocol management, screening 
procedures, inclusion/exclusion criteria, randomization, study calendar, study procedures, 
investigational product, treatment plan, AE monitoring, dose modification, guidelines of SAE 
reporting, 
data 
submission 
schedule, 
eligibility 
checklist, 
informed 
consent 
process/documentation of informed consent (when applicable), and data collection training on all 
CRFs as required per protocol.   This may include training on GCP guidelines to ensure 
compliance with all applicable rules and regulations.  Training will also include review of all 
items needed in regulatory binder. 
 
Data Collection Instruments: 
 
1. Data for this trial will be collected using Medidata RAVE, City of Hope’s electronic 
capture system. 
2. Medidata RAVE is a web based, password protected system.  It is fully compliant with 
global regulatory requirements, including 21CRF Part 11 compliant. 
3. Participating staff will be required to complete an Account Activation Form (AAF) to 
obtain access to the Medidata RAVE system once IRB approval documentation is 
received. 
4. Participating site staff will obtain log in information once they fax in the required AAF. 
5. Once their AAF is received, the participating site staff will receive their individual login 
information. 
6. The participating site staff (whether Principal Investigator or the staff collecting data at 
site) are required to take an eLearning Module within Medidata RAVE in order to obtain 
full access. 
7. The participating site staff will receive training via teleconference by COH DCC staff to 
review eCRFs that are specific to this protocol.  Continuous training will be offered to 
participating sites if any amendments affect changes to the eCRFs during the course of 
the trial. 
8. The eCRFs within Medidata RAVE for this trial will have detailed instructions in the 
form of Help Text that provide instructions for completing each required field on each 
form. 
9. Participating sites will be required to complete data collection within Medidata RAVE in 
a timely manner.  Data will be expected to be completed within 2 weeks of each subject 
visit (or as per the study protocol – if needed sooner).   
a. The Data Coordinating Center will run monthly data expectation reports that will 
list any outstanding and overdue data. 
b. The Data Coordinating Center will send via email to the participating site a report 
monthly on any missing and/or overdue data forms.  The participating site will be 
required to complete the missing and/or overdue data forms within 1 week of 
receipt of the report. 
c. If the data is not completed, the Data Coordinating Center will reach out to the 
participating site’s Principal Investigator and site staff to ensure prompt 
completion of data.   
d. If any issues continue, the Data Coordinating Center will communicate with the 
sponsor with the hope to reach out to the participating sites in order to resolve any 


  
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issues. 
10. Query reports will be generated on a monthly basis by the Data Coordinating Center. 
a. The Data Coordinating Center will send via email to the participating site a report 
monthly on any outstanding queries.  The participating site will be required to 
complete the queries within 2 weeks of receipt of the report. 
b. If the queries have not been resolved in a timely manner, the Data Coordinating 
Center will reach out to the participating site’s Principal Investigator and site staff 
to ensure prompt resolution of the queries and/or to discuss an extension on the 
due date. 
c. If the queries have not been completed in a timely manner, after discussion with 
the participating site’s Principal Investigator and site staff, the Data Coordinating 
center will communicate with the sponsor with the hope of resolving any issues. 
 
General Instructions for Completing Case Report Forms: 
 
1. All data recorded on case report forms must be verifiable in the source documents 
maintained at the participating site.  Source documents refer to all notes and reports 
contained in the subject’s medical record. 
2. When completing the initial eligibility checklist, participating sites are asked to print and 
use black ink. 
3. The subject must not be identified by name on any study document.  If a form such as a 
radiographic report or lab report is submitted, the subject’s name must be obliterated and 
replaced with the subject’s initials and registration number. 
4. All dates must be verifiable by source documents.   
 
Data Transmission:  
 
1. Registration documents including eligibility checklist, demographics and corresponding 
source documentation will be sent to the Data Coordinating Center via fax or via City of 
Hope’s Secure Mail system in order to ensure proper registration/randomization of each 
subject.  As this information may contain identifiers (patient name, medical record 
number, date of birth, sex, race, ethnicity, zip code as required for internal registration), it 
is imperative that participating sites either fax this data OR use the Secure Mail route by 
typing #secure# in the email subject line.  All participating sites will be sent out the City 
of Hope Secure Mail guide. 
2. All subjects will be granted a protocol specific number (i.e., COH-001, CED-001) that 
will be assigned by the COH Data Coordinating Center. 
3. Subsequent data collection then will take place via the web-based Medidata RAVE 
system.  Participating sites will need to ensure they have the capability and access to a 
computer and the internet in order to complete data collection. 
4. The Data Coordinating Center will at times need to contact the participating site to obtain 
information but will always refer to the protocol specific patient number. 
 
Data Analysis:  
 
Joycelynne M. Palmer, PhD, is responsible for data analysis. Details regarding the study design 


  
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and planned analyses can be found in section 10.0 of the protocol document. 
 
Quality Assurance and Monitoring 
 
1. The COH Data Coordinating staff will monitor each protocol conducted at participating 
sites to verify that the rights and well-being of human subjects are protected, the 
reported trial data are accurate, complete and verifiable from source documents, and 
that the conduct of the trial is in compliance with the currently approved 
protocol/amendment(s) with the GCP and with applicable regulatory requirements.  The 
COH Data Coordinating Center will determine the appropriate extent and nature of the 
monitoring based on considerations such as study objective, purpose, design, 
complexity, blinding, size and endpoints of the trial.  A trial may require onsite 
monitoring at the participating site or may be subject to remote monitoring.  Remote 
monitoring will involve the participating site submitting de-identified source 
documentation to the COH Data Coordinating Center.  Monitoring of that data will be 
done at COH by assuring the data captured onto CRFs is the same as the source 
documentation submitted.   
2. Each IRB approved protocol will undergo monitoring evaluations by the COH Data 
Coordinating Center staff at varying time points as determined by the Division of 
Clinical Research Information Support.  A trial may require onsite monitoring at the 
participating site or may be subject to remote monitoring.  Remote monitoring will 
involve the participating site submitting de-identified source documentation to the COH 
Data Coordinating Center.  Monitoring of that data will be done at COH by assuring the 
data captured onto CRFs is the same as the source documentation submitted.  
3. In addition, COH research personnel from the Office of Clinical Research Auditing & 
Monitoring may audit protocol compliance at participating sites at intervals decided by 
the coordinating center and their office.  Auditing is dependent upon the protocol’s phase, 
accrual rate, IND status, and results of previous evaluations.   
4. Participating sites will be informed of intended monitoring evaluations in a timely 
manner prior to the proposed visit and/or request for remote monitoring.  When informed 
of an impending monitoring evaluation (either onsite or remotely) by COH staff, the 
participating site is required to prepare for the visit by including but not limited to:  1) 
providing adequate, private space for COH staff to conduct the evaluation, 2) having a 
contact person available for periodic questions, 3) providing the medical record or 
applicable documentation for each subject monitored on the day of the visit, 4) providing 
an organized collection of regulatory documents pertaining to the study,  5) flagging all 
source documents pertinent to data collections; and/or 6) de-identifying and submitting to 
the Data Coordinating Center all source documentation for subjects.  Following any 
evaluation, an estimate of the next monitoring visit (whether onsite or remote) will be 
given to the participating site staff.   
5. The DCC will compare the subject’s records and other supporting documents with the 
data entered on the CRFs (paper or electronic).     
6. The DCC will ensure: 
 
a. That the information recorded is complete and accurate. 


  
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b. That there are no omissions of specific data elements such as the administration to 
any subject of concomitant test articles or the development of an intercurrent 
illness. 
c. Missing visits and examinations are noted in the records. 
d. Subjects failing to complete the study and the reason for each failure are noted. 
e. There is an original fully executed informed consent document in the subject 
record. 
f. That study subjects initial (and subsequently thereafter, if applicable) met 
protocol mandated eligibility criteria for study participation. 
g. That proper procedures were followed in obtaining informed consent from study 
subjects, as dictated by local regulatory guidelines (and may be subject to 
differences internationally). 
h. That source data/documents and other trial records are accurate, complete, up-to-
date and maintained. 
i. That the participating site investigator provides all the required reports, 
notification, applications and submissions. 
j. That these documents are accurate, completely, timely, legible and dated. 
 
7. The Data Coordinating center will specifically verify that: 
 
a. The data required by the protocol are reported accurately on the CRF and are 
consistent with the source data/documents. 
b. Any dose and/or therapy modifications are well documented for each of the trial 
subjects. 
c. Adverse events, serious adverse events, concomitant medications and inter-
current illnesses are reported in the CRFs in accordance with the protocol. 
d. That study procedures were performed in adherence to the protocol document and 
that deviations from written procedures were discovered and properly reported to 
the IRB. 
 
8. The findings from the visit (whether on-site or remote) will be presented to the 
participating site in the form of a detailed, written report.  This report will include a 
summary of what was reviewed and any findings concerning significant deficiencies and 
actions recommended for compliance.  The report will be provided to appropriate 
participating site staff within 21 days of the evaluation completion.  The participating site 
staff is required to provide a written response to the findings with the corrective plan of 
actions within 14 days upon receipt of the report (if corrective action is suggested). 
 
Adverse Event/Serious Adverse Event/Unanticipated Problem Reporting 
 
1. The Data Coordinating Center will be responsible for tracking, reporting and maintaining 
documentation of all serious adverse events and unanticipated problems and 
dissemination of the information to participating sites. 
2. The Data Coordinating Center will be responsible for reporting of adverse event data to 
the study sponsor (as required). 
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Section 11.0 of the protocol, as well as to report per their local institutional guidelines. 
4. The Data Coordinating Center will be responsible for distributing DSMC 
findings/updates/reviews to the participating sites for submission as per their local 
guidelines (if applicable).