A Phase I/II Study of Pomalidomide, Dexamethasone and Ixazomib vs. Pomalidomide and Dexamethasone for Patients With Multiple Myeloma Relapsing on Lenalidomide as Part of First Line Therapy
Phase: PHASE1
Conditions: Multiple Myeloma in Relapse
Sponsor: Alliance for Clinical Trials in Oncology

 
1 
Update #09 
 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
_________________________________________ 
PROTOCOL UPDATE TO ALLIANCE A061202 
_________________________________________ 
 
A PHASE I/II STUDY OF POMALIDOMIDE, DEXAMETHASONE AND IXAZOMIB VS. POMALIDOMIDE AND 
DEXAMETHASONE FOR PATIENTS WITH MULTIPLE MYELOMA RELAPSING ON LENALIDOMIDE AS PART 
OF FIRST LINE THERAPY 
 
Pomalidomide (NSC #767909, IND #120020) is supplied by Celgene Corporation and distributed by McKesson 
Specialty Pharmacy. 
Ixazomib (NSC #767907, IND #120020) is supplied by Millennium Pharmaceuticals and distributed by McKesson 
Specialty Pharmacy. 
Dexamethasone is commercially available. 
 
 
 
 
 
 
X Update: 
 
 
Status Change: 
 
 
 
 
 
 
Eligibility changes 
 
 
Activation 
 
 
 
 
 
 
Therapy / Dose Modifications / Study Calendar changes 
 
 
Closure 
 
 
 
 
 
X Informed Consent changes 
 
 
Suspension / temporary closure 
 
 
 
 
 
 
 
Scientific / Statistical Considerations changes 
 
 
Reactivation 
 
 
 
 
 
 
 
Data Submission / Forms changes 
 
 
 
 
 
 
 
 
 
Editorial / Administrative changes 
 
 
 
 
 
 
 
 
X Other: Pomalidomide CAEPR update 
 
 
 
 
 
The changes included in this update to A061202 have been made in response to the NCI Action Letter 
from 
This Action Letter is posted on the A061202 study page on the Alliance 
and CTSU websites. A revised CAEPR for pomalidomide with new risks has been added to the 
protocol. Therefore, the model consent form has been revised to incorporate these new risks, consistent 
with the NCI Model Consent Template instructions. There are no changes to the risk/benefit ratio. 
 
The proposed changes in this amendment are minor and do not affect the overall risk/benefit ratio. 
IRB approval (or disapproval) is required within 90 days. Expedited review is allowed. Please follow 
your local IRB guidelines.  
 
Re-consent is not required by the Alliance. Please follow the policy of your IRB of record regarding 
notifying patients of new information contained in this update. 
 

 
2 
UPDATES TO THE PROTOCOL: 
Section 9.3 (Comprehensive Adverse Events and Potential Risks List (CAEPR) for Pomalidomide 
(CC-4047, NSC 767909)) 
This section has been revised to include the updated pomalidomide CAEPR (Version 2.4, May 22, 2022) 
provided by CTEP. Changes from Version 2.3 to Version 2.4 include the following: 
 
Added New Risk:  
- 
Rare but Serious: Nervous system disorders - Other (Progressive multifocal 
leukoencephalopathy) 
- 
Also Reported on Pomalidomide Trials But With Insufficient Evidence for Attribution: Atrial 
fibrillation; CD4 lymphocytes decreased; CPK increased; Chest wall pain; Colonic 
perforation; Death NOS; Disease progression; Dysphasia; Erythema multiforme; Eye 
disorders - Other (eyelid swelling); Hematuria; Hyperuricemia; Ischemia cerebrovascular; 
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other (multiple 
myeloma, myelofibrosis, progression of MM); Seizure; Tumor pain; Vascular disorders - 
Other (hyperviscosity syndrome) 
 
 
Increase in Risk Attribution: 
- 
Changed to Likely from Less Likely: Anemia 
 
 
Decrease in Risk Attribution:  
- 
Changed to Rare but Serious from Less Likely: Anorexia; Bone pain; Cough; Dizziness; 
Dyspnea; Nausea; Rash maculo-papular; Thromboembolic event 
- 
Changed to Also Reported on Pomalidomide Trials But With Insufficient Evidence for 
Attribution from Less Likely: Creatinine increased; Headache; Hypercalcemia; Muscle 
cramp; Pruritus; Tremor; Vomiting; White blood cell decreased 
- 
Changed to Also Reported on Pomalidomide Trials But With Insufficient Evidence for 
Attribution from Rare but Serious: Blood and lymphatic system disorders - Other (sickle 
cell anemia with crisis); Febrile neutropenia; Sinus tachycardia 
 
 
Deleted Risk:  
- 
Less Likely: Alkaline phosphatase increased; Aspartate aminotransferase increased; Non-
cardiac chest pain 
- 
Also Reported on Pomalidomide Trials But With Insufficient Evidence for Attribution: 
Abdominal distension; Atrioventricular block complete; Hypertension; Hyperthyroidism; 
Hypomagnesemia; Hypophosphatemia; Memory impairment; Pain; Peripheral motor 
neuropathy; Urticaria 
 
_____________________________________________________________________________________ 
 
UPDATES TO THE PHASE I MODEL CONSENT: 
What possible risks can I expect from taking part in this study? 
Based on the updated CAEPR described above, the following changes have been made to the NCI 
condensed risk profile for pomalidomide (found under “Possible Side Effects of Pomalidomide”): 

 
3 
 
Added New Risk: 
- 
Rare: Abnormal unpleasant sensation; Damage to the brain which may cause changes in 
thinking and may be life-threatening; Feeling of "pins and needles" in arms and legs 
 
 
 
Increase in Risk Attribution 
- 
Changed to Common from Occasional: Anemia which may require blood transfusion 
 
 
Decrease in Risk Attribution:  
- 
Changed to Occasional from Common:  Tiredness 
- 
Changed to Rare from Occasional: Blood clot which may cause swelling, pain, shortness of 
breath; Cough, shortness of breath; Nausea; Headache; Rash 
- 
Changed to Also Reported on Pomalidomide Trials But With Insufficient Evidence for 
Attribution from Occasional (i.e., removed from the Risk Profile): Vomiting; Abnormal body 
movement; Itching 
- 
Changed to Also Reported on Pomalidomide Trials But With Insufficient Evidence for 
Attribution from Rare (i.e., removed from the Risk Profile): Abnormal heartbeat; Sickle cell 
anemia with crisis 
 
 
Provided Further Clarification:  
- 
Infection, especially when while blood cell count is low (under Occasional) is now reported 
as Infection (under Occasional). 
 
UPDATES TO THE PHASE II MODEL CONSENT: 
What possible risks can I expect from taking part in this study? 
Based on the updated CAEPR described above, the following changes have been made to the NCI 
condensed risk profile for pomalidomide (found under “Possible Side Effects of Pomalidomide”): 
 
Added New Risk: 
- 
Rare: Abnormal unpleasant sensation; Damage to the brain which may cause changes in 
thinking and may be life-threatening; Feeling of "pins and needles" in arms and legs 
 
 
 
Increase in Risk Attribution 
- 
Changed to Common from Occasional: Anemia which may require blood transfusion 
 
 
Decrease in Risk Attribution:  
- 
Changed to Occasional from Common:  Tiredness 
- 
Changed to Rare from Occasional: Blood clot which may cause swelling, pain, shortness of 
breath; Cough, shortness of breath; Nausea; Headache; Rash 
- 
Changed to Also Reported on Pomalidomide Trials But With Insufficient Evidence for 
Attribution from Occasional (i.e., removed from the Risk Profile): Vomiting; Abnormal body 
movement; Itching 
- 
Changed to Also Reported on Pomalidomide Trials But With Insufficient Evidence for 
Attribution from Rare (i.e., removed from the Risk Profile): Abnormal heartbeat; Sickle cell 
anemia with crisis 
 
 
Provided Further Clarification:  
- 
Infection, especially when while blood cell count is low (under Occasional) is now reported 
as Infection (under Occasional). 

 
4 
 
 
Replacement protocol and model consent documents have been issued. 
This study remains closed to new patient accrual. 
 
____________________________________________________________ 
 
ATTACH TO THE FRONT OF EVERY COPY OF THIS PROTOCOL 
____________________________________________________________ 

 
Version Date: 08/17/2022 
1 
Update #09 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
 
ALLIANCE A061202 
 
A PHASE I/II STUDY OF POMALIDOMIDE, DEXAMETHASONE AND IXAZOMIB VS. POMALIDOMIDE AND 
DEXAMETHASONE FOR PATIENTS WITH MULTIPLE MYELOMA RELAPSING ON LENALIDOMIDE AS PART 
OF FIRST LINE THERAPY 
 
Clinicaltrials.gov identifier: NCT02004275 
 
The Phase I portion will be a limited access study, available to the following institutions (the Phase II portion is 
open to all Alliance member institutions) 
Limited Access Participating Institutions (ALL ARE ALLIANCE Institutions): NC007/UNC Lineberger 
 
 
 
Pomalidomide (NSC #767909, Alliance IND #120020) is supplied by Celgene Corporation and distributed by McKesson 
Specialty Pharmacy. 
Ixazomib (NSC #767907, Alliance IND #120020) is supplied by Millennium Pharmaceuticals and distributed by McKesson 
Specialty Pharmacy. 
Dexamethasone is commercially available. 
Study Chair 
 
 
 
 
 
 
 
 
Myeloma Committee Chair 
Myeloma Committee Co-Chair 
Community Oncology Co-chair 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Correlative Committee Chair 
Correlative Study Co-Chair 
ECOG Champion 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary Statistician 
Secondary Statistician 
 
 
 
 
 
 
 
Protocol Coordinator 
Data Manager 
 
 
 
 
 
 
 
Participating Organizations: ALLIANCE/Alliance for Clinical Trials in Oncology, ECOG-ACRIN/ECOG-
ACRIN Cancer Research Group, SWOG/SWOG

ALLIANCE A061202 
Version Date: 08/17/2022 
2 
Update #09 
Study Resources: 
Expedited Adverse Event Reporting 
 
Medidata Rave iMedidata portal 
 
OPEN (Oncology Patient Enrollment Network) 
 
Biospecimen Management System 
 
 
Protocol Contacts: 
A061202 Nursing Contact 
 
  
 
 
A061202 Pharmacy Contact 
 
 
 
Alliance Biorepository at Ohio State University 
(OSU) 
T
 
 
 
 
 
 
Alliance Hematologic Malignancy 
Biorepository  
 
  
 
 
 
 
 
 
 
Protocol-related questions may be directed as follows: 
Questions 
Contact (via email) 
Questions regarding patient eligibility, 
treatment, and dose modification: 
Study Chair, Nursing Contact, Protocol Coordinator, 
or (where applicable) Data Manager 
Questions related to data submission, RAVE or 
patient follow-up: 
Data Manager  
Questions regarding the protocol document: 
Protocol Coordinator 
Questions related to IRB issues and model 
consent revisions: 
Regulatory Affairs Manager:  
 
Questions regarding CTEP-AERS reporting: 
Pharmacovigilance Inbox 
 
Questions regarding specimens/specimen 
submissions: 
Alliance Biorepository at Ohio State University or 
The Alliance Hematologic Malignancy 
Biorepository  
 
 

 
 ALLIANCE A061202 
Version Date: 08/17/2022 
3 
Update #09 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
For regulatory requirements: 
For patient enrollments: 
For study data submission: 
Regulatory documentation must 
be submitted to the CTSU via the 
Regulatory Submission Portal. 
 
Regulatory Submission Portal: 
(Sign in at 
 and 
select the Regulatory Submission 
sub-tab under the Regulatory tab.) 
 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU Regulatory 
Office immediately at 
 to receive further instruction 
and support. 
 
Contact the CTSU Regulatory 
Help Desk at 
 for 
regulatory assistance. 
Please refer to the patient 
enrollment section for 
instructions on using the 
Oncology Patient Enrollment 
Network (OPEN) which can 
be accessed at 
 
 
 
Contact the CTSU Help Desk 
with any OPEN-related 
questions at 
 
 
Data collection for this study will 
be done exclusively through 
Medidata Rave. Please see the 
data submission section of the 
protocol for further instructions. 
 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific page of the CTSU Member website located at 
Access 
to the CTSU members’ website is managed through the Cancer Therapy and Evaluation Program - 
Identity and Access Management (CTEP-IAM) registration system and requires user log on with 
CTEP-IAM username and password. Permission to view and download this protocol and its supporting 
documents is restricted and is based on person and site roster assignment housed in the CTSU RSS. 
 
For clinical questions (i.e. patient eligibility or treatment-related) see the Protocol Contacts, Page 
2. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail: 
CTSU General Information Line – 
All calls and 
correspondence will be triaged to the appropriate CTSU representative. 
The CTSU website is located at
 
 

ALLIANCE A061202 
Version Date: 08/17/2022 
4 
Update #09 
A PHASE I/II STUDY OF POMALIDOMIDE, DEXAMETHASONE AND IXAZOMIB VS. POMALIDOMIDE AND 
DEXAMETHASONE FOR PATIENTS WITH MULTIPLE MYELOMA RELAPSING ON LENALIDOMIDE AS PART 
OF FIRST LINE THERAPY  
Schema page 1 of 3 
 
 
Eligibility Criteria (see Section 3.0)  
Required Initial Laboratory Values 
 
Histologically confirmed diagnosis of relapsed 
symptomatic multiple myeloma. 
 
Measureable or non-measurable disease (see section 
3.2.2) 
 
Prior Treatment(s) (see section 3.2.3) 
- Progression on lenalidomide 
- Pomalidomide naïve 
- Proteasome inhibitor naïve or sensitive 
- 1 prior line of therapy 
 
Not pregnant and not nursing (see section 3.2.4) 
 
≥18 years of age  
 
ECOG Performance Status 0-2 (see Appendix I) 
 
≤ Grade 2 Peripheral Neuropathy  
 
Adequate cardiac function (see section 3.2.10) 
 
Not on strong inducers or potent inhibitors of 
CYP3A4 or CYP1A2 (see section 3.2.11) 
 
Patients with HIV infection are eligible, provided 
they meet guidelines listed in section 3.2.12 
Absolute Neutrophil 
Count (ANC) 
≥ 1.0 x 109/L 
Platelet Count 
≥ 50 x 109/L 
Calculated Creatinine 
Clearance* 
≥ 30 mL/min 
Total Bilirubin 
< 1.5 x upper limit of 
normal  
AST, ALT 
< 2.5 x upper limit of 
normal  
 
* May be assessed via the Cockcroft-Gault formula 
or 24-hour urine testing (See Appendix II). 
 
 
 

ALLIANCE A061202 
Version Date: 08/17/2022 
5 
Update #09 
A PHASE I/II STUDY OF POMALIDOMIDE, DEXAMETHASONE AND IXAZOMIB VS. POMALIDOMIDE AND 
DEXAMETHASONE FOR PATIENTS WITH MULTIPLE MYELOMA RELAPSING ON LENALIDOMIDE AS PART 
OF FIRST LINE THERAPY  
Schema page 2 of 3 
 
PHASE I (CLOSED AS OF FEBRUARY 4, 2016) 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
    *The dexamethasone dose for patients >75 years of age is 20 mg. 
 
 
 
 
Dose Escalation Schema 
Cohort 
Pomalidomide (mg) 
Ixazomib (mg) 
0 
2 
2.3 
1 
2 
3 
2 
3 
3 
3 
4 
3 
4 
4 
4 
Phase I 
If cohort 2 is the maximum tolerated dose, a dose level 2A will be pursued evaluating a 2 mg dose of 
pomalidomide and 4 mg dose of ixazomib. If cohort 3 is the maximum tolerated dose, a dose level 
3A will be pursued evaluating a 3 mg dose of pomalidomide and 4 mg dose of ixazomib.   
Pomalidomide/Dexamethasone/Ixazomib 
Cycle length: 28 days 
Pomalidomide: Orally once daily on days 1-21 out of 28 days. 
Dexamethasone: 40 mg orally once weekly on days 1, 8, 15, and 22. The dose of dexamethasone for 
patients >75 years of age is 20 mg utilizing the same schedule.  
Ixazomib: Orally once weekly on days 1, 8, and 15. 
Dose escalation will follow a standard 3+3 design (see Section 13.0). Dosing will begin with cohort 
1. Patients may remain on treatment until disease progression, unacceptable toxicity, or withdrawal 
of consent.  
Please Note: For the phase I portion of this study, patient enrollment will be facilitated using the 
Slot-Reservation System in conjunction with the Registration system on Oncology Patient 
Enrollment Network (OPEN). Prior to discussing protocol entry with the patient, all site staff must 
use the CTSU OPEN Slot Reservation System to insure that a slot on the protocol is available to the 
patient. Once a slot reservation confirmation is obtained, site staff may then proceed to enroll patients 
to this study. 
 
28-day cycles 
R
E
G
I
S
T
R
A
T
I
O
N 
Pomalidomide Days 1-21  
Dexamethasone 40 mg Days 1, 8, 15, 22* 
Ixazomib Days 1, 8, 15 

ALLIANCE A061202 
Version Date: 08/17/2022 
6 
Update #09 
A PHASE I/II STUDY OF POMALIDOMIDE, DEXAMETHASONE AND IXAZOMIB VS. POMALIDOMIDE AND 
DEXAMETHASONE FOR PATIENTS WITH MULTIPLE MYELOMA RELAPSING ON LENALIDOMIDE AS PART 
OF FIRST LINE THERAPY  
Schema page 3 of 3 
 
PHASE II 
 
Phase II Treatment  
Arm 1 (Course 1): Pomalidomide + Dexamethasone. 28-day cycles. 
Pomalidomide: 4 mg orally once daily on days 1-21. 
Dexamethasone: 40 mg orally once weekly on days 1, 8, 15 and 22. The dose of dexamethasone 
for patients > 75 years or age will be 20 mg, utilizing the same schedule. 
See Section 7.2 for the Course 2 treatment plan for patients randomized to Arm 1 who opt to 
receive the 3-drug regimen following progression.  
Arm 2: Pomalidomide + Dexamethasone + Ixazomib. 28-day cycles. 
Pomalidomide: 4 mg orally once daily on days 1-21. 
Dexamethasone: 40 mg once weekly on days 1, 8, 15 and 22. The dose of dexamethasone for 
patients > 75 years of age will be 20 mg, utilizing the same schedule. 
Ixazomib: 4 mg orally once weekly on days 1, 8 and 15.  
 
PLEASE REFER TO THE FULL PROTOCOL TEXT FOR A COMPLETE DESCRIPTION 
OF THE ELIGIBILITY CRITERIA AND TREATMENT PLAN. 
PD 
R
E
G
/ 
R
A
N
D
O
M
I
Z
E 
ARM 1 - Course 1 
Pomalidomide + 
Dexamethasone 
ARM 2 
Pomalidomide + 
Dexamethasone + 
Ixazomib 
PD* 
ARM 1 - Course 2 
Pomalidomide + 
Dexamethasone + 
Ixazomib 
Extended 
Follow-up 
PD 
Extended 
Follow-up 
* 
Patients randomized to Arm 1 may opt to switch to the 3-drug regimen following disease 
progression. These patients must be re-registered to the study. Eligibility should be reassessed 
per Section 3.3 prior to re-registration. 
Patients may remain on treatment until disease progression, unacceptable toxicity, or 
withdrawal of consent. 

ALLIANCE A061202 
Version Date: 08/17/2022 
7 
Update #09 
Table of Contents 
 
Section 
Page 
1.0 
BACKGROUND .......................................................................................................................... 9 
1.1 
IMMUNOMODULATORY DRUG/PROTEASOME INHIBITOR COMBINATION THERAPY FOR MULTIPLE 
MYELOMA ............................................................................................................................................... 9 
1.2 
THE RATIONALE FOR THE INCORPORATION OF THE PROTEASOME INHIBITOR IXAZOMIB INTO 
IMID-DEXAMETHASONE-BASED MULTIPLE MYELOMA THERAPY ......................................................... 10 
1.3 
THE EVOLVING ARMAMENTARIUM OF COMBINATION THERAPIES FOR PATIENTS WITH 
RELAPSED OR RELAPSED AND REFRACTORY MULTIPLE MYELOMA WHO HAVE RECEIVED AT LEAST 1 
PRIOR LINE OF THERAPY ....................................................................................................................... 12 
1.4 
POMALIDOMIDE AND DEXAMETHASONE .................................................................................. 14 
1.5 
REGISTRATION QUALITY OF LIFE (QOL) MEASUREMENTS ..................................................... 17 
1.6 
ESTABLISHMENT OF THE MAXIMUM TOLERATED DOSE (MTD) OF POMALIDOMIDE, IXAZOMIB, 
AND DEXAMETHASONE IN PHASE I ....................................................................................................... 17 
2.0 
OBJECTIVES ............................................................................................................................ 18 
2.1 
PRIMARY PHASE I OBJECTIVES ................................................................................................ 18 
2.2 
PRIMARY PHASE II OBJECTIVES ............................................................................................... 18 
2.3 
SECONDARY PHASE I OBJECTIVES ........................................................................................... 18 
2.4 
SECONDARY PHASE II OBJECTIVES .......................................................................................... 18 
2.5 
CORRELATIVE SCIENCE OBJECTIVES FOR PHASE II ................................................................. 19 
3.0 
PATIENT SELECTION ............................................................................................................ 19 
3.1 
ON-STUDY GUIDELINES ........................................................................................................... 19 
3.2 
ELIGIBILITY CRITERIA ............................................................................................................. 20 
3.3 
RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2)................................................................. 23 
4.0 
PATIENT REGISTRATION .................................................................................................... 25 
4.1 
PHASE I REGISTRATION REQUIREMENTS ................................................................................. 25 
4.2 
PHASE II REGISTRATION REQUIREMENTS ................................................................................ 25 
4.3 
PATIENT REGISTRATION/RANDOMIZATION ............................................................................. 25 
4.4 
STRATIFICATION FACTORS (PHASE II) ..................................................................................... 28 
4.5 
REGISTRATION TO CORRELATIVE AND COMPANION STUDIES ................................................. 29 
4.6 
RE-REGISTRATION AT THE TIME OF PROGRESSION (ARM 1 PATIENTS ONLY) ........................... 29 
5.0 
STUDY CALENDAR ................................................................................................................ 30 
5.1 
MAIN STUDY CALENDAR ......................................................................................................... 30 
5.2 
ARM 1 COURSE 2 STUDY CALENDAR ....................................................................................... 32 
6.0 
DATA AND SPECIMEN SUBMISSION ................................................................................. 34 
6.1 
DATA COLLECTION AND SUBMISSION ...................................................................................... 34 
6.2 
SPECIMEN COLLECTION AND SUBMISSION ............................................................................... 34 
7.0 
TREATMENT PLAN/INTERVENTION ................................................................................ 37 
7.1 
PHASE I (DESCRIPTION/TREATMENT PLAN)/ DEFINITION OF DLT ........................................... 38 
7.2 
PHASE II DESCRIPTION/TREATMENT PLAN .............................................................................. 40 
8.0 
DOSE AND TREATMENT MODIFICATIONS..................................................................... 42 
8.1 
ANCILLARY THERAPY, CONCOMITANT MEDICATIONS, AND SUPPORTIVE CARE ....................... 42 
8.2 
DOSE MODIFICATIONS GENERAL PRINCIPLES: ........................................................................ 44 
8.3 
DOSE MODIFICATION GUIDELINES FOR POMALIDOMIDE AND IXAZOMIB: ............................... 46 
8.4 
DOSE MODIFICATION GUIDELINES FOR DEXAMETHASONE: .................................................... 49 

 
 ALLIANCE A061202 
Version Date: 08/17/2022 
8 
Update #09 
8.5 
DOSE MODIFICATIONS FOR OBESE PATIENTS .......................................................................... 49 
9.0 
ADVERSE EVENTS ................................................................................................................. 50 
9.1 
ROUTINE ADVERSE EVENT REPORTING .................................................................................... 50 
9.2 
EXPEDITED ADVERSE EVENT REPORTING (CTEP-AERS) ........................................................ 50 
9.3 
COMPREHENSIVE ADVERSE EVENTS AND POTENTIAL RISKS LIST (CAEPR) FOR 
POMALIDOMIDE (CC-4047, NSC 767909) ............................................................................................ 54 
9.4 
COMPREHENSIVE ADVERSE EVENTS AND POTENTIAL RISKS LIST (CAEPR) FOR IXAZOMIB 
(MLN9708, NSC 767907) .................................................................................................................... 57 
10.0 
DRUG INFORMATION ........................................................................................................... 60 
10.1 
GENERAL CONSIDERATIONS: ................................................................................................... 60 
11.0 
MEASUREMENT OF EFFECT ............................................................................................... 66 
11.1 
SCHEDULE OF EVALUATIONS ................................................................................................... 66 
11.2 
DEFINITIONS OF MEASURABLE AND NON-MEASURABLE DISEASE .......................................... 67 
11.3 
GUIDELINES FOR EVALUATION OF MEASURABLE DISEASE ..................................................... 67 
11.4 
THE IMWG UNIFORM RESPONSE CRITERIA ........................................................................... 68 
12.0 
END OF TREATMENT/INTERVENTION ............................................................................ 70 
12.1 
DURATION OF TREATMENT ...................................................................................................... 70 
12.2 
DISCONTINUATION OF PROTOCOL THERAPY ........................................................................... 70 
12.3 
FOLLOW-UP FOR PATIENTS FOUND TO BE INELIGIBLE ON CASE REVIEW OR CANCEL 
PARTICIPATION PRIOR TO RECEIVING ANY PROTOCOL TREATMENT ...................................................... 71 
13.0 
STATISTICAL CONSIDERATIONS ...................................................................................... 72 
13.1 
PHASE I STUDY DESIGN ........................................................................................................... 72 
13.2 
PHASE I SAMPLE SIZE AND STUDY DURATION ........................................................................ 73 
13.3 
PHASE II STUDY DESIGN FOR PATIENTS ON FIRST LINE THERAPY WITH DISEASE PROGRESSION 
ON LENALIDOMIDE ................................................................................................................................ 73 
13.4 
PHASE II SAMPLE SIZE AND STUDY DURATION ....................................................................... 74 
13.5 
PHASE II ANALYSIS PLANS ...................................................................................................... 74 
13.6 
STUDY MONITORING (REPORTS, SUMMARIES) ......................................................................... 76 
13.7 
PRIMARY ENDPOINT COMPLETION TIME ESTIMATION ............................................................ 76 
13.8 
INCLUSION OF WOMEN AND MINORITIES ................................................................................ 77 
14.0 
CORRELATIVE AND COMPANION STUDIES .................................................................. 78 
14.1 
CORRELATIVE SCIENCE SUBSTUDY ALLIANCE A061202-ST1 ................................................ 78 
15.0 
REFERENCES........................................................................................................................... 83 
APPENDIX I: 
ECOG PERFORMANCE STATUS ........................................................................ 87 
APPENDIX II: 
COCKCROFT-GAULT FORMULA ...................................................................... 88 
APPENDIX III: REGISTRATION FATIGUE/UNISCALE ASSESSMENTS ............................... 89 
APPENDIX IV: CONGESTIVE HEART FAILURE CLASSIFICATION SYSTEM ................... 90 
APPENDIX V: 
CYTOCHROME P450 1A2 INHIBITORS AND CYTOCHROME P450 3A4 
INHIBITORS AND INDUCERS ........................................................................................................... 91 
APPENDIX VI: PATIENT MEDICATION LOGS .......................................................................... 93 
APPENDIX VII PROTEASOME INHIBITORS .............................................................................. 96 
 

ALLIANCE A061202 
Version Date: 08/17/2022 
9 
Update #09 
1.0 
BACKGROUND 
1.1 
Immunomodulatory drug/proteasome inhibitor combination therapy for multiple 
myeloma 
Multiple myeloma is the second most common hematologic malignancy in adults and associated 
with significant mortality and morbidity [1]. Fortunately, the advent of the immunomodulatory 
drugs (IMiDs), thalidomide, lenalidomide, and pomalidomide, and the proteasome inhibitors 
bortezomib and carfilzomib have significantly improved survival of patients with multiple 
myeloma [2-13]. Unfortunately, the majority of patients will experience repeated relapses and 
ultimately succumb to refractory disease. With the rapidly changing therapeutic landscape in 
multiple myeloma, it is imperative that we not only develop novel agents to improve patient 
outcomes, but understand how to better utilize these agents in combination and best sequence 
them in the continuum of myeloma therapy.  
Notable advances have been made in the understanding of optimal combination therapies of 
patients with multiple myeloma. In particular, the clinical activity of IMiD/proteasome inhibitor 
plus dexamethasone triplet combinations has been particularly promising [14-25]. In patients 
with newly-diagnosed multiple myeloma, the combination of bortezomib, thalidomide and 
dexamethasone (VDT) as induction therapy led to an increased overall response rate (ORR) and 
higher rate of deep responses (very good partial responses [VGPRs] or better) compared to either 
the thalidomide-dexamethasone or bortezomib-dexamethasone doublet [18, 24]. Importantly, 
the higher rate of VGPRs and better seen with VDT persisted after high-dose melphalan 
supported by autologous stem cell transplantation (ASCT). In the Cavo study, VDT induction 
and post-ASCT consolidation led to an improvement in progression-free survival (PFS) 
compared with thalidomide and dexamethasone, thus establishing VTD as a standard of care for 
newly-diagnosed, transplant-eligible multiple myeloma patients [18]. VTD has performed well 
in patients with relapsed multiple myeloma, as well. A phase III study comparing VDT to 
thalidomide and dexamethasone was conducted in patients with a first relapse of their multiple 
myeloma after prior ASCT [25]. As such, this was a second line therapy study. Importantly, not 
only was there an improvement in the ORR and rate of VGPRs or better, the median time to 
progression (TTP) was improved with VTD (19.5 vs 13.8 months, hazard ratio [HR] 0.59; P = 
0.001), thus establishing VTD as a standard of care in relapsed multiple myeloma, as well. 
The incorporation of the proteasome inhibitors bortezomib and carfilzomib into the 
lenalidomide-dexamethasone backbone has also led to notable gains in clinical outcomes for 
patients with multiple myeloma. The combination of lenalidomide, bortezomib and 
dexamethasone (RVD) outperformed the lenalidomide-dexamethasone doublet in patients with 
newly-diagnosed multiple myeloma not undergoing ASCT as part of their first line therapy [20]. 
Specifically, the ORR and rate of VGPRs were higher with RVD. This improvement in response 
rate not only translated into an improvement in progression-free survival (PFS, 43 vs 30 months, 
HR 0.712, P = 0.0018)) but in overall survival, as well (75 vs 64 months, HR 0.709, P = 0.025). 
Thus, RVD has become an important standard of care for patients with newly-diagnosed 
multiple myeloma. The RVD regimen has not been studied in relapsed/refractory multiple 
myeloma in the phase III setting. However, for patients with relapsed multiple myeloma who 
had received 1 – 3 prior lines of therapy, the combination of carfilzomib, lenalidomide and 
dexamethasone (CRD) led to an improvement in ORR (87.1% vs 66.7%, P <0.001), rate of 
VGPRs or better (69.9% vs 40.4%, P <0.001) and median PFS (26.3 vs 17.6 months, HR 0.69, 
P = 0.0001) compared with lenalidomide and dexamethasone [21]. It should be noted that 
patients with disease refractory to bortezomib or lenalidomide as part of last line therapy were 
not eligible to participate in this study. Thus, the CRD regimen represents a newer standard of 
care regimen for patients with relapsed multiple myeloma who have received 1 – 3 prior lines 

 
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of therapy and have bortezomib and lenalidomide naïve or sensitive disease. CRD has performed 
well in phase I/II studies of newly-diagnosed multiple myeloma patients [22]. A phase III study 
comparing RVD and CRD in newly-diagnosed multiple myeloma patients not receiving ASCT 
as part of first line therapy is ongoing and will help clarify the relative efficacy and safety of the 
two IMiD / proteasome inhibitor/dexamethasone triplets (NCT01863550).  
1.2 
The rationale for the incorporation of the proteasome inhibitor ixazomib into IMiD-
dexamethasone-based multiple myeloma therapy 
Ixazomib, or MLN9708, is a citrate ester that in aqueous solution and plasma is hydrolyzed to 
the biologically active dipeptide boronic acid proteasome inhibitor, MLN2238. Importantly, 
ixazomib has been formulated for oral administration, making it one of the first orally 
bioavailable proteasome inhibitors in clinical development. Like bortezomib, ixazomib is a 
reversible inhibitor of the β5 subunit of the proteasome. However, ixazomib has a proteasome 
dissociation half-life that is approximately 6-fold faster than bortezomib. This faster dissociation 
half-life is hypothesized to play a role in the ability of ixazomib to distribute to tumors more 
efficiently than bortezomib, owing to the fact that high levels of whole blood proteasome activity 
sequester bortezomib from sites of disease. Indeed, studies have shown an increased blood 
volume of distribution at steady state, increased tumoral proteasome inhibition, and increased 
efficacy of ixazomib compared to bortezomib in pre-clinical models of multiple myeloma [26-
28]. Importantly, synergistic activity with lenalidomide was also seen. Please see the ixazomib 
Investigator’s Brochure for further preclinical information. 
Results from two phase I studies of single agent ixazomib administered on a weekly or twice 
weekly schedule for patients with relapsed and relapsed/refractory multiple myeloma have been 
published. In the twice-weekly dosing study, escalating doses of ixazomib were administered 
on days 1, 4, 8 and 11 of a 21-day cycle. Sixty patients had enrolled on the study and 26 to the 
dose escalation cohorts. The median time from diagnosis was 4.8 years and patients had received 
a median of 4 prior lines of therapy (range 1 – 28). The MTD was 2.0 mg/m2. Of 55 patients 
evaluable for response, 6 had achieved ≥ PRs, 1 had achieved an MR, and 33 patients achieved 
stable disease (SD), thus yielding a disease control rate (DCR, or ≥ SD rate) of 76%. Eighteen 
percent of the patients remained on therapy for ≥ 12 cycles [29]. More common side effects with 
twice weekly dosing included fatigue (40% total, 7% grade 3), thrombocytopenia (42% total, 
37% ≥grade 3), nausea (42%), vomiting (25%), rash (40% total, 8% grade 3) and diarrhea (23%). 
Seventeen percent of patients had peripheral neuropathy, none of which was ≥ grade 3 in severity. 
In the weekly dosing study, escalating doses of single agent ixazomib were administered on days 
1, 8 and 15 of a 28-day cycle. The MTD on this schedule was 2.97 mg/m2. Common AEs 
included thrombocytopenia (43%, ≥ grade 3 33%), neutropenia (22%, ≥ grade 3 18%), diarrhea 
(38%, ≥ grade 3 17%), nausea (38%, ≥ grade 3 7%), vomiting (35%, ≥ grade 3 5%), decreased 
appetite (25%, ≥ grade 3 7%) and fatigue (37%, ≥ grade 3 8%). The rate of peripheral neuropathy 
was 20%, almost all of which was grade 1 or 2 in severity (1 episode of grade 3 and no episodes 
of grade 4 or 5 neuropathy were seen). Rash was seen in 22% of patients, but only 3% 
experienced ≥ grade 3 rash. For those patients treated at the MTD, the ORR was 26%, a 
respectable result for a patient population that had received a median of 4 prior lines of therapy, 
72% of whom were refractory to their last treatment regimen [30]. 
A phase I/II study was conducted evaluating the combination of ixazomib, lenalidomide and 
dexamethasone in newly-diagnosed multiple myeloma [31]. Given a terminal half-life of ~7 
days, a once weekly dosing strategy of ixazomib was chosen for combination therapy (28-day 
cycle: lenalidomide 25 mg days 1-21; dexamethasone 40 mg days 1, 8, 15, 22; and ixazomib 
days 1, 8, 15). The recommended phase II dose (RP2D) of ixazomib was determined to be 2.23 
mg/m2 
when 
combined 
with 
lenalidomide 
and 
dexamethasone. 
Population-based 
pharmacokinetic studies of several ixazomib studies demonstrated that the plasma 

 
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concentration-time profile of ixazomib can be described by a three-compartment model with 
first order elimination process. Body size did not significantly impact AUC or Cmax, supporting 
utilization of flat dosing in future studies. Thus, the recommended phase II dose (RP2D) of 
ixazomib in combination with lenalidomide and dexamethasone was found to be 4.0 mg. For the 
64 evaluable patients, the ORR was 88% with 58% of patients achieving ≥VGPRs and 27% CRs. 
The most common Grade 3/4 AEs included rash (17%), neutropenia (12%), vomiting (6%), back 
pain (7%), thrombocytopenia (8%), anemia (3%), fatigue (9%), diarrhea (6%) and nausea (5%), 
dehydration (3%), hypokalemia (6%), and hypophosphatemia (5%). Peripheral neuropathy was 
seen in 32% of patients (N=21, 4 of which were grade 3 in severity). Importantly, there was no 
PK interaction between ixazomib and lenalidomide. 
The results of a phase III study comparing lenalidomide and dexamethasone to lenalidomide, 
ixazomib and dexamethasone for patients with relapsed and/or refractory multiple myeloma who 
had received 1 – 3 prior lines of therapy were published [32]. It should be noted that patients 
with lenalidomide-refractory disease were not eligible for the study. At the first interim analysis, 
the median PFS for those receiving the 3-drug combination was superior to lenalidomide and 
dexamethasone alone (median PFS 20.6 months versus 14.7 months, respectively, HR 0.742, 
P=0.01). Patients with high risk cytogenetics derived an even greater magnitude of benefit 
(median PFS 21.4 vs 9.7 months, HR 0.54, P = 0.02). Importantly, the addition of ixazomib to 
lenalidomide and dexamethasone was well tolerated, but there was a higher incidence of 
thrombocytopenia, nausea, vomiting, diarrhea, constipation, rash and edema. Peripheral 
neuropathy was seen in 27% of patients receiving the triplet compared with 22% for those 
patients on lenalidomide and dexamethasone. The incidence of grade 3 peripheral neuropathy 
was only 2% in each arm and no grade 4 peripheral neuropathy was seen. Furthermore, the 
incidence of congestive heart failure, acute renal failure, hypertension, interstitial lung disease 
and myocardial infarction was not different between the two arms.  Based on these data, the 
FDA approved the lenalidomide, ixazomib and dexamethasone regimen for myeloma patients 
who have received at least one prior therapy in 11/2015. A phase III study evaluating 
lenalidomide, ixazomib and dexamethasone versus lenalidomide and dexamethasone in patients 
with newly-diagnosed multiple myeloma is ongoing and will help define the role of this triplet 
in the frontline setting (NCT01850524).  
The table below includes adverse events reported by Millennium from studies with ixazomib in 
combination with other agents. Attribution to a specific agent is not assigned. 
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) 

 
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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. 
Subject Incidence: A subject counts once for each preferred term. Percentages use the number 
of treated subjects as the denominator. 
1.3 
The evolving armamentarium of combination therapies for patients with relapsed or 
relapsed and refractory multiple myeloma who have received at least 1 prior line of 
therapy 
1.3.1 Lenalidomide-dexamethasone-based triplets for relapsed multiple myeloma 
Numerous regimens have recently received approval for patients with relapsed or relapsed 
and refractory multiple myeloma who have received 1 or more prior lines of therapy. Four 
triplets have been approved utilizing the lenalidomide-dexamethasone backbone; 
specifically lenalidomide and dexamethasone in combination with ixazomib, carfilzomib, 
elotuzumab and daratumumab [21, 32-34]. The triplets combining lenalidomide and 
dexamethasone with carfilzomib and ixazomib have been outlined above *see sections 1.1 
and 1.2, respectively). Elotuzumab and daratumumab are monoclonal antibodies targeting 
SLAMF7 and CD38 on plasma cells, respectively. In a phase III study of patients with 
relapsed and/or refractory multiple myeloma who had received 1 – 3 prior lines of therapy, 
the addition of elotuzumab to lenalidomide and dexamethasone led to improved ORRs (79% 
vs 66%, P <0.001) and median PFS (19.4 vs 14.9 months, HR 0.70, P <0.001) [33]. The 
triplet was well tolerated, although an increased rate of grade 3 or higher lymphopenia was 
seen, as well as grade 1 and 2 fatigue, pyrexia, edema, nasopharyngitis, diarrhea, 
constipation and cough. The combination of daratumumab with lenalidomide and 
dexamethasone was also shown to be superior to lenalidomide-dexamethasone in a phase 
III study of patients with relapsed and relapsed/refractory multiple myeloma who had 
received at least 1 prior line of therapy, with improved ORRs (92.9 vs 76.4%, P <0.001), 
high quality response rates (≥VGPRs 75.8% vs 44.2%, P <0.001) and median PFS (not 
reached vs 18.4 months, HR 0.37, P <0.001) [34]. As with elotuzumab, the addition of 
daratumumab to lenalidomide and dexamethasone was well tolerated, although there was a 
higher rate of neutropenia, nausea, vomiting, diarrhea, fatigue, pyrexia, cough, dyspnea, 
upper respiratory tract infections, nasopharyngitis and muscle spasms, most of which was 
grade 1 and 2 in severity. As such, lenalidomide and dexamethasone in combination with 
elotuzumab and daratumumab have become important standards of care in patients with 
relapsed multiple myeloma.  

 
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1.3.2 The challenge of lenalidomide-dexamethasone-based triplet therapy for relapsed 
multiple myeloma in evolving treatment paradigms 
In the above described phase III studies that led to FDA approval of 4 different 
lenalidomide-dexamethasone-based combinations for relapsed multiple myeloma, patients 
were required to have lenalidomide-sensitive or -naïve disease. As such, these data are not 
applicable to those patients with lenalidomide-refractory disease. This is important, because 
an increasing proportion of patients in the United States with newly-diagnosed multiple 
myeloma are treated with lenalidomide until disease progression, rendering their disease 
lenalidomide-refractory at the time of first disease progression. This pattern of practice has 
largely been driven by two phase III studies. The first study was a phase III trial in 
transplant-ineligible patients comparing lenalidomide and dexamethasone for a total 
duration of 18 months to indefinite lenalidomide and dexamethasone therapy until disease 
progression [35]. The median PFS was superior for those who received treatment until 
disease progression (20.7 months versus 25.5 months), and the hazard ratio (HR) for PFS 
was 0.70 (P<0.001) [35]. It should also be noted that the phase III study that demonstrated 
an improvement in median PFS and OS with RVD compared to lenalidomide and 
dexamethasone utilized lenalidomide and dexamethasone until disease progression after 
receipt of an initial 8 cycles of RVD [20]. The second study evaluated the role of 
lenalidomide as a maintenance therapy after recovery from high dose melphalan and 
autologous stem cell transplantation. Patients were treated with placebo or lenalidomide 
until disease progression. Notably, the median time to progression was 46 months in the 
lenalidomide arm compared with 27 months for those taking placebo [7]. Additionally, a 
more recent analysis has revealed an overall survival advantage with the use of lenalidomide 
maintenance after transplant (HR 0.60, P=0.001). Additional studies evaluating 
lenalidomide as a maintenance therapy after autologous stem cell transplantation have also 
demonstrated improvements in median PFS of a similar magnitude [36]. Thus, the majority 
of patients in the United States will have lenalidomide resistance at first or second 
progression. Clearly, a better understanding of optimal therapy for relapsed myeloma in the 
changing paradigm of myeloma therapy and lenalidomide resistance after 1 prior line of 
therapy is critical. 
1.3.3 Non-lenalidomide-based therapy for relapsed multiple myeloma 
Several non-lenalidomide-based regimens have recently been FDA approved for patients 
with relapsed and relapsed/refractory multiple myeloma who have received 1 or more prior 
lines of therapy. Carfilzomib and dexamethasone was compared to bortezomib and 
dexamethasone in the context of a phase III study for patients with relapsed multiple 
myeloma who had received 1 – 3 prior lines of therapy [37]. Notably, carfilzomib and 
dexamethasone was superior with regards to ORR (77% vs 63%, P <0.0001), VGPR or 
better (54% vs 29%) and median PFS (18.7 vs 9.4 months, HR 0.53, P <0.0001). However, 
it should be noted that only 38% of patients on this study had received prior lenalidomide 
(20.3 – 22% of those who had previously been treated with just 1 prior line of therapy). 
Furthermore, the median PFS for carfilzomib and dexamethasone was only 8.6 months for 
those who were refractory to lenalidomide compared with not evaluable for those with 
lenalidomide-sensitive disease (P <0.0001) [38]. Furthermore, for patients with high risk 
cytogenetics treated with carfilzomib and dexamethasone, the median PFS was only 8.8 
months as opposed to 6.0 months for those patients treated with bortezomib and 
dexamethasone [39]. These data would suggest that while the carfilzomib-dexamethasone 
doublet is active and represents an important standard of care for patients with relapsed 
multiple myeloma, there is clear room for improvement for patients with high risk 
cytogenetic or disease that is refractory to lenalidomide. Furthermore, carfilzomib and 

 
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dexamethasone was associated with a higher rate of hypertension, acute renal failure, 
pulmonary hypertension, congestive heart failure and ischemic heart disease compared with 
bortezomib and dexamethasone. For patients who are 75 years of age and older, the risk of 
grade 3 or higher congestive heart failure was 10.4% with carfilzomib and dexamethasone, 
as opposed to 3.1% with bortezomib-dexamethasone [40]. As such, the regimen must be 
used cautiously, especially for those with underlying cardiovascular comorbidity.  
The addition of daratumumab to bortezomib and dexamethasone has been shown to be 
superior to the bortezomib-dexamethasone doublet in the context of a phase III study [41]. 
Specifically, the daratumumab-bortezomib-dexamethasone combination was superior with 
regards to ORR (82.9% vs 63.2%, P <0.001), rate of high quality responses (VGPRs or 
better 59.2% vs 29.1%, P <0.001)), and median PFS (not reached vs 7.2 months, HR 0.39, 
P <001). However, only 32.9% of patients had disease refractory to IMiDs, and many of 
these IMiD-refractory patients were likely thalidomide and not lenalidomide-refractory 
given the large contribution of patient enrollment to this study outside of the United States. 
Furthermore, daratumumab is currently being evaluated in several randomized studies for 
patients with newly-diagnosed multiple myeloma. As such, barring unexpected toxicity in 
newly-diagnosed patients, it is expected that daratumumab will become an important 
component of frontline therapy. Its role in the relapsed setting after use in the frontline 
setting remains an important area for future investigation. Lastly, the combination of the 
histone deactylase inhibitor, panobinostat, with bortezomib-dexamethasone was superior to 
bortezomib and dexamethasone in the phase III setting [42]. The addition of panobinostat 
to bortezomib-dexamethasone led to improved median PFS (11.99 months vs 8.08 months, 
HR 0.63, P <0.0001). However, due to notable constitutional, gastrointestinal and 
hematologic toxicity and no signal of an OS advantage, the combination was given 
conditional approval by the FDA for patients with relapsed multiple myeloma who have 
received 2 or more prior therapies for their myeloma, including bortezomib and an IMiD. In 
this group of patients, the median PFS was 12.5 months with the triplet compared to 4.7 
months for those receiving bortezomib and dexamethasone alone [43]. Ongoing studies are 
seeking to clarify the optimal dose and schedule of panobinostat with bortezomib and 
dexamethasone, as well as its best partner myeloma regimen.  
Thus, to summarize, while notable gains have been made for patients with relapsed multiple 
myeloma who have received at least 1 prior therapy, data in patients treated with frontline 
lenalidomide-based therapy until disease progression are lacking. Furthermore, for patients 
with relapsed multiple myeloma and lenalidomide-refractory disease, there is room for 
improvement 
upon 
carfilzomib-dexamethasone 
and 
bortezomib-dexamethasone-
panobinostat, and, while the daratumumab-bortezomib-dexamethasone regimen is a 
reasonable option in this situation, daratumumab will likely make its way into frontline 
therapy in the not-too-distant future. As such, there is a compelling need to develop non-
daratumumab-based regimens in this space. 
1.4 
Pomalidomide and dexamethasone 
The IMiDs, thalidomide and lenalidomide, are currently Food and Drug Administration (FDA) 
approved for the treatment of newly-diagnosed and/or relapsed multiple myeloma and have 
played a central role in the improved survival of myeloma patients over the last decade. However, 
of a panel of amino-substituted thalidomide analogs (including lenalidomide), CC-4047, or 
pomalidomide, was the most potent inhibitor of lipopolysaccharide-mediated tumor necrosis 
factor-α production in vitro [44]. In fact, pomalidomide was ~15,000 times more potent than 
thalidomide in this regard. Subsequent studies have demonstrated promising activity of 
pomalidomide in pre-clinical models of multiple myeloma, including cell lines resistant to 

 
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conventional multiple myeloma therapy and patient multiple myeloma samples, thus providing 
the basis for further clinical development [45, 46]. 
Pomalidomide has demonstrated striking clinical activity in patients with relapsed multiple 
myeloma, including patients with lenalidomide- and dual lenalidomide/bortezomib-refractory 
disease [47-54]. An initial phase I study of single agent pomalidomide therapy was conducted 
in 24 patients with relapsed or refractory multiple myeloma. The median age of participants was 
66, and patients had received a median of 3 prior lines of therapy. Only 29% of patients had 
previously received thalidomide. Patients received 1 to 10 mg of pomalidomide daily. The 
maximum tolerated dose (MTD) was 2 mg. Hematologic toxicity was most prominent, with 6 
patients developing grade 4 neutropenia. Deep vein thrombosis was seen in 4 patients, one of 
whom had metastatic melanoma. No other grade 3 or higher non-hematologic toxicity was noted. 
Peripheral neuropathy was only seen in 3 patients and was of grade 1 severity in all cases. Four 
patients achieved a complete response (CR), 3 a very good partial response (VGPR), 6 a PR and 
4 patients an MR. Thus, the ORR was an impressive 54% and CBR 71%. Median PFS was 39 
weeks and OS 90 weeks [50]. A subsequent single arm, phase II study was conducted evaluating 
the combination of pomalidomide and dexamethasone in patients with relapsed or refractory 
multiple myeloma. Pomalidomide was administered at 2 mg on days 1-28 of a 28-day cycle and 
dexamethasone at 40 mg weekly. Sixty patients participated. The median age was 66 and median 
time from diagnosis 44 months. Thirty-seven percent and 35% of patients had received 2 and 3 
prior multiple myeloma regimens, respectively. With appropriate thromboprophylaxis (either 
aspirin, low molecular weight heparin or warfarin), only 1 patient suffered a venous 
thromboembolic event. Grade 3 or 4 fatigue and pneumonia were seen in 17% and 8% of patients, 
respectively. Grade 3 or 4 neutropenia and thrombocytopenia were seen in 32% and 3% of 
patients. The ORR was 63%, with a CR rate of 5%, VGPR rate of 28% and PR rate of 30%. 
Forty percent of patients with lenalidomide-resistant disease responded to therapy and, of 5 
patients with dual lenalidomide- and bortezomib-refractory disease, 2 had PRs and 1 a VGPR. 
The median PFS was 11.6 months [48]. 
Given the rapidly changing landscape of multiple myeloma therapy, the nature of relapsed and 
refractory disease has evolved over time. Nonetheless, pomalidomide-based therapy has 
continued to perform well in more recent studies, including in patients with lenalidomide and/or 
bortezomib-refractory disease. Thirty-four patients with relapsed, lenalidomide-refractory 
multiple myeloma were treated with pomalidomide and dexamethasone in the context of a phase 
II study. Pomalidomide was administered at 2 mg daily and dexamethasone 40 mg weekly. The 
median time from diagnosis to study participation was 62 months, and the median number of 
prior therapies was 4. Notably, the ORR was 32%, CBR 47%, median PFS 4.8 months and 
median OS 13.9 months [49]. A follow-up study from the same group compared a 2 mg vs. 4 
mg dose of pomalidomide in combination with once weekly dexamethasone for patients with 
multiple myeloma that was refractory to both lenalidomide and bortezomib. The median number 
of prior regimens for both dose cohorts was 6 and the median time from diagnosis to study 
participation was 57 and 72 months, respectively. The ORR was 25% and 29%, CBR 49% and 
43%, and median PFS 6.5 and 3.2 months, respectively [47].  
More recently, a phase I followed by randomized phase II study comparing single-agent 
pomalidomide to pomalidomide and low-dose dexamethasone in patients with relapsed and 
refractory multiple myeloma previously treated with both lenalidomide- and bortezomib-based 
therapy was conducted [51-53]. In the phase I portion of the study, the MTD of the combination 
was found to be pomalidomide administered at 4 mg on days 1-21 of a 28-day cycle and 
dexamethasone administered at 40 mg once weekly. Dosing at 5 mg was associated with an 
increased rate of dose limiting toxicity (DLT), especially neutropenia, and the need for dose 
reductions in all patients. A trend towards improved response rates was seen at the 4 mg dose 
compared with the 2 mg dose [51]. Patients enrolled in the phase II portion of the study had 

 
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previously received a median of 5 prior therapies and 62% were refractory to both lenalidomide 
and bortezomib. The ORR was 18% and 33%, CBR 31% and 45%, median PFS 2.6 months and 
4.6 months, and median OS 13.6 months and 16.5 months for patients receiving single-agent 
pomalidomide or the combination of pomalidomide and dexamethasone, respectively. Of those 
patients with lenalidomide and bortezomib-refractory disease treated with pomalidomide and 
dexamethasone, the median PFS and OS were 3.9 and 13.7 months, respectively. Toxicity with 
the combination was largely manageable, but grade 3/4 neutropenia, thrombocytopenia, anemia, 
pneumonia, fatigue, and dyspnea were seen in 41%, 19%, 22%, 22%, 14% and 13% of patients, 
respectively. Importantly, no cases of grade 3 or 4 peripheral neuropathy were seen, only 2% of 
patients suffered thromboembolic events, 3% of patients developed grade 3/4 febrile neutropenia, 
and only 2% of patients discontinued therapy due to treatment toxicity [52, 53]. A similarly 
designed phase II randomized study conducted by the IFM compared two different dosing 
schedules of pomalidomide in combination with dexamethasone (pomalidomide 4 mg on days 
1 – 21 of a 28-day cycle vs. 4 mg on days 1 – 28) [50]. No significant differences were seen in 
efficacy between the 2 arms. Grade 3 and 4 adverse events (AEs) included neutropenia 62%, 
anemia 36%, thrombocytopenia 27%, pneumonia 13%, bone pain 11%, renal failure 11% and 
dyspnea 12%. Notably, the ORR was 31% and median PFS 3.8 months and OS 13.8 months in 
patients with lenalidomide- and bortezomib-refractory multiple myeloma [54]. Based on the 
results from these studies, the pomalidomide and dexamethasone regimen was approved by the 
FDA in February of 2013 for patients with relapsed and refractory multiple myeloma who have 
received ≥2 prior lines of therapy that have included lenalidomide- and bortezomib-based 
therapy. Clearly, pomalidomide and dexamethasone represents a highly promising treatment 
strategy for patients with multiple myeloma. However, for patients with lenalidomide and 
lenalidomide/bortezomib refractory disease, there remains considerable room for improvement. 
As lenalidomide is being used increasingly as part of frontline therapy and lenalidomide is often 
continued until disease progression, rendering patients refractory to lenalidomide at first relapse, 
there is a clear need to gain further experience with pomalidomide/proteasome inhibitor 
combinations for this group of patients. Pomalidomide has been combined with carfilzomib in 
phase I and II studies [55]. However, there are no ongoing or planned randomized studies 
evaluating the impact of the addition of carfilzomib to the pomalidomide and dexamethasone 
backbone. Furthermore, the onerous schedule of carfilzomib administration makes long term 
treatment with this agent challenging. Lastly, for patients with significant cardiovascular 
comorbidities, carfilzomib may be associated with increased risk for cardiac events. The 
addition of bortezomib to pomalidomide and dexamethasone has been studied in the context of 
phase I/II studies [56, 57]. There is an ongoing phase III study evaluating the combination of 
pomalidomide, bortezomib and dexamethasone versus bortezomib and dexamethasone 
(NCT01734928). However, there are several important differences between the ongoing phase 
III study and our phase II proposal. First, patients in the phase III study are allowed to have 
received 1 – 3 prior lines of therapy and may have lenalidomide-sensitive, -naive or –refractory 
disease, thus yielding a highly heterogeneous patient population. Secondly, the ongoing phase 
III study is utilizing the bortezomib-dexamethasone doublet as the comparator arm, and we now 
know that the carfilzomib-dexamethasone doublet or the addition of daratumumab or 
panobinostat to bortezomib-dexamethasone are superior to bortezomib-dexamethasone alone in 
relapsed multiple myeloma.  
To conclude, given the well documented clinical activity of pomalidomide and dexamethasone 
in patients with lenalidomide-refractory disease; improved PK and PD characteristics of 
ixazomib compared with bortezomib; superior pre-clinical anti-tumor efficacy of ixazomib 
compared to bortezomib; and promising clinical activity of ixazomib as a single agent and in 
combination therapy with lenalidomide and dexamethasone, we hypothesize that the addition of 
ixazomib to pomalidomide and dexamethasone therapy will further improve outcomes for 

 
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Update #09 
patients with multiple myeloma whose disease is progressing on lenalidomide as part of first 
line therapy. Our study will provide the initial signal of efficacy of the pomalidomide-ixazomib-
dexamethasone regimen as compared to pomalidomide-dexamethasone in an emerging, 
important and understudied patient population, thus supporting the development and informing 
the study design of a future phase III study. 
1.5 
Registration Quality of Life (QOL) Measurements 
QOL measurements of fatigue and overall perception of QOL are routinely included in Alliance 
studies and will be assessed upon registration in this study. Evidence has arisen indicating that 
baseline single-item assessments of fatigue and overall QOL are strong prognostic indicators for 
survival in cancer patients, independent of performance status. This evidence was derived from 
two separate meta-analyses presented at ASCO, the first involving 23 NCCTG and Mayo Clinic 
Cancer Center oncology clinical trials, the second involving 43 clinical trials [58, 59]. Routine 
inclusion of these measures should be considered similar to that of including performance status, 
either as stratification or prognostic covariates. 
1.6 
Establishment of the Maximum Tolerated Dose (MTD) of Pomalidomide, Ixazomib, and 
Dexamethasone in Phase I 
A total of 26 patients consented to participate in the phase I portion of the study. Two patients 
were not treated on protocol; one patient had a platelet count that had dropped below 50 prior to 
the start of therapy and was no longer eligible; a second patient was discovered to have MDS on 
the screening marrow. Three patients were treated at dose level 1, all 3 of whom were evaluable 
for DLTs. No DLTs were encountered in these first 3 patients. Five patients were enrolled on 
dose level 2, 3 of whom were evaluable for DLTs. One patient was inevaluable for DLTs as they 
inadvertently received the dose of pomalidomide utilized in dose level 1 during their first cycle 
of therapy. A second patient was inevaluable for DLTs, as they were not treated on study as a 
result of the presence of MDS on the screening marrow evaluation. Of the 3 evaluable patients, 
none experienced DLTs. Seven patients were enrolled at dose level 3, 6 of whom were evaluable 
for DLTs. One patient did not receive protocol therapy as a result of rapid disease progression 
and clinical deterioration in the lead up to treatment. Of the 6 evaluable patients, 1 experienced 
a DLT of grade 3 febrile neutropenia resulting from sinusitis. Eleven patients were enrolled on 
dose level 4, 6 of whom were evaluable for DLTs. One patient experienced a DLT of grade 3 
febrile neutropenia. Five patients were not evaluable for DLTs: 1 due to treatment disruption 
during cycle 1 as a result of grade 2 sinus bradycardia; 1 due to treatment disruption during cycle 
1 as a result of TIAs that were present prior to the start of protocol therapy and deemed not 
treatment related; 1 patient had therapy disrupted during cycle 1 for neutropenia that was felt to 
be disease related; 1 due to treatment disruption during cycle 1 for grade 4 thrombocytopenia 
that was felt to be related to disease progression; and 1 due to treatment disruption over cycle 1 
for fatigue, rash and diarrhea that did not rise to the level of DLTs. The DLT data were reviewed 
by the Principal Investigators at the 4 participating sites and the Alliance Myeloma Committee 
Chair. Dose level 4 was deemed the MTD of the regimen by unanimous decision and the 
recommended phase II dose moving forward. It should be noted that the MTD and recommended 
phase II dose was established in lenalidomide and proteasome inhibitor dual refractory patients. 
However, we feel that the patient population in the phase II portion of the study, specifically 
patients with lenalidomide but not proteasome inhibitor refractory disease who have only 
received 1 prior line of therapy, will tolerate the combination better than the more heavily 
pretreated cohort in phase I. 
 

 
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Update #09 
2.0 
OBJECTIVES  
2.1 
Primary Phase I Objectives 
To establish the MTD for combination therapy Pomalidomide / Dexamethasone / Ixazomib 
Note: The MTD will be determined by DLTs seen in cycle 1 of therapy. Please reference section 
13.1 for the definition of DLT. The RP2D will be based on MTD; signals of cumulative toxicities 
seen during the course of treatment; and patient adherence. 
2.2 
Primary Phase II Objectives 
To assess whether the combination of pomalidomide/dexamethasone/ixazomib improves PFS 
relative to pomalidomide/dexamethasone. 
2.3 
Secondary Phase I Objectives 
2.3.1 To determine DLTs 
2.3.2 To analyze type and grade of all Serious Adverse Events (SAEs) 
2.3.3 To analyze type and grade of all Adverse Events (AEs) 
2.3.4 To analyze the reason for and incidence of dose modifications/omissions/delays 
2.3.5 To assess preliminary evidence of clinical efficacy 
2.4 
Secondary Phase II Objectives  
2.4.1 To assess whether the Overall Response Rate (ORR), Partial Response (PR), Very Good 
Partial Response (VGPR), Complete Response (CR) or stringent CR (sCR) rate differ with 
respect to treatment regimen. 
2.4.2 To assess the Clinical Benefit Rate (CBR: Minimal Response (MR) + ORR) for 
Pomalidomide/Dexamethasone/Ixazomib compared to Pomalidomide/Dexamethasone. 
2.4.3 To assess the Disease Control Rate (DCR: Stable Disease (SD) + CBR) for 
Pomalidomide/Dexamethasone/Ixazomib compared to Pomalidomide/Dexamethasone. 
2.4.4 For those patients achieving a PR or better, we will assess whether the combination of 
Pomalidomide/Dexamethasone/Ixazomib increases the Duration of Response (DOR) 
compared to Pomalidomide/Dexamethasone. 
2.4.5 To assess whether the combination of Pomalidomide/Dexamethasone/Ixazomib improves 
Overall Survival (OS) compared to those taking Pomalidomide/Dexamethasone alone. 
2.4.6 To 
assess 
Time 
to 
Next 
Treatment 
(TNT) 
for 
patients 
taking 
Pomalidomide/Dexamethasone/Ixazomib 
compared 
to 
those 
on 
Pomalidomide/Dexamethasone.  
2.4.7 To evaluate the safety of Pomalidomide/Dexamethasone/Ixazomib compared with 
Pomalidomide/Dexamethasone. 
2.4.8 For patients on the Pomalidomide/Dexamethasone arm who opt to cross-over to the 
Pomalidomide/Dexamethasone/Ixazomib arm, assessment of response rate (ORR, CBR, 
DCR) DOR, TNT, PFS, and OS will be evaluated from date of cross-over. 
2.4.9 To determine if baseline level of perceived fatigue and overall QOL is associated with OS.  

 
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Update #09 
2.5 
Correlative Science Objectives for Phase II 
As of Update #04, no new patients will be registered to the A061202-ST1 substudy which 
was designed to address these objectives. 
2.5.1 Primary Objective 
To determine the extent to which cereblon expression (via quantitative PCR and IHC) is 
associated with therapeutic response. 
2.5.2 Secondary Objectives 
2.5.2.1 To examine whether PFS or OS differs with respect to cereblon expression levels. 
2.5.2.2 To examine whether therapeutic response, PFS, and OS differs with respect to either 
the percentage of IRF-4 or c-Myc positivity in plasma cells or IHC staining intensity 
in plasma cells at baseline. 
2.5.2.3 To examine whether resistance mutations in the IMiD binding domain of cereblon 
emerge in patients with an initial response to therapy (MR or better) who then progress. 
2.5.2.4 To examine the percent agreement between cereblon expression levels at baseline and 
progression as well as the percentage of patients with expression gain or loss. 
2.5.2.5 To examine whether reduced expression of Ikaros (IKZF1) and/or Aiolos (IKZF3) 
transcription factors is associated with inferior clinical efficacy (ORR, PFS, OS). 
2.5.2.6 To determine whether resistance mutations in Ikaros and Aiolos develop in patients 
with an initial response to therapy (MR or better) who then progress. 
3.0 
PATIENT SELECTION 
For questions regarding eligibility criteria, see the Contact Information page. Please note that the 
Study Chair cannot grant waivers to eligibility requirements. 
3.1 
On-Study Guidelines 
This clinical trial can fulfill its objectives only if patients appropriate for this trial are enrolled. 
All relevant medical and other considerations should be taken into account when deciding 
whether this protocol is appropriate for a particular patient. Physicians should consider the risks 
and benefits of any therapy, and therefore only enroll patients for whom this treatment is 
appropriate. 
Physicians should consider whether any of the following may render the patient inappropriate 
for this protocol: 
 
Psychiatric illness which would prevent the patient from giving informed consent. 
 
Medical condition such as uncontrolled infection, uncontrolled diabetes mellitus or cardiac 
disease which, in the opinion of the treating physician, would make this protocol 
unreasonably hazardous for the patient. 
 
Patients who cannot swallow oral formulations of the agent(s). 
 
Patients cannot have other prior or concomitant malignancies with the exception of: 
 
Non-melanoma skin cancer 
 
In-situ malignancy 
 
Low-risk prostate cancer after curative therapy 
 
Other cancer for which the patient has been disease free for ≥ 3 years.  

 
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Update #09 
In addition: 
 
Women and men of reproductive potential, please refer to section 3.2.4.  
3.2 
Eligibility Criteria 
Use the spaces provided to confirm a patient’s eligibility by indicating Yes or No as appropriate. 
It is not required to complete or submit the following page(s). 
___ 3.2.1 Documentation of Relapsed Symptomatic Multiple Myeloma: 
Histologically confirmed diagnosis of symptomatic multiple myeloma. Relapsed disease is 
myeloma that has previously responded to prior therapy (MR or better) and subsequently 
progressed. 
___ 3.2.2 Measurable disease or non-measurable disease as defined in Section 11.0. 
Patient must have measurable disease or non-measurable disease, defined as one or more of 
the following holding true: 
Measurable disease: 
 
Serum M-protein ≥0.5 g/dL and/or 
 
Urine M-protein ≥200 mg/24 hours and/or 
 
Involved serum free light chain level ≥10 mg/dL AND an abnormal serum free light 
chain ratio  
For non-measurable disease: 
 
Baseline marrow burden of myeloma of at least 30% 
3.2.3 Prior Treatment  
___ 
Progression on lenalidomide as part of first line therapy (lenalidomide-refractory disease) 
Lenalidomide-refractory disease is defined as disease progression on or progression within 
60 days of the last dose of a lenalidomide-based treatment. [60, 61]. Patients should have 
received at least 2 cycles of a lenalidomide-based regimen to be evaluable for refractoriness. 
Examples: 1) progression on lenalidomide maintenance therapy after initial induction ± 
consolidation; 2) initial response followed by progression on continuous lenalidomide-
dexamethasone ± elotuzumab or daratumumab.  
___ 
Pomalidomide naïve disease 
___ 
Proteasome inhibitor naïve or sensitive disease. Proteasome inhibitor sensitive disease is 
defined as a PR or better to prior proteasome inhibitor-based therapy that is maintained for 
≥ 60 days from the last dose of the proteasome inhibitor. Please refer to Appendix VII for a 
list of proteasome inhibitors. 
A patient who receives induction therapy with lenalidomide, bortezomib and dexamethasone 
and achieves a PR or better but subsequently progresses on continued lenalidomide or 
lenalidomide-dexamethasone would be eligible provided the progression occurs 60 days or 
more after discontinuation of the bortezomib. Similarly, ixazomib exposure is allowed 
provided they meet the definition of proteasome inhibitor sensitive disease. 
___ 
1 prior line of systemic therapy for multiple myeloma, where a line of therapy for myeloma 
is defined as 1 or more planned cycles of single agent or combination therapy, as well as a 
planned series of treatment regimens administered in a sequential manner (e.g. lenalidomide, 
bortezomib and dexamethasone induction therapy for 4 cycles followed by autologous stem 
cell transplantation and then lenalidomide maintenance therapy would be considered 1 line 
of prior therapy). A new line of therapy begins when a planned therapy is modified to 

 
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Update #09 
include other treatment agents (alone or in combination) as a result of disease progression 
or relapse (e.g. a patient is progressing in the face of lenalidomide maintenance therapy and 
has bortezomib and dexamethasone added into their regimen). A new line of therapy also 
begins when a planned treatment-free interval is interrupted by the need to start treatment 
due to disease relapse/progression (e.g. a patient with relapsed myeloma achieves a partial 
response after a planned 8 cycles of cyclophosphamide, bortezomib and dexamethasone, 
enjoys an 8-month period off therapy but then experiences disease progression requiring re-
initiation of therapy). 
___ 
Allogeneic stem cell transplantation is allowed provided the patient is ≥ 1 year from 
transplant at time of registration, is not on immunosuppressive therapy to treat/prevent graft-
versus-host disease, has no evidence of active graft versus host disease, and no evidence of 
active infection. 
___ 
No chemotherapy or radiation therapy within 14 days prior to registration. 
___ 
No investigational therapy within 14 days prior to registration. 
___ 
No major surgery within 28 days prior to registration.  
___ 
No G-CSF (Filgrastim) or GM-CSF (Sargramostim) within 7 days of registration or 
Pegfilgrastim within 14 days of registration to meet eligibility criteria. 
___ 
No platelet transfusions within 7 days of registration to meet eligibility criteria. Note: Red 
blood cell transfusions are allowed at any time. 
___ 3.2.4 Not pregnant and not nursing 
A female of childbearing potential is a 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). 
Women of childbearing potential: 
 
must have a negative serum or urine pregnancy test with a sensitivity of at least 25 
mlU/ml no more than 14 days prior to registration and must agree to repeat this test 
within 24 hours of starting pomalidomide. 
 
must either commit to complete abstinence from heterosexual contact or begin TWO 
acceptable methods of birth control, one highly effective method and one additional 
effective (barrier) method, AT THE SAME TIME, before starting pomalidomide.  
 
must agree to ongoing pregnancy testing.  
 
must agree to not become pregnant or breast feed a child during treatment on this 
protocol. 
Men must practice complete abstinence or agree to use a condom during sexual contact with 
a female of childbearing potential, even if they have had a successful vasectomy.  
Note: All participants must be counseled at a minimum of every 28 days about pregnancy 
precautions and risks of fetal exposure. Please reference section 5.0 for details on pregnancy 
monitoring during the duration of the trial.  
___ 3.2.5 ≥18 years of age 
___ 3.2.6 ECOG Performance status 0-2 (see Appendix I) 
___ 3.2.7 Required Initial Laboratory Values: 
Absolute Neutrophil Count (ANC) 
≥ 1.0 x 109/L 
Platelet Count 
≥ 50 x 109/L 

 
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Update #09 
Calc. Creatinine Clearance* 
≥ 30 mL/min 
Total Bilirubin 
< 1.5 x upper limits of normal (ULN) 
AST and ALT 
< 2.5 x upper limits of normal (ULN) 
* 
Calculated utilizing the Cockcroft-Gault formula or 24-hour urine collection (see 
Appendix II) 
Note: G-CSF and platelet transfusions cannot be used to increase counts to meet eligibility 
criteria. Please refer to section 3.2.3. 
3.2.8 Intercurrent or Recent Illness 
Patients cannot have any of the following: 
___ 
Central nerve system involvement 
___ 
Primary refractory multiple myeloma, where primary refractory multiple myeloma is 
defined as disease that is nonresponsive – patients who have never achieved an MR or better 
– with any therapy over the course of their disease. It includes patients who never achieve 
MR or better in whom there is no significant change in M-protein and no evidence of clinical 
progression as well as patients who meet criteria for true progressive disease (PD).  
___ 
Primary or secondary plasma cell leukemia 
___ 
AL amyloidosis or POEMS syndrome 
___ 
Known active hepatitis C based on: 
+HCV antibody (confirmed) 
+HCV RNA  
Liver disease with history of positive serology 
Note: patients with a prior history of hepatitis C that has been successfully eradicated 
with antiviral therapy are eligible. 
___ 
Known hepatitis B surface antigen positivity 
___ 
Previous hypersensitivity to any of the components of the study treatment 
___ 
Prior history of erythema multiforme with thalidomide or lenalidomide treatment 
___ 3.2.9 
≤ Grade 2 Peripheral Neuropathy  
___ 3.2.10 Adequate cardiac function, defined as: 
___ 
No EKG evidence of acute ischemia 
___ 
No EKG evidence of active, clinically significant conduction system abnormalities 
___ 
No EKG evidence of >Grade 2 (>480 ms) QTc prolongation  
___ 
Prior to study entry, any EKG abnormality at screening not felt to put the patient at risk has 
to be documented by the investigator as not medically significant 
___ 
No uncontrolled angina or severe ventricular arrhythmias 
___ 
No clinically significant pericardial disease 
___ 
No history of myocardial infarction within 6 months prior to registration 
___ 
No Class 3 or higher New York Heart Association Congestive Heart Failure (see Appendix 
IV) 

 
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Update #09 
3.2.11 Concomitant Treatment  
___ 
No strong inducers of cytochrome P450 (CYP) 3A4 or CYP1A2 or strong inhibitors of 
CYP3A4 or CYP1A2 within 14 days prior to registration. 
Note: Ixazomib is a substrate of CYP3A4 and CYP1A2. See sections 8.1.12 and 10.1.3 for 
additional information about potential drug-drug and drug-food interactions with ixazomib.  
Refer to Appendix V for a list of strong inhibitors of CYP3A4 and CYP1A2. 
3.2.12 HIV Infection 
___ 
Patients with HIV infection are eligible, provided they meet all of the following criteria: 
 
No history of AIDS-defining conditions or other HIV related illness 
 
CD4+ cells nadirs >350/mm3 within 28 days prior to registration 
 
Treatment sensitive HIV and, if on anti-HIV therapy, HIV viral load < 50 
copies/mm3 within 28 days prior to registration 
Note: HIV+ patients who enroll on this study and are assigned to treatment with ixazomib 
may need to modify their anti-retroviral therapy prior to receiving protocol therapy if they 
are on strong inducers or potent inhibitors of cytochrome P450 3A4 (see section 3.2.11). 
3.3 
Re-Registration Eligibility Criteria (Step 2) 
Patients randomized to Arm 1 may opt to switch to the 3-drug regimen following disease 
progression. These patients must be re-registered to the study and meet the eligibility criteria 
below.  
___ 3.3.1 Measurable disease or non-measurable disease as defined in Section 11.0. 
Patient must have measurable disease or non-measurable disease after progression on 
Pomalidomide + Dexamethasone, defined as one or more of the following holding true: 
Measurable disease: 
 
Serum M-protein ≥0.5 g/dL and/or 
 
Urine M-protein ≥200 mg/24 hours and/or 
 
Involved serum free light chain level ≥10 mg/dL AND an abnormal serum free light 
chain ratio 
For non-measurable disease: 
 
Marrow burden of myeloma of at least 30% 
___ 3.3.2 Not pregnant and not nursing 
Women of childbearing potential: 
 
must have a negative serum or urine pregnancy test within 72 hours prior to re-
registration. 
 
must either commit to complete abstinence from heterosexual contact or begin TWO 
acceptable methods of birth control, one highly effective method and one additional 
effective (barrier) method, AT THE SAME TIME, before starting pomalidomide.  
 
must agree to ongoing pregnancy testing.  
 
must agree to not become pregnant or breast feed a child during treatment on this 
protocol. 

 
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Update #09 
Men must practice complete abstinence or agree to use a condom during sexual contact with 
a female of childbearing potential, even if they have had a successful vasectomy.  
Note: All participants must be counseled at a minimum of every 28 days about pregnancy 
precautions and risks of fetal exposure. Please reference Section 5.0 for details on pregnancy 
monitoring during the duration of the trial. 
___ 3.3.3 ECOG Performance Status 0-2 (see Appendix I) 
___ 3.3.4 Required Laboratory Values* 
Absolute Neutrophil Count (ANC) 
≥ 1.0 x 109/L 
Platelet Count 
≥ 50 x 109/L 
Calc. Creatinine Clearance* 
≥ 30 mL/min 
Total Bilirubin 
< 1.5 x upper limits of normal (ULN) 
AST and ALT 
< 2.5 x upper limits of normal (ULN) 
* Calculated utilizing the Cockcroft-Gault formula or 24-hour urine collection (see 
Appendix II) 
Note: G-CSF and platelet transfusions cannot be used to increase counts to meet eligibility 
criteria. 
___ 3.3.5 ≤ Grade 2 Peripheral Neuropathy 
3.3.6 Concomitant Treatment 
___ 
No strong inducers of cytochrome P450 (CYP) 3A4 or CYP1A2 or strong inhibitors of 
CYP3A4 or CYP1A2  
Note: Ixazomib is a substrate of CYP3A4 and CYP1A2. See section 8.1.12 and 10.1.3 for 
additional information about potential drug-drug and drug-food interactions with ixazomib. 

 
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Update #09 
4.0 
PATIENT REGISTRATION 
4.1 
Phase I Registration Requirements 
PHASE I CLOSED TO ACCRUAL AS OF FEBRUARY 04, 2016. 
• 
Informed consent: the patient must be aware of the neoplastic nature of his/her disease and 
willingly consent after being informed of the procedure to be followed, the experimental 
nature of the therapy, alternatives, potential benefits, side-effects, risks, and discomforts. 
Current human protection committee approval of this protocol and a consent form is 
required prior to patient consent and registration. 
• 
Limited access information: Enrollment into the phase I portion of the study will be 
restricted to the following Alliance sites: 1) The University of North Carolina/Lineberger 
Comprehensive Cancer Center; 2) The Dana Farber Cancer Institute; 3) The Memorial 
Sloan-Kettering Cancer Center, and 4) The Ohio State University Comprehensive Cancer 
Center. 
 
For the phase I portion of the study, patient enrollment will be facilitated using the Slot-
Reservation System in conjunction with the Registration system on Oncology Patient 
Enrollment Network (OPEN). Prior to discussing protocol entry with the patient, all site 
staff must use the CTSU OPEN Slot Reservation System to insure that a slot on the protocol 
is available to the patient. Once a slot reservation confirmation is obtained, site staff may 
then proceed to enroll patients to this study. 
 
Alliance sub-study A061202-ST1 will not be activated during the phase I portion of the 
study but will be available for the phase II portion. 
4.2 
Phase II Registration Requirements 
 
Informed consent: the patient must be aware of the neoplastic nature of his/her disease and 
willingly consent after being informed of the procedure to be followed, the experimental 
nature of the therapy, alternatives, potential benefits, side-effects, risks, and discomforts. 
Current human protection committee approval of this protocol and a consent form is 
required prior to patient consent and registration. 
 
As part of the enrollment/informed consent procedures, the patient should be counseled on 
the risk of interactions of study medications with other agents, and what to do if new 
medications need to be prescribed or if the patient is considering a new over-the-counter 
medicine or herbal product. 
 
During the consenting process and at a minimum of every 28 days, all patients must be 
counseled about pregnancy precautions and risks of fetal exposure.  
 
Enrollment into the phase II portion of the study will be available to all Alliance sites. 
 
For the Phase II portion of the study, patients will be randomized to one of two intervention 
arms: Arm 1 or Arm 2.  
4.3 
Patient Registration/Randomization  
4.3.1 CTEP Registration Procedures  
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all individuals contributing to NCI-sponsored trials to register and to renew 
their registration annually. To register, all individuals must obtain a Cancer Therapy 
Evaluation Program (CTEP) Identity and Access Management (IAM) account 
 In addition, persons with a registration type of 
Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., 

 
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Update #09 
clinical site staff requiring write access to OPEN, RAVE, or TRIAD or acting as a primary 
site contact) must complete their annual registration using CTEP’s web-based Registration 
and Credential Repository (RCR) 
 Documentation 
requirements per registration type are outlined in the table below. 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, employment, 
license, and certification) 
 
 
 
HSP/GCP training 
 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access 
all CTEP and CTSU (Cancer Trials Support Unit) websites and applications. In addition, 
IVRs and NPIVRs must list all clinical practice sites and IRBs covering their practice sites 
on the FDA Form 1572 in RCR to allow the following: 
 Added to a site roster 
 Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
 Act as the site-protocol PI on the IRB approval 
 Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL). 
Additional 
information 
can 
be 
found 
on 
the 
CTEP 
website 
at 
< 
>. For questions, please contact 
the RCR Help Desk by email at < 
 >. 
4.3.2 CTSU Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval: 
Each investigator or group of investigators at a clinical site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can be approved to enroll patients. Assignment of site 
registration status in the CTSU Regulatory Support System (RSS) uses extensive data to 
make a determination of whether a site has fulfilled all regulatory criteria including but not 
limited to the following: 
 
An active Federal Wide Assurance (FWA) number 
 
An active roster affiliation with the Lead Network or a participating organization 
 
A valid IRB approval 
 
Compliance with all protocol specific requirements. 

 
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Update #09 
 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
 
Active registration status 
 
The IRB number of the site IRB of record listed on their Form FDA 1572 
 
An active status on a participating roster at the registering site. 
Downloading Site Registration Documents: 
Site registration forms may be downloaded from the A061202 protocol page located on the 
CTSU members’ website.   
 
Go to 
and log in to the members’ area using your CTEP-IAM 
username and password 
 
Click on the Protocols tab in the upper left of your screen 
 
Either enter the protocol # in the search field at the top of the protocol tree, or 
 
Click on the By Lead Organization folder to expand 
 
Click on the Alliance link to expand, then select trial protocol A061202 
 
Click on LPO Documents, select the Site Registration Documents link, and 
download and complete the forms provided. 
Requirements for A061202 Site Registration: 
 
IRB approval (For sites not participating via the NCI CIRB; local IRB 
documentation, an IRB-signed CTSU IRB Certification Form, Protocol of Human 
Subjects Assurance Identification/IRB Certification/Declaration of Exemption 
Form, or combination is accepted)  
Submitting Regulatory Documents:  
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal, where they will be entered and tracked in the CTSU RSS. 
Regulatory Submission Portal: 
(members’ area)  Regulatory Tab  Regulatory Submission 
When applicable, original documents should be mailed to: 
 
 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately 
in order to receive further instructions 
and support.  
Checking Your Site’s Registration Status: 
You can verify your site registration status on the members’ section of the CTSU website. 
 
Go to 
and log in to the members’ area using your CTEP-IAM 
username and password 
 
Click on the Regulatory tab 
 
Click on the Site Registration tab 
 
Enter your 5-character CTEP Institution Code and click on Go 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements outlined by the Lead Network. It does not 
reflect compliance with protocol requirements for individuals participating on the protocol 
or the enrolling investigator’s status with the NCI or their affiliated networks. 

 
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Update #09 
4.3.3 OPEN Access Requirements and Procedures 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN). OPEN is a web-based registration system available on a 24/7 basis. To access 
OPEN, the site user must have an active CTEP-IAM account (check at < 
>) and a 'Registrar' role on either the LPO or participating 
organization roster. Registrars must hold a minimum of an AP registration type. 
All site staff will use OPEN to enroll patients to this study. It is integrated with the CTSU 
Enterprise System for regulatory and roster data and, upon enrollment, initializes the patient 
in the Rave database. OPEN can be accessed at 
or from the OPEN tab 
on the CTSU members’ side of the website at 
 To assign an IVR or 
NPIVR as the treating, crediting, consenting, drug shipment (IVR only), or investigator 
receiving a transfer in OPEN, the IVR or NPIVR must list on their Form FDA 1572 in RCR 
the IRB number used on the site’s IRB approval. 
Prior to accessing OPEN, site staff should verify the following: 
 
All eligibility criteria have been met within the protocol stated timeframes. 
 
All patients have signed an appropriate consent form and HIPAA authorization form 
(if applicable). 
Note: The OPEN system will provide the site with a printable confirmation of pre-
registration, registration and treatment information. Please print this confirmation for your 
records.  
To receive site reimbursement for patient participation in A061202-ST1, completion dates 
must be entered in the OPEN Funding screen post registration. Please refer to the protocol 
specific funding page on the CTSU members’ website for additional information. Timely 
entry of completion dates is recommended as this will trigger site reimbursement. 
Further instructional information is provided on the OPEN tab of the CTSU members’ side 
of the CTSU website at 
For any additional 
questions contact the CTSU Help Desk at 
 
Phase I patient enrollment: For the phase I portion of the study, patient enrollment will be 
facilitated using the Slot-Reservation System in conjunction with the Registration system in 
OPEN. Prior to discussing protocol entry with the patient, all site staff must use the CTSU 
OPEN Slot Reservation System to insure that a slot on the protocol is available to the patient.  
Once a site logs into the OPEN system during the phase I portion of the study, the number 
of slots available in the phase I dose assignment will be listed. If the current dose assignment 
is on hold, the OPEN system will indicate that registration is on hold until the next dose 
assignment is available.  
4.4 
Stratification Factors (Phase II) 
At the time of registration, patients will be randomized to treatment independently of each other 
using a dynamic allocation scheme with the following stratification factors: 
1) ISS 1 and 2 disease vs. ISS 3 (current ISS stage based off screening beta 2 microglobulin 
and albumin) 
2) Standard risk vs. high risk cytogenetics 
High risk cytogenetics: del(1p), gain of 1q, t(4;14), t(14;16), t(14; 20), del(17p) 
3) Proteasome inhibitor naïve vs. exposed 

 
 ALLIANCE A061202 
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Update #09 
4.5 
Registration to Correlative and Companion Studies 
4.5.1 Registration to Substudy described in Section 14.0  
As of Update #04, no new patients will be registered to the A061202-ST1 substudy. 
There is the A061202-ST1 substudy within Alliance A061202. This correlative science 
study must be offered to all patients enrolled on the phase II portion of Alliance A061202 
(although patients may opt to not participate). This substudy does not require separate IRB 
approval. The substudy included within Alliance A061202 is: 
• 
“Evalution of the cereblon/IRF-4/c-Myc pathway in resistance to Pomalidomide-based 
therapy”, Alliance A061202-ST1 (Section 14.1) 
If a patient answers “yes” to “Optional Sample Collections for Laboratory Studies,” 
Question #1 in the model consent for Phase II portion of the study “My coded samples and 
related coded information may be used in the research described above to learn about, 
prevent, find, or treat cancer. This may also include research on inherited traits (genes passed 
on in families),” they have consented to participate in the substudy described in Section 
14.1. The patient should be registered to Alliance A061202-ST1 at the same time they are 
registered to the treatment trial (A061202). Samples should be submitted per Section 6.2.  
4.6 
Re-registration at the time of progression (Arm 1 patients only) 
Upon confirmation of progression on Course 1 treatment (pomalidomide and dexamethasone), 
patients may elect to cross-over to Course 2 treatment (3-drug combination). Patients who opt 
to cross over must be re-registered within 14 days of confirmation of progression. Please make 
sure to reassess eligibility (section 3.3) at re-registration. Women of child-bearing potential 
must have a negative pregnancy test within 72 hours prior to re-registration. 
Re-registration procedures: 
OPEN may be accessed at 
from the OPEN tab on the CTSU website at 
 or from the OPEN Registration tab on the Alliance website. 
To enroll a patient within OPEN, institution staff must have: 
1. 
A valid and active CTEP-IAM account. This is the same user ID and password used for 
CTSU’s 
website 
(for 
more 
information 
see 
 
2. 
Enrollment of patients on Alliance coordinated protocols requires a “Registrar” role in the 
Alliance roster. Assignment of the “Registrar” role is managed through the Alliance Central 
Office via submission of a roster update form signed by the Principal Investigator of the member 
network. 
The OPEN system will provide the registering site with a printable confirmation of re-
registration. Please print the confirmation for your records. Further instructional information is 
provided on the CTSU members’ website OPEN tab, or within the OPEN URL. For any 
additional 
questions, 
contact 
the 
CTSU 
Help 
Desk 
at 
 
 
  

ALLIANCE A061202 
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30 
Update #09 
5.0 
STUDY CALENDAR 
Laboratory and clinical parameters during treatment are to be followed using individual institutional 
guidelines and the best clinical judgment of the responsible physician. It is expected that patients on 
this study will be cared for by physicians experienced in the treatment and supportive care of patients 
similar to those on this trial. 
Pre-Study Testing Intervals 
• To be completed ≤ 14 DAYS before registration: All laboratory studies, history and physical, EKG 
• To be completed ≤ 28 DAYS before registration: Bone marrow aspirate and biopsy and baseline 
scans for those with known or clinically suspected extramedullary plasmacytomas. 
• To be completed ≤ 42 DAYS before registration: Skeletal survey. 
5.1 
Main Study Calendar 
All patients in the phase I portion, patients randomized to Arm 2 in phase II, and patients 
randomized to Arm 1 in phase II who have not continued to Course 2 treatment (3 drug regimen) 
will be followed per the study calendar below. Arm 1 patients who opt to receive the 3 drug 
regimen following disease progression must be re-registered to the study and will be 
followed per the study calendar in Section 5.2. 
 
Prior to 
Registration* 
Every 28-day Cycle (±3 days) 
End of 
Treatment 
** 
Clinical 
Follow Up 
*** 
D1 
D15 
D22 
Tests & Observations 
History and physical, weight, PS 
X 
X 
X (1) 
 
X 
X 
Height 
X 
 
 
 
 
 
Pulse, Blood Pressure, Temperature, 
Respiratory Rate.  
X 
X 
X (1) 
 
X 
X 
EKG 
X 
 
 
X (2) 
 
 
Adverse Event Assessment 
 
X 
X (1) 
 
X 
X 
Patient Medication Diary 
 
X (3) 
 
 
X 
 
Registration Fatigue/Uniscale Assessment 
X (4) 
 
 
 
 
 
Laboratory Studies 
Complete Blood Count, Differential, 
Platelets 
X 
X 
X (5) 
 
X 
X 
Serum Sodium, Potassium, Chloride, 
Carbon dioxide, Blood Urea Nitrogen, 
Creatinine Glucose, Calcium, 
Magnesium, Phosphorus, Albumin 
X 
X 
X (5) 
 
X 
X 
LDH and CRP 
X 
 
 
 
 
 
β2-microglobulin 
X 
 
 
 
 
 
AST, ALT, Alkaline Phosphatase, Total 
Bilirubin  
X 
X 
X (1) 
 
X 
X 
Serum or Urine HCG 
X (6) 
X (6) 
 
 
X (6) 
 
Staging 
Tumor (M-protein) Assessment 
X (7) 
X (7) 
 
 
X (7) 
X (7) 
Bone Marrow Aspirate and Biopsy with 
Cytogenetic Evaluation  
X (8) 
X (8) 
 
 
X (8) 
X (8) 
Radiologic Tumor Measurement 
X (9) 
X (9) 
 
 
X (9) 
X (9) 
Skeletal Survey 
X (10) 
 
 
X (10) 
 
 
* 
Labs (including those completed prior to registration) may be used for day 1 of a cycle if obtained ≤ 3 days prior to treatment. 

 
 ALLIANCE A061202 
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31 
Update #09 
Otherwise, they will need to be repeated. Lab values obtained on cycle 1, day 1 must remain within the parameters set in the 
eligibility criteria before starting treatment.  
** An end-of-treatment evaluation should be performed as soon as possible after the last dose of therapy and no later than 4 weeks after 
the end of treatment, regardless of the reason for discontinuation. 
*** After discontinuation of treatment, clinical follow-up visits will occur every 4 weeks until disease progression, death, withdrawal of 
informed consent, or start of new treatment; thereafter, survival information, late adverse events, and data regarding start of new 
treatment (if applicable) are required every 3 months for a maximum of 3 years from registration. See also Section 12.0. Note: Arm 
1 patients who discontinue Course 1 treatment due to progression and who continue onto Course 2 treatment should be followed 
according to the study calendar in Section 5.2. 
1. 
To be obtained during the first two cycles of phase I only. May be obtained in the phase II portion of the study as clinically indicated 
2. 
A repeat EKG is required if a new medication that has the potential to prolong the QTcF interval is started and as clinically indicated. 
3. 
The diary must begin the day the patient starts taking the medication and must be completed per protocol and returned to the treating 
institution OR compliance must be documented in the medical record by any member of the care team. See Appendix VI.  
4. 
To be completed after registration and ≤ 7 days prior to treatment, see Section 1.4 and Appendix III. 
5. 
For patients on the phase II portion of the study and for those on the phase I portion of the study who have completed two cycles of 
therapy, a Day 15 CBC can be performed at a local laboratory not participating in the study provided the results are made available 
to the treating study health care provider within 24 hours. Day 15 chemistries for patients who have completed 2 cycles of therapy 
in phase I and phase II will be performed as clinically indicated and can also be performed at a local laboratory as described above. 
A day 15 CBC for patients who have completed 4 cycles of therapy in phase I and phase II will be performed as clinically indicated. 
6. 
For women of childbearing potential (see Section 3.2.4). Must be done within 10 – 14 days prior to registration and again within 24 
hours prior to initiation of pomalidomide. FCBP with regular or no menstruation must have a pregnancy test weekly for the first 28 
days and then every 28 days while on study treatment (including breaks in treatment); at discontinuation of pomalidomide and at 
day 28 post the last dose of pomalidomide. Females with irregular menstruation must have a pregnancy test weekly for the first 28 
days and then every 14 days while on study treatment (including breaks in treatment), at discontinuation of pomalidomide and at 
Day 14 and Day 28 post the last dose of pomalidomide). A new cycle of pomalidomide cannot be dispensed until a negative 
pregnancy test is confirmed 
7. 
M protein assessment is every 4 weeks (with each cycle of treatment). In addition, please note the assessment for the previous cycle 
should occur before treatment is given on day 1 of the subsequent cycle. Assessment includes: Serum protein electrophoresis (SPEP), 
serum immunofixation, serum free kappa and lambda light chain levels, quantitative serum IgG, IgA and IgM, 24-hour urine protein 
electrophoresis (UPEP) and immunofixation. In order to obtain an accurate determination of response and time of progression, a 
uniform approach to response assessment must be applied, and all measures of M-protein should be performed for all patients on the 
study. For patients with unmeasurable disease on 24-hour UPEP, 24-hour urine testing can be done once every other cycle. Repeat 
testing is required to confirm a response (MR or better) or disease progression and should occur no later than 28 days after 
first documentation of response or progression.  
8. 
A baseline bone marrow aspirate and biopsy should be obtained ≤28 days prior to registration. Although central review will not be 
required, the following information will be captured in the eCRFs: 1) marrow burden of myeloma. Note: flow cytometry should 
NOT be used to assess marrow burden of disease. Marrow burden should be determined by aspirate differential and CD138 
immunohistochemistry. 2) Fluorescent in situ hybridization testing for the following high-risk cytogenetic abnormalities: t(4;14), 
t(14;20), t(14;16), del(17p), del(1p), and gain of 1q21. Plasma cell purification prior to FISH testing is strongly recommended. 
A repeat bone marrow aspirate and biopsy should be performed within 14 days after CR or sCR is documented. For patients with 
non-secretory disease who are being followed for response by serial bone marrow examinations (must have ≥30% involvement of 
the marrow space prior to treatment), a repeat bone marrow aspirate and biopsy should be performed once every 2 cycles until the 
end of treatment and every 12 weeks thereafter until disease progression, death or withdrawal of consent. In these cases, the same 
method to assess marrow burden of disease should be used throughout treatment. 
9. 
Baseline scans can include either: 1) a CT or MRI, or 2) a whole body FDG-PET scan and diagnostic CT performed with both IV 
and oral contrast, and the CT acquired with 5 mm or less slice thickness. Baseline scans are NOT required for those patients who do 
not have documented or suspected measurable extramedullary plasmacytomas at the time of enrollment. Baseline scans are required 
≤28 days prior to registration for those with known or clinically suspected measurable extramedullary disease. Measurable 
extramedullary disease will require monitoring every other cycle (every 8 weeks) while on treatment (i.e. cycle 3, day 1, cycle 5, 
day 1, etc.). An end of treatment scan is required if one has not been performed within the last 8 weeks (unless treatment was stopped 
due to disease progression). Scans will need to be followed once every 12 weeks after treatment has ended until withdrawal of 
consent, disease progression or death, whichever occurs first. The same imaging modality initially used to measure disease at baseline 
should be used over the course of the study to document response/progression 
10. A baseline skeletal survey should be completed ≤42 days prior to registration. Otherwise, the skeletal survey should be repeated only 
as clinically indicated. 
 
 

 
 ALLIANCE A061202 
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32 
Update #09 
5.2 
Arm 1 Course 2 Study Calendar 
Patients randomized to Arm 1 in phase II who opt to receive the 3 drug regimen following 
disease progression must be re-registered to the study and will be followed per the study calendar 
below.  
 
Every 28-day Cycle (±3 days) 
End of 
Treatment** 
Clinical 
Follow Up*** 
D1* 
D15 
D22 
Tests & Observations 
History and physical, weight, PS 
X 
X (1) 
 
X 
X 
Height 
 
 
 
 
 
Pulse, Blood Pressure, 
Temperature, Respiratory Rate.  
X 
X (1) 
 
X 
X 
EKG 
 
 
X (2) 
 
 
Adverse Event Assessment 
X 
X (1) 
 
X 
X 
Patient Medication Diary 
X (3) 
 
 
X 
 
Laboratory Studies 
Complete Blood Count,  
Differential, Platelets 
X 
X (4) 
 
X 
X 
Serum Sodium, Potassium,  
Chloride, Carbon dioxide, Blood 
Urea Nitrogen, Creatinine 
Glucose, Calcium, Magnesium, and 
Phosphorus, Albumin 
X 
X (4) 
 
X 
X 
AST, ALT, Alkaline Phosphatase, 
Total Bilirubin,  
X 
X (1) 
 
X 
X 
Serum or Urine HCG 
X (5) 
 
 
X (5) 
 
Staging 
Tumor (M-protein) Assessment 
X (6) 
 
 
X (6) 
X (6) 
Bone Marrow Aspirate and Biopsy 
with Cytogenetic Evaluation  
 
 
 
X (7) 
X (7) 
Radiologic Tumor Measurement 
 
 
 
X (8) 
X (8) 
Skeletal Survey 
 
 
X (9) 
 
 
* 
Labs may be used for day 1 of a cycle (including those completed prior to re-registration) if obtained ≤ 3 days prior to 
treatment. Otherwise, they will need to be repeated. 
** An end-of-treatment evaluation should be performed as soon as possible after the last dose of therapy and no later than 4 weeks 
after the end of treatment, regardless of the reason for discontinuation. 
*** After discontinuation of treatment, clinical follow-up visits will occur every 4 weeks until disease progression, death, 
withdrawal of informed consent or the start of new treatment. Thereafter, survival information is required every 3 months for a 
maximum of 3 years from re-registration. See also Section 12.0. 
1. 
May be obtained in the phase II portion of the study as clinically indicated 
2. 
A repeat EKG is required if a new medication that has the potential to prolong the QTcF interval is started and as clinically 
indicated. 
3. 
The diary must begin the day the patient starts taking the medication and must be completed per protocol and returned to the 
treating institution OR compliance must be documented in the medical record by any member of the care team. See Appendix 
VI.  
4. 
Day 15 CBC can be performed at a local laboratory not participating in the study provided the results are made available to the 
treating study health care provider within 24 hours. Day 15 chemistries for patients who have completed 2 cycles of therapy 
will be performed as clinically indicated and can also be performed at a local laboratory as described above. A day 15 CBC for 
patients who have completed 4 cycles of therapy will be performed as clinically indicated. 
5. 
For women of childbearing potential. Must be done within 72 hours prior to re-registration and again within 24 hours prior to 
initiation of pomalidomide. FCBP with regular or no menstruation must have a pregnancy test weekly for the first 28 days and 

 
 ALLIANCE A061202 
Version Date: 08/17/2022 
33 
Update #09 
then every 28 days while on study treatment (including breaks in treatment); at discontinuation of pomalidomide and at day 28 
post the last dose of pomalidomide. Females with irregular menstruation must have a pregnancy test weekly for the first 28 
days and then every 14 days while on study treatment (including breaks in treatment), at discontinuation of pomalidomide and 
at Day 14 and Day 28 post the last dose of pomalidomide). A new cycle of pomalidomide cannot be dispensed until a negative 
pregnancy test is confirmed 
6. 
M protein assessment is every 4 weeks (with each cycle of treatment). In addition, please note the assessment for the previous 
cycle should occur before treatment is given on day 1 of the subsequent cycle. Assessment includes: Serum protein 
electrophoresis (SPEP), serum immunofixation, serum free kappa and lambda light chain levels, quantitative serum IgG, IgA 
and IgM, 24-hour urine protein electrophoresis (UPEP) and immunofixation. In order to obtain an accurate determination of 
response and time of progression, a uniform approach to response assessment must be applied, and all measures of M-protein 
should be performed for all patients on the study. For patients with unmeasurable disease on 24-hour UPEP, 24-hour urine 
testing can be done once every other cycle. Repeat testing is required to confirm a response (MR or better) or disease 
progression and should occur no later than 28 days after first documentation of response or progression.  
7. 
A repeat bone marrow aspirate and biopsy should be performed within 14 days after CR or sCR is documented. For patients 
with non-secretory disease who are being followed for response by serial bone marrow examinations (must have ≥30% 
involvement of the marrow space prior to treatment), a repeat bone marrow aspirate and biopsy should be performed once every 
2 cycles until the end of treatment and every 12 weeks thereafter until disease progression, death or withdrawal of consent. In 
these cases, the same method to assess marrow burden of disease should be used throughout treatment. 
8. 
The same imaging modality initially used to measure disease at baseline should be used over the course of the study to document 
response/progression 
9. 
A skeletal survey should be completed prior to start of Course 2 treatment. Otherwise, the skeletal survey should be repeated 
only as clinically indicated. 

ALLIANCE A061202 
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Update #09 
6.0 
DATA AND SPECIMEN SUBMISSION  
6.1 
Data collection and submission 
Data collection for this study will be done exclusively through the Medidata Rave clinical data 
management system. Access to the trial in Rave is granted through the iMedidata application to 
all persons with the appropriate roles assigned in Regulatory Support System (RSS).  To access 
Rave via iMedidata, the site user must have an active CTEP-IAM account (check at < 
>) and the appropriate Rave role (Rave CRA, Read-
Only, Site Investigator) on either the LPO or participating organization roster at the enrolling 
site. To the hold Rave CRA role or CRA Lab Admin role, the user must hold a minimum of an 
AP registration type. To hold the Rave Site Investigator role, the individual must be registered 
as an NPIVR or IVR. Associates can hold read-only roles in Rave. 
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned 
on the appropriate roster will be sent a study invitation e-mail from iMedidata.  To accept the 
invitation, site users must log into the Select Login
 
using their CTEP-IAM user name and password, and click on the “accept” link in the upper 
right-corner of the iMedidata page. Please note, site users will not be able to access the study in 
Rave until all required Medidata and study specific trainings are completed.  Trainings will be 
in the form of electronic learnings (eLearnings), and can be accessed by clicking on the link in 
the upper right pane of the iMedidata screen. 
Users that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata 
to activate their account.  Account activation instructions are located on the CTSU website, Rave 
tab under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance). Additional information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab at 
or by contacting the CTSU Help Desk at 
 
6.2 
Specimen collection and submission  
Central histopathology review is not required on this study. However, a baseline bone marrow 
aspirate and biopsy should be obtained ≤28 days prior to registration. The following information 
from the baseline bone marrow will be captured in the eCRFs:  
1. Marrow burden of myeloma. Note: flow cytometry should NOT be used to assess marrow 
burden of disease. Marrow burden should be determined by aspirate differential and CD138 
immunohistochemistry.  
2. Fluorescent in situ hybridization testing for the following high-risk cytogenetic 
abnormalities: t(4;14), t(14;20), t(14;16), del(17p), del(1p) and gain of 1q21. Plasma cell 
purification prior to FISH testing is strongly recommended. 
Submission of source documentation detailing the above results will be required. 
To minimize the number of bone marrow core biopsies performed, the bone marrow block from 
the initial staging evaluation (obtained in all patients) will be used for the pre-treatment 
immunohistochemical correlative studies for those patients that agree to participate in Alliance 
sub-study A061202-ST1.  

 
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Update #09 
6.2.1 Alliance Substudy A061202-ST1 
As of Update #04, no new patients will be registered to the A061202-ST1 substudy.  
For patients registered to substudy A061202-ST1: All participating institutions must ask 
patients for their consent to participate in the correlative substudies planned for Alliance 
A061202-ST1, although patient participation is optional. Biomarker studies will be 
performed. Rationale and methods for the scientific components of these studies are 
described in Section 14.0. For patients who consent to participate, formalin fixed paraffin 
embedded (FFPE) bone marrow biopsy tissue and, fresh liquid bone marrow aspirate sample 
will be collected at baseline (at the time of the staging bone marrow aspirate and biopsy) 
and at disease progression for those who achieve a ≥MR with initial therapy. 
 
Prior to initiation 
of therapy  
Attainment of 
complete 
remission 
At first disease 
Progression* 
Submit to: 
For patients registered to A061202-ST11, submit the following:  
Formalin fixed 
paraffin embedded 
block of bone 
marrow OR Bone 
Marrow Biopsy Slides 
(See section 6.2.4) 
X** 
 
X** 
ABOSU 
Fresh, liquid bone 
marrow aspirate  
5 mL in 1 or 2 
EDTA/lavender top 
tubes*** 
 
5 mL in 1 or 2 
EDTA/lavender top 
tubes*** 
Alliance 
Hematologic 
Malignancy 
Biorepository 
* 
Samples are expected from Arm 1 patients after progression on Pomalidomide + Dexamethasone 
and from Arm 2 patients after progression on Pomalidomide + Dexamethasone + Ixazomib. 
Progression samples may be collected and submitted up to 1 month after progression but must be 
obtained prior to the start of a new treatment regimen. 
** 
Bone marrow blocks/cores to be used for biomarker/TMA analyses described in Section 14.1.3 
*** Bone marrow aspirates to be used for biomarker analyses described in Section 14.1.3 
1. 
Collect and submit only from patients who consent to model consent questions #1, 2 and 3. Also 
please note: A061202-ST1 is only for patients on the phase II study. 
6.2.2 Specimen submission using the Alliance Biospecimen Management System (For 
A061202-ST1) 
USE OF THE ALLIANCE BIOSPECIMEN MANAGEMENT SYSTEM (BioMS) IS 
MANDATORY AND ALL SPECIMENS MUST BE LOGGED AND SHIPPED VIA THIS 
SYSTEM.  
BioMS is a web-based system for logging and tracking all biospecimens collected on 
Alliance trials. Authorized individuals may access BioMS at the following URL: 
using most standard web browsers (Safari, Firefox, Internet 
Explorer). For information on using the BioMS system, please refer to the ‘Help’ links on 
the BioMS web page to access the on-line user manual, FAQs, and training videos.  To 
report technical problems, such as login issues or application errors, please contact: 
For assistance in using the application or questions or problems related to 
specific specimen logging, please contact: 
 

 
 ALLIANCE A061202 
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Update #09 
After logging collected specimens in BioMS, the system will create a shipping manifest. 
This shipping manifest must be printed and placed in the shipment container with the 
specimens. 
All submitted specimens must be labeled with the protocol number (A061202), Alliance 
patient number, patient’s initials and date and type of specimen collected (e.g., serum, whole 
blood). 
A copy of the Shipment Packing Slip produced by BioMS must be printed and placed in the 
shipment with the specimens. 
Instructions for the collection of samples are included below. Please be sure to use a method 
of shipping that is secure and traceable. Extreme heat precautions should be taken when 
necessary.  
6.2.3 Bone Marrow Aspirate Submission (Alliance A061202-ST1) 
From all patients, collect 5 mL of bone marrow aspirate prior to initiation of therapy and at 
disease progression (for those with ≥MR), in an EDTA tube. If a patient has a dry tap, please 
submit the requested biopsy without the bone marrow aspirate. 
Specimens for patients registered on this study must be logged and shipped using the online 
Alliance BioMS, as described above. 
The specimens should be labeled with the study number (A061202), Alliance patient ID, 
patient’s initials, institution, and date and time of specimen procurement, and sample type. 
A copy of the Shipment Packing Slip produced by the BioMS must be printed and placed in 
the shipment with the specimens. Specimens should be sent at ambient temperature on 
the same day as collection to the Alliance Hematologic Malignancy Biorepository: 
Alliance Hematologic Malignancy Biorepository  
 
 
 
 
 
 
 
Ship specimens by overnight courier to the Alliance Hematologic Malignancy Biorepository 
the same day they are collected. Shipment on Monday through Thursday by overnight 
service to assure receipt is encouraged. Do not ship specimens on Fridays or Saturdays. 
Please be sure to use a method of shipping that is secure and traceable.  
For the baseline bone marrow aspirate submission: Because sites may be awaiting local 
lab results to confirm eligibility on the day of specimen collection, patients may not yet be 
registered in order to obtain a patient ID number for logging these specimens in BioMS. In 
this case, please use the “BioMS Specimen Log and Shipping Manifest Form” for 
submission of the prior to initiation of therapy bone marrow aspirate. The form is posted on 
the “Supplemental Materials” page of the A061202 study page on the Alliance website. 
Please follow all instructions on the form. A copy of this form must accompany specimens 
with the shipment. The CRA responsible for the specimens MUST contact the biorepository 
to inform them of patient registration IDs AND screen failures once an eligibility 
determination has been made locally. Once patients are registered to the trial, their 
specimens should be backlogged in BioMS, and the packing slip created must be forwarded 
to the biorepository.  

 
 ALLIANCE A061202 
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Update #09 
6.2.4 Paraffin-Embedded Block of Bone Marrow (A061202-ST1) 
For patients who consent to participate in A061202-ST1, bone marrow blocks will be used 
for the analyses described in Section 14.1.2. The bone marrow block obtained at the time of 
the baseline staging bone marrow aspirate and biopsy will be used as the baseline biopsy for 
those participating in A061202-ST1. 
Paraffin blocks of formalin fixed bone marrow tissue obtained prior to initiation of therapy 
and at disease progression should be sent to the Alliance Biorepository at Ohio State 
University (ABOSU).  
The Alliance has instituted special considerations for the small percentage of hospitals 
whose policy prohibits long-term storage of blocks, and the smaller percentage of hospitals 
whose policies prohibit release of any block. Those institutions unable to send the formalin 
fixed paraffin embedded bone marrow biopsy tissue block may instead send 12 unstained 
bone marrow biopsy tissue sections, 3-4 microns thick on charged glass slides appropriate 
for immunohistochemical staining. These should be sent to the Alliance Biorepository at 
Ohio State University (ABOSU) at the address below. If there are questions about this policy, 
please call the ABOSU at 
 
The goal of the ABOSU is to provide investigators with quality histology sections for their 
research while maintaining the integrity of the tissue. All paraffin blocks that are to be stored 
at the ABOSU will be vacuum packed to prevent oxidation and will be stored at 4º C to 
minimize degradation of cellular antigens. For these reasons it is preferred that the ABOSU 
bank the block until the study investigator requests thin sections. Please contact the ABOSU 
if additional assurances with your hospital pathology department are required. 
The specimens should be labeled with the study number (A061202), Alliance patient ID, 
patient’s initials, institution, and date and time of specimen procurement, and sample type. 
A copy of the Shipment Packing Slip produced by the BioMS must be printed and placed in 
the shipment with the specimens. Specimens should be sent at ambient temperature to the 
Alliance Biorepository at Ohio State University (ABOSU): 
Innovation Centre  
  
 
  
  
 
Ship specimens by overnight courier to the Alliance ABOSU Monday through Thursday by 
overnight service to assure receipt is encouraged. Do not ship specimens on Fridays or 
Saturdays. Please be sure to use a method of shipping that is secure and traceable. Ship 
specimens to the Alliance ABOSU. 
7.0 
TREATMENT PLAN/INTERVENTION 
Protocol treatment is to begin ≤ 7 days of registration.  
Pomalidomide, dexamethasone and ixazomib are administered as flat doses and not based on weight 
or body surface area. Pomalidomide should be administered at approximately the same time each day. 
Please refer to Section 8.1 for ancillary/supportive therapy, Section 8.2 for instructions regarding 
dose modifications and Section 10.0 for drug formulation, availability and preparation. 
It is acceptable for individual chemotherapy doses to be delivered ≤ a 24-hour (business day) window 
before and after the protocol-defined date for Day 1 of a new cycle. For example, if the treatment due 
date is a Friday, the window for treatment includes the preceding Thursday through the following 
Monday. If a patient forgets to take their dexamethasone or ixazomib on the scheduled day, they can 

 
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take it up to 72 hours late. If >72 hours have elapsed, the dose should be omitted and not made up. 
Subsequent doses of dexamethasone and ixazomib will be administered on the original schedule. 
Missed pomalidomide doses will not be made up. In addition, patients are permitted to have a new 
cycle of chemotherapy delayed up to 7 days for major life events (e.g., serious illness in a family 
member, major holiday, vacation that cannot be rescheduled) without this being considered a protocol 
violation. Documentation to justify this delay should be provided. Treatment will continue until 
disease progression, unacceptable toxicity despite appropriate supportive care and dose 
modifications, or withdrawal of informed consent. 
7.1 
Phase I (Description/Treatment Plan)/ Definition of DLT 
All patients on the phase I portion of the study will receive the combination of pomalidomide, 
dexamethasone and ixazomib. The dose of pomalidomide and ixazomib will be dictated by the 
dose cohort to which a patient is assigned. All patients will receive either a 40 mg (≤75 years 
old) or 20 mg (>75 years old) dose of dexamethasone. Patients will be assigned to a new dose 
cohort only after it has been determined that the MTD has not been exceeded in the previous 
dose cohort (see Section 13.0 for details).  
Protocol therapy will consist of pomalidomide, dexamethasone and ixazomib administered over 
a 28-day cycle. Pomalidomide will be administered orally on days 1 through 21. It is 
recommended that pomalidomide be taken at night. Ixazomib will be given orally on days 1, 8 
and 15. Patients ≤ 75 years of age will receive a 40 mg dose of dexamethasone and those over 
the age of 75 will receive a 20 mg dose of dexamethasone orally on days 1, 8, 15 and 22 (weekly). 
Dexamethasone should be taken with food, preferably in the morning when possible. A patient 
medication diary will be used to assess adherence to therapy. 
Please refer to Section 5.0 for details regarding required evaluations (history and physicals, vital 
signs and performance status assessment, laboratory testing, myeloma assessments, etc). 
Given the increased risk of venous thromboembolic events with the use of pomalidomide and 
dexamethasone, thromboprophylaxis is required while patients are on protocol therapy and 
should consist of either aspirin (81 mg or 325 mg daily), a prophylactic dose of low molecular 
weight heparin (e.g. enoxaparin 40 mg SC daily), warfarin targeting an INR of 2 – 3, or other 
equivalent. Thromboprophylaxis should be held in the presence of ≥grade 3 thrombocytopenia 
(see section 8.2 for details). For patients with poor oral intake and frequent ≥grade 3 
thrombocytopenia, low molecular weight heparin is preferred over warfarin. 
Proteasome inhibitor-based therapy is associated with an increased risk of herpes zoster 
reactivation. As such, patients on treatment with ixazomib are required to receive herpes zoster 
reactivation prophylaxis (e.g. valacyclovir 500 mg orally once to twice daily or its equivalent).  
For the phase I portion of the protocol, filgrastim, sargramostim and pegfilgrastim cannot be 
used during cycle 1 of therapy but can be used in subsequent cycles as clinically indicated (see 
sections 8.1 and 8.2 for details).  
Given the high rates of pneumonia seen in this patient population, anti-bacterial prophylaxis is 
recommended for patients with ≥grade 3 neutropenia (e.g. levofloxacin or its equivalent) and/or 
significant immunoparesis (low immunoglobulin levels). 
Please see section 8.1 for additional information regarding ancillary therapy. 
A new cycle of therapy cannot begin until the ANC has recovered to 1.0 x 109/L, the platelet 
count to 50 x 109/L and all other criteria for resumption of therapy have been met (please refer 
to section 8.2 for details). 

 
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7.1.1 Phase I- Determination of Maximum Tolerated Dose (MTD) 
Dose Levels 
All patients on the phase I portion of the study will receive the combination of pomalidomide, 
dexamethasone and ixazomib. The dose of pomalidomide and ixazomib will be dictated by 
the dose cohort to which a patient is assigned. All patients will receive either a 40 mg (≤75 
years old) or 20 mg (>75 years old) dose of dexamethasone. Patients will be assigned to a 
new dose cohort only after it has been determined that the MTD has not been exceeded in 
the previous dose cohort (see section 13.0 for details). 
Table 7.1.1- Phase I Dose Finding Plan 
Dose level 
Pomalidomide (mg) 
Days 1 – 21 
Dexamethasone (mg) 
Days 1, 8, 15, 22 
Ixazomib (mg) 
Days 1, 8, 15 
0 
2 
40 (20 for > 75 years) 
2.3 
*1 
2 
40 (20 for > 75 years) 
3 
2 
3 
40 (20 for > 75 years) 
3 
3 
4 
40 (20 for > 75 years) 
3 
4 
4 
40 (20 for > 75 years) 
4 
* 
Starting dose level  
 
If cohort 2 is the maximum tolerated dose, a dose level 2A will be pursued evaluating 
a 2 mg dose of pomalidomide and 4 mg dose of ixazomib. If cohort 3 is the maximum 
tolerated dose, a dose level 3A will be pursued evaluating a 3 mg dose of pomalidomide 
and 4 mg dose of ixazomib. 
 
Three to 6 patients will be treated at each dose level and observed for a minimum of 
28 days to assess adverse events in cycle 1 before new patients are treated. Intra-patient 
escalation of dosing is allowed if it has been determined that the MTD has not been 
exceeded for the next dose level, and the patient has not required any dose 
modifications or delays as a result of adverse events related to protocol therapy. 
Patients who have had their dexamethasone dose reduced as a result of AEs will be 
eligible for dose escalation of the pomalidomide and ixazomib if they otherwise meet 
criteria to do so. The MTD will be determined by DLTs seen in cycle 1 of therapy 
(please refer to section 13.1 for details regarding definition of the MTD and criteria for 
dose level escalation and de-escalation). 
 
Phase I conference calls will be held every other week and are mandatory for all sites 
with a patient registered on the phase I portion of the study. These calls will be used to 
review adverse events, assess study enrollment and address any questions that arise 
over the course of the study. These calls can be attended by the Principal Investigator, 
a Co-Investigator or Study Coordinator at that site. In addition, a Dose Escalation 
conference call will be held immediately after a dose cohort has completed accrual and 
all patients have been treated for 28 days (1 cycle). All phase I Principal Investigators 
should participate in these calls.  
7.1.2 Definitions of DLT 
DLTs will be determined during cycle 1 of therapy. Adverse events will be graded per 
CTCAE, version 4.0.  
For this protocol, DLT will be defined by the following adverse events at least possibly 
related to study therapy: 
Grade 3 or higher non-hematologic adverse events, with the following exceptions: 
 
Alopecia is not expected but is not considered a DLT 

 
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 
Nausea, vomiting and diarrhea will only be considered DLTs if they cannot be 
adequately managed with optimal supportive care (see section 8.1 and 8.2) 
 
Grade 3 or 4 hypergylcemia due to dexamethasone will only be considered a DLT if it 
cannot be controlled with appropriate therapy. 
Grade 4 hematologic adverse events, with the following exceptions: 
 
Grade 4 lymphopenia is expected with this regimen and will not be construed as a DLT 
 
Grade 4 neutropenia will only be considered a DLT if it lasts longer than 7 days  
 
Grade 4 thrombocytopenia will only be considered a DLT if it lasts longer than 7 days 
or is associated with a ≥grade 3 bleeding event. 
The maximum tolerated dose is the dose level where at most 1 out of 6 patients treated at 
that dose level report a DLT and the next higher dose level is such that 2 or more patients 
treated at that dose level reported a DLT. If the planned dose levels are exhausted without 
observing a dose level where 2 or more patients treated at that dose level reported a DLT 
then the recommended phase II dose will be dose level #4 (the highest dose level tested). 
7.2 
Phase II Description/Treatment Plan 
Patients on the phase II portion of the study will be randomly assigned to the combination of 
pomalidomide and dexamethasone (Treatment Arm 1) or the combination of pomalidomide, 
dexamethasone and ixazomib (Treatment Arm 2). The dose of pomalidomide and 
dexamethasone in Treatment Arm 1 will be the same as the FDA approved dosing for the 
combination (see below). In Treatment Arm 2, the dose of pomalidomide will be 4 mg and the 
dose of ixazomib will be 4 mg. All patients will receive either a 40 mg (≤75 years old) or 20 mg 
(>75 years old) dose of dexamethasone.  
Treatment Arm 1: Pomalidomide and dexamethasone 
Protocol therapy will consist of pomalidomide and dexamethasone administered over a 28-day 
cycle. Pomalidomide will be administered at 4 mg orally daily for days 1 through 21. It is 
recommended that pomalidomide be taken at night. Patients ≤ 75 years of age will receive a 40 
mg dose of dexamethasone and those over the age of 75 will receive a 20 mg dose of 
dexamethasone orally on days 1, 8, 15 and 22 (weekly). Dexamethasone should be taken with 
food, preferably in the morning when possible. A patient medication diary will be used to assess 
adherence to therapy.  
At the time of progression: If a patient experiences disease progression on pomalidomide and 
dexamethasone alone (as defined in section 11.0), they will be allowed to continue on to Course 
2 treatment, where they will receive the combination of pomalidomide, dexamethasone and 
ixazomib. Patients should remain on the dose of pomalidomide and dexamethasone they 
tolerated in Course 1. The ixazomib dose should be 4 mg. Note: Patients who opt to continue to 
Course 2 treatment must be re-registered to the study within 14 days of confirmation of 
progression per section 4.6. Treatment should begin ≤ 3 days following re-registration. 
Treatment Arm 2: Pomalidomide, dexamethasone and ixazomib 
Protocol therapy will consist of pomalidomide, dexamethasone and ixazomib administered over 
a 28-day cycle. Pomalidomide will be administered at 4 mg orally daily for days 1 through 21. 
It is recommended that pomalidomide be taken at night. Patients ≤ 75 years of age will receive 
a 40 mg dose of dexamethasone and those over the age of 75 will receive a 20 mg dose of 
dexamethasone orally on days 1, 8, 15 and 22 (weekly). Dexamethasone should be taken with 
food, preferably in the morning when possible. Ixazomib will be administered at 4 mg orally on 
days 1, 8 and 15. A patient medication diary will be used to assess adherence to therapy.  

 
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Ancillary Therapy for Patients on Treatment Arms 1 and 2 
Please refer to section 5.0 for details regarding required evaluations (history and physicals, vital 
signs and performance status assessment, laboratory testing, myeloma assessments, etc). 
Given the increased risk of venous thromboembolic events with the use of pomalidomide and 
dexamethasone, thromboprophylaxis is required while patients are on protocol therapy and 
should consist of either aspirin (81 mg or 325 mg), a prophylactic dose of low molecular weight 
heparin (e.g. enoxaparin 40 mg SC daily) or warfarin targeting an INR of 2 – 3, or other 
equivalent. Thromboprophylaxis should be held in the presence of ≥grade 3 thrombocytopenia 
(see section 8.2 for details). For patients with poor oral intake and frequent ≥grade 3 
thrombocytopenia, low molecular weight heparin is preferred over warfarin. 
Proteasome inhibitor-based therapy is associated with an increased risk of herpes zoster 
reactivation. As such, patients on treatment with ixazomib are required to receive herpes zoster 
reactivation prophylaxis (e.g. valacyclovir 500 mg orally once to twice daily or its equivalent). 
Filgrastim, sargramostim and pegfilgrastim can be used at any time during the study as clinically 
indicated (see sections 8.1 and 8.2 for details). 
Given the high rates of pneumonia seen in this patient population, anti-bacterial prophylaxis is 
recommended for patients with ≥grade 3 neutropenia (e.g. levofloxacin or its equivalent) and/or 
significant immunoparesis (low immunoglobulin levels). 
Please see section 8.1 for additional information regarding ancillary therapy. 
A new cycle of therapy cannot begin until the ANC has recovered to 1.0 x 109/L, the platelet 
count to 50 x 109/L and all other criteria for resumption of therapy have been met (please refer 
to section 8.1 and 8.2 for details). 
Table 7.2a: Phase II Dosing – Treatment Arm 1 
Agent 
Dose 
Route 
Days 
Course 1 
Pomalidomide 
4 mg 
Orally 
Days 1 – 21 
Dexamethasone 
40 mg (20 mg for those 
> 75 years of age) 
Orally 
Days 1, 8, 15 and 22 
Course 2* 
Pomalidomide 
Dose tolerated in 
Course 1 
Orally 
Days 1 – 21 
Dexamethasone 
Dose tolerated in 
Course 1 
Orally 
Days 1, 8, 15, and 22 
Ixazomib 
4 mg 
Orally 
Days 1, 8, and 15 
* Following progression on Course 1 treatment, patients in Arm 1 may opt to receive Course 2 
treatment. These patients must be re-registered to the study prior to starting Course 2. 
Table 7.2b: Phase II Dosing – Treatment Arm 2 
Agent 
Dose 
Route 
Days 
Pomalidomide 
4 mg  
Orally 
Days 1 – 21 
Dexamethasone 
40 mg (20 mg for those 
> 75 years of age) 
Orally 
Days 1, 8, 15 and 22 
Ixazomib  
4 mg 
Orally 
Days 1, 8 and 15 

 
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8.0 
DOSE AND TREATMENT MODIFICATIONS 
8.1 
Ancillary therapy, concomitant medications, and supportive care 
 
Suspend thromboprophylaxis in presence of platelet count < 50,000. Resume prophylaxis 
as soon as platelet count ≥ 50,000. If bleeding requiring medical intervention occurs while 
on thromboprophylaxis, treating physician should weigh risks and benefits of continuing 
thromboprophylaxis. 
 
For dyspepsia due to dexamethasone, institute H2 blocker or proton pump inhibitor 
 
For edema due to dexamethasone, institute diuretic as clinically appropriate 
8.1.1 Patients should not receive any other agent which would be considered treatment for 
the primary neoplasm or impact the primary endpoint. 
8.1.2 Patients should receive full supportive care while on this study. This includes blood 
product support (e.g. packed red blood cells and platelets), antibiotic treatment, and 
treatment of other newly diagnosed or concurrent medical conditions. All blood products 
and concomitant medications such as antibiotics, antidiarrheals, analgesics, and/or 
antiemetics received from the first day of study treatment administration until the end of 
treatment visit will be recorded in the medical records. 
8.1.3 Treatment with hormones or other chemotherapeutic agents may not be administered 
except for steroids given for adrenal failure or hormones administered for non-disease-
related conditions (e.g., insulin for diabetes). Use of dexamethasone and other steroidal 
antiemetics is prohibited in this protocol. Patients who need a therapeutic course of a 
corticosteroid for a non-myeloma related condition (e.g. bronchospasm related to a 
respiratory tract infection) should be discussed with the Study Chair. For more urgent 
corticosteroid indications, treatment may proceed and discussed with the Study Chair 
thereafter. Any corticosteroid administration should be documented, along with reason for 
treatment and doses. 
8.1.4 Antiemetics may be used at the discretion of the treating physician and are strongly 
encouraged given the fact that nausea and vomiting are expected side effects of this 
treatment regimen.  
8.1.5 Diarrhea: This should be managed conservatively with loperamide or its equivalent. The 
recommended dose of loperamide is 4 mg at first onset of diarrhea, followed by 2 mg every 
2-4 hours until diarrhea free (maximum 16 mg/day). 
In the event of grade 3 or 4 diarrhea, the following supportive measures are allowed: 
hydration, octreotide, and antidiarrheals.  
If grade 3 or 4 diarrhea is associated with fever or neutropenia (grade 3 or 4), broad-spectrum 
antibiotics should be prescribed. Patients with grade 3 or 4 diarrhea or any diarrhea 
associated with nausea and vomiting should be evaluated for need of intravenous fluids, 
correction of electrolyte imbalances, and consideration for whether hospitalization is 
necessary. 
8.1.6 Radiation Therapy. Palliative radiation therapy while on study treatment may not be 
administered with the exception of radiation therapy to a pathological fracture site to 
enhance bone healing or to treat post-fracture pain that is refractory to narcotic analgesics. 
Symptomatic lesions, or ones that may produce disability (e.g., unstable femur) should be 
irradiated prior to study initiation, provided other measurable disease is present. Please hold 

 
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dexamethasone, pomalidomide and ixazomib if radiation therapy is performed, treatment 
can resume as soon as radiation therapy is complete.  
Patients who require radiation therapy during protocol treatment for reasons other than the 
exceptions outlined above will be removed from protocol therapy due to disease progression.  
8.1.7 Alliance Policy Concerning the Use of Growth Factors 
Blood products and growth factors should be utilized as outlined in the protocol (see section 
8.2) and as clinically warranted following institutional policies and recommendations.  
Epoetin (EPO): Please note that there is an increased risk of thrombosis related to EPO. As 
such, given the additional risk of thrombosis with pomalidomide-based therapy, caution 
must be exercised when using it in this patient population and its routine use discouraged. 
Filgrastim (G-CSF) and sargramostim (GM-CSF) 
1. Utilization of filgrastim (G-CSF)/pegfilgrastim and sargramostim (GM-CSF) for 
management of neutropenia encountered on this study should follow guidelines 
outlined in the dose modifications section (see section 8.2). GCSF/GMCSF is not 
permitted in patients during cycle 1 of treatment in the phase I study.  
2. The use of white blood cell growth factors not otherwise specified in the protocol 
should follow published guidelines of the American Society of Clinical Oncology 2006 
Update of Recommendations for the Use of White Blood Cell Growth Factors: An 
Evidence-Based, Clinical Practice Guideline. J Clin Oncol 24(19): 3187-3205, 2006. 
3. Filgrastim/pegfilgrastim and sargramostim may not be used: 
a. To avoid dose reductions, delays or to allow for dose escalations specified in the 
protocol. 
b. For the treatment of febrile neutropenia the use of CSFs should not be routinely 
instituted as an adjunct to appropriate antibiotic therapy. However, the use of CSFs 
may be indicated in patients who have prognostic factors that are predictive of 
clinical deterioration such as pneumonia, hypotension, multi-organ dysfunction 
(sepsis syndrome) or fungal infection, as per the ASCO guidelines.  Investigators 
should therefore use their own discretion in using the CSFs in this setting.  The use 
of CSF (filgrastim/pegfilgrastim or sargramostim) must be documented and 
reported. 
c. If filgrastim/pegfilgrastim or sargramostim are used, they must be obtained from 
commercial sources. 
8.1.8 Bisphosphonates (e.g. zoledronic acid, pamidronic acid) may be used at the discretion of 
the treating physician. 
8.1.9 Thromboprophylaxis. The combination of pomalidomide and dexamethasone increases 
the risk of venous thromboembolic events. As such, thromboprophylaxis is required for all 
patients on this study. Thromboprophylaxis may consist of either aspirin (81 or 325 mg 
daily), a prophylactic dose of low molecular weight heparin (e.g. enoxaparin 40 mg SC 
daily), warfarin, targeting an INR of 2 – 3 or an equivalent strategy. However, 
thromboprophylaxis should be held for those patients who experience ≥grade 3 
thrombocytopenia. For patients with poor oral intake and frequent ≥grade 3 
thrombocytopenia, low molecular weight heparin is preferred over warfarin. 
Smoking cessation, avoiding dehydration, and avoiding extended periods of inactivity 
should be encouraged to decrease risk of thrombosis.  

 
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8.1.10 Herpes zoster reactivation prophylaxis. Patients on proteasome inhibitor-based regimens 
are at increased risk of herpes zoster reactivation. Therefore, all patients who receive 
ixazomib should receive appropriate prophylaxis (e.g. valacyclovir 500 mg orally once to 
twice daily or its equivalent). Patients receiving only pomalidomide and dexamethasone on 
Treatment Arm 1 of the phase II portion of the study do not need to receive herpes zoster 
reactivation prophylaxis unless they cross-over to receive ixazomib. 
8.1.11 Bacterial infection prophylaxis. Prophylaxis against bacterial infection is not mandated. 
However, it must be recognized that participants on this study represent a patient population 
at high risk of bacterial infections due to the presence of immunoparesis and frequent 
neutropenia. Additionally, ≥grade 3 pneumonia was a common adverse event encountered 
in pomalidomide studies. Therefore, anti-bacterial prophylaxis is strongly recommended for 
patients with ≥grade 3 neutropenia and/or significant immunoparesis (low immunoglobulin 
levels) (e.g. a fluoroquinolone or its equivalent). In addition, use of prophylactic IVIG 
therapy is allowed if clinically indicated. 
8.1.12 Strong CYP3A4 and CYP1A2 inducers and inhibitors: Use of strong CYP3A4 and 
CYP1A2 inducers or inhibitors is not allowed while patients are treated on this study. 
Patients should be educated on potential drug interactions. A wallet-size card providing 
information for patients regarding potential drug interactions has been made available at the 
study-specific page of the CTSU. Please refer to Appendix V for a list of strong inhibitors 
and inducers of CYP3A4 and CYP1A2.  
8.1.13 Patients with impaired renal function, high tumor burdens, and diabetes and obesity may be 
at increased risk for tumor lysis syndrome (TLS) with pomalidomide-based therapy. As such, 
consider increased monitoring for TLS during cycle 1 in these patients. 
8.1.14 Patients should be encouraged to receive pneumococcal and influenza vaccinations if 
appropriate.  
8.2 
Dose Modifications General Principles: 
 
GCSF/GMCSF are not permitted in patients during cycle 1 of treatment in the phase 
I study unless a DLT has already occurred and their use is indicated. 
 
If the start of a new cycle of therapy is delayed for >21 days beyond the originally planned 
start date as a result of adverse events at least possibly attributable to study treatment, 
protocol therapy will be discontinued.  
 
Omitted doses of therapy should not be made up.  If more than 7 days of treatment in any 
individual cycle are missed, the remainder of the cycle should be omitted and dosing 
resumed with the next cycle of therapy. 
 
If multiple adverse events are seen, administer dose based on the greatest reduction required 
for any single adverse event observed. Reductions or increases apply to treatment given in 
the preceding cycle and are based on adverse events observed since the prior evaluation. 
 
Pomalidomide, dexamethasone and ixazomib will not be re-escalated once dose reduced. 
 
A new cycle of therapy cannot begin until the ANC has recovered to 1.0 x 109/L, the platelet 
count to 50 x 109/L, and all other protocol therapy related and unrelated adverse events have 
improved to grade 1 or baseline. If grade 2 toxicities persist but the treating physician feels 
it is in the best interested of the patient to continue therapy (e.g. fatigue), contact the Study 
Chair to help determine the best course of action. 
 
If an adverse event can be attributed to a specific agent or agents, the non-implicated agent(s) 
may be continued without modification of the dose or schedule if appropriate.  

 
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 
Dose delays may occur as a result of adverse events that are related or unrelated to protocol 
therapy. However, dose modifications and drug discontinuations will only be applied to 
adverse events that are at least possibly related to protocol therapy.  
8.2.1 Pomalidomide Dose Levels 
Please note that the pomalidomide starting dose in the phase I portion of the protocol will 
be dictated by the dose level to which the patient is assigned. 
Table 8.2.1-Pomalidomide Dose Levels  
Dose 
Level 
Pomalidomide 
(Days 1 – 21 of a 
28-day cycle) 
 Pomalidomide 
(Days 1 – 21 of a 
28-day cycle) 
Pomalidomide 
(Days 1 – 21 of a 
28-day cycle) 
0* 
 
4 mg 
3 mg 
2 mg 
-1 
 
3 mg 
2 mg 
1 mg 
-2 
 
2 mg 
1 mg 
Not applicable 
-3 
1 mg 
Not applicable 
Not applicable 
*Dose level 0 refers to the starting dose. 
8.2.2 Ixazomib Dose Levels 
Please note that the ixazomib starting dose in the phase I portion of the protocol will be 
dictated by the dose level to which the patient is assigned. 
Table 8.2.2- Ixazomib Dose Levels 
Dose 
Level 
Ixazomib (Days 1, 
8 and 15 of a 28-
day cycle) 
Ixazomib (Days 
1, 8 and 15 of a 
28-day cycle) 
Ixazomib (Days 
1, 8 and 15 of a 
28-day cycle) 
0* 
 
4 mg 
3 mg 
2.3 mg 
-1 
 
3 mg 
2.3 mg 
Not applicable 
-2 
 
2.3 mg 
Not applicable 
Not applicable 
*Dose level 0 refers to the starting dose. 
8.2.3 Dexamethasone Dose Levels 
The starting dose for dexamethasone is 40 mg for patients ≤ 75 years of age, 20 mg for 
patients >75 years of age. 
Table 8.2.3- Dexamethasone Dose Levels 
Dose 
Level 
Dexamethasone 
(Days 1, 8, 15, 22 
of a 28-day cycle) 
Dexamethasone 
(Days 1, 8, 15, 22 
of a 28-day cycle) 
0* 
 
40 mg 
20 mg 
-1 
 
20 mg 
12 mg 
-2 
 
12 mg 
8 mg 

 
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Dose 
Level 
Dexamethasone 
(Days 1, 8, 15, 22 
of a 28-day cycle) 
Dexamethasone 
(Days 1, 8, 15, 22 
of a 28-day cycle) 
-3 
8 mg 
Not applicable 
*Dose level 0 refers to the starting dose. 
8.3 
Dose Modification Guidelines for Pomalidomide and Ixazomib: 
 
A new cycle of therapy cannot begin until the ANC has recovered to 1.0 x 109/L, the platelet 
count to 50 x 109/L, and all other protocol therapy-related and -unrelated adverse events 
have improved to grade 1 or baseline. If grade 2 toxicities persist but the treating physician 
feels it is in the best interest of the patient to continue therapy (e.g. fatigue), contact the 
Study Chair to help determine the best course of action. 
 
If an adverse event can be attributed to a specific agent or agents, the non-implicated 
agent(s) may be continued without modification of the dose or schedule if appropriate. 
 
Dose delays may occur as a result of adverse events that are related or unrelated to protocol 
therapy. However, dose modifications and drug discontinuations will only be applied 
to adverse events that are at least possibly related to protocol therapy.  
8.3.1 Hematologic Toxicity: 
 
During CYCLE 1 ONLY (for patients on the phase I portion of the study. Dose 
modifications apply to any day of the treatment cycle): 
 
For grade 4 neutrophil count decrease OR for any grade febrile neutropenia, delay 
pomalidomide and ixazomib until recovery to grade 2 neutrophil count (ANC ≥ 1000). 
Restart at SAME dose level for both pomalidomide and ixazomib. 
o NOTE: G-CSF or GM-CSF may NOT be used during the phase I portion of 
the trial cycle 1 but should be considered for cycle 2 and beyond if deemed 
clinically appropriate. Patients on the phase II portion of the study may receive 
G-CSF during any cycle as clinically indicated. 
o If a patient on the phase I portion of the protocol has already met criteria for a 
DLT in cycle 1 and would benefit from continue participation in the study as 
determined by the treating investigator, G-CSF may be used as clinically 
indicated for the remainder of cycle 1.  
 
For grade 4 platelet count decrease, delay pomalidomide and ixazomib until recovery 
to grade 2 platelet count (platelet ≥ 50,000). Restart at SAME dose level for both 
pomalidomide and ixazomib 
During CYCLE 2 and BEYOND for those on the phase I portion of the study, 
CYCLE 1 and BEYOND for those on the phase II portion. (Dose modifications apply 
to any day of the treatment cycle): 
 
For grade 4 neutrophil count decrease OR for any grade febrile neutropenia, delay 
pomalidomide and ixazomib until recovery to grade 2 neutrophil count (ANC ≥ 1000). 
Restart at same dose IF toxicity occurred without the use of G-CSF or GM-CSF and G-
CSF or GM-CSF are going to be used with subsequent protocol therapy. Restart at 1 
dose level decreased for pomalidomide if toxicity occurred with the use of G-CSF or 
GM-CSF, or if G-CSF or GM-CSF will not be used upon re-initiation of protocol 
therapy. If grade 4 neutrophil count decrease recurs despite a lowering of the 
pomalidomide to 2 mg, restart at 1 dose level decreased for ixazomib. 

 
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Update #09 
 
For grade 4 platelet count decrease, delay pomalidomide and ixazomib until recovery 
to grade 2 platelet count (platelet ≥ 50,000). Restart at 1 dose level decreased for both 
pomalidomide and ixazomib. 
 
The phase I experience with this regimen revealed more significant neutropenia and 
thrombocytopenia for those patients with a large burden of disease at baseline. If a large 
disease burden is felt to be a significant contributor to grade 4 neutrophil and/or platelet 
count decrease, clearance to resume therapy without a dose reduction of the 
pomalidomide and/or ixazomib must be approved by the Study Chair. In such a case, if 
grade 4 neutrophil and/or platelet count decrease recurs despite a reduction in disease 
burden, the dose modifications above should be implemented. 
8.3.2 Skin Toxicity: 
 
For grade 2 or higher skin ulceration, discontinue pomalidomide and ixazomib 
 
For grade 3 erythema multiforme, discontinue pomalidomide and ixazomib 
 
For grade 3 acneiform rash, delay pomalidomide and ixazomib until grade 1, then 
restart at 1 dose level decreased for pomalidomide and ixazomib 
 
For grade 3 maculo-papular rash, delay pomalidomide and ixazomib until grade 1, 
then restart at 1 dose level decreased for pomalidomide and ixazomib 
 
For grade 4 rash any type, discontinue pomalidomide and ixazomib 
 
For Stevens-Johnson syndrome, discontinue pomalidomide and ixazomib 
 
For toxic epidermal necrolysis, discontinue pomalidomide and ixazomib 
8.3.3 Allergic Reaction: 
 
For grade 2 allergic reaction, delay the offending agent (pomalidomide OR ixazomib) 
until recovery to grade 1 then restart at 1 dose level decreased for the offending agent 
(pomalidomide OR ixazomib) 
 
For grade 3 allergic reaction, discontinue the offending agent (pomalidomide OR 
ixazomib) 
 
For any grade anaphylaxis, discontinue the offending agent (pomalidomide OR 
ixazomib) 
8.3.4 GI Toxicity: 
 
For grade 3 or 4 diarrhea that persists despite optimal supportive care, delay 
pomalidomide and ixazomib until recovery to grade 1, then restart at 1 dose level 
decreased for pomalidomide and ixazomib. 
 
For grade 3 or 4 nausea or vomiting that persists despite optimal supportive care, delay 
pomalidomide and ixazomib until recovery to grade 1, then restart at 1 dose level 
decreased for pomalidomide and ixazomib. 
8.3.5 Neurotoxicity: 
 
For grade 2 sensory and or motor neuropathy in patients with baseline grade 0 or 1 
neuropathy, delay pomalidomide and ixazomib until at patient’s baseline neuropathy 
then resume at 1 dose level decreased for pomalidomide and ixazomib 
 
For new onset neuropathic pain regardless of grade, delay pomalidomide and ixazomib 
until pain is resolved/controlled, then restart at 1 dose level decreased for 
pomalidomide and ixazomib 

 
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Update #09 
 
For grade 3 sensory and or motor neuropathy, delay pomalidomide and ixazomib until 
recovery to grade 1 OR to patient’s baseline neuropathy, then restart at 1 dose level 
decreased for pomalidomide and discontinue ixazomib. 
 
For grade 4 sensory or motor neuropathy, discontinue pomalidomide and ixazomib. 
8.3.6 Nephrotoxicity: 
 
For grade 2 creatinine increased, delay pomalidomide and ixazomib until recovery to 
grade 1, then restart pomalidomide and ixazomib at same dose. 
 
For grade 3 creatinine increased, discontinue pomalidomide. For grade 3 creatinine 
increased, delay ixazomib until recovery to grade 1, then restart at same dose 
 
For grade 4 creatinine increased, discontinue ixazomib and pomalidomide 
 
For grade 3 hyponatremia, delay ixazomib until recovery to grade 2, then restart at 1 
dose level decreased for ixazomib 
 
For grade 4 hyponatremia, discontinue ixazomib 
 
For grade 3 hypophosphatemia (despite oral replacement therapy), delay ixazomib until 
recovery to grade 2, then restart at 1 dose level decreased for ixazomib 
 
For grade 4 hypophosphatemia (despite oral replacement therapy), discontinue 
ixazomib 
 
For grade 3 hypokalemia (despite oral replacement therapy), delay ixazomib until 
recovery to grade 2, then restart at 1 dose level decreased for ixazomib 
 
For grade 4 hypokalemia (despite oral replacement therapy), discontinue ixazomib 
8.3.7 Vascular: 
 
For grade 1 thromboembolic event that occurs while not on thromboprophylaxis or 
therapeutic anticoagulation, delay pomalidomide until thromboprophylaxis is initiated 
and then restart pomalidomide at the same dose. 
 
For grade 2 or higher thromboembolic event that occurs while not on 
thromboprophylaxis or therapeutic anticoagulation, delay pomalidomide until 
anticoagulation is initiated and at stable dose, and then restart pomalidomide at same 
dose 
 
For grade 1 thromboembolic event that occurs while on thromboprophylaxis, delay 
pomalidomide until it is ensured that therapeutic anticoagulation is at stable dose, and 
then restart pomalidomide at same dose. 
 
For grade 2 or 3 thromboembolic event that occurs while on thromboprophylaxis, delay 
pomalidomide until therapeutic anticoagulation is initiated and at stable dose, and then 
restart pomalidomide at 1 dose level decreased 
 
For grade 4 thromboembolic event that occurs while on thromboprophylaxis, 
discontinue pomalidomide 
 
For grade 1 thromboembolic event that occurs while on therapeutic anticoagulation, 
delay pomalidomide until it is ensured that anticoagulation is at stable dose, and then 
restart pomalidomide at 1 dose level decreased 
 
For grade 2,3,4 thromboembolic event that occurs while on therapeutic anticoagulation, 
discontinue pomalidomide  

 
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8.3.8 Respiratory: 
 
 
For grade 3 dyspnea, delay pomalidomide until recovery to grade 1 then restart 
pomalidomide at 1 dose level decreased.  
 
For grade 4 dyspnea, discontinue pomalidomide. 
8.3.9 Other: 
 
For grade 3 non-hematologic toxicity not specified above, delay offending agent 
(pomalidomide or ixazomib) until recovery to grade1, then restart at 1 dose level 
decreased.  
 
For grade 4 non-hematologic toxicity not specified above, discontinue pomalidomide 
or ixazomib. 
8.4 
Dose Modification Guidelines for Dexamethasone: 
8.4.1 GI Toxicity: 
For grade 3 or 4 dyspepsia, despite optimal supportive care, delay dexamethasone until 
recovery to grade 1, then restart at 1 dose level decreased 
8.4.2 Edema: 
For grade 3 or 4 edema, despite optimal supportive care, delay dexamethasone until recovery 
to grade 1, then restart at 1 dose level decreased 
8.4.3 Psychiatric: 
 
For grade 2 agitation, anxiety, delirium, depression, hallucinations, mania, personality 
change, psychosis, or confusion, delay dexamethasone until resolution to grade 1, then 
restart at 1 dose level decreased 
 
For grade 3 or 4 agitation, anxiety, delirium, depression, hallucinations, mania, 
personality change, psychosis, or confusion, discontinue dexamethasone  
8.4.4 Metabolism: 
For grade 3 or 4 hyperglycemia, despite optimal supportive care, delay dexamethasone until 
grade 1, then restart at 1 dose level decreased 
8.4.5 Musculoskeletal: 
For grade 3 or 4 generalized muscle weakness, delay dexamethasone until grade 1, then 
restart at 1 dose level decreased 
8.4.6 Other: 
 
For grade 3 non-hematologic toxicity not specified above, delay offending agent 
(dexamethasone) until recovery to grade 1, then restart at 1 dose level decreased.  
 
For grade 4 non-hematologic toxicity not specified above, discontinue dexamethasone 
8.5 
Dose Modifications for Obese Patients  
Dose modifications for obese patients are not applicable to this study. Pomalidomide, ixazomib 
and dexamethasone dosing is not based on body weight or body surface area.  
 

 
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Update #09 
9.0 
ADVERSE EVENTS 
The prompt reporting of adverse events is the responsibility of each investigator engaged in clinical 
research, as required by Federal Regulations. Adverse events must be described and graded using the 
terminology and grading categories defined in the NCI’s Common Terminology Criteria for Adverse 
Events (CTCAE), Version 4.0. However, CTCAE version 5.0 must be used for serious AE reporting 
through 
CTEP-AERS 
as 
of 
April 
1, 
2018. 
The 
CTCAE 
is 
available 
at 
 
Attribution 
to 
protocol 
treatment for each adverse event must be determined by the investigator and reported on the required 
forms, using the codes provided. 
9.1 
Routine adverse event reporting 
Adverse event data collection and reporting, which are required as part of every clinical trial are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents. Adverse events are reported in a routine manner at scheduled 
times according to the study calendar in Section 5.0. For this trial, please use the forms for 
routine AE reporting in Rave. 
Solicited Adverse Events: The following adverse events are considered "expected" and their 
presence/absence should be solicited, and severity graded, at baseline and for each cycle of 
treatment. 
CTCAE v4.0 Term 
CTCAE v4.0 System Organ Class (SOC) 
Neutrophil count decreased 
Investigations 
Platelet count decreased 
Investigations 
Lymphocyte count decreased  
Investigations 
Anemia 
Blood and lymphatic system disorders 
Rash maculo-papular 
Skin and subcutaneous tissue disorders 
Thromboembolic event 
Vascular disorders 
Hemorrhage/Bleeding events 
Distributed throughout multiple SOCs 
Peripheral sensory neuropathy  
Nervous system disorders 
Diarrhea 
Gastrointestinal disorders 
Nausea 
Gastrointestinal disorders 
Vomiting 
Gastrointestinal disorders 
Fatigue 
General disorders and administration site conditions 
Febrile neutropenia 
Blood and lymphatic system disorders 
9.2 
Expedited Adverse event reporting (CTEP-AERS) 
Investigators are required by Federal Regulations to report serious adverse events as defined 
below. Alliance investigators are required to notify, the Alliance Central Office, the Study Chair, 
and their Institutional Review Board if a patient has an adverse event requiring expedited 
reporting. All such events must be reported in an expedited manner using the NCI Adverse Event 
Expedited Reporting System (CTEP-AERS). The Alliance requires investigators to route all 

 
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Update #09 
expedited adverse event reports through the Alliance Central Protocol Operations Program 
Office for Alliance-coordinated studies. Be sure to read this entire protocol section, as 
requirements are described in both the table and the bullet points following the table. The 
additional instructions or exclusions are protocol specific, and in the case of a conflict, the 
additional instructions or exclusions supersede the table. The descriptions and grading scales 
found in the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will 
be utilized for reporting beginning April 1, 2018. A copy of the CTCAE version 5.0 can be 
downloaded 
from 
the 
CTEP 
web 
site 
 
All 
reactions 
determined to be “reportable” in an expedited manner must be reported using the Cancer 
Therapy Evaluation Program Adverse Event Reporting System (CTEP-AERS), accessed via the 
CTEP website, 
 
9.2.1 Phase 1 and Early Phase 2 Studies: Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under a CTEP or non-CTEP IND within 30 Days of 
Treatment1  
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, 
whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
Death 
A life-threatening adverse event  
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 
24 hours  
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
A congenital anomaly/birth defect.  
Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may jeopardize 
the patient or subject and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI 
via CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 Timeframes 
Resulting in Hospitalization 
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar Days 
Not resulting in 
Hospitalization ≥ 24 hrs 
Not required 
NOTE:   Protocol-specific exceptions to expedited reporting of serious adverse events are found in the 
Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
“24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour 
report. 
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar 
days of learning of the AE. 

 
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1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
Effective Date:  May 5, 2011 
Additional Instructions or Exclusions to CTEP-AERS: 
 All adverse events reported via CTEP-AERS (i.e., serious adverse events) should also be 
forwarded to your local IRB, according to local IRB policies. 
 Alliance A061202 uses two drugs under an Alliance IND. These reporting requirements should 
be followed for all agents (any arm) in this trial. 
 Grade 1-3 nausea or vomiting and hospitalization resulting from such do not require CTEP-
AERS reporting, but should be reported via routine AE reporting.  
 Grade 1-3 fatigue and hospitalization resulting from such do not require CTEP-AERS 
reporting, but should be reported via routine AE reporting.  
Grade 1-3 hyperglycemia with hospitalization resulting from such do not require CTEP-AERS 
reporting, but should be reported via routine AE reporting 
Grade 3 hyperglycemia does not require CTEP-AERS reporting, but should be reported via 
routine AE reporting 
Grade 1-3 insomnia, psychosis, depression with hospitalization resulting from such do not 
require CTEP-AERS reporting, but should be reported via routine AE reporting 
Grade 3 insomnia, psychosis, depression do not require CTEP-AERS reporting, but should be 
reported via routine AE reporting. 
Grade 1-3 fluid retention and edema, hypertension with hospitalization resulting from such do 
not require CTEP-AERS reporting, but should be reported via routine AE reporting 
Grade 3 fluid retention and edema, hypertension do not require CTEP-AERS reporting, but 
should be reported via routine AE reporting 
Grade 1-3 hematosuppression (leukopenia, neutropenia, lymphopenia, anemia, and 
thrombocytopenia) with hospitalization resulting from such do not require CTEP-AERS 
reporting, but should be reported via routine AE reporting 
 Grade 3 hematosuppression (leukopenia, neutropenia, lymphopenia, anemia, and 
thrombocytopenia) does not require CTEP-AERS reporting, but should be reported via routine 
AE reporting 
 Death due to progressive disease should be reported as Grade 5 “Disease progression” in the 
system organ class (SOC) “General disorders and administration site conditions.” Evidence 
that the death was a manifestation of underlying disease (e.g., radiological changes suggesting 
tumor growth or progression: clinical deterioration associated with a disease process) should 
be submitted. 
 All new malignancies must be reported through CTEP-AERS whether or not they are thought 
to be related to either previous or current treatment. All new malignancies should be reported, 
i.e. solid tumors (including non-melanoma skin malignancies), hematologic malignancies, 
myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML), and in situ tumors.  

 
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Update #09 
Secondary Malignancy:  
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm.  
CTEP requires all secondary malignancies that occur following treatment with an agent under 
an NCI IND/IDE be reported via CTEP-AERS. Three options are available to describe the 
event:  
 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML])  
 
Myelodysplastic syndrome (MDS)  
 
Treatment-related secondary malignancy  
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
Second Malignancy:  
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine reporting 
unless otherwise specified. 
 Whenever possible, the CTEP-AERS reports for new malignancies should include tumor 
pathology, history or prior tumors, prior treatment/current treatment including duration, any 
associated risk factors or evidence regarding how long the new malignancy may have been 
present, when and how the new malignancy was detected, molecular characterization or 
cytogenetics of the original tumor (if available) and of any new tumor, and new malignancy 
treatment and outcome, if available. 
 All pregnancies and suspected pregnancies (including a positive pregnancy test regardless of 
age or disease state) occurring in female patients during therapy or within 28 days after 
completion of treatment on A061202 must be reported via CTEP-AERS. In CTCAE version 
5.0, use the event term, “pregnancy, puerperium, and perinatal condition-other, pregnancy 
(grade 3)”. Include the potential risk of exposure of the fetus to the agent(s) in the CTEP-
AERS “Description of Events”. 
o CTEP-AERS reports should be amended upon completion of the pregnancy to report 
pregnancy outcome (e.g. normal, spontaneous abortion, therapeutic abortion, fetal 
death, congenital abnormalities). 
o In CTCAE version 5.0, pregnancy loss is defined as “Death in utero,” and any 
pregnancy loss should be reported expeditiously as Grade 4 “Pregnancy loss” under the 
Pregnancy, puerperium and perinatal conditions SOC. A pregnancy loss should NOT 
be reported as a Grade 5 event under the Pregnancy, puerperium and perinatal 
conditions SOC as currently CTEP-AERS recognizes this event as a patient death. 
o The CTEP-AERS report should be amended for any neonatal deaths or complications 
occurring within 28 days of birth independent of attribution. Infant deaths occurring 
after 28 days considered to be related to in utero exposure to the agents used in this trial 
should be reported via CTEP-AERS. 
o A neonatal death should be reported expeditiously as Grade 4, “Death neonatal” under 
the General disorders and administration SOC. 
o Congenital abnormalities should be reported as “congenital familial and genetic 
disorders-other, specify”. 

 
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Update #09 
o If a female partner of a male patient becomes pregnant, the male patient should notify 
the investigator, and the pregnant female partner should be advised to call their 
healthcare provider. CTEP-AERS reporting is not required 
 The reporting of adverse events described in the table above is in addition to and does not 
supplant the reporting of adverse events as part of the report of the results of the clinical trial, 
e.g. cooperative group data reporting. 
9.3 
Comprehensive Adverse Events and Potential Risks List (CAEPR) for Pomalidomide (CC-
4047, NSC 767909) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column 
and is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that 
are protocol specific exceptions to expedited reporting to NCI (except as noted below). Refer to 
the 
'CTEP, 
NCI 
Guidelines: 
Adverse 
Event 
Reporting 
Requirements' 
for further 
clarification. Frequency is provided based on 2133 patients. Below is the CAEPR for 
Pomalidomide (CC-4047). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next 
to the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required. 
Version 2.4, May 22, 20221 
 
 Adverse Events with Possible  
 Relationship to Pomalidomide (CC-4047)2 
 (CTCAE 5.0 Term) 
[n= 2133] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia3 
 
 
 Anemia3 (Gr 2) 
CARDIAC DISORDERS 
  
 
 
Myocardial infarction4 
  
GASTROINTESTINAL DISORDERS 
  
 
Constipation 
 
 Constipation (Gr 2) 
 
Diarrhea 
 
 Diarrhea (Gr 2) 
 
 
Nausea 
 Nausea (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema limbs 
 
 Edema limbs (Gr 2) 
 
Fatigue 
 
 Fatigue (Gr 2) 
 
Fever 
 
 Fever (Gr 2) 
 
 
Sudden death NOS 
  
HEPATOBILIARY DISORDERS 
  
 
 
Hepatic failure 
  
IMMUNE SYSTEM DISORDERS 
  
 
 
Anaphylaxis 
  
INFECTIONS AND INFESTATIONS 
  
 
Infection5 
 
 Infection5 (Gr 2) 
\INVESTIGATIONS 
  

 
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Update #09 
 
 Adverse Events with Possible  
 Relationship to Pomalidomide (CC-4047)2 
 (CTCAE 5.0 Term) 
[n= 2133] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
Alanine aminotransferase 
increased 
 
  
 
Blood bilirubin increased 
 
  
 
Lymphocyte count decreased  
  
Neutrophil count 
decreased 
 
 
 Neutrophil count decreased (Gr 2)  
 
Platelet count decreased 
 
 Platelet count decreased (Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
  
 
 
Anorexia 
 Anorexia (Gr 2) 
 
Hyperkalemia 
 
  
 
Hyponatremia 
 
  
 
 
Tumor lysis syndrome 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Back pain 
 
  
 
 
Bone pain 
 Bone pain (Gr 2) 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS 
AND POLYPS) 
  
 
 
Neoplasms benign, malignant 
and unspecified (incl cysts 
and polyps) - Other (second 
primary malignancies) 2 
  
 
 
Treatment related secondary 
malignancy2 
  
NERVOUS SYSTEM DISORDERS 
  
 
Depressed level of 
consciousness 
 
  
 
 
Dizziness 
 Dizziness (Gr 2) 
 
 
Dysesthesia 
  
 
 
Paresthesia 
  
 
Peripheral sensory neuropathy  
  
 
 
Nervous system disorders   - 
Other (progressive multifocal 
leukoencephalopathy) 
  
 
 
Stroke4 
  
PSYCHIATRIC DISORDERS 
  
 
Confusion 
 
  
 
 
Hallucinations 
  
RENAL AND URINARY DISORDERS 
  
 
Acute kidney injury 
 
  
 
Urinary retention 
 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
 
Cough 
 Cough (Gr 2) 
 
 
Dyspnea 
 Dyspnea (Gr 2) 
 
 
Pneumonitis 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
 
Rash maculo-papular 
 Rash maculo-papular (Gr 2) 
 
 
Skin and subcutaneous tissue 
disorders - Other (DRESS 
syndrome) 
  

 
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Update #09 
 
 Adverse Events with Possible  
 Relationship to Pomalidomide (CC-4047)2 
 (CTCAE 5.0 Term) 
[n= 2133] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
 
Stevens-Johnson syndrome2 
  
 
 
Toxic epidermal necrolysis 
  
VASCULAR DISORDERS 
  
 
 
Thromboembolic event4 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all Principal 
Investigators at the time of revision.  The current version can be obtained by contacting
  
Your name, the name of the investigator, the protocol and the agent should be included in the e-mail. 
 
2While not observed in human trials of pomalidomide, teratogenic effects (birth defects), thromboembolic events 
increases in secondary malignancy, tumor lysis syndrome, Stevens-Johnson syndrome, and thyroiditis/hypothyroidism 
are known events for this class of agents that include thalidomide and lenalidomide. 
 
3Sickle cell crises in patients with SCD is a rare but serious event.  
 
4Venous thromboembolic events (e.g., deep vein thrombosis and pulmonary embolism) and arterial thromboembolic 
events (e.g., myocardial infarction and stroke) have been observed to occur more frequently in multiple myeloma 
patients treated with pomalidomide and dexamethasone. 
  
5Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
Adverse events reported on Pomalidomide (CC-4047) trials, but for which there is insufficient evidence to 
suggest that there was a reasonable possibility that Pomalidomide (CC-4047) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other (sickle cell 
anemia with crisis)3; Febrile neutropenia 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Heart failure; Sinus tachycardia 
EAR AND LABYRINTH DISORDERS - Vertigo 
EYE DISORDERS - Blurred vision; Eye disorders - Other (eyelid swelling) 
GASTROINTESTINAL DISORDERS - Abdominal pain; Colonic perforation; Dry mouth; Dyspepsia; 
Enterocolitis; Vomiting 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Death NOS; Disease 
progression; Malaise 
IMMUNE SYSTEM DISORDERS - Allergic reaction 
INVESTIGATIONS - CD4 lymphocytes decreased; CPK increased; Creatinine increased; Weight gain; Weight loss; 
White blood cell decreased 
METABOLISM 
AND 
NUTRITION 
DISORDERS 
- 
Dehydration; 
Hypercalcemia; 
Hyperglycemia; 
Hyperuricemia; Hypocalcemia; Hypokalemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Chest wall pain; Generalized 
muscle weakness; Muscle cramp; Myalgia; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other (multiple myeloma, myelofibrosis, progression of 
MM); Tumor pain 
NERVOUS SYSTEM DISORDERS - Dysphasia; Headache; Intracranial hemorrhage; Ischemia cerebrovascular; 
Seizure; Syncope; Tremor 
PSYCHIATRIC DISORDERS - Anxiety; Depression; Insomnia 
RENAL AND URINARY DISORDERS - Hematuria   
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Pelvic pain 

 
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Update #09 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Epistaxis; Nasal congestion; 
Oropharyngeal pain; Postnasal drip; Productive cough; Pulmonary hypertension; Respiratory failure; Respiratory, 
thoracic and mediastinal disorders - Other (sputum discolored) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Erythema multiforme; Hyperhidrosis; 
Pruritus 
VASCULAR DISORDERS - Vascular disorders - Other (hyperviscosity syndrome) 
 
Note: Pomalidomide (CC-4047) in combination with other agents could cause an exacerbation of any adverse event 
currently known to be caused by the other agent, or the combination may result in events never previously associated 
with either agent. 
9.4 
Comprehensive Adverse Events and Potential Risks List (CAEPR) for Ixazomib 
(MLN9708, NSC 767907) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column 
and is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that 
are protocol specific exceptions to expedited reporting to NCI (except as noted below). Refer to 
the 
'CTEP, 
NCI 
Guidelines: 
Adverse 
Event 
Reporting 
Requirements' 
for 
further clarification. Frequency is provided based on 1122 patients. Below is the CAEPR for 
MLN9708 (Ixazomib citrate). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next 
to the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required. 
 
Version 2.1, March 26, 20221 
 
 Adverse Events with Possible  
 Relationship to MLN9708 (Ixazomib citrate) 
 (CTCAE 5.0 Term) 
[n= 1122] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
  
 
 
Thrombotic thrombocytopenic 
purpura 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
  
 
Constipation 
 
  
Diarrhea 
 
 
 Diarrhea (Gr 2) 
Nausea 
 
 
 Nausea (Gr 2) 
Vomiting 
 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
 
Edema limbs 
  
Fatigue 
 
 
 Fatigue (Gr 2) 
 
Fever 
 
 Fever (Gr 2) 
HEPATOBILIARY DISORDERS 
  
 
 
Hepatobiliary disorders - Other 
(hepatotoxicity)2 
  

 
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 Adverse Events with Possible  
 Relationship to MLN9708 (Ixazomib citrate) 
 (CTCAE 5.0 Term) 
[n= 1122] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
INFECTIONS AND INFESTATIONS 
  
 
Upper respiratory infection 
 
 Upper respiratory infection 
(Gr 2) 
INVESTIGATIONS 
  
 
Neutrophil count decreased 
 
 Neutrophil count decreased 
(Gr 2) 
 
Platelet count decreased 
 
 Platelet count decreased (Gr 
2) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Back pain 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Headache 
 
  
 
Nervous system disorders - 
Other (peripheral neuropathies 
NEC, peripheral neuropathy, 
peripheral motor neuropathy) 
 
 Nervous system disorders - 
Other (peripheral 
neuropathies NEC, 
peripheral neuropathy, 
peripheral motor neuropathy) 
(Gr 2) 
 
Peripheral sensory neuropathy  
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
  
 
Dyspnea 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 2) 
 
1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all Principal 
Investigators at the time of revision. The current version can be obtained by contacting 
  
Your name, the name of the investigator, the protocol and the agent should be included in the e-mail. 
 
2Drug-induced liver injury, hepatocellular injury, hepatic steatosis, hepatitis cholestatic and hepatotoxicity have each 
been reported in <1% of patients treated with MLN9708. Events of liver impairment have been reported. Monitor 
hepatic enzymes regularly and adjust dosing for Grade 3 or 4 symptoms.  
 
Adverse events reported on MLN9708 (Ixazomib citrate) trials, but for which there is insufficient evidence to 
suggest that there was a reasonable possibility that MLN9708 (Ixazomib citrate) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Febrile neutropenia 
CARDIAC DISORDERS - Myocardial infarction 
EYE DISORDERS - Blurred vision; Retinal detachment 
GASTROINTESTINAL DISORDERS - Enterocolitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Disease progression; Flu like 
symptoms; Malaise 
HEPATOBILIARY DISORDERS - Bile duct stenosis 
INFECTIONS AND INFESTATIONS - Bronchial infection; Fungemia; Infections and infestations - Other 
(Parainfluenza Infection); Lung infection; Pharyngitis; Sepsis; Shingles; Sinusitis 

 
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INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fall; Injury, poisoning and procedural 
complications - Other (femoral neck fracture); Spinal fracture 
INVESTIGATIONS - Aspartate aminotransferase increased; Lymphocyte count decreased; White blood cell 
decreased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypokalemia; Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain; Muscle weakness lower limb; 
Myalgia; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other (non-Hodgkin’s lymphoma); Neoplasms benign, 
malignant and unspecified (incl cysts and polyps) - Other (plasma cell myeloma); Tumor pain 
NERVOUS SYSTEM DISORDERS - Dizziness; Dysgeusia 
PSYCHIATRIC DISORDERS - Insomnia 
RENAL AND URINARY DISORDERS - Acute kidney injury 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchial obstruction 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Erythema multiforme; Pruritus 
VASCULAR DISORDERS - Hypotension 
 
Note: MLN9708 (Ixazomib citrate) in combination with other agents could cause an exacerbation of any adverse event 
currently known to be caused by the other agent, or the combination may result in events never previously associated 
with either agent. 
 
 

 
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10.0 DRUG INFORMATION 
10.1 
General Considerations: 
 
Pomalidomide, ixazomib and dexamethasone will be administered at flat doses. Therefore, 
dosing will not be based on body weight or body surface area. 
 
Qualified personnel who are familiar with procedures that minimize undue exposure to 
themselves, others and the environment should undertake the handling and disposal of the 
agents used in this study.  
 
Institutions should follow their own policies for handling and disposal of the agents used in 
this study.  
10.1.1 Dexamethasone (Decadron) (NSC # 34521) 
Procurement 
Dexamethasone is commercially available and therefore is to be purchased by a third party. 
This drug will not be supplied by the NCI. 
Formulation 
Dexamethasone is available in seven potencies (0.5 mg, 0.75 mg, 1mg, 1.5 mg, 2 mg, 4 mg, 
and 6 mg) in tablet form. 
Storage and Stability 
Store tablets at room temperature between 15ºC and 30ºC (59ºF and 86ºF). 
Preparation 
Refer to package insert for complete dispensing instructions.  
Administration 
In this study dexamethasone is administered orally.  
Drug Interactions 
Antacids may decrease the bioavailability of dexamethasone. Separate doses by two or more 
hours. 
Pharmacokinetics 
Metabolism: Hepatic; Subtrate of CYP3A4 (Major) 
Half-life elimination: Normal renal function: 1.8-3.5 hours; Biological half-life: 36-54 hours 
Time to peak, serum: Oral: 1-2 hours;  
Excretion: Urine and feces 
Adverse Events 
Possible adverse events associated with the use of dexamethasone are:  
Gastrointestinal: Nausea, vomiting, anorexia, increased appetite, weight gain; aggravation 
of peptic ulcers. 
Dermatologic: Rash, skin atrophy, facial hair growth, acne, facial erythema, ecchymoses. 
Genitourinary: Menstrual changes (amenorrhea, menstrual irregularities).  
Neurologic: Insomnia, euphoria, headache, vertigo, psychosis, depression, seizures, muscle 
weakness. 
Cardiovascular: Fluid retention and edema, hypertension; rarely, thrombophlebitis.  
Ocular: Cataracts, increased intraocular pressure, exophthalmos.  

 
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Metabolic: Hyperglycemia, decreased glucose tolerance, aggravation or precipitation of 
diabetes mellitus, adrenal suppression (with Cushingoid features), hypokalemia.  
Hematologic: Leukocytosis.  
Other: Osteoporosis (and resulting back pain), appearance of serious infections including 
herpes zoster, varicella zoster, fungal infections, Pneumocystis carinii, tuberculosis; muscle 
wasting; delayed wound healing; suppression of reactions to skin tests. 
Nursing Guidelines 
Monitor regularly for hypertension, CHF and other evidence of fluid retention. 
Advise patient of possible mood or behavioral changes, i.e., depression, euphoria, insomnia, 
even psychosis. Instruct patient to report any suspected changes to healthcare team. 
Assess for symptoms of gastric ulcer, heartburn, or gastritis.  Instruct patient to report 
symptoms to healthcare team if unable to control. 
Evaluate signs of infection, particularly local candidal infections and treat appropriately. 
Monitor blood glucose frequently. 
Instruct patient to report frequent, unrelenting headaches or visual changes to healthcare 
team. 
Advise patient that easy bruising is a side effect. 
When administered orally, give with food or milk. 
Observe for signs of hyperglycemia. 
Observe for subtle signs of infection (fever, pain). 
10.1.2 Pomalidomide (Pomalyst, CC-4047) (NSC# 767909, Alliance IND# 120020) 
Procurement 
Pomalidomide will be provided by Celgene and distributed by McKesson Specialty 
Pharmacy in accordance with Celgene Corporation’s Pomalyst REMS™ requirements, all 
physicians who prescribe pomalidomide for study patients in this trial, and all patients 
enrolled in this trial, must be registered and must comply with all requirements of the 
Pomalyst REMS™ program. The order form is found on the study website. McKesson 
Specialty Pharmacy will ship patient-specific supplies to the institution. Only enough 
pomalidomide for one cycle of therapy will be supplied for each patient for each cycle. 
Storage and Stability 
Store drug at controlled room temperature, between 68-77 ºF (20-25ºC) or as indicated on 
the manufacturer’s label. The expiration date is indicated on the label. 
Only enough study drug for one cycle of therapy may be dispensed with each cycle of 
therapy. 
Preparation 
Pomalidomide (CC-4047) capsules can be 0.5-mg gelatin capsules (size 4 reddish brown), 
1-mg gelatin capsules (size 4 reddish brown), 2-mg (size 2 reddish-brown), 3-mg and 4-mg 
gelatin capsules (size 2 reddish-brown), and 5-mg gelatin capsules (size 1 reddish-brown), 
containing CC-4047, mannitol, pregelatinized starch, and sodium stearyl fumarate. 
Pomalidomide (CC-4047) capsules are supplied in high density polyethylene (HDPE) 
containers fitted with induction seals and child-resistant plastic closures or PVC/PCTFE 
blister with push-through foil. 

 
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Administration 
Pomalidomide is administered by mouth at approximately the same time each day. Capsules 
should be swallowed whole, and should not be broken, chewed or opened. 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. Patients should be instructed never to 
give this medicinal product to another person and to return any unused capsules to the study 
doctor at the end of treatment. 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.  
Drug Interactions 
Based on in vitro metabolism data, pomalidomide did not inhibit or induce CYPP450 
isoenzymes or inhibit several studied transporters (P-glycoprotein, BCRP, OAT1, OAT3, 
OATP1B1, OATP1B3 and OCT2). Therefore, pomalidomide is not likely to precipitate 
drug-drug interactions due to inhibition or induction when co-administered with cytochrome 
P-450 substrates or with substrates of these transporters. 
Since pomalidomide is eliminated in humans via multiple pathways, it is not anticipated that 
co-administration of an inhibitor or inducer of cytochrome P450 isoenzymes will have a 
significant impact on pomalidomide pharmacokinetics. The potential for clinically relevant 
drug-drug interactions when pomalidomide is co-administered with inhibitors of P-
glycoprotein has not been evaluated. 
Pharmacokinetics 
a) 
Absorption – oral absorption has been moderately rapid with first dose Cmax occurring 
in 1.5 to 4 hrs. More than 70% of the pomalidomide dose is absorbed in humans. A 
high fat meal decreased the rate of absorption but had minimal effect on overall extent 
of absorption. 
b) 
Distribution – Apparent volume of distribution in healthy subjects ranged from 74-138 
L across a dose range of 1 to 10 mg daily. Pomalidomide protein binding in human 
plasma is low to moderate (15.8% for R-enantiomer, 42.2% for S-enantiomer) and the 
binding is concentration independent in the concentration range of 30 and 1000 ng/mL.  
Drug distributes into semen.  
c) 
Metabolism – Eight metabolites were detected in plasma, each at exposures < 10% of 
the plasma pomalidomide.  CYP-dependent metabolites accounted for approximately 
43% of the excreted radioactivity, while non-CYP dependent hydrolytic metabolites 
accounted for 25%, and excretion of unchanged pomalidomide accounted for 10%. 
d) 
Excretion – In healthy patients, 72.8% of the dose was recovered in urine and 15.5% 
was recovered in feces. Less than 3% of the dose is excreted as unchanged 
pomalidomide in the urine. The geometric mean terminal elimination half-life (t1/2) of 
pomalidomide was approximately 7.5 hours. 
Adverse Events 
Common known potential toxicities, > 10%   
Blood and lymphatic system disorders: Anemia, leukopenia, neutropenia, thrombocytopenia, 
lymphopenia 
Gastrointestinal disorders: Constipation, diarrhea, nausea, vomiting General disorders:  
Asthenia, chills, fatigue, pyrexia, pain, peripheral edema 
Infections and infestations: Bronchitis, pneumonia, upper respiratory tract infection, urinary 
tract infection, nasopharyngitis 

 
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Metabolism and nutrition disorders: Decreased appetite, hyperglycemia, hyponatremia, 
hypercalcaemia, hypocalcaemia, hypokalemia 
Musculoskeletal and connective tissue disorders: Musculoskeletal chest pain, back pain, 
muscle spasm, arthralgia, musculoskeletal pain, pain in extremity, muscular weakness, bone 
pain 
Nervous system disorders:  Dizziness, tremor 
Psychiatric disorders:  Insomnia, confusional state 
Renal and urinary tract disorders:  Renal failure 
Respiratory, thoracic and mediastinal disorders:  Dyspnea, cough, dyspnea exertional, 
epistaxis 
Skin and subcutaneous tissue disorders:  Rash, hyperhidrosis, night sweats, dry skin 
Less common known potential toxicities, 1% - 10%:  
Blood and lymphatic system disorders:  Febrile neutropenia 
Cardiac disorders: Atrial fibrillation, cardiac failure congestive, tachycardia 
Eye disorders: Blurred vision 
Gastrointestinal disorders: Abdominal pain, dry mouth, upper abdominal pain 
General disorders: Chest pain 
Infections and infestations: Candidiasis, oral candidiasis, sinusitis, bronchopneumonia 
Metabolism and nutrition disorders: Hyperkalemia, dehydration, hypophosphatemia, 
hypoalbuminemia, hypomagnesemia 
Nervous system disorders:  Headache, dysgeusia, peripheral neuropathy, somnolence, 
syncope, lethargy 
Psychiatric disorders: Anxiety, altered mood, depression 
Renal and urinary tract disorders:  Acute renal failure 
Respiratory, thoracic and mediastinal disorders:  Pulmonary embolism, oropharyngeal pain, 
productive cough, dysphonia, nasal congestion 
Skin and subcutaneous tissue disorders:  Pruritus 
Vascular disorders: Deep vein thrombosis, hypotension, hypertension 
Rare known potential toxicities, <1% (Limited to important or life-threatening): Secondary 
cancer, interstitial lung disease, respiratory distress, hyperbilirubinemia. 
Pomalidomide (CC-4047) was found to be teratogenic in a developmental study in rabbits. 
Pomalidomide therefore is considered as having the potential to cause teratogenic effects in 
humans. Celgene therefore mandates the fetal exposure risk management described below. 
Patients will be counseled in accordance with the Celgene Pregnancy Prevention Counseling 
Program (CPPCP) by a trained counselor. A minimum of two counselors must be identified 
at each site for this purpose. 
 
All subjects (male and females with or without childbearing potential) must agree to 
abstain from donating tissue (including blood or blood products and semen or sperm) 
while taking study drug and for 28 days after the last dose of study drug. 
 
Pomalidomide (CC-4047) must not be administered to pregnant or lactating females. 
 
Females of Child-Bearing Potential (FCBP) must have two negative pregnancy tests 
(sensitivity of at least 25 mIU/mL) prior to starting study drug.  The first pregnancy test 
must be performed within 10-14 days prior to the start of study drug and the second 

 
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pregnancy test must be performed within 24 hours prior to the start of study drug.  The 
patient may not receive study drug until the study doctor has verified that the results of 
these pregnancy tests are negative. 
 
Sexually active FCBP must agree to use protocol-specified contraceptive methods at 
least 28 days before, during participation in the clinical studies and for at least 28 days 
after discontinuation from the study. 
 
Sexually active males (including those who have had a vasectomy) must agree to use 
protocol-specified contraceptive methods during participation in the clinical studies and 
for at least 28 days after discontinuation from the study (additional precaution due to 
lack of data on effect on male sexual organs and sperm). 
 
Pomalidomide (CC-4047) should not be handled by non-patient FCBP or non-patient 
partners of PCBP unless gloves are worn. 
Caution should be exercised when enrolling subjects known to be at risk of developing 
torsade de pointes. To date, clinical data reveal variable QTc values and modest, infrequent 
and inconsistent changes that do not reveal any clear trend or pattern of QTc prolongation, 
and do not appear to have significantly translated into symptomatic or clinically meaningful 
events. 
Neutropenia was the most frequently reported grade 3/4 AE in subjects with 
relapsed/refractory MM. The majority of these occurred without associated infection and 
neutropenia was the dose limiting toxicity.  
Routine hematologic monitoring and dose modification as specified in the protocol are 
recommended to manage hematologic toxicities, especially neutropenia. 
Subjects receiving pomalidomide (CC-4047) have developed venous thromboembolic 
events (DVTs and PEs) reported as SAEs. Anticoagulant prophylaxis is recommended as a 
precaution per protocol. 
Nursing Guidelines 
Agent is known to be teratogenic in rabbits. Therefore all women who are pregnant or who 
could become pregnant should not handle the agent outside of the original packaging. 
Chemotherapy gloves should be worn if contact is necessary. 
Because of the similarity of this agent to thalidomide certain precautions MUST be 
employed by all subjects on protocol and for 4 weeks after discontinuation of agent. Instruct 
patients the following must be adhered to: No donation of tissue/blood/semen/sperm; 
sexually active males/ females must use protocol-specific contraception (regardless of 
fertility status-i.e. history of vasectomy). 
Cytopenias are common (neutropenia most common). Monitor CBC closely and instruct 
patient to report any signs/symptoms of infection or unusual bruising or bleeding to the 
study team. 
Thrombotic events have been reported. Anticoagulation prophylaxis may be recommended. 
Instruct patients to report any problems with bleeding, extremity pain or swelling, or 
shortness of breath to the study team immediately.  
Patients may experience cough, URI, pneumonia, or sinusitis. Instruct patients to report 
respiratory symptoms to the study team. 
Gastrointestinal side effects consisting of diarrhea, constipation, stomatitis, nausea, 
decreased appetite, and abdominal pain have been seen. Treat symptomatically and monitor 
for effectiveness. 

 
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10.1.3 Ixazomib (MLN9708) (Supplied) (NSC# 767907 Alliance IND# 120020) 
Procurement 
Ixazomib will be provided by Millennium Pharmaceuticals: A Takeda Oncology Company 
and distributed by McKesson Specialty Pharmacy. The order form is found on the study 
website. At the end of the study, any unused supplies should be destroyed on site according 
to institutional procedures.  
Product complaints are verbal, written or electronic expression of dissatisfaction with the 
identity, strength, purity, quality or stability of a drug. Product complaints are not the 
same as adverse events. Any such product complaints about ixazomib should be reported 
to the Alliance Central Protocol Operations Program Office. 
Storage and Stability 
Ixazomib capsules, individually packaged in foil-foil blisters of three capsules with child 
resistant paper backing, should be stored unopened. Do not store above 30°C (86°F). Do not 
freeze. 
Ixazomib that is dispensed to the patient for take-home dosing should remain in the blister 
packaging until the point of use. Only a one-month supply (3 capsule; 1 blister card) may 
be dispensed at a time. Patients should be instructed to store the blister card in the 
refrigerator. Patients will be instructed to store the blister card in the refrigerator.  
Preparation 
The ixazomib capsule drug product formulation consists of drug substance, microcrystalline 
cellulose, talc, and magnesium stearate. Three different capsule strengths are manufactured: 
2.3, 3.0, and 4.0 mg; each capsule strength has a unique color. Dosage strength is stated as 
the active boronic acid. Ixazomib capsules are individually packaged in blisters with a paper 
backing for child resistance. 
Ixazomib drug product is a cytotoxic anticancer drug. As with other potentially toxic 
compounds, caution should be exercised when handling ixazomib. 
Administration 
Ixazomib capsules must be administered by mouth as intact capsules and are not intended 
to be opened or manipulated in any way. Capsules should be taken on an empty stomach 
(no food for 2 hours before and 1 hour after) with approximately 8 oz (1 cup) of water. 
Missed doses can be taken as soon as the patient remembers if the next schedule dose is 72 
hours or more away. In case of vomiting, the dose should not be repeated 
Pharmacokinetics and Drug Interactions  
Data is available from two weekly dosing studies, one in multiple myeloma (C16004, 
escalating BSA dosing) and one in amyloidosis patients (C16007, dose levels 4 and 5.5 mg). 
PK data in these two patient populations appear to be similar. 
Oral Ixazomib is absorbed rapidly with a Tmax of approximately 0.5 to 2 hours, absolute 
bioavailability is reported to be 67%. The terminal half-life following multiple dosing is 5-
7 days. Results of a population PK analysis (N = 137) show that there is no relationship 
between body surface area or body weight and clearance. Based on these data, a 
recommendation was made for fixed dosing clinical trials. Ixzaomib is eliminated primarily 
by hepatic metabolism, with <3% of a dose excreted in the urine. In vitro studies 
demonstrate metabolism by CYP3A4 (34.2%), 1A2 (30.7%), 2D6 (14.7%), 2C9 (12.1%), 
2C19 (4%). Based on these in vitro studies, the potential exists for increased exposure when 
Ixazomib is administrated concomitantly with strong inhibitors of CYP3A4 or 1A2. 
Ixazomib is not an inhibitor of CYP isoenzymes.  

 
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Ixazomib AUC in combination with lenalidomide and dexamethasone appear similar to 
single-agent ixazomib. This suggests that there is no readily apparent effect of co-
administration of lenalidomide and dexamethasone on the clinical PK of ixazomib. 
Adverse Events 
See the current version of the Investigator’s Brochure for more complete information 
including potential risks, as well as recommendations for clinical monitoring and medical 
management of toxicity. 
Adverse events reported with single agent oral ixazomib to date include (all severity grades): 
Blood and lymphatic system disorders- Anemia (21%)  
Investigations: thrombocytopenia (41%), neutropenia (16%), leukopenia (10%) 
Gastrointestinal disorders – diarrhea (38%), nausea (47%), vomiting (35%), abdominal pain 
(14%), constipation (14%) 
General disorders and administration site conditions – fatigue (49%), fever (21%), 
peripheral edema (10%) 
Skin and subcutaneous tissue disorders – rash, maculo-papular (12%) 
Respiratory, thoracic and mediastinal disorders- cough (15%), dyspnea (14%) 
Nervous system disorders- headache (14%), dizziness (12%) 
Metabolism and nutrition disorders- anorexia (27%), dehydration (14%) 
Musculoskeletal and connective tissue disorders- arthralgia (14%), back pain (12%) 
Infections and infestations- upper respiratory infection (14%) 
Nursing Guidelines 
Capsules must be administered intact and should not be opened or manipulated in any way. 
Additionally, capsules should remain in the blister packs until they are ready to be taken. 
Capsules should be taken on an empty stomach with 8 oz of water. 
Thrombocytopenia has been observed with this agent. Monitor platelet count and instruct 
patients to report any unusual bruising or bleeding to the study team. 
GI side effects have been seen (nausea, diarrhea, vomiting), treat symptomatically and 
monitor for effectiveness of intervention. 
Rash has been seen. Instruct patients to report any rash to study team. 
Assess patient’s concomitant medications, including over the counter and supplements. 
Ixazomib is metabolized through both CYP and non-CYP enzymes, and drug to drug 
interactions exist. Instruct patients not to start any new medications or supplements without 
checking with the study team first.  
11.0 MEASUREMENT OF EFFECT 
Response and progression will be evaluated in this study using the International Myeloma Working 
Group uniform response criteria. The International Myeloma Working Group has also endorsed the 
inclusion of minimal response (MR) for relapsed/refractory myeloma as adapted from the European 
Group for Blood and Marrow Transplantation (EBMT). Therefore, MRs will be evaluated as part of 
this study, as well [61, 62]. 
11.1 
Schedule of Evaluations  
For the purposes of this study, patients should be reevaluated for biochemical response on day 
1 of each treatment cycle, the end of treatment visit (if appropriate) and every 4 weeks thereafter 

 
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until disease progression, death, the start of a new treatment or withdrawal of consent. The start 
of a new treatment cycle does NOT need to be delayed awaiting the results of the disease 
assessment. 
A response (≥MR) or progression of disease should be followed up with a confirmatory 
evaluation as soon as possible but no later than 28 days after the initial documentation of 
response or progression. For time-to-event analyses, the date of the first documented 
progression or response should be used. Determination of a complete response (CR) or 
stringent complete response (sCR) requires a confirmatory bone marrow examination. A second 
bone marrow examination is not needed for additional confirmation of CR or sCR. 
For patients with non-secretory disease who are being followed for response by serial bone 
marrow examinations (must have ≥30% involvement of the marrow space prior to treatment), a 
repeat bone marrow aspirate and biopsy should be performed once every 2 cycles (prior to 
registration, cycle 3, day 1, cycle 5, day 1, etc), at the end of treatment (if not performed within 
the previous 8 weeks) and every 12 weeks thereafter until disease progression, death or 
withdrawal of consent. In these cases, the same method to assess marrow burden of disease 
should be used throughout treatment. A repeat bone marrow is not required for confirmation of 
response under these circumstances. 
For patients with measurable extramedullary plasmacytomas, patients should be reevaluated 
once every 2 cycles (8 weeks) while on protocol treatment, the end of treatment visit (if not 
performed within the previous 8 weeks) and once every 12 weeks thereafter until disease 
progression, death, withdrawal of consent or the start of new treatment, utilizing the same 
imaging modality used at initial screening (CT, MRI or PET/CT). A repeat scan is not required 
for confirmation of radiographic response or progression. 
11.2 
Definitions of Measurable and Non-Measurable Disease 
11.2.1 Measureable Disease  
Disease assessments by serial monitoring of the monoclonal protein are to be performed if 
the patient meets at least 1 of the following criteria: 
1. Serum M protein ≥0.5 g/dL and/or 
2. Urine M protein ≥200 mg/24 hours and/or 
3. Involved serum free light chain≥10 mg/dL AND an abnormal serum free light chain 
ratio 
11.2.2 Non-Measureable Disease 
Patients who do not meet criteria outlined in section 11.2.1 will be considered to have non-
measureable (non-secretory) disease. However, if a patient does not have measurable 
disease by one of the 3 above criteria, they can still be followed with serial bone marrow 
examinations for response, provided the marrow burden of myeloma is at least 30% at 
registration or at re-registration for Arm 1 patients who go on to Course 2 treatment. 
11.3 
Guidelines for Evaluation of Measurable Disease 
11.3.1 Measurement Methods:  
 
Determination of biochemical response requires a serum protein electrophoresis and 
immunofixation, 24-hour urine protein electrophoresis and immunofixation and serum 
free light chain test at each scheduled evaluation of response for all patients. All 
measurements must be performed in all patients at the times indicated in Section 5.0. 
Quantitative serum immunoglobulins and 24-hour urine light chain quantitation via 

 
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nephelometry should not be used as a substitute for determining response. Additionally, 
measurement of an entire region of the serum protein electrophoresis cannot be used as 
a substitute for measurement of the M protein. For example, an IgA kappa M protein 
that falls within the beta region of the serum protein electrophoresis should not be 
monitored solely by assessment of the quantitative IgA level or measurement of the 
protein concentration in the entire beta region of the serum protein electrophoresis. 
 
Any serologic and/or urine testing that indicates a response (≥MR) or disease 
progression (PD) should be confirmed as soon as possible after the initial assessment of 
response/progression but no later than 28 days. 
 
For patients with measurable extramedullary plasmacytomas, the same method of 
assessment and the same technique must be used to characterize each identified and 
reported lesion at registration and during treatment.  
 
For patients with non-secretory disease who are being followed for response by serial 
bone marrow examinations, the same method to assess marrow burden of disease should 
be used throughout treatment. A repeat bone marrow is not required for confirmation of 
response under these circumstances. 
11.3.2 Acceptable Modalities for Measurable Extramedullary Disease: 
• 
Conventional CT and MRI: This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less. If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness. 
As with CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of disease.  
The lesions should be measured on the same pulse sequence. Ideally, the same type of 
scanner should be used and the image acquisition protocol should be followed as closely 
as possible to prior scans. Body scans should be performed with breath-hold scanning 
techniques, if possible. 
• 
PET-CT: If the site can document that the CT performed as part of a PET-CT is of 
identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT 
portion of the PET-CT can be used for RECIST measurements and can be used 
interchangeably with conventional CT in accurately measuring cancer lesions over time.   
• 
Physical Examination: For superficial non-nodal lesions, physical examination is 
acceptable, but imaging is preferable, if both can be done. In the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, 
is recommended. 
11.4 
THE IMWG Uniform Response Criteria 
International Myeloma Working Group (IMWG) Uniform Response Criteria + Definition 
of Minimal Response (MR) as Adopted from the EBMT Criteria 
The IMWG uniform response criteria will be used for determining response to therapy and 
progression of disease. Minimal response, as adapted from the EBMT, will also be assessed [61, 
62]. Source documentation for all biochemical and radiographic evaluations of disease will be 
collected for confirmation of response and disease progression. 

 
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Table 11.4- THE IMWG Uniform Response Criteria 
Response Category 
Response Criteria 
Response Criteria for Disease 
Measurable by Serum FLC 
Testing Only 
Complete Response 
(CR) 
Negative serum immunofixation and 24-hour urine 
immunofixation, disappearance of all extramedullary 
plasmacytomas (if present at baseline) and <5% plasma 
cells on repeat bone marrow examination. 
All other criteria for CR met + 
normal serum free light chain 
ratio. 
Stringent Complete 
Response (sCR) 
All criteria for CR must be met + normal serum free 
light chain ratio + absence of clonal plasma cells on 
bone marrow examination by immunohistochemistry or 
2- to 4-color flow cytometry. 
All other criteria for sCR met + 
normal serum free light chain 
ratio. 
Very Good Partial 
Response (VGPR) 
Serum and urine M-protein detectable on 
immunofixation testing but not on electrophoresis OR 
≥90% reduction in serum M-protein plus urine M-
protein <100 mg/24 hours. 
≥90% reduction in the 
difference between the involved 
and uninvolved serum free light 
chain level. 
Partial Response 
(PR) 
≥50% decrease in the serum M-protein + ≥90% 
reduction in the urine M-protein OR to <200 mg/24 
hours + ≥50% reduction in the size of extramedullary 
plasmacytomas (if present at baseline).* 
≥50% reduction in the 
difference between the involved 
and uninvolved serum free light 
chain level. 
Minimal Response 
(MR) 
25% - 49% decrease in the serum M-protein + 50 – 
89% reduction in the urine M-protein + 25% – 49% 
reduction in the size of extramedullary plasmacytomas 
(if present at baseline) + no increase in size or number 
of lytic bone lesions (development of compression 
fracture does not exclude response).* 
 
Stable Disease (SD) 
Not meeting criteria for CR, sCR, VGPR, PR, MR or progressive disease (PD) 
Progressive Disease 
(PD) 
Increase of ≥25% from lowest response value (nadir)** in any of the following: 
1) Serum M-protein (absolute increase must be ≥0.5 g/dL) AND/OR: 
2) Urine M-protein (absolute increase must be ≥200 mg/24 hours) AND/OR: 
3) For patients without a measurable serum or urine M-protein but measurable 
disease by serum free light chain testing: Difference between the involved and 
uninvolved serum free light chain level (absolute increase must be ≥10 mg/dL) 
AND/OR: 
4) For patients without a measurable serum or urine M-component or serum free 
light chain level: % marrow involvement with myeloma (absolute increase must 
be ≥10%). 
Definite development of new bone lesions or extramedullary plasmacytomas or definite 
increase in the size of existing bone lesions or extramedullary plasmacytomas. 
Hypercalcemia (corrected serum calcium > 11.5 mg/dL) attributable to myeloma (e.g not 
due to omitted doses of biophosphonate). 
 
* 
For patients who do not have measurable disease by M-protein measurement or serum free light 
chain levels but ≥30% involvement of the marrow at baseline, a ≥50% reduction of bone marrow 
involvement is required to meet criteria for a PR. 
** The lowest response value (nadir) does not have to be a value that has been confirmed by repeat 
measurement. 

 
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12.0 END OF TREATMENT/INTERVENTION 
12.1 
Duration of Treatment  
12.1.1 Phase I cohort and patients randomized to Arm 2 in Phase II: 
 Patients who have not progressed and have not experienced unacceptable toxicity will 
continue on therapy at their current dose level until disease progression, unacceptable 
toxicity, withdrawal of consent, start of non-protocol anti-cancer treatment, or death.  
 Those patients who have not progressed and who have experienced an unacceptable 
adverse event may be eligible for re-treatment at a lower dose. (See section 8.0.) 
12.1.2 Patients randomized to Arm 1 in Phase II 
 Patients who have not progressed and have not experienced unacceptable toxicity will 
continue on Course 1 therapy at their current dose level until disease progression, 
unacceptable toxicity, withdrawal of consent, start of non-protocol anti-cancer treatment, 
or death. 
 Those patients who have not progressed and who have experienced an unacceptable 
adverse event may be eligible for re-treatment at a lower dose of Course 1 treatment (see 
section 8.0). 
 Patients who discontinue Course 1 treatment due to disease progression may choose to 
receive Course 2 treatment. These patients must be re-registered to the study and will be 
followed per the study calendar in section 5.2. Patients may remain on Course 2 treatment 
until disease progression, initiation of non-protocol treatment, refusal, unacceptable 
toxicity, or death. 
12.2 
Discontinuation of Protocol Therapy 
12.2.1 Criteria for discontinuation of protocol therapy include: 
 Request by the patient to withdraw from protocol treatment 
 Disease progression 
 Unacceptable toxicity 
 Inter-current illness  
 Administration of alternative treatment  
 Pregnancy 
12.2.2 Follow-up after treatment discontinuation 
Phase I cohort and patients randomized to Arm 2 in Phase II:  
 Patients who discontinue treatment for reasons other than progression or start of non-
protocol treatment will enter the clinical follow-up period, where they will be followed 
per the study calendar in section 5.1 for a maximum of 3 years from registration.  
 Patients who begin non-protocol treatment or who experience disease progression during 
treatment or clinical follow-up will enter the extended follow-up phase, where they will 
be followed for survival and late adverse events every 3 months for a maximum of 3 
years from registration. 
Patients randomized to Arm 1 in Phase II: 
 Patients who discontinue Course 1 treatment for reasons other than disease progression 
or start of non-protocol treatment will enter the clinical follow-up period, where they will 

 
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be followed per the study calendar in section 5.1 for a maximum of 3 years from 
registration.  
 Patients who discontinue Course 1 treatment due to disease progression and choose not 
to receive Course 2 treatment will enter the extended follow-up phase, where they will 
be followed for survival and late adverse events every 3 months for a maximum of 3 
years from registration. 
 Patients who discontinue Course 2 treatment for reasons other than disease progression 
or start of non-protocol treatment will enter the clinical follow-up period, where they will 
be followed per the study calendar in section 5.2 for a maximum of 3 years from re-
registration.  
 Patients who discontinue Course 2 treatment due to disease progression will enter the 
extended follow-up phase, where they will be followed for survival and late adverse 
events every 3 months for a maximum of 3 years from re-registration. 
 Patients in clinical follow-up who have disease progression or begin non-protocol 
treatment will enter the extended follow-up phase, where they will be followed for 
survival and late adverse events every 3 months for a maximum of 3 years from 
registration or re-registration. 
12.3 
Follow-up for patients found to be ineligible on case review or cancel participation prior 
to receiving any protocol treatment  
12.3.1 Patients who cancel participation prior to receiving any protocol treatment 
Study participants who are registered to the trial but who never receive study intervention 
(regardless of eligibility) will go off study. On study forms, baseline measurement forms, 
baseline laboratory forms, baseline patient status forms, and baseline supporting forms are 
to be submitted.  No research specimens are to be submitted.  Any further treatment is at the 
discretion of the patient’s medical team. 
12.3.2 Patients found to be ineligible prior to the start of any protocol treatment 
A study participant who is registered to the trial but does not meet all of the eligibility criteria 
will be deemed ineligible upon case review.  Patients found to be ineligible prior to the start 
of any protocol treatment will go off study.  On study forms, baseline measurement forms, 
baseline laboratory forms, baseline patient status forms, and baseline supporting forms are 
to be submitted.  No research specimens are to be submitted.  Any further treatment is at the 
discretion of the patient’s medical team. 
12.3.3 Patients found to be ineligible after starting any protocol treatment 
 
Patients who are deemed ineligible after registering may continue protocol treatment, 
provided the treating physician, study chair, and executive officer agree there are no 
safety concerns if the patient continues protocol treatment. All scans, tests, and data 
submission are to continue as if the patient were eligible. Notification of the local IRB 
may be necessary per local IRB policies. 
 
Patients who are deemed ineligible after registering and do not continue protocol 
treatment should complete all case report forms required prior to treatment 
discontinuation as well as the end of treatment form.  No further follow-up is required. 

 
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13.0 STATISTICAL CONSIDERATIONS 
This study began with a phase I tolerability/toxicity assessment followed by a phase II component in 
adult patients with lenalidomide and proteasome inhibitor refractory multiple myeloma. 
The phase II portion opened on 7/15/2016 and then temporarily closed to enrollment on June 1, 2017 
having enrolled 12 patients (6 patients per arm) due to the regulatory approvals of daratumumab alone 
or in combination with pomalidomide and dexamethasone for the treatment of relapsed multiple 
myeloma patients with double (lenalidomide and proteasome inhibitor) refractory disease. The phase 
II portion of the trial was redesigned to assess the impact on PFS of the addition of ixazomib to the 
combination of pomalidomide and dexamethasone in patients with lenalidomide-refractory multiple 
myeloma who received 1 prior line of therapy.  
The treatment course, adverse events, and clinical outcomes (response, duration of response, 
progression-free survival times, and overall survival times) of the patients with double (lenalidomide 
and proteasome inhibitor) refractory disease who met eligibility criteria and began treatment will be 
summarized descriptively.  No formal comparisons of the two treatment arms will be undertaken. 
13.1 
Phase I Study Design 
The phase I portion of this trial is designed to assess tolerability and toxicity profiles for the 
combination therapy of Pomalidomide, Dexamethasone and Ixazomib. As such, it will follow a 
standard “3 +3” dose escalation design: Starting with the first cohort, 3 to 6 patients will be 
treated at this and each subsequent dose level.  
All eligible patients who have begun treatment will be included in the determination of the 
maximum tolerated dose. Descriptive statistics will be used to summarize the frequency and 
severity of adverse events and the incidence of dose reductions and delays. 
13.1.1 MTD Definition and Determination 
The maximum tolerated dose (MTD) is defined as the highest dose level where at most 1 
patient (of the 6 treated) develops a DLT, and 2 or more of the 3 to 6 patients developed a 
DLT at the next higher dose level unless the MTD is identified as dose level 4.  
MTD Determination: 
 
The first cohort of three patients will be treated at the starting dose level 1.  
 
Three patients will be treated at a given dose level combination and observed for at least  
28 days (1 cycle) from start of treatment to assess toxicity.  
 
If DLT is not seen in any of the 3 patients, 3 new patients will be accrued and treated at 
the next higher dose level. If DLT is seen in 2 or 3 of 3 patients treated at a given dose 
level, then the next 3 patients will be treated at the next lower dose level, if only 3 
patients were enrolled and treated at this lower dose level.  
 
If DLT is seen in 1 of 3 patients treated at a given dose level, up to 3 additional patients 
will be enrolled and treated at the same dose level. If DLT is seen in at least one of these 
additional three patients (≥2 of 6), the MTD will have been exceeded, and further 
accrual will cease to this cohort. If dose-limiting toxicity (DLT) is not seen in any of the 
three additional patients, 3 new patients will be accrued and treated at the next higher 
dose level.  
 
After enrolling 6 patients on a specific dose level, if DLT is observed in at least 2 of 6 
patients, then the MTD will have been exceeded and defined as the previous dose unless 
only 3 patients were treated at the lower dose level. In that case, 3 additional patients 
will be treated at this lower dose level such that a total of 6 patients are treated at the 
MTD to more fully assess the toxicities associated with the MTD. 

 
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13.1.2 Definition of DLT 
For this protocol, dose-limiting toxicity (DLT) will be defined by the following adverse 
events at least possibly related to study therapy:  
Grade 3 or higher non-hematologic toxicity, with the following exceptions: 
 
Alopecia is not expected but would not be considered a DLT 
 
Nausea, vomiting and diarrhea will only be considered a DLT if it cannot be adequately 
managed with optimal supportive care 
 
Grade 3 or 4 hyperglycemia due to dexamethasone will only be considered a DLT if it 
cannot be controlled with appropriate therapy 
Grade 4 hematologic toxicity, with the following exceptions: 
 
Grade 4 lymphopenia is expected with this regimen and will not be construed as a DLT 
 
Grade 4 neutropenia will only be considered a DLT if it lasts longer than 7 days despite 
appropriate supportive care 
 
Grade 4 thrombocytopenia will only be considered a DLT if it lasts longer than 7 days 
or is associated with a ≥grade 3 bleeding event 
13.2 
Phase I Sample Size and Study Duration 
The phase I component of this study will open at a limited number of sites using a slot reservation 
system, thus we anticipate an accrual rate of 2 eligible patients per month. Based on this low 
accrual rate, the minimum sample size is 4 patients (2 experiencing DLTs at dose level 1 prior 
to a third accrual and 2 at dose level 0), for a minimum duration of < 4 months (1 month accrual 
+ < 1 month follow up per cohort). The maximum phase I sample size is 24 patients, 6 patients 
per dose level evaluation 1, 2, 3, and 4, which would take 20 months to complete (2.5 months 
[1.5 accrual + 1 follow up] per each 3 patient cohort). 
13.3 
Phase II Study Design for patients on first line therapy with disease progression on 
lenalidomide 
A randomized phase II clinical trial will be conducted to assess the impact on PFS of the addition 
of ixazomib to the combination of pomalidomide and dexamethasone in patients with multiple 
myeloma relapsing on lenalidomide as part of first line therapy. 
The primary endpoint is progression-free survival (PFS), defined as the time from randomization 
to the date the International Myeloma Working Group (IMWG) criteria for disease progression 
is met [60, 61]. If a patient initiates another anti-cancer treatment prior to disease progression, 
they will be censored at the date of initiation of this treatment. 
Patients will be randomized to treatment using the Pocock-Simon algorithm balancing the 
distribution of the following stratification factors between the two treatment arms: 
1) 
ISS 1-2 disease vs. ISS 3 disease (current ISS stage based off screening beta 2 
microglobulin and albumin) 
2) 
High risk cytogenetics features: yes vs. no 
High risk cytogenetics features include: del(1p), gain of 1q, t(4;14), t(14;16), t(14; 20), 
del(17p) 
3) 
Prior treatment with a proteasome inhibitor: yes vs. no 
Analysis Cohort: All patients meeting the eligibility criteria who have signed a consent form, 
have been randomized, and have begun treatment will be evaluable for assessment of all clinical 
endpoints. Patients will be included in the treatment group they were randomized to, regardless 

 
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of their actual treatment or duration of treatment. Summary statistics for patient and tumor 
characteristics, eligibility rates, length of follow-up, and treatment acceptance rates will be 
determined by assigned treatment arm. 
13.4 
Phase II Sample Size and Study Duration 
13.4.1 Determination of Sample Size 
 
It is anticipated the median time to progression with the combination of pomalidomide 
and dexamethasone is 6 months in patients refractory to lenalidomide based therapy but 
proteasome inhibitor naïve or sensitive to a proteasome inhibitor. We would consider 
the addition of ixazomib to pomalidomide and dexamethasone significant if the median 
PFS time was increased to at least 12 months in this patient population. 
 
It is anticipated that the accrual rate will be 5 patients per month based on accrual history 
of a randomized phase 2 clinical trial in refractory multiple myeloma comparing 
pomalidomide to pomalidomide plus dexamethasone. 
 
It is assumed that the PFS times for each treatment regimen follow an exponential 
distribution and the hazard of disease progression with pomalidomide and 
dexamethasone is proportional (and constant across time) to the hazard of disease 
progression with pomalidomide and dexamethasone plus ixazomib. 
With a sample size of 70 patients (35 patients per Arm) enrolled over a 15 month period and 
followed for a minimum of 15 months after the close of enrollment and 57 disease 
progressions observed during this 30 month period, a one sided alpha=0.10 log rank test 
will have a 90% chance of detecting an increase in median PFS time from 6 months to 12 
months with the addition of Ixazomib to pomalidomide and dexamethasone. That is, under 
these conditions, there will be adequate power to detect a hazard ratio of 2.0 or greater. 
An additional 3 patients may be enrolled to replace patients who have signed a consent form 
but withdraw consent before any protocol treatment is administered or is found to be 
ineligible before any protocol treatment is administered. 
13.4.2 Accrual Time and Study Duration 
We anticipate the accrual period will be 15 months and the follow-up after the close of 
enrollment will be 15 months. With an additional 6 months for data preparation and analysis, 
it is anticipated that the primary efficacy findings of the phase II portion of this trial will be 
available to the study team approximately 36 months after activation. 
13.5 
Phase II Analysis Plans 
13.5.1 Arm 1 Course 1 and Arm 2 
 
Progression-free survival (PFS): defined as the time from randomization to the date 
the International Myeloma Working Group (IMWG) criteria for disease progression is 
met [60, 61]. If a patient initiates another anti-cancer treatment prior to disease 
progression, they will be censored at the date of initiation of this treatment. 
The distribution of PFS for each treatment arm will be estimated using the Kaplan-
Meier method. Cox modeling will be used to obtain a point and interval estimate of the 
hazard of disease progression among those randomized to the 3 drug regimen relative 
to disease progression among those randomized to the 2 drug regimen adjusted for 
patient and disease characteristics. 
 
Overall Response Rate (ORR), Complete Response (CR), and Clinical Benefit 
Rate (CBR): The proportion of patients meeting the criteria for the response of interest 

 
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will be calculated as the number of patients with the response of interest documented 
during treatment (Arm 1: Course 1 treatment and Arm 2 treatment) divided by the total 
number of patients randomized and who have begun treatment on that treatment arm. 
For each treatment arm, a point and interval estimate of ORR, CR, and CBR will be 
obtained using the properties of the binomial distribution. 
 
Duration of Response: Duration of response is defined as the time from when a PR 
or better is first documented during treatment (Arm 1: Course 1 treatment and Arm 2 
treatment) to date of progression or death. If a patient has not progressed or died, the 
patient will be censored at the date of last clinical follow-up for this disease if no 
alternative treatment was initiated. Otherwise, the patient will be censored on the date 
alternative treatment was begun.  
The distribution of response durations for each treatment arm will be estimated using 
the Kaplan-Meier method. 
 
Overall Survival (OS): defined as the time from randomization to death due to any 
cause. 
The distribution of OS for each treatment arm will be estimated using the Kaplan-
Meier method. As this study was not designed to test whether OS differs with respect 
to treatment, hypothesis testing will not be carried out to assess whether OS differs 
with respect to treatment at the time of the primary efficacy analysis of this trial. 
Instead, stratified Cox modeling will be used to obtain a point and interval estimate of 
the hazard of death among those randomized to the 3 drug regimen relative to death 
among those randomized to the 2 drug regimen, adjusting for patient and disease 
characteristics. 
 
Adverse Events: adverse events will be assigned a grade of severity and attribution 
using the CTCAE criteria. The frequency and severity of adverse events documented 
during treatment prior to progression or the initiation of another treatment be tabled. 
13.5.2 Arm 1 Course 2 
 
Progression-free survival (PFS): Progression free survival in this setting is defined 
as the time from the start of Course 2 (3 drug regimen) to the date the International 
Myeloma Working Group (IMWG) criteria for disease progression is met [60, 61]. If 
a patient initiates another anti-cancer treatment prior to disease progression, they will 
be censored at the date of initiation of this treatment. 
The distribution of PFS times will be estimated using the Kaplan-Meier method.  
 
Overall Response Rate (ORR), Complete Response (CR), and Clinical Benefit 
Rate (CBR): The proportion of patients meeting the criteria for the response of interest 
will be calculated as the number of patients with the response of interest documented 
during Course 2 treatment divided by the total number of patients who have begun 
Course 2 treatment. 
A point and interval estimate of ORR, CR, and CBR will be obtained using the 
properties of the binomial distribution. Cross tables of the best response during Course 
1 treatment with best response during Course 2 treatment will be constructed. 
 
Duration of Response: Duration of response is defined as the time from when a PR 
or better is first documented during Course 2 treatment to date of progression or death. 
If a patient has not progressed or died, the patient will be censored at the date of last 
clinical follow-up for this disease if no alternative treatment was initiated. Otherwise, 
the patient will be censored on the date alternative treatment was begun.  

 
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The distribution of response durations will be estimated using the Kaplan-Meier 
method. 
 
Overall Survival (OS): defined as the time from start of Course 2 treatment to death 
due to any cause. 
The distribution of OS times will be estimated using the Kaplan-Meier method.  
 
Adverse Events: adverse events will be assigned a grade of severity and attribution 
using the CTCAE criteria. The frequency and severity of adverse events documented 
during Course 2 treatment prior to progression or the initiation of another treatment be 
tabled. 
13.5.3 Interim Analysis Design for Primary Endpoint 
During the course of the study, we will monitor accrual assumptions and recommend 
changes to the DSMB if assumptions do not appear appropriate. 
One interim analysis is planned after 75% of the required events have been observed to 
evaluate whether the addition of ixazomib to pomalidomide plus dexamethasone increased 
PFS survival time relative to pomalidomide plus dexamethasone alone. To preserve the 
Type I error rate, the Lan-DeMets error spending rate function with the O’Brien-Fleming 
boundaries will be applied. Findings will be presented to the DSMB for their recommended 
course of action. 
Information 
fraction  
Alpha spent 
 
Boundary 
to reject H0 
0.75 
0.058 
-1.576 
1.0 
0.100 
-1.380 
The interim futility stopping rule proposed by Weiand, Schroeder, and O’Fallon will be 
applied as soon as 50% of the expected number of events associated with the sample size 
have occurred [63]. If the rate of patients experiencing progression on the ixazomib + 
pomalidomide/dexamethasone treatment arm is greater than the rate of patients progressing 
on the pomalidomide/dexamethasone arm, it will be assumed that the addition of ixazomib 
does not significantly improve PFS, and the study team will discuss termination of trial 
enrollment with the DSMB. 
13.6 
Study Monitoring (reports, summaries) 
As a randomized phase II trial, this study will be monitored by the Alliance Data and Safety 
Monitoring Board (DSMB). The DSMB follows the Alliance Policies and Procedures for all 
randomized phase II trials. The DSMB will review accrual, toxicity, and interim analyses results. 
All summary findings of the DSMB will be communicated to study investigators by the Alliance. 
In addition the Alliance Statistical Data Center will submit quarterly reports to CTEP by 
electronic means using the Clinical Data Update System.  
We will hold at least once monthly teleconferences to be attended by the study investigators or 
their representatives, the principal investigator, data management, and the statistical data center 
to review adverse events, accrual and other issues that arise over the course of the study. This 
teleconference is only required for those sites with patients on study. 
13.7 
Primary Endpoint Completion Time Estimation  
Based on aforementioned accrual rates and a phase II start date of 07/15/2016, we would 
estimate a Primary Completion Date of 12/31/2018. 

 
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13.8 
Inclusion of Women and Minorities 
All studies must address the issue of inclusion of women and minorities in clinical research and 
whether gender or race/ethnicity differences in the intervention effect are to be expected.  
PLANNED ENROLLMENT REPORT  
Racial 
Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American Indian/ 
Alaska Native 
0 
0 
0 
0 
0 
Asian 
1 
1 
0 
0 
2 
Native Hawaiian 
or Other Pacific 
Islander 
0 
0 
0 
0 
0 
Black or African 
American 
4 
5 
0 
0 
9 
White 
22 
38 
1 
1 
62 
More Than One 
Race 
0 
0 
0 
0 
0 
Total 
27 
44 
1 
1 
73 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, 
India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and 
Vietnam. (Note: Individuals from the Philippine Islands have been recorded as Pacific 
Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial 
groups of Africa. Terms such as “Haitian” or “Negro” can be used in addition to 
“Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 
 
 

 
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14.0 CORRELATIVE AND COMPANION STUDIES  
As of Update #04, no new patients will be registered to A061202-ST1. 
14.1 
Correlative Science Substudy Alliance A061202-ST1  
Evaluation of the cereblon/IRF-4/c-Myc pathway in resistance to Pomalidomide-based therapy.  
14.1.1 Background 
Cereblon, IRF-4 and c-Myc in IMiD Resistance 
Recently, significant progress has been made in better understanding the mechanistic basis 
of IMiD activity in multiple myeloma. In 2010, investigators determined that the 
teratogenicity of the IMiDs is mediated by their binding to the protein cereblon [64]. 
Cereblon forms part of an E3 ubiquitin ligase complex with damaged DNA binding protein 
1 (DDB1) and Cul4A. The IMiDs bind cereblon and modify the substrate specificity of this 
E3 ubiquitin ligase complex. By extension, more recent pre-clinical studies have 
demonstrated that the cytotoxicity of the IMiDs in myeloma cells also requires expression 
of and IMiD binding to cereblon [65, 66]. Notably, multiple myeloma cell lines with innate 
resistance to the IMiDs, a multiple myeloma cell line with acquired resistance to the IMiDs 
after prolonged incubation with increasing concentrations of lenalidomide, and multiple 
myeloma samples from patients with IMiD-resistant disease frequently had reduced 
expression of cereblon. Additionally, shRNA knockdown of cereblon conferred resistance 
in IMiD-sensitive multiple myeloma cell lines. More recently, cereblon expression was 
retrospectively evaluated using gene expression profiles from 53 patients treated on a series 
of pomalidomide studies at the Mayo Clinic. Notably, the partial response rate or better was 
0% for those with a cereblon expression level of <0.81, 19% for those with a cereblon 
expression level of 0.81 – 0.90 and 33% for those with an expression level of >0.90 [67]. 
Interestingly, both shRNA-mediated silencing of cereblon expression and treatment of 
myeloma cells with IMiDs led to down-regulation of IRF-4 and c-Myc expression. 
Moreover, although IRF-4 expression was down-regulated in lenalidomide-sensitive cell 
lines, its expression was unchanged in resistant myeloma cells treated with lenalidomide. 
Given the critical role of the transcription factors IRF-4 and c-Myc in myeloma cell survival 
[68, 69], it is hypothesized that down-regulation of these factors is critical for IMiD-
mediated cytotoxicity. However, it must be recognized that pomalidomide retains activity 
in a sizable proportion of patients with lenalidomide refractory disease, suggesting that there 
must be additional pathways to IMiD resistance beyond decreased expression of cereblon. 
Based on previous studies, high cereblon expression appears positively correlated with 
response to IMiDs. However, we anticipate identifying patients who initially respond but 
then progress on pomalidomide despite high expression of cereblon. We may find that over- 
or under-expression of particular cereblon isoforms, such as those lacking the IMiD binding 
domain, correlate with resistance [70]. Alternatively, resistance could potentially be 
explained by the emergence of point mutations in cereblon that prevent IMiD binding but 
allow cereblon to retain its native function. This situation would be analogous to mutations 
in the BCR-ABL kinase domain of CML patients that impart resistance to tyrosine kinase 
inhibitors. Although these types of mutations have not yet been thoroughly evaluated in MM 
patients, we believe that this study is particularly well suited for investigating this potentially 
important pathway of IMiD resistance. In support of this possible mechanism of resistance, 
a cereblon mutation was recently identified in a patient with extramedullary multiple 
myeloma [71]. 
Most recently, several groups have determined a critical role for the transcription factors 
Ikaros (IKZF1) and Aiolos (IKZF3) in IMID-mediated cytotoxicity [72-74]. Specifically, 

 
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upon binding of IMIDs to cereblon in multiple myeloma cells, the E3 ubiquitin ligase 
complex substrate specificity changes, preferentially binding and ubiquitinating Ikaros and 
Aiolos, thus targeting them for degradation through the proteasome [72, 73]. Importantly, 
Ikaros and Aiolos are important in plasma cell development, highly expressed in multiple 
myeloma, and drive transcription of IRF4. Additionally, their down regulation is required 
for IMID-mediated cytotoxicity [72, 73]. Early retrospective data from gene expression 
profiling would suggest that patients with the lowest quartile of IKZF1 expression are less 
likely to respond to pomalidomide and dexamethasone and have an inferior overall survival. 
In contrast, responses to bortezomib were no different between those with low or high 
IKZF1 expression, thus demonstrating a potentially drug class specific effect on outcome 
[74].  
14.1.2 Objectives 
Primary Objective: 
 
To determine the extent of which cereblon expression (via quantitative PCR and IHC) 
is associated with therapeutic response. 
Secondary Objectives: 
 
To examine whether PFS differs with respect to cereblon expression levels from 
baseline aspirates.  
 
To examine whether therapeutic response or PFS differs with respect to either the 
percentage of IRF-4 or c-Myc positivity in plasma cells or IHC staining intensity in 
plasma cells in samples obtained prior to start of protocol treatment. 
 
To examine whether resistance mutations in the IMiD binding domain of cereblon 
emerge in patients with response to therapy and then progress. 
 
To examine the concordance between cereblon expression levels prior to the start of 
protocol treatment and progression as well as the percentage of patients with 
expression gain or loss.  
 
To examine whether reduced expression of Ikaros (IKZF1) and Aiolos (IKZF3) 
transcription factors is associated with inferior clinical efficacy (ORR, PFS, OS). 
 
To determine whether resistance mutations in Ikaros and Aiolos develop in patients 
with an initial response to therapy (MR or better) who then progress. 
Our correlative aims should help validate cereblon mRNA expression level as a marker of 
response to pomalidomide therapy and establish appropriate cut points for expression level 
utilizing quantitative PCR for validation in future studies. Additionally, it is not known 
whether IRF-4, c-Myc, Ikaros or Aiolos are affected in cases of IMiD resistance where 
cereblon expression is intact. We will therefore look at expression of these factors to get 
preliminary information as to whether or not they are down-regulated in cases of IMiD 
resistance, irrespective of cereblon expression.  
In addition, plasma cell RNA leftover from the planned analyses performed as part of 
A061202-ST1 will be stored for future correlative studies as new insights into the basis of 
IMiD and proteasome inhibitor resistance emerge. Similarly, unstained bone marrow biopsy 
recuts will be also stored for potential use in future correlative studies. Plasma cell depleted 
bone marrow will be stored as a frozen cell pellet for use in potential future studies requiring 
DNA and/or RNA. 

 
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14.1.3 Methods 
Sample collection 
Bone marrow aspirates and biopsies will be obtained at baseline (with the mandatory staging 
marrow aspirate and biopsy), and for those with an initial MR or better, a bone marrow 
aspirate and biopsy will be obtained at disease progression, both to be used in correlative 
analyses. Samples will be tested for cereblon mRNA expression by RT-PCR and for 
immunohistochemical markers such as cereblon, IRF-4, c-Myc, Ikaros and Aiolos. Other 
immunohistochemical markers including BLIMP-1, which has been shown to be important 
for the maintenance of plasma cells [75], may be performed as well and correlated with 
outcome. Cereblon expression will also be assessed via RT-PCR and immunohistochemistry 
at the time of disease progression for those with an initial response (MR or better) to therapy. 
Samples from patients with an initial response to therapy (MR or better) followed by disease 
progression will also be evaluated for the emergence of putative resistance mutations in the 
IMiD binding domain of cereblon. 
Sample processing and facilities 
Correlative studies will be performed in the laboratory of Todd W. Kelley, M.D., Associate 
Professor, Department of Pathology, University of Utah and Medical Director of Molecular 
Hematopathology at ARUP Laboratories (Salt Lake City UT, an enterprise of the University 
of Utah Department of Pathology). The necessary equipment, including real-time PCR 
instruments, DNA sequencers, automated immunostainers and microscopic slide scanners, 
are available for this project at ARUP Laboratories. Bone marrow aspirates will be routed 
through the Alliance Hematologic Malignancy Biorepository located at Ohio State 
University. The Alliance Hematologic Malignancy Biorepository will perform CD138-
based isolation of plasma cells from the aspirates. Isolated plasma cells will be pelleted, 
frozen at -70C, then be sent to Todd Kelley’s laboratory in Utah for RNA extraction and 
analysis. FFPE bone marrow biopsy tissue blocks will be routed through the Alliance 
Biorepository, also located at Ohio State. The bone marrow cells remaining after plasma 
cell shave been removed will be pelleted and stored frozen at the Alliance Hematologic 
Malignancy Biorepository for use in potential future studies. This will provide an 
opportunity for studying other hematopoietic components that may be important in the 
disease process, particularly the myeloid fraction. 
Scientists at Celgene have developed and validated a monoclonal antibody (CRBN65) for 
accurate immunohistochemical evaluation of cereblon protein expression in FFPE tissue 
[76]. This antibody has been made available for use in this study but only through a reference 
laboratory (Quest) contracted by Celgene. This laboratory has also validated Ikaros and 
Aiolos immunohistochemical stains and these will be performed as well. Therefore, 
unstained tissue recuts from the bone marrow biopsies will be sent to Quest for staining for 
these markers. 
Cereblon expression and sequencing 
Bone marrow aspirates will be available at baseline and at the time of progression. Viable 
CD138-positive cells will be isolated from the bone marrow aspirate samples using a bead-
based positive selection kit (Stem Cell Technologies). Total RNA will then be extracted 
from myeloma cells using a commercially available RNA extraction kit (Qiagen). 
Importantly, this RNA will be used for the subsequently described studies but will also be 
archived and available for potential future studies including gene expression profiling.  
Cereblon mRNA expression will be evaluated by converting 100 ng of total RNA into 
random-primed cDNA using the Superscript III First Strand cDNA Synthesis Kit 
(Invitrogen). The cDNAs will then be assayed in duplicate with primer and hydrolysis probe 

 
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(TaqMan probe) mixes specific for the different isoforms of cereblon that have been 
identified [70] and the reference genes GAPDH (ABI Cat. # Hs03929097) and TBP (ABI 
Cat. # Hs00427621) using TaqMan Universal PCR Master Mix (Life Technologies). 
Samples will then be assayed on a Roche Lightcycler (LC480) real time PCR instrument 
and analyzed with the absolute quant/second derivative max option. In this manner, 
expression of the various isoforms will be separately normalized across all samples to 
expression of the housekeeping genes GAPDH and TBP. Normalized cereblon mRNA 
expression for the measured isoforms in myeloma cells will be correlated with therapeutic 
response and other clinical efficacy measures. 
We will also sequence the IMiD binding domain of cereblon in patients who initially 
respond to pomlidomide-based therapy (MR or better) but then progress. If mutations are 
identified, we will go back to the baseline samples of these specific cases and evaluate for 
the presence of cereblon mutations at study entry to determine whether the mutations were 
present at baseline or acquired over the course of treatment. In addition, if mutations are 
identified in acquired pomalidomide resistance, we will screen baseline samples in all 
patients to determine if mutations present at baseline predict for lack of response to 
pomalidomide-based treatment (pending additional funding). The IMiD binding region of 
cereblon has been mapped to the C-terminal 104 amino acids, particularly residues Y384 
and W386.40 Briefly, RNA from myeloma cells will be converted to cDNA, as above, and 
subjected to PCR amplification using primers flanking the IMiD binding domain of cereblon. 
The resulting amplicons will then be subjected to DNA sequencing using an ABI 3700 DNA 
sequencer (Life Technologies). Sequences will be analyzed using Mutation Surveyer 
software (Softgenetics).   
Immunohistochemical analysis 
Formalin fixed paraffin embedded (FFPE) bone marrow biopsy tissue will be available from 
patients at baseline and at progression (for those who achieve an initial MR or better). These 
samples will be subjected to immunohistochemical (IHC) staining in order to evaluate 
plasma cells for expression of cereblon, IRF-4 and c-Myc protein. Briefly, tissue sections 
will be cut onto slides then subjected to double IHC staining with antibodies to CD138 
(expressed in a membrane pattern) to identify plasma cells, and either IRF-4 or c-Myc. Thus, 
the double staining combinations will be CD138/IRF-4 and CD138/c-Myc. Double 
immunostaining with a combination of membrane and nuclear antigens is a simple but 
effective method to limit quantification of staining to a particular cell population of interest. 
IHC staining will be performed on a Ventana automated immunostaining system (Roche). 
IRF-4 and c-Myc expression will be digitally quantified in CD138-positive plasma cells 
using an automated microscopic slide scanner (Aperio) and image analysis software. The 
relative percentage of IRF-4 and c-Myc positivity in plasma cells and the relative staining 
intensity in plasma cells will be derived using image analysis. These findings will then be 
correlated with therapeutic response. Additional immunohistochemical markers, 
particularly BLIMP-1, may also be analyzed in this fashion and also correlated with outcome. 
Cereblon/CD138, Ikaros and Aiolos/CD138 double immunohistochemical staining will be 
performed at Quest Laboroatories as outlined above. The resulting immunostains will be 
analyzed and interpreted by Quest pathologists using an algorithm validated by Celgene 
(unpublished communication). Cereblon, Ikaros and Aiolos immunohistochemical protein 
expression data derived from these analyses will be correlated with outcome as outlined 
below. 
14.1.4 Analysis Plans 
Based on previous experience, we can expect between 65 and 72 samples obtained prior to 
start of treatment from consenting patients based on a 50%-80% consent rate.  

 
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The ability to detect differences in clinical outcome with respect to biomarker profile is 
primarily dependent on the consent rate, access to viable samples, and the prevalence of the 
biomarker poor risk group. 
At present, there is no historical data by which to determine risk categories for the 
biomarkers of interest. As such, we will examine in each treatment arm separately the 
following cut points as a potential means to define risk groups: 25th percentile, median, and 
75th percentile of the biomarker distribution in that treatment arm. For each dichotomization 
of the biomarker, the parameters from fitting a univariate logistic regression model will be 
used to obtain a point and interval estimate of the odds of response in the biomarker high 
cohort relative to the biomarker low cohort in that treatment arm. This will lead to insights 
into which if any of cut points should be used for further testing of the biomarker.  
The candidate dichotomization from the analysis of the response data will be used to 
examine whether PFS differs with respect to these risk groups. For each biomarker the 
parameters from fitting a univariate Cox regression model will be used to obtain a point and 
interval estimate of the hazard of progression in the biomarker high cohort relative to the 
biomarker low cohort in a given treatment arm. 
The correlative studies in this protocol will give us preliminary data as to the proportion of 
pomalidomide resistance that is associated with reduced expression of cereblon and its 
downstream targets. The data derived from this study will be used to appropriately power 
future prospective studies of lenalidomide- or pomalidomide-based therapy.  
 
 

 
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15.0 REFERENCES 
1. 
Siegel, R., et al., Cancer statistics, 2013. CA Cancer J Clin, 2013. 63(1): p. 11-30.  
2. 
Kumar, S.K., et al., Improved survival in multiple myeloma and the impact of novel therapies. 
Blood, 2008. 111(5): p. 2516-20.  
3. 
Dimopoulos, M., et al., Lenalidomide plus dexamethasone for relapsed or refractory multiple 
myeloma. N Engl J Med, 2007. 357(21): p. 2123-32.  
4. 
Weber, D.M., et al., Lenalidomide plus dexamethasone for relapsed multiple myeloma in North 
America. N Engl J Med, 2007. 357(21): p. 2133-42.  
5. 
Zonder, J.A., et al., Lenalidomide and high-dose dexamethasone compared with dexamethasone as 
initial therapy for multiple myeloma: a randomized Southwest Oncology Group trial (S0232). 
Blood, 2010. 116(26): p. 5838-41.  
6. 
Palumbo, A., et al., Continuous Lenalidomide Treatment for Newly Diagnosed Multiple Myeloma. 
New England Journal of Medicine, 2012. 366(19): p. 1759-1769.  
7. 
McCarthy, P.L., et al., Lenalidomide after Stem-Cell Transplantation for Multiple Myeloma. New 
England Journal of Medicine, 2012. 366(19): p. 1770-1781.  
8. 
Mateos, M.V., et al., Bortezomib plus melphalan and prednisone compared with melphalan and 
prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent 
therapy in the phase III VISTA trial. J Clin Oncol, 2010. 28(13): p. 2259-66.  
9. 
Richardson, P.G., et al., A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J 
Med, 2003. 348(26): p. 2609-17.  
10. 
Richardson, P.G., et al., Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final 
time-to-event results of the APEX trial. Blood, 2007. 110(10): p. 3557-60.  
11. 
Richardson, P.G., et al., Bortezomib or High-Dose Dexamethasone for Relapsed Multiple 
Myeloma. New England Journal of Medicine, 2005. 352(24): p. 2487-2498.  
12. 
San Miguel, J.F., et al., Bortezomib plus Melphalan and Prednisone for Initial Treatment of 
Multiple Myeloma. New England Journal of Medicine, 2008. 359(9): p. 906-917.  
13. 
Rajkumar, S.V., et al., Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-
dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label 
randomised controlled trial. Lancet Oncol, 2010. 11(1): p. 29-37.  
14. 
Richardson, P.G., et al., Lenalidomide, bortezomib, and dexamethasone combination therapy in 
patients with newly diagnosed multiple myeloma. Blood, 2010. 116(5): p. 679-86.  
15. 
Richardson, P.G., et al., Multicenter, phase I, dose-escalation trial of lenalidomide plus bortezomib 
for relapsed and relapsed/refractory multiple myeloma. J Clin Oncol, 2009. 27(34): p. 5713-9.  
16. 
Jakubowiak, A.J., et al., Lenalidomide, bortezomib, pegylated liposomal doxorubicin, and 
dexamethasone in newly diagnosed multiple myeloma: a phase 1/2 Multiple Myeloma Research 
Consortium trial. Blood, 2011. 118(3): p. 535-43.  
17. 
Pineda-Roman, M., et al., VTD combination therapy with bortezomib-thalidomide-dexamethasone 
is highly effective in advanced and refractory multiple myeloma. Leukemia, 2008. 22(7): p. 1419-
27.  
18. 
Cavo, M., et al., Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus 
dexamethasone as induction therapy before, and consolidation therapy after, double autologous 
stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. 
Lancet, 2010. 376(9758): p. 2075-85.  
19. 
Palumbo, A., et al., Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with 
bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of 
multiple myeloma: a randomized controlled trial. J Clin Oncol, 2010. 28(34): p. 5101-9.  
20. 
Durie, B.G., et al., Bortezomib with lenalidomide and dexamethasone versus lenalidomide and 
dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate 
autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet 
Oncol, 2017. 389(10068): p. 519-527.  

 
 ALLIANCE A061202 
Version Date: 08/17/2022 
84 
Update #09 
21. 
Stewart, A.K., et al., Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple 
myeloma. N Engl J Med, 2015. 372(2): p. 142-52.  
22. 
Jakubowiak, A.J., et al., A phase 1/2 study of carfilzomib in combination with lenalidomide and 
low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood, 2012. 120(9): p. 
1801-9.  
23. 
Wang, M., et al., Phase 2 dose-expansion study (PX-171-006) of carfilzomib, lenalidomide, and 
low-dose dexamethasone in relapsed or progressive multiple myeloma. Blood, 2013. 122(18): p. 
3122-8.  
24. 
Moreau, P., et al., Bortezomib plus dexamethasone versus reduced-dose bortezomib, thalidomide 
plus dexamethasone as induction treatment before autologous stem cell transplantation in newly 
diagnosed multiple myeloma. Blood, 2011. 118(22): p. 5752-8.  
25. 
Garderet, L., et al., Superiority of the triple combination of bortezomib-thalidomide-dexamethasone 
over the dual combination of thalidomide-dexamethasone in patients with multiple myeloma 
progressing or relapsing after autologous transplantation: the MMVAR/IFM 2005-04 Randomized 
Phase III Trial from the Chronic Leukemia Working Party of the European Group for Blood and 
Marrow Transplantation. J Clin Oncol, 2012. 30(20): p. 2475-82.  
26. 
Chauhan, D., et al., In vitro and in vivo selective antitumor activity of a novel orally bioavailable 
proteasome inhibitor MLN9708 against multiple myeloma cells. Clin Cancer Res, 2011. 17(16): p. 
5311-21.  
27. 
Kupperman, E., et al., Evaluation of the proteasome inhibitor MLN9708 in preclinical models of 
human cancer. Cancer Res, 2010. 70(5): p. 1970-80.  
28. 
Lee, E.C., et al., Antitumor activity of the investigational proteasome inhibitor MLN9708 in mouse 
models of B-cell and plasma cell malignancies. Clin Cancer Res, 2011. 17(23): p. 7313-23.  
29. 
Richardson, P.G., et al., Phase 1 study of twice-weekly ixazomib, an oral proteasome inhibitor, in 
relapsed/refractory multiple myeloma patients. Blood, 2014. 124(7): p. 1038-46.  
30. 
Kumar, S.K., et al., Phase 1 study of weekly dosing with the investigational oral proteasome 
inhibitor ixazomib in relapsed/refractory multiple myeloma. Blood, 2014. 124(7): p. 1047-55.  
31. 
Kumar, S.K., et al., Safety and tolerability of ixazomib, an oral proteasome inhibitor, in 
combination with lenalidomide and dexamethasone in patients with previously untreated multiple 
myeloma: an open-label phase 1/2 study. The Lancet Oncology, 2014. 15(13): p. 1503-1512.  
32. 
Moreau, P., et al., Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N 
Engl J Med, 2016. 374(17): p. 1621-34.  
33. 
Lonial, S., et al., Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma. N Engl J 
Med, 2015. 373(7): p. 621-31.  
34. 
Dimopoulos, M.A., et al., Daratumumab, Lenalidomide, and Dexamethasone for Multiple 
Myeloma. N Engl J Med, 2016. 375(14): p. 1319-1331.  
35. 
Benboubker, L., et al., Lenalidomide and dexamethasone in transplant-ineligible patients with 
myeloma. N Engl J Med, 2014. 371(10): p. 906-17.  
36. 
Attal, M., et al., Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. 
N Engl J Med, 2012. 366(19): p. 1782-91.  
37. 
Dimopoulos, M.A., et al., Carfilzomib and dexamethasone versus bortezomib and dexamethasone 
for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, 
open-label, multicentre study. Lancet Oncol, 2016. 17(1): p. 27-38.  
38. 
Moreau, P., et al., Impact of prior treatment on patients with relapsed multiple myeloma treated 
with carfilzomib and dexamethasone vs bortezomib and dexamethasone in the phase 3 ENDEAVOR 
study. Leukemia, 2017. 31(1): p. 115-122.  
39. 
Chng, W.J., et al., Carfilzomib-dexamethasone vs bortezomib-dexamethasone in relapsed or 
refractory multiple myeloma by cytogenetic risk in the phase 3 study ENDEAVOR. Leukemia, 2017. 
31(6): p. 1368-1374.  

 
 ALLIANCE A061202 
Version Date: 08/17/2022 
85 
Update #09 
40. 
Ludwig, H., et al., Carfilzomib and dexamethasone vs bortezomib and dexamethasone in patients 
with relapsed multiple myeloma: results of the phase 3 study ENDEAVOR (NCT01568866) 
according to age subgroup. Leuk Lymphoma, 2017. 58(10): p. 2501-2504.  
41. 
Palumbo, A., et al., Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma. N Engl 
J Med, 2016. 375(8): p. 754-66.  
42. 
San-Miguel, J.F., et al., Panobinostat plus bortezomib and dexamethasone versus placebo plus 
bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple 
myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol, 2014. 15(11): p. 
1195-206.  
43. 
Richardson, P.G., et al., Panobinostat plus bortezomib and dexamethasone in previously treated 
multiple myeloma: outcomes by prior treatment. Blood, 2016. 127(6): p. 713-21.  
44. 
Muller, G.W., et al., Amino-substituted thalidomide analogs: potent inhibitors of TNF-alpha 
production. Bioorg Med Chem Lett, 1999. 9(11): p. 1625-30.  
45. 
Hideshima, T., et al., Thalidomide and its analogs overcome drug resistance of human multiple 
myeloma cells to conventional therapy. Blood, 2000. 96(9): p. 2943-50.  
46. 
Davies, F.E., et al., Thalidomide and immunomodulatory derivatives augment natural killer cell 
cytotoxicity in multiple myeloma. Blood, 2001. 98(1): p. 210-6.  
47. 
Lacy, M.Q., et al., Pomalidomide plus low-dose dexamethasone in myeloma refractory to both 
bortezomib and lenalidomide: comparison of 2 dosing strategies in dual-refractory disease. Blood, 
2011. 118(11): p. 2970-5.  
48. 
Lacy, M.Q., et al., Pomalidomide (CC4047) plus low-dose dexamethasone as therapy for relapsed 
multiple myeloma. J Clin Oncol, 2009. 27(30): p. 5008-14.  
49. 
Lacy, M.Q., et al., Pomalidomide (CC4047) plus low dose dexamethasone (Pom/dex) is active and 
well tolerated in lenalidomide refractory multiple myeloma (MM). Leukemia, 2010. 24(11): p. 
1934-9.  
50. 
Schey, S.A., et al., Phase I study of an immunomodulatory thalidomide analog, CC-4047, in 
relapsed or refractory multiple myeloma. J Clin Oncol, 2004. 22(16): p. 3269-76.  
51. 
Richardson, P.G., et al., Phase 1 study of pomalidomide MTD, safety, and efficacy in patients with 
refractory multiple myeloma who have received lenalidomide and bortezomib. Blood, 2013. 
121(11): p. 1961-7.  
52. 
Richardson, P.G., et al., Pomalidomide alone or in combination with low-dose dexamethasone in 
relapsed and refractory multiple myeloma: a randomized phase 2 study. Blood, 2014. 123(12): p. 
1826-32.  
53. 
Jagannath, S., et al., Pomalidomide (POM) with Low-Dose Dexamethasone (LoDex) in Patients 
(Pts) with Relapsed and Refractory Multiple Myeloma Who Have Received Prior Therapy with 
Lenalidomide (LEN) and Bortezomib (BORT): Updated Phase 2 Results and Age Subgroup 
Analysis. Blood, 2012. 120(21). [suppl; abstr 450] 
54. 
Leleu, X., et al., Pomalidomide plus low-dose dexamethasone is active and well tolerated in 
bortezomib and lenalidomide-refractory multiple myeloma: Intergroupe Francophone du Myelome 
2009-02. Blood, 2013. 121(11): p. 1968-75.  
55. 
Shah, J.J., et al., Carfilzomib, pomalidomide, and dexamethasone for relapsed or refractory 
myeloma. Blood, 2015. 126(20): p. 2284-90.  
56. 
Paludo, J., et al. Pomalidomide, Bortezomib and Dexamethasone (PVD) for Patients with Relapsed, 
Lenalidomide Refractory Multiple Myeloma. Blood, 2017. DOI: 10.1182/blood-2017-05-782961. 
[Epub ahead of print] 
57. 
Richardson, P.G., et al. Pomalidomide, bortezomib and low-dose dexamethasone in lenalidomide-
refractory 
and 
proteasome 
inhibitor-exposed 
myeloma. 
Leukemia, 
2017. 
DOI: 
10.1038/leu.2017.173. [Epub ahead of print] 
58. 
Sloan, J., et al., A patient-level pooled analysis of the prognostic significance of baseline fatigue 
for overall survival (OS) among 3,915 patients participating in 43 North Central Cancer Treatment 

 
 ALLIANCE A061202 
Version Date: 08/17/2022 
86 
Update #09 
Group (NCCTG) and Mayo Clinic Cancer Center (MC) oncology clinical trials. J Clin Oncol, 
2009. 27(15s). [suppl; abstr 9599] 
59. 
Tan, A., et al., A patient-level meta-analytic investigation of the prognostic significance of baseline 
quality of life (QOL) for overall survival (OS) among 3,704 patients participating in 24 North 
Central Cancer Treatment Group (NCCTG) and Mayo Clinic Cancer Center (MC) oncology 
clinical trials. J Clin Oncol, 2008. 26(15s). [suppl; abstr 9515] 
60. 
Anderson, K.C., et al., Clinically relevant end points and new drug approvals for myeloma. 
Leukemia, 2008. 22(2): p. 231-9.  
61. 
Rajkumar, S.V., et al., Consensus recommendations for the uniform reporting of clinical trials: 
report of the International Myeloma Workshop Consensus Panel 1. Blood, 2011. 117(18): p. 4691-
5.  
62. 
Durie, B.G., et al., International uniform response criteria for multiple myeloma. Leukemia, 2006. 
20(9): p. 1467-73.  
63. 
Wieand, S., et al., Stopping when the experimental regimen does not appear to help. Stat Med, 
1994. 13(13-14): p. 1453-8.  
64. 
Ito, T., et al., Identification of a primary target of thalidomide teratogenicity. Science, 2010. 
327(5971): p. 1345-50.  
65. 
Lopez-Girona, A., et al., Cereblon is a direct protein target for immunomodulatory and 
antiproliferative activities of lenalidomide and pomalidomide. Leukemia, 2012. 26(11): p. 2326-
35.  
66. 
Zhu, Y.X., et al., Cereblon expression is required for the antimyeloma activity of lenalidomide and 
pomalidomide. Blood, 2011. 118(18): p. 4771-9.  
67. 
Schuster, S., et al., Cereblon Expression Predicts Response, Progression Free and Overall Survival 
After Pomalidomide and Dexamethasone Therapy in Multiple Myeloma. Blood, 2012. 120(21). 
[suppl; abstr 194] 
68. 
Shaffer, A.L., et al., IRF4 addiction in multiple myeloma. Nature, 2008. 454(7201): p. 226-231. 
[10.1038/nature07064] 
69. 
Lopez-Girona, A., et al., Lenalidomide downregulates the cell survival factor, interferon regulatory 
factor-4, providing a potential mechanistic link for predicting response. Br J Haematol, 2011. 
154(3): p. 325-36.  
70. 
Gandhi, A.K., et al., Detection and Quantification of Cereblon Protein and mRNA in Multiple 
Myeloma Cell Lines and Primary CD138+multiple Myeloma Cells. Blood, 2012. 120(21). [suppl; 
abstr 4043] 
71. 
Egan, J., et al., The Myeloma Genome in Drug Refractory Extra-Medullary Disease Identifies 
Mutations in Proteasome, Cereblon and Glucocorticoid Pathways. Blood, 2012. 120(21). [suppl; 
abstr 3698] 
72. 
Kronke, J., et al., Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple 
myeloma cells. Science, 2014. 343(6168): p. 301-5.  
73. 
Lu, G., et al., The myeloma drug lenalidomide promotes the cereblon-dependent destruction of 
Ikaros proteins. Science, 2014. 343(6168): p. 305-9.  
74. 
Zhu, Y.X., et al., Identification of cereblon-binding proteins and relationship with response and 
survival after IMiDs in multiple myeloma. Blood, 2014. 124(4): p. 536-45.  
75. 
Shapiro-Shelef, M., et al., Blimp-1 is required for maintenance of long-lived plasma cells in the 
bone marrow. J Exp Med, 2005. 202(11): p. 1471-6.  
76. 
Gandhi, A.K., et al., Measuring cereblon as a biomarker of response or resistance to lenalidomide 
and pomalidomide requires use of standardized reagents and understanding of gene complexity. 
Br J Haematol, 2014. 164(2): p. 233-44.  
 
 

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APPENDIX I: 
ECOG PERFORMANCE STATUS  
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity. Fully active, able to carry on all pre-disease 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 (e.g., 
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. 
 

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APPENDIX II: COCKCROFT-GAULT FORMULA 
Creatinine Clearance = (140 – age) x weight (kg) x 0.85 (for females) 
 
 
 
 
 
72 X Serum Creatinine (mg/dL) 
 
 

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APPENDIX III: REGISTRATION FATIGUE/UNISCALE ASSESSMENTS 
 
Registration Fatigue/Uniscale Assessments 
 
At patient registration, this form is to be administered by a nurse/CRA, completed by the patient, 
and recorded on the Registration Fatigue/Uniscale Assessments Form (see Forms Packet). 
 
If needed, this appendix can be adapted to use as a source document.  A booklet containing this 
assessment does not exist – please do not order this booklet. 
 
 
 
 
How would you describe: 
 
your level of fatigue, on the average in the past week including today? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
Fatigue 
 
 
 
 
 
 
 
 
 
Fatigue 
as bad  
as it can be 
 
your overall quality of life in the past week including today? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
As bad as 
it can be 
 
 
 
 
 
 
 
 
 
As good as 
it can be 
 
 

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APPENDIX IV: CONGESTIVE HEART FAILURE CLASSIFICATION SYSTEM  
 
New York Heart Association Congestive Heart Failure Classification System 
Class 
Functional Capacity 
Objective 
Assessment 
I 
Patients with cardiac disease but without resulting 
limitations of physical activity. Ordinary physical activity 
does not cause undue fatigue, palpitation, dyspnea, or 
anginal pain. 
No objective 
evidence of 
cardiovascular 
disease. 
II 
Patients with cardiac disease resulting in slight limitation 
of physical activity. They are comfortable at rest. 
Ordinary physical activity results in fatigue, palpitation, 
dyspnea, or anginal pain.  
Objective evidence of 
minimal 
cardiovascular 
disease. 
III 
Patients with cardiac disease resulting in marked 
limitation of physical activity. They are comfortable at 
rest. Less than ordinary activity causes fatigue, 
palpitation, dyspnea, or anginal pain.  
Objective evidence of 
moderately severe 
cardiovascular 
disease.  
IV 
Patients with cardiac disease resulting in inability to carry 
on any physical activity without discomfort. Symptoms 
of heart failure or of the anginal syndrome may be 
present even at rest. If any physical activity is 
undertaken, discomfort is increased. 
Objective evidence of 
severe cardiovascular 
disease.  
 

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APPENDIX V: CYTOCHROME P450 1A2 INHIBITORS AND CYTOCHROME P450 3A4 INHIBITORS AND 
INDUCERS  
Strong CYP1A2 inhibitors 
Moderate CYP1A2 inhibitors 
Fluvoxamine 
Cimetidine 
Ciprofloxacin 
 
This database of CYP inhibitors was compiled from the Indiana University School of 
Medicine’s “Clinically Relevant” Table. Strong inhibitors are predicted to increase 
CYP3A4 substrates >5-fold, and moderate inhibitors are predicted to increase CYP3A4 
substrates  ≥2-fold but <5-fold.  
 
Please note that this is not an all-inclusive list.  Any new medications 
prescribed or complementary therapies should be assessed for their potential to 
inhibit or induce CYP1A2. 
 
For the latest publically available updates please visit the Indiana University 
School of Medicine Drug Interaction Database at: 
 
 
 
Cytochrome P450 3A4 Inhibitors and Inducers: 
Strong CYP3A4 inhibitors 
Moderate CYP3A4 inhibitors 
CYP3A4 inducers 
Clarithromycin 
Aprepitant 
Avasimibe 
Conivaptan 
Atazanavir 
Barbiturates 
Grapefruit juice 
Cimetidine 
Bosentan 
Indinavir 
Ciprofloxacin 
Carbamazepine 
Itraconazole 
Darunavir 
Efavirenz 
Ketoconazole 
Diltiazem 
Etravirine 
Lopinavir 
Erythromycin 
Systemic glucocorticoids* 
Mibefradil 
Fluconazole 
Modafenil 
Nefazodone 
Tofisopam 
Nafcillin 
Nelfinavir 
Verapamil 
Nevirapine 
Posaconazole 
Amprenavir 
Oxcarbazepine 
Ritonavir 
Fosamprenavir 
Phenobarbital 
Saquinavir 
Imatinib 
Phenytoin 
Telithromycin 
Elvitegravir 
Pioglitazone  
Troleandomycin 
Tipranavir 
Rifabutin, rifapentine 
Voriconazole 
 
Rifampin 
 
 
St. John's wort 
 
 
Talviraline 
 
 
Tipranavir 
 
 
Topiramate 
 
 
Troglitazone  
This database of CYP inhibitors was compiled from the Indiana University School of Medicine’s “Clinically Relevant” Table 
and from the University of Washington’s Drug Interaction Database based on in vitro studies. Strong inhibitors are predicted 

 
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Strong CYP3A4 inhibitors 
Moderate CYP3A4 inhibitors 
CYP3A4 inducers 
to increase CYP3A4 substrates >5-fold, and moderate inhibitors are predicted to increase CYP3A4 substrates  ≥2-fold but <5-
fold.  
This database of CYP inducers was compiled from the FDA’s “Guidance for Industry, Drug Interaction Studies” from the 
Indiana University School of Medicine’s “Clinically Relevant” Table; and from Pursche et al. Curr Clin Pharm.2008;3:198-
203. 
*Although dexamethasone is an inducer of CYP3A4, ixazomib pharmacokinetics do not appear to be affected by 
dexamethasone. 
 
Herbal therapies with potential CYP3A4 interactions: St. John’s Wort and gingko biloba.  
 
Foods with potential CYP3A4 interactions: Grapefruit or grapefruit juice, grapefruit hybrids, Seville oranges, 
pummelos and exotic citrus fruits (e.g. starfruit). 
 
Please note that this is not an all-inclusive list.  Any new medications prescribed or complementary therapies 
should be assessed for their potential to inhibit or induce CYP3A4. 
 
For the latest publically available updates please visit the Indiana University School of Medicine Drug Interaction 
Database at: 
 
 
 
 

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APPENDIX VI: PATIENT MEDICATION LOGS  
POMALIDOMIDE MEDICATION LOG 
Pill Diary for Alliance Protocol A061202: A Phase I/II Study of Pomalidomide, Dexamethasone 
and Ixazomib VS Pomalidomide and Dexamethasone for Patients with Multiple Myeloma 
Relapsing on Lenalidomide as Part of First Line Therapy  
 
Number of Capsules Given:____________ 
Capsule Bottle(s) returned:  Circle Yes or No 
Total Daily Dose:________________ 
 
Number of Capsules returned:_____________ 
(To be Completed by RN)  
 
PLEASE FILL OUT AND BRING THIS SHEET TO ALL VISITS. 
 
 
 
 
 
CYCLE #: _______  # of WEEKS___________ 
DAY 
Medication 
DATE 
TIME 
# of XX mg Capsules 
taken 
Comments 
Example 
Pomalidomide 
07/01/12 
9:00 
 
AM 
1 XX mg capsules taken 
+ 2 XX mg capsules 
taken 
 
1 
Pomalidomide 
 
 
 
 
 
2 
Pomalidomide 
 
 
 
 
 
3 
Pomalidomide 
 
 
 
 
 
4 
Pomalidomide 
 
 
 
 
 
5 
Pomalidomide 
 
 
 
 
 
6 
Pomalidomide 
 
 
 
 
 
7 
Pomalidomide 
 
 
 
 
 
8 
Pomalidomide 
 
 
 
 
 
9 
Pomalidomide 
 
 
 
 
 
10 
Pomalidomide 
 
 
 
 
 
11 
Pomalidomide 
 
 
 
 
 
12 
Pomalidomide 
 
 
 
 
 
13 
Pomalidomide 
 
 
 
 
 
14 
Pomalidomide 
 
 
 
 
 
15 
Pomalidomide 
 
 
 
 
 
16 
Pomalidomide 
 
 
 
 
 
17 
Pomalidomide 
 
 
 
 
 
18 
Pomalidomide 
 
 
 
 
 
19 
Pomalidomide 
 
 
 
 
 
20 
Pomalidomide 
 
 
 
 
 
21 
Pomalidomide 
 
 
 
 
 
  
Patient Signature: _________________________________________Date:__________ 
  
 Consenting Professional/Research RN Signature: ______________Date:__________  
 
Comments:_____________________________________________________________ 

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DEXAMETHASONE MEDICATION LOG 
Pill Diary for Alliance Protocol A061202: A Phase I/II Study of Pomalidomide, Dexamethasone 
and Ixazomib VS Pomalidomide and Dexamethasone for Patients with Multiple Myeloma 
Relapsing on Lenalidomide as Part of First Line Therapy  
 
Number of Tablets Given:____________ 
Tablet Bottle(s) returned:  Circle Yes or No 
Total Daily Dose:________________ 
 
Number of Tablets returned:_____________ 
(To be Completed by RN)  
 
PLEASE FILL OUT AND BRING THIS SHEET TO ALL VISITS. 
 
 
 
 
CYCLE #: _______  # of WEEKS___________ 
DAY 
Medication 
DATE 
TIME 
# of XX mg tablets taken Comments 
Example 
Dexamethasone 
07/01/12 
9:00 
 
AM 
1 XX mg tablets taken + 
2 XX mg tablets taken 
 
1 
Dexamethasone 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
6 
 
 
 
 
 
 
7 
 
 
 
 
 
 
8 
Dexamethasone 
 
 
 
 
 
9 
 
 
 
 
 
 
10 
 
 
 
 
 
 
11 
 
 
 
 
 
 
12 
 
 
 
 
 
 
13 
 
 
 
 
 
 
14 
 
 
 
 
 
 
15 
Dexamethasone 
 
 
 
 
 
16 
 
 
 
 
 
 
17 
 
 
 
 
 
 
18 
 
 
 
 
 
 
19 
 
 
 
 
 
 
20 
 
 
 
 
 
 
21 
 
 
 
 
 
 
22 
Dexamethasone 
 
 
 
 
 
  
Patient Signature: _________________________________________Date:__________ 
  
 Consenting Professional/Research RN Signature: ______________Date:__________  
 
Comments:_____________________________________________________________ 
 

 
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IXAZOMIB MEDICATION LOG 
Pill Diary for Alliance Protocol A061202: A Phase I/II Study of Pomalidomide, Dexamethasone 
and Ixazomib VS Pomalidomide and Dexamethasone for Patients with Multiple Myeloma 
Relapsing on Lenalidomide as Part of First Line Therapy  
 
Number of Capsules Given:____________ 
Blister Pack returned:  Circle Yes or No 
Total Daily Dose:________________ 
 
Number of Capsules returned:_____________ 
(To be Completed by RN)  
 
PLEASE FILL OUT AND BRING THIS SHEET TO ALL VISITS. 
 
 
 
 
CYCLE #: _______  # of WEEKS___________ 
DAY 
Medication 
DATE 
TIME 
# of XX mg Capsules 
taken 
Comments 
Example 
Ixazomib 
07/01/12 
9:00 
 
AM 
1 XX mg capsules taken 
+ 2 XX mg capsules 
taken 
 
1 
Ixazomib 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
6 
 
 
 
 
 
 
7 
 
 
 
 
 
 
8 
Ixazomib 
 
 
 
 
 
9 
 
 
 
 
 
 
10 
 
 
 
 
 
 
11 
 
 
 
 
 
 
12 
 
 
 
 
 
 
13 
 
 
 
 
 
 
14 
 
 
 
 
 
 
15 
Ixazomib 
 
 
 
 
 
  
Patient Signature: _________________________________________Date:__________ 
  
 Consenting Professional/Research RN Signature: ______________Date:__________  
 
Comments:_____________________________________________________________

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APPENDIX VII PROTEASOME INHIBITORS 
 
Drug  
Commercial Name 
Investigational Name 
Bortezomib 
Velcade 
PS-341 
Carfilzomib 
Kyprolis 
PR-171 
Ixazomib 
Ninlaro 
MLN9708 
Oprozomib 
 
ONX-0912 
Marizomib 
 
NPI-0052