Clinical trial NCT02440464
Conditions: Multiple Myeloma
Keywords: Multiple Myeloma Allogeneic Transplant Maintenance Therapy Anti-Myeloma Agents Hematologic Disorders
Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
Start date: 2015-08-01; Completion date: 2020-10-01
Enrollment: 57 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is designed to compare progression-free survival (PFS) from randomization among patients randomized on the BMT CTN 1302 protocol, "Multicenter Phase II, Double-blind Placebo Controlled Trial of Maintenance Ixazomib after Allogeneic Hematopoietic Stem Cell Transplantation for High Risk Multiple Myeloma". It is hypothesized that Ixazomib maintenance therapy will result in improved PFS in patients with high-risk multiple myeloma following Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) compared to placebo.

Detailed description:
The study is designed as a Phase II, multi-center double-blind trial that randomizes patients with high risk Multiple Myeloma to Ixazomib maintenance or placebo 60-120 days after allogeneic HSCT. The primary objective of this randomized trial is to compare progression free survival from randomization as a time to event endpoint between patients randomized to Ixazomib maintenance or placebo. Secondary objectives are to describe for each treatment arm: rates of grade II-IV and III-IV Graft-Versus-Host-Disease (GVHD), chronic GVHD, best disease response rates, disease progression, transplant related mortality, overall survival, rates of Grade ≥ 3 toxicity according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0, incidence of infections, and health-related quality of life.

Arms: arm 1: Allogeneic HSCT and Fludarabine/Melphalan/Bortezomib conditioning followed by Ixazomib maintenance arm 2: Allogeneic HSCT and Fludarabine/Melphalan/Bortezomib conditioning followed by placebo maintenance.
Interventions: intervention 1: Allogeneic HSCT intervention 2: Fludarabine intervention 3: Melphalan intervention 4: Bortezomib intervention 5: Ixazomib intervention 6: Placebo
Intervention descriptions: intervention 1: Eligible patients with a Human Leukocyte Antigen (HLA)-matched related or unrelated donor will undergo allogeneic hematopoietic stem cell transplant at Day 0. For GVHD prophylaxis, patients will be given Tacrolimus from Day -3 until at least 6 months following initiation, at an intravenous daily dose of 0.015 mg/kg. This will be combined with an intravenous administration of Methotrexate at 5 mg/m2 on Days +1, +3, +6, and +11. intervention 2: Patients will receive conditioning treatment before and after HSCT. Fludarabine will be given at 30 mg/m2 intravenously on Day -6 through Day -3. intervention 3: Melphalan will be given at 70 mg/m2 intravenously on Days -4 and -3. intervention 4: Bortezomib will be administered at 1.3 mg/m2 intravenously on Day -3. intervention 5: Between 60 and 120 days following HSCT, patients randomized to the experimental arm will receive Ixazomib maintenance. Maintenance will begin at 3-mg oral doses on Days 1, 8, and 15 of a 28-day cycle. This will increase to 4-mg doses on the same cycle schedule, following successful completion of 3 cycles at the previous dosage, for a total of 12 cycles. intervention 6: Between 60 and 120 days following HSCT, patients randomized to the control group will be given 3 mg of placebo orally on Days 1, 8, and 15 of a 28-day cycle. This will increase to 4-mg doses on the same cycle schedule following successful completion of 3 cycles of placebo maintenance at the 3-mg dose. This will continue for a total of 12 cycles.

Protocol documents:
Prot_SAP_ICF_000.pdf: 
 


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Core Participating Centers: 
Affiliate Participating Centers: 
City of Hope 
Advocate Lutheran General Hospital 
Dana Farber/Brigham & Women’s Hospital Consortium 
Medical University of South Carolina 
Dana Farber/Brigham & Women’s Hospital 
Hackensack University Medical Center 
Massachusetts General Hospital 
Henry Ford Hospital 
Duke University Medical Center 
University of Alabama 
Fred Hutchinson Cancer Research Center 
University of California San Diego 
H. Lee Moffitt Cancer Center 
University of Kentucky 
Medical College of Wisconsin 
University of Nebraska 
Memorial Sloan Kettering Cancer Center 
University of Wisconsin 
Mount Sinai Consortium 
West Virginia University 
Mount Sinai/Icahn School of Medicine 
Vanderbilt University 
Northside Hospital Atlanta Consortium 
Northside Hospital 
Ohio State Consortium 
Ohio State University 
Roswell Park Cancer Institute 
University of North Carolina 
Virginia Commonwealth University 
Oregon Health and Science University Consortium 
Cleveland Clinic 
Case Western Reserve University 
Loyola University 
University of Florida Consortium 
Emory University 
University of Michigan Consortium 
Karmanos Cancer Center 
University of Minnesota 
University of Pennsylvania 
Washington University 


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PROTOCOL SYNOPSIS – BMT CTN 1302 PROTOCOL 
 
Multicenter Phase II, Double-blind Placebo Controlled Trial of Maintenance Ixazomib 
after Allogeneic Hematopoietic Stem Cell Transplantation for High Risk Multiple 
Myeloma 
 
Co-Principal Investigators: Qaiser Bashir, Parameswaran Hari, Taiga Nishihori 
 
Study Design: 
The study is designed as a Phase II, multi-center double-blind trial 
that randomizes patients with high risk MM to ixazomib 
maintenance or placebo 60-120 days after allogeneic hematopoietic 
transplantation (HCT). 
 
Primary Objective: 
The primary objective of this randomized trial is to compare 
progression free survival from randomization as a time to event 
endpoint between patients randomized to ixazomib maintenance or 
placebo. 
 
Secondary Objectives: Secondary objectives are to describe for each treatment arm: rates 
of grade II-IV and III-IV acute GVHD, chronic GVHD, best disease 
response rates, disease progression, transplant related mortality, 
overall survival, rates of Grade  3 toxicity according to the 
Common Terminology Criteria for Adverse Events (CTCAE) 
Version 4.0, incidence of infections, and health-related quality of 
life. 
 
Eligibility Criteria: 
Patients aged ≥ 18.0 years and ≤ 70.0 years at the time of enrollment, 
with: 
 
1) high risk multiple myeloma in partial response (PR) or better 
with no prior progression and are ≤ 24.0 months from 
autologous HCT (single or planned tandem), or are ≤ 24.0 
months from initiation of systemic anti-myeloma therapy with 
no autologous HCT; or 
2) high risk multiple myeloma in very good partial response 
(VGPR) or better with 1 prior progression which occurred ≤ 
24.0 months after autologous HCT (single or planned tandem), 
or ≤ 24.0 months after initiation of systemic anti-myeloma 
therapy with no autologous HCT; or 
3) standard risk multiple myeloma in VGPR or better with 1 prior 
progression which occurred ≤ 24.0 months from autologous 
HCT (single or planned tandem); or 
4) plasma cell leukemia in VGPR or better with no prior 
progression and are ≤ 18.0 months after autologous HCT, or are 


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≤ 18.0 months after initiation of systemic anti-myeloma therapy 
with no autologous HCT 
Patients must have a HLA-matched related or unrelated donor 
willing to donate peripheral blood progenitor cells and meet one of 
the following criteria: 
a. A sibling donor who is a 6/6 match at HLA–A and –B 
(intermediate or higher resolution) and –DRB1 (at high 
resolution using DNA-based typing) OR 
b. A related donor (other than sibling) who is a 8/8 match for 
HLA–A, –B, –C (at intermediate or higher resolution) and 
–DRB1 (at high resolution using DNA-based typing) OR 
c. An unrelated donor who is an 8/8 match at HLA–A, –B, 
–C, and –DRB1 (at high resolution using DNA-based 
typing) 
Treatment Description: All patients will undergo conditioning regimen with fludarabine 
(120 mg/m2), melphalan (140 mg/m2) and bortezomib (1.3 mg/m2 ) 
combination. GVHD prophylaxis will use the combination of 
tacrolimus 
and 
methotrexate. 
Randomization 
to 
ixazomib 
maintenance or placebo will occur at the time of maintenance 
therapy initiation (between Days 60 and 120 post-transplant). 
Maintenance with ixazomib will consist of 12 x 28-day cycles at a 
dose of 3 mg on Days 1, 8 and 15, with adjustments depending on 
toxicity. Ixazomib will continue for a maximum of 12 cycles (28 
days/cycle). Patients randomized to placebo will follow the same 
treatment and dose schedule as those randomized to ixazomib 
maintenance. 
 
Accrual: 
The sample size for this study is 110 randomized patients with a 
target enrollment of 138 patients to achieve that sample size. 
 
Accrual Period: 
The estimated accrual period is 3 years 
 
Study Duration: 
Patients will be followed for 2 years post transplant for all endpoints. 
In addition, patients will be followed only for second primary 
malignancies until all patients have completed 2 years of follow up. 
 
Interim Analysis: 
There will be no formal interim analysis for futility or efficacy for 
this trial. 
 
Stopping Guidelines: 
The key safety endpoints to be monitored  are  the rate of  TRM  at 
Day 100 post-transplant in all transplanted subjects, Grade III-IV 
acute GVHD at Day 100 post-transplant, and Grade III-IV acute 
GVHD rates at Day 60 post-randomization within treatment arm. 
Monitoring of the key safety endpoints will be conducted monthly, 
and if rates significantly exceed pre-set thresholds, the NHLBI will 


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be notified in order that the DSMB can be advised. The stopping 
guidelines serve as a trigger for consultation with the DSMB for 
additional review. Policies and composition of the DSMB are 
described in the BMT CTN's Manual of Procedures (MOP). 


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STUDY SCHEMA 
Aim: To determine the impact of maintenance and allogeneic transplant in high risk multiple myeloma 
 
Inclusion Criteria 
1. Age ≥ 18.0 and ≤ 70.0 years at the time of enrollment 
2. Patient must meet ONE of the disease criteria outlined 
in table 1 below. 
3. Patients must have a HLA-matched related or unrelated 
peripheral blood stem cell donor that meet one of the 
following criteria: A sibling donor who is a 6/6 match 
at HLA–A and–B (intermediate or higher resolution) 
and –DRB1 (at high resolution using DNA-based 
typing) OR a related donor (other than sibling) who is a 
8/8 match for HLA–A, –B, –C (at intermediate or 
higher resolution) and –DRB1 (at high resolution using 
DNA-based typing) OR an unrelated donor who is an 
8/8 match at HLA–A, –B, –C, and –DRB1 (at high 
resolution using DNA-based typing). 
4. Cardiac function: Ejection fraction > 40% 
5. Estimated creatinine clearance greater than 40 
mL/minute 
6. Pulmonary function: DLCO ≥ 40% (adjusted for 
hemoglobin) and FEV1 ≥ 50% 
7. Liver function: total bilirubin < 2x the upper limit of 
normal and ALT/AST < 2.5x the upper normal limit 
8. Effective methods of birth control as described in the 
protocol 
9. Voluntary written consent must be given before 
performance of any study related procedure not part of 
standard medical care, with the understanding that 
consent may be withdrawn by the patient at any time 
without prejudice to future medical care. 
Exclusion Criteria 
1. Karnofsky Performance Score < 70% 
2. Prior allogeneic HCT 
3. Non secretory multiple myeloma (defined as 
normal serum and urine immunofixation and 
normal serum free light chain assay). 
4. Uncontrolled bacterial, viral or fungal infections 
(undergoing appropriate treatment and with 
progression of clinical symptoms). 
5. Seropositive for the human immunodeficiency 
virus (HIV). 
6. Active Hepatitis B or C determined by serology 
and/or NAAT. 
7. Hypersensitivity to bortezomib, boron or mannitol. 
8. Grade 2 or higher sensory peripheral neuropathy. 
9. Myocardial infarction within 6 months prior to 
enrollment or New York Heart Association 
(NYHA) Class III or IV heart failure (see 
Appendix D), uncontrolled angina, severe 
uncontrolled ventricular arrhythmias, or 
electrocardiographic evidence of acute ischemia or 
active conduction system abnormalities. Prior to 
study entry, any ECG abnormality at screening 
must be documented by the investigator as not 
medically relevant. 
10. Pre-planned pre-emptive or prophylactic 
administration of donor lymphocytes. 
11. CNS involvement with MM (CSF positivity for 
plasma cells or a parenchymal CNS plasmacytoma 
12. Presence of fluid collection that interferes with 
methotrexate clearance. 
13. Known GI disease or GI procedure that could 
interfere with the oral absorption of MLN9708 
(ixazomib). 
14. Prior cancers except resected basal cell carcinoma 
or treated cervical carcinoma in situ. Cancer treated 
with curative intent ≥ 5 years previously will be 
allowed. Cancer treated with curative intent < 5 
years, which is in remission, will be reviewed on a 
case-by-case basis by the Protocol Officer or one 
of the Protocol Chairs 
15. Multi-organ involvement by amyloidosis or 
evidence of amyloidosis-related organ dysfunction. 
16. Received radiation therapy within ≤ 3.0 weeks 
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Table 1: Disease Criteria for Eligible Patients 
 
Disease 
Disease 
Status 
Prior 
Progression 
Prior Therapy/Auto HCT 
High Risk1 Multiple Myeloma 
≥ PR 
None 
≤ 24.0 months after autologous HCT (single or 
planned tandem), or after initiation of systemic 
anti-myeloma therapy with no autologous HCT 
High Risk1 Multiple Myeloma 
≥ VGPR2 
1 
progression or relapse ≤ 24.0 months after 
autologous HCT (single or planned tandem), or 
after initiation of systemic anti-myeloma therapy 
with no autologous HCT 
Standard Risk Multiple 
Myeloma 
≥ VGPR2 
1 
progression or relapse ≤ 24.0 months after single 
or planned tandem autologous HCT 
Plasma Cell Leukemia 
≥ VGPR 
None 
≤ 18.0 months after autologous HCT, or after 
initiation of systemic anti-myeloma therapy 
 
 
 
Immune Suppression Taper: 
Patients without GVHD 
Tacrolimus 
- 
Taper to initiate at least Day 90 and completely 
off at Day 180. 
Primary endpoint: 
- Progression free survival as a time to event endpoint from 
randomization 
Secondary endpoints: 
- Grades II-IV and III-IV acute GVHD 
- Chronic GVHD 
- Best response 
- Disease progression 
- Treatment-related mortality 
- Toxicity 
- Rates of infections 
- Overall survival 
- Rate of non-randomization 
- Health-Related Quality of Life 
 
 
 
 
 
 
 
 
 
1High Risk is defined as one or more of the following detected at any time prior to enrollment: del13 by conv. 
karyotyping only; hypodiploidy, 1q amplification or 1p deletion, t(4;14), t(14;16), t(14;20) or deletion of 17p by FISH 
or conv. karyotyping; or high risk criteria based on GEP. 
2Patients with one prior progression without measurable monoclonal paraprotein at the time of disease progression or 
relapse (< 1.0 g/dl in serum or < 200 mg/24 hrs in urine) may be considered to have met VGPR criteria if < 5% plasma 
cells in bone marrow and ≥ 90% decline in the difference between involved and uninvolved FLC levels from baseline 
(time of progression/relapse). 
Patients with IgG kappa multiple myeloma receiving daratumumab: International Myeloma Working Group criteria 
for VGPR may not be achieved since daratumumab is known to increase the IgG kappa spike. In such cases the FLC 
and marrow may be used to establish VGPR, as above, with prior approval from the protocol co-chairs. 


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≥ 18.0 years to ≤ 70.0 years 
High Risk Multiple Myeloma ≤ 24.0 months from anti-myeloma therapy without 
progression OR High Risk Multiple Myeloma with progression ≤ 24.0 months from 
anti-myeloma therapy OR 
Standard Risk Progression ≤ 24.0 months from prior autoHCT OR 
Plasma Cell Leukemia ≤ 18.0 months from anti-myeloma therapy 
 
OUTLINE OF TREATMENT PLAN 
 
 
 
 
Randomization 
(Day +60 to +120) 
Fludarabine/Melphalan/Bortezomib 
Conditioning Regimen (Day -6 to -3) 
+ 
PBSC Infusion (Day 0) 
Placebo Maintenance 
Therapy x12 cycles 
Ixazomib Maintenance 
Therapy x12 cycles 


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TABLE OF CONTENTS 
1. 
BACKGROUND AND RATIONALE ......................................................................... 1-1 
1.1. 
Multiple Myeloma and Risk Stratification ...................................................................... 1-1 
1.2. 
Impact of Novel Agents in High risk Multiple Myeloma ................................................ 1-2 
1.3. 
Current Status of Allogeneic Hematopoietic Cell Transplantation for Multiple 
Myeloma ..................................................................................................................... 1-4 
1.4. 
Autologous HCT Followed by Allogeneic HCT with Nonmyeloablative Conditioning 1-4 
1.5. 
Impact of Chromosomal Abnormalities on Outcomes after allogeneic HCT .................. 1-7 
1.6. 
Bortezomib ....................................................................................................................... 1-8 
1.6.1. 
Scientific Background ................................................................................................. 1-8 
1.6.2. 
Clinical Experience ..................................................................................................... 1-8 
1.7. 
Use of Bortezomib during and after Allogeneic HCT ................................................... 1-11 
1.7.1. 
Pre-clinical Data ........................................................................................................ 1-11 
1.7.2. 
Clinical Data on Bortezomib after Allogeneic HCT ................................................. 1-12 
1.7.3. 
Combining Bortezomib with Allogeneic HCT ......................................................... 1-12 
1.7.4. 
Bortezomib for GVHD Prophylaxis .......................................................................... 1-13 
1.7.5. 
Modified Conditioning Regimen .............................................................................. 1-13 
1.8. 
Ixazomib (MLN9708) .................................................................................................... 1-13 
1.8.1. 
Preclinical Experience ............................................................................................... 1-13 
1.8.2. 
Clinical Experience ................................................................................................... 1-13 
1.8.3. 
Pharmacokinetics and Drug Metabolism .................................................................. 1-14 
1.8.4. 
Clinical Trial Experience Using the Oral Formulation of MLN9708 ....................... 1-14 
1.8.5. 
Overview of the Oral Formulation of MLN9708 ...................................................... 1-16 
1.8.6. 
Relapsed and/or Refractory Multiple Myeloma ........................................................ 1-18 
1.8.7. 
Newly Diagnosed Multiple Myeloma (NDMM) ...................................................... 1-21 
1.9. 
Rationale for the Study .................................................................................................. 1-22 
2. 
STUDY DESIGN ............................................................................................................ 2-1 
2.1. 
Study Overview................................................................................................................ 2-1 
2.2. 
Hypothesis and Objectives ............................................................................................... 2-1 
2.2.1. 
Hypothesis ................................................................................................................... 2-1 
2.2.2. 
Primary Objectives ...................................................................................................... 2-1 
2.2.3. 
Secondary Objectives .................................................................................................. 2-1 
2.3. 
Patient Eligibility ............................................................................................................. 2-2 
2.3.1. 
Inclusion Criteria ......................................................................................................... 2-2 
2.3.2. 
Exclusion Criteria........................................................................................................ 2-4 
2.3.3. 
Donor Exclusion Criteria ............................................................................................ 2-5 
2.3.4. 
Patient Eligibility Criteria to Begin Maintenance Therapy ......................................... 2-5 
2.3.5. 
Patient Exclusion Criteria to Begin Maintenance Therapy ......................................... 2-6 
2.4. 
Treatment Plan ................................................................................................................. 2-7 
2.4.1. 
Conditioning Regimen (Fludarabine/Melphalan/Bortezomib) ................................... 2-7 
2.4.1.1. 
Dosing for Melphalan, Fludarabine, and Methotrexate .......................................... 2-7 
2.4.1.2. 
Renal insufficiency dose adjustment for fludarabine .............................................. 2-7 
2.4.2. 
GVHD Prophylaxis (Tacrolimus/Methotrexate) ......................................................... 2-8 
2.4.3. 
Donor Peripheral Blood Stem Cell Infusion ............................................................... 2-8 


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2.4.4. 
Randomization to Placebo or Ixazomib Maintenance Therapy .................................. 2-8 
2.4.5. 
Ixazomib/Placebo Initiation ........................................................................................ 2-9 
2.4.5.1. 
Record of Administration ....................................................................................... 2-9 
2.4.5.2. 
Dose Escalation in the Absence of Toxicities ......................................................... 2-9 
2.4.5.3. 
Ixazomib or Placebo Dose Reduction ................................................................... 2-10 
2.4.5.4. 
Initiation of a New Cycle of Ixazomib or Placebo ............................................... 2-10 
2.4.5.5. 
Treatment Adherence ............................................................................................ 2-11 
2.4.6. 
Discontinuation of Maintenance ............................................................................... 2-13 
2.5. 
Supportive Care ............................................................................................................. 2-14 
2.5.1. 
Tapering of GVHD Prophylaxis ............................................................................... 2-14 
2.5.2. 
Donor Lymphocyte Infusions ................................................................................... 2-14 
2.5.3. 
Management of Acute Graft-versus-Host Disease .................................................... 2-15 
2.5.4. 
Management of Chronic Graft-versus-Host Disease ................................................ 2-15 
2.5.5. 
Management of other Toxicities ............................................................................... 2-15 
2.5.5.1. 
Nausea and/or Vomiting ....................................................................................... 2-15 
2.5.5.2. 
Diarrhea................................................................................................................. 2-15 
2.5.5.3. 
Erythematous Rash With or Without Pruritus ...................................................... 2-15 
2.5.5.4. 
Thrombocytopenia ................................................................................................ 2-16 
2.5.5.5. 
Neutropenia ........................................................................................................... 2-16 
2.5.5.6. 
Fluid Deficit .......................................................................................................... 2-17 
2.5.5.7. 
Hypotension .......................................................................................................... 2-17 
2.5.5.8. 
Posterior Reversible Encephalopathy Syndrome .................................................. 2-17 
2.5.5.9. 
Transverse Myelitis ............................................................................................... 2-17 
2.5.6. 
Progressive Multifocal Leukoencephalopathy (PML) .............................................. 2-17 
2.5.7. 
Infection .................................................................................................................... 2-18 
2.5.8. 
Bisphosphonates ........................................................................................................ 2-18 
2.5.9. 
Radiation Therapy ..................................................................................................... 2-18 
2.5.10. 
Immunizations Schedule ........................................................................................... 2-18 
2.5.11. 
Post-Transplant Blood Products ................................................................................ 2-18 
2.5.12. 
Prohibited Therapy .................................................................................................... 2-18 
2.6. 
Participants Risks ........................................................................................................... 2-19 
2.6.1. 
Therapy Toxicities .................................................................................................... 2-20 
2.6.2. 
Bortezomib ................................................................................................................ 2-20 
2.6.3. 
Fludarabine ................................................................................................................ 2-22 
2.6.4. 
Melphalan .................................................................................................................. 2-22 
2.6.5. 
Methotrexate ............................................................................................................. 2-22 
2.6.6. 
Tacrolimus................................................................................................................. 2-22 
2.6.7. 
Ixazomib .................................................................................................................... 2-23 
2.7. 
Study Drug Supply ......................................................................................................... 2-24 
2.7.1. 
Melphalan, Fludarabine, Tacrolimus and Methotrexate ........................................... 2-24 
2.7.2. 
Bortezomib ................................................................................................................ 2-24 
2.7.3. 
Maintenance Study Drug (Ixazomib and Placebo) ................................................... 2-26 
2.8. 
Blinding Procedures ....................................................................................................... 2-29 
2.9. 
Unblinding Procedures ................................................................................................... 2-29 
3. 
STUDY ENDPOINTS AND DEFINITIONS............................................................... 3-1 
3.1. 
Definition of Disease Status ............................................................................................. 3-1 


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3.1.1. 
International Uniform Response Criteria .................................................................... 3-1 
3.1.2. 
Response Categories ................................................................................................... 3-1 
3.1.3. 
Progressive Disease (PD) ............................................................................................ 3-2 
3.2. 
Primary Endpoint ............................................................................................................. 3-3 
3.3. 
Secondary Endpoints........................................................................................................ 3-3 
3.3.1. 
Acute GVHD ............................................................................................................... 3-3 
3.3.2. 
Chronic GVHD ........................................................................................................... 3-4 
3.3.3. 
Response to Treatment ................................................................................................ 3-4 
3.3.4. 
Disease Progression .................................................................................................... 3-4 
3.3.5. 
Treatment-Related Mortality (TRM) .......................................................................... 3-4 
3.3.6. 
Overall Survival .......................................................................................................... 3-4 
3.3.7. 
Toxicity ....................................................................................................................... 3-4 
3.3.8. 
Infections ..................................................................................................................... 3-4 
4. 
PATIENT REGISTRATION, ENROLLMENT AND EVALUATION ................... 4-1 
4.1. 
Enrollment Procedures ..................................................................................................... 4-1 
4.2. 
Study Monitoring ............................................................................................................. 4-1 
4.2.1. 
Follow-Up Schedule.................................................................................................... 4-1 
4.3. 
Patient Evaluations ........................................................................................................... 4-4 
4.3.1. 
Pre-Transplant Evaluations and Requirements ........................................................... 4-4 
4.3.2. 
Evaluations after Enrollment and Prior to Transplant ................................................. 4-5 
4.3.3. 
Post-Transplant Evaluations and Requirements .......................................................... 4-5 
4.3.4. 
Pre-Maintenance Evaluations and Requirements ........................................................ 4-6 
4.3.5. 
Evaluations During Maintenance Therapy .................................................................. 4-7 
4.3.6. 
Evaluations for Non-Randomized Patients ................................................................. 4-8 
4.4. 
Data Reporting ............................................................................................................... 4-15 
4.4.1. 
Criteria for Forms Submission .................................................................................. 4-15 
4.4.2. 
Reporting Patient Deaths ........................................................................................... 4-15 
4.4.3. 
Adverse Event Reporting .......................................................................................... 4-15 
4.4.3.1. 
Definitions............................................................................................................. 4-15 
4.4.3.2. 
BMT CTN Adverse Event Reporting Guidelines ................................................. 4-15 
4.4.3.3. 
Adverse Event Reporting Following Progression ................................................. 4-16 
4.4.3.4. 
Additional Adverse Event Reporting Requirements with Respect to 
Bortezomib and Ixazomib/Placebo ....................................................................... 4-16 
4.4.3.5. 
Procedures for Reporting Exposure to Bortezomib and/or Ixazomib during 
Pregnancy and Birth Events .................................................................................. 4-16 
4.4.3.6. 
Reporting of Second Primary Malignancies (SPMs) ............................................ 4-17 
4.4.4. 
CIBMTR Data Reporting .......................................................................................... 4-17 
5. 
STATISTICAL CONSIDERATIONS ......................................................................... 5-1 
5.1. 
Study Design and Objectives ........................................................................................... 5-1 
5.1.1. 
Accrual ........................................................................................................................ 5-1 
5.1.2. 
Randomization ............................................................................................................ 5-1 
5.1.3. 
Primary Endpoint ........................................................................................................ 5-1 
5.1.4. 
Primary Hypothesis ..................................................................................................... 5-1 
5.2. 
Sample Size and Power Calculations ............................................................................... 5-2 
5.3. 
Interim Analysis ............................................................................................................... 5-3 


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5.4. 
Safety Stopping Guidelines .............................................................................................. 5-4 
5.4.1. 
TRM at Day 100 PostTransplant Stopping Guideline ................................................ 5-4 
5.4.2. 
Acute GVHD at Day 100 Post-Tranpslant Stopping Guideline .................................. 5-6 
5.4.3. 
Acute GVHD at Day 60 Post-Randomization Stopping Guideline ............................ 5-6 
5.5. 
Demographics and Baseline Characteristics .................................................................... 5-7 
5.6. 
Analysis Plan ................................................................................................................... 5-7 
5.6.1. 
Analysis of the Primary Endpoint ............................................................................... 5-7 
5.6.2. 
Analysis of Secondary Endpoints ............................................................................... 5-8 
5.6.2.1. 
Acute GVHD of grades III-IV ................................................................................ 5-8 
5.6.2.2. 
Chronic GVHD (cGVHD) ...................................................................................... 5-8 
5.6.2.3. 
Response to treatment ............................................................................................. 5-8 
5.6.2.4. 
Progression .............................................................................................................. 5-8 
5.6.2.5. 
Overall survival ....................................................................................................... 5-8 
5.6.2.6. 
Treatment-related mortality .................................................................................... 5-8 
5.6.2.7. 
Incidence of toxicities grade  3 ............................................................................. 5-8 
5.6.2.8. 
Incidence of infections ............................................................................................ 5-9 
5.6.2.9. 
Health Quality of Life ............................................................................................. 5-9 
5.6.2.10. 
Rate of Non-Randomization ................................................................................... 5-9 
5.6.3. 
Secondary Analysis – Time from Transplant .............................................................. 5-9 
5.6.3.1. 
Treatment Policy Estimation ................................................................................... 5-9 
5.6.3.2. 
Analysis in the Event of Study Arm Closure ........................................................ 5-10 
 
Appendix A: Plasma Cell Leukemia Response Criteria ............................................................. A-1 
Appendix B: Patient Informed Consent Form .............................................................................B-1 
Appendix C: Laboratory Procedures ...........................................................................................C-1 
Appendix D: HCT-Specific Comorbidity Index Score............................................................... D-1 
Appendix E: Karnofsky Performance Status Scale .....................................................................E-1 
Appendix F: New York Heart Association (NYHA) Classification of Cardiac Disease ............ F-1 
Appendix G: Human Subjects .................................................................................................... G-1 
Appendix H: Known Anticipated Risks of Bortezomib & Ixazomib ......................................... H-1 
Appendix I: Adverse Event Reporting.......................................................................................... I-1 
Appendix J: Derivation of a Sequential Test Statistic for Censored Exponential Data................J-1 
Appendix K: Product Complaints for Bortezomib and Ixazomib .............................................. K-1 
Appendix L: Ancillary Minimal Residual Disease Assessment ……………………………….L-1 
Appendix M: References ............................................................................................................M-1 


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CHAPTER 1 
1. 
BACKGROUND AND RATIONALE 
 
1.1. Multiple Myeloma and Risk Stratification 
 
Chromosomal abnormalities can be detected in up to 90% of patients with multiple myeloma 
(MM).1 Several chromosomal abnormalities detected by conventional karyotyping or fluorescence 
in situ hybridization (FISH) have significant implications on patient outcomes. Among those 
associated with poor outcomes and considered to be high risk disease by the International 
Myeloma Consensus Recommendations include, chromosomal 13 or 13q deletion, t(4;14) and 
del(17p) by conventional cytogenetics, and t(4;14), t(14;16), and del(17p) detected by FISH.2 
High-risk MM remains incurable and autologous hematopoietic cell transplantation (HCT) only 
results in transient disease control at best in part due to intrinsic and/or acquired drug resistance.3- 
5 Several large scale studies have helped characterize the high risk chromosomal abnormality in 
MM and the results are summarized in Table 1.1. 
 
TABLE 1.1: SIGNIFICANCE OF CHROMOSOMAL CHANGES ON SURVIVAL 
IN MYELOMA PATIENTS 
 
Study 
N 
Therapeutic modalities 
Chromosomal abnormality 
(Cytogenetics and/or FISH) 
Outcomes 
IFM991 (IFM99- 
026/IFM99- 
037/IFM99-048) 
1064 
• IFM99-02: auto HCT, 
thalidomide maintenance vs. 
placebo 
• IFM99-03: auto HCT, 
followed by sibling donor RIC 
allogeneic HCT 
• IFM99-04: tandem auto HCT 
with anti-IL6 antibody (vs. 
none) 
• del(13): 48% 
• t(11;14): 21% 
• t(4;14): 14% 
• hyperdiploidy: 39% 
• MYC translocations: 13% 
• del(17p): 11% 
• Univariate analysis: del(13), t(4;14), 
nonhyperdiploidy, and del(17p) 
negatively impacted EFS and OS. 
• Multivariate analysis: t(4;14) and 
del(17p) were prognostic for EFS and 
OS. 
ECOG9486/ 
ECOG94879 
351 
Conventional chemotherapy 
• del(13): 54.2% 
t(4;14): 12.7% 
• t(14;16): 4.6% 
• t(11;14): 15.8% 
• del(17p): 10.7% 
• Univariate analysis: 
t(4;14)(p16.3;q32), 
t(14;16)(q32;q32), del(17p13.1), and 
del(13) had inferior OS. 
t(4;14)(p16.3;q32), t(14;16)(q32;q32) 
and del(13) had worse PFS. 
del(17p13.1) was of marginal 
significance for PFS. 
Spanish GEM- 
200010 
260 
6 cycles of VBCMP/VBAD 
followed by auto HCT 
• t(11;14): 13% 
• t(4;14): 11% 
• t(14;16): 3% 
• P53 deletion: 8.5% 
• t(4;14), RB or P53 deletions had 
shorter survival. 
• RB deletions without other 
abnormality had similar outcomes (as 
no FISH abnormality) 
• Multivariate analysis: t(4;14) and RB 
deletion with other abnormalities (age 
> 60, higher S-phase cells, or 
advanced stage) retained their 
independent prognostic significance 
Canadian 
Expanded 
Access 
Program11 
130 
Rev/Dex for relapsed/refractory 
MM 
• del(13q): 41.5% 
• t(4;14): 21.5% 
• del(17p13): 9.2% 
• del(13q) or del(17p13) resulted in a 
lower response rate. 
• del(17p13) with shorter survivals (OS 
4.7 months) 
Abbreviations: auto, autologous; del, deletion; ECOG, Eastern Cooperative Oncology Group; EFS, event free survival; FISH, fluorescence in situ 
hybridization; HCT, hematopoietic cell transplantation; IFM, Intergroupe Francophone du Mye´lome; IL, interleukin; MM, multiple myeloma; OS, 
overall survival; PFS, progression-free survival; RB, retinoblastoma; Rev/Dex, lenalidomide (Revlimid) and dexamethasone; RIC, reduced 
intensity conditioning; VBCMP/VBAD, vincristine, BCNU, cyclophosphamide, melphalan, prednisone/vincristine, BCNU, adriamycin, and 
dexamethasone 


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1-2 
 
 
 
Multiple studies have shown inferior survivals in MM patients harboring high risk chromosomal 
abnormalities including del(13) by cytogenetics, and t(4;14), t(14;16) and del(17) by FISH.1,9-11 
MM patients with retinoblastoma (RB) deletions (chromosome 13) without other abnormalities by 
FISH have similar outcomes with MM patients without chromosomal abnormalities (46 vs. 54 
months, P = .3),10 however, detection of del(13) by conventional cytogenetics remains a marker 
of poor prognosis.12 Deletion of 17p13 carries extremely poor prognosis and is associated with a 
shorter overall survival (OS), more aggressive disease, extramedullary involvement (including 
CNS) and hypercalcemia.13- 16 In a report of 105 MM patients treated with high-dose melphalan 
followed by autologous HCT, patients with TP53 deletions had a lower median progression-free 
survival (PFS) of 11.8 months vs. 25 months for those without deletions (p=0.08), and OS was 
14.6 months vs. 45.9 months, respectively.14 
 
Chromosome 1 abnormalities also portend poor prognosis.17- 19 The group from Mayo Clinic 
reported that translocations involving chromosome 1p were associated with an elevated plasma 
cell labeling index (P = .004)17. In univariate analysis, structural abnormalities of chromosome 1 
showed inferior 5-year OS (18.3% for 1p deletions and 23.1% for 1p translocations). Frequency 
of chromosome band 1q21 amplification (Amp1q21) was investigated by the University of 
Arkansas group.20 Amp1q21 was seen in 43% of newly diagnosed MM and 72% of relapsed MM. 
Newly diagnosed MM patients with Amp1q21 had inferior 5-year event free survival (EFS) and 
OS after tandem transplant (under Total Therapy 2 protocol) at 38% and 62%, respectively. 
Multivariate analysis demonstrated Amp1q21 being an independent poor prognostic factor.20 The 
group developed a 70-gene model using a gene expression profiling (GEP) on purified plasma 
cells.18 Thirty percent of the 70 high risk genes mapped to chromosome 1 (P < .001). The ratio of 
mean expression levels of up-regulated to down-regulated genes defined a high risk score which 
was present in 13% of MM patients with shorter durations of complete response (CR), EFS, and 
OS.18 The high risk score was also an independent predictor of outcomes in multivariate analysis 
(P < .001). 
 
Based on abovementioned studies, high risk MM can be considered as those with any of the 
following chromosomal changes detected by FISH: t(4;14), t(14;16), del (17p), and abnormalities 
of chromosome 1 (1q21 amplifications; 1p deletion); deletion 13 or hypodiploidy by cytogenetics. 
 
1.2. Impact of Novel Agents in High risk Multiple Myeloma 
 
Recent data suggest that bortezomib based regimens may be effective in overcoming poor risk 
cytogenetic features which may in part be due to a central role of NF-B pathway in MM 
pathogenesis and the activity of bortezomib through the pathway.21 Several studies evaluating the 
impact of novel agents on treatment outcomes in high risk MM are summarized in Table 1.2. 


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TABLE 1.2: INFLUENCE OF BORTEZOMIB ON MYELOMA OUTCOMES ON 
SELECTED STUDIES 
 
Study 
N 
High risk features 
Treatment 
Outcomes 
PETHEMA22 
60 (newly 
diagnosed, 
HCT 
ineligible) 
• Rb deletion by FISH 
(n=13) vs. no deletion 
(n=20) 
• IgH translocations by 
FISH (n=8) vs. no IgH 
(n=20) 
VMP 
• RR: 100% vs. 66% for Rb deletion vs. no (P 
= .16) 
• RR: 88% vs. 82% for Rb deletion vs. no (P 
= .7) 
• PFS and EFS were similar in patients with 
Rb deletion or IgH translocation 
SUMMIT 
investigators23 
202 
(relapsed/ 
refractory) 
Chromosome 13 deletion 
(15%) 
bortezomib ± 
dexamethasone 
Multivariate analysis: Increased CRP (P = 
.011) and abnormal cytogenetics (P = .01) 
were associated with shortened TTP, but not 
chromosome 13 deletion 
Total Therapy 
324 
303 (newly 
diagnosed) 
• 70 gene-defined GEP 
high risk 
Total therapy 3 
(bortezomib containing, 
including tandem 
autologous HCT) 
• GEP-defined FGFR3 subgroup had 
superior CR duration, EFS, and OS 
compared to TT2 (no bortezomib) 
• Shorter EFS and OS for t(4;14) in TT2 was 
not seen in TT3 
VISTA trial25 
682 (newly 
diagnosed, 
HCT 
ineligible) 
• t(4;14), t(14;16), or 
17p deletion (n=26 vs 
n=142 with standard 
cytogenetic profiles) 
VMP 
• Same rate of CR (28%), similar TTP (P = 
.55), and OS (P = .99) with standard 
cytogenetic profiles. 
• Results similar with inclusion of 13q 
deletion patients (n=75). 
IFM26 
507 (newly 
diagnosed, 
< 65 yrs, 
HCT 
eligible) 
• t(4;14): n=106 
• del(17p): n=54 
• (compared to VAD 
treated population) 
Bortezomib + 
dexamethasone x 4 cycles 
(before autologous HCT) 
• Improved EFS and OS with bortezomib in 
t(4;14) patients: 4-year OS 63% vs. 32%; P 
< .001 
• No difference for EFS (P = .32) and OS (P 
= .49) in del(17p) patients 
GMMG-HD3/ 
GMMG-HD427 
315 (newly 
diagnosed, 
HCT 
eligible) 
• t(4;14): 13% 
• del(17p13):10% 
• +1q21: 36% 
• Induction: VAD x3 or 
related regimens 
(n=244), TAD (n=29), or 
PAD (n=42) 
• Maintenance: a-IFN 
(n=118), thalidomide 
(n=66), bortezomib 
(n=37), or none (n=94) 
• 3-year PFS with del(13q14), +1q21, and 
del(17p13) were 27% (vs. 46%; P = .013), 
24% (vs. 50%; P = .018), and 50% (vs. 
81%; P = .018). 
• On multivariate analysis, t(4;14) and 
del(17p13) significantly impacted PFS and 
OS 
HOVON- 
65/GMMG- 
HD428 
354 (Newly 
diagnosed, 
HCT 
eligible) 
• t(4;14): 14.2% 
• del(17p13): 10.6% 
• +1q21: 32.3% 
• Arm A: VAD, 
autologous HCT, 
thalidomide maintenance 
• Arm B: PAD, 
autologous HCT, 
bortezomib maintenance 
• del(17p13) was independent predictor for 
PFS (P < .001) and OS (P < .001) in arm A, 
however, no significant effect on PFS (P = 
.28) and OS (P = .12) was seen in arm B. 
• Median PFS 26.2 months (arm B) vs. 12 
months (arm A) in del(17p13); P = .024 
• 3-year OS 69% (arm B) vs. 17% (arm A) in 
del (17p13); P =.028 
Abbreviations: CR, complete response; CRP, C-reactive protein; EFS, event free survival; FGFR3, fibroblast growth factor receptor 3; FISH, 
fluorescence in situ hybridization; GEP, gene expression profiling; HCT, hematopoietic cell transplantation; IFM, Intergroupe Francophone du 
Mye´lome; IgH, immunoglobulin heavy chain; PAD, bortezomib, Adriamycin, and dexamethasone; PFS, progression-free survival; Rb, 
retinoblastoma; RR, response rate; SUMMIT, Study of Uncontrolled Myeloma Managed with Proteasome Inhibition Therapy; TAD, thalidomide, 
adriamycin, and dexamethasone; TT, Total Therapy; TTP, time to progression; VAD, vincristine, adriamycin, and dexamethasone; VMP, 
bortezomib (Velcade), melphalan, and prednisone 
 
Taken together, the addition of novel agents, like bortezomib, may overcome known adverse 
prognostic features such as t(4;14).24,25,27,29 However, conflicting results of bortezomib regarding 
the survival advantage for MM patients with del(17p) have been reported.27,29,30 Outcomes of MM 
patients with high risk chromosomal abnormality remain poor and there is a significant unmet need 
for the development of effective therapy. 


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1.3. Current Status of Allogeneic Hematopoietic Cell Transplantation for Multiple 
Myeloma 
 
Allogeneic HCT remains the only potentially curative option for MM; however, the exact place of 
this modality in the treatment algorithm of MM is controversial. Recent reports from two large US 
centers where majority of MM patients had relapsed or refractory disease at the time of allogeneic 
HCT showed long-term OS being generally between 20% and 40%.31,32In a report by the European 
Group for Blood and Marrow Transplantation (EBMT), 229 MM patients received an allograft 
with reduced intensity conditioning (RIC), and transplant-related mortality (TRM) at 1-year was 
22%. The 3-year OS and PFS were 41% and 21%, respectively.33 The adverse PFS was associated 
with chemoresistant disease (relative risk (RR) of 2.9), suggesting no benefit with progressive 
disease. Chronic GVHD was associated with better OS and PFS underscoring the importance of a 
graft-versus-myeloma effect.33 Overall, the results of allogeneic HCT have continued to improve 
significantly over the years as was seen in a steady decline in TRM by the Center for International 
Blood and Marrow Transplant Research (CIBMTR) analysis.34 However the relapse after 
allogeneic HCT remains a challenge,34 and the emerging data suggest that the outcomes of 
allogeneic HCT could be further improved with the use of novel agents.35 
 
1.4. Autologous HCT Followed by Allogeneic HCT with Nonmyeloablative Conditioning 
 
The encouraging results of RIC allogeneic HCT renewed the interest in further optimizing this 
treatment modality. A strategy of autologous HCT followed by RIC allogeneic HCT was 
introduced. In an early report by the Seattle group, 52 patients received a single fraction of 2-Gy 
total body irradiation (TBI) and allogeneic HCT from human leukocyte antigen (HLA)-identical 
siblings with mycophenolate mofetil (MMF) and cyclosporin (CSA) GVHD prophylaxis after 
initial autologous HCT. The CR rate was 57% with an overall response rate (ORR) of 83%. The 
OS was 78% with a median follow-up of 552 days.36 In a similar approach, 17 patients with MM, 
after autografting with high dose melphalan, received a RIC regimen consisting of fludarabine 
(180 mg/m2), melphalan (100 mg/m2), and anti-thymocyte globulin (ATG: 30 mg/kg) followed by 
an allografting from related (n=7), mismatched related (n=2), or unrelated (n=8) donors. Day +100 
TRM was 11% and CR rate increased from 18% after autologous HCT to 73% after allogeneic 
HCT.37 Long-term outcomes of 102 MM patients from Seattle where allogeneic HCT from HLA 
matched siblings were performed with 2-Gy TBI, with or without fludarabine (30 mg/m2 on Days 
-4 through -2) following auto HCT.38 
 
The 5-year non-relapse mortality (NRM) was 18% with a CR-rate of 65%. The 5-year OS and PFS 
were 64% and 36%, respectively.38 Only limited cytogenetic data were available and cytogenetic 
abnormalities did not impact TRM, PFS, or OS. Using a similar approach, the Italian group treated 
100 newly diagnosed MM patients in a prospective multicenter trial where patients received VAD 
induction, followed by high dose melphalan and autologous HCT, then allografting from HLA- 
matched sibling donors with 2-Gy TBI conditioning.39 GVHD prophylaxis was MMF and CSA. 
The CR was 53%. Cumulative incidence of grade II-IV acute GVHD was 38% with 50% rate of 
extensive chronic GVHD. TRM was 11.4%. The median EFS was 3.1 years and the median OS 
was not reached after a median follow-up of 5 years. Several randomized trials have compared 
tandem autologous HCT with autologous followed by RIC allogeneic HCT approach and the 
results are summarized in Table 1.4.1.40- 47 


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TABLE 1.4.1: RANDOMIZED CLINICAL TRIALS COMPARING TANDEM 
AUTOLOGOUS HCT WITH AUTOLOGOUS HCT FOLLOWED BY 
RIC ALLOGENEIC HCT 
 
Study 
Era/ 
Patients/ 
Donor 
N/Age 
Induction 
Conditioning/ 
GVHD prophylaxis 
TRM/GVHD 
Response 
Garban et al7 
(IFM99-03/99- 
04) 
• 2000-2004 
• DSS I-III, 
del13 by FISH, 
2MG > 
3mg/L 
• MRD 
• N=284 
• IFM99- 
03=65 (46 
completed 
therapy) 
• IFM99- 
04=219 (166 
completed 
therapy) 
• Age <65 
• VAD x 3-4 
• Collection 
• MEL200 
• IFM99-03: If MRD 
available, Bu (2mg/kg/d PO 
x 2 days) + Flu (25 mg/m2/d 
x 5 days) + ATG (2.5 
mg/kg/d x 5 days) 
• GVHD: CSA+MTX 
• IFM 99-04: If no MRD 
available, randomized to (A) 
2nd auto HCT, Dex (40mg x 
4 days) + MEL220 or (B) 2nd 
auto HCT MEL220 + Dex + 
B-E8 (250 mg total dose) 
• IFM99-03: 
TRM 10.9% 
• Grade II-IV 
aGVHD=23.9 
% 
• cGVHD: 
extensive 
35.7% 
• IFM99-03: 
• ≥ VGPR: 37.8% at 
1 mo after auto 
HCT and 62.2% at 
2 mo after allo 
HCT 
• IFM99-04: ≥ 
VGPR was 34% 
after 1st auto HCT 
and 51% after 2nd 
auto HCT 
Bruno et al.40 
• 1998-2004 
• DSS II or III 
• N=162 
• 80 had MRD, 
58 completed 
allo HCT 
• 82 had no 
MRD, 46 
completed 
• Age ≤ 65 
• VAD x 2-3 
• Cy 3-4 g/m2 ± 
paclitaxel 250 mg 
→ G-CSF 
mobilization 
• If MRD + →MEL200 → 
allo HCT TBI 200cGy 
• GVHD: CSA+MMF 
• If no MRD; refused allo 
HCT; or ineligible donor → 
double auto MEL100 or 
MEL140-200 
• TRM similar 
(P = .09) after 
median f/u 45 
mo 
• Grade II-IV 
aGVHD 43%; 
extensive 
cGVHD 32% 
at 2-yr* 
• Allo vs Auto 
• CR rate: 55% 
(auto-allo) vs. 
26% (tandem auto: 
P = .004) 
Rosiñol et al.43 
(PETHEMA/G 
EM-2000) 
• 1999-2004 
• 280 eligible 
but only 110 
received 2nd 
HCT 
• Age < 70 yr 
• VBMCP/VBAD 
x 6 → 1st auto 
HCT, if < nCR, 
then 2nd auto 
HCT (CVB or 
MEL200) or allo. 
• If MRD and < 65 
→ allo (n=25), or 
2nd auto 
HCT(n=85) 
• MEL200 + auto HCT 
• RIC allo HCT: Flu 25 mg/m2 
x 5 days + MEL70 x 2 days 
• GVHD: CSA+MTX 
• TRM 16% 
(allo) vs. 5% 
(auto: P = .09) 
• Grade II-IV 
aGVHD 32% 
• cGVHD 66% 
• CR rate: 40% 
(allo) vs. 11% 
(auto: P = .001) 
Krishnan et 
al.45 
(BMT CTN 
0102) 
• 2003-2007 
• Standard-risk 
disease defined 
as: 2MG<4 
mg/L & no del 
13 by 
cytogenetics 
• No progression 
after initial 
chemo 
• N=710 
• tandem auto 
(SR n=436; 
HR n=48) 
• auto-allo (SR 
n= 111; HR 
n=37) 
• Age <70 yr 
• At least 3 cycles 
of chemo 
• MEL200 
• If MRD available: auto-allo 
(TBI 200cGy) 
• GVHD: CSA+MMF 
• If No MRD: tandem auto 
• MEL200 → randomized to 
observation vs. thalidomide 
200mg/d + Dex 40/d x 4 
consecutive days/month x 1- 
yr 
• TRM: 4% 
(auto) vs 11% 
(allo: P < 
.0001) 
• Grade II-IV 
aGVHD at 
100-d 26% 
• cGVHD at 2- 
yr 54% 
• CR-rate: 45% 
(auto) vs. 58% 
(allo: P = .007) 
Björkstrand et 
al.48,49 
(EBMT/NMA 
M 2000) 
• 2001-2005 
• ≥ SD on 1st line 
therapy. 
• FISH del13q14 
n=214; 
• del13 in 92; 
(tandem auto 
HCT, n=63; 
auto-allo HCT, 
n=29) 
• N=357 
• If MRD, then 
auto-allo 
(n=91) 
• If no donor, 
then tandem 
auto HCT 
(n=249) 
• Age < 70 yr 
• VAD or similar 
(no novel agents) 
• MEL200 → 
• Allo = Flu 30 mg/m2/d x 3 
days + TBI 2Gy (n=91) 
• GVHD: CSA+MMF 
• 2nd auto MEL200 (n=104) 
• or no treatment (n=145) 
• NRM at 60 
mo: 18% (allo) 
vs. 3% (auto: 
P < .001) 
• aGVHD: 
grade II 9%, 
grade III 8%, 
grade IV 2% 
• extensive 
cGVHD 23% 
• CR-rate within 60 
mo: 56% (allo) vs. 
44% (auto: P .007) 
Lokhorst et 
al.46 
(HOVON- 
50/54) 
• 2003- 
• DSS II-III 
• N=260 
• (donor = 122; 
no donor = 
138) 
• Age:18-65 yr 
• HOVON-50 
• VAD or TAD 
• Stem cell harvest 
with CAD 
(Cy+Adria+Dex) 
• MEL 200 → maintenance 
with IFN or thalidomide (50 
mg/d) 
• N=3 received 2nd auto HCT 
• If had MRD → HOVON-54 
(allo) 
• TBI 2Gy 
• NRM: 16% 
(donor) vs. 3% 
(No donor: P 
< .001) 
• aGVHD=48% 
• Grade III=4% 
• Grade IV=5% 
• CR rate: 43% 
(donor) vs. 37% 
(no donor: P = .67) 


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Study 
Era/ 
Patients/ 
Donor 
N/Age 
Induction 
Conditioning/ 
GVHD prophylaxis 
TRM/GVHD 
Response 
• GVHD: CSA+MMF 
• extensive 
cGVHD 55% 
Knop et al47 
(German 
DSMM V) 
• 10/2002 – 
03/2007 
• High risk 
patients (del 13 
by FISH; 
newly 
diagnosed; 
DSS II-III) 
• MRD & MUD 
• N=199 
• (allo 
performed in 
126 – 76 
MUDs) 
• (2nd auto 
HCT in 73) 
• Age ≤ 60 
(median age 
53) 
• Anthracycline/De 
x based induction 
x 4 → MEL auto 
HCT 
• After 1st auto HCT 
randomized to 2nd auto HCT 
with MEL or allo-HCT 
• Allo: Flu 30 mg/m2 x 3 days) 
+ MEL140 
• (ATG for MUDs) 
• TRM at 2-yr 
12.7% (allo) 
• CR rate: 59% 
(allo) vs. 32% 
(tandem auto: P = 
.003) 
Abbreviations: aGVHD, acute GVHD: allo, allogeneic; ATG, anti-thymocyte globulin; auto, autologoush; B-E8, anti-IL-6 antibody; bu, busulfan; 
2MG, beta-2 microglobulin; cGVHD, chronic GVHD; CI, cumulative incidence; CR, complete response; CSA, cyclosporin; CVB, 
cyclophosphamide, etoposide, and BCNU; Cy, cyclophosphamide; del13, deletion 13; Dex, dexamethasone; DSS, Durie-Salmon staging; FISH, 
fluorescence in situ hybridization; flu, fludarabine; G-CSF, granulocyte-colony stimulating factor; GVHD, graft-versus-host-disease; HR, high risk; 
IFM, Intergroupe Francophone du Mye´lome; MEL200, high dose melphalan at 200 mg/m2; MMF, mycophenolate mofetil; MRD, matched related 
donor; MTX, methotrexate; NRM, non-relapse mortality; SR, standard risk; TAD, thalidomide, adriamycin, and dexamethasone; TBI, total body 
irradiation; TRM, transplant-related mortality; VAD, vincristine, adriamycin (doxorubicin), dexamethasone; VBCMP/VBAD, vincristine, BCNU, 
cyclophosphamide, melphalan, prednisone/vincristine, BCNU, adriamycin, and dexamethasone; VGPR, very good partial response; yr, year 
*No association between aGVHD, or cGVHD and response. 
Giaccone et al.41 Unchanged results after longer follow up of 7-years. The RR to salvage therapies was significantly higher and OS from relapse 
was significantly longer after the allograft then the 2nd autograft (P = 0.01). 
 
As summarized in Table 1.4.2, two randomized trials have shown superiority of autologous 
followed by RIC allogeneic HCT approach leading to better PFS and OS,40,48,49 and one 
randomized trial demonstrated superior PFS.43 The other trials including the largest trial performed 
in the US by the BMT CTN (BMT CTN 0102, Krishnan and Pasquini et al.) showed that while 
allogeneic HCT is associated with superior CR rate, the PFS and OS are similar to tandem 
autologous HCT approach. The TRM is generally higher with allogeneic HCT and it is conceivable 
that, with recent reductions seen in early TRM, the outcomes with allogeneic HCT may improve, 
particularly in patients with high risk disease in whom the outcomes remain dismal regardless of 
the therapy used45. 
 
TABLE 1.4.2: COMPARISON OF OUTCOMES BETWEEN TANDEM AUTOLOGOUS 
HCT AND AUTOLOGOUS FOLLOWED BY RIC ALLOGENEIC HCT IN 
PROSPECTIVE RANDOMIZED TRIALS 
 
Study 
Transplant type 
TRM 
CR rate 
EFS/PFS 
OS 
Relapse rate 
Garban et al7 
tandem auto HCT 
5% 
35 m 
47.2 m (P = 
.07) 
auto/allo HCT 
10.9% at 100-day 
31.7 m 
35 m 
Bruno et al40 
tandem auto HCT 
2% (CI at 2-yr) 
26% 
29 m 
54 m 
auto/allo HCT 
10% (CI at 2-yr) 
55% (P = 
.004) 
35 m (P = 
.02) 
80 m (P = 
.01) 
Knop et al47 
tandem auto HCT 
- 
32% 
72% (P = 
.22) 
auto/allo HCT 
12.7% 
59% (P = 
.003) 
60% 
Rosiñol et al43 
tandem auto HCT 
5% 
11% 
31 m 
58 m 
auto/allo HCT 
16% (P = .07) 
40% (P = 
.001) 
not reached (P 
= .08) 
not reached 
(P = .9) 
Krishnan and 
Pasquini et al45 
tandem auto HCT 
4% (CI at 3-yr) 
45% 
46% (P = 
.671) 
80% (P 
=.191) 
auto/allo HCT 
11% (CI at 3-yr) 
58% (P = 
.007) 
43% 
77% 


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Study 
Transplant type 
TRM 
CR rate 
EFS/PFS 
OS 
Relapse rate 
Björkstrand et al48,49 
tandem auto HCT 
3% (CI at 3-yr) 
41% at 60m 
12% at 96 m 
36% at 96 m 
82% (P = 
.0002) 
 
auto/allo HCT 
13% (CI at 3-yr; P = 
.0004) 
50% at 60m 
22% at 96 m 
(P = .027) 
49% at 96 m 
(P = .03) 
60% 
Lokhorst et al46** 
tandem auto HCT & 
maintenance post 1st 
auto HCT 
3% 
22% at 6 ys 
55% at 6 yr 
77% 
 
auto/allo HCT 
16% (P < .001) 
28% at 6 yr 
55% at 6 yr 
55% 
Abbreviations: allo, allogeneic; auto, autologous; CI, cumulative incidence; CR, complete response; EFS, event-free survival; HCT, hematopoietic 
cell transplantation; m, month(s); OS, overall survival; PFS, progression-free survival; TRM, treatment-related mortality; yr, year 
*Trend towards increased OS with tandem autologous HCT 
**PFS longer for patients who actually received allogeneic HCT 
 
1.5. Impact of Chromosomal Abnormalities on Outcomes after allogeneic HCT 
 
There is an unmet need for better therapeutic approaches for MM patients with high risk 
chromosomal abnormalities. Allogeneic HCT may have a role for such patients; however, the 
prospective transplant trials have fully addressed this question due to a limited number of patients. 
There are limited data from retrospective studies suggesting benefits of allogeneic HCT in patients 
with high risk chromosomal abnormalities such as t(4;14). In a German study of 101 MM patients 
treated with allogeneic HCT with fludarabine/melphalan ± ATG conditioning, the impact of 
genetic abnormality detected by FISH was evaluated.50 Patients with del(17p13) achieved less CR 
(7% vs. 56%; P = .001). Univariate analysis demonstrated a higher relapse rate in patients with 
del(13q14) (P = .006) and del(17p13) (P = .003). In multivariate analyses, only del(13q14) (hazard 
ratio (HR): 2.34; P = .03) and del(17p13) (HR: 2.24; P = .0.04) significantly influenced the 
incidence of relapse, whereas for EFS, only age (HR 2.8; P = .01) and del(17p13) (HR: 2.05; P = 
.03) retained their negative prognostic value. No difference was seen for t(4;14), suggesting that it 
might be overcome by allogeneic HCT.50 In a retrospective multicenter French registry study of 
143 MM patients transplanted between 1999 and 2008, impact high risk cytogenetics was 
analyzed.51 Nineteen received myeloablative conditioning regimens while RIC regimens were 
used in 77%, with inclusion of ATG in 48%. Patients with t(4;14), del(17p), or t(14;16) were 
grouped as poor risk group. There were no significant differences between the two groups 
(standard vs. high) for 3-year PFS, OS and progression rate. The data indicated that allogeneic 
HCT could potentially benefit high risk MM population.51 In a single center retrospective analysis 
by El-Cheikh et al., the feasibility of matched unrelated donor (MUD) allogeneic HCT for MM 
patients was highlighted.52 Forty-three high risk MM including relapsed disease (n=30), newly 
diagnosed with high risk cytogenetic (del13q, del17, or t(4;14), or less than PR after autologous 
HCT, were treated with RIC allogeneic HCT (MUD, n=17; MRD, n=23). Conditioning regimens 
were fludarabine-busulfan-ATG (n=33) or fludarabine-TBI 2Gy (n=7). At 2 years, OS and PFS 
were 59% and 42% for MUD, and 66% and 44% for MRD, respectively (P = .241).52 In the updated 
EBMT NMAM-2000 study, superior outcomes of patients with chromosome 13 deletion by 
cytogenetics were reported after autologous HCT followed by RIC allogeneic HCT. The PFS and 
OS were 21% and 47% vs 5% (P = .026), and 31% (P = .154) with autologous followed by RIC 
allogeneic HCT and tandem autologous HCT, respectively.49 The observation suggests that RIC 
allogeneic HCT might overcome poor prognostic impact of del(13).49 In summary, the 
chromosomal abnormality is important in defining high risk MM, however, emergent data suggest 
that allogeneic HCT may at least partly be able to overcome the poor risk conferred by these 
genetic changes. Prospective clinical trials with novel transplant approaches are needed to better 
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1.6. Bortezomib 
 
Bortezomib for Injection is a small-molecule proteasome inhibitor developed by Millennium 
Pharmaceuticals, Inc., (Millennium) as a novel agent to treat human malignancies. Bortezomib is 
currently approved by the United States Food and Drug Administration (US FDA) for the 
treatment of patients with multiple myeloma (MM). It is also indicated for the treatment of patients 
with mantle cell lymphoma (MCL) who have received at least 1 prior therapy. In the European 
Union (EU), bortezomib in combination with melphalan and prednisone is indicated for the 
treatment of patients with previously untreated MM who are not eligible for high dose 
chemotherapy with bone marrow transplant. Bortezomib is indicated as monotherapy for the 
treatment of progressive MM in patients who have received at least 1 prior therapy and who have 
already undergone or are unsuitable for bone marrow transplantation. 
 
1.6.1. 
Scientific Background 
 
By inhibiting a single molecular target, the proteasome, bortezomib affects multiple signaling 
pathways. The antineoplastic effect of bortezomib likely involves several distinct mechanisms, 
including inhibition of cell growth and survival pathways, induction of apoptosis, and inhibition 
of expression of genes that control cellular adhesion, migration, and angiogenesis. Thus, the 
mechanisms by which bortezomib elicits its antitumor activity may vary among tumor types, and 
the extent to which each affected pathway is critical to the inhibition of tumor growth could also 
differ. Bortezomib has a novel pattern of cytotoxicity in National Cancer Institute (NCI) in vitro 
and in vivo assays.53 In addition, bortezomib has cytotoxic activity in a variety of xenograft tumor 
models, both as a single agent and in combination with chemotherapy and radiation.54-66 Notably, 
bortezomib induces apoptosis in cells that over-express bcl-2, a genetic trait that confers 
unregulated growth and resistance to conventional chemotherapeutics.67 
 
The mechanisms of action leading up to apoptosis have been more clearly defined and include 
initiation of the unfolded protein response and direct/indirect effects on various molecular targets, 
including cell cycle control proteins p27 and p21, cyclins, signal transduction molecules, 
transcription factors c-jun and HIF1-, tumor suppressor protein p53, angiogenesis factors, and 
many others. Bortezomib is thought to be efficacious in multiple myeloma via its inhibition of 
nuclear factor B (NF-B) activation, its attenuation of interleukin-6 (IL-6)-mediated cell growth, 
a direct apoptotic effect, and possibly anti-angiogenic and other effects.68-75 
 
1.6.2. 
Clinical Experience 
 
To date, more than 436,000 patients have been treated with bortezomib, including patients treated 
through Millennium-sponsored clinical trials, Investigator-Initiated Studies, the US NCI Cancer 
Therapy Evaluation Program (CTEP), and with commercially available drug. Bortezomib has 
been commercially available since 13 May 2003. 
 
The overall goal of the Millennium phase 1 program was to determine the MTD and dose-limiting 
toxicity (DLT) of bortezomib in a number of therapeutic settings involving subjects with various 
advanced malignancies. In a phase 1 trial in patients with refractory hematologic malignancies, 
the MTD for a twice weekly dosing for 4 weeks of a 42-day cycle was 1.04 mg/m2/dose, with 


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DLTs of thrombocytopenia, hyponatremia, hypokalemia, fatigue, and malaise.76 The toxicity was 
greatest during the third and fourth weeks of therapy. In the 3-week schedule of bortezomib 
monotherapy (4 doses, given on Days 1, 4, 8, and 11 of a 21-day treatment cycle), the DLT 
occurred at 1.56 mg/m2/dose (3 subjects with Grade 3 diarrhea and 1 with peripheral sensory 
neuropathy). Therefore, the MTD at this schedule was 1.3 mg/m2/dose. In a 35-day treatment 
cycle with 4 weekly doses of bortezomib monotherapy, the MTD was 1.6 mg/m2/dose and DLT 
included hypotension, tachycardia, diarrhea, and syncope. 
 
In phase 1 clinical studies, antitumor activity was reported in subjects with Non-Hodgkin’s 
Lymphoma (NHL), MM, Waldenström’s Macroglobulinemia, squamous cell carcinoma of the 
nasopharynx, bronchoalveolar carcinoma of the lung, renal cell carcinoma, and prostate cancer.77- 
80 
The safety and efficacy of bortezomib in subjects with MM were investigated in two phase 2 
clinical studies, studies M34100-024 (subjects with first relapse)81 and M34100-025 (subjects with 
second or greater relapse and refractory to their last prior therapy).82 In M34100-025, 202 heavily 
pretreated subjects with refractory MM after at least 2 previous treatments received bortezomib, 
1.3 mg/m2 on Days 1, 4, 8, and 11 of a 21-day treatment cycle. The European Group for Blood 
and Marrow Transplant (EBMT) response criteria, as described by Blade83 were utilized to 
determine disease response. Complete responses (CRs) were observed in 4% of subjects, with an 
additional 6% of patients meeting all criteria for CR but having a positive immunofixation test. 
Partial response (PR) or better was observed in 27% of subjects, and the overall response rate (CR, 
PR, and minor response [MR] combined) was 35%. Seventy percent of subjects experienced stable 
disease or better. 
 
The phase 3 study (M34101-039)84, also referred to as the APEX study, was designed to determine 
whether bortezomib provided benefit (time to progression [TTP], response rate, and survival) to 
patients with relapsed or refractory MM relative to treatment with high dose dexamethasone. The 
study was also designed to determine the safety and tolerability of bortezomib relative to high dose 
dexamethasone, and whether treatment with bortezomib was associated with superior clinical 
benefit and quality of life relative to high dose dexamethasone. A total of 669 patients were 
enrolled and 663 patients received study drug (bortezomib: 331; dexamethasone: 332). Patients 
randomized to bortezomib received 1.3 mg/m2 IV push twice weekly on Days 1, 4, 8, and 11 of a 
3-week cycle for up to 8 treatment cycles as induction therapy, followed by 1.3-mg/m2 bortezomib 
weekly on Days 1, 8, 15, and 22 of a 5-week cycle for 3 cycles as maintenance therapy. Patients 
randomized to dexamethasone received oral dexamethasone 40 mg once daily on Days 1 to 4, 9 to 
12, and 17 to 20 of a 5-week cycle for up to 4 treatment cycles as induction therapy, followed by 
dexamethasone 40 mg once daily on Days 1 to 4 of a 4-week cycle for 5 cycles as maintenance 
therapy. The EBMT response criteria were utilized to determine disease response. There was a 
78% increase in TTP for the bortezomib arm. Median TTP was 6.2 months for the bortezomib 
arm and 3.5 months for the dexamethasone arm (p < 0.0001). CR + PR was 38% with bortezomib 
versus 18% with dexamethasone (p  0.0001). CR was 6% with bortezomib versus  1% with 
dexamethasone (p < 0.0001). The CR + nCR (near CR) rate was 13% with bortezomib versus 2% 
with dexamethasone. In patients who had received only 1 prior line of treatment (bortezomib: 
132; dexamethasone: 119), CR + PR was 45% with bortezomib vs 26% with dexamethasone (p = 
0.0035). With a median 8.3 months of follow-up, overall survival was significantly longer (p = 


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0.0013) for patients on the bortezomib arm versus patients on the dexamethasone arm. The 
probability of survival at 1 year was 80% for the bortezomib arm versus 66% for the 
dexamethasone arm, which represented a 41% decreased relative risk of death in the first year with 
bortezomib (p = 0.0005). In patients who had received only 1 prior line of treatment, the 
probability of survival at 1 year was 89% for the bortezomib arm versus 72% for the 
dexamethasone arm, which represented a 61% decreased relative risk of death in the first year with 
bortezomib (p = 0.0098). Updated response rates and survival data were reported for M34101- 
039.85 The updated CR + PR rate was 43% with bortezomib. The CR + nCR rate was 16% with 
bortezomib. With a median 22 months of follow-up, overall survival was significantly longer for 
patients on the bortezomib arm versus patients on the dexamethasone arm. The median overall 
survival was 29.8 months (95% CI: 23.2, not estimable) for the bortezomib arm vs 23.7 months 
(95% CI: 18.7, 29.1) for the dexamethasone arm (hazard ratio = 0.77, p = 0.0272). The probability 
of survival at 1 year was 80% for the bortezomib arm versus 67% for the dexamethasone arm (p = 
0.0002). 
 
The safety and efficacy of bortezomib in relapsed or refractory mantle cell lymphoma (MCL) were 
investigated in an international, phase 2, multicenter study M34103-053, also referred to as the 
PINNACLE study.86 The single-arm study was designed to evaluate the response rates, duration 
of response (DOR), TTP, overall survival (OS), and safety of bortezomib treatment in patients 
with relapsed or refractory mantle cell lymphoma. For 141 evaluable patients, the response rate 
was 31% (8% CR/unconfirmed CR [Cru]). Median time to response was 40 days (range 31-204 
days). The median number of cycles administered across all patients was 4; in responding patients, 
the median number of cycles was 8. The median DOR by algorithm was 9.2 months and 
13.5 months in patients with CR/CRu. Median TTP for both groups was 6.2 months. With a 
median follow-up of 13.4 months, overall survival had not been reached. The most commonly 
reported adverse events (AEs) were fatigue, peripheral neuropathy, and gastrointestinal events. A 
time-to-event update to the PINNACLE study87 was reported after a median follow-up of 26.4 
months. TTP was 6.7 months for all patients, 12.4 months in all responders. The median DOR 
was 9.2 months in all responders and had not been reached in patients achieving CR/Cru. Overall 
survival was 23.5 months in all patients and 36 months in patients with CR/Cru. Survival at 12 
months was 69% overall and 91% in responding patients. 
 
The phase 3 study (MMY 3002) known as the VISTA study, evaluated the safety and efficacy of 
the combination of bortezomib, melphalan, and prednisone in previously untreated multiple 
myeloma patients who were not candidates for stem cell transplant.88 The study was designed to 
determine the benefit of adding bortezomib to MP (melphalan and prednisone) as assessed by TTP. 
Patients (682) were randomized to receive nine 6-week cycles of melphalan 9mg/m2 and 
prednisone 60 mg/m2 on Days 1 to 4, alone or in combination with bortezomib 1.3 mg/m2 by IV 
bolus on Days 1, 4, 8, 11, 22, 25, 29, and 32 during Cycles 1 to 4, and on Days 1, 8, 22, and 29 
during Cycles 5 to 9. Response was evaluated every 3 weeks using the EBMT criteria. At a 
preplanned interim analysis, the independent data monitoring committee recommended that the 
study be stopped since the prespecified statistical boundary end point of TTP had been crossed. 
Response rates were 30% with 4% CR. The rates of partial response or better were 71% in the 
bortezomib (VMP) group compared to 34% in the MP group (p = 0.001). With follow-up of 16.3 
months, the TTP for the VMP group was 24 months compared to 16.6 months in the MP group (p 


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= 0.000001) and was associated with a 52% reduced time to progression. The median DOR was 
19.9 months in the VMP group and 13.1 months in the MP group. Overall survival had not been 
reached in either group. Hematologic toxicity was similar in both groups. The incidence of 
peripheral sensory neuropathy and gastrointestinal symptoms was higher in the VMP group. The 
incidence of herpes zoster was 3% in patients in the VMP group who received antiviral 
prophylaxis. Fifteen percent of patients in the VMP group discontinued therapy due to AEs 
compared to 14% in the MP group. 
 
The VISTA study update after extended follow-up of 25.9 months,89 confirmed a survival benefit 
for the VMP group. Overall survival was not reached in either group: VMP group (75) deaths, 3 
year OS 72%; MP group (111) deaths, 3 year OS 59% (p = 0.0032). Patients on VMP were less 
likely to start second-line therapy (VMP 38% vs MP 57% at the time of data cut-off) with a longer 
time to next therapy (TNT) and treatment free interval (TFI). Of the MP patients who received 
subsequent therapy, 43% went on to receive bortezomib. 
 
Based on investigator-reported best responses to subsequent therapies, patients relapsing after 
therapy with a novel agent were not intrinsically more resistant than after receiving a traditional 
agent. 
 
In the VISTA study, VMP was associated with prolonged TTP, TNT, TFI, and OS. Patients were 
successfully treated with subsequent IMiD-based therapy and retreated with bortezomib. After 
36.7 months follow-up, OS continued to be superior for VMP. The OS for VMP had not yet been 
reached compared to MP (43.1 months).90 In an updated analysis of overall survival based on 387 
deaths (median follow-up 60.1 months), the median overall survival for VMP was 56.4 months 
and the MP was 43.1 months, with a hazard ration of 0.695 (95% CI: 0.57, 0.85)91. 
 
1.7. Use of Bortezomib during and after Allogeneic HCT 
 
Recent studies have shown that the outcomes of MM patients undergoing autologous HCT can be 
significantly improved with the post HCT maintenance therapy.92- 95 On the other hand, there is 
only limited information available regarding maintenance therapy following allogeneic HCT. 
Several pre-clinical and clinical studies have suggested that bortezomib can be safely used 
following allogeneic HCT, without exacerbation of GVHD and with good clinical responses. In 
addition, the data suggest that administration of bortezomib with allogeneic HCT may decrease 
the risk of GVHD while preserving graft-versus tumor (GVT) effect. 
 
1.7.1. 
Pre-clinical Data 
 
Bortezomib has been shown to promote apoptosis of alloreactive T cells during GVHD in murine 
models via reduction of 20S proteasome function and diminished NF-B activity.96 In murine 
models of HLA-mismatched allogeneic HCT, early administration of bortezomib protects against 
acute GVHD without impairing engraftment with preservation of GVT responses.97,98 However, 
delayed administration of bortezomib (5-7 days after BMT) resulted in significant acceleration of 
GVHD-dependent morbidity with significant increases of type 1 tumor necrosis factor  (TNF-) 
receptor transcription in gastrointestinal cells and with significant increases of TNF-, interleukin 


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1, and IL-6 levels in the serum.97 In another study, it was demonstrated that CD4+ T cells are the 
primary source of TNF- during the early phases of GVHD and bortezomib-induced GVHD- 
dependent mortality was preventable by depletion of CD4+ T cells from the donor graft.99 In 
addition, bortezomib may exert immunomodulatory activity by modulating toll-like receptor 
induced activation of dendritic cells.100 Bortezomib may selectively deplete alloreactive T cells 
where NF-B expression is increased.101 Other group has also shown that NF-B is a critical 
regulator of alloresponsiveness and bortezomib is effective in preventing early post transplant 
GVHD lethality in murine models.102 
 
1.7.2. 
Clinical Data on Bortezomib after Allogeneic HCT 
 
The efficacy of bortezomib for MM patients relapsing after allogeneic HCT has been 
reported.103,104 Bruno et al. reported an overall response rate of 61% and CR rate of 22% with 
bortezomib ± steroids in MM patients who relapsed after allogeneic HCT.105 In a report from 
European centers, donor-lymphocyte infusion (DLI) was given to MM patients with relapsed 
(n=48) and persistent (n=15) disease following nonmyeloablative allogeneic HCT.106 The median 
OS after DLI was 23.6 months which was probably long due to the fact that 83.3% of patients not 
responding or relapsing after DLI were sensitive to additional treatment with thalidomide and 
bortezomib.106 Kröger et al. reported the use of bortezomib on 18 MM patients without progressive 
disease after RIC allogeneic HCT (the median time: 268 days) to enhance or maintain remission 
status.107 Severe neuropathy (grade III/IV) was only observed in patients treated concomitantly 
with cyclosporine (3 vs. 0; P = .06). The number of circulating CD3+ cells declined significantly 
(P = .03). There was only a mild aggravation of existing acute or chronic GVHD of the skin with 
bortezomib (3/18).107 In another report, 37 patients with progressive (n=32) or residual (n=5) MM 
after RIC allogeneic HCT received bortezomib with (n=26) or without (n=11) dexamethasone.108 
Overall response rate was 73% (n=27; 7 CR; 7 VGPR; 13 PR) and only 2 patients experienced 
reactivation or worsening of GVHD symptoms. Thirty two MM patients who achieved on PR after 
allogeneic HCT were treated with DLI.109 If no CR was achieved, the patients were treated with 
thalidomide, lenalidomide, or bortezomib. Overall, 27% patients converted to CR after DLI, which 
was increased to 59% with addition of novel agents. There was no correlation between 
achievement of CR and incidence of acute and chronic GVHD. 
 
The use of bortezomib after allogeneic HCT is deemed efficacious to control MM and does not 
appear to exacerbate GVHD. 
 
1.7.3. 
Combining Bortezomib with Allogeneic HCT 
 
Several groups combined bortezomib to high dose melphalan for MM and showed promising 
results.110,111,112 Bortezomib has been combined with RIC conditioning regimen of fludarabine and 
melphalan. Twenty two MM patients with multiple myeloma in first VGPR or CR received 
allogeneic HCT at Moffitt Cancer Center.113 Conditioning consisted of fludarabine, melphalan and 
bortezomib given at 1.3 mg/m2 on Day -3 (n=13) and fludarabine and melphalan (n=9). Stringent 
CR was achieved in 68% of patients at their best responses after allogeneic HCT. The 2-year PFS 
and OS were 74.8% and 77.5%, respectively. NRM at 6 months was non-relapse mortality of 
10.5%.113 The regimen of fludarabine, melphalan and bortezomib was deemed feasible. Overall, 


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these data provide evidence that use of bortezomib in peri-transplant period is effective and is 
associated with reasonable response rates and possibly a protective effect on GVHD. 
 
Currently, there is no consensus on maintenance therapy following allogeneic HCT.114, 115 Among 
other novel agents, lenalidomide has also been used after allogeneic HCT in 30 MM patients in 
the HOVON76 trial.115 However, lenalidomide maintenance was poorly tolerated and patients also 
had rapid onset of GVHD. Further studies are thus needed to demonstrate the safety of efficacy of 
lenalidomide maintenance after allogeneic HCT. 
 
1.7.4. 
Bortezomib for GVHD Prophylaxis 
 
Bortezomib has been tested for GVHD prevention with encouraging results. Early administration 
of bortezomib after mismatched allogeneic HCT protects against acute GVHD without adversely 
effecting engraftment. In a phase II/II clinical trial, 45 patients with hematological malignancies 
undergoing 1 or 2 antigen or allele HLA-mismatched allogeneic HCT received GVHD prophylaxis 
with tacrolimus + low dose methotrexate + bortezomib at 1 of 3 dose levels.116,117 Conditioning 
regimen consisted of fludarabine (30 mg/m2 IV) and busulfan (0.8 mg/kg) on Days -5 through -2. 
Bortezomib dose levels were 1, 1.3, and 1.5 mg/m2 IV on Days +1, +4, and + 7. The dose level 1.3 
mg/m2 was identified as the maximum tolerated dose. The 180-day cumulative incidence of grade 
II-IV acute GVHD was 22% and 1-year cumulative incidence of chronic GVHD was 29%. The 2- 
year cumulative incidence of NRM and relapse were 11% and 38%, respectively. 
 
1.7.5. 
Modified Conditioning Regimen 
 
Patients who were enrolled prior to Version 2.0 of the protocol received post-transplant bortezomib 
on Days -2, +1, +4, and +7. Following the transplant of 15 patients on study, the protocol-specified 
conditioning regimen was modified due to the incidence of unanticipated toxicities among patients 
early post-transplant. Beginning with protocol Version 2.0, patients will receive the modified 
conditioning regimen described in Table 2.4.3, which reduces the bortezomib to one dose pre- 
transplant, and early post-transplant toxicity will be monitored closely. 
 
1.8. Ixazomib (MLN9708) 
 
1.8.1. 
Preclinical Experience 
 
Please refer to the current MLN9708 Investigator’s Brochure (IB). 
 
1.8.2. 
Clinical Experience 
 
As of 27 March 2013, preliminary clinical data is available for a total of 653 patients across 13 
studies., sponsor-led phase 1 or phase 1/2 studies evaluating both twice-weekly and weekly dosing 
schedules. MLN9708 is available in both intravenous and oral formulations. Regardless of the 
route of administration in the twice-weekly dosing schedule, MLN9708 is given on Days 1, 4, 8, 
and 11 of a 21-day cycle; in the weekly dosing schedule, the drug is given on Days 1, 8, and 15 of 
a 28-day cycle. To date, the development of oral MLN9708 has focused on multiple myeloma 
[relapsed and/or refractory and newly diagnosed] and a different yet related plasma cell dyscrasia, 


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systemic light chain (AL) amyloidosis. A clinical pharmacology study looking at drug-drug 
interactions, the effect of food, and bioavailability also uses the oral formulation. Details of these 
trials can be found in ClinicalTrials.gov and the MLN9708 IB. 
 
1.8.3. 
Pharmacokinetics and Drug Metabolism 
 
Clinical IV and PO pharmacokinetic (PK) data show that MLN9708 (measured as the biologically 
active boronic acid form of MLN9708 [MLN2238]) has multi-exponential disposition with a rapid 
initial phase that is largely over by 4 hours. Oral MLN9708 is rapidly absorbed with a median 
time to first maximum plasma concentration (Tmax) of approximately 0.5 to 2.0 hours and 
terminal t1/2 after multiple dosing of approximately 5 to 7 days118. Results of a population PK 
analysis (N = 137) show that there is no relationship between body surface area (BSA) or body 
weight and clearance (CL). Also, based on stochastic simulations for fixed dose, exposures are 
independent of the individual patient’s BSA119. Based on these data, a recommendation was 
made for fixed dosing in clinical trials. An absolute bioavailability of 67% was determined for 
MLN9708 using the population PK analysis. Please refer to the current IB for information on the 
PK for IV doses of MLN9708. 
 
Metabolism appears to be the major route of elimination for MLN9708, with negligible urinary 
excretion of the parent drug (< 5% of dose). In vitro studies of liver microsomes show that 
MLN9708 is metabolized by multiple cytochrome P450 enzymes (CYPs) and non-CYP 
enzymes/proteins. The rank order of relative biotransformation activity of the 5 major human CYP 
isozymes is 3A4 (34.2%) > 1A2 (30.7%) > 2D6 (14.7%) > 2C9 (12.1%) > 2C19 (< 1%). 
MLN9708 is not an inhibitor of CYPs 1A2, 2C9, 2C19, 2D6, or 3A4, nor is it a time-dependent 
inhibitor of CYP3A4/5. The potential for MLN9708 treatment to produce drug-drug interactions 
(DDIs) via CYP inhibition is inferred to be low; however, there may be a potential for DDIs with 
a concomitant strong CYP3A4 or CYP1A2 inhibitor or inducer because of the potential for first- 
pass metabolism when MLN9708 is administered via the PO route and because of the moderate 
contribution of CYP3A4- and CYP1A2-mediated metabolism of MLN9708 in human liver 
microsomes. MLN9708 may be a weak substrate of P-glycoprotein (P-gp), breast cancer 
resistance protein (BCRP), and multidrug resistance associated protein (MRP2) efflux pump 
transporters. MLN9708 is not an inhibitor of P-gp, BCRP, and MRP2. The potential for DDIs 
with substrates or inhibitors of P-gp, BCRP, and MRP2 is, therefore, inferred to be low. 
 
Clinical Study C16009 (Arm 1) with ketoconazole, a strong CYP3A4 inhibitor, showed a 2-fold 
increase in area under the plasma concentration versus time curve (AUC) in the presence of 
ketoconazole. This resulted in the continued exclusion of strong CYP3A4 inhibitors in 
ongoing/planned clinical studies. 
 
Further details on these studies are provided in the IB. 
 
1.8.4. 
Clinical Trial Experience Using the Oral Formulation of MLN9708 
 
In the 7 studies actively enrolling patients to investigate oral MLN9708 in patients with differing 
malignancies (multiple myeloma, AL amyloidosis, nonhematologic cancers, and lymphoma), a 
total of 242 patients have been treated as of 30 April 2012. These patients have been treated with 


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different doses of MLN9708, either as a single agent treatment or in combination with currently 
clinically available treatments. Information regarding the ongoing studies, patient populations, and 
doses investigated are included in Table 1.8.1. 
 
Table 1.8.1 
Ongoing Studies of Oral MLN9708 
 
Trial/ 
Population 
Description 
Doses Investigated 
C16003 
PO, twice weekly (TW), single agent 
0.24-2.23 mg/m2, TW 
MTD: 2 mg/m2 
DLT: rash, thrombocytopenia 
RRMM 
N = 58 
C16004 
PO, weekly (W), single agent 
0.24-3.95 mg/m2, W 
MTD: 2.97 mg/m2 
DLT: rash, nausea, vomiting, diarrhea 
RRMM 
N = 52 
C16005 
NDMM 
N = 65 
PO, W, combination with LenDex 
28 day cycle 
1.68-3.95 mg/m2, W 
MTD: 2.97 mg/m2 
DLT: nausea, vomiting, diarrhea, syncope 
RP2D*: 4 mg fixed (switched to fixed dosing in 
phase 2, relevant to 2.23 mg/m2) 
C16006 
PO, TW (Arm A- 42 day cycle) and W 
(Arm B- 28 day cycle), combination 
with melphalan and prednisone 
Arm A*: 3-3.7 mg, fixed dose, TW 
DLT: rash, thrombocytopenia, subileus 
Arm B*: 5.5 mg, fixed dose, W 
DLT: Esophageal ulcer 
NDMM 
N = 28 
C16007 
PO, W, single agent 
4-5.5 mg, fixed dose*, W 
MTD: 4 mg 
DLT: thrombocytopenia, dirrhea, dyspnea, acute 
rise in creatinine, cardiac arrest 
RR-AL 
N = 6 
C16008 
NDMM 
N=11 
PO, TW, combination with LenDex 21 
day cycle 
3-3.7 mg fixed dose* W 
MTD: 4 mg 
DLT: 
C16009 
Solid 
tumors, 
Lymphomas 
N = 22 
PO, W, single agent 
5.5 mg fixed dose* W 
C16010 
RRMM 
N = 1 
PO, W, combination with LenDex 
4 mg fixed dose* W 
TB- 
MC010034 
RRMM 
N = 5 
PO, W, single agent in 1s part of study 
then in combination with LenDex in 2nd 
part 
3 mg fixed dose* W 
DLT: thrombocytopenia, nausea, hypertension, 
diarrhea 
Abbreviations: RRAL = Relapsed or refractory Primary systemic light chain (AL) amyloidosis; BSA = body 
surface area ; DLT = dose-limiting toxicity; IV = intravenuously; LenDex = lenalidomide plus 
dexamethasone; MTD = maximum tolerated dose; NDMM = newly diagnosed multiple myeloma; PO = 
orally; RRMM = relapsed and/or refractory multiple myeloma; RPh2D = recommended phase 2 dose 
* Approximate body surface area (BSA) and fixed dosing equivalence: 3 mg ~ equivalent to 1.68 mg/m2 
BSA dosing; 4 mg ~ equivalent to 2.23 mg/m2 BSA dosing; and 5.5 mg ~ equivalent to 2.97 mg/m2 BSA 
dosing. 


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1.8.5. 
Overview of the Oral Formulation of MLN9708 
 
The emerging safety profile indicates that oral MLN9708 is generally well tolerated with 
predominant toxicities largely reversible, able to be monitored by routine clinical examinations 
and manageable by dose reductions, discontinuation, or standard supportive care. From experience 
from phase 1 through 2 studies the major toxicities can be managed to allow repeat treatment 
cycles over periods extending beyond 24 months. 
 
In the 4 ongoing studies (C16003, C16004, C16007, and C16009) investigating single-agent oral 
MLN9708 in patients with differing malignancies (multiple myeloma, AL amyloidosis, 
nonhematologic cancers, and lymphoma), a total of 146 patients have been treated as of 30 April 
2012. These patients have been treated with different doses of MLN9708 as they are all phase 1 
trials. An overview of the most frequent (at least 10%) AEs occurring in the pooled safety 
population from single-agent oral MLN9708 Studies (C16003, C16004, C16007, and C16009) is 
shown in Table 1.8.2. 
 
Table 1.8.2 
Summary of Most Common (At Least 10% of Total) All Grade 
Treatment-Emergent Adverse Events (TEAE) (Oral MLN9708 
Single-Agent [C16003/4/7/9] Safety Population) 
 
Primary System Organ Class 
Preferred Term and Incidence 
N=146 
n (%) 
Subjects with at Least One Adverse Event 135 (92) 
Gastrointestinal disorders 102 (70) 
Nausea 68 (47); Diarrhea 55 (38); Vomiting 51 (35); 
Abdominal pain 21 (14); Constipation 21 (14) 
General disorders and administration site conditions 98 
(67) 
Fatigue 71 (49); Pyrexia 31 (21); Edema peripheral 15 
(10) 
Blood and lymphatic system disorders 77 (53) 
Thrombocytopenia 60 (41); Anemia 30 (21); Neutropenia 
23 (16); Leukopenia 15 (10) 
Nervous system disorders 63 (43) 
Headache 20 (14); Dizziness 18 (12) 
Metabolism and nutrition disorders 60 (41) 
Decreased appetite 39 (27) Dehydration 21 (14) 
Respiratory, thoracic and mediastinal disorders 60 (41) Cough 22 (15); Dyspnea 21 (14) 
Skin and subcutaneous tissue disorders 60 (41) 
Rash macular 17 (12) 
Musculoskeletal and connective tissue disorders 56 
(38) 
Arthralgia 20 (14); Back pain 17 (12) 
Infections and infestations 54 (37) 
Upper respiratory tract infection 21 (14) 
Source: MLN9708 Investigator’s Brochure Edition 7 
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 


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In the 3 studies actively enrolling patients to investigate oral MLN9708 in combination with 
standard combination regimens in patients with newly diagnosed multiple myeloma, a total of 96 
patients have been treated as of 30 April 2012. These patients have been treated with different 
doses of MLN9708 in combination with lenalidomide and dexamethasone in 2 trials (C16005 and 
C16008) and with melphalan and prednisone in 1 trial (C16006). The most frequent (at least 10%) 
adverse events occurring in the pooled safety population from Studies C16005, C16006, and 
C16008 is shown in Table 1.8.3. In combinations trials, related is defined as possibly related to 
any drug in the combination regimen, not just specifically related to MLN9708. 
 
Table 1.8.3 
Summary of Most Common (At Least 10% of Total) TEAE (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) 
Diarrhea 22 (23) 
General disorders and administration site conditions 64 
(67) 
Fatigue 37 (39); Edema peripheral 20 (21); Pyrexia 19 
(20) 
Skin and subcutaneous tissue disorders 57 (59) 
Rash 13 (14) 
Nervous system disorders 46 (48) 
Neuropathy peripheral 13 (14); Dysgeusia 12 (13) 
Dizziness 11 (11) 
Musculoskeletal and connective tissue disorders 45 
(47) 
Back pain 18 (19); Muscle spasms 10 (10) 
Blood and lymphatic system disorders 42 (44) 
Thrombocytopenia 28 (29); Anemia 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) Dyspnea 13 (14); Cough 11 (11) 
Psychiatric disorders 23 (24) 
Insomnia 15 (16) 
Source: MLN9708 Investigator’s Brochure Edition 7. 
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. 
 
The clinical experience with MLN9708 also shows early signs of antitumor activity as evidenced 
by at least a 50% reduction in disease burden in some patients and prolonged disease stabilization 
in others across all ongoing trials. The antitumor activity has been seen with single-agent 
MLN9708, when combined with established therapies, and across the malignancies studied 
(advanced solid tumors120, non-Hodgkin’s disease, Hodgkin’s disease121, relapsed and/or 
refractory multiple myeloma122,123, relapsed or refractory systemic light chain amyloidosis124, and 
newly diagnosed multiple myeloma 125,126,127 to date. 


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Though additional data are needed to characterize the clinical benefit of this drug, the emerging 
data supports the ongoing development of MLN9708. 
 
1.8.6. 
Relapsed and/or Refractory Multiple Myeloma 
 
Study C16004 is an open-label, dose-escalation, phase 1 study of MLN9708 administered weekly 
on Days 1, 8, and 15 of a 28-day cycle in adult patients with RRMM. Patients with MM enrolled 
in the dose-escalation component of the study have relapsed following at least 2 lines of therapy, 
which must have included bortezomib, thalidomide (or lenalidomide), and corticosteroids. The 
dose-escalation phase of the trial has completed. In this study, 2 of 3 patients experienced protocol- 
defined DLTs (Grade 3 rash and Grade 3 nausea, vomiting, and diarrhea) at a dose of 3.95 mg/m2. 
As per protocol, subsequent patients were treated at 1 dose level below (2.97mg/m2) where 1 of 6 
patients experienced a DLT (Grade 3 nausea, vomiting, and diarrhea). The MTD of weekly oral 
MLN9708 was determined to be 2.97 mg/m2. 
 
Once the MTD was established, cohorts of patients representing the heterogeneous patient 
population currently seen in clinical practice were enrolled in order to further evaluate the safety, 
tolerability, efficacy, PK, and pharmacodynamics of oral MLN9708. The MTD expansion cohorts 
enrolling are: 
1. Relapsed and Refractory expansion cohort [refractory is defined as disease progression 
while on therapy or within 60 days after the last dose of therapy]; 
2. Carfilzomib expansion cohort 
3. Proteasome Inhibitor-Naïve expansion cohort. 
4. VELCADE-Relapsed expansion cohort 
 
Final study results are not available for this ongoing trial, but preliminary data suggest MLN9708 
has antitumor activity in heavily pretreated MM patients, with durable responses/disease control, 
and is generally well tolerated128,129. 
 
As of the 30 April 2012 data cut, these patients are considered heavily pretreated as evidenced by 
a median number of 4 (range 1–13) prior lines of therapy, with 66% refractory to the last line of 
therapy. Patients have received a median of 2 cycles of therapy (range, 1- 11). Five patients have 
achieved objective response: 1 patient achieved a VGPR and 4 patients achieved a PR. 
Additionally, 15 patients achieved durable disease stabilization for up to 9.5 months. At data cut- 
off, 15 patients remain on treatment; discontinuation of treatment was primarily due to progressive 
disease (69%). 
 
A summary of the safety profile of patients treated in Study C16004 is outlined in Table 1.8.4. 
Overall, 92% of patients experienced a TEAE of any grade and of any cause. Peripheral 
neuropathy was limited to Grade 1/ 2 in 6 patients, with 3 patients reporting baseline Grade 1 PN 
at study entry. 


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Table 1.8.4  Study C16004, Oral Mln9708, Single Agent, Given Weekly: 
Most Common TEAE as of 30 April 12 (N= 52) 
Most Common (> 20%) Any Grade and Irrespective 
of Cause 
Thrombocytopenia (54%) 
Fatigue (48%) 
Nausea (44%), diarrhea (44%) 
Vomiting (37%) 
Decreased appetite (33%) 
Rash* (31%) 
Anemia (25%) 
Neutropenia (23%) 
Drug-Related Grade  3 in > 5% of patients 
Thrombocytopenia (38%) 
Diarrhea and neutropenia 17% (each), fatigue and 
lymphopenia 10% (each), nausea and decreased 
appetite 8% (each) and vomiting 6% 
Source: MLN9708 Investigator’s Brochure Edition 7 
* Rash includes preferred terms of rash macular, rash, maculo-papular, rash morbilliform, rash pruritic, 
pruritus,, rash erythematous, exfoliative rash, and rash popular 
 
Dose reductions required were due to AEs that included rash, neutropenia, thrombocytopenia, 
diarrhea, nausea, vomiting, dehydration, hypotension, increase in serum creatinine, abdominal 
pain, ileus, fatigue, and pneumonia. The AEs reported for the 5 patients who were required to 
discontinue treatment included Grade 2 MLN9708-related nausea/vomiting in 1 patient treated 
above the MTD, Grade 3 MLN9708-related diarrhea in a second patient, related Grade 3 
thrombocytopenia, related Grade 2 dyspnea, and not related Grade 4 elevation in creatinine(1 
patient each). There were no on-study deaths. 
 
Study C16007 is evaluating single agent weekly, Day 1, 8, and 15 of a 28-day cycle, oral dosing 
in patients with RRAL after at least 1 prior therapy. The objectives of this study are to determine 
the safety, tolerability, and MTD, as well as to determine hematologic and organ response rates in 
this patient population. The starting dose level was selected from Study C16004 as previously 
described. In Study C16007 the dose was switched from the BSA-based dosing to the fixed dose, 
thereby the 4.0 mg fixed starting dose in Study C16007 corresponds to the 2.23 mg/m2 dose (one 
dose level below MTD) from Study C16004. This study is currently enrolling patients in the dose- 
expansion portion of the trial. 
 
As of 30 April 2012, 14 patients have been treated in this study. At the first dose level of 4.0 mg, 
1 of 6 patients experienced a protocol-defined DLT (that is, thrombocytopenia that lasted more 
than 2 weeks, which met the definition of a DLT due to the delay in starting Cycle 2). As per 
protocol, the dose was escalated to 5.5 mg for the next cohort of patients where 2 of 5 patients 
experienced a DLT (Grade 3 diarrhea, n=1; and Grade 2 dyspnea, Grade 2 acute rise in serum 
creatinine, and Grade 4 cardiac arrest, n=1). The latter patient did not appear to have cardiac AL 
amyloidosis by echocardiogram on study entry, but did have substantial renal involvement. After 
the occurrence of this DLT, diagnoses included cardiac involvement and CHF. The MTD of 
weekly oral MLN9708 was determined to be 4 mg. Following the establishment of the MTD, 


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patients are currently being enrolled in to 1 of 2 cohorts: proteasome inhibitor naïve or proteasome 
inhibitor exposed130. 
 
As of the 30 April 2012 data cut, the patients enrolled in the study are considered heavily 
pretreated, as evidenced by a median number of 3 prior lines of therapy (range 1–7), with 38% and 
46% of patients having been previously treated with bortezomib and lenalidomide, respectively. 
To be eligible for the study, patients must have amyloid involvement of the heart, kidney, or both; 
at the data cut the organ involvement distribution was 6, 4, and 4 patients, respectively. Patients 
have received a median of 2.5 cycles of therapy (range, 1-12). Eight patients remain on treatment. 
Early signs of activity have been reported. There were 11 patients who have received at least 1 
cycle of therapy with completed response assessments (9 in the 4.0 mg [MTD] cohort and 2 in the 
5.5 mg cohort). The overall hematologic response rate at MTD is 56% (5 patients achieved a 
hematologic response [4 VGPR and 1 PR]; 3 patients showed no change, and 1 patient had an early 
progression. 
 
A summary of the safety profile of patients treated in Study C16007 is outlined in Table 1.8.5. 
Overall, 86% of patients experienced a TEAE of any grade and of any cause. 
 
Table 1.8.5  Study C16007, Oral MLN9708, Single Agent Given Weekly, 
Most Common TEAE as of 30 April 12 (N = 14) 
Most Common (> 20%) 
Nausea (50%) 
Any Grade and Irrespective of Cause 
Fatigue (36%) 
Thrombocytopenia (29%) 
Diarrhea (29%) 
Decreased Appetite (21%) 
Peripheral Edema (21%) 
Dyspnea (21%) 
Abdominal pain (21%) 
Drug-Related Grade  3 in more than 3 Patients 
Thrombocytopenia 5 patients, rash 3 patients, 
dehydration 2 patients, fatigue 2 patients 
Source: MLN9708 Investigator’s Brochure Edition 7 
 
One patient discontinued study drug administration due to a TEAE (patient with DLT of acute rise 
in serum creatinine, dyspnea, and cardiac arrest treated at 5.5 mg, as noted above). No death has 
been reported. 
 
The potential risks reported with MLN9708 use, pooled from all studies using the oral 
formulations, were anticipated based on preclinical data and previous experience with VELCADE 
and are noted in the MLN9708 IB and ICF documents. Regardless of whether MLN9708 is 
administered on the once weekly or twice weekly dosing schedule, there is consistency among the 
type of TEAEs reported, despite some differences in the frequency and severity of the reported 
events. While the predominant potential toxicities may be severe in some cases, they are largely 
reversible, and can be managed by routine clinical monitoring and standard medical interventions, 


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which may include dose reductions and supportive care. Please refer to the MLN9708 IB for 
further information. 
 
1.8.7. 
Newly Diagnosed Multiple Myeloma (NDMM) 
 
In Study C16005, MLN9708 is given weekly (Days 1, 8, and 15), in combination with 
lenalidomide (Days 1-21), and dexamethasone (Days 1, 8, 15, and 22) in a 28-day cycle. 
Enrollment to this study is closed. 
 
Clinical data as of 30 April 2012 is available. The MTD in Study C16005 was determined to be 
2.97 mg/m2 given weekly in a 28-day cycle with LenDex. The DLTs were urticarial rash, 
dizziness, nausea, orthostatic hypotension, vomiting, diarrhea, and syncope. The recommended 
phase 2 dose (RP2D) estimation was established following evaluation of the available data from 
the phase 1 portion of the trial which included, but was not limited to, analyses of efficacy results 
and adverse events (Grade 3/4 AEs, SAEs, all grades peripheral neuropathy, and treatment 
discontinuation). Given that the dose of MLN9708 at 2.97 mg/m2 compromised the maximal 
dosing of lenalidomide and that the dose of 2.23 mg/m2 is very tolerable and clinically active, 
Millennium designated 2.23 mg/m2 as the RP2D after evaluation of the data and discussion with 
investigators. The RP2D of 2.23 mg/m2 has been translated into a fixed dose of 4mg based on the 
results from the population PK analysis. Enrollment in this study has been completed; final study 
results are not available, but preliminary data suggests oral MLN9708 given weekly plus 
lenalidomide and dexamethasone in a 28-day cycle appears well tolerated with manageable 
toxicity and encouraging antitumor activity. 
 
In Study C16005, 15 of 15 (100%) patients in the dose escalation portion of the study experienced 
at least 1 TEAE irrespective of grade or causality. At the MTD across all dose expansion cohorts 
49 of 53 patients (including 3 patients from the dose escalation cohort [92%]) reported at least 1 
TEAE irrespective of grade or causality. In the MTD cohorts, fatigue was the most common AE 
reported (38%). Other common AEs reported include nausea (32%), constipation (30%), upper 
respiratory infection (23%), and peripheral edema (21%). Skin toxicity, primarily erythematous 
rash, occurred in 62% of patients (of note, rash is an overlapping toxicity with MLN9708 and 
lenalidomide). Peripheral neuropathy was reported in 13% of patients; Grade 3 in 1 patient. 
 
A summary of the overall safety profile of patients treated in Study C16005 is outlined in Table 
1.8.6. Overall, 100% of 65 patients experienced at least one TEAE of any grade and of any cause. 


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Table 1.8.6 
Study C16005: Oral MLN9708 Given Weekly In Combination With 
Lenalidomide And Dexamethasone, Most Common TEAE as of 30 April 2012 
Most Common (> 20%) Any Grade and Irrespective of 
Cause 
Fatigue (37%) 
Nausea (34%) 
Constipation (31%) 
Vomiting (28%) 
Diarrhea (26%) 
Thrombocytopenia (23%) 
Upper respiratory tract infection (22%) 
Anemia and edema peripheral ( 20% each) 
Drug-Relateda Grade  3 in  2 Patients 
Nausea, vomiting (n=3 each) 
Thrombocytopenia, lymphopenia, rash pruritic (n=2 each ) 
Source: MLN9708 Investigator’s Brochure Edition 7. 
a Related means to ANY drug in the study drug combination. 
 
The most common drug-related SAEs reported in Study C16005 as of 30 April 2012 include 
pneumonia, infection, diverticulitis, localized infection, gastrointestinal hemorrhage, respiratory 
syncytial virus (RSV) pneumonia fecaloma, pyrexia, pneumonia respiratory syncytial viral, non- 
cardiac chest pain, peripheral edma, asthenia, hyponatremia vomiting, diarrhea, nausea, chest pain, 
dehydration, anemia, dizziness, peripheral sensory neuropathy, orthostatic hypotension, embolism, 
muscular weakness, acute renal failure, blood creatinine increased, maculopapular rash, atrial 
fibrillation, syncope, hypotension, and deep vein thrombosis, and back pain. 
 
As of the clinical data cutoff, 4 patients have discontinued treatment due to TEAEs including 
gastrointestinal haemorrhage, angioedema, syncope, and RSV pneumonia. One death was reported 
for a patient with RSV pneumonia; the event was deemed by the investigator to be related to 
treatment with MLN9708. 
 
1.9. Rationale for the Study 
 
The treatment outcomes of high risk multiple myeloma patients remain suboptimal even in the era 
of novel agents and abundance of available regimens. There is considerable unmet need to improve 
their therapeutic outlook and the role of allogeneic HCT in this population remains to be defined. 
The introduction of reduced intensity regimen has resulted in reduced TRM in allogeneic HCT for 
patients with myeloma. Emerging single center experience supports the feasibility of reduced 
intensity conditioning regimen of fludarabine, melphalan plus bortezomib in patients with multiple 
myeloma111. However, myeloma relapse still need to be reduced in order to maximize the 
efficiency of this therapeutic approach in high risk patients. This clinical trial addresses these two 
challenges with allogeneic HCT. First, the addition of bortezomib to the conditioning regimen can 
optimize the anti-myeloma effect of melphalan against malignant plasma cells. Second, the 
addition of a novel maintenance drug may further reduce the risk of disease relapse long enough 
in order for the graft versus myeloma to take effect. 
 
Given the small number of myeloma patients treated with an allogeneic transplant at individual 
institutions, we propose to perform a multicenter study evaluating the conditioning regimen of 
fludarabine, melphalan plus bortezomib followed by allogeneic HCT from a HLA-matched related 
or unrelated donor in patients with high risk multiple myeloma. Patients will be randomized to 


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placebo-controlled maintenance therapy of ixazomib (MLN9708) after allografting and the 
maintenance therapy will be prescribed for one year. The study will assess the novel conditioning 
regimen in high risk population as well as the efficacy of ixazomib in preventing disease 
relapse/progression following allogeneic HCT. The results of this trial will assist in understanding 
the role of this novel agent in post allogeneic HCT maintenance and will assist in designing a 
definitive trial for this population with high risk multiple myeloma. 


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CHAPTER 2 
2. 
STUDY DESIGN 
 
2.1. Study Overview 
 
This is a multicenter, phase II, double-blind placebo controlled prospective trial, which randomizes 
patients with high risk multiple myeloma to maintenance ixazomib or matching placebo 60-120 
days after allogeneic HCT with Peripheral Blood Stem Cells (PBSC). Patients will undergo a 
conditioning regimen with a fludarabine, melphalan and bortezomib combination followed by 
HLA-matched related or unrelated donor allografting. GVHD prophylaxis will be the combination 
of tacrolimus and methotrexate. 
 
The starting doses of ixazomib and placebo are 3 mg, administered orally once a day on Days 1, 
8, and 15 of a 28-day cycle. After 3 cycles of maintenance therapy at 3 mg, ixazomib and placebo 
dose will be increased to 4 mg if the drug is tolerated. Dose escalation and de-escalation on BOTH 
treatment arms may be performed depending on tolerability or development of adverse reactions. 
No dose re-escalation is permitted following a dose reduction. The planned dose of oral ixazomib 
and placebo ranges from 2.3 mg per day to 4 mg per day on Days 1, 8, and 15 of a 28-day cycle 
for 12 cycles maximum. To maintain the blind in patients receiving placebo, the number/dose of 
placebo capsules administered will be identical to the number/dose of ixazomib capsules the 
patient would receive if randomized to ixazomib. 
 
2.2. Hypothesis and Objectives 
 
2.2.1. 
Hypothesis 
 
Ixazomib maintenance therapy results in improved progression-free survival in patients with high 
risk multiple myeloma after allogeneic HCT. 
 
2.2.2. 
Primary Objectives 
 
To compare progression-free survival as a time to event endpoint from the time of randomization 
between patients randomized to ixazomib versus placebo maintenance in patients with high risk 
multiple myeloma. 
 
2.2.3. 
Secondary Objectives 
 
Below are the secondary objectives for each arm of maintenance therapy, when applicable. 
1. Estimate cumulative incidence of grades II-IV and III-IV acute GVHD. 
2. Estimate cumulative incidence of chronic GVHD. 
3. Estimate best disease response rates. 
4. Estimate cumulative incidence of disease progression rates. 
5. Estimate overall survival rates. 


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6. Estimate cumulative incidence of treatment related mortality rates. 
7. Estimate the incidence of grade ≥ 3 adverse events. 
8. Estimate the incidence of infections. 
9. Describe health-related quality of life 
10. Additionally, we will estimate the proportion of patients who are willing and able to be 
randomized to maintenance and describe the frequencies of events that preclude 
randomization. 
11. Estimates for the primary and key secondary endpoints for each arm of maintenance 
therapy will be described post transplant. 
 
2.3. Patient Eligibility 
 
Patients must meet specified eligibility criteria to be registered on the study. 
 
2.3.1. 
Inclusion Criteria 
 
1. Age  18.0 years and ≤ 70.0 years at the time of enrollment. 
2. Patients must meet ONE of the criteria outlined in either a, b, c, OR d: 
a. Patients with high risk multiple myeloma in partial response (PR) or better with 
no prior progression and are ≤ 24.0 months after autologous HCT (single or 
planned tandem), or are ≤ 24.0 months after initiation of systemic anti-myeloma 
therapy for patients without prior autologous HCT; or 
i. High risk is defined by the presence of any one of the following 
detected at any time prior to enrollment: deletion of chromosome 13 
by conventional cytogenetics, hypodiploidy, abnormality in 
chromosome 1(1q amplification or 1p deletion), t(4;14), t(14;16), 
t(14;20) or deletion of 17p by fluorescence in situ hybridization 
(FISH) or conventional karyotyping; high risk criteria based on 
commercially available gene expression profiling (GEP)1 
b. Patients with high risk multiple myeloma (see criterion 2.a.i. above) in very good 
partial response (VGPR) or better with 1 prior progression which occurred ≤ 24.0 
months after autologous HCT (single or planned tandem), or ≤ 24.0 months after 
initiation of systemic anti-myeloma therapy for patients without prior autologous 
HCT; or 
i. Patients with one prior progression without measurable monoclonal 
paraprotein at the time of disease progression or relapse (< 1.0 g/dl in 
serum or < 200 mg/24hrs in urine) may be considered to have met 
VGPR criteria if < 5% plasma cells in bone marrow and ≥ 90% decrease 
 
1 Patients with high risk multiple myeloma based on GEP alone require approval by the BMT CTN 1302 Study Chairs 
prior to enrollment. 


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in the difference between involved and uninvolved FLC levels from 
baseline (time of progression/relapse). 
ii. In patients with IgG kappa MM receiving daratumumab: International 
Myeloma Working Group criteria for VGPR may not be achieved since 
daratumumab is known to increase the IgG kappa spike. In such cases 
the FLC and marrow may be used to establish VGPR, as above, with 
prior approval from the protocol co-chairs. 
c. Patients with standard risk multiple myeloma in VGPR or better (see criteria 2.b.i. 
and 2.b.ii. above) at the time of enrollment with 1 prior progression ≤ 24.0 months 
from single or planned tandem autologous HCT; or 
d. Patients with primary plasma cell leukemia in VGPR or better with no prior disease 
progression and are ≤ 18.0 months after autologous HCT, or are ≤ 18.0 months 
after initiation of anti-myeloma therapy without prior autologous HCT. 
3. Patients must have a related or unrelated donor willing and able to donate peripheral blood 
stem cells that meets one of the following criteria: 
a. A sibling donor who is a 6/6 match at HLA–A and –B (intermediate or higher 
resolution) and –DRB1 (at high resolution using DNA-based typing) and must be 
willing to donate peripheral blood stem cells and meet institutional criteria for 
donation OR 
a. A related donor (other than sibling) who is a 8/8 match for HLA–A, –B, –C (at 
intermediate or higher resolution) and –DRB1 (at high resolution using DNA-based 
typing) and must be willing to donate peripheral blood stem cells and meet 
institutional criteria for donation OR 
b. An unrelated donor who is an 8/8 match at HLA–A, –B, –C, and –DRB1 (at high 
resolution using DNA-based typing) and must be willing to donate peripheral blood 
stem cells and meet institutional criteria for donation. 
4. Cardiac function: Ejection fraction > 40% 
5. Estimated or calculated creatinine clearance greater than 40 mL/minute (using the 
Cockcroft-Gault formula and actual body weight) 
6. Pulmonary function: DLCO ≥ 40% (adjusted for hemoglobin) and FEV1 ≥ 50% 
7. Liver function: total bilirubin < 2x the upper limit of normal and ALT/AST < 2.5x the 
upper normal limit (patients with Gilbert’s Disease are permitted to exceed the defined 
bilirubin value of 2x the upper limit of normal, however measurements of direct bilirubin 
should be done to confirm this diagnosis). 
8. Female subjects (unless postmenopausal for at least 1 year before the screening visit, or 
surgically sterilized), agree to practice two (2) effective methods of contraception at the 
same time, or agree to practice true abstinence when this is in line with the preferred and 
usual lifestyle of the subject (periodic abstinence [eg, calendar, ovulation, symptothermal, 
post-ovulation methods] and withdrawal are not acceptable methods of contraception) 


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through 90 days after the last dose of maintenance therapy (see Section 2.6.2 for definition 
of postmenopausal). 
9. Male subjects (even if surgically sterilized) must agree to one of the following: practice 
effective barrier contraception (see Section 2.6.4.1 for list of barrier methods), or practice 
true abstinence when this is in line with the preferred and usual lifestyle of the subject. 
Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and 
withdrawal are not acceptable methods of from the time of signing the informed consent 
through 90 days after last dose of maintenance therapy. 
10. Voluntary written consent must be given before performance of any study related 
procedure not part of standard medical care, with the understanding that consent may be 
withdrawn by the patient at any time without prejudice to future medical care. 
11. Able to comply with the study visit schedule and other protocol requirements. 
 
2.3.2. 
Exclusion Criteria 
 
1. Karnofsky Performance Score < 70% 
2. Prior allogeneic HCT 
3. Patient with purely non-secretory multiple myeloma [absence of monoclonal protein (M 
protein) in serum as measured by electrophoresis and immunofixation and the absence of 
Bence Jones protein in the urine defined by the use of conventional electrophoresis and 
immunofixation techniques and the absence of involved serum free light chain > 100 
mg/L]. 
4. Planned pre-emptive/prophylactic administration of donor lymphocytes (as per section 
2.5.2) 
5. Central Nervous System (CNS) involvement with multiple myeloma defined as CSF 
positivity for plasma cells or a parenchymal CNS plasmacytoma 
6. Patients with uncontrolled bacterial, viral or fungal infections (currently taking medication 
and with progression or no clinical improvement) at time of enrollment. 
7. Presence of fluid collection (ascites, pleural, or pericardial effusion) that interferes with 
methotrexate clearance or makes methotrexate use contraindicated. 
8. Patients seropositive for the human immunodeficiency virus (HIV). 
9. Patient with active Hepatitis B or C determined by serology and/or NAAT. 
10. Patients with hypersensitivity to bortezomib, boron or mannitol. 
11. Known GI disease or GI procedure that could interfere with the oral absorption or tolerance 
of MLN9708 (ixazomib) including difficulty swallowing. 
12. Known allergy to any of the study medications, their analogues, or excipients in the various 
formulations of any agent. 
13. Patients with ≥ grade 2 sensory peripheral neuropathy. 


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14. Myocardial infarction within 6 months prior to enrollment or New York Heart Association 
(NYHA) Class III or IV heart failure (see Appendix D), uncontrolled angina, severe 
uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia 
or active conduction system abnormalities. Prior to study entry, any ECG abnormality at 
screening must be documented by the investigator as not medically relevant. 
15. Female patients who are lactating or pregnant 
16. Prior malignancies except resected basal cell carcinoma or treated cervical carcinoma in 
situ. Cancer treated with curative intent ≥ 5 years previously will be allowed. Cancer treated 
with curative intent < 5 years, which is in remission, will be reviewed on a case-by-case 
basis by the Protocol Officer or one of the Protocol Chairs. 
17. Patients with multi-organ involvement by amyloidosis or evidence of amyloidosis related 
organ dysfunction. 
18. Failure to have fully recovered (i.e., no toxicities > Grade 1 by CTCAE version 4.0) from 
the reversible effects of prior chemotherapy. 
19. Patient with serious medical of psychiatric illness likely to interfere with participation on 
this clinical study 
20. Participation in clinical trials with other investigational agents not included in this trial, ≤ 
14.0 days of enrollment on this trial and throughout its duration. 
21. Patients who have received radiation therapy within 3 weeks before transplant. Enrollment 
of subjects who require concurrent radiotherapy (which must be localized in its field size) 
should be deferred until the radiotherapy is completed and 3 weeks have elapsed since the 
last date of therapy. 
22. Patients unable or unwilling to adhere to the study assessment schedule. 
 
2.3.3. 
Donor Exclusion Criteria 
 
1. Donors will be excluded if they are an identical twin of the recipient. 
2. Females who are pregnant (positive serum β HCG) or uninterruptible breastfeeding will be 
excluded. 
3. HIV seropositive donors will be excluded. 
4. Donors receiving experimental therapy or investigational agents will be excluded unless 
approved by the protocol chairs and protocol officer. 
5. Donors not willing and able to donate PBSC will be excluded 
 
Related and unrelated donors will be identified according to institutional guidelines. 
 
2.3.4. 
Patient Eligibility Criteria to Begin Maintenance Therapy 
 
In order to be eligible for randomization, patients must have sufficiently recovered from their 
allogeneic transplant. Between Day +60 and Day +120 after allogeneic HCT, patients will be 


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randomized to receive either ixazomib maintenance or placebo. If patients do not meet the 
eligibility criteria for initiating maintenance, they will continue to be followed per the protocol. 
 
Eligibility criteria for initiating maintenance are as follows: 
1. Platelet count ≥ 75,000/mm3 
2. Absolute neutrophil count (ANC) ≥ 1,000/mm3. 
3. Total bilirubin < 2x the upper limit of the normal range (ULN), except in patients with 
Gilbert’s syndrome. 
4. ALT/AST < 2.5x the upper normal limit 
5. No ≥ grade 2 visceral (gut or liver) acute GVHD. No ≥ Grade 3 any other acute GVHD. 
6. Patient should not have disease progression of myeloma (according to Section 3.1.3) 
7. Peripheral Neuropathy ≤ Grade 3 or Grade 2 with pain by CTCAE version 4.0 criteria 
8. Patients must be tolerating GVHD prophylaxis. 
9. Females of childbearing potential (FCBP)2 must have a negative serum pregnancy test 
with a sensitivity of at least 50 mIU/mL within 14.0 days of initiating maintenance 
 
2.3.5. 
Patient Exclusion Criteria to Begin Maintenance Therapy 
 
1. Female patients who are lactating 
2. Presence of non-hematologic toxicities that have not resolved to < Grade 1 by CTCAE 
version 4.0 
3. Patients who have received radiotherapy ≤ 14.0 days before initiating maintenance. Use 
of radiation therapy ≤ 14.0 days before administration of maintenance study drug in the 
absence of disease progression may be permitted with written study chair and/or 
protocol officer approval. 
4. Central nervous system involvement with multiple myeloma defined as CSF positivity 
for plasma cells or a parenchymal CNS plasmacytoma 
5. Infection requiring systemic antibiotic therapy or other serious infection < 14.0 days 
before initiating maintenance therapy. 
6. Patients who have received systemic treatment, ≤ 14.0 days before the first dose of 
maintenance therapy, with strong CYP3A inducers (rifampin, rifapentine, rifabutin, 
carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John’s wort 
7. Inability to swallow oral medication, inability or unwillingness to comply with the drug 
administration requirements, or gastrointestinal (GI) procedure that could interfere with 
the oral absorption or tolerance of treatment 
 
 
2A female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral 
oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses 
at any time in the preceding 24 consecutive months).menses at any time in the preceding 24 consecutive months). 


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2.4. Treatment Plan 
 
Patients meeting the eligibility criteria for transplant/enrollment will be treated with conditioning 
regimen of fludarabine, melphalan and bortezomib. GVHD prophylaxis consists of tacrolimus 
and methotrexate. 
 
2.4.1. 
Conditioning Regimen (Fludarabine/Melphalan/Bortezomib)113 
Patients will receive fludarabine 30 mg/m2 (when creatinine clearance 40 – 70 mL/min, reduce to 
24 mg/m2) from Day -6 to Day -3, melphalan 70 mg/m2 on Day -4 and Day -3 intravenously, and 
bortezomib on Day -3 at 1.3 mg/m2 intravenously (Table 2.4.2). On Day 0, patients will receive 
the donor peripheral blood stem cells. 
 
Dose of bortezomib will be determined based on the actual body surface area (BSA). See 
Section 2.4.1.1. for dosing guidelines for fludarabine and melphalan. 
 
2.4.1.1. 
Dosing for Melphalan, Fludarabine, and Methotrexate 
 
The following guidelines should be utilized to determine the appropriate dosing for the 
administration of fludarabine, melphalan, and methotrexate. 
For patients who weigh less than 125% of their ideal body weight (IBW), dosing should be based 
on actual body weight. Ideal and actual body weight units are in kilograms (kg), and calculations 
are based on gender. The calculation for IBW is explained in Table 2.4.2. 
 
Table 2.4.2 Calculation of IBW Based on Gender 
 
Standard1 
Metric2 
Males 
IBW = 50kg + 2.3 kg/inch over 60” 
IBW = 50kg + 2.3kg·[(height in meters– 1.52)/0.025] 
Females 
IBW=45.5kg +2.3kg/inch over 60” 
IBW=4.5kg + 2.3kg·[(height in meters – 1.52)/0.025] 
1For patients shorter than 5ft, subtract 2.3 kg/inch. 
2For patients shorter than 1.52 m, subtract 2.3kg for each 2.5 cm below 1.52 m. 
AIBW = IBW + [(0.25) x (actual body weight – IBW)] 
 
2.4.1.2. 
Renal insufficiency dose adjustment for fludarabine 
 
Patients with moderate renal impairment (creatinine clearance 40 – 70 mL/min) should receive 
reduced dose of fludarabine at 24 mg/m2 (20% dose reduction). Fludarabine should not be 
administered to patients with severely impaired renal function (creatinine clearance < 40 mL/min). 


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Table 2.4.3 
 
Day -6 
Day -5 
Day -4 
Day -3 
Day -2 
Day -1 
Day 0 
Fludarabine 30 mg/m2 IV 
X 
X 
X 
X 
Melphalan 70 mg/m2 IV 
X 
X 
Bortezomib 1.3 mg/m2 IV 
X 
PBSC infusion 
X 
 
2.4.2. 
GVHD Prophylaxis (Tacrolimus/Methotrexate) 
 
A combination of tacrolimus and methotrexate will be administered for GVHD prophylaxis. 
 
Tacrolimus will be administered beginning Day -3 of allogeneic HCT and will be continued for a 
minimum of 6 months. The initial dose should be calculated based on institutional guidelines to 
achieve an intravenous daily dose of 0.015 mg/kg/day. Subsequent doses are targeted to achieve 
whole blood levels between 5 and 10 ng/mL. When a patient is switched from IV to PO tacrolimus, 
the dose is increased by three- to four-fold to adjust for the lower bioavailability of oral compound 
to intravenous tacrolimus. Determinations of blood levels should be performed at least once 
weekly for the first 3 months. Dose reductions should be made if the toxicities are present or whole 
blood levels are above the recommended therapeutic range, following the institutional guidelines. 
Tacrolimus taper may begin 3 months post-allogeneic HCT in the absence of GVHD. Patients who 
are required to stop tacrolimus due to toxicity should be placed on another immunosuppressive 
agent according to institutional guidelines. 
 
Methotrexate will be given at 5 mg/m2/day IV on Days +1, +3, +6 and + 11 (a total of 4 doses). 
The Day +1 methotrexate should be administered no sooner than 24 hours after the completion 
of the stem cell infusion. See Section 2.4.1.2. for methotrexate dosing guidelines. 
 
2.4.3. 
Donor Peripheral Blood Stem Cell Infusion 
 
The target for CD34+ peripheral blood stem cell collection from matched donors will be 5 to 10 x 
106/kg of recipient body weight. Related donor peripheral blood stem cells will be mobilized with 
granulocyte-colony stimulating factor (G-CSF) according to institutional guidelines. For unrelated 
donors, National Marrow Donor Program (NMDP) protocols will be followed for stem cell 
mobilization and collection. T-cell replete stem cell grafts without manipulation will be used. 
 
2.4.4. 
Randomization to Placebo or Ixazomib Maintenance Therapy 
 
Prior to initiating therapy patients must meet the eligibility criteria outlined in section 2.3.3. If 
patients do not meet the criteria to proceed with maintenance at any time, they will continue to be 
followed per the protocol for the duration of the study. 
 
Between Day +60 and Day +120 after allogeneic HCT, patients will be randomized to receive 
either ixazomib maintenance therapy or placebo. Maintenance therapy must begin within 7 days 
of randomization. 


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2.4.5. 
Ixazomib/Placebo Initiation 
 
The starting doses of ixazomib and placebo are 3 mg, administered orally once a day on Days 1, 
8, and 15 on a 28-day cycle. Only enough ixazomib and placebo for one cycle of therapy will be 
supplied to the patient each cycle according to randomization assignment. Assigned treatment will 
be administered for a maximum of 12 cycles (28-days/cycle). 
 
Dosing will be in the morning at approximately the same time each day. Ixazomib and placebo 
capsules should be swallowed whole, and should not be broken, chewed or opened. If a dose of 
ixazomib or placebo 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 unless there is greater than 72 hours before the 
next dose. If the patient vomits after taking a dose, the patient should not repeat the dose but 
should resume dosing at the time of the next scheduled dose. Patients who take more than the 
prescribed dose of ixazomib or placebo should be instructed to seek emergency medical care if 
needed and contact study staff immediately. 
 
Dose escalation and de-escalation on both treatment arms will be performed depending on 
tolerability or development of adverse reactions (Sections 2.4.5.2 and 2.4.5.3). Subjects will be 
evaluated for adverse events (AEs) at each visit using the NCI CTCAE criteria v4.0. Subjects 
experiencing AEs may need study treatment modifications (per Treatment Modification 
Guidelines, Table 2.4.3). The planned dose of oral ixazomib and placebo ranges from 2 mg per 
day to 4 mg per day. All dosing is on Days 1, 8, and 15 on a 28-day cycle. 
 
2.4.5.1. 
Record of Administration 
 
Accurate records will be kept of all ixazomib administration (including prescribing and dosing) 
and entered in the source documents. 
 
2.4.5.2. 
Dose Escalation in the Absence of Toxicities 
 
If no toxicity occurs after completing 3 cycles of ixazomib or placebo at 3 mg/day on Days 1, 8, 
and 15 of a 28-day cycle, the dose of ixazomib or placebo will be escalated to the next dose level 
of 4 mg/day on Days 1, 8, and 15 of a 28-day cycle (Table 2.4.3). The dose of ixazomib or placebo 
will be maintained at 4 mg PO on Days 1, 8, and 15 of a 28-day cycle until the patient reaches a 
total of 12 cycles as long as no significant toxicities are encountered. 
 
If the patient experiences toxicity requiring reduction of ixazomib or placebo dose, this level will 
be maintained for all subsequent cycles unless further toxicities occur. No dose re-escalation is 
permitted. 


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TABLE 2.4.4: Ixazomib/Placebo Dose Reduction Steps 
 
Dose Level 1 
4 mg PO daily on Days 1, 8, and 15 of a 28-day cycle 
Dose Level 0 (starting dose) 
3 mg PO daily on Days 1, 8, and 15 of a 28-day cycle 
Dose Level -1 
2.3 mg PO daily on Days 1, 8, and 15 of a 28-day cycle 
Off Maintenance 
Patient should discontinue all maintenance treatment 
 
 
2.4.5.3. 
Ixazomib or Placebo Dose Reduction 
 
Ixazomib and placebo dose modifications (Table 2.4.4) will be made according to the Treatment 
Modification Guidelines (Table 2.4.5). Grading of toxicity will be based on CTCAE version 4.0. 
 
2.4.5.4. 
Initiation of a New Cycle of Ixazomib or Placebo 
 
A new course of maintenance may begin on the scheduled Day 1 of a new cycle if: 
• The ANC is ≥ 1,000/mm3 (growth factor use is permitted) 
• The platelet count is ≥ 75,000/mm3, without platelet transfusion within the last 3 days 
• No ≥ grade 2 visceral (gut or liver) acute GVHD. No ≥ Grade 3 any acute GVHD 
• No severe chronic GVHD 
• Not receiving systemic chronic GVHD therapy in addition to steroids and calcineurin 
inhibitors for treatment of mild to moderate chronic GVHD 
• Any other drug related adverse event that may have occurred has resolved to ≤ grade 1 
severity including drug related rash, allergic reaction/hypersensitivity or sinus 
bradycardis/other cardiac arrhythmia. (see Table 2.4.4) 
• No suspected pregnancy 
• Not receiving a prohibited therapy (see Section 2.5.11) 
 
If these conditions are not met prior to Day 1 of a new cycle, the subject will be evaluated weekly 
and a new cycle of maintenance will not be initiated until the toxicity has resolved as described 
above. Following resolution of toxicities, the day that maintenance is initiated will be Day 1 of the 
new cycle. 
 
If maintenance was stopped during the previous cycle and restarted with a one-level dose reduction 
and no subsequent interruptions were required, then that reduced dose level will be initiated on 
Day 1 of the new cycle. 
 
If ixazomib or placebo dosing was omitted for the remainder of the previous cycle, or if a new 
cycle is delayed due to toxicity newly encountered on the scheduled Day 1, then the new cycle 
will be started with a one-level dose reduction when the toxicity has resolved as described above. 


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If unable to start new cycle for any reason (e.g. toxicity, surgery, medical condition) within 56 
days of planned cycle, patient will discontinue maintenance and continue to be followed for all 
study endpoints. 
 
2.4.5.5. 
Treatment Adherence 
 
Research center personnel will review the dosing instructions with subjects. Subjects will be asked 
to bring any unused study drug and empty study drug containers to the research center at their next 
visit. Any unused ixazomib should be disposed of in accordance with Millennium’sguidelines. 
 
Table 2.4.5: Treatment Modifications Guidelines for Ixazomib or Placebo– Maintenance 
 
NCI CTCAE v4 
Day 1 
Day 8 
Day 15 
Day 16-28 of Cycle 
Desquamating 
(blistering) rash- any 
grade 
Discontinue 
IXAZOMIB or 
PLACEBO 
Discontinue 
IXAZOMIB or 
PLACEBO 
Discontinue 
IXAZOMIB or 
PLACEBO 
Discontinue 
IXAZOMIB or 
PLACEBO 
Erythema 
multiforme ≥ Grade 
3 
Discontinue 
IXAZOMIB or 
PLACEBO 
Discontinue 
IXAZOMIB or 
PLACEBO 
Discontinue 
IXAZOMIB or 
PLACEBO 
Discontinue 
IXAZOMIB or 
PLACEBO 
Peripheral 
Neuropathy 
New or worsening 
Grade 1 w/ pain or 
Grade 2; Hold 
IXAZOMIB or 
PLACEBO until 
toxicity has resolved 
to ≤ Grade 1without 
pain 
New or worsening 
Grade 2 w/ pain or 
Grade 3; If the 
toxicity has resolved 
to ≤ Grade 1without 
pain, restart 
IXAZOMIB or 
PLACEBO at the next 
lower dose level in the 
next cycle. 
Grade 4; Discontinue 
IXAZOMIB or 
PLACEBO 
Grade 1 w/ pain or 
Grade 2; Hold 
IXAZOMIB or 
PLACEBO until 
toxicity has resolved 
to ≤ grade 1without 
pain 
Grade 2 or Grade 3 
w/ pain; If the 
toxicity has resolved 
to ≤ grade 1without 
pain, restart 
IXAZOMIB or 
PLACEBO at the 
next lower dose level 
in the next cycle. 
Grade 4; Discontinue 
IXAZOMIB or 
PLACEBO 
Grade 1 w/ pain or 
Grade 2; Hold 
IXAZOMIB or 
PLACEBO until 
toxicity has resolved 
to ≤ grade 1without 
pain 
Grade 2 or Grade 3 
w/ pain; If the 
toxicity has resolved 
to ≤ grade 1without 
pain, restart 
IXAZOMIB or 
PLACEBO at the 
next lower dose level 
in the next cycle. 
Grade 4; Discontinue 
IXAZOMIB or 
PLACEBO 
Grade 1 w/ pain or 
Grade 2; Hold 
IXAZOMIB or 
PLACEBO until 
toxicity has 
resolved to ≤ grade 
1without pain 
Grade 2 or Grade 3 
w/ pain; If the 
toxicity has 
resolved to ≤ grade 
1without pain, 
restart IXAZOMIB 
or PLACEBO at the 
next lower dose 
level in the next 
cycle. 
Grade 4; 
Discontinue 
IXAZOMIB or 
PLACEBO 


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NCI CTCAE v4 
Day 1 
Day 8 
Day 15 
Day 16-28 of Cycle 
Allergic reaction or 
hypersensitivity 
Grade 2-3; Hold 
IXAZOMIB or 
PLACEBO 
Grade 4: Discontinue 
IXAZOMIB or 
PLACEBO 
Grade 2-3; Hold 
IXAZOMIB or 
PLACEBO 
If the toxicity has 
resolved to ≤ grade 1, 
restart IXAZOMIB 
or PLACEBO at the 
next lower dose level 
in the next cycle. 
Grade 4: Discontinue 
IXAZOMIB 
Grade 2-3; Hold 
IXAZOMIB or 
PLACEBO 
If the toxicity has 
resolved to ≤ grade 1, 
restart IXAZOMIB 
or PLACEBO at the 
next lower dose level 
in the next cycle. 
Grade 4: Discontinue 
IXAZOMIB or 
PLACEBO 
If the toxicity 
resolves to ≤ grade 
1, restart 
IXAZOMIB or 
PLACEBO at the 
next lower dose 
level in the next 
cycle. 
Grade 4: 
Discontinue 
IXAZOMIB or 
PLACEBO 
Glomerular filtration 
rate (Creatinine 
Clearance) 
≥ Grade 3; Hold 
IXAZOMIB or 
PLACEBO 
≥ Grade 3; Hold 
IXAZOMIB or 
PLACEBO 
If creatinine 
clearance has 
improved to ≤ grade 
2, restart 
IXAZOMIB or 
PLACEBO at the 
next lower dose level 
in the next cycle. 
≥ Grade 3; Hold 
IXAZOMIB 
If creatinine 
clearance has 
improved to ≤ grade 
2, restart 
IXAZOMIB or 
PLACEBO at the 
next lower dose level 
in the next cycle. 
If creatinine 
clearance improves 
to ≤ grade 2, restart 
IXAZOMIB or 
PLACEBO at the 
next lower dose 
level in the next 
cycle. 
Diarrhea (assessed as 
IXAZOMIB related) 
≥Grade 2; Hold 
IXAZOMIB or 
PLACEBO 
≥Grade 2; Hold 
IXAZOMIB or 
PLACEBO 
If the toxicity has 
resolved to < grade 2, 
restart IXAZOMIB 
or PLACEBO at the 
next lower dose level 
in the next cycle. 
≥Grade 2; Hold 
IXAZOMIB or 
PLACEBO 
If the toxicity has 
resolved to < grade 2, 
restart IXAZOMIB 
or PLACEBO at the 
next lower dose level 
in the next cycle. 
If the toxicity 
resolves to ≤ grade 
2, restart 
IXAZOMIB or 
PLACEBO at the 
next lower dose 
level in the next 
cycle. 
Nausea (assessed as 
IXAZOMIB related) 
≥Grade 3; Hold 
IXAZOMIB or 
PLACEBO 
≥Grade 3; Hold 
IXAZOMIB or 
PLACEBO 
If the toxicity has 
resolved to ≤ grade 2, 
restart IXAZOMIB 
or PLACEBO at the 
next lower dose level 
in the next cycle. 
≥Grade 3; Hold 
IXAZOMIB 
If the toxicity has 
resolved to ≤ grade 2, 
restart IXAZOMIB 
or PLACEBO at the 
next lower dose level 
in the next cycle. 
If the toxicity 
resolves to ≤ grade 
2, restart 
IXAZOMIB or 
PLACEBO at the 
next lower dose 
level in the next 
cycle. 


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NCI CTCAE v4 
Day 1 
Day 8 
Day 15 
Day 16-28 of Cycle 
Other non- 
hematologic toxicity 
(assessed as 
IXAZOMIB related) 
≥Grade 3; Hold 
IXAZOMIB or 
PLACEBO 
≥Grade 3; Hold 
IXAZOMIB or 
PLACEBO 
If the toxicity 
resolves to ≤ grade 2, 
restart IXAZOMIB 
or PLACEBO at the 
next lower dose level 
in the next cycle. 
≥Grade 3; Hold 
IXAZOMIB or 
PLACEBO 
If the toxicity 
resolves to ≤ grade 2, 
restart IXAZOMIB 
or PLACEBO at the 
next lower dose level 
in the next cycle. 
If the toxicity 
resolves to ≤ grade 
2, restart 
IXAZOMIB or 
PLACEBO at the 
next lower dose 
level in the next 
cycle. 
Neutropenia 
≥Grade 3 (ANC 
<1,000/mm3); Hold 
IXAZOMIB or 
PLACEBO 
≥Grade 3 (ANC 
<1,000/mm3); Hold 
IXAZOMIB or 
PLACEBO 
If the toxicity has 
resolved to ≤ grade 2 
(ANC ≥ 1,000/mm3), 
restart IXAZOMIB 
or PLACEBO at the 
next lower dose level 
in the next cycle. 
≥Grade 3 (ANC 
<1,000/mm3); Hold 
IXAZOMIB or 
PLACEBO 
If the toxicity has 
resolved to ≤ grade 2 
(ANC ≥ 1,000/mm3), 
restart IXAZOMIB 
or PLACEBO at the 
next lower dose level 
in the next cycle. 
If the toxicity 
resolves to ≤ grade 
2 (ANC ≥ 
1,000/mm3), restart 
IXAZOMIB or 
PLACEBO at the 
next lower dose 
level in the next 
cycle. 
Thrombocytopenia 
Platelet count 
<75,000/mm3; Hold 
IXAZOMIB or 
PLACEBO. 
Platelet count 
<50,000/mm3; Hold 
IXAZOMIB or 
PLACEBO 
If the platelet count 
becomes ≥ 
50,000/mm3, restart 
IXAZOMIB or 
PLACEBO at the 
next lower dose level 
in the next cycle. 
Platelet count 
<50,000/mm3; Hold 
IXAZOMIB or 
PLACEBO 
If the platelet count 
becomes ≥ 
50,000/mm3, restart 
IXAZOMIB or 
PLACEBO at the 
next lower dose level 
in the next cycle. 
If the platelet count 
becomes ≥ 
75,000/mm3, restart 
IXAZOMIB or 
PLACEBO at the 
next lower dose 
level in the next 
cycle. 
• Please consult NCI CTCAE v4.0 http://ctep.cancer.gov/reporting/ for complete Grade descriptions. The “≥ Grade 3” descriptions listed 
above are minimums. 
 
2.4.6. 
Discontinuation of Maintenance 
 
Treatment will continue until maximal duration of maintenance therapy is reached (twelve 28-day 
cycles), or the occurrence of any of the following events: 
• Disease progression 
• Adverse event(s) that, in the judgment of the Investigator/Medical Monitor, may cause 
severe or permanent harm or which rule out continuation of maintenance study drug. 
• Graft failure 
• Development of grade III-IV acute GVHD 
• Development of severe chronic GVHD 


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• Suspected pregnancy 
• Inability to start planned cycle of ixazomib within 56 days of intended start date of each 
cycle. 
• Major violation of the study protocol (to include subject noncompliance with study 
medications or protocol-specified procedures) at the discretion of the Protocol Officer. 
• Withdrawal of consent 
• The subject is lost to follow up 
• Death 
• Patient is unable to complete 12 cycles of maintenance therapy within 18 months of 
initiating maintenance therapy. 
• Patient is receiving a prohibited therapy (see section 2.5.11) 
 
2.5. Supportive Care 
 
The following medications/supportive therapies are recommended during study participation, as 
applicable: 
• The antiemetic regimen(s) will be based on institutional guidelines. 
• Antimicrobials: Antibacterial, antiviral and antifungal prophylaxis during and after 
allogeneic HCT are recommended and will be administered based on local institutional 
guidelines. Consideration of prophylaxis for herpes zoster virus is recommended during 
maintenance therapy. 
• For the prevention of hepatotoxicity, ursodiol will be given at 300 mg PO BID if < 90 kg, 
or 300 mg PO in a.m. and 600 mg PO in p.m. if ≥ 90 kg. 
• Pain control with opioid analgesics and transfusional support will be provided per the 
institutional guidelines. 
 
2.5.1. 
Tapering of GVHD Prophylaxis 
 
Institutional practice should be followed for tapering immunosuppressive therapy in the absence 
of GVHD. However, the protocol recommends full immunosuppression for at least 3 months after 
stem cell infusion and taper completion by 6 months. 
 
2.5.2. 
Donor Lymphocyte Infusions 
 
Pre-emptive / Prophylactic administration of donor lymphocytes is not permitted in this protocol. 
Donor Lymphocyte infusion for treatment of falling donor cell chimerism must be approved by 
Protocol Chair or Officer before the procedure. 


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2.5.3. 
Management of Acute Graft-versus-Host Disease 
 
Grade I-II Acute GVHD – Manage per institutional guidelines and per requirements for starting 
a new cycle of maintenance in section 2.4.5.4 
 
Grade III-IV Acute GVHD – Discontinue study drug and treat per institutional guidelines. 
 
2.5.4. 
Management of Chronic Graft-versus-Host Disease 
 
Mild or Moderate Chronic GVHD - Manage per institutional guidelines. Study drug can be 
continued. If the patient requires systemic chronic GVHD therapy in addition to steroids and 
calcineurin inhibitors, then the study drug should be discontinued. 
 
Severe Chronic GVHD - The study drug should be discontinued. 
 
2.5.5. 
Management of other Toxicities 
 
Management of toxicities will be done according to institutional guidelines. The approaches listed 
below are recommendations for patients without confirmed GVHD. 
 
2.5.5.1. 
Nausea and/or Vomiting 
 
Standard anti-emetics including 5-hydroxytryptamine 3 serotonin receptor antagonists are 
recommended for emesis if it occurs once treatment is initiated; prophylactic anti-emetics may 
also be considered at the physician’s discretion. Dexamethasone should not be administered as an 
anti-emetic. Fluid deficit should be corrected before initiation of study drug and during treatment. 
 
2.5.5.2. 
Diarrhea 
 
Prophylactic antidiarrheals will not be used in this protocol. However, diarrhea should be managed 
according to clinical practice, including the administration of antidiarrheals once infectious causes 
are excluded. Fluid intake should be maintained to avoid dehydration. Fluid deficit should be 
corrected before initiation of treatment and during treatment. 
 
2.5.5.3. 
Erythematous Rash With or Without Pruritus 
 
As with bortezomib, rash with or without pruritus has been reported with ixazomib, primarily at 
the higher doses tested and when given with agents where rash is an overlapping toxicity. The 
rash may range from limited erythematous areas, macular and/or small papular bumps that may or 
may not be pruritic over a few areas of the body, to a more generalized eruption that is 
predominately on the trunk or extremities. Rash has been most commonly characterized as 
maculopapular or macular. To date, when it does occur, rash is most commonly reported within 
the first 3 cycles of therapy. The first incidence of rash events occurred early during treatment, 
and there was no evidence of increased frequency of rash with prolonged exposure. The rash is 
often transient, self-limiting (resolves without medical intervention), and is typically Grade 1 to 2 
in severity. 


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Symptomatic measures such as antihistamines or corticosteroids (oral or topical) have been 
successfully used to manage rash and have been used prophylactically in subsequent cycles. The 
use of a topical, IV, or oral steroid (eg, prednisone ≤ 10 mg per day or equivalent) is permitted. 
Management of a Grade 3 rash may require intravenous antihistamines or corticosteroids. 
Administration of ixazomib (and/or other causative agent if given in combination) should be 
modified per protocol and re-initiated at a reduced level from where rash was noted (also, per 
protocol). 
 
In line with clinical practice, dermatology consult and biopsy of Grade 3 or higher rash or any 
SAE involving rash is recommended. Prophylactic measures should also be considered if a patient 
has previously developed a rash (eg, using a thick, alcohol-free emollient cream on dry areas of 
the body or oral or topical antihistamines). The rare risks of Stevens-Johnson Syndrome, toxic 
epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms syndrome 
(DRESS), and pemphigus vulgaris have been reported in studies when ixazomib (or placebo) has 
been given in a multi-therapy regimen with concomitant medications known to cause rash and/or 
in the setting of confounding Treatment Emergent Adverse Events (TEAEs). These severe and 
potentially life-threatening or deadly conditions may involve rash with skin peeling and mouth 
sores, which should be managed symptomatically according to standard medical practice. Punch 
biopsies for histopathological analysis are encouraged at the discretion of the investigator. Study 
medications should be discontinued in the event of severe, potentially life-threatening rash. 
 
2.5.5.4. 
Thrombocytopenia 
 
Blood counts should be monitored regularly as outlined in the protocol with additional testing 
obtained according to standard clinical practice. Thrombocytopenia may be severe but has been 
manageable with clinical monitoring and platelet transfusions according to standard clinical 
practice. Ixazomib administration should be modified as noted as per dose modification 
recommendations in the protocol when thrombocytopenia occurs (see Table 6-2). Therapy can be 
reinitiated at a reduced level upon recovery of platelet counts. A rare risk is thrombotic 
thrombocytopenic purpura (TTP), a rare blood disorder where blood clots form in small blood 
vessels throughout the body characterized by thrombocytopenia, petechiae, fever, or possibly more 
serious signs and symptoms. TTP should be managed symptomatically according to standard 
medical practice. 
 
2.5.5.5. 
Neutropenia 
 
Blood counts should be monitored regularly as outlined in the protocol with additional testing 
obtained according to standard clinical practice. Neutropenia may be severe but has been 
manageable. Growth factor support is not required but may be considered according to standard 
clinical practice. Ixazomib administration should be modified as noted as per dose modification 
recommendations in the protocol when neutropenia occurs (see Table 6-2). Therapy can be 
reinitiated at a reduced level upon recovery of ANCs. 


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2.5.5.6. 
Fluid Deficit 
 
Dehydration should be avoided since ixazomib may cause vomiting, diarrhea, and dehydration. 
Acute renal failure has been reported in patients treated with ixazomib, commonly in the setting 
of the previously noted gastrointestinal toxicities and dehydration. 
 
Fluid deficit should be corrected before initiation of study drug and as needed during treatment to 
avoid dehydration. 
 
2.5.5.7. 
Hypotension 
 
Symptomatic hypotension and orthostatic hypotension with or without syncope have been reported 
with ixazomib. Blood pressure should be closely monitored while the patient is on study treatment 
and fluid deficit should be corrected as needed, especially in the setting of concomitant symptoms 
such as nausea, vomiting, diarrhea, or decreased appetite. Patients taking medications and/or 
diuretics to manage their blood pressure (for either hypo- or hypertension) should be managed 
according to standard clinical practice, including considerations for dose adjustments of their 
concomitant medications during the course of the trial. Fluid deficit should be corrected before 
initiation of study drug and as needed during treatment to avoid dehydration. 
 
2.5.5.8. 
Posterior Reversible Encephalopathy Syndrome 
 
Posterior reversible encephalopathy syndrome, which ultimately resolved, has been reported with 
ixazomib. This condition is characterized by headache, seizures and visual loss, as well as abrupt 
increase in blood pressure. Diagnosis may be confirmed by magnetic resonance imaging (MRI). 
If the syndrome is diagnosed or suspected, symptom-directed treatment should be maintained until 
the condition is reversed by control of hypertension or other instigating factors. 
 
2.5.5.9. 
Transverse Myelitis 
 
Transverse myelitis has also been reported with ixazomib. It is not known if ixazomib causes 
transverse myelitis; however, the possibility that ixazomib may have contributed to transverse 
myelitis cannot be excluded. Transverse myelitis should be managed according to standard 
medical practice. 
 
2.5.6. 
Progressive Multifocal Leukoencephalopathy (PML) 
 
PML, which may be fatal, has occurred in less than 1% of oncology patients receiving ixazomib 
in combination with other cancer therapies. It is not known whether ixazomib causes PML; 
however, the possibility that ixazomib may have contributed to PML cannot be excluded. In the 
event of occurrence of PML, ixazomib should be discontinued and supportive care provided as 
needed. 


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2.5.7. 
Infection 
 
Prophylaxis for infection and surveillance for infection, such as CMV reactivation, is per 
institutional guidelines. Investigators should consider the use of antiviral prophylaxis for herpes 
zoster during maintenance therapy. 
 
2.5.8. 
Bisphosphonates 
 
Intravenous bisphosphonates [either zolendronic acid or pamidronate according to institutional 
preference] may be initiated (or re-initiated) after the allogeneic hematopoietic cell transplantation 
according to local institutional practice. 
 
2.5.9. 
Radiation Therapy 
 
Radiation therapy is not permitted to be given in concurrence with the conditioning regimen or ≤ 
14.0 days of initiating maintenance therapy. After transplantation, radiation may be administered 
for the following indications in the absence of disease progression after consultation with the 
Medical Monitor or one of the Protocol Chairs and a radiation oncologist: 
1. Palliation of pain from bone lesions; 
2. Prevention of pathologic fractures; 
3. Relief of spinal cord compression or nerve root compression. 
 
The radiation oncologist will determine dose and duration of radiation to be administered. 
Radiation to the liver or lungs should be avoided. 
 
2.5.10. Immunizations Schedule 
 
Immunizations should be administered according to institutional guidelines. 
 
2.5.11. Post-Transplant Blood Products 
 
Transfusion thresholds for blood product support should be per institutional guidelines. All blood 
products will be irradiated. 
 
2.5.12. Prohibited Therapy 
 
Concomitant use of other anti-cancer therapies, other anti-myeloma maintenance or investigational 
agents is not permitted while subjects are receiving study drug during the treatment phase of the 
study. 
 
The following medications and procedures are prohibited during the maintenance therapy: 
 
Systemic treatment with any of the following metabolizing enzyme inducers should be avoided 
unless there is no appropriate alternative medication for the patient to use. (Rationale: If there were 
to be a drug-drug interaction (DDI) with an inducer, ixazomib exposure woulddecreased): 


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• Strong CYP3A inducers: rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, and 
phenobarbital 
 
The following medicinal products and procedures are prohibited during the maintenance therapy: 
• Excluded foods and dietary supplements include St. John’s wort and Gingko biloba 
• Any antineoplastic treatment except for drugs in this treatment regimen. 
• Platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days 
before maintenance study drug dosing. 
• Adjuvant hormone therapy for breast or prostate cancer. 
 
2.6. Participants Risks 
 
Recipients of allogeneic transplantation incur risks from pre-transplant conditioning and post 
transplant therapy, which must be weighed against the risk of the disease for which the transplant 
is prescribed. Major risks following transplantation include: 1) Pancytopenia: the intent of the 
allogeneic transplant is to replace the hematopoietic organ and decrease in hematopoiesis is a direct 
consequence of transplantation. Blood counts are temporarily low after the conditioning regimens 
and patients are transfusion dependents. During the pancytopenia period other complications may 
occur such as infection and bleeding diathesis. 2) Infection, which can be bacterial, viral, parasitic, 
or fungal. Often, these infections are life-threatening, particularly when caused by viral or fungal 
agents, and are associated with high mortality in the transplant population; 3) Graft Failure which 
is a result of non engraftment or loss of donor derived hematopoiesis after successful engraftment. 
Graft failure is an uncommon complication and is associated with a high risk of mortality; 4) End 
Organ Damage of one or more major organs may occur as a result of reactions to drugs (e.g., 
melphalan, antibiotics, anti-fungal medications, etc.), and as a result of destructive processes (e.g., 
infection, etc.) and may have a fatal outcome; 5) Relapse or Progression of MM may become 
active after transplantation; 6) GVHD: is a common complication of transplant and will be 
assessed as an outcome in this clinical trial. Patients may develop acute GVHD which most 
frequently occurs 100 days from the transplant (though it is not limited to this timeframe) and 
chronic GVHD which is mostly observed beyond 2 months from transplantation. GVHD may 
result in significant morbidity and mortality after transplantation; 7) Hepatic Veno-Occlusive 
Disease: is a complication related to the conditioning regimen and result in liver failure. This is an 
uncommon complication after transplants with reduced intensity conditioning as prescribed in this 
protocol; 8) Thrombotic Microangiopathy: is a drug induced complication often seen with 
calcineurin inhibitors used for GVHD prophylaxis. This complication is uncommon and it results 
in multi organ failure; 9) Second Primary Malignancy: exposure to chemotherapy increases the 
risk of development of second primary malignancies after transplantation. Additionally, patients 
with multiple myeloma have a higher risk of developing second primary malignancies. However, 
there is no evidence to date which suggests that exposure to proteasome inhibitors increases this 
risk; 10) Unknown Toxicities may occur in any individual patient due to multiple events and 
cumulative effects which may involve any and all organs, including the brain. Brain damage can 
result in severe loss of cognitive or neurologic function; and, 11) Death. These risks may or may 
not be increased by the post transplant therapies to be evaluated in this protocol. 


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2.6.1. 
Therapy Toxicities 
 
All toxicities will be graded using the Common Terminology Criteria for Adverse Events 
(CTCAE) v4.0 with BMT specific definitions when appropriate. 
 
2.6.2. 
Bortezomib 
 
To date, more than 436,000 patients have been treated with bortezomib in both clinical trials 
investigating its use in hematological malignancies and solid tumors, and in patients who were 
treated with commercially available bortezomib. 
 
Prescribing physicians and health care practitioners are referred to their locally approved product 
label for bortezomib regarding Indications and Usage, Contraindications, Warnings, and 
Precautions. 
 
The known anticipated risks of bortezomib therapy are presented in Appendix H. These risks are 
grouped according to the combined frequency observed in an integrated analysis of AEs in 
sponsored clinical studies of single-agent bortezomib dosed at 1.3 mg/m2 twice weekly on a 21-
day schedule, in patients with multiple myeloma and mantle cell lymphoma. 
 
The most common bortezomib side effects include: 
• Hematologic: anemia, neutropenia, thrombocytopenia, leucopenia, lymphopenia 
• Neurologic: asthenia, dizziness, anxiety, syncope, headache, insomnia, fever, rigors, chills, 
peripheral neuropathy, and leukoencephalopathy, including reversible posterior 
leukoencephalopathy syndrome 
• Pulmonary: cough, dyspnea, pleural effusion, pneumonitis, interstitial pneumonia, edema 
acute respiratory distress syndrome (ARDS) 
• Cardiovascular: hypotension, tachycardia, atrial fibrillation, palpitation, congestive heart 
failure, bradycardia, atrial flutter, atrioventricular block, arrhythmia, cardiac failure, 
cardiac arrest, pericardial effusion, pericarditis 
• Infectious: reactivations of herpes zoster, opportunistic infections 
• Gastrointestinal: weight loss, decreased appetite, anorexia, constipation, dehydration, 
diarrhea, heartburn, dyspepsia, stomatitis, nausea, vomiting, ileus, GI perforation, acute 
pancreatitis 
• Metabolic: hyperglycemia, hypoglycemia, hyponatremia, hypokalemia, hypercalcemia 
• Renal: renal failure 
• Neuromuscular and skeletal: arthralgias, back pain, bone pain, muscle cramp and myalgias 
• Cutaneous: alopecia 
• Miscellaneous: rash, hemorrhage, blurred vision, deafness, hepatitis, hyperbilirubinemia, 
peripheral edema 


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Other medical events of interest that are considered not causally related to bortezomib include 
hepatic failure and QT prolongation. Fatal outcomes have been reported. 
 
Women of childbearing potential should avoid becoming pregnant while being treated with 
bortezomib. Genotoxicity testing has shown that bortezomib is negative in the in vitro Ames assay 
and in the in vivo micronucleus assay, but it is a clastogen in the in vitro chromosomal aberration 
assay. 
 
Additional details on the potential risks of bortezomib may be found in the current Investigator’s 
Brochure and Appendix H. 
 
Bortezomib Precautions and Restrictions 
It is not known what effects bortezomib has on human pregnancy or development of the embryo 
or fetus. Therefore, female patients participating in this study should avoid becoming pregnant, 
and male patients should avoid impregnating a female partner. Non-sterilized female patients of 
reproductive age and male patients should use effective methods of contraception through defined 
periods during and after study treatment as specified below. 
 
Female patients must meet 1 of the following: 
• Postmenopausal for at least 1 year before the screening visit. Postmenopausal is defined 
as the time after which a woman has experienced twelve (12) consecutive months without 
a menstrual period. 
• Surgically sterile 
• If they are of childbearing potential (i.e., not postmenopausal or surgically sterile), agree 
to practice 2 effective methods of contraception from the time of signing the informed 
consent form through 12 months post transplant, or agree to completely abstain from 
heterosexual intercourse. It is strongly recommended that at least 1 of these 2 methods be 
‘highly effective’ (see Table 2.6.1). 
 
Table 2.6.1: Methods of Contraception 
 
Highly Effective Methods 
Other Effective Methods (barrier methods) 
Intra-uterine devices (IUD) 
Latex condom 
Hormonal contraceptives (birth control pills/oral 
contraceptives, injectable contraceptives, 
contraceptive patches, or contraceptive implants) 
Diaphragm with spermicide 
Cervical cap 
Sponge 
If one of the highly effective methods cannot be used, using 2 effective methods at the same time is 
recommended. 
 
Male patients, even if surgically sterilized (i.e., status post-vasectomy) must agree to one (1) of 
the following: 
• Practice effective barrier contraception during the entire study treatment period and 
through a minimum of 30 days after the last dose of maintenance study drug, or completely 
abstain from heterosexual intercourse. 


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2.6.3. 
Fludarabine 
 
Fludarabine (Flu) can lower the white blood cell count, in particular the CD4+ T-cells. The 
immunosuppression observed with the use of Flu increases the risk of infection, which can be life 
threatening. Hematopoietic suppression and immunosuppression are expected to occur as a direct 
effect of the antimetabolite. The most serious toxicity of Flu is neurological, and may consist of 
both peripheral neuropathy and encephalopathy. Toxicity can be manifested by fatigue, weakness, 
paresthesias, visual disturbances, somnolence and coma, that usually develop between 30 and 60 
days from therapy. The incidence of serious neurological toxicity has been 36% in patients treated 
with ≥ 96 mg/m2 per day for 5-7 days,131 a dose > 3 times higher than used in this protocol. Other 
adverse effects include fever, nausea, vomiting, diarrhea, stomatitis, skin rash, cough and 
idiopathic pneumonitis. 
 
2.6.4. 
Melphalan 
 
High dose melphalan is well tolerated by patients when they are supported with blood component 
transfusions, PBSC/marrow transplantation and broad-spectrum antibiotics. The duration of 
profound bone marrow suppression decreases with the use of PBSC infusion and colony 
stimulating factors. Gastrointestinal toxicity, which includes severe stomatitis, esophagitis and 
diarrhea, can be severe or life-threatening. Most patients receiving high dose melphalan will 
require parental narcotics for mucositis-related pain, IV hydration; may require IV alimentation 
and broad spectrum IV antibiotics. Despite moderate to severe symptoms in many patients, 
recovery is the norm, coincident with recovery of granulocytes. Other toxicities reported include 
pulmonary fibrosis and interstitial pneumonitis, skin hypersensitivity, vasculitis, alopecia, 
hemolytic anemia, and allergic reactions. 
 
See the FDA-approved package insert for a comprehensive list of adverse events. 
 
2.6.5. 
Methotrexate 
 
The most frequently reported adverse reactions associated with methotrexate use as GVHD 
prophylaxis include: 
• Neurologic: fever, dizziness, chills, undue fatigue 
• Gastrointestinal: ulcerative stomatitis, nausea, abdominal distress, diarrhea 
• Hematologic: leucopenia, anemia, and suppressed hematopoiesis (leading to infection) 
• Miscellaneous: abnormal liver tests, kidney failure, and pulmonary complications after 
transplantation 
 
2.6.6. 
Tacrolimus 
 
Tacrolimus side effects include: 
• Cardiovascular: hypertension 


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• Neurologic: confusion, dizziness, insomnia, seizures, tremors, changes in how clearly one 
can think 
• Gastrointestinal: nausea, vomiting 
• Hematologic: microangiopathic hemolytic anemia, thrombocytopenia 
• Endocrine and metabolic: hypomagnesemia, hypokalemia, hypocalcemia, hyperlipidemia 
• Miscellaneous: unwanted hair growth, changes in vision, liver problems, reversible renal 
insufficiency, infections and post transplant lymphoproliferative disorders 
• Reversible posterior leukoencephalopathy syndrome [RPLS] 
• Posterior reversible encephalopathy syndrome [PRES] (headache, confusion, seizures, and 
vision loss caused by very high blood pressure that comes on quickly) 
 
2.6.7. 
Ixazomib 
 
Please refer to the current MLN9708 (ixazomib) Investigator’s Brochure (IB). 
 
MLN9708 is a modified dipeptide boronic acid proteasome inhibitor similar to bortezomib, which 
has a known safety profile. The most frequent AEs reported to date in the ongoing MLN9708 
studies are noted in the IB and informed consent document (Appendix B). However, it is possible 
that MLN9708 will have toxicities that were not previously observed in or predicted from such 
sources. Patients will be monitored closely for anticipated toxicities. 
 
MLN9708 shows early signs of antitumor activity as evidenced by at least a 50% reduction in 
disease burden in some patients and prolonged disease stabilization in others across all ongoing 
trials.120,,,,,,127 
 
This study will be conducted in compliance with the protocol, good clinical practice (GCP), 
applicable regulatory requirements, and International Conference on Harmonisation (ICH) 
guidelines. 
 
The known anticipated risks of ixazomib are presented in the ixazomib investigator’s brochure 
which can be found on the BMT CTN SharePoint Website (https://bmtctnsp.net/). 
 
Pregnancy 
It is not known what effects MLN9708 has on human pregnancy or development of the embryo or 
fetus. Therefore, female patients participating in this study should avoid becoming pregnant, and 
male patients should avoid impregnating a female partner. Nonsterilized female patients of 
reproductive age group and male patients should use effective methods of contraception through 
defined periods during and after study treatment as specified below. 
 
Female patients must meet 1 of the following criteria: 
• Postmenopausal for at least 1 year before the screening visit, OR 


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• Surgically sterile, OR 
• If they are of childbearing potential, agree to practice 2 effective methods of contraception 
(see Table 2.6), at the same time, from the time of signing the informed consent form 
through 90 days after the last dose of maintenance study drug, AND 
• Agree to practice true abstinence when this is in line with the preferred and usual lifestyle 
of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, post- 
ovulation methods] and withdrawal are not acceptable methods of contraception.) 
 
Male patients, even if surgically sterilized (ie, status postvasectomy), must agree to 1 of the 
following: 
• Agree to practice effective barrier contraception during the entire study treatment period 
and through 90 days after the last dose of maintenance study drug, OR 
• Agree to practice true abstinence when this is in line with the preferred and usual lifestyle 
of the subject. (Periodic abstinence (eg, calendar, ovulation, symptothermal, post- 
ovulation methods] and withdrawal are not acceptable methods of contraception.) 
 
2.7. Study Drug Supply 
 
2.7.1. 
Melphalan, Fludarabine, Tacrolimus and Methotrexate 
 
These drugs are commercially available agents and will be administered per local institutional 
guidelines. 
 
2.7.2. 
Bortezomib 
 
Drug Supply, Preparation, Handling and Storage: 
Bortezomib for Injection is a sterile lyophilized powder for reconstitution and is supplied in vials 
containing bortezomib and mannitol at a 1:10 ratio. For example, vials containing 3.5 mg of 
bortezomib contain 35 mg of mannitol. 
 
Vials containing lyophilized bortezomib for Injection should be stored according to the label 
requirements. For the United States, store at USP Controlled Room Temperature which is 25ºC 
(77ºF); for Europe, do not store above 30ºC (86ºF); excursions permitted from 15 to 30ºC (59- 
86ºF). To date, stability data indicate that the lyophilized drug product is stable for at least 18 
months when stored under the recommended conditions. Stability studies are ongoing, and 
Millennium Pharmaceuticals, Inc. will notify the investigator should this information be revised 
during the conduct of the study. 
 
Bortezomib is cytotoxic. As with all cytotoxic drugs, caution is required when preparing and 
handling bortezomib solutions. Cytotoxic drugs should only be handled by staff specially trained 
in the safe handling of such preparations. The use of gloves and other appropriate protective 
clothing is recommended. In case of skin contact, wash the affected area immediately and 
thoroughly with soap and water for at least 15 minutes. If product contacts eye, immediately flush 


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eye thoroughly with water for at least 15 minutes. Always contact a physician after any form of 
body contact. All materials that have been used for preparation should be disposed of according 
to standard practices. A log must be kept of all disposed materials. 
 
Drug is available in sterile, single-use vials containing 3.5 mg of bortezomib. Each vial of 
bortezomib for Injection should be reconstituted under a laminar flow biological cabinet (hood) 
within 8 hours before dosing with 3.5 mL of normal (0.9%) saline, Sodium Chloride Injection 
USP, so that the reconstituted solution contains bortezomib at a concentration of 1 mg/mL. Prior 
to reconstitution the vials should remain in the cartons to protect them from light. Dissolution is 
completed in approximately 10 seconds. The reconstituted solution is clear and colorless, with a 
final pH of 5 to 6. Reconstituted bortezomib should be administered promptly and in no case more 
than 8 hours after reconstitution. 
 
Administration: 
Drug will be administered only to eligible patients under the supervision of the investigator or 
identified subinvestigator(s). Patients may be treated on an outpatient basis, if possible. 
 
The drug will be prepared under the supervision of a pharmacist, or appropriately qualified and 
trained personnel. The amount (in mg) of drug to be administered will be determined based on 
body surface area. Body surface area is to be calculated based on body weight using a standard 
nomogram or calculation. The dose should be calculated on the day of administration (Day -3 pre- 
transplant). 
 
The appropriate amount of bortezomib will be drawn from the injection vial and administered as 
an IV push over 3 to 5 seconds followed by a standard saline flush or through a running IV line. 
Vials are for single-use administration. 
 
Drug Ordering: 
Bortezomib will be supplied to participating centers from the BMT CTN 1302 Central Pharmacy. 
Refer to the BMT CTN 1302 Study Drug Guide for additional information regarding study drug 
supply and ordering, or contact the BMT CTN 1302 DCC Protocol Coordinator. 
 
Drug Accountability: 
Accountability for the drug at all study sites is the responsibility of the Principal Investigator. The 
investigator will ensure that the drug is used only in accordance with this protocol. Drug 
accountability records indicating the drug’s delivery date to the site, inventory at the site, use by 
each patient, and disposal of the drug (if applicable) will be maintained by the clinical site. 
Accountability records will include dates, quantities, lot numbers, expiration dates, and patient 
numbers. 
 
Drug Destruction: 
Investigational bortezomib (expired or end of study) will be destroyed on site according to the 
institution’s standard operating procedure. Be sure to document removal and destruction on drug 
accountability logs. 


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2.7.3. 
Maintenance Study Drug (Ixazomib and Placebo) 
 
Ixazomib Mechanism of Action 
Ixazomib is a boronate proteasome inhibitor that is a reversible inhibitor of primarily the 
chymotrypsin-like activity of the 20S proteasome. 
 
Human Safety of Ixazomib and Pharmacology 
Ixazomib has a shorter dissociation half-life compared to bortezomib and has demonstrated greater 
tissue penetration compared with bortezomib in preclinical studies. Ixazomib is orally available 
and has been shown to inhibit NF-kB activation. In vitro and in vivo studies have demonstrated 
antitumor activity in MM and other hematologic malignancies. 
 
Oral ixazomib is rapidly absorbed and substantially bioavailable, it is rapidly hydrolyzed into 
MLN2238, the biologically active form. An analysis of four phase I monotherapy studies of IV 
and oral ixazomib showed that for twice-weekly dosing, the Day 1 and Day 11 extrapolated 
immediate post-IV bolus plasma concentration of MLN2238 (C0) was roughly dose proportional 
over the dose range (0.125 to 2.34 mg/m2)[96]. In contrast, both the Day 1 and Day 11 dosing 
interval plasma concentration-time AUCs showed dose proportional increases only over the higher 
dose range (1 to 2.34 mg/m2). There was approximately 3–4 fold accumulation of MLN2238 by 
Day 11 on the twice-weekly schedule. For weekly IV dosing of ixazomib, only lower dose levels 
had been studied by then (0.125 to 1.4 mg/m2) but the PK behavior appeared to be similar to that 
for twice-weekly dosing, with the exception that MLN2238 accumulated to a lesser degree 
(approximately 2-fold). Following oral administration of ixazomib capsules, there was rapid 
absorption of MLN2238 (Tmax approximately 1 hr). At the doses studied to date (0.24 to 1.2 mg/m2) 
for twice-weekly and weekly dosing of ixazomib, systemic exposures achieved with oral dosing 
were similar to those achieved with IV dosing on the same schedule, indicating that the oral 
bioavailability of MLN2238 is substantial. 
 
In a population pharmacokinetic (PK) analysis of pooled data from 4 phase I studies, absolute 
bioavailability was estimated to be 62%[97]. Based on simulations using the final population PK 
model, there was no difference in concentration-time profile or exposures (AUC or Cmax) between 
the BSA-based and the flat doses, supporting a switch from BSA-based dosing to flat dosing in all 
ongoing and planned clinical studies. 
 
Maintenance therapy will be double-blinded and placebo capsules will be the same appearance 
and dosage as ixazomib. All the approaches described in Section 2.7.3 for ixazomib apply to 
placebo. 
 
Precautions and Handling: 
MLN9708 (ixazomib) is an anticancer drug and as with other potentially toxic compounds caution 
should be exercised when handling MLN9708 capsules. 
 
Packaging and Labeling: 
The maintenance study drug ixazomib will be provided by Millennium. Both maintenance study 
drugs will be blinded prior to shipment to the participating institution. They will be packaged and 


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labeled identically, with no drug identifying information. The packaging labels will fulfill all 
requirements specified by governing regulations. 
 
The capsules are individually packaged in cold form foil-foil blisters in a child-resistant package. 
The 2.3, 3.0, and 4.0 mg capsules are supplied as a 1 x 3 blister card in a child-resistant cardboard 
wallet. 
 
Availability (Ixazomib): 
Maintenance study drug will be supplied by Millennium as capsules of 2.3, 3.0 and 4.0 mg 
ixazomib. 
 
Hazardous agent; use appropriate precautions for handling and disposal. 
 
Availability (Placebo): 
Placebo will be supplied by Millennium as capsules of similar size, color, and shape to ixazomib. 
Like ixazomib, the placebo will be available in 2.3, 3.0, and 4.0 mg capsules. 
 
Preparation: 
For blistered material, the capsules are packaged in cold form foil-foil blisters with a paper backing 
for child-resistance. Both maintenance study drugs will be provided by Millennium and distributed 
to participating centers via the BMT CTN 1302 Central Pharmacy. 
 
Storage and Stability: 
Upon receipt at the investigative site, ixazomib or placebo (study drug) should remain in the blister 
and carton provided until use or until drug is dispensed. The container should be stored at the 
investigative site refrigerated at 2°C to 8°C (36°F to 46°F) and must not be frozen. Ensure that the 
drug is used before the retest expiry date provided by Millennium. Expiry extensions will be 
communicated accordingly with updated documentation to support the extended shelf life. 
 
In countries where local regulations permit, study drug capsules dispensed to the patient for take- 
home dosing should remain in the blister packaging and refrigerated as noted above until the point 
of use. The investigative site is responsible for providing the medication to the patient in the correct 
daily dose configurations. 
 
Comprehensive instructions should be provided to the patient in order to ensure compliance with 
dosing procedures. Patients who are receiving take-home medication should be given only 1 cycle 
of medication at a time. Patients should be instructed to store the medication refrigerated at 2°C to 
8°C (36°F to 46°F) for the duration of each cycle. Patients should be instructed to return their 
empty blister packs to the investigative site, rather than discarding them. Reconciliation will occur 
accordingly when the patient returns for their next cycle of take-home medication. Any extreme 
in temperature should be reported as an excursion and should be dealt with on a case-by-case basis. 
 
Because study drug is an investigational agent, it should be handled with due care. 
 
Patients should be instructed not to chew, break, or open capsules. In case of contact with broken 
capsules, raising dust should be avoided during the clean-up operation. The product may be 


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harmful by inhalation, ingestion, or skin absorption. Gloves and protective clothing should be worn 
during clean-up and return of broken capsules and powder to minimize skin contact. 
 
The area should be ventilated and the site washed with soap and water after material pick-up is 
complete. The material should be disposed of as hazardous medical waste in compliance with 
federal, state, and local regulations. 
 
In case of contact with the powder (e.g., from a broken capsule), skin should be washed 
immediately with soap and copious amounts of water for at least 15 minutes. In case of contact 
with the eyes, copious amounts of water should be used to flush the eyes for at least 15 minutes. 
Medical personnel should be notified. Patients are to be instructed on proper storage, 
accountability, and administration of study drug, including that study drug is to be taken as intact 
capsules. 
 
Administration: 
All protocol-specific criteria for administration of maintenance study drug must be met and 
documented before drug administration. Maintenance study drug will be administered or 
dispensed only to eligible patients under the supervision of the investigator or identified 
subinvestigator(s). Patients should be monitored for toxicity, as necessary, and doses of study 
drug should be modified as needed to accommodate patient tolerance to treatment; this may 
include symptomatic treatment, dose interruptions, and adjustments of study drug dose (see 
Section 2.4.5.5). 
 
Patients should be instructed to swallow study drug capsules whole, with water, and not to break, 
chew, or open the capsules. Maintenance study drug should be taken on an empty stomach (no 
food or drink) at least 1 hour before or 2 hours after a meal. Each capsule should be swallowed 
separately with a sip of water. A total of approximately 8 ounces (240 mL) of water should be 
taken with the capsules. 
 
If a dose of study drug 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. If the patient vomits after taking a dose, the 
patient should not repeat the dose but should resume dosing at the time of the next scheduled dose. 
 
Drug Ordering: 
Maintenance study drug (ixazomib and placebo) will be shipped to participating centers from the 
BMT CTN 1302 Central Pharmacy. Patient-specific supplies of maintenance study drug will be 
distributed to sites in capsules of different strengths according to the prescribed dose. The drug 
will be provided in single cycle blister packs, and the central pharmacy will ship three cycles (one 
quarter) of drug per order. Upon completion of a cycle, centers need to confirm dosage for the 
subsequent cycle and request a new shipment of a study drug if a dose adjustment is necessary. 
Centers will need to request maintenance study drug at the end of every quarter. Refer to the BMT 
CTN 1302 Study Drug Guide for additional information regarding study drug supply and ordering, 
or contact the BMT CTN 1302 DCC Protocol Coordinator. 


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Drug Accountability: 
Accountability for study drug at all study sites is the responsibility of the Principal Investigator. 
The investigator will ensure that the drug is used only in accordance with this protocol. Drug 
accountability records indicating the drug’s delivery date to the site, inventory at the site, use by 
each patient, and return or disposal of the drug will be maintained by the clinical site. 
Accountability records will include dates, quantities, lot numbers, expiration dates, and patient 
numbers. 
 
Drug Destruction: 
Study drug (expired or end of study) will be destroyed on site according to the institution’s standard 
operating procedure. Be sure to document removal and destruction on drug accountability logs. 
 
2.8. Blinding Procedures 
 
Assignment to ixazomib or placebo will be done according to computer-based randomization 
results. All treatment assignments will be blinded to study investigators, physicians, 
investigational pharmacists, and patients. The randomization assignment will determine patient- 
specific supplies for the entire maintenance period and it will be identified according to the 
patient’s and center’s identification numbers. 
 
2.9. Unblinding Procedures 
 
Maintenance study drug will be un-blinded for all patients upon study analyses or if deemed 
appropriate by the DSMB. Request for un-blinding for unique situations will be reviewed by the 
study team and DSMB in a case by case basis. 
 
Unblinding of maintenance study drug assignment will be considered in cases that impact safety 
to patients. Any investigator who wants to request an unblinding prior to protocol-defined study- 
wide unblinding should send their request to BMTCTN1302unblinding@emmes.com. Requests 
should include the following information: 
- 
Name of Investigator along with his/her telephone number and email address 
- 
Name of institution 
- 
Participant ID 
- 
A detailed description of the issue surrounding the request for unblinding. 
 
Upon its receipt, the unblinding request will be discussed, and any additional information needed 
will be obtained from the investigator who initiated the request. A response will be provided 
within one business day following review by the Protocol Chair(s) and/or Protocol Officer, DSMB, 
and NHLBI, where applicable. 
 
In case of unblinding, the study participant might be taken off protocol directed interventions. 
Recommendations on whether the study interventions will continue after unblinding will be 
dependent on individual cases and deliberated by the DSMB. 


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CHAPTER 3 
3. 
STUDY ENDPOINTS AND DEFINITIONS 
 
3.1. Definition of Disease Status 
 
Patients’ disease status at each data collection period will be evaluated based on the International 
Uniform Response Criteria. Until disease progression, all disease classifications are relative to the 
patient’s disease status prior to allogeneic transplant (i.e. study entry). At time of disease 
progression, disease classifications are relative to the patient’s best response since time of study 
entry. 
 
3.1.1. 
International Uniform Response Criteria 
 
Response and disease progression assessments will follow the International Uniform Response 
Criteria. For additional information on assessing response in patients with plasma cell leukemia 
see Appendix A. 
 
3.1.2. 
Response Categories 
 
Stringent Complete Response (sCR): 
sCR requires, in addition to CR (defined below), all of the following: 
• Normal free light chain ratio (FLC). 
• Absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescencea. 
 
Complete Response (CR): 
CR requires all of the following: 
• Absence of the original monoclonal paraprotein in serum and urine by routine 
electrophoresis and by immunofixation. The presence of new monoclonal bands consistent 
with oligoclonal immune reconstitution does not exclude CR. 
• Less than 5% plasma cells in a bone marrow aspirate and also on trephine bone biopsy, if 
biopsy is performed. 
• No increase in size or number of lytic bone lesions on radiological investigations 
(development of a compression fracture does not exclude CR)*. 
• Disappearance of soft tissue plasmacytomas. 
*If not clinically indicated, radiographs are not required to document CR. 
 
Patients in whom some, but not all, the criteria for CR are fulfilled are classified as partial 
responses (see below), providing the remaining criteria satisfy the requirements for partial 
response. This includes patients in whom routine electrophoresis is negative but in whom 
immunofixation has not been performed. 


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Very Good Partial Remission (VGPR) 
VGPR requires, in addition to PR (defined below), all of the following: 
• Serum or urine paraprotein detectable by immunofixation but not on electrophoresis 
OR 
• Greater than or equal to 90% reduction in serum paraprotein plus urine paraprotein < 100 
mg/24hrs 
For free light chain only disease, VGPR requires a 90% reduction of involved light chain. 
For patients without measurable monoclonal paraprotein at the time of relapse or progression, 
VGPR requires a 90% reduction in the difference between involved and uninvolved free light chain 
level, and < 5% plasma cells in the bone marrow. 
 
Partial Response (PR) 
PR requires one of the following: 
• Greater than or equal to 50% reduction in the level of the serum monoclonal paraprotein 
and reduction in 24 hour urinary monoclonal paraprotein either by greater than or equal to 
90% or to < 200 mg/24 hours in light chain disease. 
• If the only measurable non-bone marrow parameter is FLC, greater than or equal to 50% 
reduction in the difference between involved and uninvolved FLC levels or a 50% decrease 
in level of involved FLC with 50% decrease in ratio, 
• If the bone marrow is the only measurable parameter, greater than or equal to 50% reduction 
in bone marrow plasma cells given that the baseline count was greater or equal to 30%, 
• Greater than or equal to 50% reduction in the size of soft tissue plasmacytomas if present at 
baseline (by radiography or clinical examination). 
 
Stable Disease (SD) 
• Patients who do not meet criteria for sCR, CR, VGPR, partial response or progressive 
disease (section 3.1.1.2) are considered to have stable disease (SD). 
 
3.1.3. 
Progressive Disease (PD) 
 
Disease Progression (PD) 
Progression from CR or sCR requires one or more of the following: 
• A reappearance of serum monoclonal paraprotein, with a level of at least 0.5 g/dL. 
• 24-hour urine protein electrophoresis with at least 200 mg paraprotein/24 hours. 
• Abnormal FLC levels of > 10 mg/dl, only in patients without measurable paraprotein in 
the serum and urine. 
• At least 10% plasma cells in a bone marrow aspirate or on trephine biopsy. 
• Definite increase in the size of existing bone lesions or soft tissue plasmacytomas. 


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• Development of new bone lesions or soft tissue plasmacytomas. 
• Development of hypercalcemia (corrected serum Ca > 11.5 mg/dL or > 2.8 mmol/L) not 
attributable to any other cause. 
 
Progressive Disease (PD) 
For patients not in CR or sCR, progressive disease requires one or more of the following measured 
from the lowest possible value: 
• > 25% increase in the level of the serum monoclonal paraprotein, which must also be an 
absolute increase of at least 0.5 g/dL. 
• > 25% increase in 24-hour urine protein electrophoresis, which must also be an absolute 
increase of at least 200 mg/24 hours. 
• Absolute increase in the difference between involved and uninvolved FLC levels (absolute 
increase must be >10 mg/dl), only in patients without measurable paraprotein in the serum 
and urine. 
• > 25% increase in plasma cells in a bone marrow aspirate or on trephine biopsy, which 
must also be an absolute increase of at least 10%. 
• Definite increase in the size of existing bone lesions or soft tissue plasmacytomas. 
• Development of new bone lesions or soft tissue plasmacytomas. 
• Development of a compression fracture does not exclude continued response and may not 
indicate progression. 
• Development of hypercalcemia (corrected serum Ca > 11.5 mg/dL or > 2.8 mmol/L) not 
attributable to any other cause. 
 
3.2. Primary Endpoint 
 
The primary endpoint is to compare progression-free survival as a time to event endpoint from 
randomization between patients randomized to ixazomib and placebo maintenance in high risk 
multiple myeloma. Patients are considered a failure of the primary endpoint if they die or suffer 
from disease progression as defined above or if they initiate non-protocol anti-myeloma therapy. 
The time to this event is the time from randomization to progression, death, or initiation of non- 
protocol anti myeloma therapy whichever comes first. 
 
3.3. Secondary Endpoints 
 
3.3.1. 
Acute GVHD 
 
Acute GVHD will be graded according to the BMT CTN MOP. The time of onset of acute grades 
II-IV GVHD and grades III-IV GVHD will be recorded, as well as the maximum grade achieved. 


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3.3.2. 
Chronic GVHD 
 
Chronic GVHD will be scored according to the BMT CTN MOP. The time of onset of limited and 
extensive chronic GVHD will be recorded. 
 
3.3.3. 
Response to Treatment 
 
The event is the best response (sCR, CR, VGPR or PR) after randomization. Best response after 
allogeneic transplant will also be described. 
 
3.3.4. 
Disease Progression 
 
Disease progression as defined above will be the event of this outcome. Patients with prior CR 
will only be considered an event if they meet the progression criteria, disease relapse (i.e 
reappearance of original M spike) below the levels defined as progression will not be considered 
an event for this outcome. 
 
3.3.5. 
Treatment-Related Mortality (TRM) 
 
The event for TRM is any death that occurs in the absence of post-allogeneic HCT progression. 
Multiple myeloma progression is considered a competing risk for this event. 
 
3.3.6. 
Overall Survival 
 
Time to overall survival is defined as the time to death from any cause or for surviving patients, to last 
follow-up. The event for overall survival is death from any cause and surviving patients will be 
censored at the last date of follow-up. 
 
3.3.7. 
Toxicity 
 
All grades ≥ 3 toxicities according to CTCAE, version 4 will be tabulated for each intervention arm. 
The proportion of patients developing grade ≥ 3 AE across intervention arms will be compared. 
 
3.3.8. 
Infections 
 
The incidence of definite and probable viral, fungal and bacterial infections will be tabulated for each 
intervention arm. All Grade 2 and 3 infections will be reported according to the BMT CTN MOP. 
 
3.3.9 Rate of Non-Randomization 
 
The proportion of patients not achieving randomization by Day 120 post-allogeneic HCT will be 
described. 


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3.3.10 Health Quality of Life 
 
The FACT-BMT version 4.0 instrument is comprised of a general core questionnaire: the FACT- 
G, which evaluates the health-related quality of life (HQL) of patients receiving treatment for 
cancer, and a specific module, BMT Concerns, that addresses disease and treatment-related 
questions specific to bone marrow transplant. The FACT-G consists of four subscales developed 
and normed in cancer patients: Physical Well-being, Social/Family Well-being, Emotional Well- 
being, and Functional Well-being. Each subscale is positively scored, with higher scores 
indicating better functioning. The FACT-BMT Total, which is the grand total of all items in the 
FACT-G and BMT modules, will be used as the outcome measure in summarizing the FACT- 
BMT data. 
 
The MOS SF-36 instrument is a general assessment of health quality of life with eight components: 
Physical Functioning, Role Physical, Pain Index, General Health Perceptions, Vitality, Social 
Functioning, Role Emotional, and Mental Health Index. Each domain is positively scored, 
indicating that higher scores are associated with positive outcome. This scale has been widely 
applied in a variety of outcome studies and is being used in this protocol as a generic measure of 
quality of life. To facilitate comparison of the results with published norms, the Physical 
Component Summary (PCS) and Mental Component Summary (MCS) will be used as the outcome 
measures in summarizing the SF-36 data. 
 
HQL will be described from pre-transplant to last follow up at 24 months post transplant. 
Additionally, HQL will be compared between the maintenance arms utilizing the FACT-BMT self 
report, transplant specific questionnaire and the generic quality of life tool (SF-36). The 
questionnaires will be scored according to standard procedures. The self-report questionnaires 
will be completed prior to transplant, prior to randomization, 6 months after maintenance initiation, 
at time of maintenance completion and 24 months after transplant. Comparisons of quality of life 
will be done between maintenance arms at each of the time points after randomization. Only 
English and Spanish speaking patients are eligible to participate in the HQL component of this 
trial. 
 
3.3.11 Post-Transplant Endpoints 
 
Estimates for the primary and key secondary endpoints for each arm of maintenance therapy will 
be described post transplant. 


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CHAPTER 4 
4. 
PATIENT REGISTRATION, ENROLLMENT AND EVALUATION 
 
4.1. Enrollment Procedures 
 
Enrollment onto the BMT CTN 1302 trial is a multi-step process and must be conducted by an 
authorized user at the clinical center. The following must be completed, in the below order, to 
enroll a patient onto trial: 
1. Demographics Form 
2. Segment 0 Enrollment Form – documents the patient’s consent to participate in the trial 
3. HLA Form – documents that the patient-donor HLA match score meets protocol 
requirements 
4. Segment A Enrollment Form – documents that the patient meets the protocol’s eligibility 
criteria (Section 2.3.1. through Section 2.3.3.) 
A patient is not considered enrolled onto the trial, thus no protocol-prescribed treatment can be 
initiated, until the Segment A Enrollment Form is successfully saved and a confirmation screen is 
provided indicating the enrollment was successful. Once the patient is enrolled, the Transplant 
Form must be completed in order to populate a visit schedule in the Forms Grid. 
After the patient has adequately recovered from their transplant, he or she will be screened for 
eligibility for the randomized maintenance portion of the trial. If the patient is found to be eligible, 
the Segment B Enrollment Form must be completed between 60 and 120 days post-transplant to 
document that the patient meets the maintenance eligibility criteria (Section 2.3.4. through Section 
2.3.5.). Successfully saving this form randomizes the patient. Maintenance study drug cannot be 
ordered until the Segment B Enrollment Form is completed and a confirmation screen with a 
randomization assignment is provided. 
Refer to the BMT CTN 1302 Forms Guide for further guidance on the enrollment procedures and 
forms completion. 
 
4.2. Study Monitoring 
 
4.2.1. 
Follow-Up Schedule 
 
The follow-up schedule for study visits post transplant and post initiation of maintenance are 
outlined below in Tables 4.2.1a and 4.2.1b, respectively. The follow-up schedule is the intended 
schedule; however, the date of the follow-up evaluations may vary due to delays in treatment or 
treatment interruption related to Adverse Events and toxicities. The visit window for the scheduled 
evaluations is included in Tables 4.2.1a and 4.2.1b. The follow up period is 2 years post-transplant, 
however there will be an extended reporting period for second primary malignancies (SPMs), 
which ends once all patients have completed 2 years of follow up. A detailed description of each 
of the forms and the procedures required for forms completion and submission can be found in the 
BMT CTN 1302 Forms Guide. 


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Table 4.2.1a: Follow-Up Schedule 
Post-Transplant/Prior to Maintenance 
 
Study Visit 
Target Day Post Transplant 
Baseline 
 42 days prior to transplant 
1 week 
7  2 days 
2 week 
14  2 days 
3 week 
21  2 days 
4 week 
28  2 days 
5 week 
35  2 days 
6 week 
42  2 days 
7 week 
49  2 days 
8 week 
56  2 days 
9 week 
63  2 days 
10 week 
70  2 days 
11 week 
77  2 days 
12 week 
84  2 days 
13 week 
91  2 days 
14 week 
98  2 days 
Day 1001,2 
100  7 days 
Day 1201,2 
120  7 days 
1 Patients that proceed to maintenance therapy prior to Day 100 will begin to follow the study schedule outlines 
in table 4.2.1b: Follow-Up Schedule Post-Maintenance. 
2If the pre-randomization visit falls within + 7 days of visit 100 or visit 120 the assessments can be conducted 
during the same visit. 


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Table 4.2.1b: Follow-Up Schedule Post- Maintenance for 
All Randomized Patients 
 
Study Visit 
Target Day Post-Maintenance1 
Baseline (Pre- 
maintenance) 
≤ 14 days pre-maintenance 
Cycle 12 
Day 1  7 days 
Cycle 22 
Day 29  7 days 
Cycle 3 
Day 57  7 days 
Cycle 4 
Day 85  7 days 
Cycle 5 
Day 113  7 days 
Cycle 6 
Day 141  7 days 
Cycle 7 
Day 169  7 days 
Cycle 8 
Day 197  7 days 
Cycle 9 
Day 225  7 days 
Cycle 10 
Day 253  7 days 
Cycle 11 
Day 281  7 days 
Cycle 12 
Day 309  7 days 
28-day follow up after 
last dose 
Day 339  7 days 
(28 days after last dose) 
1 The date of the follow-up evaluations may vary due to delays in treatment or treatment interruption related to 
adverse events and toxicities. 
2 Patients will be followed weekly for cycles 1 and 2, and monthly otherwise 
 
 
Table 4.2.1c: Follow-Up Schedule After Day 120 Post-Transplant for 
Non-Randomized Patients1 
 
Study Visit 
Target Day Post Transplant 
6 months post 
transplant 
Day 180 + 7 days 
12 months post 
transplant 
Day 365 + 7 days 
18 months post 
transplant (18T) 
Day 540  14 days 
24 months post 
transplant (24T) 
Day 730  14 days 
1All patients must be followed for SPMs until the last enrolled patient has completed 2 years of follow up. 


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Table 4.2.1d: Follow-Up Schedule Endpoint Assessments for 
Randomized Patients1 
 
Endpoints 
Days From Transplant 
18 months post 
transplant (18T) 
Day 540 
14 days 
24 months post 
transplant (24T) 
Day 730 
14 days 
1All patients must be followed for SPMs until the last enrolled patient has completed 2 years of follow up. 
 
4.3. Patient Evaluations 
 
4.3.1. 
Pre-Transplant Evaluations and Requirements 
 
The following observations will be made < six weeks before enrollment: 
1. History and physical examination, height and weight 
2. Karnofsky performance score 
3. HCT- Specific Comorbidity Index score. 
4. CBC with differential and platelet count, bilirubin, alkaline phosphatase, AST and ALT 
5. Estimated creatinine clearance, using the Cockcroft-Gault formula and actual body weight. 
6. Infectious disease markers to include: CMV antibody, Hepatitis panel (HepA Ab, HepB 
SAb, HepB SAg, HepB Core Ab, HepC Ab), herpes simplex virus, syphilis, HIV and 
HTLV I/II antibody, and varicella zoster. 
7. EKG and LVEF (may be performed < 12 weeks before enrollment). 
8. Pulmonary function tests, including DLCO and FEV1 (may be performed < 12 weeks 
before enrollment). 
9. HLA Typing (donor and recipient) as described in Chapter 2 (if not already performed). 
10. Pregnancy test per institutional practices for females of child-bearing potential (i.e., not 
postmenopausal or surgically sterile as per Section 2.6.2). NOTE: pregnancy test must 
be performed ≤ 14 days before enrollment 
11. Laboratory Disease Evaluation: 
a. Quantitative serum immunoglobulin levels. 
b. Serum protein electrophoresis (SPEP). 
c. 24 hour urine collection to determine protein excretion, urine electrophoresis 
(UPEP). 
d. Immunofixation of urine and serum protein regardless of SPEP and UPEP results. 
e. Serum free light chain ratios (FLC) 
12. Skeletal bone survey to include cranium, axial skeleton and proximal long bones 
13. 12-lead electrocardiogram (ECG) 


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4.3.2. 
Evaluations after Enrollment and Prior to Transplant 
 
The following evaluations must be completed after enrollment in to BMT CTN 1302 and prior to 
transplant. 
1. Health-related quality of life assessment, SF-36 and FACT-BMT (for English and 
Spanish speaking patients only). 
2. Optional Samples for Future and Ancillary Research (Appendix C) 
a. Peripheral Blood: single 36 mL sample of your blood (approximately 7 
teaspoons) will be collected for future research and immune reconstitution 
assessment 
b. Bone Marrow: bone marrow aspirate (10 mL) collection for future research and 
MRD assessment 
3. Bone Marrow Evaluation: unilateral bone marrow biopsy and aspirate are indicated to 
assess disease status prior to transplantation 
 
4.3.3. 
Post-Transplant Evaluations and Requirements 
 
The following evaluations are after the allogeneic HCT. These evaluations will occur as indicated 
below and in Table 4.3.1. 
1. Physical examination and appropriate lab evaluations to assess GVHD and other morbidity 
weekly starting at Day 7 post-transplant through Day 98 post-transplant, then at Day 120 
post-transplant. 
2. Assessment for Toxicities at Days 28, 56 and 100 post-transplant 
3. CBC with manual differential to be performed weekly from Day 0 until engraftment. CBCs 
will be performed per institutional guidelines from the time of engraftment through 
randomization. post transplant. 
4. Liver Functions and Blood Chemistries: total bilirubin, alkaline phosphatase, AST, ALT 
per institutional guidelines prior to randomization. 
5. Sorted or unsorted chimerism analysis (peripheral blood or bone marrow) at Days 56 and 
100 post-transplant1. Chimerism may be evaluated in bone marrow, whole blood or blood 
cell fractions, including CD3, CD33, or CD15 fraction. The actual measurement dates may 
be within +/- 7 days of the recommended time points. 
6. Laboratory Disease Response Assessment required at Days 56 and 120 post-transplant 
a. Quantitative serum immunoglobulin levels. 
b. Serum protein electrophoresis (SPEP). 
c. 24-hour urine collection to determine protein excretion, urine electrophoresis 
(UPEP). 
 
1The chimerism analyses at Day 180 and 365 should align with the chimerism analyses required at Cycles 3 and 9 of 
maintenance therapy. See table 4.3.2. 


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d. Immunofixation of urine and serum protein regardless of SPEP and UPEP results. 
e. Serum free light chain ratios (FLC) 
7. Bone Marrow Evaluation: unilateral bone marrow biopsy and aspirate are required only to 
confirm CR in patients. 
8. Optional Samples for Future and Ancillary Research (Appendix C) 
a. Peripheral Blood: single 36 mL sample of blood (approximately 7 teaspoons) will 
be collected for future research and immune reconstitution assessment at Day 28 
post-transplant. For patients who delayed the initiation of maintenance or do not 
proceed to maintenance, blood collection will be done at Day 100, 180 and 365 
post transplant. 
9. Data on occurrence of infections recorded as per BMT CTN MOP. 
 
4.3.4. 
Pre-Maintenance Evaluations and Requirements 
 
The following evaluations to determine eligibility for randomization to maintenance therapy will 
be done ≤ 14 days prior to initiation of maintenance therapy (see Table 4.3.2). If found 
eligible, randomization must occur ≤ 7 days prior to initiation of maintenance. 
1. Physical examination and appropriate lab evaluations to assess GVHD and other morbidity 
2. Karnofsky performance score 
3. CBC with differential, platelet count 
4. Estimated creatinine clearance, using the Cockcroft-Gault formula and actual body weight. 
5. Liver Functions and blood chemistries: total bilirubin, alkaline phosphatase, AST, ALT 
6. Thyroid Stimulating Hormone (TSH) 
7. Pregnancy test, serum HCG (sensitivity of at least 50 mIU/mL). 
8. Laboratory Disease Evaluation2: 
• Quantitative serum immunoglobulin levels. 
• Serum protein electrophoresis (SPEP). 
• 24-hour urine collection to determine protein excretion, urine electrophoresis 
(UPEP). 
• Immunofixation of urine and serum protein regardless of SPEP and UPEP results. 
• Serum free light chain ratios (FLC) 
9. Bone Marrow Evaluation: unilateral bone marrow biopsy and aspirate are required only to 
confirm CR in patients. 
10. Skeletal bone survey to include cranium, axial skeleton and proximal long bones 
 
2 Laboratory Disease Evaluations performed at Day 60 and Day 120 post-transplant can be used as evaluations prior 
to maintenance therapy if they are ≤ 14 days prior to the initiation of maintenance therapy. 


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11. Sorted or unsorted chimerism analysis (peripheral blood or bone marrow). The chimerism 
analysis technique (sorted or unsorted) is at the discretion of the transplant center but must 
be utilized consistently while on maintenance study drug. 
12. Assessment for Toxicities 
13. Health-related quality of life assessment, SF-36 and FACT-BMT (for English and Spanish 
speaking patients only). 
14. Optional Samples for Future and Ancillary Research (Appendix C) 
a. Peripheral Blood: single 36 mL sample of blood (approximately 7 teaspoons) will 
be collected for future research and immune reconstitution assessment 
b. Bone Marrow: bone marrow aspirate (10 mL) collection for future research and 
MRD assessment 
 
4.3.5. 
Evaluations During Maintenance Therapy 
 
Upon initiation of maintenance, weekly laboratory monitoring and GVHD assessment is required 
during Cycles 1 and 2, within a window of ± 2 days. Laboratory monitoring is required once every 
cycle for all cycles thereafter. Patient visits are mandatory for planned Cycles 1-12 and 28 days 
after the last dose of maintenance study drug, unscheduled visits and laboratory monitoring may 
take place as needed. 
 
The following required observations are after initiation of maintenance therapy. These evaluations 
will occur as indicated below and in Table 4.3.2. 
1. Physical examination and appropriate lab evaluations to assess acute and chronic GVHD 
and other morbidities weekly from 7 days after the initiation of maintenance until 60 days; 
after 60 days they are required once every cycle. 
2. CBC with differential, platelet count weekly for Cycle 1 and monthly otherwise. 
3. Laboratory Disease Evaluation required every 3 months: 
a. Quantitative serum immunoglobulin levels. 
b. Serum protein electrophoresis (SPEP). 
c. 24-hour urine collection to determine protein excretion, urine electrophoresis 
(UPEP). 
d. Immunofixation of urine and serum protein regardless of SPEP and UPEP results. 
e. Serum free light chain ratios (FLC) 
4. Bone Marrow Evaluation: unilateral bone marrow biopsy and aspirate are required only to 
confirm CR in patients. 
5. Thyroid Stimulating Hormone (TSH) to be obtained every three months. 
6. Skeletal Survey to include cranium, axial skeleton and proximal long bones is required ≤ 
28 days of the last dose of maintenance, but otherwise may be performed as clinically 
indicated during the course of the study at the discretion of the transplant physician. 


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7. Sorted or unsorted chimerism analysis (peripheral blood or bone marrow) every six months 
during treatment with maintenance study drug and as otherwise clinically indicated, at the 
discretion of the transplant physician. The chimerism analysis technique (sorted or 
unsorted) is at the discretion of the transplant center but must be utilized consistently while 
on maintenance study drug. 
8. Assessment and appropriate lab evaluations for toxicities at Cycles 1, 2, 3, 4, 6, 9, 12 and 
≤ 28 days after the last dose of maintenance study drug. 
9. Health-related quality of life assessment, SF-36 and FACT-BMT (for English and Spanish 
speaking patients only) after Cycle 6, ≤ 28 days after the last dose of maintenance study 
drug and at 2 years post-transplant (24T). 
10. Accurate records will be kept of all maintenance study drug prescription and 
administration. No more than one cycle of maintenance study drug will be dispensed to 
the patient at a time 
11. Optional Samples for Future Research collected at the timepoints listed below and in table 
4.3.2. 
a. Peripheral Blood: single 36 mL sample of blood (approximately 7 teaspoons) will 
be collected for future research and immune reconstitution assessment at cycles 2 
(~100 days post-transplant), 5 (~180 days post transplant), 10 (~1 year post- 
transplant) and within 28 days of the last dose of maintenance study drug. 
b. Bone Marrow: bone marrow aspirate (10 mL) collection for future research and 
MRD assessment will occur within 28 days of the last dose of maintenance study 
drug 
 
4.3.6. 
Evaluations for Non-Randomized Patients 
 
Patients who are not randomized for any reason should be followed at the time points outlined in 
tables 4.2.1A and 4.2.1C. 
 
The following evaluations will occur after Day 120 post transplant for non-randomized patients. 
These evaluations will occur as indicated below and in Table 4.3.3. 
1. Physical examination and appropriate lab evaluations to assess acute and chronic GVHD 
at 6 months and 12 months. 
2. CBC with differential, platelet count at 6 months, 12 months, 18 months, and 2 years 
post- transplant. 
3. Laboratory Disease Evaluation required at 6 months, 12 months, 18 months, and 2 years 
post-transplant: 
a. Quantitative serum immunoglobulin levels. 
b. Serum protein electrophoresis (SPEP). 
c. 24-hour urine collection to determine protein excretion, urine electrophoresis 
(UPEP). 


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d. Immunofixation of urine and serum protein regardless of SPEP and UPEP results. 
e. Serum free light chain ratios (FLC) 
4. Bone Marrow Evaluation: unilateral bone marrow biopsy and aspirate are required only to 
confirm CR in patients. 
5. Skeletal bone survey to include cranium, axial skeleton and proximal long bones at 18 
months and 2 years post-transplant. 
6. Assessment for toxicities at 6 months, 12 months, 18 months, and 2 years post-transplant. 
7. Health-related quality of life assessment, SF-36 and FACT-BMT (for English- and 
Spanish-speaking patients only) at 2 years post-transplant. 


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Table 4.3.1: Patient Clinical Assessments (Pre/Post-Transplant) 
 
Study Assessments/ 
Testing 
Baseline 
  
 
Weeks Post Transplant 
Days Post 
Transplant 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10-14 
100 
120 
History, physical exam, weight and height 
X 
Karnofsky performance status 
X 
HCT-Specific Comorbidity Index score 
X 
HLA typing (donor and recipient) 
X 
CBC1, differential, platelet count, and blood chemistries2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Estimated Creatinine Clearance3 
X 
Infectious disease markers4 
X 
EKG and LVEF5 
X 
DLCO and FEV15 
X 
Pregnancy test6 
X 
Quantitative serum immunoglobulins11 
X 
X 
X 
SPEP and immunofixation11 
X 
X 
X 
24 Hour Urine for UPEP, protein excretion and immunofixation11 
X 
X 
X 
Serum free light chain ratio11 
X 
X 
X 
Bone marrow aspirate and biopsy11 
X12 
X7 
X7 
Optional blood sample for immune reconstitution and future research 
X12 
X10 
X10 
Optional bone marrow aspirate for MRD and future research 13 
X12 
Skeletal Survey 
X 
ECG 
X 
Health-Related Quality of Life14 
X12 
Chimerism8 
X 
X 
GVHD assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Toxicity assessment9 
X 
X 
X 


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1 CBC with manual differential to be performed weekly from Day 0 until engraftment. CBCs will be performed per institutional guidelines from the time of 
engraftment through randomization. 
2 Blood chemistries include: bilirubin, alkaline phosphatase, AST and ALT. Blood chemistries performed per institutional guidelines through randomization. 
3 Estimated creatinine clearance is calculated using the Cockcroft-Gault formula and actual body weight. 
4 Infectious disease titers include: CMV, Hepatitis panel (HepA Ab, HepB SAb, HepB SAg, HepB Core Ab, HepC Ab), herpes simplex virus, syphilis, HIV and 
HTLV I/II antibody, and varicella zoster. 
5 May be performed within 12 weeks of enrollment 
6 Pregnancy test must be performed < 14 days from enrollment. Pregnancy test is required for females of child-bearing potential and may be performed per 
institutional practices. 
7 Bone Marrow aspirate and biopsy required only to confirm CR in patients 
8 Chimerism may be evaluated in bone marrow, whole blood or blood cell fractions, including CD3 and CD33 or CD15 fraction. The actual measurement dates 
may be within +/- 7 days of the recommended time points. 
9 The toxicity assessment will include a review of all toxicities experienced during the entire assessment period and the highest grade for each toxicity during 
the assessment period will be recorded on the Toxicity form in AdvantageEDC. 
10 Peripheral blood for future research will be collected at Day 28 post-transplant. For patients who are delayed in initiating maintenance or not eligible to start 
maintenance additional blood collection for future research will be done at Days 100, 180 and 365. 
11 Myeloma response assessment for patients who are not randomized will be repeated at day 120 post transplant and every 6 months until completion of study 
period (2 years post transplant) 
12 These assessments should be performed after enrollment on BMT CTN 1302 through the AdvantageEDC system but prior to transplant. 
13 Minimial residual assessment will be done in bone marrow aspirate centrally at Roswell Park Cancer Institute. See Appendix C for procedures and Appendix L 
for details. 
14 English- and Spanish-speaking patients only. 


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Table 4.3.2: Patient Clinical Assessments for Randomized Patients (Pre/Post-Maintenance) 
 
Study Assessments/Testing1 
≤ 14 days 
prior to 
initiation of 
maintenance 
Cycle (28 days/cycle) 
Days post 
transplant2 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Follow 
Up 
18T 
24T 
Karnofsky performance status 
X 
CBC, differential, platelet count, and blood 
chemistries3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TSH 
X 
X 
X 
X 
X 
Estimated Creatinine Clearance4 
X 
Pregnancy test (serum HCG (sensitivity of at least 
50 mIU/mL)) 
X 
Quantitative serum immunoglobulins 
X 
X 
X 
X 
X 
X 
X 
X 
SPEP and immunofixation 
X 
X 
X 
X 
X 
X 
X 
X 
24 Hour Urine for UPEP, protein excretion and 
immunofixation 
X 
X 
X 
X 
X 
X 
X 
X 
Serum free light chain ratio 
X 
X 
X 
X 
X 
X 
X 
X 
Bone marrow aspirate and biopsy 
X5 
X5 
X5 
X5 
X5 
Skeletal Survey6 
X 
X 
X 
X 
Chimerism7 
X 
X 
X 
Chronic and Acute GVHD assessment8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Toxicity assessment9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Health-Related Quality of Life10 
X 
X 
X 
X 
Optional blood sample for immune reconstitution 
and future research11,13 
X 
X 
X 
X 
X 
Optional bone marrow aspirate for MRD 
assessment and future research12,13 
X 
X 


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1 Weekly laboratory monitoring (± 2 days) is required during Cycles 1 and 2. Laboratory monitoring is required once every cycle for all other cycles. 
2 See table 4.2.1d for target dates for these endpoint assessments. 
3 Blood chemistries include: bilirubin, alkaline phosphatase, AST and ALT. 
4 Estimated creatinine clearance is calculated using the Cockcroft-Gault formula and actual body weight. 
5 Bone Marrow aspirate and biopsy required only to confirm CR in patients. 
6 Assessment to be performed more frequently if clinically indicated. 
7 Chimerism may be evaluated in bone marrow, whole blood or blood cell fractions, including CD3 and CD33 or CD15 fraction. The actual measurement 
dates may be within +/- 7 days of the recommended time points and may be performed more frequently if clinically indicated. 
8 GVHD assessments will be done weekly from 7 days post-maintenance intiation until 60 days post-maintenance initiation; after 60 days they will be done once 
every cycle. 
9The toxicity assessment will include a review of all toxicities and appropriate lab evaluations experienced during the entire assessment period and the highest 
grade for each toxicity during the assessment period will be recorded on the Toxicity form in AdvantageEDC. 
10 Health quality of life assessment, SF-36 and FACT-BMT, should be completed prior to Maintenance, after cycle 6 of maintenance, within 28 days of 
completing maintenance therapy, and at 2 years post-transplant (24T) for English- and Spanish-speaking patients only. 
11 Blood Samples for future research will be collected prior to randomization, at initiation of cycle 2 or approximately day 100 post transplant at cycle 5 or 
approximately day 180 post transplant, at cycle 10 or approximately 1 year post transplant and one month after completion of maintenance. Blood samples taken 
prior to maintenance, at Cycle 5, and after Cycle 12 will also be sent for immune reconstitution analysis at Roswell Park Cancer Institute. See Appendix C for 
procedures and Appendix L for details. 
12 Minimal residual assessment will be done in bone marrow aspirate centrally at Roswell Park Cancer Institute. See Appendix C for procedures and Appendix L 
for details. 
13 Optional blood and bone marrow samples must be collected ≤ 14 days prior to the initiation of maintenance therapy. The samples should be collected AFTER 
randomization and BEFORE initiation of maintenance therapy, however samples collected prior to randomization that fall within this window may be accepted. 


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Table 4.3.3: Patient Clinical Assessments for Non-Randomized Patients (After 120 Days Post-Transplant) 
 
Study Assessments/Testing 
Months Post 
Transplant 
6 
12 
18 
24 
CBC, differential, platelet count, and blood 
chemistries1 
X 
X 
X 
X 
Quantitative serum immunoglobulins 
X 
X 
X 
X 
SPEP and immunofixation 
X 
X 
X 
X 
24 Hour Urine for UPEP, protein excretion and 
immunofixation 
X 
X 
X 
X 
Serum free light chain ratio 
X 
X 
X 
X 
Bone marrow aspirate and biopsy 
X5 
X5 
X5 
X5 
Skeletal Survey2 
X 
X 
Chronic and Acute GVHD assessment 
X 
X 
Toxicity assessment3 
X 
X 
X 
X 
Health-Related Quality of Life4 
X 
Optional blood sample for future and immune 
reconstitution research 
X 
X 
1 Blood chemistries include: bilirubin, alkaline phosphatase, AST and ALT. 
2 Assessment to be performed more frequently if clinically indicated. 
3 The toxicity assessment will include a review of all toxicities and appropriate lab evaluations experienced during the entire assessment period and the 
highest grade for each toxicity during the assessment period will be recorded on the Toxicity form in AdvantageEDC. 
4 Health quality of life assessment, SF-36 and FACT-BMT should be completed at 2 years post-transplant. 
5 Required only to confirm CR and as clinically indicated. 


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4.4. Data Reporting 
 
4.4.1. 
Criteria for Forms Submission 
 
Forms that are not entered into AdvantageEDCSM within the specified time will be considered 
delinquent. A missing form will continue to be requested either until the form is entered into the 
AdvantageEDCSM and integrated into the Data and Coordinating Center’s (DCC) master database, 
or until an exception is granted and entered into the Missing Form Exception File. 
 
4.4.2. 
Reporting Patient Deaths 
 
Recipient death information must be entered into AdvantageEDCSM within 24 hours of knowledge 
of the patient’s death. If the cause of death is unknown at that time, it need not be recorded at that 
time. However, once the cause of death is determined, the form must be updated in 
AdvantageEDCSM. 
 
4.4.3. 
Adverse Event Reporting 
 
Reporting of adverse event on the BMT CTN 1302 trial has unique requirements due to the 
addition of bortezomib and ixazomib as part of the protocol. Adverse event reporting requirements 
are summarized below and further described in Appendix I. 
 
4.4.3.1. 
Definitions 
 
Adverse Event: An adverse event (AE) is any undesirable sign, symptom or medical condition or 
experience that develops or worsens in severity after starting the first dose of study treatment or 
any procedure specified in the protocol, even if the event is not considered to be related to the 
study. 
 
Expectedness: An adverse event can be Expected or Unexpected 
• Expected adverse events are those that have been previously identified as resulting from 
administration of the agent. For the purposes of this study, an adverse event is considered 
expected when it appears in the current adverse event list, the Investigator’s Brochure, the 
package insert or is included in the informed consent document as a potential risk. 
• Unexpected adverse events are those that vary in nature, intensity or frequency from 
information in the current adverse event list, the Investigator’s Brochure, the package 
insert, or when it is not included in the informed consent document as a potential risk. 
 
4.4.3.2. 
BMT CTN Adverse Event Reporting Guidelines 
 
It is BMT CTN policy that AEs must be reported even if the investigator is unsure whether a 
relationship exists between the adverse event and the use of the study treatment. Reporting of AEs 
for BMT CTN 1302 will be consistent with the BMT CTN Manual of Procedures. Additional 
requirements specific to this protocol are outlined below and in Appendix I. 


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In BMT CTN studies, expected adverse events are reported via the web-based electronic data 
capture system, AdvantageEDC. Events are captured on calendar-driven case report forms (e.g., 
Toxicity 
and 
Hematology/Chemistry) 
or 
event-driven 
case 
report 
forms 
(e.g., 
Relapse/Progression, Secondary Graft Failure, and Death). Additionally, any expected grade 4 
event not collected on another form must be reported through the expedited AE reporting system 
via AdvantageEDC. 
 
Unexpected, grades 3-5 AEs, irrespective of the attribution of the event to the study drug/ 
procedure/treatment, will be reported through the expedited AE reporting system via 
AdvantageEDC, and will be graded according to the NCI Common Terminology Criteria for 
Adverse Events (CTCAE), Version 4.0. The BMT CTN 1302 protocol has two distinct 
interventions; transplant and maintenance therapy. Determination of expectedness for events 
occurring post-transplant and/or post-maintenance therapy will be at the discretion of the 
investigator as described in Appendix I, section I.3. Unexpected, grades 4-5 AEs must be 
reported within 24 hours of knowledge of the event. Unexpected, grade 3 AEs must be 
reported within three business days of knowledge of the event. The NHLBI Data and Safety 
Monitoring Board will receive summary reports of all adverse experiences at least twice yearly. 
 
4.4.3.3. 
Adverse Event Reporting Following Progression 
 
If a patient meets the protocol defined definition of progression (see Chapter 3), Unexpected Grade 
3-5 Adverse Events and events listed in Appendix I are no longer required to be reported on the 
Adverse Event Form once the patient is more than 30 days from their last dose of maintenance 
treatment. However, SPMs should continue to be reported within three business days of the 
knowledge of the event through the end of the study follow-up period. 
 
4.4.3.4. 
Additional Adverse Event Reporting Requirements with Respect to Bortezomib and 
Ixazomib/Placebo 
 
Millennium Pharmaceuticals, Inc. (MPI) is supplying bortezomib and ixazomib for this study and 
a description of additional adverse event reporting requirements for this study is detailed in 
Appendix I. The additional adverse event reporting period for bortezomib begins at the time of 
bortezomib administration and continues for 30 days. Due to the blinding of maintenance, the 
additional adverse event reporting period for ixazomib applies for all participants who receive 
maintenance and begins with the first dose of maintenance and continues until 30 days after the 
last dose of maintenance (ixazomib or placebo). Along with the additional adverse event reporting 
requirements, any adverse event reported through the expedited AE reporting system will include 
the investigator’s assessment of relationship to bortezomib and maintenance therapy (unrelated, 
unlikely, possible, probable, definite, or not applicable). 
 
4.4.3.5. 
Procedures for Reporting Exposure to Bortezomib and/or Ixazomib during Pregnancy 
and Birth Events 
 
If a woman becomes pregnant or suspects that she is pregnant while receiving bortezomib and/or 
ixazomib/placebo for this study, she must inform the Investigator immediately and permanently 
discontinue study drug. The pregnancy, suspected pregnancy, or positive pregnancy test must be 


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reported within 24 hours of the Investigator’s knowledge of the pregnancy. The event must be 
reported through the expedited AE reporting system via AdvantageEDCSM. 
 
The Investigator will follow the subject until completion of the pregnancy, and must report the 
outcome of the pregnancy and neonatal status as a follow-up to the original expedited AE report 
in AdvantageEDC. 
 
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, the Investigator must also immediately report the pregnancy as detailed above. Every 
effort should be made to follow the pregnancy for the final pregnancy outcome. 
 
4.4.3.6. 
Reporting of Second Primary Malignancies (SPMs) 
 
All second primary malignancies (SPM), excluding non-melanoma skin cancers, experienced by 
patients enrolled on the BMT CTN 1302 study must be reported within three business days of 
knowledge of the event using the Adverse Event forms (AE1-AE6) in AdvantageEDC. The Event 
Description of the Adverse Event forms should include histologic type. Reporting of SPMs in 
AdvantageEDC is required until all patients have completed 2 years of follow up. 
 
4.4.3.7 Adverse Event Reporting Following an SPM 
 
Adverse Event reporting following an SPM is dependent on the treatment received for the reported 
SPM. 
- 
If a patient experiences an SPM resulting in permanent discontinuation of maintenance 
and initiation of non-protocol systemic therapy, Unexpected Grade 3-5 Adverse Events 
and events listed in Appendix I are no longer required to be reported on the Adverse 
Event Form once the patient is more than 30 days from their last dose of maintenance. 
- 
If a patient experiences an SPM that does not result in permanent discontinuation of 
maintenance, Adverse Events will continue to be reported as per section 4.4.3 and 
Appendix I of the protocol. 
- 
Requests to discontinue Adverse Event Reporting for events that do not meet the 
criteria above will be considered on a case by case basis. 
 
4.4.4. 
CIBMTR Data Reporting 
 
Centers participating in BMT CTN trials must register pre- and post transplant outcomes on all 
consecutive hematopoietic stem cell transplants done at their institution during their time of 
participation to the Center for International Blood and Marrow Transplant Research (CIBMTR). 
Registration is done using procedures and forms of the Stem Cell Transplant Outcomes Database 
(SCTOD). (Note: Federal legislation requires submission of these forms for all US allotransplant 
recipients.) Enrollment in BMT CTN 1302 must be indicated on the SCTOD pre-transplant 
registration form. Additionally, CIBMTR pre- and post- transplant Comprehensive Report Forms 
must also be submitted for all patients enrolled on this trial. CIBMTR forms will be submitted 
directly to the CIBMTR at the times specified on the Form Submission Schedule. 


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Reporting of all SPMs is also required on CIBMTR follow up forms for patients during their 2- 
year participation on BMT CTN 1302, the extended follow-up period (until all patients have 
completed 2 years of follow up), and beyond. 


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CHAPTER 5 
5. 
STATISTICAL CONSIDERATIONS 
 
5.1. Study Design and Objectives 
 
The study is designed as a Phase II, randomized, multicenter double-blind, placebo controlled 
prospective comparative study of ixazomib maintenance therapy versus a placebo following 
allogeneic HCT for high risk multiple myeloma. The premise is that ixazomib will increase 
progression-free survival in patients as compared to a placebo. Patients will be enrolled prior to 
initiation of the conditioning regimen. Patients who are eligible at 60-120 days post transplant will 
be randomized to maintenance therapy or placebo and evaluated for the primary comparison of 
progression-free survival. Patients who are transplanted but not randomized will be followed for 
secondary endpoints. The target sample size is 110 patients randomized. We assume that 20% of 
patients will fail to meet criteria for randomization and so plan to enroll 138 patients receiving 
HCT in order to achieve the targeted number of randomized patients. Note that the conditioning 
regimen was changed in Version 2.0 of the protocol. The target sample size of 110 randomized 
patients was retained and the primary analysis will contain data from all randomized patients 
independent of the conditioning regimen. 
 
5.1.1. 
Accrual 
 
It is estimated that three years of accrual will be necessary to enroll the targeted sample size. 
 
5.1.2. 
Randomization 
 
Randomization will occur prior to initiation of maintenance therapy (approximately 60-120 days 
post transplant). Subjects eligible to initiate maintenance therapy will be randomized at a ratio of 
1:1 between the treatment arms using permuted blocks of random sizes. Randomization will be 
stratified on number of prior progressions (none versus one or more). 
 
5.1.3. 
Primary Endpoint 
 
The primary endpoint of this study is progression-free survival (PFS) post-randomization treated 
as a time to event endpoint. Subjects achieving randomization will be eligible for the primary 
comparison. Death from any cause, progression, or initiation of anti-myeloma therapy as defined 
in Chapter 3 will be considered events for this endpoint. Patients will be censored at 2-years post 
transplant. 
 
5.1.4. 
Primary Hypothesis 
 
The primary null hypothesis of the study is that there is no difference in time to PFS post- 
randomization among randomized subjects receiving Ixazomib vs. Placebo maintenance therapy. 
 
Ho: 
HRixazomib vs placebo≥1 
Ha: 
HRixazomib vs placebo<1 


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5.2. Sample Size and Power Calculations 
 
To estimate the baseline event rate and determine the sample size, we used data from the high risk 
stratum of BMT CTN 010245. BMT CTN 0102 defined high risk patients using presence of del13q 
by standard karyotyping or beta-2 microglobulin >4mg/L; 28 patients were biologically assigned 
to an autologoustransplant followed by an HLA-matched sibling transplant(auto-allo). The post- 
allogeneic transplant results are shown in Table 5.2.1. 
 
Table 5.2.1: BMT CTN 0102: Patients With High Risk Myeloma Assigned to Auto-Allo 
Transplantation 
 
0102 high risk allo 
(n=28)* 
All Patients 
PFS % 
Alive and free of disease at day 100 
PFS % (n=25) 
3 month 
89 
100 
6 month 
75 
84 
12 month 
61 
68 
18 month 
54 
60 
24 month 
50 
56 
*In this table, time points are post transplant 
 
The target sample size is 110 patients randomized. It is anticipated that 10% of subjects will 
experience an event (death or progression) prior to randomization and another 10% will be 
otherwise ineligible for maintenance, therefore, in order to achieve 110 randomized patients, we 
anticipate enrolling 138 transplanted patients. 
 
A piecewise-linear progression-free survival curve was assumed for randomized placebo subjects 
and fit to probabilities 85%, 70%, 60% and 55% at 3, 9, 15, and 21 months post-randomization 
(approximately 6, 12, 18, and 24 months post transplant). Table 5.2.2 shows the power to detect 
various hazard ratios for a one-sided log rank test with a type I error of 10%. The design assumes 
patients are randomized on approximately Day 90 and censored at 21 months post-randomization. 
Power calculations were performed using SAS version 9.3. 
 
Table 5.2.2: Probability of Rejecting the Null Hypothesis of Greater Than or Equal to 
Hazards in Placebo and Maintenance Arms 
 
Hazard Ratio among 
Randomized Subjects 
Ixazomib vs Placebo 
PFS Probability for 
Randomized Ixazomib Subjects 
at 21 Months Post- 
Randomization 
Probability 
of Rejecting 
Null 
Hypothesis 
0.37 
80.2% 
94.1% 
0.42 
77.8% 
89.9% 
0.48 
75.0% 
82.8% 
0.6 
69.9% 
63.5% 
1.00 
55.0% 
10% 


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By randomizing post transplant, the observed difference between treatment arms is more 
pronounced than if randomization occurred prior to transplant. As a secondary analysis, PFS from 
transplant for each maintenance strategy will also be estimated as described in section 5.6.3. As 
the main objective of this trial is to assess whether maintenance is a promising approach for high 
risk patients undergoing allogeneic transplantation, the type I error and primary hypothesis are 
one-sided to allow detection of an effect size in line with expected benefits of maintenance therapy. 
This is not intended to be a definitive trial but instead provide possible evidence of a benefit while 
exposing a limited number of subjects to the potential risks of maintenance therapy. 
 
5.3. Interim Analysis 
 
There will be no formal interim analysis for futility or efficacy for this trial. We will prospectively 
monitor the percentage of patients not achieving randomization to ensure feasibility and to monitor 
the assumptions included in the sample size and power considerations. Centers with such patients 
not enrolled by Day 90 will be contacted. Furthermore, the test described below will serve as a 
trigger to identify if the rate of non-randomization exceeds what is expected. 
 
Version 2.0 of the protocol changed the conditioning regimen by removing post-transplant 
bortezomib due to unanticipated early toxicities. Monitoring of the proportion of patients not 
achieving randomization will be restarted among patients transplanted with the new regimen. This 
approach allows the new transplant regimen to be monitored independently of the original 
regimen, as the new regimen is anticipated to have less toxicity and, thus, likely a higher proportion 
of patients achieving randomization. 
 
The proportion of patients not achieving randomization by Day 120 will be monitored using a 
binomial Sequential Probability Ratio Test (SPRT). Monitoring for non-randomization will be 
performed monthly beginning after the third month of enrollment until four months after the last 
subject is transplanted. At least three events must be observed in order to trigger review. The 
binomial SPRT can be represented graphically. At each monthly interim analysis, the sufficient 
statistics are plotted against each other, with total number of patients on the y-axis and the total 
number of observed events on the x-axis. The continuation region of the test is defined by two 
parallel lines. Only the upper boundary will be used to protect against an excess proportion of 
non-randomized patients. If the graph rises above the upper boundary, the SPRT rejects the null 
hypothesis, and concludes that there are more non-randomized patients than predicted by the total 
number of patients who have reached the evaluation time point. Otherwise, the SPRT continues 
until the last subject has reached the evaluation time point for that guideline. 
 
A SPRT contrasting 20% versus 30% 120-day incidence of non-randomization results in decision 
boundaries with a common slope of 0.248 and an upper intercept of 3.63, with nominal type I and 
II errors of 12% and 15%, respectively. 
 
The actual operating characteristics of this truncated test, shown in Table 5.3.1, were determined 
in a simulation study that assumed uniform accrual of 138 individuals over a three-year time period 
and the last monitoring occurred at month 40 (3 years plus 120 days). 


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Table 5.3.1: Operating Characteristics of Sequential Testing Procedure From a Simulation 
Study With 100,000 Replications 
 
Proportion of Eligible Patients Not Randomized at Day 120 
 
True 120-Day Rate 
20% 
23% 
27% 
30% 
Probability Reject Null 
0.09 
0.26 
0.63 
0.84 
Mean Month Stopped 
38.2 
34.9 
27.6 
21.8 
Mean # Not Randomized by Day 120 
26.2 
27.3 
24.5 
20.6 
Mean # Patients Enrolled 
131.0 
118.5 
90.8 
68.9 
 
The testing procedure for non-randomization rejects the null hypothesis in favor of the alternative 
9% of the time when the true 120 day rate is 20%, and 84% of the time when the rate is 30%. This 
corresponds to a type I error rate of  = 0.09 and a type II error rate of  = 0.16. On average, if 
the true rate of non-randomization is 30%, the DSMB will be consulted 22 months after the trial 
has opened, when 21 patients did not achieve randomization out of 69 patients enrolled. 
 
5.4. Safety Stopping Guidelines 
 
Monitoring of key safety endpoints, Treatment Related Mortality (TRM) and aGVHD will be 
conducted monthly, and if rates significantly exceed pre-set thresholds, the NHLBI will be notified 
in order that the DSMB can be advised. Policies and composition of the DSMB are described in 
the BMT CTN's Manual of Procedures. The stopping guidelines serve as a trigger for consultation 
with the DSMB for additional review. The key safety endpoints to be monitored are the rate of 
TRM at Day 100 post-transplant in all transplanted subjects, Grades III-IV aGVHD at Day 100 
post-transplant, and Grades III-IV aGVHD rates at Day 60 post-randomization within treatment 
arm. Monitoring TRM post- transplant in all subjects will guard against poor outcomes resulting 
from the use of allogeneic transplants in high risk multiple myeloma subjects and monitoring the 
rate of severe aGVHD will allow assessment of severe transplant toxicity. Monitoring aGVHD 
rates post-randomization within treatment arm will protect against unexpectedly high aGVHD as 
a result of the maintenance therapy. Monitoring within arm will allow the DSMB to potentially 
close a single treatment arm if poor outcomes are observed. An extension of the sequential 
probability ratio test (SPRT) for censored exponential data will be used for monitoring, as 
described in greater detail below and in Appendix I. 
 
5.4.1. 
TRM at Day 100 PostTransplant Stopping Guideline 
 
The TRM stopping guideline below was restarted with the implementation of Version 2.0 of the 
protocol to allow the safety monitoring to be conditioning regimen-specific, i.e., the guideline 
below will focus on participants receiving the new conditioning regimen only. Note that due to the 
small number of randomized participants prior to Version 2.0 of the protocol, the sample size 
estimate for the stopping guideline was retained at 138, as that itself is an estimate based off an 
assumption of 20% transplanted, but not randomized. 


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This sequential testing procedure conserves type I error at 5% across all of the monthly 
examinations for a treatment arm. The SPRT can be represented graphically. At each monthly 
interim analysis, the total time on study is plotted against the total number of endpoints (e.g., 
patients experiencing death without relapse/progression). The continuation region of the SPRT is 
defined by two parallel lines. Only the upper boundary will be used for monitoring to protect 
against excessive 100-day TRM. If the graph crosses the upper boundary, the SPRT rejects the 
null hypothesis, and concludes that there are more events than predicted by the observed time on 
study. Otherwise, the SPRT continues until enrollment reaches the maximum. 
 
This procedure assumes a censored exponential distribution for the time until TRM during the first 
100 days, and censors follow-up time after 100 days. Only deaths that occur on or before the 
patient has been followed for 100 days are counted. Total time on study is computed as time from 
transplant to death, or to 100 days, whichever comes first, summed for all patients on study. 
 
The usual measures of performance of an SPRT are the error probabilities  and  of rejecting H0 
when  = 0 and of accepting H1 when  = 1, respectively, and the expected sample size E(N|i). 
The tests to be used in this protocol were developed from the following SPRT: 
 
A SPRT contrasting 10% versus 25% 100-day TRM, which results in decision boundaries with a 
common slope of 0.66 and an upper intercept of 2.54, with nominal type I and II errors of 7% and 
10%, respectively. 
 
The actual operating characteristics of this truncated test, shown in Table 5.4.1, were determined 
in a simulation study that assumed uniform accrual of 138 individuals over a three-year time period 
with monitoring occurring monthly for 40 months 
 
Table 5.4.1: Operating Characteristics of Sequential Testing Procedure From a Simulation 
Study with 100,000 Replications 
 
Treatment-Related Mortality at Day 100 POST-TRANSPLANT 
 
True 100-Day Rate 
10% 
15% 
20% 
25% 
Probability Reject Null 
0.04 
0.35 
0.83 
0.98 
Mean Month Stopped 
39.7 
31.9 
18.7 
10.7 
Mean # Endpoints in 100 Days 
13.3 
16.2 
12.8 
8.8 
Mean # Patients Enrolled 
133.8 
109.9 
68.4 
40.9 
 
For example, the testing procedure rejects the null hypothesis in favor of the alternative 4% of the 
time when the true 100-day TRM incidence is 10%, and 98% of the time when the rate is 25%. 
This corresponds to a type I error rate of  = 0.04 and a type II error rate of  = 0.02. When the 
true 100-day TRM incidence is 20%, on average, the DSMB will be consulted 19 months after 
opening, when 13 events have been observed in 68 patients. 


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5.4.2. 
Acute GVHD at Day 100 Post-Tranpslant Stopping Guideline 
 
This monitoring guideline was added in Version 2.0 of the protocol. The purpose was to monitor 
for unanticipated severe aGVHD in the post-allogeneic transplant setting. Monitoring will be 
performed via the censored exponential SPRT. The hypothesis that post-randomization Day 100 
Grade III-IV aGVHD  10% will be tested against the alternative that it is > 10% each month. The 
SPRT contrasting 10% versus 25% results in decision boundaries with a common slope of 0.66 
and an upper intercept of 2.54, with nominal type I and II errors of 7% and 10%, respectively. The 
actual operating characteristics of this truncated test, shown in Table 5.4.2, were determined in a 
simulation study that assumed uniform accrual of 138 individuals over a three-year time period, 
with monitoring occurring monthly for 40 months 
 
TABLE 5.4.2: OPERATING CHARACTERISTICS OF SEQUENTIAL TESTING 
PROCEDURE FROM A SIMULATION STUDY WITH 100,000 REPLICATIONS 
 
ACUTE GVHD GRADE III-IV AT DAY 100 POST TRANSPLANT 
 
True 100-Day Rate 
10% 
15% 
20% 
25% 
Probability Reject Null 
0.04 
0.24 
0.83 
0.99 
Mean Month* Stopped 
39.7 
31.8 
18.7 
10.7 
Mean # Endpoints in 100 Days 
13.4 
16.2 
12.8 
8.8 
Mean # Patients Randomized 
133.8 
109.6 
68.5 
40.8 
*Time from Transplant 
 
For example, the testing procedure rejects the null hypothesis in favor of the alternative 4% of the 
time when the true 100-day Grade III-IV aGVHD rate is 10%, and 83% of the time when the rate 
is 20%. When the true Grade III-IV aGVHD rate is 20%, on average, the DSMB will be consulted 
19 months after transplantation begins, when 13 events have been observed in 69 patients. 
 
5.4.3. 
Acute GVHD at Day 60 Post-Randomization Stopping Guideline 
 
This monitoring guideline was modified in protocol Version 2.0 to shorten the assessment 
timeframe from 100 days to 60d days. The guideline will focus on all randomized patients 
independent of transplant regimen. 
 
A similar procedure will be applied to monitor for aGVHD Grades III-IV. The hypothesis that 
post-randomization Day 60 Grade III-IV aGVHD  8% will be tested against the alternative that 
it is > 8% each month. The SPRT contrasting 8% versus 23% results in decision boundaries with 
a common slope of 0.95 and an upper intercept of 2.24, with nominal type I and II errors of 7% 
and 10%, respectively. 
 
The actual operating characteristics of this truncated test, shown in Table 5.4.2, were determined 
in a simulation study that assumed uniform accrual of 55 individuals per arm over a three-year 
time period with monitoring occurring monthly for 38 months 


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Table 5.4.2: Operating Characteristics of Sequential Testing Procedure From a Simulation 
Study with 100,000 Replications 
 
Acute GVHD Grade III-IV at Day 100 
 
True 60-Day Rate 
8% 
13% 
18% 
23% 
Probability Reject Null 
0.04 
0.27 
0.63 
0.88 
Mean Month* Stopped 
37.0 
32.6 
25.0 
17.8 
Mean # Endpoints in 60 Days 
4.3 
6.1 
6.6 
6.0 
Mean # Patients Randomized 
53.6 
47.6 
37.3 
27.1 
*Time from Randomization 
 
For example, the testing procedure rejects the null hypothesis in favor of the alternative 4% of the 
time when the true 60-day Grade III-IV aGVHD rate is 8%, and 88% of the time when the rate is 
23%. This corresponds to a type I error rate of  = 0.04 and a type II error rate of  = 0.12. When 
the true Grade III-IV aGVHD rate is 18%, on average, the DSMB will be consulted 26 months 
after randomization begins, when 7 events have been observed in 37 patients. In the event that 
randomization is closed due to excess toxicity on one of the treatment arms, the alternate arm 
would remain open due to the importance of the secondary analysis as described in Section 5.6.3.2 
 
5.5. Demographics and Baseline Characteristics 
 
Demographic and baseline characteristics will be summarized for all patients. Characteristics to 
be examined are: age, gender, race/ethnicity, Karnofsky/Lansky performance status, prior HCT, 
number of prior progressions, disease risk characteristics, disease response, donor type, time from 
transplant to initiation of maintenance therapy, and transplant regimen. Between groups 
comparisons will be performed for continuous variables via a non-parametric test and for 
categorical variables, via the chi-square test. 
 
5.6. Analysis Plan 
 
5.6.1. 
Analysis of the Primary Endpoint 
 
The primary outcome of the trial is progression-free survival post-randomization. Progression or 
initiation of anti-myeloma therapy (as defined in Chapter 3) and death from any cause will be 
considered as events. The primary analysis will be performed using a one-sided log-rank test with 
a type I error of 10% among patients randomized to either maintenance or placebo. Patients will 
be censored at 2-years post transplant. Due to the dual questions being addressed by this blinded 
study (effects of allogeneic transplant and effects of maintenance therapy post-allogeneic 
transplant), the primary analysis will be completed after all randomized subjects have been 
followed for two years post transplant allowing both questions to be addressed without risking 
premature unblinding. Note that while the transplant regimen was modified in Version 2.0 of the 
protocol, the primary analysis will include all randomized patients. A secondary sensitivity 
analysis will look at randomized patients stratified by transplant regimen, but is not powered to 
detect regimen effect. 


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5.6.2. 
Analysis of Secondary Endpoints 
 
5.6.2.1. 
Acute GVHD of grades III-IV 
 
Cumulative incidence of acute GVHD grades III-IV from randomization will be estimated using 
the cumulative incidence function, treating death prior to aGVHD as the competing risk. 
Cumulative incidence of aGVHD from randomization will be compared between treatment arms 
using Gray’s test. 
 
5.6.2.2. 
Chronic GVHD (cGVHD) 
 
Cumulative incidence of cGVHD from randomization will be estimated using the cumulative 
incidence function, treating death prior to cGVHD as the competing risk. Cumulative incidence of 
cGVHD from randomization will be compared between treatment arms using Gray’s test. 
 
5.6.2.3. 
Response to treatment 
 
Best response (sCR, CR, VGPR, or PR) after randomization will be compared between treatment 
groups using a chi-square test. Additionally, responses at 12 months and 18 months post- 
randomization will be assessed in each arm. These will be summarized separately for patients in 
CR at the time of randomization vs. those who were in less than a CR. Finally, best response at 
Day 60 (prior to randomization) will be reported for all transplanted patients. 
 
5.6.2.4. 
Progression 
 
Cumulative incidence of progression from randomization will be estimated using the cumulative 
incidence function, treating death in remission as a competing risk. Cumulative incidence of 
progression from randomization will be compared between the treatment arms using Gray’s test. 
 
5.6.2.5. 
Overall survival 
 
Overall survival (OS) from randomization will be estimated for each treatment group using the 
Kaplan-Meier estimator and compared between the groups using the log-rank test. 
 
5.6.2.6. 
Treatment-related mortality 
 
The event is death occurring from causes other than progression. Cumulative incidence of 
treatment-related mortality (TRM) from randomization will be estimated using cumulative 
incidence function, treating progression as a competing risk. Cumulative incidence of TRM from 
randomization will be compared between the treatment arms using Gray’s test. 
 
5.6.2.7. 
Incidence of toxicities grade  3 
All Grade  3 toxicities will be tabulated by grade for each treatment arm, by type of toxicity as 
well as the peak grade overall. Toxicity frequencies will be described for each time interval as 


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well as cumulative over time. The cumulative incidence of Grade  3 toxicity will be compared 
between treatment arms at 6, 12 and 18 months post randomization. 
 
5.6.2.8. 
Incidence of infections 
 
The number of infections and the number of patients experiencing infections will be tabulated by 
type of infection, severity, and time period after randomization. The cumulative incidence of 
severe, life-threatening, or fatal infections, treating death as a competing event, will be compared 
between the two treatment arms at 6, 12 and 18 months post randomization. 
 
5.6.2.9. 
Health Quality of Life 
 
Health quality of life will be described from time of pre transplant to time prior to randomization 
utilizing the FACT-BMT self report, transplant specific questionnaire and the generic quality of 
life tool, the SF-36. Comparisons between maintenance treatment groups will be performed prior 
to maintenance, 6 months after start of maintenance and at 24 months after transplant. Only 
English and Spanish speaking patients are eligible to participate in the HQL component of this 
trial 
 
5.6.2.10. Rate of Non-Randomization 
 
The proportion of patients not achieving randomization by Day 120 post allogeneic HCT will be 
reported. Reasons for not initiating maintenance will be described. 
 
5.6.3. 
Secondary Analysis – Time from Transplant 
 
The following secondary analyses focus on time from transplant and analysis in the event of a 
study arm closure. Note that with the change to the transplant regimen in Version 2.0, the 
following analyses will be modified to look at an effect within each maintenance strategy and 
estimate a regimen-specific effect within each maintenance strategy, although the study is not 
specifically powered to look at a regimen difference. 
 
5.6.3.1. 
Treatment Policy Estimation 
 
While time from randomization is used for the primary analysis, estimates of the primary and key 
secondary endpoints from time of transplant are also clinically relevant. A secondary analysis will 
estimate PFS and overall survival for each maintenance strategy using the inverse weighted 
estimators of Lunceford et al132. Similarly, cumulative incidence of aGVHD grade III-IV, chronic 
GVHD, progression, and TRM from transplant will be estimated for each maintenance strategy 
using the inverse weighted estimator of Yavuz133. 
 
This analysis is similar to that of a dynamic or adaptive treatment trial (please note this does not 
refer to an adaptive design) where responders to an upfront treatment are randomized after a period 
on trial to a second treatment. Here the response is eligibility for initiation of maintenance and 
there is only one upfront treatment (allogeneic transplant). This provides two possible treatment 
regimens: 1) allogeneic transplant followed by ixazomib for subjects able and willing to tolerate 


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maintenance and standard of care for all other subjects and 2) allogeneic treatment followed by no 
maintenance for eligible subjects and standard of care for other subjects. Note that under the second 
strategy all subjects receive standard of care. For this trial, three distinct groups of subjects exist: 
1) subjects randomized to ixazomib, 2) subjects randomized to no maintenance (i.e. placebo) and 
3) subjects not able or willing to be randomized. Weights are based on response and the inverse 
probability of being assigned to a treatment strategy. To estimate outcomes for the first treatment 
strategy (allogeneic transplant followed by ixazomib if possible), subjects randomized to ixazomib 
will receive a weight of 2, subjects not achieving randomization will receive a weight of 1, and 
subjects randomized to no maintenance will receive a weight of zero. Thus, the ixazomib treatment 
strategy is estimated based on a mixture of outcomes from subjects receiving ixazomib (who 
represent another similar subject who could have been randomized to ixazomib but was not) and 
those not achieving randomization. A similar weighted approach will be used for the allogeneic 
transplant followed by no maintenance treatment strategy. 
 
5.6.3.2. 
Analysis in the Event of Study Arm Closure. 
 
In addition to pre-specified monitoring guidelines for acute GVHD Grades II-IV. The DSMB 
periodically reviews interim data to ensure patient safety. If a decision is made to close a study 
arm due to excess or unanticipated toxicities (i.e. death, progression, GVHD, etc) there is clinical 
interest in continuing accrual to the alternative arm as the impact of allogeneic transplant in this 
patient population is not well established. 
 
For analysis purposes, continuing accrual when randomization has been closed will create four 
distinct groups of subjects: 1) Randomized to ixazomib, 2) Randomized to placebo, 3) Not 
Randomized, 4) Enrolled after randomization is closed. The weights from Lunceford et al are based 
on response, the probability of being randomized to one treatment or the other, and randomized 
treatment assignment. Non-randomized subjects are spread equally across treatment arms. As the 
probability of randomization is 0.5, a subject randomized to a maintenance strategy receives a 
weight of 2 compared to non-responders (weight of 1) and patients randomized to the alternate 
strategy (weight of 0). 
 
Consider the scenario where the ixazomib arm is closed and subjects continue to accrue to the 
placebo arm (a similar situation would apply if the placebo arm is closed). The weight for subject 
i is given by: Qi = 1 − Ri + π−1RiZi where Ri is a binary indicator for response, π is the 
randomization probability and Zi is a binary indicator of 0 for ixazomib and 1 for placebo. 
 
To estimate outcomes for allogeneic transplant followed by no maintenance, Group 1 subjects 
(Ri=1, Zi=0, π=0.5) would receive a weight of zero as their treatment was inconsistent with this 
strategy (Qi  = 1 − 1 + 0.5−1 ∗ 1 ∗ 0 = 0). Group 2 subjects (Ri=1, Zi=1, π=0.5) would receive a 
weight of 2 (Qi = 1 − 1 + 0.5−1 ∗ 1 ∗ 1 = 2) as their treatment was consistent, they responded 
and were randomized. Group 3 subjects (Ri=0 and Zi unknown) would receive a weight of 1 (Qi = 
1 − 0 + π−1 ∗ 0 ∗ Zi = 1) as they did not respond. Finally Group 4 subjects could be broken down 
into non-responders ((Ri=0) and responders (Ri=1, Zi=1, π=1). Note that the randomization 
probability is now 1 as both the randomization is closed and as a result all group 4 subjects would 


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receive a weight of 1 (Qi = 1 − 0 + π−1 ∗ 0 ∗ Zi = 1 for non-responders and Qi = 1 − 1 + 1−1 ∗ 
1 ∗ 1 = 1 for responders). 
 
As the primary hypothesis can no longer be feasibly tested the secondary analysis could still be 
powered based on a desired confidence interval width for PFS 2 years post-allogeneic transplant. 
The original sample size was 138 transplanted subjects with 110 randomized. Table 5.6.1 shows 
confidence interval widths based on a binomial proportion for a variety of sample sizes. The 
Kaplan-Meier estimate reduces to the binomial proportion in the absence of censoring and minimal 
censoring is anticipated given the short follow-up (2 years) and hard endpoint of progression or 
death. 
 
Table 5.6.1: 95% Confidence Interval Width for 2 Year Progression Free Survival 
Assuming a Probability of 0.5 and Minimal Censoring 
 
Number 
Transplanted 
Asymptotic 
Continuity Correction 
Width 
Lower 
Upper 
Width 
Lower 
Upper 
60 
0.25 
0.37 
0.63 
0.27 
0.37 
0.64 
70 
0.23 
0.38 
0.62 
0.25 
0.38 
0.62 
80 
0.22 
0.39 
0.61 
0.23 
0.38 
0.62 
90 
0.21 
0.40 
0.60 
0.22 
0.39 
0.61 
100 
0.20 
0.40 
0.60 
0.21 
0.40 
0.60 
110 
0.19 
0.41 
0.59 
0.20 
0.40 
0.60 
120 
0.18 
0.41 
0.59 
0.19 
0.41 
0.59 
138 
0.17 
0.42 
0.58 
0.17 
0.41 
0.59 
 
Note Table 5.6.1 is based on the variance for a binomial proportion of progression-free survival 
probability of 50% at 2 years based on the BMT CTN 0102 data. Actual width of the confidence 
interval may vary depending on the censoring pattern and number of patients in each of the 
groups. 


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A-1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX A 
PLASMA CELL LEUKEMIA RESPONSE CRITERIA 


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APPENDIX A 
PLASMA CELL LEUKEMIA RESPONSE CRITERIA 
 
Stringent Complete Response (sCR): 
sCR required in addition to CR (defined below), all of the following: 
• Absence of malignant plasma cells in the bone marrow by flow cytometry 
• Absence of malignant plasma cells in peripheral blood by flow cytometry 
• Normal free light chain ratio (FLC) 
 
Complete Response (CR) 
CR requires all of the following: 
• Less than 5% plasma cells in a bone marrow aspirate 
• Absence of plasma cells in peripheral blood 
• Absence of the original monoclonal paraprotein in serum and urine by routine 
electrophoresis and by immunofixation1. 
• Absence of extramedullary disease 
 
Very Good Partial Response (VGPR) 
VGPR requires all of the following: 
• Less than 5% plasma cells in a bone marrow aspirate 
• Absence of plasma cells in the peripheral blood 
• Greater than or equal to 90% reduction of serum monoclonal paraprotein plus paraprotein 
<100 mg/24hrs2 
• Absence of extramedullary disease 
 
Partial Response (PR) 
Partial response requires all of the following: 
• Between 5% and 25% plasma cells in a bone marrow aspirate 
• Between 1% and 5% plasma cells in the peripheral blood 
• Greater than or equal to 50% reduction of serum monoclonal paraprotein and reduction in 
24- hour urinary monoclonal paraprotein by greater than or equal to 90% plus less than 
200 mg/24hr3 
 
 
1 If the serum and urine M-Protein are unmeasurable, a normal serum kappa/lambda FLC ratio is also required. 
2 If the serum and urine M-Protein are unmeasurable, a greater than or equal to 90% decrease in the difference between 
involved and uninvolved FLC levels is required instead of the M-Protein. 
3 If the serum and urine M-Protein are unmeasurable, a great than or equal to 50% decrease in the difference between 
involved and uninvolved FLC levels is required instead of the M-Protein. 


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• Greater than or equal to 50% reduction in the size of extramedullary disease 
 
Stable Disease (SD) 
• Patients who do not meet the criteria for sCR, Cr, VGPR, PR or progressive disease 
(defined below) are considered to have stable disease (SD) 
 
Progressive Disease (PD) 
Progressive disease requires on or more of the following. 
• Greater than 25% increase in the plasma cells in a bone marrow aspirate, or an absolute 
increase of greater than or equal to 10% 
• Greater than 5% absolute increase in plasma cells in the peripheral blood 
• Greater than 25% increase in the level of the serum monoclonal paraprotein with an 
absolute increase of greater than or equal to 5 g/L 
• Greater than 25% increase in the 24-hour urine protein electrophoresis with an absolute 
increase of at least 200 mg/24 hours 
• Hypercalcemia 
• Definite increase in lytic bone lesions 
• Definite increase in the size or number of extramedullary disease. 


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APPENDIX B 
PATIENT INFORMED CONSENT FORM 


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Version 3.0 dated December 19, 2017 
B-2 
 
 
 
Informed Consent to Participate in Research 
 
 
 
 
 
Your Name: 
  
 
 
 
Study Title: 
Multicenter Phase II, Double-Blind Placebo Controlled Trial of 
Maintenance Ixazomib after Allogeneic Hematopoietic Stem Cell 
Transplantation for High Risk Multiple Myeloma 
 
Protocol: 
BMT CTN 1302 
 
Principal 
Investigator: 
Insert local PI information 
 
Sponsor: 
The National Institutes of Health (NIH) is sponsoring this study by 
providing financial support for the coordination of this study through the 
Blood and Marrow Transplant Clinical Trials Network (BMT CTN). 


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1. Introduction 
 
We invite you to join this clinical trial, also known as a research study. You are being asked to 
join because: 
 
▪ You are at least 18 and no older than 70 years of age. 
 
▪ You have high risk multiple myeloma (MM), a cancer of the plasma cells that begins in 
your bone marrow, OR your MM returned after an autologous transplant. 
 
▪ You have a closely matched related or unrelated peripheral blood stem cell donor. 
 
Because there’s no cure for MM, maintenance treatment (chemotherapy) is given to slow the 
return of your disease after an allogeneic transplant. We are doing this study to learn if 
maintenance treatment (chemotherapy) works better to control your disease than placebo (pill 
that doesn’t have any active maintenance drugs). 
 
For this study, the type of allogeneic transplant you will get is called a peripheral blood stem 
cell (PBSC) transplant. Your doctor also wants to use a reduced-intensity or non- 
myeloablative conditioning regimen for your transplant. 
 
This study will take at least 3 years and will include 138 participants. Your participation will last 
2 years. After that time, selected additional data will be collected until all patients on the study 
have been followed for 2 years. 
 
This Consent Form will tell you about the purpose of the study, the possible risks and benefits, 
other options available to you, and your rights as a participant in the study. 
 
Everyone who takes part in research at [insert facility name] should know that: 
 
▪ Being in any research study is voluntary. 
 
▪ You may or may not benefit from being in the study. Knowledge we gain from this study 
may benefit others. 
 
▪ If you join the study, you can quit the study at any time. 
 
▪ If you decide to quit the study, it will not affect your care at [insert name of facility or 
institution]. 
 
▪ Please ask the study staff questions about anything that you do not understand, or if you 
would like to have more information. 


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▪ You can ask questions now or any time during the study. 
 
▪ Please take the time you need to talk about the study with your doctor, study staff, and your 
family and friends. It is your decision to be in the study. If you decide to join, please sign and 
date the end of the Consent Form. 
 
You and your doctor will discuss other treatment choices if you do not want to participate in this 
study. 
 
2. Study Background 
 
The National Institutes of Health (NIH), through the Blood and Marrow Transplant Clinical 
Trials Network (BMT CTN), are providing staff support and money for this research study. The 
BMT CTN and the NIH will make decisions about how to manage the study. 
 
For this study, you will receive a type of allogeneic transplant called peripheral blood stem cell 
(PBSC) transplant. Allogeneic transplant is a common treatment for patients with high risk MM. 
Having high risk MM means that: 
 
▪ 
Your doctor found abnormal cells when he or she looked at the genetics of your bone marrow 
cells, OR 
 
▪ 
Your disease came back (relapsed) less than 24 months after an autologous transplant, OR 
 
▪ 
You have a fast growing type of myeloma called plasma cell leukemia. 
 
An allogeneic transplant uses blood-making cells from a family member or an unrelated donor to 
remove and replace your abnormal blood cells. With a PBSC transplant, the donor cells come 
from his or her blood stream. 
 
Your doctor also wants to use a reduced-intensity or non-myeloablative conditioning regimen for 
your transplant. The conditioning regimen is the chemotherapy used to destroy the diseased cells 
before you get your donor cells. A reduced-intensity or non-myeloablative conditioning regimen 
uses lower doses of chemotherapy. 
 
There’s no cure for MM. After transplant, the disease will almost always return, or relapse. Some 
patients may keep getting treatment after transplant called maintenance treatment. Maintenance 
treatment is given to slow down relapse. 


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3. Study Purpose 
 
We are inviting you to take part in this study because you have cancer of the plasma cells, your 
disease is high risk or relapsed after autologous transplant, and an allogeneic transplant is a 
treatment option for you. We are doing this study to learn more about ways to prevent or delay 
relapse of multiple myeloma (MM). 
 
We will use 2 treatments to see which one is better at preventing or delaying relapse of MM 
(Table 1). 
 
This study will help doctors make the best choice about treatment after allogeneic transplant for 
patients with MM. 
 
Table 1. Study Treatment Groups 
 
Treatment Group A (allogeneic transplant 
and experimental maintenance treatment) 
Treatment Group B (allogeneic transplant 
and no maintenance treatment) 
▪ 
Fludarabine 
▪ 
Melphalan 
▪ 
Bortezomib 
▪ 
Allogeneic peripheral blood stem cell 
transplant 
▪ 
Tacrolimus 
▪ 
Methotrexate 
▪ 
Ixazomib (experimental maintenance pill) 
▪ Fludarabine 
▪ Melphalan 
▪ Bortezomib 
▪ Allogeneic peripheral blood stem cell 
transplant 
▪ Tacrolimus 
▪ Methotrexate 
▪ 
Placebo (no maintenance) 
 
4. Rights to Ask Questions and/or Withdraw 
 
You have the right to ask questions about the study at any time. If you have questions about your 
rights as a participant or you want to leave the study, please contact: 
 
[insert contact info] 


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Being in this study is voluntary. You can choose not to be in this study or leave this study at any 
time. If you choose not to take part or leave this study, it will not affect your regular medical care 
in any way. 
 
Your study doctor and study staff will be available to answer any questions that you may have 
about taking part in or leaving this study. 
 
5. Study Treatment and Tests 
 
We will check your health before you start treatment, while you receive treatment, and for 2 
years after your transplant. After that time, selected additional data will be collected until all 
patients on the study have been followed for 2 years. 
 
Before You Start Your Treatment 
 
You will need to have several check-ups and tests to see if you can be in the study. All patients 
participating in this study need to have a matched donor. These check-ups and tests are part of 
your regular cancer and transplant care. You may need to have them even if you do not join the 
study. See Table 2. Timeline of Tests for Your Transplant for a schedule of when we will give 
you the physical tests. 
 
During Your Treatment 
 
Conditioning Regimen Before Transplant 
 
The conditioning regimen is the chemotherapy you will receive before you get your donor cells. 
This helps the donor cells start to grow and make new cells in your bone marrow (engraft). It 
also helps to kill cancer cells. The regimen includes fludarabine, melphalan, and bortezomib, 
given by intravenous infusion (IV) in your arm. How often you will get these drugs is shown in 
Table 3. 
 
1. Six days before your transplant, we will start giving you fludarabine, which you will get for 4 
days. 
2. Then, 4 days before your transplant, we will give you melphalan, which you will get for 2 
days. 
3. We will give you bortezomib once 3 days before your transplant. 
 
You will have check-ups during the conditioning regimen to see how well your organs are 
working. If your organs are not working properly, your doctor will lower the dose of the 
chemotherapy drugs. 


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▪ 
Infusion of Peripheral Blood Stem Cells (Transplant) 
 
On your transplant day (Day 0), the donor cells (stem cells) will be given to you through your 
catheter, like a blood transfusion. The cells will travel to your bone marrow where they will start 
to make healthy, new blood cells. 
 
Table 2. Timeline of Tests for Your Transplant 
 
Tests 
Weeks Before/After Transplant 
Days After 
Transplant 
-2 
1 
2 
3 
4 
5 
6 
7 
8 
9 
100 
120 
Medical history 
X 
Blood tests for cell counts, liver 
and kidney function 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Heart and lung function tests 
X 
Pregnancy test 
X 
Tests to see how much cancer 
you have 
X 
X 
X 
Bone marrow tests 
X 
X 
X 
Optional blood sample for 
future research (if you consent) 
X 
X 
X 
Optional bone marrow sample 
for research (if you consent) 
X 
Tests to see how many donor 
cells you have 
X 
Tests for GVHD 
X 
X 
X 
X 
X 
X 
X 
X X2 
X 
Questionnaire about your 
Quality of Life1 
X 
 
1English- and Spanish-speaking patients only. 
2Tests for GVHD will continue weekly until 14 weeks after transplant 


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Table 3: Timeline of Transplant and GVHD Drugs 
 
Drug 
Treatment Day 
-6 
-5 
-4 
-3 
-2 
-1 
0* +1 +3 +4 +6 +7 +8 
+11 
Fludarabine 
X 
X 
X 
X 
Melphalan 
X 
X 
Bortezomib 
X 
PBSC 
infusion 
X 
Tacrolimus 
Tacrolimus will be given on a timeline that is determined by the institution’s 
guidelines 
Methotrexate 
X 
X 
X 
X 
*Day 0 = day of transplant 
 
▪ GVHD Prevention Drugs 
 
You will be given drugs (tacrolimus and methotrexate) to prevent graft-versus-host disease 
(GVHD). GVHD is a common side effect of allogeneic transplant. It’s a medical condition that 
can become very serious. GVHD happens because of differences between your own immune 
cells (host) and the immune cells from your donor (graft). Your new immune system, or the 
donated cells, might see your cells as foreign and attack them. 
 
GVHD can cause: 
 
▪ 
Skin rashes 
 
▪ 
Nausea (feeling sick to your stomach) 
 
▪ 
Vomiting (throwing up) 
 
▪ 
Diarrhea 
 
▪ 
Liver damage 
 
▪ 
Hepatitis or jaundice 
 
▪ 
Increased risk of infection 


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We will give you tacrolimus by pill or IV beginning 3 days before your transplant. We will give 
you less and less until we stop it completely. This can take several months. 
 
After Your Transplant 
 
To prevent GVHD, we will also give you methotrexate by IV on Days 1, 3, 6, and 11 after your 
transplant (Table 3). 
 
We will test (evaluate) your health during the study. You will be watched closely for any signs 
and symptoms of GVHD. See Table 2. Timeline of Tests for Your Transplant for a schedule 
of when we will give you the physical tests. 
 
Before Your Maintenance Treatment 
 
At least 14 days before you start maintenance therapy, we will check to make sure you are 
healthy enough to start maintenance treatment. See Table 4. Timeline of Tests for Your 
Maintenance Treatment for a schedule of when we will give you the physical tests. If you are 
not healthy enough to start maintenance therapy, you will continue to be followed on this study 
until two years after your transplant regardless of what treatment you receive. 
 
Randomization 
 
We will use a computer program to assign you by chance to treatment group A or B. You won’t be 
able to choose your group. Once you are assigned to a group, you can’t change to the other group. 
The study doctor can’t change your group either. You will have an equal chance of being placed in 
either group. 
 
During Your Maintenance Treatment 
 
▪ 
Treatment Group A: Ixazomib 
 
If you are assigned to Treatment Group A, we will give you ixazomib as a pill on Days 1, 8, and 
15 of each cycle (28 days in each cycle). This means that you will take ixazomib once a week for 
3 weeks, and then have 1 week off. We will repeat the cycle 12 times or for about 1 year. 
 
▪ Treatment Group B: Placebo 
 
If you are assigned to Treatment Group B, we will give you the placebo as a pill (sugar pill). The 
placebo pills will look exactly like ixazomib, but don’t have any drugs or treatment. We will give 
you the placebo pill on Days 1, 8, and 15 of each cycle (28 days in each cycle). This means that 
you will take the placebo once a week for 3 weeks, and then have 1 week off. We will repeat the 
cycle 12 times or for about 1 year. 


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▪ 
Maintenance Treatment Dose (Treatment Group A and B) 
 
It’s important that you take the pill at the same time with each dose. Also, you will have to keep a 
record of the pills you take. This means that you will write down what day and time you take every 
pill. 
 
We will watch your health closely during maintenance treatment, including how well your 
organs work (function). We will raise your dose for Cycle 4 if your organs handle the treatment 
well. We will lower your dose if your organs don’t handle the treatment well. 
 
We won’t start a new Cycle until your organ function returns to normal. If we lower your dose 
and then your organ function returns to normal, we won’t raise your dose again. 
 
We will stop the maintenance treatment if: 
 
▪ Your disease progresses 
 
▪ 
You have a serious side effect, like severe diarrhea or skin rash 
 
▪ You have low blood cell counts 
 
▪ You have serious GVHD 
 
▪ You are a woman and become pregnant, or there is a chance that you are pregnant 
 
▪ You go more than 56 days before starting a new maintenance treatment cycle 
 
▪ You are unable to complete 12 cycles of maintenance treatment within 18 months of starting 
therapy 
 
▪ You don’t follow the study directions, or 
 
▪ You choose to leave the study. 
 
We will watch your health closely, especially if we change your treatment dose. You will need to 
have several check-ups and tests during your maintenance treatment. These tests are shown in 
Table 4. Timeline of Tests for Your Maintenance Treatment. 


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Table 4. Timeline of Tests for Your Maintenance Treatment 
 
Tests 
Cycle (28 days in each cycle) 
Month1 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Follow 
Up 
18 
24 
Tests for 
toxicities, and 
infections 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tests for 
GVHD 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood tests for 
cell counts, 
liver and kidney 
function 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tests to see 
how many 
donor cells you 
have 
X 
X 
X 
Tests to see 
how much 
cancer you still 
have 
X 
X 
X 
X 
X 
X 
X 
Tests to see 
how well your 
immune system 
is recovering 
X 
X 
X 
X 
X 
X 
X 
X 
Bone marrow 
tests 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy 
blood test 
X 
Optional blood 
samples for 
research (if you 
consent) 
X 
X 
X 
X 
X 
Optional bone 
marrow samples 
for research (if 
you consent) 
X 
X 
Questionnaire 
about your 
Quality of Life2 
X 
X 
X 
X 
1After 24 months of follow up, patients will continue to be monitored for the development of new cancers. This follow 
up period will end when all patients have been followed for 2 years. 
2 English- and Spanish-speaking patients only. 


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6. Risks and Discomforts 
 
You may have side effects while on the study. Side effects can range from mild to serious. The 
risks and discomforts of peripheral blood stem cell transplant are the same if you join this study, 
or if you don’t join this study. 
 
You might do better or worse with a standard transplant. Your healthcare team may give you 
medicines to help with side effects like nausea (feeling sick to your stomach). In some cases, side 
effects can last a long time or may never go away. 
 
Risks of Medications 
 
The risks of the chemotherapy drugs, and or radiation you get as part of the treatment are listed 
below. How often patients get each of the side effects are shown in Table 5. Risks and Side 
Effects. 
 
All immune suppressive drugs, except for bortezomib and ixazomib, are commonly used in 
allogeneic transplant. 
 
Table 5. Risks and Side Effects 
 
Likely 
What it means: This type of side effect is expected in more than 20% 
of patients. This means that 21 or more patients out of 100 might get 
this side effect. 
Less Likely 
What it means: This type of side effect is expected in 20% of patients 
or fewer. This means that 20 patients or fewer out of 100 might get this 
side effect. 
Rare, but Serious 
What it means: This type of side effect is expected in fewer than 2% 
of patients. This means that 1 or 2 patients (or fewer) out of 100 might 
get this side effect. It doesn’t happen very often, but is serious when it 
does. 


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Melphalan 
 
Likely 
(May happen in more than 
20% of patients) 
Less Likely 
(May happen in less than 
20% of patients) 
Rare, but Serious 
(May happen in less than 2% 
of patients) 
▪ Loss of appetite 
▪ Constipation 
▪ Diarrhea 
▪ Nausea (feeling sick to 
your stomach) and 
vomiting (throwing up) 
▪ Temporary hair loss 
▪ Sensitive skin 
▪ Infection 
▪ Low number of white 
blood cells 
▪ Low number of platelets in 
the blood with increased 
risk of bleeding 
▪ Anemia (low number of 
red blood cells) 
▪ Mouth sores 
▪ Sore throat (red with 
swelling) 
▪ Skin breakdown (if drug 
leaks from vein) 
▪ Changes in heart beat 
that cause you to dizzy, 
faint and short of breath 
▪ Hepatitis (swelling of the 
liver) 
▪ Kidney failure 
▪ Weight loss 
▪ Feeling weak 
▪ Allergic reaction 
▪ Lung infection 
▪ Scarring of lung tissue 
▪ Seizure 
▪ Vasculitis (inflammation 
of blood vessels) 
▪ Low blood pressure 
▪ Excessive perspiration 
▪ Sterility (unable to have 
children) 
▪ Liver damage 
▪ Heart stops beating 
▪ Cancer of bone marrow 
cells 


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Bortezomib (Velcade®) 
 
Likely 
(May happen in more than 
10% of patients) 
Less Likely 
(May happen in less than 10% of 
patients) 
Rare, but Serious 
(May happen in less than 1% of 
patients) 
▪ Anemia (low number 
of red blood cells) 
▪ Low number of 
platelets in the blood 
with increased risk of 
bleeding 
▪ Feeling weak and 
uncomfortable 
▪ Feeling tired 
▪ Fever, with shaking 
chills 
▪ Weight loss because 
not feeling hungry 
▪ Constipation 
▪ Diarrhea 
▪ Nausea and vomiting 
▪ Upset stomach or pain 
in the belly 
▪ Pain, numbness and 
tingling in hands and 
feet 
• Lowered white blood 
cells called neutrophils 
that may increase your 
▪ Low number of white blood 
cells 
▪ Low blood pressure 
▪ Changes in heart beat and 
feeling dizzy, faint and short 
of breath 
• Heartburn, acid reflux and 
stomach bloating 
▪ Bleeding in stomach or lungs 
▪ Blood in urine 
▪ Fluid build-up around the 
lungs 
▪ Confusion 
▪ Mouth or throat sores 
▪ Changes in the way things 
taste 
▪ Abnormal liver tests 
▪ Blurred vision 
▪ Redness and swelling in the 
eye 
▪ Nose bleeds 
▪ Coughing up blood 
▪ Reversible posterior 
leukoencephalopathy 
syndrome [RPLS]/Posterior 
reversible encephalopathy 
syndrome [PRES] 
(headache, confusion, 
seizures, and vision loss 
caused by very high blood 
pressure that comes on 
quickly) 
▪ Hepatitis (swelling of the 
liver) and liver failure 
▪ Pancreatitis (swelling of the 
intestines, stomach, or 
pancreas) 
▪ Swelling and fluid build-up 
in and around the lungs or 
heart 
▪ Hearing loss 
▪ Bleeding in the brain 
▪ Loss of some or all vision in 
one or both eyes 


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Likely 
(May happen in more than 
10% of patients) 
Less Likely 
(May happen in less than 10% of 
patients) 
Rare, but Serious 
(May happen in less than 1% of 
patients) 
risk of infection and is 
uncommonly 
associated with fever; 
commonly you may 
have lowered white 
blood cells called 
lymphocytes or have 
lowered red blood 
cells, white blood cells 
and platelets at the 
same time. 
▪ Skin rash with itching 
and redness 
▪ Insomnia (trouble 
sleeping) 
▪ Anxiety (feeling 
worried and nervous) 
▪ Aches, pain and 
weakness in arm and 
leg muscles, joints and 
bones 
▪ Cough 
▪ Headache 
▪ Flu-like symptoms 
such as chills, sore 
throat, and runny nose 
▪ Edema (swelling in the 
arms and legs with 
weight gain) 
▪ Changes in blood sugar 
▪ Changes in levels of sodium, 
calcium and potassium in the 
blood 
▪ New or worse heart failure 
▪ Infections of the bladder, 
sinuses, mouth, throat, 
stomach, intestines and skin 
▪ Infections in the blood that 
can lead to death 
• Kidney function that gets 
worse 
• Fungal infections in the 
mucous membrane such as 
the mouth and throat and 
uncommonly in the skin and 
nails 
• Muscular weakness 
▪ Encephalopathy (brain 
disorder that can lead to 
death) 
▪ Sore mouth and throat 
▪ Allergic reactions (swelling, 
of the skin, face or throat) that 
can lead to death 
▪ Blistering rash with skin 
peeling and mouth sores that 
can lead to death 
▪ Pain, swelling and red skin 
where bortezomib is injected 
▪ Intestinal blockage 
▪ Fast death of cancer cells that 
can hurt organs like the 
kidneys 
▪ Severe muscle weakness and 
paralysis 


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Likely 
(May happen in more than 
10% of patients) 
Less Likely 
(May happen in less than 10% of 
patients) 
Rare, but Serious 
(May happen in less than 1% of 
patients) 
• Herpes virus such as 
shingles (herpes zoster) 
that can sometimes 
cause local pain that 
does not go away for a 
while and herpes 
simplex virus. 
Shingles can 
sometimes spread over 
large parts of the body. 
Both may also affect 
the eyes or brain, but 
this is uncommon 
• Hair loss 
 
 
Fludarabine 
 
Likely 
(May happen in more 
than 20% of patients) 
Less Likely 
(May happen in less than 
20% of patients) 
Rare, but Serious 
(May happen in less than 2% 
of patients) 
▪ Mouth sores 
▪ Nausea and vomiting 
▪ Diarrhea 
▪ Low number of white 
blood cells 
▪ Low number of 
platelets in the blood 
▪ Pain, numbness and 
tingling in the hands and 
feet 
▪ Feeling sleepy 
▪ Weakness 
▪ Changes in heartbeat 
▪ Loss of appetite 
▪ Coma 
▪ Inflammation of the lungs 
▪ Cough 
▪ Interstitial pneumonia (type 
of lung disease) 
▪ Agitation or nervousness 
▪ Confusion 


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with increased risk of 
bleeding 
▪ Anemia (low number 
of red blood cells) 
▪ Infection 
▪ Pneumonia 
▪ Fever, with chills 
▪ Swelling of hands and 
feet 
▪ Changes in vision 
▪ Cough 
▪ Skin rash 
▪ Severe brain injury and 
death 
▪ Kidney damage that could 
require dialysis 


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Methotrexate 
 
Likely 
(May happen in more than 20% 
of patients) 
Less Likely 
(May happen in less than 20% 
of patients) 
Rare, but Serious 
(May happen in less than 
2% of patients) 
▪ Low number of white blood 
cells 
▪ Infection 
▪ Feeling tired 
▪ Sensitivity to the sun 
(sunburn easily) 
▪ Bruise easily 
▪ Changes in skin 
▪ Mouth and throat sores 
▪ Loss of appetite 
▪ Diarrhea 
▪ Temporary hair loss 
▪ 
Nausea and vomiting 
▪ Abdominal pain 
▪ Fever, with chills 
▪ Anemia (low number of 
red blood cells) 
▪ Low number of platelets 
in the blood with 
increased risk of bleeding 
▪ Kidney damage or failure 
▪ High number of liver 
enzymes in the blood 
▪ Feeling dizzy 
▪ Inflammation of the 
lungs 
▪ Scarring of lung tissue 
▪ Changes in vision 
▪ Skin rash 


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Tacrolimus (FK506, Prograf®) 
 
Likely 
(May happen in more than 20% of 
patients) 
Less Likely 
(May happen in less than 
20% of patients) 
Rare, but serious 
(May happen in less than 
2% of patients) 
▪ Kidney problems 
▪ Low magnesium, calcium, and 
potassium in the blood 
▪ High blood pressure 
▪ Tremors (shaking) 
▪ High cholesterol 
▪ Low number of platelets in the 
blood with increased risk of 
bleeding 
▪ Infection 
▪ Nausea and vomiting 
▪ Liver problems 
▪ Foggy thinking 
▪ Trouble sleeping 
▪ Unwanted hair growth 
▪ Confusion 
▪ Reversible posterior 
leukoencephalopathy 
syndrome [RPLS]/ 
Posterior reversible 
encephalopathy 
syndrome [PRES] 
(headache, confusion, 
seizures, and vision 
loss caused by very 
high blood pressure 
that comes on quickly) 
▪ Seizures 
▪ Changes in vision 
▪ Feeling dizzy 
▪ The body stops making 
red blood cells (can lead 
to anemia) 
▪ Lymphoproliferative 
disorder (the body 
makes too many 
lymphocyte cells) 
 
It is very important that you do not eat grapefruit or drink grapefruit juice while taking 
Tacrolimus. Grapefruit has an ingredient called bergamottin, which can affect some of the 
treatment drugs used in this study. Common soft drinks that have bergamottin are Fresca, 
Squirt, and Sunny Delight. 


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Ixazomib (MLN9708) 
 
Likely 
(May happen in more than 
10% of patients) 
Less Likely 
(May happen in less than 10% 
of patients) 
Rare, but Serious 
(May happen in less than 
1% of patients) 
▪ Low number of platelets 
in the blood with 
increased risk of bleeding 
▪ Skin rash 
▪ Feeling tired 
▪ Feeling weak 
▪ Nausea and vomiting 
▪ Diarrhea 
▪ Constipation 
▪ Pain, numbness and 
tingling in hands and feet 
▪ Anemia (low number of 
red blood cells) 
▪ Low number of white 
blood cells 
▪ Infection 
▪ Loss of appetite 
▪ Lung infection 
(pneumonia) 
▪ Changes in levels of 
potassium, calcium, sodium, 
and magnesium in the blood 
▪ Flu-like symptoms such as 
chills, sore throat, runny nose, 
and sinus and throat infections 
▪ Kidney failure that can 
require dialysis 
▪ Shingles virus 
▪ Rash with skin peeling 
and mouth sores that can 
lead to death 
▪ Posterior reversible 
encephalopathy syndrome 
(PRES) (headache, 
confusion, seizures and 
vision loss caused by very 
high blood pressure that 
comes on quickly) 
▪ Progressive multifocal 
leukoencephalopathy 
(PML), a rare infection in 
the brain caused by a 
virus1 
▪ Inflammation of the 
spinal cord with damage 
to nerves 
▪ Fast death of cancer cells 
that can hurt organs like 
the kidneys 
▪ Heart muscle injury 
(congestive heart failure) 
or lung tissue damage that 
can lead to death 
▪ Liver failure 


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▪ Muscle weakness 
▪ Swelling of the hands, 
feet, ankles or lower legs 
▪ Upset stomach or pain in 
the belly or back 
▪ Low blood pressure 
1PML has been observed rarely (< 0.1%) in patients taking ixazomib. It is not known if ixazomib may contribute to 
the development of PML in this patient. 
 
Researchers for other studies of ixazomib are still watching patients to see how well they do on 
it. For this reason, there may be side effects that we don’t know about yet. Also, we don’t know 
if the side effects in the Less Likely group are caused by ixazomib, the patient’s disease, or other 
drugs. 
 
Ixazomib and bortezomib should not be taken if you have ever had an allergic reaction to 
boron or products that contain boron. Other drugs and supplements may affect the way 
Ixazomib works. It’s important to tell your doctor about all drugs and treatments (for example, 
over-the-counter medicines and vitamins) you are taking while you are in this study. 
 
Previous Experience with Bortezomib 
 
The doctors who are conducting the study have gained some experience with a similar 
conditioning regimen used earlier in this study. They found that some patients who received 4 
doses of bortezomib suffered a higher rate of expected severe side effects (including death) 
within 30 days of transplant. Because of these unanticipated early complications, the study 
doctors have reduced the number of doses of bortezomib given as a part of this study to one for 
new patients. 
 
Risk to the Unborn 
The treatments in this study have not been proven to be safe at any stage of pregnancy or nursing 
(breast feeding). If you are pregnant or nursing, you can’t join this study. 
 
Women and men must refrain from all acts of vaginal sex (abstinence) or use 2 types of effective 
birth control while receiving chemotherapy, drugs to prevent GVHD, and maintenance treatment. 
You must use effective birth control during the entire study and for 90 days after stopping 
maintenance treatment. Effective birth control is defined as the following: 
 
1. Consistent use of birth control pills 


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2. Injectable birth control methods (Depo-Provera, Norplant) 
 
3. Tubal sterilization or male partner who has undergone a vasectomy 
 
4. Placement of an IUD (intrauterine device) 
 
5. Use of a diaphragm with contraceptive jelly and/or condoms with contraceptive foam every 
time you have sex. 
 
You do not need to use effective birth control only if you are a woman and cannot have children 
because you: 
 
▪ Had an effective tubal ligation (your tubes were tied), OR 
 
▪ Had a hysterectomy (your ovaries and uterus were removed), OR 
 
▪ Went through menopause (post-menopausal; i.e., have not had a menstrual period for at least 
12 consecutive months). 
 
Reproductive Risks 
 
The drugs used in this research study may damage your reproductive organs, affect your ability to 
have children, or cause birth defects if you take them while you are pregnant or nursing. 
 
Both women who can become pregnant and their male partners should use birth control while on 
this study and for 90 days after maintenance treatment is stopped. If you or your partner 
becomes pregnant during this study, you must tell the study doctor immediately. 
Your doctor will discuss the risks to your unborn child and options with you. 
 
It is important that females who aren’t pregnant or nursing don’t become pregnant while part of 
the study. If you are a woman and become pregnant while on this study, we will stop the 
maintenance treatment drug right away. 
 
Your study doctor will watch your health closely while you are pregnant. 
 
▪ 
Females who join the study 
If you are female and can become pregnant, you will need to take a pregnancy test before you 
start the study. You should discuss ways to prevent pregnancy while you’re in the study. Some 
women might experience irregular menstrual cycles or their cycle might stop forever. This 
doesn’t mean that you can’t become pregnant. You must still use 2 effective forms of birth 
control during the study and continue with it for 90 days after you finish maintenance treatment. 


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Be sure to talk with your doctor about options for fertility planning, like storing your eggs, 
before starting chemotherapy treatment. 
 
▪ 
Males who join the study 
If you are male, your body may not be able to produce sperm (become sterile). Be sure to talk 
with your doctor about options for fertility planning, like banking your sperm, before starting 
chemotherapy treatment. 
 
Risks of Transplant 
 
The following problems may happen after transplant. These problems might happen if you have 
a transplant as part of the study or as standard care: 
 
Graft-Versus-Host Disease (GVHD) 
GVHD develops when the white blood cells, which are called T cells, in the donor cells attack 
your body. You are more likely to get GVHD if your donor’s tissue does not closely match your 
tissue. 
 
There are 2 kinds of GVHD: acute and chronic. Acute GVHD usually develops within the first 3 
months after transplant. Chronic GVHD usually develops later and lasts longer. 
 
You may experience these side effects with acute GVHD: 
 
▪ Skin rash 
 
▪ Nausea (feeling sick to your stomach) 
 
▪ Vomiting (throwing up) 
 
▪ Diarrhea 
 
▪ Abdominal (stomach area) pain 
 
▪ Problems with your liver (your doctor will run tests for this) 
 
▪ Infection 
 
You may experience these side effects with chronic GVHD: 
 
▪ Skin rash 
 
▪ Hair loss 


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▪ Thickened skin 
 
▪ Joint stiffness (knees, elbows, fingers) 
 
▪ Dry eyes 
 
▪ Dry mouth 
 
▪ Liver disease (your doctor will run tests for this) 
 
▪ Weight loss 
 
▪ Diarrhea 
 
▪ 
Infection 
 
We don’t know for sure if you will develop acute or chronic GVHD. The chance that you will 
get GVHD is 10-30%. This means that 10 to 30 people out of 100 might develop it. Your doctor 
will watch you closely for GVHD and treat it if it happens. 
 
To know for sure if you have acute or chronic GVHD, we may do a biopsy of your skin. A 
biopsy is where we take a small piece of your skin and look at it under a microscope for signs of 
GVHD. There’s a small chance that we might also do a biopsy of your intestine and liver. Risks 
of biopsy may include pain, infection, or bleeding. 
 
In most cases, GVHD can be treated. If GVHD does not respond to the drugs, your doctor will 
talk with you about other treatment options. If you choose a different treatment option, we will 
give you information about the side effects. 
 
You may need to be treated for GVHD for many months or years. GVHD treatments can cause 
your immune system to become very weak if it goes on for a long time. This means you may 
develop more infections and need to be admitted to the hospital often. GVHD can be very 
serious and hard to treat. It might also cause death. 
 
Slow recovery of blood counts 
The red blood cells, white blood cells, and platelets can be slow to recover after transplant. Until 
your blood counts recover, you will need blood and platelet transfusions. You’ll be at risk for 
bleeding and infections. We may give you a drug called Filgrastim to speed up the recovery of 
the white blood cells as much as possible and lower the chance of bleeding and infections. 
 
Graft (donor cells) failure or rejection 


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Some patients’ bodies reject the donor cells (graft) with an allogeneic transplant. Also, a certain 
amount of your old blood and marrow cells will remain in your body. 
 
If your body rejects the donor cells, your doctor may need to give you a donor lymphocyte 
infusion (DLI). A DLI is an extra dose of the donor cells. You may also get another transplant, 
but this is rare. If you need a DLI or second transplant, your doctor will explain the risks and 
benefits. 
 
Damage to the vital organs in your body 
Your vital organs include your heart, lungs, liver, intestines, kidneys, bladder and brain. The 
chemotherapy and GVHD drugs may hurt these organs. You may develop lung problems from 
chemotherapy or an infection. 
 
Some patients can have veno-occlusive disease (VOD) of the liver. Patients with VOD become 
jaundiced (yellow skin), have problems with their liver, retain too much water (feel swollen and 
uncomfortable), and have stomach swelling and pain. 
 
If there is serious damage to your vital organs, you may have to stay in the hospital longer or 
return to the hospital after your transplant. Many patients get better, but these complications can 
cause permanent damage to your organs or death. 
 
Serious infections 
It may take many months for your immune system to recover from the chemotherapy, GVHD 
and maintenance therapy drugs. There is an increased risk of infection during this time when 
your body is healing. We will give you drugs to reduce the chance of infection, but they may not 
work. If you have an infection, you may have to stay in the hospital longer or return to the 
hospital after transplant. Many patients get better, but some infections can cause death. 
 
Return of disease 
 
Your disease may come back even if the transplant is successful at first. Your doctor will discuss 
your treatment options with you if your disease returns and you are removed from study. 
 
Development of a new cancer 
 
In rare cases, a new type of cancer may develop from the donor cells. The risk of developing a new 
cancer after allogeneic transplant is less than 2% (1 or 2 patients (or fewer) out of 100). 
 
Unforeseen Risks 
New risks might appear at any time during the study. These risks might be different from what is 
listed in this Consent Form. We will promptly tell you about new information that may affect 


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your decision to take part in the study. We may learn new things about allogeneic transplants, 
GVHD prevention treatment, or maintenance treatment that might make you want to stop being in 
the study. If this happens, we will let you know so you can decide if you want to continue in the 
study. 
 
Other Treatments or Medicines 
 
Some medicines react with each other, and it is important that you tell the study doctor or staff 
about any other drugs, treatments, or medicines you are taking. This includes non-prescription or 
over-the-counter medicines, vitamins, and herbal treatments. 
 
It is also important that you tell the study staff about any changes to your medicines while you’re 
in the study. 
 
For more information about risks and side effects, ask your study doctor. 
 
7. Alternative Treatments 
 
Participation in this study is optional. If you choose not to take part, you may still receive non- 
transplant treatments or an autologous or an allogeneic transplant to treat your disease. The 
treatment and evaluations you would receive could be very similar to what would receive if you 
join this study. 
 
Your study doctor will talk with you about your options. If you decide not to participate in this 
study, your medical care will not be affected in any way. 
 
Your other choices may include: 
 
▪ Treatment with other drugs, radiation, or a combination of drugs and radiation without a 
transplant. 
 
▪ An allogeneic (donor) blood or marrow transplant that is not part of the study, or another 
type of transplant 
 
▪ Participation in another clinical trial, if available (check with your doctor) 
 
▪ No treatment for your blood cancer at this time 
 
▪ Comfort care 
 
Every treatment option has benefits and risks. Talk with your doctor about your treatment 
choices before you decide if you will take part in this study. 


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8. Possible Benefits 
 
Taking part in this study may or may not make your health better. The information from this 
study will help doctors learn more about drugs used to treat multiple myeloma. 
 
This information could help people with multiple myeloma who may need a transplant in the 
future. 
 
9. New Information Available During the Study 
 
During this research study, the study doctors may learn about new information about the study drugs 
or the risks and benefits of the study. If this happens, they will tell you about the new information. 
The new information may mean that you can no longer participate in the study, or that you may not 
want to continue in the study. 
 
If this happens, the study doctor will stop your participation in the study and will offer you all 
available care to suit your needs and medical conditions. 
 
10. 
Privacy, Confidentiality and Use of Information 
 
Your privacy is very important to us. The study doctors will make every effort to protect it. The 
study doctors have a privacy permit to help protect your records if there is a court 
case. However, some of your medical information may be given out if required by law. If this 
should happen, the study doctors will do their best to make sure that any information that goes 
out to others will not identify who you are. If information from this study is published or 
presented at scientific meetings, your name and other personal information will not be used. 
 
All your medical and demographic information (such as race and ethnicity, gender and 
household income) will be kept private and confidential. (Name of Transplant Center) and the 
organizations listed below will not disclose your participation by any means of communication 
to any person or organization, except by your written request, or permission, or unless required 
by federal, state or local laws, or regulatory agencies. 
 
Individuals authorized by the organizations below will have access to your research and medical 
information. They may use this information for inspections or audits to study the outcomes of 
your treatment. In agreeing to participate, you consent to such inspections and to the copying of 
parts of your records, if required by these organizations. 
 
Information about your transplant from your original medical records may be seen or sent to 
national and international transplant registries, including: 


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▪ /Institution/ 
 
▪ The Center for International Blood and Marrow Transplant Research (CIBMTR) 
 
▪ The National Marrow Donor Program (NMDP) 
 
▪ The Food and Drug Administration (FDA) 
 
▪ The National Institutes of Health (NIH), which include the National Heart, Lung, and Blood 
Institute (NHLBI) and the National Cancer Institute (NCI) 
 
▪ Data and Coordinating Center of the Blood and Marrow Transplant Clinical Trials Network 
(BMT CTN) 
 
▪ Data and Safety Monitoring Board (DSMB), not part of /Institution/ 
 
▪ Study investigators. 
 
▪ Millennium, its collaborators or designees 
 
We will not identify you by name in any publications or reports that come from these organizations 
or groups. 
 
Information that does not include personally identifiable information about this study has been or 
will be submitted, at the appropriate and required time, to the government-operated clinical trial 
registry data bank, which contains registration, results, and other information about registered 
studies. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. law. This website will not include information that can identify you. At most, the 
website will include a summary of the results. You can search this website at any time. 
 
Data regarding your clinical situation, including follow-up after 2 years, may be obtained from 
the CIBMTR, which captures information on all U.S. transplants. 
 
For questions about access to your medical records, please contact /name/ at /number. 
 
11. 
Ending Your Participation 
 
The study doctor or the study sponsor may stop the study at any time, and we may ask you to 
leave the study. We may ask you to leave the study if you do not follow directions or if you 
suffer from side effects of the treatment. If we ask you to leave the study, the reasons will be 
discussed with you. Possible reasons to end your participation in this study include: 


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▪ You do not meet the study requirements. 
 
▪ You need a medical treatment not allowed in this study. 
 
▪ The study doctor decides that it would be harmful to you to stay in the study. 
 
▪ You are having serious side effects. 
 
▪ You become pregnant. 
 
▪ You cannot keep appointments or take study drugs as directed. 
 
▪ The study is stopped for any reason. 
 
You could have serious health risks if you stop treatment during the conditioning process before 
you receive your transplant. If you stop taking the immune suppressing drugs (see Section 6: 
Risks and Discomforts) too soon after transplant, your body could reject the donor stem cells or 
you could develop serious complications and possibly die. 
 
We ask that you talk with the research doctor and your regular doctor before you leave the study. 
Your doctors will tell you how to stop safely and talk with you about other treatment choices. 
 
If you decide to leave this study after getting the study treatment, or are asked to leave by your 
doctor for medical reasons, you will need to come back to the doctor’s office for tests for your 
safety. Even if you leave the study, the information collected from your participation will be 
included in the study evaluation, unless you specifically ask that it not be included. 
 
12. 
Physical Injury as a Result of Participation 
 
It is important that you tell your doctor, 
 
[investigator's name(s)] or study 
staff if you feel that you have been injured because of taking part in this study. You can tell the 
doctor in person or call him/her at 
[telephone number]. 
 
You will get all available medical treatment if you are injured from taking part in this study. You 
and/or your health plan will be charged for this treatment. The study will not pay for medical 
treatment. 
 
In case you are injured in this study, you do not lose any of your legal rights to ask for or receive 
payment by signing this form. 
 
13. 
Compensation or Payment 


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You will not be paid for your participation in this research study. You will not get compensation or 
reimbursement for any extra expenses (travel, meals, etc.) you may have through your participation 
on this trial. 
 
Your participation in this research study may contribute to the development of commercial 
products from which Millennium Pharmaceuticals, Inc. or others, may derive an economic 
benefit. You will have no rights to any patents or discoveries arising from this research, and you 
will receive no economic benefit. 
 
14. 
Costs and Reimbursements 
 
Most of the visits for this research study are standard medical care for your allogeneic transplant 
and will be billed to your insurance company. You and/or your health plan/insurance company 
will need to pay for some or all of the costs of standard treatment in this study. The study drugs 
bortezomib, ixazomib, and placebo will be provided by Millennium at no cost to you or your 
insurance. 
 
You or your insurance will not be charged for optional blood samples for research on this study. 
You will not pay for any extra tests that are being done for the study. Some health plans will not 
pay these costs for people taking part in studies. Check with your health plan or insurance 
company to find out if they will pay. 
 
For questions about your costs, financial responsibilities, and/or medical insurance coverage for 
your transplant and this study, please contact /Center/ Financial Counselor at /Number/. 
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage. You can 
print a copy of the “Clinical Trials and Insurance Coverage” information from this Web site. 
 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them 
to send you a free copy. 
 
15. 
For More Information 
 
If you need more information about this study, or if you have problems while taking part in this 
study, you can contact the study doctor or his/her staff. 
 
They can be reached at the telephone numbers listed here: 
[Insert name and contact details] 


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16. 
Contact Someone about Your Rights 
 
If you wish to speak to someone not directly involved in the study, or if you have any complaints 
about any aspect of the project, the way it is being conducted or any questions about your rights as a 
research participant, then you may contact: 
 
[Insert appropriate contact details] 
 
The ethical aspects of this study have been reviewed and approved by [name of IRB]. 
 
17. 
Blood and Tissue Samples for Future Research (Optional) 
 
This section of the informed consent form is about future research studies that will use blood and 
tissue samples from people who are taking part in the main study. You may choose to give 
samples for these future research studies if you want to. You can still be a part of the main study 
even if you say 'no' to give samples for future research studies. 
 
Researchers are trying to learn more about how the human body processes the drugs used for 
transplant and how the body recovers after transplant. This research is meant to gain knowledge 
that may help people in the future and make transplants even more successful. 
 
If you agree to provide blood and tissue samples, here is what will happen: 
 
▪ We will collect extra blood samples at the same time you have routine blood tests done. The 
amount of blood collected from you is about 7 teaspoons (36 mL) each time. 
 
▪ We will collect blood samples at seven different dates in the study (see Tables 3 and 4): 
 
o 2 weeks or less before transplant 
 
o 4 weeks after transplant 
 
o 2 weeks before maintenance treatment is started 
 
o Cycles 2, 5 and 10 of maintenance treatment 
 
o 28 days or less after your last dose of maintenance treatment 
 
▪ We will collect three bone marrow tissue samples at the same time you have routine bone 
marrow biopsies done. The amount of tissue collected from you is about 2 teaspoons (10 mL) 
each time. We will collect samples at three different dates in the study (see Tables 3 and 4): 
 
o 2 weeks or less before transplant 


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o 2 weeks before maintenance treatment is started 
 
o 28 days or less after your last dose of maintenance treatment 
 
▪ Some of your samples will be stored and some will be used for research right now. The 
samples to be stored will be sent to the BMT CTN Repository for processing and storage. A 
repository is a place that protects, stores, and sends out samples for approved research 
studies. All seven of the blood samples will be sent to the BMT CTN Repository to be stored. 
A small amount of three out of the seven blood samples will be sent to Roswell Park Cancer 
Institute for a research study looking at how fast your immune system recovers after the 
transplant. There were will be no additional blood samples collected. All research samples, 
including the ones that will be stored, will be given a barcode that cannot be linked to you by 
future researchers testing your samples.  The link between your patient identification and 
your sample barcode will be held in your study records at [Insert Site Name] only. 
 
▪ The liquid bone marrow collected will be sent to the BMT CTN Repository and to Roswell 
Park Cancer Institute for testing. The bone marrow samples going to the BMT CTN 
Repository will be processed and stored similar to blood samples. The bone marrow samples 
sent to Roswell Park Cancer Institute will be tested to detect multiple myeloma cells. This 
test is called minimal residual disease and it will assist in understanding how much this 
treatment is controlling the cancer. 
 
▪ Materials stored in the Repository will be used mainly by clinicians and researchers in the 
BMT CTN network. In the future, the unused research samples and clinical data will be made 
available outside of this network. 
 
▪ Researchers can apply to study the materials stored in the Repository. The BMT CTN 
Steering Committee and/or the BMT CTN Executive Committee must approve each request 
before they will share samples or information with researchers. This is to make sure that the 
investigators requesting the samples are qualified, and that the research is of high quality. 
 
▪ DNA from your stored blood samples might be used in genome-wide association (GWA) 
studies for a future project either done or supported by the National Institutes of Health 
(NIH). Genome-wide association studies are a way for scientists to find genes that have a 
role in human disease or treatment. Each study can look at hundreds of thousands of genetic 
changes at the same time. 
 
If your coded samples are used in such a study, the researcher is required to add your test 
results and sample information into a shared, public research database. This public 
database is called the NIH Genotype and Phenotype Database and it is managed by the 


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National Center for Biotechnology Information (NCBI). The NCBI will never have any 
information that would identify you, or link you to your information or research samples. 
 
Some general things you should know about letting us store your blood samples for research are: 
 
▪ We will only store samples from people who give us permission. 
 
▪ Research is meant to gain knowledge that my help people in the future. You will not get any 
direct benefit from taking part. Additionally, you or your doctor will not be given results and 
they will not be added to your medical record. 
 
▪ A possible risk is the loss of confidentiality about your medical information. We will use 
safety measures with both your samples and clinical information to make sure that your 
personal information will be kept private. The chance that this information will be given to 
someone else is extremely small. 
 
▪ Your blood and tissue samples will be used only for research and will not be sold. The 
research done with your blood may help to develop new products in the future. You will not 
get paid for any samples or for any products that may be developed from current or future 
research. 
 
You can change your mind at any time about allowing us to use your samples and health 
information for research. 
 
We ask that you contact [Principal Investigator] in writing and let him/her know you do not want 
us to use your research samples or health information for research. His/her mailing address is on 
the first page of this form. However, samples and information that have already been shared with 
other researchers cannot be taken back or destroyed. 
 
Making Your Choice 
 
Please read each sentence below and think about your choice. After reading each sentence, 
please indicate your choice below. If you have any questions, please talk to your doctor or nurse, 
or call our research review board at 
. 
 
No matter what you decide to do, it will not affect your care. 
 
Statement of Consent for Research Samples 
The purpose of storing blood and tissue samples, the procedures involved, and the risks and 
benefits have been explained to me. I understand that if I provide consent, the liquid part of my 
bone marrow will be assessed for minimal residual disease and that my blood samples will be 
used to assess how quickly my immune system recovers. I have asked all the questions I have at 


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this time and I have been told whom to contact if I have more questions. I have been told that I 
will be given a signed copy of this consent form to keep. 
 
I understand that I do not have to allow the use of my blood and tissue for research. If I decide to 
not let you store research samples now or in the future, it will not affect my medical care in any 
way. 
 
I voluntarily agree that my blood, tissue, and information can be stored indefinitely by the BMT 
CTN and/or NHLBI Repositories for research to learn about, prevent, or treat health problems. I 
also understand that my DNA and health information may or may not be used in genome-wide 
association studies. 
 
Blood 
 
❑ I agree to allow my blood samples to be stored for future and immune reconstitution research. 
 
❑ I do not agree to allow my blood samples to be stored for future and immune reconstitution 
research. 
 
Bone marrow 
 
❑ I agree to allow my bone marrow tissue samples to be stored for future and MRD research. 
 
❑ I do not agree to allow my bone marrow tissue samples to be stored for future and MRD 
research. 
 
 
 
 
Signature 
Date 


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Health Insurance Portability and Accountability Act 1 (HIPAA1) Authorization to use and 
disclose individual health information for research purpose 
 
A. Purpose: 
 
As a research participant, I authorize the Principal Investigators and the researcher’s staff to use 
and disclose my individual health information for the purpose of conducting the research study: 
 
A Multi-Center Phase II, Double-blind Placebo Controlled Trial of Maintenance Ixazomib after 
Allogeneic Hematopoietic Cell Transplantation for High Risk Multiple Myeloma 
 
B. Individual Health Information to be Used or Disclosed: 
 
My individual health information that may be used or disclosed to do this research includes: 
 
▪ Demographic information (for example, date of birth, sex, weight) 
 
▪ Medical history (for example, diagnosis, complications with prior treatment) 
 
▪ Findings from physical exams 
 
▪ Laboratory test results obtained at the time of work up and after transplant (for example, 
blood tests, biopsy results) 
 
C. Parties Who May Disclose My Individual Health Information: 
 
The researcher and the researcher’s staff may collect my individual health information from: 
 
[List hospitals, clinics or providers from which health care information can be requested] 
 
D. Parties Who May Receive or Use My Individual Health Information: 
 
The individual health information disclosed by parties listed in item c and information disclosed 
by me during the course of the research may be received and used by the following parties: 
 
Dr. Parameswaran Hari, Co-Principal Investigator 
Dr. Taiga Nishihori, Co-Principal Investigator 
Dr. Qaiser Bashir, Co-Principal Investigator 
 
 
 
 
 
1 HIPAA is the Health Insurance Portability and Accountability Act of 1996, a federal law related to privacy of health information 


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Millennium, its collaborators or designees 
Study Sponsors 
▪ National Heart, Lung, and Blood Institute (NHLBI) and the National Cancer Institute (NCI), 
both of the National Institutes of Health (NIH), 
 
▪ Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Data and Coordinating 
Center 
 
▪ U.S. government agencies that are responsible for overseeing research such as the Food and 
Drug Administration (FDA) and the Office of Human Research Protections (OHRP) 
 
▪ U.S. government agencies that are responsible for overseeing public health concerns such as 
the Centers for Disease Control (CDC) and federal, state and local health departments. 
 
E. Right to Refuse to Sign this Authorization: 
 
I do not have to sign this Authorization. If I decide not to sign the Authorization, I will not be 
allowed to participate in this study or receive any treatment related to research that is provided 
through the study. 
 
My decision not to sign this authorization will not affect any other treatment, payment, or 
enrollment in health plans or eligibility for benefits. 
 
F. Right to Revoke: 
 
I can change my mind and withdraw this authorization at any time by sending a written notice to 
the Principal Investigator to inform the researcher of my decision. 
 
If I withdraw this authorization, t he researcher may only use and disclose the protected health 
information already collected for this research study. No further health information about me 
will be collected by or disclosed to the researcher for this study. 
 
G. Potential for Re-disclosure: 
 
My individual health information disclosed under this authorization may be subject to re- 
disclosure outside the research study and no longer protected. 
 
Examples include potential disclosures for law enforcement purposes, mandated reporting or 
abuse or neglect, judicial proceedings, health oversight activities and public health measures. 


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H. Genetic Information Nondiscrimination Act (GINA) 
 
A new federal law (2009), called the Genetic Information Nondiscrimination Act (GINA) 
generally makes it illegal for health insurance companies, group health plans, and employers of 15 
or more persons to discriminate against you based on your genetic information. 
 
Health insurance companies and group health plans may not request your genetic information that 
we get from this research. This means that they must not use your genetic information when 
making decisions regarding insurability. Be aware that this new federal law will not protect you 
against genetic discrimination by companies that sell life insurance, disability insurance, or long- 
term care insurance. 
 
I. This authorization does not have an expiration date. 


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TITLE: A Multi-Center Phase II, Double-Blind Placebo Controlled Trial of Maintenance 
Ixazomib after Allogeneic Hematopoietic Cell Transplantation for High Risk Multiple Myeloma 
PROTOCOL NUMBER: BMT CTN #1302 
PRINCIPAL INVESTIGATOR: 
Name: 
Address: 
Email: 
Phone: 
Fax: 


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Version 3.0 dated December 19, 2017 
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I have read and understood this Consent Form. The nature and purpose of the research study has 
been explained to me. 
▪ I have had the chance to ask questions, and understand the answers I have been given. I 
understand that I may ask questions at any time during the study. 
▪ I freely agree to be a participant in the study. 
▪ I understand that I may not directly benefit from taking part in the study. 
▪ I understand that, while information gained during the study may be published, I will not be 
identified and my personal results will stay confidential. 
▪ I have had the chance to discuss my participation in this research study with a family member 
or friend. 
▪ I understand that I can leave this study at any time, and doing so will not affect my current care 
or prevent me from receiving future treatment. 
▪ I understand that I will be given a copy of this signed consent form. 
 
 
Participant Name 
Date 
 
 
Signature 
Date 
 
I certify that I have provided a verbal explanation of the details of the research study, including 
the procedures and risks. I believe the participant has understood the information provided. 
 
Name of Counseling Physician 
Date 
 
 
Signature of Counseling Physician 
Date 


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APPENDIX C 
LABORATORY PROCEDURES 


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LABORATORY PROCEDURES 
 
Collection of OPTIONAL Samples for Future Ancillary Studies 
Bone marrow aspirate and blood will be collected from patients who signed consent to provide 
samples for minimal residual disease (MRD) testing and future research. Sample collection will 
be done at the transplant center and will require minimum processing. Once the samples are 
collected at specified time points they will be shipped on the day of collection to the BMT CTN 
Central Processing Laboratory for final processing and storage at the BMT CTN Research Biologic 
Repository, and for bone marrow aspirates an aliquot will be submitted to the Department of Flow 
and Image Cytometry at Roswell Park Cancer Institute. These samples will be tracked through 
GlobalTrace. 
 
• Bone Marrow Aspirate Samples 
Patients who consented for marrow sample collection for MRD and future research studies 
will have 10 mL of bone marrow aspirate collected at three time points (1) baseline 
(preferably in one single procedure along with standard of care aspirate collection prior to 
allogeneic transplant), (2) prior to initiation of maintenance (time of randomization), and 
(3) < 28days after the last dose of study drug during maintenance. Samples will be collected 
in heparin anticoagulant coated tubes. Two aliquots of bone marrow aspirate will be 
collected; the first aliquot of 2-4mL will be used for MRD testing, the second aliquot of 6- 
8mL will be collected for future research. The first tube for MRD testing will be shipped 
to the project laboratory at Roswell Park Cancer Institute (RPCI). The second tube will be 
shipped to the BMT CTN Central Processing Laboratory for further processing and storage. 
Both tubes are shipped at ambient temperature. These samples will be tracked through 
GlobalTrace. 
 
• Peripheral Blood Research Specimens 
Patients who consented for peripheral blood sample collection for future research studies 
will have 36 mL blood samples collected at 7 time points: (1) baseline (at enrollment), (2) 
28 days after transplant (3) prior to initiation of maintenance (time of randomization), (4- 
6) at the start of the 2nd, 5th and 10th cycle of maintenance therapy and (7) < 28 days after 
the last dose of study drug during maintenance. An aliquot of 10mL from the 30 mL 
collected for PBMC preparation will be directed to immune reconstitution studies at the 
RPCI laboratory. The time points that the PBMC sample should be aliquotted are: 
 
(1) prior to initiation of maintenance (time of randomization), (2) at the start of 5th cycle of 
maintenance therapy and (3) ≤ 28 days after the last dose of study drug during maintenance. 


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SCHEDULE OF LABORATORY EVALUATIONS 
 
Type of Sample 
Type of Processing 
Dates Samples Obtained 
Shipping Specifications 
Storage 
Location 
Patient 
Research Bone 
Marrow 
Aspirate 
10 mL bone 
marrow aspirate 
Collect bone marrow 
aspirate sample and 
place in a 10 mL fill, 
green top plastic BD 
Vacutainer® tube, 
containing Sodium- 
Heparin anticoagulant. 
Gently mix sample by 
inversion 8-10 times to 
mix sample well with 
heparin anticoagulant. 
At enrollment, ≤ 14 days prior to 
initiation of maintenance1, and ≤ 28 
days after the last dose of maintenance 
study drug. 
Bone marrow aspirate 
sample will be shipped at 
ambient temperature on the 
day of collection, to the 
BMT CTN Research 
Repository by priority 
overnight FED EX delivery 
for processing and final 
frozen storage of marrow 
aliquots. 
BMT CTN 
Research 
Repository 
No additional sample 
processing is required. 
Bone Marrow 
2-4 mL bone 
Processed as part of the 
At enrollment, ≤ 14 days prior to 
Bone marrow aspirate 
- 
Aspirate for 
marrow aspirate 
original 10 mL bone 
initiation of maintenance1, and ≤ 28 
sample will be shipped at 
MRD testing 
(aliquot of 2-4 
marrow aspirate as 
days after the last dose of maintenance 
ambient temperature on the 
mL from the 
described above. 
study drug. 
day of collection, to the 
initial bone 
Department of Flow and 
marrow aspirate 
Image Cytometry at 
collected, as 
Roswell Park Cancer 
above) 
Institute by priority 
overnight FED EX delivery 
for immunophenotyping. 


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Type of Sample 
Type of Processing 
Dates Samples Obtained 
Shipping Specifications 
Storage 
Location 
Patient 
Research 
Peripheral 
Blood 
Specimen 
(Serum) 
6 mL peripheral 
blood 
Collect blood sample in 
a Red/Gray Top BD 
SST™ Tube with Silica 
Clot Activator & 
Polymer Gel. Let 
sample sit upright in 
rack for 30 minutes. 
Centrifuge for 10 
minutes. Gel barrier 
will form separating the 
serum specimen from 
clot. Prepare tube for 
transport along with 
other research samples. 
At enrollment, 28 days after transplant, 
≤ 14 days prior to initiation of 
maintenance1, at the start of the 2nd, 5th, 
and 10th cycles of maintenance therapy, 
and < 28 days after the last dose of 
maintenance study drug. 
Serum blood tube will be 
shipped at ambient 
temperature on the day of 
collection, to the BMT 
CTN Research Repository 
by priority overnight FED 
EX delivery for processing 
and final frozen storage of 
serum aliquots. Guidelines 
for specimen handling and 
shipment to the BMT CTN 
Central Processing 
Laboratory/BMT CTN 
Research Repository is 
detailed in the 1302 
Research Sample Guide. 
BMT CTN 
Research 
Repository 
Patient 
Research 
Peripheral 
Blood 
Specimen 
(PBMC) 
30 mL 
peripheral blood 
Collect peripheral 
blood sample in three 
10 mL fill, green top 
plastic BD Vacutainer® 
tube, containing 
Sodium-Heparin 
anticoagulant. Gently 
mix sample by 
inversion 8-10 times to 
mix sample well with 
heparin anticoagulant. 
No additional sample 
processing is required. 
At enrollment, 28 days after transplant, 
≤ 14 days prior to initiation of 
maintenance1, at the start of the 2nd, 5th, 
and 10th cycles of maintenance therapy, 
and < 28 days after the last dose of 
maintenance study drug. 
PBMC blood tubes will be 
shipped at ambient 
temperature on the day of 
collection, to the BMT 
CTN Research Repository 
by priority overnight FED 
EX delivery for processing 
and final frozen storage of 
isolated viable PBMC 
aliquots. Guidelines for 
specimen handling and 
shipment to the BMT CTN 
Central Processing 
Laboratory/BMT CTN 
Research Repository is 
detailed in the 1302 
Research Sample Guide. 
BMT CTN 
Research 
Repository 


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Type of Sample 
Type of Processing 
Dates Samples Obtained 
Shipping Specifications 
Storage 
Location 
Peripheral 
Blood 
Specimen for 
Immune- 
reconstitution 
(PBMC) 
10 mL 
peripheral 
blood2 
Collect peripheral 
blood sample in one 10 
mL fill, green top 
plastic BD Vacutainer® 
tube, containing 
Sodium-Heparin 
anticoagulant. Gently 
mix sample by 
inversion 8-10 times to 
mix sample well with 
heparin anticoagulant. 
No additional sample 
processing is required. 
≤ 14 days prior to initiation of 
maintenance1, at the start of the 5th 
cycle of maintenance therapy, and ≤ 28 
days after the last dose of maintenance 
study drug. 
PBMC sample will be 
shipped at ambient 
temperature on the day of 
collection, to the 
Department of Flow and 
Image Cytometry at 
Roswell Park Cancer 
Institute by priority 
overnight FED EX delivery 
for immunophenotyping. 
- 
1Optional blood and bone marrow samples must be collected ≤ 14 days prior to the initiation of maintenance therapy. The samples should be collected AFTER 
randomization and BEFORE initiation of maintenance therapy, however samples collected prior to randomization that fall within this window may be accepted. 
2The collection of PBMC for immune reconstitution will be an aliquot of the 30 mL collected for future research at the time points specified above. 


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APPENDIX D 
HCT-SPECIFIC COMORBIDITY INDEX SCORE 


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HCT-SPECIFIC COMORBIDITY INDEX SCORE 
 
Comorbidities 
Definition 
Score 
Migraine/headache 
0 
Osteoporosis 
0 
Osteoarthritis 
0 
Hypertension 
0 
Gastrointestinal 
Including inflammatory bowel disease 
0 
Mild pulmonary 
DLCo and/or FEV1 >80% or 
Dyspnea on moderate activity 
0 
Mild renal 
Serum creatinine 1.2-2 mg/dl 
0 
Endocrine 
0 
Bleeding 
0 
Coagulopathy 
Deep venous thrombosis or pulmonary embolism 
0 
Asthma 
0 
Arrhythmia 
1 
Myocardial 
Coronary artery disease, congestive HF, history of 
medically documented MI, EF50% 
1 
Mild hepatic 
Chronic hepatitis, Bilirubin >ULN- 1.5 X ULN, or 
AST/ALT >ULN-2.5XULN 
1 
Cerebro-vascular 
accident 
History of transient ischemic attack or cerebro-vascular 
accident 
1 
Morbid obesity 
1 
Diabetes 
Requiring treatment 
1 
Depression/anxiety 
1 
Infection 
Requiring continuation of treatment after Day 0 
1 
Rheumatologic 
SLE, RA, polymyositis, mixed CTD, polymyalgia 
rheumatica 
2 
Moderate pulmonary 
DLCo and/or FEV1 66-80% or 
Dyspnea on slight activity 
2 
Peptic ulcer 
Patients who have required treatment 
2 
Moderate-severe renal 
Serum creatinine >2 mg/dl, on dialysis, or prior renal 
transplantation 
2 
Valvular heart disease 
Except mitral valve prolapse 
3 
Prior solid tumor 
Requiring treatment with chemotherapy 
3 
Moderate-severe hepatic 
Liver cirrhosis, Bilirubin >1.5 X ULN, or AST/ALT 
>2.5XULN 
3 
Severe pulmonary 
DLCo and/or FEV1 65% or 
Dyspnea at rest or requiring oxygen 
3 
Total score is the sum of all comorbidities present at time of transplantation. 


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APPENDIX E 
KARNOFSKY PERFORMANCE STATUS SCALE 


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KARNOFSKY PERFORMANCE STATUS SCALE 
 
Index 
Specific Criteria 
General 
100 
Normal, no complaints, no evidence of 
disease. 
Able to carry on normal activity; 
no special care needed. 
90 
Able to carry on normal activity, minor signs 
or symptoms of disease. 
80 
Normal activity with effort, some signs or 
symptoms of disease. 
70 
Care for self, unable to carry on normal 
activity or to do work. 
Unable to work, able to live at 
home and care for most personal 
needs, varying amount of 
assistance needed. 
60 
Requires occasional assistance from others but 
able to care for most needs. 
50 
Requires considerable assistance from others 
and frequent medical care 
40 
Disabled, requires special care and assistance. 
Unable to care for self, requires 
institutional or hospital care or 
equivalent, disease may be rapidly 
progressing. 
30 
Severely disabled, hospitalization indicated, 
but death not imminent. 
20 
Very sick, hospitalization necessary, active 
supportive treatment necessary. 
10 
Moribund 
0 
Dead 


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APPENDIX F 
NEW YORK HEART ASSOCIATION (NYHA) 
CLASSIFICATION OF CARDIAC DISEASE 


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NEW YORK HEART ASSOCIATION (NYHA) 
CLASSIFICATION OF CARDIAC DISEASE 
 
The following table presents the NYHA classification of cardiac disease. 
 
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 
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 G 
HUMAN SUBJECTS 


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G-2 
 
 
 
 
HUMAN SUBJECTS 
 
1. Subject Consent 
 
A conference will be held with the patient and family to discuss this study and alternative 
treatments available for the treatment of the underlying disease. The conference will be conducted 
by the Principal Investigator or other designated physician. Potential risks associated with the 
study interventions should be discussed as objectively as possible. Consent will be obtained using 
an IRB-approved consent. 
 
The BMT CTN will provide a template of the consent form to each center. Each center will 
customize the template according to their local requirements and submit it for review by the local 
Internal Review Board (IRB). The DCC will verify the adequacy of the consent forms prior to 
submission to the IRB. Each center must provide evidence of IRB approval. 
 
 
2. Confidentiality 
 
Confidentiality will be maintained by individual names being masked and assigned a patient 
identifier code. The code relaying the patient’s identity with the ID code will be kept separately 
at the center. The ID code will be transmitted to the network. 
 
 
3. Participation of Women and Minorities and Other Populations 
 
Women and ethnic minorities and other populations will be included in this study. Accrual of 
women and minorities at each center will be monitored to determine whether their rates of 
enrollment are reflective of the distribution of potentially eligible women and minorities expected 
from data reported to the CIBMTR and from published data on incidence of MM in these groups. 
Centers will be notified if their rates differ significantly from those expected and asked to develop 
appropriate recruitment strategies. 


BMT CLINICAL TRIALS NETWORK 
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H-1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX H 
KNOWN ANTICIPATED RISKS OF BORTEZOMIB 


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Table H-1 
Known Anticipated Risks of Bortezomib by MedDRA System Organ Class, 
Observed Incidence, and Preferred Term 
System Organ Class- Observed Incidence 
Preferred Term 
Blood and Lymphatic System Disorders 
Most common 
Thrombocytopenia*, anemia* 
Very common 
Neutropenia* 
Common 
Lymphopenia, pancytopenia*, leukopenia*, febrile 
neutropenia 
Cardiac Disorders 
Common 
Tachycardia, atrial fibrillation, palpitations, cardiac 
failure congestive* 
Uncommon 
Cardiogenic shock*, atrial flutter, cardiac tamponade*, 
bradycardia, atrioventricular block complete, arrhythmia, 
cardiac arrest, cardiac failure, arrhythmia, pericardial 
effusion, pericarditis, pericardial disease, 
cardiopulmonary failure 
Ear and Labyrinth Disorders 
Uncommon 
Deafness, hearing impaired 
Eye Disorders 
Common 
Blurred vision, conjunctivitis, conjunctival hemorrhage 
Gastrointestinal Disorders 
Most common 
Constipation, diarrhea*, nausea, vomiting* 
Very common 
abdominal pain (excluding oral and throat) 
Common 
Dyspepsia, pharyngolaryngeal pain, gastroesophageal 
reflux, abdominal distension, gastritis, stomatitis, mouth 
ulceration, dysphagia, gastrointestinal hemorrhage*, 
lower gastrointestinal hemorrhage*± rectal hemorrhage 
Uncommon 
Eructation, gastrointestinal pain, tongue ulceration, 
retching, upper gastrointestinal hemorrhage*, 
hematemesis*, oral mucosal petechiae, ileus paralytic*, 
ileus, odynophagia, enteritis, colitis, esophagitis, 
enterocolitis, diarrhea hemorrhagic, acute pancreatitis*, 
intestinal obstruction 
General Disorders and Administration Site Conditions 
Most common 
Fatigue, pyrexia 
Very common 
Chills, edema peripheral, asthenia 
Common 
Neuralgia, lethargy, malaise, chest pain, mucosal 
inflammation* 
Uncommon 
Injection site pain, injection site irritation, injection site 
phlebitis, general physical health deterioration*, 
catheter-related complication 
Hepatobiliary Disorders 
Uncommon 
Hyperbilirubinemia, hepatitis* 


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Table H-1 
Known Anticipated Risks of Bortezomib by MedDRA System Organ Class, 
Observed Incidence, and Preferred Term 
System Organ Class- Observed Incidence 
Preferred Term 
Immune System Disorders 
Uncommon 
Drug hypersensitivity, angioedema 
Infections and Infestations 
Very common 
Upper respiratory tract infection, nasopharyngitis, 
pneumonia*, Herpes zoster* 
Common 
Lower respiratory tract infection*, sinusitis, pharyngitis, 
oral candidiasis, urinary tract infection*, sepsis, 
bacteremia*, cellulitis, Herpes simplex, bronchitis, 
gastroenteritis*, infection 
Uncommon 
Septic shock*, catheter-related infection*, skin 
infection*, Herpes zoster disseminated*, lung infection, 
infusion site cellulitis, catheter site cellulitis, infusion 
site infection, urosepsis*, Aspergillosis*, tinea infection, 
Herpes zoster ophthalmic, Herpes simplex ophthalmic, 
meningoencephalitis herpetic, varicella, empyema, 
fungal esophagitis 
Injury, Poisoning, and Procedural Complications 
Common 
Fall 
Uncommon 
Subdural hematoma 
Investigations 
Common 
Weight decreased, alanine aminotransferase (ALT) 
increased, aspartate aminotransferase (AST) increased, 
blood alkaline phosphatase increased, liver function test 
abnormal, blood creatinine increased* 
Uncommon 
Gamma-glutamyltransferase (GGT) increased, oxygen 
saturation decreased*, blood albumin decreased, ejection 
fraction decreased* 
Metabolism and Nutritional Disorders 
Very common 
Decreased appetite, anorexia, dehydration* 
Common 
Hyperglycemia, hypoglycemia, hyponatremia, 
hypokalemia, hypercalcemia* 
Musculoskeletal and Connective Tissue Disorders 
Very common 
Bone pain, myalgia, arthralgia, back pain 
Common 
Muscular weakness 
Uncommon 
Limb discomfort 
Neoplasms, Benign, Malignant, and Unspecified (including cysts and polyps) 
Uncommon 
Tumor lysis syndrome* 


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Table H-1 
Known Anticipated Risks of Bortezomib by MedDRA System Organ Class, 
Observed Incidence, and Preferred Term 
System Organ Class- Observed Incidence 
Preferred Term 
Nervous System Disorders 
Most common 
Peripheral neuropathy (including all preferred terms 
under the MedDRA High-level term Peripheral 
neuropathy NEC) 
Very common 
Paresthesia, dizziness excluding vertigo, headache 
Common 
Polyneuropathy, syncope, dysesthesia, dysgeusia, 
postherpetic neuralgia 
Uncommon 
Convulsion, loss of consciousness, ageusia, 
encephalopathy, paralysis*, autonomic neuropathy, 
reversible posterior leukoencephalopathy syndrome, 
posterior reversible encephalopathy syndrome  
Psychiatric Disorders 
Very common 
Anxiety, insomnia 
Common 
Confusional state 
Uncommon 
Delirium 
Renal and Urinary Disorders 
Common 
Renal impairment*, renal failure*, hematuria 
Uncommon 
Micturition disorder 
Respiratory, Thoracic, and Mediastinal Disorders 
Very common 
Cough, dyspnea 
Common 
Epistaxis, dyspnea exertional, pleural effusion*, 
rhinorrhea, hypoxia*, pulmonary edema 
Uncommon 
Hemoptysis*, acute respiratory distress syndrome*, 
respiratory failure*, pneumonitis*, lung infiltration, 
pulmonary alveolar hemorrhage*, interstitial lung 
disease*, pulmonary hypertension*, pleurisy, pleuritic 
pain 
Skin and Subcutaneous Tissue Disorders 
Very common 
Rash, alopecia 
Common 
Rash pruritic, rash erythematous, urticaria, petechiae 
Uncommon 
Cutaneous vasculitis, leukocytoclastic vasculitis 
Vascular Disorders 
Common 
Hypotension*, orthostatic hypotension 
Uncommon 
Cerebral hemorrhage* 
Source: VELCADE® (bortezomib) for Injection Investigator’s Brochure Edition 16. 
Most common =  30%, Very common = 10% to 29%, Common = 1% to 9%, Uncommon = < 1%. 
* Fatal outcomes have been reported. 
 Indicates a Preferred term not listed in the source table, however the event is deemed medically important and so is included. 
 Effective MedDRA update to version 14.0, the term ‘reversible posterior leukoencephalopathy syndrome’ updated to ‘posterior 
reversible encephalopathy syndrome (PRES)’. 


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Table H-2 
Reports of Adverse Reactions From Postmarketing Experience 
System Organ Class- Preferred Term 
Observed 
Incidencea 
Blood and lymphatic system disorders 
Disseminated intravascular coagulation 
Rare 
Cardiac Disorders 
Atrioventricular block complete 
Rare 
Cardiac tamponade 
Rare 
Ear and labyrinth disorders 
Deafness bilateral 
Rare 
Eye Disorders 
Ophthalmic herpes 
Rare 
Optic neuropathy 
Rare 
Blindness 
Rare 
Gastrointestinal Disorders 
Acute pancreatitis 
Rare 
Ischemic colitis 
Rare 
Hepatobiliary disorders 
Hepatitis 
Uncommon 
Liver failure 
Unknown 
Infections and infestations 
Herpes meningoencephalitis 
Rare 
Septic shock 
Rare 
Progressive multifocal leukoencephalopathy 
Very rare 
Immune System Disorders 
Angioedema 
Rare 
Nervous System Disorders 
Autonomic neuropathy 
Rare 
Dysautonomia 
Unknown 
Encephalopathy 
Rare 
Respiratory, thoracic and mediastinal disorders: 
Acute diffuse infiltrative pulmonary diseaseb 
Rare 
Acute respiratory distress syndrome (ARDS) 
Rare 
Interstitial pneumonia 
Rare 
Lung infiltration 
Rare 


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H-6 
 
 
 
 
Pneumonitis 
Rare 
Pulmonary hypertension 
Rare 
Skin and subcutaneous system disorders 
Acute febrile neutrophilic dermatosis 
Unknown 
Toxic epidermal necrolysis 
Unknown 
Source: VELCADE® (bortezomib) for Injection Investigator’s Brochure Edition 16. 
a Incidence is assigned using the following convention: very common ( 1/10); common ( 1/100 and  1/10); uncommon ( 1/1000 
and  1/100); rare ( 1/10,000 and  1/1000 ); very rare ( 1/10,000, including isolated reports). 
b Acute diffuse infiltrative pulmonary disease is a MedDRA Lower Level Term which corresponds to a Preferred Term of Interstitial 
lung disease. 


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APPENDIX I 
ADVERSE EVENT REPORTING 


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APPENDIX I 
ADVERSE EVENT REPORTING 
I.1 Adverse Event Reporting 
 
Adverse events (AEs) will be collected on calendar-driven forms and event-driven forms in 
AdvantageEDC. 
 
The calendar-driven forms are those that appear in the AdvantageEDC Forms Grid for each 
enrolled patient at designated time points (e.g., Day 28 post transplant) throughout the course of 
the study. Completion of a calendar-driven form is expected by the Target Date for the given 
assessment period. 
 
Calendar-driven forms for the BMT CTN 1302 study are as follows: 
• 
Toxicity Form: this form documents all expected toxicities for the BMT CTN 1302 study; each 
toxicity is also assigned a grade, based on the NCI CTCAE Version 4.0. 
• 
Hematology/Chemistry Form: this form documents selected hematology (CBC/differential) and 
blood chemistry results. 
• 
Follow-Status Form: this form documents the status of each patient at various intervals on the 
study. 
 
Event-driven forms must be completed when a certain event triggers the appearance of the form 
in the AdvantageEDC Forms Grid. Most often the event-driven form is triggered by information 
entered on the Follow-up Status Form. Event-driven forms for the BMT CTN 1302 study are as 
follows: 
• 
Re-Admission/Hospitalization Form: this form documents all hospital admissions, including the 
admission for transplant for this study. 
• 
Infection Form: this form documents infections from Day 0 (date of transplant) through the 1-year 
post-transplant follow-up period. 
• 
Secondary Graft Failure Form: this form captures the details associated with secondary graft 
failure. DO NOT report secondary graft failure as an Unexpected, Grade 3-5 Adverse Event. 
• 
Progression/Relapse Form: the form captures detailed information associated with progression or 
relapse of the primary disease. DO NOT report progression or relapse as an Unexpected, Grade 3- 
5 Adverse Event. 
• 
Death Form: this form documents the death of a patient from the time of study enrollment and 
randomization through the 1-year post-transplant follow-up period. 
• 
Bortezomib SAE Screening Form: this form captures basic information on all SAEs occurring 
from the time of bortezomib administration through 30 days after. 
• 
Adverse Event Forms: this series of forms captures details on adverse events that are both 
unexpected and grades 3-5, based on the NCI CTCAE Version 4.0, regardless of attribution to any 
of the study interventions. These forms are also used to collect information on any SAE event 
required by the additional adverse event reporting requirements. These events require expedited 


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reporting and will be reviewed by the Medical Monitor at the BMT CTN Data and Coordinating 
Center (DCC) within 2 business days of receiving the summary of the adverse event from the 
transplant center. If the Medical Monitor requires additional information to make his/her 
assessment, the transplant center will have 4 business days to respond to the request for additional 
information. 
 
I.2 Reporting Expected Toxicities 
Expected toxicities for all patients enrolled on BMT CTN 1302 will be collected on the BMT CTN 
1302 Calendar-Driven Toxicity Form and some of the event-driven forms (Infection, 
Readmission/Hospitalization, Progression/Relapse, Graft Failure and Death forms). Any grade 4 
expected event not collected on the calendar-driven toxicity or specified event- driven form must 
be reported through the expedited AE reporting system in AdvantageEDC. 
 
I.3 Reporting Second Primary Malignancies 
 
All second primary malignancies (SPMs), excluding non-melanoma skin cancers, 
experienced by participants enrolled on the BMT CTN 1302 study must be reported within 
three business days of knowledge of the event using the Adverse Event forms (AE1-AE6) in 
AdvantageEDC. The Event Description of the Adverse Event forms should include histologic 
type. Reporting of SPMs in AdvantageEDC is required until all patients have completed 2 years 
of follow up. 
 
I.3.1 Adverse Event Reporting Following an SPM 
 
Adverse Event reporting following an SPM is dependent on the treatment received for the reported 
SPM. 
• If a patient experiences an SPM resulting in permanent discontinuation of maintenance and 
initiation of non-protocol systemic therapy, Unexpected Grade 3-5 Adverse Events and 
events listed in Appendix I are no longer required to be reported on the Adverse Event Form 
once the patient is more than 28 days from their last dose of maintenance. 
• If a patient experiences an SPM that does not result in permanent discontinuation of 
maintenance, Adverse Events will continue to be reported as per section 4.4.3 and Appendix 
I of the protocol. 
• Requests to discontinue Adverse Event Reporting for events that do not meet the criteria 
above will be considered on a case by case basis. 
 
I.4 Reporting Unexpected, Grade 3-5 Adverse Events 
 
All Unexpected, Grade 3-5 Adverse Events should be reported for every patient enrolled on 
the study from the time of enrollment until 2 years post transplant. Additional Adverse Event 
reporting applies to patients dependent on the treatment received on the study. Determination of 
the expectedness of adverse events should be differentiated between the initial transplant or 
maintenance therapy at the discretion of the investigator. For example, oral mucositis would be an 
expected risk associated with transplantation, but the investigator should assess the expectedness 
for oral mucositis during maintenance. 


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I.4.1 Adverse Event Reporting Following Progression 
 
If a patient meets the protocol-defined definition of progression (see Chapter 3), Unexpected 
Grade 3-5 Adverse Events and events listed in Appendix I are no longer required to be reported 
on the Adverse Event Form once the patient is more than 28 days from their last dose of 
maintenance. However, SPMs should continue to be reported within three business days of the 
knowledge of the event through the end of the study follow-up period. 
 
I.5 Adverse Event Reporting For Bortezomib 
 
This section outlines the adverse event reporting requirements for all patients receiving 
Bortezomib on BMT CTN 1302. Millennium Pharmaceuticals, Inc. (MPI) is supplying bortezomib 
for all patients enrolled on this study. MPI has additional adverse event reporting requirements for 
all patients who receive study bortezomib. 
 
In addition to the standard BMT CTN guidelines for reporting adverse events (see Chapter 
4, Section 4.4.3), MPI is requiring the reporting of all Serious Adverse Events (SAEs) that occur 
from the time of bortezomib administration (Day -3) through 30 days after. This includes 
events meeting the definition of a Serious Adverse Event, per 21 CFR 312.32, as follows: 
 
Serious Adverse Event: A serious adverse event (SAE) is any adverse event that results in one of 
the following outcomes, regardless of causality and expectedness: 
• Results in death 
• Is life-threatening. Life-threatening means that the person was at immediate risk of 
death from the reaction as it occurred, i.e., it does not include a reaction which 
hypothetically might have caused death had it occurred in a more severe form. 
• Requires or prolongs inpatient hospitalization (i.e., the event required at least a 24- 
hour hospitalization or prolonged a hospitalization beyond the expected length of stay). 
Hospitalization admissions and/or surgical operations scheduled to occur during the 
study period, but planned prior to study entry are not considered SAEs if the illness or 
disease existed before the person was enrolled in the trial, provided that it did not 
deteriorate in an unexpected manner during the trial (e.g., surgery performed earlier 
than planned). 
• Results in persistent or significant disability/incapacity. Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions. 
• Is a congenital anomaly or birth defect; or 
• Is an important medical event when, based upon appropriate medical judgment, it 
may jeopardize the participant and require medical or surgical intervention to prevent 
one of the outcomes listed above. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home; blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 


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Medical and scientific judgment should be exercised in deciding whether expected reporting is 
also appropriate in situations other than those listed above. For example, important medical events 
may not be immediately life threatening or result in death or hospitalization but may jeopardize 
the subject or may require intervention to prevent one of the outcomes listed in the definition above 
(eg, suspected transmission of an infectious agent by a medicinal product is considered a Serious 
Adverse Event). Any event is considered a Serious Adverse Event if it is associated with clinical 
signs or symptoms judged by the investigator to have a significant clinical impact. 
 
I.5.1 Reporting Timelines for Events Occuring During Bortezomib Reporting Period 
 
• Fatal and Life-Threatening events must be reported in AdvantageEDC within 24 hours, of the 
investigator’s observation or awareness of the event. 
• All Other Serious events (non-fatal/non-life-threatening) must be reported in AdvantageEDC 
within 3 calendar days of the investigator’s observation or awareness of the event. 
 
I.5.2 How to Report Serious Adverse Events During Bortezomib Reporting Period 
 
All SAEs will be reported in AdvantageEDC by completing the Bortezomib SAE Screening Form. 
All SAEs also require completion of the Adverse Event Forms (AE1-AE6), unless any of the 
following SAEs are determined to be unrelated or unlikely related to the bortezomib, then the 
Adverse Event Forms are not required: 
 
• Neutropenia 
• Thrombocytopenia 
• Anemia 
• Minor bleeding episodes (i.e. epistaxis) 
• Graft-versus-host disease (GVHD) 
• Graft failure 
• Hepatic veno-occlusive disease (VOD) 
• Thrombotic microangiopathy (TMA) 
 
Accurate completion of the Bortezomib SAE and/or Adverse Event forms will allow the DCC to 
provide MPI with the details they require to fully understand each event, so it is critical that all 
fields are filled in and comprehensive supporting source documents for the event (PHI redacted) 
are uploaded to the appropriate forms. 
 
If an adverse event does not meet the criteria of an SAE, it will require reporting on the Adverse 
Event form if it is both unexpected and grade 3-5 based on the BMT CTN standard reporting 
guidelines. 
 
I.6 Adverse Event Reporting Beginning 30 Days After Bortezomib 
 
This section outlines the adverse event reporting requirements for all patients beginning 30 days 
after the final dose of bortezomib until the first dose of maintenance. If the patient does not initiate 


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maintenance therapy, the requirements outlined within this section should be followed until 2 years 
post transplant. 
 
Table I-1 lists adverse events and toxicities for this study, as well as the form in AdvantageEDC 
that is used to document the event. 
 
TABLE I-1: ADVERSE EVENTS FOR BMT CTN 1302 BEGINNING 30 DAYS AFTER 
BORTEZOMIB ADMINISTRATIONBY ORGAN SYSTEM 
 
Adverse Event 
Collection Type 
Collection Form1 
AUDITORY DISORDERS 
Hearing loss 
Calendar-Driven 
Toxicity 
BLOOD AND LYMPHATIC DISORDERS 
Anemia 
Calendar-Driven 
Toxicity 
Neutropenia 
Calendar-Driven 
Toxicity 
Thrombocytopenia 
Calendar-Driven 
Toxicity 
Thrombotic thrombocytopenic 
purpura/ Thrombotic 
microangiopathy 
Calendar-Driven 
Toxicity 
CARDIAC DISORDERS 
Cardiac arrhythmia 
Calendar-Driven 
Toxicity 
Hypertension 
Calendar-Driven 
Toxicity 
Hypotension 
Calendar-Driven 
Toxicity 
Left ventricular systolic dysfunction 
Calendar-Driven 
Toxicity 
Myocardial infarction 
Calendar-Driven 
Toxicity 
New or worsening heart failure 
Calendar-Driven 
Toxicity 
Pericardial effusion 
Calendar-Driven 
Toxicity 
Pericarditis 
Event-Driven 
Adverse Event Form 
Peripheral edema 
Calendar-Driven 
Toxicity 
Restrictive cardiomyopathy 
Calendar-Driven 
Toxicity 
GASTROINTESTINAL DISORDERS 
Abdominal pain 
Calendar-Driven 
Toxicity 
Anorexia 
Calendar-Driven 
Toxicity 
Constipation 
Calendar-Driven 
Toxicity 
Diarrhea 
Calendar-Driven 
Toxicity 
Dysgeusia (taste alteration) 
Calendar-Driven 
Toxicity 
Dyspepsia (heartburn) 
Calendar-Driven 
Toxicity 
Gastroenteritis 
Calendar-Driven 
Toxicity 
Intestinal obstruction 
Event-Driven 
Adverse Event Form 
Nausea 
Calendar-Driven 
Toxicity 
Oral mucositis 
Calendar-Driven 
Toxicity 
Vomiting 
Calendar-Driven 
Toxicity 
GENERAL DISORDERS 
Fatigue 
Calendar-Driven 
Toxicity 


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Adverse Event 
Collection Type 
Collection Form1 
Fever 
Calendar-Driven 
Toxicity 
HEPATOBILIARY/PANCREAS DISORDERS 
Abnormal liver function tests 
Calendar-Driven 
Toxicity 
Hepatitis 
Event-Driven 
Adverse Event Form 
Liver failure 
Event-Driven 
Adverse Event Form 
Pancreatitis 
Calendar-Driven 
Toxicity 
HEMORRHAGIC DISORDERS 
Intracranial 
Event-Driven 
Adverse Event Form 
Gastrointestinal 
Calendar-Driven 
Toxicity 
Genitourinary 
Calendar-Driven 
Toxicity 
Pulmonary/Upper respiratory 
Calendar-Driven 
Toxicity 
IMMUNE SYSTEM DISORDERS 
Allergic reaction 
Event-Driven 
Adverse Event Form 
Anaphylaxis (swelling of the skin 
and/or swelling of the face or throat) 
Event-Driven 
Adverse Event Form 
INFECTIONS 
Fungal infections of the mouth and 
throat 
Event-Driven 
Infection 
Herpes virus/shingles 
Event-Driven 
Infection 
Infections of the bladder, sinuses, 
throat, stomach and intestines, and 
skin 
Event-Driven 
Infection 
Sepsis 
Event-Driven 
Infection 
METABOLISM AND NUTRITION DISORDERS 
Hypercalcemia 
Calendar-Driven 
Toxicity 
Hyperglycemia 
Calendar-Driven 
Toxicity 
Hypoglycemia 
Calendar-Driven 
Toxicity 
Hypokalemia 
Calendar-Driven 
Toxicity 
Hyponatremia 
Calendar-Driven 
Toxicity 
Tumor lysis syndrome 
Event-Driven 
Adverse Event Form 
MUSCULOSKELETAL AND TISSUE DISORDERS 
Arthralgia 
Calendar-Driven 
Toxicity 
Myalgia 
Calendar-Driven 
Toxicity 
Muscle weakness (generalized or 
specific area) 
Calendar-Driven 
Toxicity 
NERVOUS SYSTEM DISORDERS 
Anxiety 
Calendar-Driven 
Toxicity 
Confusion 
Calendar-Driven 
Toxicity 
Depression 
Calendar-Driven 
Toxicity 
Dizziness 
Calendar-Driven 
Toxicity 
Encephalopathy 
Event-Driven 
Adverse Event Form 
Headache 
Calendar-Driven 
Toxicity 
Insomnia 
Calendar-Driven 
Toxicity 


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Adverse Event 
Collection Type 
Collection Form1 
Neuropathy 
Event-Driven 
Adverse Event Form 
Reversible posterior 
leukoencephalopathy syndrome 
(PRES) 
Event-Driven 
Adverse Event Form 
Seizure 
Event-Driven 
Adverse Event Form 
Severe muscle weakness/paralysis 
Event-Driven 
Adverse Event Form 
Somnolence 
Calendar-Driven 
Toxicity 
Syncope (fainting) 
Calendar-Driven 
Toxicity 
OCULAR/VISUAL DISORDERS 
Blurred vision 
Calendar-Driven 
Toxicity 
Conjunctivitis 
Calendar-Driven 
Toxicity 
Sudden loss of vision 
Event-Driven 
Adverse Event Form 
RENAL DISORDERS 
Cystitis Non-infective 
Calendar-Driven 
Toxicity 
Acute kidney injury 
Calendar-Driven 
Toxicity 
Chronic kidney disease 
Calendar-Driven 
Toxicity 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
Bronchitis 
Calendar-Driven 
Infection 
Cough 
Calendar-Driven 
Toxicity 
Dyspnea 
Calendar-Driven 
Toxicity 
Hypoxia 
Calendar-Driven 
Toxicity 
Pleural effusion 
Calendar-Driven 
Toxicity 
Pneumonia 
Calendar-Driven 
Infection 
Sinusitis 
Calendar-Driven 
Toxicity 
Sore throat 
Calendar-Driven 
Toxicity 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
Pruritis 
Calendar-Driven 
Toxicity 
Rash 
Calendar-Driven 
Toxicity 
Hyperhidrosis (excessive sweating) 
Calendar-Driven 
Toxicity 
VASCULAR DISORDERS 
Capillary leak syndrome 
Calendar-Driven 
Toxicity 
Thromboembolic event 
Calendar-Driven 
Toxicity 
OTHER 
Pregnancy 
Event-Driven 
Adverse Event Form 
Second primary malignancy 
Event-Driven 
Adverse Event Form 
Other unexpected grade 3-5 AE 
Event-Driven 
Adverse Event Form 
 
1Events determined to be at least possibly related to bortezomib that occur more than 30 days from 
the last dose may be reported via the Bortezomib SAE Screening Form and Adverse Event Form 
at the discretion of the investigator. 
 
I.7 Adverse Event Reporting POST Randomization: 


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This section outlines the reporting requirements for patients who are randomized. All randomized 
patients must adhere to each required level of event reporting as outlined in this section. 
 
1.7.1 Reporting Serious Adverse Events During Maintenance Therapy 
 
The following section outlines adverse event reporting requirements for patients beginning with 
the first dose of maintenance therapy until 30 days after the final dose of maintenance therapy. 
 
All serious adverse events that meet the SAE criteria outlined in I.1 above will require 
reporting through the event-driven AE mechanism in Advantage EDC from the first dose of 
maintenance therapy through 30 days after the last dose of maintenance therapy and 
regardless of relationship. 
Post-randomization period AE data collection: 
• 
Re-Admission/Hospitalization Form: this form documents all hospital admissions that occur after 
randomization. Any hospitalizations that occur from the first dose until 30 days from last dose of 
maintenance will also require submission of the Adverse Event Forms. 
• 
Infection Form: this form documents infections that occur after randomization. If the infection 
fulfills the SAE definition and occurs from the first dose until 30 days after the last dose of 
maintenance, the Adverse Event Forms will be required. 
• 
Death Form: this form documents the death of a patient. If death is associated with an adverse 
event and it occurs from the first dose through 30 days after the last dose of maintenance, the 
Adverse Event Forms will be required. 
• 
Adverse Event Forms: this series of forms captures details on adverse events that are both 
unexpected and grades 3-5, based on the NCI CTCAE Version 4.0, regardless of attribution to any 
of the study interventions. These forms are also used to collect information on any SAE event from 
the first dose of maintenance therapy through 30 days after the last dose by the additional adverse 
event reporting requirements. These events require expedited reporting and will be reviewed by the 
Medical Monitor at the BMT CTN Data and Coordinating Center (DCC) within 2 business days of 
receiving the summary of the adverse event from the transplant center. If the Medical Monitor 
requires additional information to make his/her assessment, the transplant center will have 4 
business days to respond to the request for additional information. 


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APPENDIX J 
DERIVATION OF A SEQUENTIAL TEST STATISTIC FOR 
CENSORED EXPONENTIAL DATA 


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0 
1 
 
 
Background – The Sequential Probability Ratio Test 
 
 
Let f (., ) be the density function for random variable X. According to Neyman and Pearson, the 
most powerful test of H 0 : =  o versus H1 : = 1 decides in favor of H 1 or H 0 if Ln  c or 
n 
Ln  c , respectively, where 
Ln =  f (xi ;1 ) / f (xi ; 0 ) is the likelihood ratio, and 
i 
c is 
determined to have the size  . When the sample size is not fixed in advance, further improvement 
is possible by using Wald’s Sequential Probability Ratio Test (SPRT). The SPRT continues to 
sample as long as B  Ln  A for some constant B  1  A , stops sampling and decides in favor of 
H1 as soon as Ln  A , and stops sampling and decides in favor of H 0 as soon as Ln  B . 
 
The usual measures of performance of such a procedure are the error probabilities 
and  of 
rejecting H 0 when  =  0 , and of accepting H 0 when  = 1 , respectively, and the expected 
sample size E(N |  j )  E j (N ) . Wald and Wolfowitz showed that among all tests, sequential or 
not, for which Pr0 (reject H 0 )   and Pr1 (reject H 0 )   , and for which E j (N ) are finite, j=0,1, 
the SPRT with error probabilities 
and  minimizes E0 (N ) and E1 (N ) . If, in addition, the 
x1, x2,... are independent and identically distributed (i.i.d.) with density function 
f (x, ) , with 
monotone likelihood ratio in 
decreasing power function. 
 (x) , then any SPRT for testing  0 against 1 (  0 ) has non- 
For the SPRT with error probabilities 
and  , the SPRT boundaries are given approximately by 
A = (1 −  ) /  and B =  /(1 −  ) . 
The operating characteristics of the SPRT are given by 
O( , ,  , , ) = ( Ah( ) − 1) /( Ah( ) − Bh( ) ) 
 ( f (x;1 ) / f (x, 2 ))h( ) f (x; )dx = 1 . 
where h( ) is the non-trivial solution to the equation 
 
The formula E(N; ) = [[(1 − O( )]log A + O( ) log B]/ E(z; ) provides the average sample number 
for an arbitrary  . The sample size distribution is very highly skewed, Var(N )  [E(N )]2 . Thus 
we will consider a truncated test with maximum sample size of 
operating characteristics of the test. 
N 0 and simulate to obtain the 


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n 
n 
n 
n
n
 
 
Derivation of the SPRT for Censored Exponential Survival Times 
 
Suppose that we wish to construct a sequential test for the composite null hypothesis that the rate 
of overall mortality at an early time point t is less than or equal to p0 versus the alternative 
hypothesis that it is greater than or equal to p0. Let us assume that the survival times, T1, T2 ,..., Tn , 
are i.i.d. with exponential density function f (T , ) = e−T . Although an exponential model may 
not fit well for overall mortality, it usually provides a reasonable model over a short time frame 
for modeling toxicity, so in all discussion below we assume that exponential survival times are 
censored at time point t. In the exponential parameterization, a t-day survival rate of p0 translates 
into a mean survival of µ0=-t/ln(1-p0) (rate parameter 0 = -ln(1-p0)/t). . 
The SPRT is derived with reference to a simple null and alternative hypothesis for the rate 
parameter, in this case, H0 : = o versus H1 : = 1 . The log-likelihood ratio for the exponential 
in 
the 
presence 
of 
censoring 
is 
log f (xi ;1 ) − log f (xi ,0 ) = d (log(1 ) − log(0 )) − (1 −0 )Ti , where d is the number of 
i 
i 
i 
events. The SPRT can be represented graphically when plotting the number of deaths (d) on the 
n 
y axis against the total time on study Ti 
i 
bounded by two parallel lines given by 
on the x axis. The continuation region in terms of d is 
 
log(B) 
 +  
(1 −0 ) 
 
n T   d   
log( A) 
 +  
(1 −0 ) 
 
n   
T
 
(log  − log )  (log − log )  
i
 
(log  − log )  (log − log )  
i
 
 
1 
0     
1 
0  i 
 
1 
0     
1 
0  i 
with 
common 
slope 
(1 −0 ) / (log1 − log0 ) , and 
intercepts 
log A / (ln1 − ln0) 
and 
log B / (ln1 − ln0 ) , for the upper and lower bounds, respectively. For monitoring purposes, at an 
interim analysis calendar time point s, suppose that d(s) events have occurred and that the total 
time on study is Ti (s) .The cumulative number of events d(s) is plotted on the y axis against the 
i 
total time on study, Ti (s) .  When this graph crosses the upper boundary, the null hypothesis is 
i 
rejected. In practice, monitoring will be scheduled monthly after the start of enrollment to the 
study. 
 
A truncated version of the SPRT can be obtained by specifying a maximum sample size. We 
truncate the SPRT by declaring that if the test has failed to terminate after the maximum sample 
size, that the null hypothesis will be accepted. Since the probability that the untruncated SPRT 
would reject the null at the maximum sample size is negligible, it makes little difference how the 
final boundary value is selected, and this rule is chosen for simplicity. The operating 
characteristics of this proposed truncated SPRT for censored exponential data can be estimated by 
simulation. 


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APPENDIX K 
PRODUCT COMPLAINTS FOR BORTEZOMIB AND IXAZOMIB 


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K-2 
 
 
 
 
PRODUCT COMPLAINTS FOR BORTEZOMIB AND IXAZOMIB 
 
 
A product complaint is a verbal, written, or electronic expression which implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product. Individuals who 
identify a potential product complaint situation should immediately contact MedComm Solutions 
(see below) and report the event. Whenever possible, the associated product should be maintained 
in accordance with the label instructions pending further guidance from a Millennium quality 
representative. 
 
A medication error is a preventable event that involves an identifiable patient and that leads to 
inappropriate medication use, which may result in patient harm. While overdoses and underdoses 
constitute medication errors, doses missed inadvertently by a patient do not. Individuals who 
identify a potential medication error situation should immediately contact MedComm Solutions 
(see below) and report the event. 
 
 
For product complaints, contact: 
Phone: 1-844-ONC-TKDA (1-844-662-8532) 
E-mail: GlobalOncologyMedinfo@takeda.com 
FAX: 1-800-881-6092 
Hours: Mon-Fri, 9 a.m. – 7 p.m. ET 
 
 
Product complaints and medication errors in and of themselves are not AEs. If a product complaint 
or medication error results in an SAE, then the appropriate forms in AdvantageEDC should be 
completed (refer to Section 4.7 Adverse Event Reporting). 


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APPENDIX L 
MINIMAL RESIDUAL DISEASE ANCILLARY STUDY 


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BMT CTN 1302 Ancillary Study 
Assessment of minimal residual disease (MRD) and immune reconstitution by 
flow cytometry to analyze the efficacy and immune-related effects of ixazomib 
maintenance post-allogeneic BMT 
 
1.0. 
Objectives: 
 
1.1. To determine the level of minimal residual disease (MRD) using a comprehensive 
immunophenotyping 
panel 
before 
alloBMT, 
before 
starting 
maintenance 
ixazomib/placebo and at 18 months after alloBMT. 
1.1.1. Estimate the rate of conversion from detectable to undetectable minimal residual 
disease with alloBMT (at time of staging D+60 to 120). 
1.1.2. Compare the rate of conversion from detectable to undetectable minimal residual 
disease between time of randomization between ixazomib maintenance vs placebo 
and 18 months post-alloBMT. 
1.2. To describe the changes in immune cell subpopulations using a comprehensive 
immune reconstitution panel before alloBMT, before starting maintenance 
ixazomib/placebo and at one year after alloBMT. 
1.2.1. Explore the relationship of immune cell populations with development of acute 
and/or chronic GVHD. 
1.2.2. Explore the relationship of immune cell populations with MM disease staging and 
PFS. 
1.2.3. Explore the relationship of immune cell populations with TRM and OS. 
 
2.0. 
Preliminary Data and Background: 
 
There is increasing evidence of the role of the immune system in controlling and/or eradicating 
minimal residual disease (MRD) in multiple myeloma (MM). Novel agents, combined with 
allogeneic BMT, have the potential to be harnessed to accomplish long-term disease control and 
perhaps a cure for MM. Studying the role of immune cell subsets in relation to detection of MRD 
and long-term PFS may improve our understanding of myeloma cell biology and the immune cell 
subsets that are potent myeloma cell-killers. 
 
We are currently measuring MRD as a NIH-funded ancillary study to BMT CTN 0702 (PRIMeR 
study). The parent trial (STaMINA) recently closed to accrual. The first specific aim of the 
PRIMeR study is to assess the correlation of MRD with traditional MM staging (SPEP, SIFE, 
UPEP, UIFE, sFLC ratio). The analysis of baseline/pre-autologous BMT samples and staging 
should be ready to start in the spring 2014. These initial analyses will help guide and refine the 
immunophenotyping panel for MRD which is proposed in this study. Having the same flow 
cytometry laboratory perform and analyze the MRD for both the 0702 and 1302 trials will insure 
consistency and the ability to draw inferences between the 2 treatment strategies (auto/allo BMT). 
We recently presented preliminary data at ASH 2013 of immune cell subpopulations before and 
after autologous BMT for MM. Several immune cell subsets were strongly correlated with early 


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absolute lymphocyte (ALC) recovery, as well as PFS and OS. Our analysis demonstrated, 
however, that these immune cell subsets were independent of traditional MM staging, and 
therefore convey information in addition to MRD. We propose that in the alloBMT setting, the 
immune cell profiles of MM patients will be even more meaningful and may predict additional 
outcomes, such as acute and chronic GVHD, and may help guide future treatments to manipulate 
the immune system to eradicate residual myeloma post-alloBMT. The BMT CTN 1302 trial 
provides a unique opportunity to study the role of ixazomib maintenance post-alloBMT in immune 
surveillance/eradication of MRD in MM. 
 
3.0. 
Study eligibility: 
 
All 138 patients enrolled on BMT CTN 1302 are eligible. 
 
4.0. 
Outcomes: 
 
The results of this ancillary study can provide preliminary data of the ability of ixazomib vs 
placebo to eradicate MRD in myeloma patients post-alloBMT. In addition, we will generate 
preliminary data evaluating the impact of immune cell subsets on the efficacy of ixazomib, their 
association with acute and chronic GVHD, and overall prognosis (PFS/OS) which will provide 
critical information on potential ways the immune system may be harnessed in future studies to 
improve patient outcomes after alloBMT for myeloma. 
 
Future exploratory analyses could compare the impact of autoBMT (BMT CTN 0702) vs alloBMT 
(BMT CTN 1302) on clearance of MRD as well as the prognostic impact of MRD positivity by 
immunophenotyping on long-term PFS and OS. 
 
5.0. 
Summary of methods: 
 
Currently, we have the capability to perform up to 10-color flow panels in a CLIA accredited 
clinical flow cytometry laboratory. This will allow the following panels to be run: 
CD38/LD/CD45/CD56/CD138/CD19/CD20/CD81 
CD38/LD/CD45/ CD28/ CD138/CD27/CD19/CD117 
CD38/LD/CD45/cLambda/CD138/CD19/cKappa 
 
For detection of minimal residual disease (myeloma) (recommended in Rawstron et al, 2008) and 
under consideration by the NIH/FDA Detection of Myeloma MRD consensus committee (PKW 
personal communication): 
 
Our preliminary analysis of MRD in BMT CTN 0702 (STaMINA/PRIMeR) will determine the 
best gating strategy and the importance of measuring cytoplasmic light chain expression. Data will 
be analyzed per our standard methodology, using a common series of macros and templates and 
scored on a sample-by-sample basis for each of these parameters. A minimum of 2x106 events are 
acquired with a sensitivity of less than 0.01%. These mAb combinations make a sensitive and 
specific panel for detection of MRD. However the acquisition, analysis and interpretation adds 


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complexity to the analysis and may impact wide-spread reproducibility in some centers with 
limited flow cytometric capabilities. 
 
For immune reconstitution/immune cell subpopulations: 
Cell Subsets 
Antibody Pannels 
Inflammatory 
Monocytes 
&DC 
CD11c 
CD123 
DUMP 
HLADR 
CD14 
CD45 
CD163 
CD16 
RTE, CD4 & 
CD8 Naïve & 
Memory 
CD31 
CD28 
CD8 
CD3 
CD45RA 
CD4 
CCR7 
CD45RO 
Tregs (1) 
CD25 
CD39 
CD73 
CD3 
CD178 
CD45RA 
CD127 
CD4 
NKs (1) 
CD57 
CD314 
CD16 
CD3 
CD159a 
CD45 
CD33 
CD56 
γd T Cells 
V Delta 1 
V Delta 2 
CD8 
CD3 
αβ TCR 
CD45 
CD25 
γd TCR 
B Cells 
IgM 
CD319 
IgD 
CD19 
CD27 
CD45 
CD138 
CD38 
 
Time points of Sample collection 
 
Bone marrow aspirate will be used for the MRD assessment collected at three timepoints: prior to 
transplant, prior to initiation of maintenance and one month after completion of maintenance. 
According to the experience of previous clinical trials with the rate of agreement in providing bone 
marrow aspirates for research purposes, and the proportion of patients having a marrow performed 
to confirm complete response, we estimate that we will obtain 120 samples at baseline, 50 samples 
prior to initiation of maintenance, and 30 samples upon completion of maintenance. 
 
Peripheral blood for immunereconstitutional assays will be collected prior to initiation of 
maintenance, at the start of cycle 5 of maintenance and one month after completion of 
maintenance. The numbers of peripheral blood samples estimated at each timepoint are 100 
samples prior to maintenance, 65 at cycle 5, and 50 at completion of maintenance. 
 
6.0. 
References: 
 
Hahn T, Zhang Y, Paiva B, Chen GL, Wallace PK, McCarthy PL. Analysis of immune cell 
populations before and after autologous hematopoietic stem cell transplant (AHCT) for multiple 
myeloma: association with early recovery of absolute lymphocyte count and progression-free 
survival. Blood 122: 3348, 2013. 
 
Rawstron AC, Child JA, de Tute RM, Davies FE, Gregory WM, Bell SE, Szubert AJ, Navarro- 
Coy N, Drayson MT, Feyler S, Ross FM, Cook G, Jackson GH, Morgan GJ, Owen RG. Minimal 
residual disease assessed by multiparameter flow cytometry in multiple myeloma: impact on 
outcome in the Medical Research Council Myeloma IX Study. J Clin Oncol 31(20): 2540-7, 
2013. 
 
Rawstron AC, Orfao A, Beksac M, Bezdickova L, Brooimans RA, Bumbea H, Dalva K, Fuhler 
G, Gratama J, Hose D, Kovarova L, Lioznov M, Mateo G, Morilla R, Mylin AK, Omede P, 
Pellat-Deceunynck C, Perez Andres M, Petrucci M, Ruggeri M, Rymkiewicz G, Schmitz A, 
Schreder M, Seynaeve C, Spacek M, de Tute RM, Van Valckenborgh E, Weston-Bell N, Owen 


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RG, San Miguel JF, Sonneveld P, Johnsen HE, European Myeloma Network. Report of the 
European Myeloma Network on multiparametric flow cytometry in multiple myeloma and 
related disorders. Haematologica 93(3): 431-8, 2008. 
 
Knight A, Mackinnon S, Lowdell MW. Human Vdelta1 gamma-delta T cells exert potent 
specific cytotoxicity against primary multiple myeloma cells. Cytotherapy 14(9):1110-8, 2012. 
 
Kroger N, Badbaran A, Lioznov M, Schwarz S, Zeschke S, Hildebrand Y, Ayuk F, Atanackovic 
D, Schilling G, Zabelina T, Bacher U, Klyuchnikov E, Shimoni A, Nagler A, Corradini P, Fehse 
B, Zander A. Post-transplant immunotherapy with donor-lymphocyte infusion and novel agents 
to upgrade partial into complete and molecular remission in allografted patients with multiple 
myeloma. Exp Hematol 37(7): 791-8, 2009. 
 
Atanackovic D, Cao Y, Luetkens T, Panse J, Faltz C, Arfsten J, Bartels K, Wolschke C, 
Eiermann T, Zander AR, Fehse B, Bokemeyer C, Kroger N. CD4+CD25+FOXP3+ T regulatory 
cells reconstitute and accumulate in the bone marrow of patients with multiple myeloma 
following allogeneic stem cell transplantation. Haematologica 93(3):423-30, 2008. 
 
Pessoa de Magalhaes RJ, Vidriales MB, Paiva B, Fernandez-Gimenez C, Garcis-Sanz R, Mateos 
MV, Gutierrez NC, Lecrevisse Q, Blanco JF, Hernandez J, de las Heras N, Martinez-Lopez J, 
Roig M, Costa ES, Ocio EM, Perez-Andres M, Maiolino A, Nucci M, De La Rubia J, Lahuerta 
JJ, San-Miguel JF, Orfao A, Spanish Myeloma Group (GEM), Grupo Castellano-Leones de 
Gammapatias Monoclonoales, cooperative study groups. Analysis of the immune system of 
multiple myeloma patients achieving long-term disease control by multidimensional flow 
cytometry. Haematologica 98(1):79-86, 2013. 
 
Paiva B, Gutierrez NC, Rosinol L, Vidriales MB, Montalban MA, Martinez-Lopez J, Mateos 
MV, Cibeira MT, Cordon L, Oriol A, Terol MJ, Echeveste MA, de Paz R, de Arriba F, Palomera 
L, de la Rubia J, Diaz-Mediavilla J, Sureda A, Gorosquieta A, Alegre A, Martin A, Hernandez 
MT, Lahuerta JJ, Blade J, San Miguel JF, PETHEMA/GEM Cooperative Study Groups. High- 
risk cytogenetics and persistent minimal residual disease by multiparameter flow cytometry 
predict unsustained complete response after autologous stem cell transplantation in multiple 
myeloma. Blood 119(3):687-91, 2012. 


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APPENDIX M 
REFERENCES 


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REFERENCES 
 
 
1 Avet-Loiseau H, Attal M, Moreau P, et al. Genetic abnormalities and survival in multiple 
myeloma: the experience of the Intergroupe Francophone du Myelome. Blood. 2007;109(8):3489- 
3495. 
 
2 Munshi NC, Anderson KC, Bergsagel PL, et al. Consensus recommendations for risk 
stratification in multiple myeloma: report of the International Myeloma Workshop Consensus 
Panel 2. Blood. 2011;117(18):4696-4700. 
 
3 Rajkumar SV, Kyle RA. Multiple myeloma: diagnosis and treatment. Mayo Clin Proc. 
2005;80(10):1371-1382. 
 
4 Gertz MA, Lacy MQ, Dispenzieri A, et al. Clinical implications of t(11;14)(q13;q32), 
t(4;14)(p16.3;q32), and -17p13 in myeloma patients treated with high-dose therapy. Blood. 
2005;106(8):2837-2840. 
 
5 Palumbo A, Anderson K. Multiple myeloma. N Engl J Med. 2011;364(11):1046-1060. 
 
6 Attal M, Harousseau JL, Leyvraz S, et al. Maintenance therapy with thalidomide improves 
survival in patients with multiple myeloma. Blood. 2006;108(10):3289-3294. 
 
7 Garban F, Attal M, Michallet M, et al. Prospective comparison of autologous stem cell 
transplantation followed by dose-reduced allograft (IFM99-03 trial) with tandem autologous stem 
cell transplantation (IFM99-04 trial) in high-risk de novo multiple myeloma. Blood. 
2006;107(9):3474-3480. 
 
8 Moreau P, Hullin C, Garban F, et al. Tandem autologous stem cell transplantation in high-risk 
de novo multiple myeloma: final results of the prospective and randomized IFM 99-04 protocol. 
Blood. 2006;107(1):397-403. 
 
9 Fonseca R, Blood E, Rue M, et al. Clinical and biologic implications of recurrent genomic 
aberrations in myeloma. Blood. 2003;101(11):4569-4575. 
 
10 Gutierrez NC, Castellanos MV, Martin ML, et al. Prognostic and biological implications of 
genetic abnormalities in multiple myeloma undergoing autologous stem cell transplantation: 
t(4;14) is the most relevant adverse prognostic factor, whereas RB deletion as a unique abnormality 
is not associated with adverse prognosis. Leukemia : official journal of the Leukemia Society of 
America, Leukemia Research Fund, UK. 2007;21(1):143-150. 
 
11 Reece D, Song KW, Fu T, et al. Influence of cytogenetics in patients with relapsed or refractory 
multiple myeloma treated with lenalidomide plus dexamethasone: adverse effect of deletion 
17p13. Blood. 2009;114(3):522-525. 


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12 Chiecchio L, Protheroe RK, Ibrahim AH, et al. Deletion of chromosome 13 detected by 
conventional cytogenetics is a critical prognostic factor in myeloma. Leukemia : official journal 
of the Leukemia Society of America, Leukemia Research Fund, UK. 2006;20(9):1610-1617. 
 
13 Xiong W, Wu X, Starnes S, et al. An analysis of the clinical and biologic significance of TP53 
loss and the identification of potential novel transcriptional targets of TP53 in multiple myeloma. 
Blood. 2008;112(10):4235-4246. 
 
14 Chang H, Yeung J, Qi C, Xu W. Aberrant nuclear p53 protein expression detected by 
immunohistochemistry is associated with hemizygous P53 deletion and poor survival for multiple 
myeloma. British journal of haematology. 2007;138(3):324-329. 
 
15 Fonseca R, Barlogie B, Bataille R, et al. Genetics and cytogenetics of multiple myeloma: a 
workshop report. Cancer research. 2004;64(4):1546-1558. 
 
16 Chang H, Sloan S, Li D, Keith Stewart A. Multiple myeloma involving central nervous system: 
high frequency of chromosome 17p13.1 (p53) deletions. British journal of haematology. 
2004;127(3):280-284. 
 
17 Debes-Marun CS, Dewald GW, Bryant S, et al. Chromosome abnormalities clustering and its 
implications for pathogenesis and prognosis in myeloma. Leukemia : official journal of the 
Leukemia Society of America, Leukemia Research Fund, UK. 2003;17(2):427-436. 
 
18 Shaughnessy JD, Jr., Zhan F, Burington BE, et al. A validated gene expression model of high- 
risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1. 
Blood. 2007;109(6):2276-2284. 
 
19 Avet-Loiseau H, Li C, Magrangeas F, et al. Prognostic significance of copy-number alterations 
in multiple myeloma. Journal of clinical oncology : official journal of the American Society of 
Clinical Oncology. 2009;27(27):4585-4590. 
 
20 Hanamura I, Stewart JP, Huang Y, et al. Frequent gain of chromosome band 1q21 in plasma- 
cell dyscrasias detected by fluorescence in situ hybridization: incidence increases from MGUS to 
relapsed myeloma and is related to prognosis and disease progression following tandem stem-cell 
transplantation. Blood. 2006;108(5):1724-1732. 
 
21 Keats JJ, Fonseca R, Chesi M, et al. Promiscuous mutations activate the noncanonical NF- 
kappaB pathway in multiple myeloma. Cancer cell. 2007;12(2):131-144. 
 
22 Mateos MV, Hernandez JM, Hernandez MT, et al. Bortezomib plus melphalan and prednisone 
in elderly untreated patients with multiple myeloma: results of a multicenter phase 1/2 study. 
Blood. 2006;108(7):2165-2172. 


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23 Richardson PG, Barlogie B, Berenson J, et al. Clinical factors predictive of outcome with 
bortezomib in patients with relapsed, refractory multiple myeloma. Blood. 2005;106(9):2977- 
2981. 
 
24 Pineda-Roman M, Zangari M, Haessler J, et al. Sustained complete remissions in multiple 
myeloma linked to bortezomib in total therapy 3: comparison with total therapy 2. British journal 
of haematology. 2008;140(6):625-634. 
 
25 San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for 
initial treatment of multiple myeloma. The New England journal of medicine. 2008;359(9):906- 
917. 
 
26 Avet-Loiseau H, Leleu X, Roussel M, et al. Bortezomib plus dexamethasone induction improves 
outcome of patients with t(4;14) myeloma but not outcome of patients with del(17p). Journal of 
clinical oncology : official journal of the American Society of Clinical Oncology. 
2010;28(30):4630-4634. 
 
27 Neben K, Jauch A, Bertsch U, et al. Combining information regarding chromosomal aberrations 
t(4;14) and del(17p13) with the International Staging System classification allows stratification of 
myeloma patients undergoing autologous 
stem cell transplantation. 
Haematologica. 
2010;95(7):1150-1157. 
 
28 Neben K, Lokhorst HM, Jauch A, et al. Administration of bortezomib before and after 
autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 
17p. Blood. 2012;119(4):940-948. 
 
29 Neben K, Lokhorst HM, Jauch A, et al. Administration of bortezomib before and after 
autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 
17p. Blood. 2012;119(4):940-948. 
 
30 Avet-Loiseau H, Leleu X, Roussel M, et al. Bortezomib plus dexamethasone induction improves 
outcome of patients with t(4;14) myeloma but not outcome of patients with del(17p). J Clin Oncol. 
2010;28(30):4630-4634. 
 
31 Bensinger W, Rotta M, Storer B, et al. Allo-SCT for multiple myeloma: a review of outcomes 
at a single transplant center. Bone marrow transplantation. 2012. 
 
32 Bashir Q, Khan H, Orlowski RZ, et al. Predictors of prolonged survival after allogeneic 
hematopoietic stem cell transplantation for multiple myeloma. American journal of hematology. 
2012;87(3):272-276. 


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33 Crawley C, Lalancette M, Szydlo R, et al. Outcomes for reduced-intensity allogeneic 
transplantation for multiple myeloma: an analysis of prognostic factors from the Chronic 
Leukaemia Working Party of the EBMT. Blood. 2005;105(11):4532-4539. 
 
34 Kumar S, Zhang MJ, Li P, et al. Trends in allogeneic stem cell transplantation for multiple 
myeloma: a CIBMTR analysis. Blood. 2011;118(7):1979-1988. 
 
35 El-Cheikh J, Crocchiolo R, Boher JM, et al. Allogeneic transplant for myeloma in the era of new 
drugs: have the outcomes improved? Leukemia & lymphoma. 2012. 
 
36 Maloney DG, Molina AJ, Sahebi F, et al. Allografting with nonmyeloablative conditioning 
following cytoreductive autografts for the treatment of patients with multiple myeloma. Blood. 
2003;102(9):3447-3454. 
 
37 Kroger N, Schwerdtfeger R, Kiehl M, et al. Autologous stem cell transplantation followed by a 
dose-reduced allograft induces high complete remission rate in multiple myeloma. Blood. 
2002;100(3):755-760. 
 
38 Rotta M, Storer BE, Sahebi F, et al. Long-term outcome of patients with multiple myeloma after 
autologous hematopoietic cell transplantation and nonmyeloablative allografting. Blood. 
2009;113(14):3383-3391. 
 
39 Bruno B, Rotta M, Patriarca F, et al. Nonmyeloablative allografting for newly diagnosed 
multiple myeloma: the experience of the Gruppo Italiano Trapianti di Midollo. Blood. 
2009;113(14):3375-3382. 
 
40 Bruno B, Rotta M, Patriarca F, et al. A comparison of allografting with autografting for newly 
diagnosed myeloma. The New England journal of medicine. 2007;356(11):1110-1120. 
 
41 Giaccone L, Storer B, Patriarca F, et al. Long-term follow-up of a comparison of 
nonmyeloablative allografting with autografting for newly diagnosed myeloma. Blood. 
2011;117(24):6721-6727. 
 
42 van Rhee F, Crowley J, Barlogie B. Allografting or autografting for myeloma. The New England 
journal of medicine. 2007;356(25):2646-2648; author reply 2646-2648. 
 
43 Rosinol L, Perez-Simon JA, Sureda A, et al. A prospective PETHEMA study of tandem 
autologous transplantation versus autograft followed by reduced-intensity conditioning allogeneic 
transplantation in newly diagnosed multiple myeloma. Blood. 2008;112(9):3591-3593. 
 
44 Moreau P, Garban F, Attal M, et al. Long-term follow-up results of IFM99-03 and IFM99-04 
trials comparing nonmyeloablative allotransplantation with autologous transplantation in high-risk 
de novo multiple myeloma. Blood. 2008;112(9):3914-3915. 


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45 Krishnan A, Pasquini MC, Logan B, et al. Autologous haemopoietic stem-cell transplantation 
followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with 
multiple myeloma (BMT CTN 0102): a phase 3 biological assignment trial. The lancet oncology. 
2011;12(13):1195-1203. 
 
46 Lokhorst HM, van der Holt B, Cornelissen JJ, et al. Donor versus no donor comparison of newly 
diagnosed myeloma patients included in the HOVON 50 multiple myeloma study. Blood. 2012. 
 
47 Stefan Knop PL, Holger Hebart, Ernst Holler, Monika Engelhardt. Allogeneic Stem Cell 
Transplant Versus Tandem High-Dose Melphalan for Front-Line Treatment of Deletion 13q14 
Myeloma – An Interim Analysis of the German DSMM V Trial. Blood. 2009;114: Abstract 51. 
 
48 Bjorkstrand B, Iacobelli S, Hegenbart U, et al. Tandem autologous/reduced-intensity 
conditioning allogeneic stem-cell transplantation versus autologous transplantation in myeloma: 
long-term follow-up. Journal of clinical oncology : official journal of the American Society of 
Clinical Oncology. 2011;29(22):3016-3022. 
 
49 Gahrton G, Iacobelli S, Bjorkstrand B, et al. Autologous/reduced-intensity allogeneic stem cell 
transplantation vs autologous transplantation in multiple myeloma: long-term results of the 
EBMT-NMAM2000 study. Blood. 2013;121(25):5055-5063. 
 
50 Schilling G, Hansen T, Shimoni A, et al. Impact of genetic abnormalities on survival after 
allogeneic hematopoietic stem cell transplantation in multiple myeloma. Leukemia : official 
journal of the Leukemia Society of America, Leukemia Research Fund, UK. 2008;22(6):1250- 
1255. 
 
51 Roos-Weil D, Moreau P, Avet-Loiseau H, et al. Impact of genetic abnormalities after allogeneic 
stem cell transplantation in multiple myeloma: a report of the Societe Francaise de Greffe de 
Moelle et de Therapie Cellulaire. Haematologica. 2011;96(10):1504-1511. 
 
52 El-Cheikh J, Crocchiolo R, Boher JM, et al. Comparable outcomes between Unrelated and 
Related donors after Reduced Intensity Conditioning Allogeneic hematopoietic Stem Cell 
Transplantation in patients with high risk Multiple Myeloma. European journal of haematology. 
2012. 
 
53 Adams J, Palombella VJ, Sausville EA, Johnson J, Destree A, Lazarus DD, et al. Proteasome 
inhibitors: a novel class of potent and effective antitumor agents. Cancer Res 1999;59(11):2615- 
22. 
 
54 Teicher BA, Ara G, Herbst R, Palombella VJ, Adams J. The proteasome inhibitor PS-341 in 
cancer therapy. Clin Cancer Res 1999;5(9):2638-45. 


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55 Cusack JC, Jr., Liu R, Houston M, Abendroth K, Elliott PJ, Adams J, et al. Enhanced 
chemosensitivity to CPT-11 with proteasome inhibitor PS-341: implications for systemic nuclear 
factor-kappaB inhibition. Cancer Res 2001;61(9):3535-40. 
 
56 LeBlanc R, Catley LP, Hideshima T, Lentzsch S, Mitsiades CS, Mitsiades N, et al. Proteasome 
inhibitor PS-341 inhibits human myeloma cell growth in vivo and prolongs survival in a murine 
model. Cancer Res 2002;62(17):4996-5000. 
 
57 Williams S, Pettaway C, Song R, Papandreou C, Logothetis C, McConkey DJ. Differential 
effects of the proteasome inhibitor bortezomib on apoptosis and angiogenesis in human prostate 
tumor xenografts. Mol Cancer Ther 2003;2(9):835-43. 
 
58 Nawrocki ST, Bruns CJ, Harbison MT, Bold RJ, Gotsch BS, Abbruzzese JL, et al. Effects of 
the proteasome inhibitor PS-341 on apoptosis and angiogenesis in orthotopic human pancreatic 
tumor xenografts. Mol Cancer Ther 2002;1(14):1243-53. 
 
59 Satou Y, Nosaka K, Koya Y, Yasunaga JI, Toyokuni S, Matsuoka M. Proteasome inhibitor, 
bortezomib, potently inhibits the growth of adult T-cell leukemia cells both in vivo and in vitro. 
Leukemia 2004;18:1357-63. 
 
60 Boccadoro M, Morgan G, Cavenagh J. Preclinical evaluation of the proteasome inhibitor 
bortezomib in cancer therapy. Cancer Cell Int 2005;5:18. 
 
61 Goel A, Dispenzieri A, Geyer SM, Greiner S, Peng KW, Russell SJ. Synergistic activity of the 
proteasome inhibitor PS-341 with non-myeloablative 153-Sm-EDTMP skeletally targeted 
radiotherapy in an orthotopic model of multiple myeloma. Blood 2006;107(10):4063-70. 
 
62 Mitsiades N, Mitsiades CS, Richardson PG, Poulaki V, Tai YT, Chauhan D, et al. The 
proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional 
chemotherapeutic agents: therapeutic applications. Blood 2003;101(6):2377-80. 
 
63 Sayers TJ, Brooks AD, Koh CY, Ma W, Seki N, Raziuddin A, et al. The proteasome inhibitor 
PS-341 sensitizes neoplastic cells to TRAIL-mediated apoptosis by reducing levels of c-FLIP. 
Blood 2003;102(1):303-10. 
 
64 Yu C, Rahmani M, Conrad D, Subler M, Dent P, Grant S. The proteasome inhibitor 
bortezomib interacts synergistically with histone deacetylase inhibitors to induce apoptosis in 
Bcr/Abl+ cells sensitive and resistant to STI571. Blood 2003;102(10):3765-74. 


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65 O'Connor OA, Smith EA, Toner LE, Teruya-Feldstein J, Frankel S, Rolfe M, et al. The 
combination of the proteasome inhibitor bortezomib and the bcl-2 antisense molecule oblimersen 
sensitizes human B-cell lymphomas to cyclophosphamide. Clin Cancer Res. 2006;12(9):2902- 
11. 
 
66 David E, Sun SY, Waller EK, Chen J, Khuri FR, Lonial S. The combination of the farnesyl 
transferase inhibitor lonafarnib and the proteasome inhibitor bortezomib induces synergistic 
apoptosis in human myeloma cells that is associated with down-regulation of p-AKT. Blood 
2005;106(13):4322-9. 
 
67 McConkey DJ, Pettaway C, Elliott P, Adam J, Papandreou C, Herrmann JL, et al. The 
proteasome as a new drug target in metastatic prostate cancer. In: 7th Annual Genitourinary 
Oncology Conference; 1999 February 1999; Houston, TX. 
 
68 Hideshima T, Richardson P, Chauhan D, Palombella VJ, Elliott PJ, Adams J, et al. The 
proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance 
in human multiple myeloma cells. Cancer Res 2001;61(7):3071-6. 
 
69 Obeng EA, Carlson LM, Gutman DM, Harrington WJ Jr, Lee KP, Boise LH. Proteasome 
inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Blood 
2006;107(12):4907-16. 
 
70 Ling YH, Liebes L, Ng B, Buckley M, Elliott PJ, Adams J, et al. PS-341, a novel proteasome 
inhibitor, induces Bcl-2 phosphorylation and cleavage in association with G2-M phase arrest and 
apoptosis. Mol Cancer Ther 2002;1(10):841-9. 
 
71 Yang Y, Ikezoe T, Saito T, Kobayashi M, Koeffler HP, Taguchi H. Proteasome inhibitor PS- 
341 induces growth arrest and apoptosis of non-small cell lung cancer cells via the JNK/c- 
Jun/AP-1 signaling. Cancer Sci 2004;95(2):176-80. 
 
72 Kaluz S, Kaluzova M, Stanbridge EJ. Proteasomal inhibition attenuates transcriptional activity 
of hypoxia-inducible factor 1 (HIF-1) via specific effect on the HIF-1alpha C-terminal activation 
domain. Mol Cell Biol 2006;26(15):5895-907. 
 
73 An WG, Hwang SG, Trepel JB, Blagosklonny MV. Protease inhibitor-induced apoptosis: 
accumulation of wt p53, p21WAF1/CIP1, and induction of apoptosis are independent markers of 
proteasome inhibition. Leukemia 2000;14(7):1276-83. 


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74 Roccaro AM, Hideshima T, Raje N, Kumar S, Ishitsuka K, Yasui H, et al. Bortezomib 
mediates antiangiogenesis in multiple myeloma via direct and indirect effects on endothelial 
cells. Cancer Res 2006;66(1):184-91. 
75 Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Fanourakis G, Gu X, et al. Molecular 
sequelae of proteasome inhibition in human multiple myeloma cells. Proc Natl Acad Sci U S A 
2002;99(22):14374-9. 
 
76 Orlowski RZ, Stinchcombe TE, Mitchell BS, Shea TC, Baldwin AS, Stahl S, et al. Phase I 
Trial of the Proteasome Inhibitor PS-341 in Patients with Refractory Hematologic Malignancies. 
J Clin Oncol 2002;20(22):4420-7. 
 
77 Orlowski RZ, Stinchcombe TE, Mitchell BS, Shea TC, Baldwin AS, Stahl S, et al. Phase I 
Trial of the Proteasome Inhibitor PS-341 in Patients with Refractory Hematologic Malignancies. 
J Clin Oncol 2002;20(22):4420-7. 
 
78 Aghajanian C, Soignet S, Dizon DS, Pien CS, Adams J, Elliott PJ, et al. A Phase I Trial of the 
Novel Proteasome Inhibitor PS341 in Advanced Solid Tumor Malignancies. Clin Cancer Res 
2002;8(8):2505-11. 
 
79 Papandreou CN, Daliani DD, Nix D, Yang H, Madden T, Wang X, et al. Phase I trial of the 
proteasome inhibitor bortezomib in patients with advanced solid tumors with observations in 
androgen-independent prostate cancer. J Clin Oncol 2004;22(11):2108-21. 
 
80 Dimopoulos MA, Anagnostopoulos A, Kyrtsonis MC, Castritis E, Bitsaktsis A, Pangalis GA. 
Treatment of relapsed or refractory Waldenström's macroglobulinemia with bortezomib. 
Haematologic. 2005;90(12):1655-8. 
 
81 Jagannath S, Barlogie B, Berenson J, Siegel D, Irwin D, Richardson PG, et al. A phase 2 study 
of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol 2004;127(2):165- 
72. 
 
82 Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, et al. A Phase 2 
Study of Bortezomib in Relapsed, Refractory Myeloma. N Engl J Med 2003;348(26):2609-17. 
 
83 Bladé J, Samson D, Reece D, Apperley J, Bjorkstrand B, Gahrton G, et al. Criteria for 
evaluating disease response and progression in patients with multiple myeloma treated by high- 
dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. 
European Group for Blood and Marrow Transplant. Br J Haematol 1998;102(5):1115-23. 


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84 Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, et al. 
Bortezomib or High-Dose Dexamethasone for Relapsed Multiple Myeloma. N Engl J Med 
2005;352(24):2487-98. 
85 Richardson P, Sonneveld P, Schuster M, Irwin D, Stadtmauer E, Facon T, et al. Bortezomib 
Continues Demonstrates Superior Efficacy Compared with High-Dose Dexamethasone in 
Relapsed Multiple Myeloma: Updated Results of the APEX Trail. Blood 2005;106(11):Abstract 
2547. 
 
86 Fisher R, Bernstein S, Kahl B, Djulbegovic B, Robertson M, de Vos S, et al. Multicenter Phase 
II Study of Bortezomib in Patients With Relapsed or Refractory Mantle Cell Lymphoma. J Clin 
Oncol 2006;24(30):4867-74. 
 
87 Goy A, Bernstein S, Kahl B, Djulbegovic B, Robertson M, Vos S, et al. Durable Responses 
with Bortezomib in Patients with Relapsed or Refractory mantle Cell Lymphoma: Updated 
Time-to-Event Analyses of the Multicenter PINNACLE Study. Blood 2007;110:Abstract 125. 
 
88 San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, et al. 
Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J 
Med 2008;359(9):906-17. 
 
89 San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, et al. 
Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J 
Med 2008;359(9):906-17. 
 
90 Mateos M-V, Richardson PG, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, et al. 
Bortezomib plus melphalan-prednisone continues to demonstrate a survival benefit vs 
melphalan-prednisone in the phase III VISTA trial in previously untreated multiple myeloma 
after 3 years' follow-up and extensive subsequent therapy use. Blood 2009;114:Abstract 3859. 
 
91 San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, et al. Continued Overall Survival 
Benefit After 5 Years’ Follow-up with Bortezomib-Melphalan-Prednisone (VMP) Versus 
Melphalan-Prednisone (MP) in Patients with Previously Untreated Multiple Myeloma, and No 
Increased Risk of Second Primary Malignancies: Final Results of the Phase 3 VISTA Trial. Blood 
2011;118:Abstract 476 
 
92 Palumbo A, Gay F, Falco P, et al. Bortezomib as induction before autologous transplantation, 
followed by lenalidomide as consolidation-maintenance in untreated multiple myeloma patients. 
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 
2010;28(5):800-807. 


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93 McCarthy P, Owzar, K, Anderson, KC, et al. Phase III intergroup study of lenalidomide versus 
placebo maintenance therapy following single autologous stem cell transplant for multiple 
myeloma: CALBG 100104. J Clin Oncol. 2010;28:577s. 
 
94 Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance after stem-cell 
transplantation for multiple myeloma. N Engl J Med. 2012;366(19):1782-1791. 
 
95 McCarthy PL, Owzar K, Hofmeister CC, et al. Lenalidomide after stem-cell transplantation for 
multiple myeloma. N Engl J Med. 2012;366(19):1770-1781. 
 
96 Sun K, Welniak LA, Panoskaltsis-Mortari A, et al. Inhibition of acute graft-versus-host disease 
with retention of graft-versus-tumor effects by the proteasome inhibitor bortezomib. Proceedings 
of the National Academy of Sciences of the United States of America. 2004;101(21):8120-8125. 
 
97 Sun K, Wilkins DE, Anver MR, et al. Differential effects of proteasome inhibition by bortezomib 
on murine acute graft-versus-host disease (GVHD): delayed administration of bortezomib results 
in increased GVHD-dependent gastrointestinal toxicity. Blood. 2005;106(9):3293-3299. 
 
98 Vodanovic-Jankovic S, Hari P, Jacobs P, Komorowski R, Drobyski WR. NF-kappaB as a target 
for the prevention of graft-versus-host disease: comparative efficacy of bortezomib and PS-1145. 
Blood. 2006;107(2):827-834. 
 
99 Sun K, Li M, Sayers TJ, Welniak LA, Murphy WJ. Differential effects of donor T-cell cytokines 
on outcome with continuous bortezomib administration after allogeneic bone marrow 
transplantation. Blood. 2008;112(4):1522-1529. 
 
100 Nencioni A, Schwarzenberg K, Brauer KM, et al. Proteasome inhibitor bortezomib modulates 
TLR4-induced dendritic cell activation. Blood. 2006;108(2):551-558. 
 
101 Blanco B, Perez-Simon JA, Sanchez-Abarca LI, et al. Bortezomib induces selective depletion 
of alloreactive T lymphocytes and decreases the production of Th1 cytokines. Blood. 
2006;107(9):3575-3583. 
 
102 O'Shaughnessy MJ, Vogtenhuber C, Sun K, et al. Ex vivo inhibition of NF-kappaB signaling 
in alloreactive T-cells prevents graft-versus-host disease. American journal of transplantation : 
official journal of the American Society of Transplantation and the American Society of Transplant 
Surgeons. 2009;9(3):452-462. 
 
103 Tosi P, Zamagni E, Cangini D, et al. Complete remission upon bortezomib-dexamethasone 
therapy in three heavily pretreated multiple myeloma patients relapsing after allogeneic stem cell 
transplantation. Annals of hematology. 2006;85(8):549-551. 


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104 Kuroda J, Kobayashi T, Tsutsumi Y, et al. Bortezomib for post-allogeneic hematopoietic stem 
transplantation relapse and GVHD in multiple myeloma: a single institute experience. 
International journal of hematology. 2010;92(4):669-672. 
 
105 Bruno B, Patriarca F, Sorasio R, et al. Bortezomib with or without dexamethasone in relapsed 
multiple myeloma following allogeneic hematopoietic cell transplantation. Haematologica. 
2006;91(6):837-839. 
 
106 van de Donk NW, Kroger N, Hegenbart U, et al. Remarkable activity of novel agents 
bortezomib and thalidomide in patients not responding to donor lymphocyte infusions following 
nonmyeloablative allogeneic stem cell transplantation in multiple myeloma. Blood. 
2006;107(8):3415-3416. 
 
107 Kroger N, Zabelina T, Ayuk F, et al. Bortezomib after dose-reduced allogeneic stem cell 
transplantation for multiple myeloma to enhance or maintain remission status. Experimental 
hematology. 2006;34(6):770-775. 
 
108 El-Cheikh J, Michallet M, Nagler A, et al. High response rate and improved graft-versus-host 
disease following bortezomib as salvage therapy after reduced intensity conditioning allogeneic 
stem cell transplantation for multiple myeloma. Haematologica. 2008;93(3):455-458. 
 
109 Kroger N, Badbaran A, Lioznov M, et al. Post-transplant immunotherapy with donor- 
lymphocyte infusion and novel agents to upgrade partial into complete and molecular remission in 
allografted patients with multiple myeloma. Experimental hematology. 2009;37(7):791-798. 
 
110 Nishihori T, Alekshun TJ, Shain K, et al. Bortezomib salvage followed by a Phase I/II study of 
bortezomib plus high-dose melphalan and tandem autologous transplantation for patients with 
primary resistant myeloma. Br J Haematol. 2012;157(5):553-563. 
 
111 Roussel M, Moreau P, Huynh A, et al. Bortezomib and high-dose melphalan as conditioning 
regimen before autologous stem cell transplantation in patients with de novo multiple myeloma: a 
phase 2 study of the Intergroupe Francophone du Myelome (IFM). Blood. 2010;115(1):32-37. 
 
112 Lonial S, Kaufman J, Tighiouart M, et al. A phase I/II trial combining high-dose melphalan and 
autologous transplant with bortezomib for multiple myeloma: a dose- and schedule-finding study. 
Clin Cancer Res. 2010;16(20):5079-5086. 
 
113 Nishihori T, Ochoa-Bayona JL, Kim J, et al. Allogeneic hematopoietic cell transplantation for 
consolidation of VGPR or CR for newly diagnosed multiple myeloma. Bone Marrow Transplant. 
2013. 


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114 Lokhorst H, Einsele H, Vesole D, et al. International Myeloma Working Group consensus 
statement regarding the current status of allogeneic stem-cell transplantation for multiple 
myeloma. J Clin Oncol. 2010;28(29):4521-4530. 
 
115 Kneppers E, van der Holt B, Kersten MJ, et al. Lenalidomide maintenance after 
nonmyeloablative allogeneic stem cell transplantation in multiple myeloma is not feasible: results 
of the HOVON 76 Trial. Blood. 2011;118(9):2413-2419. 
 
116 Koreth J, Stevenson KE, Kim HT, et al. Bortezomib, tacrolimus, and methotrexate for 
prophylaxis of graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell 
transplantation from HLA-mismatched unrelated donors. Blood. 2009;114(18):3956-3959. 
 
117 Koreth J, Stevenson KE, Kim HT, et al. Bortezomib-based graft-versus-host disease 
prophylaxis in HLA-mismatched unrelated donor transplantation. Journal of clinical oncology : 
official journal of the American Society of Clinical Oncology. 2012;30(26):3202-3208. 
 
118 Gupta, N., et al., Clinical Pharmacokinetics of Intravenous and Oral MLN9708, An 
Investigational Proteasome Inhibitor: An Analysis of Data From Four Phase 1 Monotherapy 
Studies. Blood (ASH Annual Meeting Abstracts), 2010. 116(21): p. abstr 1813. 
 
119 Gupta, N., M. Saleh, and K. Venkatakrishnan. Flat-Dosing Versus BSA-Based Dosing for 
MLN9708, An Investigational Proteasome Inhibitor: Population Pharmacokinetic (PK) Analysis 
of Pooled Data From 4 Phase-1 Studies in 53rd ASH Annual Meeting and Exposition. 2011. San 
Diego, CA. 
 
120 Chow, L.Q., et al. MLN9708, an investigational proteasome inhibitor, in patients with solid 
tumors; Updated phase 1 results in Head and Neck Symposium. 2012. Phoenix, AZ 
 
121 Assouline, S., et al. Once-weekly MLN9708, an investigational proteasome inhibitor, in 
patients with relapsed/refractory lymphoma: results of a phase 1 dose-escalation study in 17th 
EHA Annual Congress. 2012. Amsterdam, the Netherlands. 
 
122 Lonial, S., et al. Phase I study of twice-weekly dosing of the investigational oral proteasome 
inhibitor MLN9708 in patients (pts) with relapsed and/or refractory multiple myeloma (MM) in 
ASCO Annual Meeting. 2012. Chicago, Illinois. 
 
123 Kumar, S., et al. Oral weekly MLN9708, an investigational proteasome inhibitor, in 
combination with lenalidomide and dexamethasone in patients (pts) with previously untreated 
multiple myeloma (MM): A phase I/II study in ASCO Annual Meeting. 2012. Chicago, Illinois. 
 
124 Merlini, G., et al. MLN9708, a Novel, Investigational Oral Proteasome Inhibitor, in Patients 
with Relapsed or Refractory Light-Chain Amyloidosis (AL): Results of a Phase 1 Study in 54th 
ASH Annual Meeting and Exposition. 2012. Atlanta, Georgia. 


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125 Kumar, S. et al. A Phase 1/2 Study of Weekly MLN9708, an Investigational Oral Proteasome 
Inhibitor, in Combination with Lenalidomide and Dexamethasone in Patients with Previously 
Untreated Multiple Myeloma (MM) in 54th ASH Annual Meeting and Exposition. 2012. Atlanta, 
Georgia. 
 
126Richardson, P.G., et al. MLN9708, an investigational proteasome inhibitor, in combination with 
lenalidomide and dexamethasone in previously untreated multiple myeloma patients (pts): 
Evaluation of weekly and twice-weekly dosing in 17th EHA Annual Congress. 2012. Amsterdam, 
the Netherlands. 
 
127 San Miguel, J., et al. Oral MLN9708, an an investigational proteasome inhibitor, in 
combination with melphalan and prednisone in patients with previously untreated multiple 
myeloma: a phase 1 study in 17th EHA Annual Congress. 2012. Amsterdam, the Netherlands. 
 
128 Kumar S., et al. Weekly Dosing of the Investigational Oral Proteasome Inhibitor MLN9708 in 
Patients with Relapsed and/or Refractory Multiple Myeloma: Results From a Phase 1 Dose 
Escalation Study in 53rd ASH Annual Meeting and Exposition. 2011. San Diego, CA 
 
129 Kumar S., et al. Weekly dosing of the investigational oral proteasome inhibitor MLN9708 in 
patients (pts) with relapsed/refractory multiple myeloma (MM): A phase I study in ASCO Annual 
Meeting. 2012. Chicago, Illinois. 
 
130 Sanchorawala V., et al. Poster Presentation: Phase 1 study of MLN9708, a novel, 
investigational oral proteasome inhibitor, in patients with relapsed or refractory light-chain 
amyloidosis. XIII International Symposium on Amyloidosis, Groningen, The Netherlands 2012. 
 
131 Grever M, Leiby J, Kraut E, et al. A comprehensive phase I and II clinical investigation of 
fludarabine phosphate. Semin Oncol 1990;17 (Suppl. 8)(5):39-48. 
 
132 Lunceford JK, Davidian M, and Tsiatis AA (2002), Estimation of Survival Distributions of 
Treatment Policies in Two-Stage Randomization Designs in Clinical Trials, Biometrics 58: 48-57. 
133 Yavusm I. (2013) Non-Parametric Interference and regression analysis for cumulative 
incidence fuction under two-stage randomization. Doctoral Dissertation, University of Pittsburgh.