Clinical trial NCT02902965
Conditions: Multiple Myeloma
Keywords: Bruton's Tyrosine Kinase Bortezomib Dexamethasone Ibrutinib
Sponsor: Pharmacyclics Switzerland GmbH
Start date: 2016-09-20; Completion date: 2018-10-26
Enrollment: 74 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase 2 open-label study to evaluate the efficacy and safety of ibrutinib in combination with bortezomib and dexamethasone for patients with relapsed or relapsed and refractory multiple myeloma.

Detailed description:
Bruton's tyrosine kinase (Btk) is an enzyme that is present in hematopoeitic cells other than T cells and is necessary for downstream signal transduction from various hematopoietic receptors including the B cell receptor as well as some Fc, chemokine and adhesion receptors, and is crucial for both B cell development and osteoclastogenesis. Although down-regulated in normal plasma cells, Btk is highly expressed in the malignant cells from many myeloma patients and some cell lines. Ibrutinib is a potent and specific inhibitor of Btk currently in Phase 2 and 3 clinical trials. The current study is designed and intended to determine the safety and efficacy of ibrutinib in combination with bortezomib and dexamethasone in subjects with relapsed/relapsed and refractory multiple myeloma.

Arms: arm 1: None
Interventions: intervention 1: Ibrutinib intervention 2: Bortezomib intervention 3: Dexamethasone
Intervention descriptions: intervention 1: Ibrutinib 840 mg orally, once daily continuously starting day 1 of cycle 1 until confirmed disease progression, unacceptable toxicity or other protocol specified reason for discontinuation intervention 2: Cycles 1-8: (21-day cycle): Bortezomib 1.3 mg/m\^2 sub-cutaneously on days 1, 4, 8, and 11 of each Cycle Cycles 9-12: (42-day cycle): Bortezomib 1.3 mg/m\^2 sub-cutaneously on days 1, 8, 22 and 29 of each Cycle intervention 3: Cycles 1-8: (21-day cycle): Dexamethasone 20 mg orally on days 1, 2, 4, 5, 8, 9, 11 and 12 of each cycle Cycles 9-12: (42-day cycle): Dexamethasone 20 mg orally on days 1, 2, 8, 9, 22, 23, 29 and 30 of each cycle Cycles 13+ (28-day cycle): Dexamethasone 40 mg orally once weekly

Dose adjustment of dexamethasone to 10 mg on days specified during cycles 1-12 and 20 mg weekly during cycles 13+ is recommended for subjects \>75 years of age.

Following implementation of Protocol Amendment 4, dexamethasone administration was reduced to Days 1, 4, 8 and 11 during each 21-day cycle (Cycles 1-8) and on Days 1, 8, 22, 29 on each 42-day cycle (Cycles 9-12) and unchanged thereafter.

Protocol documents:
Prot_000.pdf: 
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PROTOCOL 
TITLE: 
An Open-label study of Ibrutinib in Combination with 
Bortezomib and Dexamethasone in Subjects with Relapsed or 
Relapsed and Refractory Multiple Myeloma 
PROTOCOL NUMBER: 
PCYC-1139-CA 
STUDY DRUG: 
Ibrutinib (PCI-32765) 
EudraCT NUMBER: 
2015-005105-36 
SPONSOR MEDICAL 
MONITOR: 
Edyta Dobkowska, MD 
Pharmacyclics Switzerland GmbH 
Phone: +41 (52)5560840 
Fax: 
+41 (76) 392 2152 
Email: edobkowska@ch.pcyc.com 
SPONSOR: 
Pharmacyclics Switzerland GmbH 
Mühlentalstrasse 36  
8200 Schaffhausen 
Switzerland 
DATE FINAL 
18 November 2015 
Amendment 1: 
29 February 2016 
Amendment 2: 
08 December 2016 
Amendment 3: 
18 January 2017 
Amendment 4: 
12 May 2017 
Confidentiality Statement 
This document contains confidential information of Pharmacyclics and Pharmacyclics Switzerland GmbH 
that must not be disclosed to anyone other than the recipient study staff and members of the institutional 
review board/ethics committee. This information cannot be used for any other purpose other than the 
evaluation or conduct of the clinical study without the prior written consent of Pharmacyclics. 




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TABLE OF CONTENTS 
PROTOCOL APPROVAL PAGE ...............................................................................................2 
TABLE OF CONTENTS ..............................................................................................................3 
LIST OF APPENDICES ...............................................................................................................7 
LIST OF FIGURES .......................................................................................................................8 
SYNOPSIS ......................................................................................................................................9 
ABBREVIATIONS ......................................................................................................................15 
1.
BACKGROUND ...........................................................................................................18
1.1. 
Multiple Myeloma ..........................................................................................................18 
1.1.1. 
Existing Therapies and Unmet Need in Relapsed or Relapsed and Refractory 
Multiple Myeloma ..........................................................................................................19 
1.1.2. 
BTK Inhibition as a Treatment Option for MM .............................................................20 
1.2. 
Ibrutinib Overview .........................................................................................................21 
1.2.1. 
Summary of Nonclinical Data ........................................................................................22 
1.2.1.1. Pharmacology .................................................................................................................22 
1.2.1.2. Safety Pharmacology and Toxicology ...........................................................................22 
1.2.2. 
Summary of Clinical Data ..............................................................................................23 
1.2.2.1. Pharmacokinetics and Product Metabolism ...................................................................23 
1.2.3. 
Summary of Clinical Safety ...........................................................................................23 
1.2.3.1. Monotherapy Studies ......................................................................................................23 
1.2.3.2. Combination Therapy Studies ........................................................................................24 
1.2.4. 
Risks ...............................................................................................................................25 
1.2.4.1. Bleeding-related Events .................................................................................................25 
1.2.4.2. Infections ........................................................................................................................25 
1.2.4.3. Cytopenias ......................................................................................................................25 
1.2.4.4. Interstitial Lung Disease (ILD) ......................................................................................25 
1.2.4.5. Atrial Fibrillation ............................................................................................................25 
1.2.4.6. Non-melanoma Skin Cancer ..........................................................................................26 
1.2.4.7. Tumor Lysis Syndrome ..................................................................................................26 
1.2.4.8. Diarrhea ..........................................................................................................................26 
1.2.4.9. Rash ................................................................................................................................26 
1.2.4.10. Hypertension ..................................................................................................................26 
1.2.5. 
Summary of Clinical Data with Ibrutinib in MM ..........................................................26 
1.2.5.1. PCYC-1111-CA .............................................................................................................26 
1.2.5.2. PCYC-1119-CA .............................................................................................................27 
1.2.5.3. PCYC-1139-CA Safety Overview .................................................................................28 
1.3. 
Bortezomib (VELCADE®) Description .........................................................................29 
1.3.1. 
Pharmacokinetics and Product Metabolism ...................................................................29 
1.3.2. 
Summary of Clinical Data for Bortezomib and Dexamethasone in MM .......................30 
1.3.3. 
Summary of Clinical Safety for Bortezomib ..................................................................31 
1.4. 
Justification of Study Design and Dose Rationale .........................................................31 
2.
STUDY OBJECTIVE ..................................................................................................33
2.1. 
Primary Objective ..........................................................................................................33 
2.2. 
Secondary Objective(s) ..................................................................................................33 
2.3. 
Exploratory Objectives ...................................................................................................34 


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3.
STUDY DESIGN ..........................................................................................................34
3.1. 
Overview of Study Design .............................................................................................34 
3.2. 
Statement of Compliance ...............................................................................................37 
4.
SUBJECT SELECTION ..............................................................................................37
4.1. 
Inclusion Criteria ............................................................................................................37 
4.2. 
Exclusion Criteria ...........................................................................................................38 
5.
TREATMENT OF SUBJECTS ..................................................................................40
5.1. 
Enrollment ......................................................................................................................40 
5.2. 
Study Treatment .............................................................................................................40 
5.3. 
Ibrutinib ..........................................................................................................................40 
5.3.1. 
Formulation, Packaging, and Storage of Ibrutinib .........................................................40 
5.3.2. 
Dosage and Administration of Ibrutinib .........................................................................41 
5.3.3. 
Dose Hold, Reduction or Discontinuation of Ibrutinib ..................................................41 
5.3.4. 
Dose Modification of Ibrutinib ......................................................................................42 
5.3.5. 
Dose Modification for Hepatic Impaired Subjects .........................................................44 
5.4. 
Bortezomib .....................................................................................................................44 
5.4.1. 
Formulation, Packaging, and Storage of Bortezomib ....................................................44 
5.4.2. 
Dosage, Preparation and Administration of Bortezomib ...............................................44 
5.4.3. 
Dose Hold, Reduction or Discontinuation of Bortezomib .............................................45 
5.4.4. 
Dose Modification of Bortezomib ..................................................................................45 
5.5. 
Dexamethasone ..............................................................................................................47 
5.5.1. 
Formulation, Packaging, and Storage of Dexamethasone ..............................................47 
5.5.2. 
Dosage and Administration of Dexamethasone .............................................................47 
5.5.3. 
Dose Modification of Dexamethasone ...........................................................................48 
5.6. 
Prophylaxis and Treatment of Infections in Multiple Myeloma ....................................49 
5.7. 
Overdose .........................................................................................................................50 
5.7.1. 
Ibrutinib ..........................................................................................................................50 
5.7.2. 
Bortezomib .....................................................................................................................50 
5.7.3. 
Dexamethasone ..............................................................................................................50 
5.8. 
Criteria for Permanent Discontinuation of Study Treatment .........................................50 
6.
CONCOMITANT MEDICATIONS/PROCEDURES ..............................................50
6.1. 
Concomitant Medications ..............................................................................................50 
6.1.1. 
Permitted Concomitant Medications ..............................................................................50 
6.1.2. 
Medications to be Used with Caution ............................................................................51 
6.1.2.1. CYP3A Inhibitors/Inducers ............................................................................................51 
6.1.2.2. Drugs that may Have Their Plasma Concentrations Altered by Ibrutinib .....................52 
6.1.2.3. QT Prolonging Agents ...................................................................................................52 
6.1.2.4. Concomitant Use of Antiplatelet Agents and Anticoagulants........................................52 
6.1.3. 
Prohibited Concomitant Medications .............................................................................53 
6.2. 
Guidelines for Ibrutinib Management with Surgeries or Procedures .............................53 
6.2.1. 
Minor Procedures ...........................................................................................................53 
6.2.2. 
Major Procedures ...........................................................................................................53 
6.2.3. 
Emergency Procedures ...................................................................................................53 
7.
STUDY EVALUATIONS ............................................................................................54
7.1. 
Screening/Administrative ...............................................................................................54 
7.1.1. 
Informed Consent ...........................................................................................................54 


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7.1.2. 
Confirm Eligibility .........................................................................................................54 
7.1.3. 
Medical History and Demographics ...............................................................................54 
7.1.4. 
Prior and Concomitant Medications ...............................................................................54 
7.1.5. 
Adverse Events ...............................................................................................................54 
7.2. 
Assessments ...................................................................................................................55 
7.2.1. 
Eye-related Symptom Assessment .................................................................................55 
7.2.2. 
Physical Examination, Height, and Weight ...................................................................55 
7.2.3. 
Eastern Cooperative Oncology Group (ECOG) Performance Status .............................55 
7.2.4. 
Vital Signs ......................................................................................................................55 
7.2.5. 
Follow-up for Other Malignancies .................................................................................55 
7.3. 
Clinical Laboratory Assessments ...................................................................................55 
7.3.1. 
Hematology ....................................................................................................................55 
7.3.2. 
Serum Chemistry ............................................................................................................56 
7.3.3. 
Creatinine Clearance ......................................................................................................56 
7.3.4. 
Coagulation Studies ........................................................................................................56 
7.3.5. 
Hepatitis Serologies ........................................................................................................56 
7.3.6. 
Pregnancy Test ...............................................................................................................56 
7.3.7. 
C-reactive Protein and Serum β2-microglobulin ...........................................................56 
7.4. 
Diagnostic/Procedures ....................................................................................................56 
7.4.1. 
Electrocardiogram ..........................................................................................................56 
7.5. 
Efficacy Assessments .....................................................................................................57 
7.5.1. 
Serum and Urine Protein Electrophoresis ......................................................................58 
7.5.2. 
Serum Free Light Chain Assay ......................................................................................58 
7.5.3. 
Serum and Urine Immunofixation ..................................................................................58 
7.5.4. 
Quantitative Serum Immunoglobulins ...........................................................................58 
7.5.5. 
Bone Radiologic Assessment .........................................................................................58 
7.5.6. 
Bone Marrow Biopsy and/or Aspirate ...........................................................................59 
7.5.7. 
Assessment of Minimal Residual Disease (MRD) .........................................................59 
7.6. 
Biomarker, Correlative and Special Studies ..................................................................59 
7.6.1. 
Pharmacokinetics ...........................................................................................................59 
7.6.2. 
Biomarkers .....................................................................................................................60 
7.6.2.1. Genetic and Molecular Prognostic Markers ...................................................................60 
7.6.3. 
Serum Carboxy-terminal Collagen Crosslinks (CTX) ...................................................60 
7.7. 
Sample Collection and Handling ....................................................................................61 
7.8. 
Survival and Subsequent Anti-cancer Therapies............................................................61 
7.8.1. 
Survival ..........................................................................................................................61 
7.8.2. 
Subsequent Anti-cancer Therapies .................................................................................61 
8.
STUDY PROCEDURES ..............................................................................................61
8.1. 
Overview ........................................................................................................................61 
8.2. 
Screening Phase ..............................................................................................................61 
8.2.1. 
Screening Visit ...............................................................................................................62 
8.3. 
Treatment Phase .............................................................................................................63 
8.3.1. 
Cycle 1, Day 1 ................................................................................................................63 
8.3.2. 
Cycle 1-8, Days 4 and 11 ...............................................................................................64 
8.3.3. 
Cycle 1-12, Day 8 ...........................................................................................................64 
8.3.4. 
Cycle 2, Day 1 ................................................................................................................64 


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8.3.5. 
Cycle 2, Day 2 ................................................................................................................65 
8.3.6. 
Cycles 3-12, Day 1 (odd cycles) ....................................................................................65 
8.3.7. 
Cycles 4-12, Day 1 (even cycles) ...................................................................................66 
8.3.8. 
Cycles 9-12, Days 22 and 29 ..........................................................................................66 
8.3.9. 
Cycle 13 and Beyond, Day 1 (odd cycles) .....................................................................67 
8.3.10. 
Cycle 14 and Beyond, Day 1 (even cycles) ...................................................................67 
8.3.11. 
Suspected PD Visit .........................................................................................................68 
8.3.12. 
End-of-Treatment Visit ..................................................................................................68 
8.4. 
Follow-up Phase .............................................................................................................69 
8.4.1. 
Response Follow-up .......................................................................................................69 
8.4.2. 
Long-Term Follow-up ....................................................................................................69 
9. 
SUBJECT COMPLETION AND WITHDRAWAL .................................................70 
9.1. 
Completion .....................................................................................................................70 
9.2. 
Withdrawal from Study Treatment ................................................................................70 
9.3. 
Withdrawal from Study (Study Exit) .............................................................................70 
10. 
STATISTICAL METHODS ........................................................................................71 
10.1. 
Analysis Populations ......................................................................................................71 
10.1.1. 
All-treated Population ....................................................................................................71 
10.1.2. 
Response-evaluable Population ......................................................................................71 
10.1.3. 
Safety Population ...........................................................................................................71 
10.1.4. 
Additional Analysis Populations ....................................................................................71 
10.2. 
Sample Size Determination ............................................................................................72 
10.3. 
Subject Information ........................................................................................................72 
10.4. 
Efficacy Analyses ...........................................................................................................72 
10.4.1. 
Primary Endpoint ...........................................................................................................72 
10.4.2. 
Secondary Endpoints ......................................................................................................73 
10.5. 
Analysis Methods ...........................................................................................................73 
10.5.1. 
Primary Efficacy Analyses .............................................................................................73 
10.5.2. 
Secondary Efficacy Analysis .........................................................................................73 
10.5.3. 
Exploratory Efficacy Analysis .......................................................................................74 
10.5.4. 
Pharmacokinetic Analyses .............................................................................................74 
10.5.4.1. Ibrutinib ..........................................................................................................................74 
10.5.4.2. Bortezomib .....................................................................................................................74 
10.5.5. 
Biomarker Analysis Plan ................................................................................................75 
10.5.6. 
Safety Analyses ..............................................................................................................75 
10.5.6.1. Sponsor Safety Review Committee ................................................................................76 
10.5.7. 
Interim Analysis .............................................................................................................76 
10.5.8. 
Primary Analysis ............................................................................................................77 
10.5.9. 
Subgroup Analysis .........................................................................................................77 
11. 
ADVERSE EVENT REPORTING .............................................................................77 
11.1. 
Adverse Event Definitions and Classifications ..............................................................77 
11.1.1. 
Adverse Events ...............................................................................................................77 
11.1.2. 
Serious Adverse Events ..................................................................................................78 
11.1.3. 
Unexpected Adverse Events ...........................................................................................79 
11.1.4. 
Severity Criteria (Grade 1-5) ..........................................................................................79 
11.1.5. 
Causality (Attribution) ...................................................................................................79 


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11.2. 
Documenting and Reporting of Adverse Events ............................................................80 
11.2.1. 
Special Reporting Situations ..........................................................................................80 
11.2.2. 
Adverse Event Reporting Procedures.............................................................................80 
11.2.2.1. All Adverse Events .........................................................................................................80 
11.2.2.2. Expedited Reporting Requirements for Serious Adverse Events ...................................81 
11.2.3. 
Other Malignancies ........................................................................................................82 
11.2.4. 
Pregnancy .......................................................................................................................82 
11.2.4.1. Pregnancy Reporting ......................................................................................................82 
11.2.5. 
Eye-Related Adverse Events ..........................................................................................83 
11.2.6. 
Adverse Events of Special Interest .................................................................................83 
11.2.6.1. Major Hemorrhage .........................................................................................................83 
12.
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS ..............83
12.1. 
Regulatory and Ethical Compliance ...............................................................................83 
12.2. 
Research Ethics Board (REB) and Independent Ethics Committee (IEC) Approval.....83 
12.3. 
Informed Consent ...........................................................................................................84 
12.4. 
Quality Control and Quality Assurance .........................................................................84 
12.5. 
Protected Subject Health Information Authorization .....................................................84 
12.6. 
Study Files and Record Retention ..................................................................................85 
12.7. 
Case Report Forms and Record Maintenance ................................................................86 
12.8. 
Investigational Study Drug Accountability ....................................................................86 
12.9. 
Study Monitoring/Audit Requirements ..........................................................................86 
12.10. 
Investigator Responsibilities ..........................................................................................87 
12.11. 
Sponsor Responsibilities ................................................................................................87 
12.12. 
Financial Disclosure .......................................................................................................88 
12.13. 
Liability and Clinical Trial Insurance ............................................................................88 
12.14. 
Protocol Amendments ....................................................................................................88 
12.15. 
Publication of Study Results ..........................................................................................89 
12.16. 
Study Discontinuation ....................................................................................................89 
12.17. 
Study Completion ...........................................................................................................89 
13.
REFERENCES .............................................................................................................90
14.
APPENDICES ..............................................................................................................93
LIST OF APPENDICES 
Appendix 1. 
Schedule of Assessments .....................................................................................94 
Appendix 2. 
ECOG Status Scores.............................................................................................98 
Appendix 3. 
Cockcroft-Gault Formula for Estimating Creatinine Clearance ..........................99 
Appendix 4. 
Lines of Therapy ................................................................................................100 
Appendix 5. 
Inhibitors and Inducers of CYP3A .....................................................................101 
Appendix 6. 
International Myeloma Working Group Response Criteria (Rajkumar 2011) ...102 
Appendix 7. 
International Staging System (ISS) for Myeloma Criteria (Greipp 2005) .........104 
Appendix 8. 
Child-Pugh Score for Subjects with Liver Impairment ......................................105 
LIST OF IN-TEXT TABLES 
Table 1: 
Ibrutinib Dose Modification Guidance ........................................................................43 


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Table 2: 
Ibrutinib Dose Modifications .......................................................................................43 
Table 3: 
Dose Modification or Interruption for Bortezomib Toxicity .......................................46 
Table 4: 
Dose Reduction of Bortezomib ....................................................................................47 
Table 5: 
Dose Modification of Dexamethasone.........................................................................49 
Table 6: 
Pharmacokinetic Sample Schedule for Ibrutinib and Bortezomib ...............................60 
LIST OF FIGURES 
Figure 1: Study Design Schematic ..............................................................................................36 


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SYNOPSIS 
Study Title 
An Open-label study of Ibrutinib in Combination with Bortezomib and 
Dexamethasone in Subjects with Relapsed or Relapsed and Refractory Multiple 
Myeloma 
Protocol Number 
PCYC-1139-CA 
Study Phase 
2 
Study Duration 
Approximately 3 years 
Centers 
Multicenter – International 
Population 
Relapsed or relapsed and refractory multiple myeloma (MM) 
Study Treatment 
Ibrutinib will be supplied as 140 mg hard gelatin capsules for oral (PO) 
administration. 
Bortezomib will be supplied as a 3.5 mg single use vial for subcutaneous (SC) 
administration. 
Dexamethasone will be supplied as tablets in various strengths for PO 
administration 
Objectives 
Primary Objective: 
•
To evaluate Progression-Free Survival (PFS) according to International
Myeloma Working Group (IMWG) response criteria (Rajkumar 2011) in
subjects with relapsed or relapsed and refractory MM.
Secondary Objectives: 
•
Overall Response Rate (≥PR)
•
PFS Rate at Landmark Points
•
Duration of Response (DOR)
•
Overall Survival (OS)
•
Time to Progression (TTP)
•
To evaluate the safety and tolerability of ibrutinib in combination with
bortezomib and dexamethasone.
Exploratory Objectives: 
•
To evaluate the pharmacokinetics of ibrutinib and bortezomib when dosed in
combination with dexamethasone
•
To evaluate potential prognostic and predictive biomarkers relative to
treatment outcomes (including gene expression profiles [GEP], secreted
proteins, bone turnover and/or immunophenotyping) in subjects with
relapsed or relapsed and refractory MM.
•
To assess the utilization and outcomes of subsequent anti-cancer therapies in
subjects with relapsed or relapsed and refractory MM.


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Study Design 
The study will be conducted as an open-label, international, multicenter study of 
ibrutinib in combination with bortezomib and dexamethasone in subjects with 
MM who have received 2or 3 prior lines of therapy and have demonstrated 
disease progression following the completion of the last line of therapy.  
Approximately 125 subjects will be enrolled.  
Inclusion Criteria 
Refer to Section 4 for 
the complete and 
detailed list of 
inclusion/exclusion 
criteria. 
Disease Related 
• 
Subjects with MM who have received 2-or 3 prior lines of 
therapy (Appendix 4) and have demonstrated disease progression since the 
completion of the most recent treatment regimen.  
o 
Subjects may have received prior bortezomib treatment but must not be 
refractory or non-responsive (see exclusion criteria 5). 
• 
Measurable disease is defined by at least ONE of the following: 
o 
Serum monoclonal protein (SPEP) ≥1 g/dL (for subjects with IgA, IgD, 
IgE or IgM multiple myeloma SPEP ≥0.5 g/dL) 
o 
Urine monoclonal protein (UPEP) ≥200 mg on 24 hour electrophoresis 
Laboratory 
• 
Adequate hematologic function for at least 7 days prior to Screening and 
dosing independent of platelet transfusion and growth factor support, with 
the exception of pegylated G-CSF (pegfilgrastim) and darbopoeitin which 
require adequate hematologic function at least 14 days prior to Screening 
and dosing. Adequate hematologic function is defined as:  
o 
Absolute neutrophil count ≥1500 cells/mm3 (1.5 x 109/L)   
o 
Platelet count ≥75,000 cells/mm3 (75 x 109/L) 
• 
Adequate hepatic and renal function defined as: 
o 
Serum aspartate transaminase (AST) or alanine transaminase (ALT) 
≤ 2.5 x upper limit of normal (ULN) 
o 
Creatinine Clearance ≥30 mL/min (by Cockcroft-Gault estimation OR 
as measured by 24 hour urine collection) 
o 
Total Bilirubin ≤1.5 x ULN  
• 
PT/INR ≤1.5 x ULN and PTT (aPTT)≤1.5 x ULN (unless abnormalities are 
unrelated to coagulopathy or bleeding disorder). When treated with warfarin 
or other vitamin K antagonists, then INR ≤3.0. 
Demographic 
• 
Male and female ≥ 18 years of age 
• 
Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 


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Exclusion Criteria: 
Disease-Related 
• 
Primary refractory disease defined as nonresponsive in patients who have 
never achieved a minimal response or better with any therapy. 
• 
History of plasma cell leukemia, primary amyloidosis, POEMS syndrome 
within 12 months prior to first administration of study treatment.  
Concurrent Conditions 
• 
Recent prior chemotherapy 
o 
Alkylators (eg, melphalan, cyclophosphamide) and/or anthracyclines 
<21 days prior to first administration of study treatment 
o 
High dose corticosteroids, immunomodulatory agents (IMiDs) or 
proteasome inhibitors (PI) <14 days prior to first administration of study 
treatment 
o 
Monoclonal antibody <2 weeks prior to first administration of study 
treatment 
• 
Prior exposure to BTK inhibitors 
• 
Refractory or non-responsive to prior PI therapy (bortezomib or carfilzomib) 
o 
Refractory is defined as progression on treatment or within 60 days of 
completion.  
o 
Non-responsive is defined as failure to achieve ≥MR per IMWG 
response criteria (Rajkumar 2011). 
• 
History of hypersensitivity reactions to prior bortezomib, to boron, mannitol 
or nitrogen.  
• 
History of other malignancies, except:  
o 
Malignancy treated with curative intent and with no known active 
disease present for ≥3 years before the first administration of study 
treatment and felt to be at low risk for recurrence by treating physician. 
o 
Adequately treated non-melanoma skin cancer or lentigo maligna 
without evidence of disease. 
o 
Adequately treated carcinoma in situ without evidence of disease.  
• 
Peripheral neuropathy Grade ≥2 or Grade 1 with pain at Screening 
• 
Prior allogeneic stem cell transplant 
• 
Recent infection requiring systemic treatment that was completed <7 days 
before the first administration of study treatment and/or uncontrolled active 
systemic infection. 
• 
Unresolved toxicities from prior anti-cancer therapy, defined as having an 
event not resolved to Common Terminology Criteria for Adverse Event 
(CTCAE, version 4.03), Grade ≤1, or to the levels dictated in the 
inclusion/exclusion criteria with the exception of alopecia. 
• 
Known bleeding disorders (eg, von Willebrand’s disease or hemophilia) 
• 
History of stroke or intracranial hemorrhage within 6 months prior to 
enrollment. 
• 
Known history of human immunodeficiency virus (HIV) or active with 
hepatitis C virus (HCV) or hepatitis B virus (HBV). Subjects who are 


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positive for hepatitis B core antibody, hepatitis B surface antigen (HbsAg), 
or hepatitis C antibody must have a negative polymerase chain reaction 
(PCR) result before enrollment. Those who are PCR positive will be 
excluded. 
• 
Major surgery within 4 weeks of first administration of study treatment. 
• 
Any life-threatening illness, medical condition, including uncontrolled 
Diabetes Mellitus, or organ system dysfunction that, in the opinion of the 
investigator, could compromise the subject’s safety or put the study 
outcomes at undue risk. 
• 
Currently active, clinically significant hepatic impairment (≥ mild hepatic 
impairment according to the Child-Pugh classification [Appendix 8]) 
• 
Currently active, clinically significant cardiovascular disease, such as 
uncontrolled arrhythmia or Class 3 or 4 congestive heart failure as defined 
by the New York Heart Association Functional Classification; or a history of 
myocardial infarction, unstable angina, or acute coronary syndrome within 
6 months prior to enrollment. 
• 
Unable to swallow capsules or malabsorption syndrome, disease 
significantly affecting gastrointestinal function, or resection of the stomach 
or small bowel, symptomatic inflammatory bowel disease or ulcerative 
colitis, or partial or complete bowel obstruction. 
• 
Subjects who received a strong cytochrome P (CYP) 450 3A inhibitor within 
7 days prior to the first administration of study treatment or subjects who 
require continuous treatment with a strong CYP 3A inhibitor 
(see Appendix 5). 
• 
Female subjects who are pregnant, or breastfeeding, or planning to become 
pregnant while enrolled in this study or within 90 days of last dose of study 
drug. Male subjects who plan to father a child while enrolled in this study or 
within 90 days after the last dose of study drug. 
• 
Unwilling or unable to participate in all required study evaluations and 
procedures. 
• 
Unable to understand the purpose and risks of the study and to provide a 
signed and dated informed consent form (ICF) and authorization to use 
protected health information (in accordance with national and local subject 
privacy regulations). 
Study Treatment 
This study will be conducted as an open-label, international, multicenter study. 
Eligible subjects will receive ibrutinib in combination with bortezomib and 
dexamethasone until progressive disease, unacceptable toxicity or other protocol 
specified reason for discontinuation. 
Cycles 1-8: 
Each cycle will be 21-days in length. Subjects will be dosed ibrutinib 840 mg 
daily, orally (PO) continuously beginning on Day 1 of Cycle 1. Bortezomib will 
be dosed at 1.3 mg/m2 subcutaneous (SC) on days 1, 4, 8 and 11 of each cycle. 
Dexamethasone will be dosed at 20 mg orally (PO) on day of each bortezomib 
dose. 
Cycles 9-12: 
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daily, orally (PO) continuously. Bortezomib will be dosed at 1.3 mg/m2 
subcutaneous (SC) on days 1, 8 and 22 and 29 of each cycle. Dexamethasone will 
be dosed at 20 mg orally (PO) on day of each bortezomib dose. 
Cycle 13 and Beyond: 
Each cycle will be 28-days in length. Subjects will be dosed ibrutinib 840 mg 
daily, orally (PO) continuously. Dexamethasone will be dosed at 40 mg orally 
(PO) once weekly. 
 
Cycles 1-8 
Cycles 9-12 
Cycle 13 and Beyond 
(21-day cycle) 
(42-day cycle) 
(28-day cycle) 
Ibrutinib 
Continuous 
Continuous 
Continuous 
Bortezomib 
Days 1, 4, 8, 11 
Days 1, 8, 22, 29 
NA 
Dexamethasone† 
Days 1, 4, 8, 11 
Days 1, 8, 22, 29 
Once weekly 
† Dose adjustment of dexamethasone is recommended for subjects >75 years of age to 
10 mg on days specified in the protocol during Cycles 1-12 and to 20 mg on days 
specified in the protocol for Cycles 13 and beyond, however, this will be at 
investigator’s discretion with dose modification guidelines followed per protocol for 
toxicity.  
Concomitant 
Therapy  
Refer to Section 6 for information on concomitant therapy. 
Safety Plan 
The safety of this study will be monitored in accordance with the Sponsor’s 
Pharmacovigilance Committee procedures. Adverse events (AEs) and serious 
adverse events (SAEs) will be reviewed by the Sponsor on an ongoing basis to 
identify safety concerns. 
The Sponsor or designee will review data on the safety of ibrutinib in 
combination with bortezomib and dexamethasone after approximately 6 subjects 
have completed at least 1 cycle (21 days of treatment). If a new safety signal is 
identified with the study treatment combination, enrollment will be held pending 
further evaluation and/or an amendment to the protocol.  
In addition to standard surveillance activities throughout the conduct of the 
study, the Sponsor will implement an internal safety review committee to review 
the incidence, severity and outcome of infections on this study as well as any 
other potential safety signals approximately every 6 weeks. The committee will 
include, at minimum, representatives from Clinical Science, Drug Safety, and 
Biometrics to review all available AE and SAE data. Depending on the outcome 
of the internal safety reviews, the Sponsor may decide to implement an 
amendment, or terminate the study. 
Statistical Methods 
and Data Analysis 
All efficacy analyses will be performed using the all treated population.  
Primary Efficacy Analysis: 
The median progression free survival (mPFS) will be assessed based on IMWG 
response criteria and will be tested against a historical control of 8 months vs 
12 months. The point estimate of mPFS and the corresponding 2-sided 
Brookmeyer-Crowley 95% confidence interval with the log-log-transformed 
Greenwood variance estimate will be calculated. The null hypothesis will be 
rejected at the 0.025 significance level if the lower bound of the confidence 
interval is greater than 8 months. 
 


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Secondary Efficacy Analysis: 
The ORR will be estimated and the corresponding exact binomial 95% 
confidence interval will be calculated. 
The distribution of PFS, DOR, OS, and TTP will be estimated using the 
Kaplan-Meier method. The PFS rates and survival rates at landmark points will 
also be summarized based on Kaplan-Meier point estimates. 
Safety Analysis: 
Detailed tabulations of safety data (AEs, clinical laboratory tests and other safety 
endpoints) will be summarized for all subjects receiving the study treatment. 
Summary statistics will include means, standard deviations, and medians for 
continuous variables and proportions for categorical variables. 
The end of the study will occur approximately 2 years after the last subject is 
enrolled, or the Sponsor terminates the study, whichever comes first. 
Interim Analysis 
An interim analysis to assess the PFS distribution is planned after approximately 
80% of the subjects have been enrolled or 2 months before the projected 
completion of enrollment, whichever comes earlier. At the time of the interim 
analysis, the distribution of 1 and 2 to 3 prior lines of therapy and prior exposure 
to bortezomib will be reassessed to validate the initial hypothesis based on the 
actual subject population enrolled. The final timing of the interim analysis, as 
well as the responsible party to perform the interim analysis, will be specified in 
the SAP or a separate Interim Analysis Plan. The purpose of the interim analysis 
is to assess the actual distribution of PFS based on the interim data, and estimate 
the probability of success of the study. The outcome of the interim analysis may 
lead to a futility stop of the study, continue the study as planned, or an adaptation 
of the sample size according to the interim analysis plan.  
Sample Size 
Determination 
N = 125 
The primary endpoint is mPFS. Assuming that the PFS follows an exponential 
distribution, a sample size of approximately 125 eligible subjects will provide 
80% power at a 1-sided 0.025 significance level to test the null hypothesis of 
mPFS ≤8 months vs ≥12 months under the alternative hypothesis. The 2-sided 
95% Brookmeyer-Crowley confidence interval with the log-log-transformed 
Greenwood variance estimate for mPFS will be calculated to test the hypotheses. 
An mPFS of 8.1 months was observed in the PANORAMA-1 Study where a 
similar patient population was treated with bortezomib and dexamethasone 
(Richardson 2014). This hypothesis for mPFS with the revised enrollment to only 
include 2-3 prior lines of therapy without enrollment limitations for prior 
bortezomib exposure is further supported by recent data in the ENDEAVOR 
Study demonstrating similar outcome (Moreau 2016). The sample size of 
approximately 125 subjects is determined by simulation method assuming that 
the PFS follows an exponential distribution and the mPFS is 12 months with 
ibrutinib in combination with bortezomib and dexamethasone. In addition, an 
enrollment period of 20 months with an average enrollment rate of 6 subjects per 
month and the time of primary analysis at 12 months after the last subject 
enrolled into the study were also assumed in the simulation. 
 
 


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ABBREVIATIONS 
AE 
adverse event 
ALT 
alanine transaminase  
AST 
Serum aspartate transaminase 
AUC 
area under the curve 
BCR 
B-cell receptor 
BTK 
Bruton’s tyrosine kinase  
BUN 
blood urea nitrogen 
CBR 
Clinical benefit rate 
CI 
confidence interval 
CLL 
chronic lymphocytic leukemia 
Cmax 
maximum observed plasma concentration 
CTCAE 
Common Terminology Criteria for Adverse Events 
CR 
complete response  
CT 
computed tomography 
CYP 
cytochrome P 
DCB 
duration of clinical benefit 
DLT 
dose limiting toxicity 
DMC 
Data Monitoring Committee  
DNA 
deoxyribonucleic acid 
DOR 
duration of response  
EBMT 
European Group for Blood and Marrow Transplantation  
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
electronic data capture 
eCRF 
electronic case report form 
EMA 
European Medicines Agency 
EMR 
electronic medical records 
EOT 
End-of-Treatment 
EU 
European Union 
FCBP 
female of childbearing potential 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte-colony stimulating factor 
GEP 
gene expression profiling 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation  
IEC 
Independent Ethics Committee 


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Ig 
Immunoglobulin 
IHC 
Immunohistochemistry 
IL-6 
interleukin-6 
ILD 
interstitial lung disease 
IMiD(s) 
Immunomodulatory agent(s) 
IMWG 
International Myeloma Working Group 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IUD 
Intrauterine device 
IV 
Intravenous 
LDH 
lactate dehydrogenase 
MCL 
mantle cell lymphoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligrams 
MGUS 
monoclonal gammopathy of undertermined significance  
MIP-1α 
macrophage inhibitory protein-1α  
MM 
multiple myeloma 
MR 
minimal response 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
MZL 
marginal zone lymphoma 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NCCN 
National Comprehensive Cancer Network 
NF-κΒ 
nuclear factor κB  
NK 
natural killer (cells) 
ORR 
overall response rate (ORR = CR + PR) 
OS 
overall survival 
PCR 
polymerase chain reaction 
POEMS 
polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, 
skin abnormalities 
PD 
progressive disease 
PE 
pulmonary embolism 
PET 
positron emission tomography 
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
PI 
proteasome inhibitors 
PK 
pharmacokinetic(s) 
PO 
per os (oral) 
PR 
partial response 
PROs 
patient reported outcomes 
aPTT 
activated partial thromboplastin time 
PT 
prothrombin time 


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QTc 
corrected QT interval (Fridericia formula) 
RBC 
red blood cells 
REB 
Research Ethics Board 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
ASCT 
Autologous stem cell transplantation 
SCARs 
severe cutaneous adverse reactions 
SD 
stable disease 
SJS 
Stevens-Johnson syndrome 
SOPs 
standard operating procedures 
SPEP 
serum protein electrophoresis 
T1/2 
mean half life  
TEAE(s) 
Treatment-emergent adverse event(s) 
TLS 
Tumor Lysis Syndrome 
Tmax 
median time to maximum plasma concentration  
TTP 
time-to-progression 
ULN 
upper limit of normal 
UPEP 
urine protein electrophoresis 
US 
United States 
WBC 
White blood cells 
WM 
Waldenström’s Macroglobulinemia 
 
 


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1. 
BACKGROUND 
1.1. 
Multiple Myeloma 
Multiple myeloma (MM) is a plasma-cell malignancy that is associated with monoclonal 
immunoglobulin (M protein) production, osteolytic bone lesions, hypercalcemia, anemia, and 
renal failure. MM is the second most common hematological cancer in Europe representing 15% 
of blood cancers and ~1% of all cancers (King 2014) with approximately 39,000 new cases 
diagnosed per year (Ferlay, accessed Nov 2015). The Swedish Family Cancer Database, 
covering over 10.5 million individuals in Sweden, estimated that the 2001-03 age-standardized 
incidence rates for men and women were 4.79 per 100 000 and 3.43 per 100 000, respectively. 
Incidence increased over time between the periods 1961-65 and 2001-03 for both males and 
females (10.6% and 24.3%, respectively) (Altieri 2006). Similar incidence rates were reported 
for South East England in 2004, 5.5 per 100,000 and 3.5 per 100,000 for males and females, 
respectively (Renshaw 2010). MM incidence is strongly related to age where 43% of diagnosed 
cases in the UK between 2009 and 2011 were 75 years and older. Incidence rates sharply 
increases starting from age 55-59 years old (10.5 per 100 000 for males and 7 per 100 000 
females) with the highest rate in those aged 85 and older (67.6 and 36 per 100 000 for males and 
females, respectively) (Cancer Research UK, accessed Sept 2015).  
Five-year prevalence, which is defined as all patients alive at a time point and diagnosed with 
MM within the past 5 years, for multiple European nations was estimated based on cancer 
registries in each region (Crocetti 2013). The years estimated varied by region but all fell within 
the period between 2002 and 2006. For men, the 5-year prevalence was 14 per 100 000, 19 per 
100 000, 16 per 100 000, 19 per 100 000 for the Nordic countries, Italy, France, and Australia, 
respectively. All 5-year prevalences were consistency lower in females, 10 per 100 000, 14 per 
100 000, 12 per 100 000, and 12 per 100 000 for the Nordic countries, Italy, France, and 
Australia, respectively.  
Based on data from the Thames Cancer Registry in South East England, during 2000-2004, 
5-year survival was 22% and 21% in 60 years and older males and female, respectively. 
Five-year survival has improved for both males and females around the globe, eg, 5-year survival 
rates in South East England increased by 7% in males and 3% in females from 1990-1994 to 
2000-2004 (Renshaw 2010).  
Myeloma cell growth occurs within bones and specifically involves the bone marrow. Its clinical 
hallmarks include bone destruction, which may be manifested by lytic lesions, severe osteopenia, 
pathologic fractures and hypercalcemia, and impaired bone marrow function, which may result 
in anemia, thrombocytopenia, and neutropenia. Bone destruction in particular is a major cause of 
severe and disabling morbidity in myeloma. Bone lesions are present in the majority of patients 
at presentation and nearly all patients by the time the disease runs its course. Myeloma cells 
typically secrete 1 (or rarely more) monoclonal paraprotein (M-protein) molecule, which may be 
intact immunoglobulin (usually IgG or IgA; rarely IgD, IgE, or IgM) or free (κ or λ) light chains. 
Examples of completely nonsecretory myeloma are rare. Myeloma M-proteins can cause 


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numerous complications including renal insufficiency, amyloidosis, hyperviscosity, and 
neuropathy. The various direct and indirect destructive effects of myeloma cells render MM 
patients highly symptomatic and challenging to manage. In addition, these patients are subject to 
greater morbidity and higher mortality compared to those with the more common subtypes of 
lymphoma.  
Myeloma cells are highly dependent upon the bone marrow microenvironment, including the 
presence of certain cytokines (eg, interleukin-6 [IL-6]), chemokines, macromolecules in the 
extracellular matrix, and supportive cells (stromal cells), for their growth and survival. Crucial 
cytokines and chemokines are secreted into the microenvironment by bone marrow (BM) stromal 
cells, and some by the MM cells themselves. Adhesion of MM cells to BM stromal cells triggers 
secretion of cytokines, which augment MM cell growth and survival and confers drug 
resistance (Roodman 2010b). Vascular endothelial growth factor, basic fibroblast growth 
factor-2, and other factors secreted by MM and/or BM stromal cells promote angiogenesis, and 
thereby further support tumor cell growth and survival. More recently, much progress has been 
made in elucidating the role of osteoclasts in the development of lytic lesions and in reciprocally 
contributing to a microenvironment supportive of myeloma cell growth and progression. 
Multiple myeloma cells stimulate osteoclastogenesis by secretion of factors including receptor 
activator of nuclear factor κB (NF-κΒ) ligand (RANKL), IL-6, and macrophage inhibitory 
protein-1α (MIP-1α), while osteoclasts themselves may produce IL-6, as well as interact with 
stromal cells. These interactions contribute to a favorable microenvironment for myeloma cell 
adhesion and proliferation (Kawano 1988, Roodman 2004, Aggarwal 2006, Roodman 2010a, 
Roodman 2010b, Roodman 2011). 
1.1.1. 
Existing Therapies and Unmet Need in Relapsed or Relapsed and Refractory 
Multiple Myeloma 
Although improvements in progression-free survival (PFS) and overall survival (OS) have 
occurred in the last decade, even with the best available approved agents, almost all patients are 
known to eventually relapse. The choice of treatment and intensity is dependent upon patient 
age, co-morbidities, residual treatment related toxicities, and response to previous therapies. 
Thus, no preferred regimen has been identified for the treatment of these patients and the 
therapeutic options for patients following first relapse are similar (Dimopoulos 2015).  
Combination regimens are generally preferred over monotherapy. Current treatment options 
available for relapsed disease according to ESMO guidelines include the use of salvage 
transplant, targeted agents (ie, proteasome inhibitors [PI] or immodulatory agents [IMiDs], 
chemotherapy (ie, cyclophosphamide, bendamustine, doxorubicin, vincristine, cisplatin, 
etoposide, and melphalan) and corticosteroids as well as the participation in a clinical trial 
assessing novel combinations and agents with novel mechanisms of action (Moreau 2013). 
Treatment options in the relapsed setting can also be dependent on the duration of response to 
prior therapy and the associated toxicity profile. Retreatment with the prior regimen may be 
suitable if a long duration of response was obtained following a short course of treatment 
(Dimopoulos and Terpos 2010). The European Medicines Agency (EMA) has approved 


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lenalidomide in combination with dexamethasone and bortezomib either alone as single agent or 
in combination pegylated doxorubicin for relapsed and refractory MM, however, bortezomib is 
most widely used in combination with dexamethasone in the relapsed setting (Moreau 2013).  
In the relapsed MM setting, bortezomib has shown activity as a single agent and in combination 
with dexamethasone as well as part of multi-drug regimens. A retrospective matched-pairs 
analysis of bortezomib and dexamethasone vs bortezomib monotherapy across three clinical 
trials also demonstrated significantly higher ORR and longer median PFS and median TTP in 
patients with MM treated at first relapse with bortezomib and dexamethasone compared to 
treatment with bortezomib alone (Dimopoulos 2013).  
In 2015, panobinostat (Farydak®) received US Food and Drug Administration and European 
Union (EU) EMA approval in combination with bortezomib and dexamethasone for patients with 
MM after having received at least 2 prior treatments including bortezomib and an 
immunomodulatory agent. A Phase 3, randomized, double-blind trial (PANORAMA 1) 
evaluated the efficacy and safety of panobinostat, a pan-deacetylase inhibitor, in combination 
with bortezomib and dexamethasone compared to placebo in combination with bortezomib and 
dexamethasone in patients with relapsed MM. Patients were required to have 1-3 prior therapies 
and not be refractory to prior bortezomib treatment. Of the 768 patients enrolled, 387 patients 
received panobinostat, bortezomib and dexamethasone. The combination of panobinostat, 
bortezomib and dexamethasone demonstrated significant improvement in PFS compared to 
bortezomib and dexamethasone alone with median PFS of 11.99 months compared to 
8.08 months, respectively. The improvement in PFS was observed in a subgroup analysis which 
included patients who received prior IMiDs and bortezomib with ≥2 prior lines of therapy. The 
median PFS was increased by 7.8 months, the DOR was increased by approximately 5 months 
and the median TTP was increased by 7.7 months in comparison to bortezomib and 
dexamethasone alone (San Miguel 2015). 
Despite the significant improvements made with bortezomib as a standard backbone therapy for 
MM, there remains an unmet need as patients relapse and/or become refractory following 
treatment with bortezomib. The addition of novel agents to existing standard therapies may 
further improve efficacy outcomes. 
1.1.2. 
BTK Inhibition as a Treatment Option for MM 
Bruton’s tyrosine kinase (BTK) plays a key role in the development and function of normal 
B cells through activation of the B-cell receptor (BCR) signaling pathway and mediates their 
biological activities such as growth, adhesion and migration. BTK is also expressed in various 
B cell malignancies including chronic lymphocytic leukemia (CLL), mantle cell lymphoma 
(MCL) and Waldenström’s Macroglobulinemia (WM) and has been implicated in deregulated 
proliferation, homing to the tumor microenvironment and metastasis to other organs.  


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While BTK expression is reduced in normal plasma cells, its expression in MM cell lines and 
primary patient samples is increased when assessed by both immunoblotting and gene expression 
profile analysis (Tai 2012, Bam 2013). Up-regulation of BTK is seen across all disease settings 
of MM from monoclonal gammopathy of undertermined significance (MGUS) to plasma cell 
leukemia, with no observed differences between samples across International Staging System 
(ISS) stages or MM subtypes (Elias 2013). 
There have been several reports describing the potential role of BTK in MM and the impact of its 
inhibition on their phenotypes in vitro and in vivo. First, BTK is expressed in patient-derived 
MM samples and in established MM cell lines. Second, genetic or pharmacological inhibition of 
BTK resulted in direct inhibition of cell growth, adhesion and migration induced by either 
intrinsic and/or extrinsic signal(s). Third, BTK indirectly promote MM pathogenesis through 
stimulation of osteoclast development (osteoclastogenesis) and their functional activity of 
creating a MM tumor microenvironment induced by RANKL and M-CSF. In experimental 
models of osteoclast functions/activities in vitro and in vivo, BTK inhibition by ibrutinib has 
been shown to inhibit the bone resorption and the release of osteoclast-derived tumor growth 
factors by osteoclasts. 
Yang et al. recently reported that expression of BTK mRNA in MM cell lines and 
patient-derived MM cells is highly enriched in the CD138-fraction or a side population, a 
sub-population of cells that show higher efflux of DNA-binding dye Hoechst33342 
(Jakubikova 2011), both of which are believed to contain stem-like cells with tumor-initiating 
potential, when compared to the CD138+ cells or main population (Yang 2015). Increased BTK 
expression in such population of cells is associated with clonogenic growth, increased expression 
of pluripotent/embryonic stem cell genes, and potential resistance to many standard myeloma 
treatments. In contrast, knockdown of BTK impeded these effects in vitro. Furthermore, BTK 
inhibition with a small molecule in the xenograft model of MM reduced serum IgG2b levels and 
extended the survival of host animals (Yang 2015). 
These preclinical study results for BTK inhibitors against MM cells clearly differentiate 
themselves from other established therapeutic agents and provide a scientific rationale for 
investigation of ibrutinib as a therapeutic option for MM as a new combination partner with a 
novel mechanism of action. 
1.2. 
Ibrutinib Overview 
Ibrutinib (IMBRUVICA®) is a first-in-class, potent, orally administered, covalently binding 
inhibitor of Bruton’s tyrosine kinase (BTK) co-developed by Pharmacyclics and Janssen 
Research & Development LLC (collectively referred to as the Sponsor) for the treatment of 
B-cell malignancies.  
Ibrutinib has been approved in many regions, including the United States (US) and European 
Union (EU), for indications including treatment of patients with mantle cell lymphoma (MCL) 
who have received at least 1 prior therapy, patients with chronic lymphocytic leukemia 


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(CLL)/small lymphocytic lymphoma (SLL), including CLL/SLL with a deletion of the short arm 
of chromosome 17 (del17p), Waldenström’s macroglobulinemia (WM), and marginal zone 
lymphoma (MZL) who require systemic therapy and have received at least one prior 
anti-CD20-based therapy. For the most up to date and comprehensive nonclinical and clinical 
information regarding ibrutinib background, safety, efficacy, and in vitro and in vivo preclinical 
activity and toxicology of ibrutinib, always refer to the latest version of the ibrutinib 
Investigator's Brochure (IB) and/or the applicable regional labeling information. 
1.2.1. 
Summary of Nonclinical Data 
1.2.1.1. 
Pharmacology 
Ibrutinib was designed as a selective and covalent inhibitor of BTK (Pan 2007). In vitro, 
ibrutinib is a potent inhibitor of BTK activity (IC50 = 0.39 nM). The irreversible binding of 
ibrutinib to cysteine-481 in the active site of BTK results in sustained inhibition of BTK catalytic 
activity and enhanced selectivity over other kinases that do not contain a cysteine at this position. 
When added directly to human whole blood, ibrutinib inhibits signal transduction from the B-cell 
receptor and blocks primary B-cell activation (IC50 = 80 nM) as assayed by anti-IgM stimulation 
followed by CD69 expression (Herman 2011). 
For the most up to date and comprehensive nonclinical pharmacology information regarding 
ibrutinib, please refer to the current ibrutinib IB. 
1.2.1.2. 
Safety Pharmacology and Toxicology 
No treatment-related effects were observed in the central nervous system or respiratory system in 
rats at any dose tested. Further, no treatment-related corrected QT interval (QTc) prolongation 
effect was observed at any tested dose in a cardiovascular study using telemetry-monitored dogs. 
Based on data from rat and dog including general toxicity studies up to 13 weeks duration, the 
greatest potential for human toxicity with ibrutinib is predicted to be in lymphoid tissues 
(lymphoid depletion) and the gastrointestinal tract (soft feces/diarrhea with or without 
inflammation). Additional toxicity findings seen in only one species with no observed human 
correlate in clinical studies to date include pancreatic acinar cell atrophy (rat), minimally 
decreased trabecular and cortical bone (rat) and corneal dystrophy (dog). In studies in pregnant 
rats and rabbits, ibrutinib administration was associated with malformations (teratogenicity) at 
ibrutinib doses that result in approximately 14 and 2 times the exposure (area under the 
concentration-time curve [AUC]) in patients administered the dose of 560 mg daily, respectively. 
Fetal loss and reduced fetal body weights were also seen in treated pregnant animals. 
Carcinogenicity studies have not been conducted with ibrutinib. In vitro and in vivo genetic 
toxicity studies showed that ibrutinib is not genotoxic. No effects on fertility or reproductive 
capacities were observed in a study in male and female rats. 


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For the most up to date and comprehensive nonclinical safety pharmacology and toxicology 
information regarding ibrutinib, please refer to the current ibrutinib IB. 
1.2.2. 
Summary of Clinical Data 
1.2.2.1. 
Pharmacokinetics and Product Metabolism 
Following oral administration of ibrutinib at doses ranging from 420 to 840 mg/day, exposure to 
ibrutinib increased dose-proportionally with substantial intersubject variability. The mean 
terminal plasma elimination half life (t1/2) of ibrutinib ranged from 4 to 13 hours, with a median 
time to maximum plasma concentration (Tmax) of 2 hours. Despite the doubling in mean systemic 
exposure when dosed with food, the favorable safety profile of ibrutinib allows dosing with or 
without food. Ibrutinib is extensively metabolized primarily by cytochrome P450 (CYP) 3A4. 
The on-target effects of metabolite PCI-45227 are not considered clinically relevant. Steady-state 
exposure of ibrutinib and PCI-45227 was less than 2-fold of first dose exposure implying non-
clinically relevant accumulation. Less than 1% of ibrutinib is excreted renally. Ibrutinib exposure 
is not altered in patients with creatinine clearance (CrCl) > 30 mL/min. Patients with severe renal 
impairment or patients on dialysis have not been studied. Following single dose administration, 
the AUC of ibrutinib increased 2.7-, 8.2- and 9.8-fold in subjects with mild (Child-Pugh class A), 
moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment compared to 
subjects with normal liver function. A higher proportion of Grade 3 or higher adverse reactions 
were reported in patients with B-cell malignancies (CLL, MCL and WM) with mild hepatic 
impairment based on NCI organ dysfunction working group (NCI-ODWG) criteria for hepatic 
dysfunction compared to patients with normal hepatic function.   
For the most up to date and comprehensive pharmacokinetics (PK) and product metabolism 
information regarding ibrutinib, please refer to the current ibrutinib IB.  
1.2.3. 
Summary of Clinical Safety 
A brief summary of safety data from monotherapy and combination therapy studies is provided 
below. For the most up to date and most comprehensive safety information regarding ibrutinib, 
please refer to the current ibrutinib IB. Additional safety information may be available for 
approved indications in regional prescribing labels where the study is conducted (eg, USPI, 
SmPC).  
1.2.3.1. 
Monotherapy Studies  
Pooled safety data from a total of 1318 subjects treated with ibrutinib monotherapy in 13 studies 
that have completed primary analysis or final analysis as of the 31 May 2016 cutoff date for the 
current Investigator’s Brochure update in B-cell malignancies are summarized below.  


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The most frequently reported treatment-emergent adverse events (TEAEs) in subjects receiving 
ibrutinib as monotherapy (N=1318): 
Most frequently reported TEAEs 
≥15% a   
Most frequently reported Grade 3 or 
4 TEAEs ≥3% b   
Most frequently reported Serious 
TEAEs ≥2% c   
Diarrhea 
Neutropenia 
Pneumonia 
Fatigue 
Pneumonia 
Atrial fibrillation 
Nausea 
Thrombocytopenia 
Febrile neutropenia 
Cough 
Anemia 
Pyrexia 
Pyrexia  
Hypertension   
 
Anemia  
Diarrhea 
 
Neutropenia  
Atrial fibrillation 
 
Upper respiratory tract infection 
 
 
Thrombocytopenia    
 
 
Oedema peripheral    
 
 
a Source is Table 6 of ibrutinib IB (v10), b source is Table 8 of ibrutinib IB (v10), c source is Table 9 of 
ibrutinib IB (v10). 
1.2.3.2. 
Combination Therapy Studies 
Pooled safety data from a total of 423 subjects treated with various therapies in combination with 
ibrutinib from 4 studies conducted in subjects with B-cell malignancies are briefly summarized 
below. Therapies used in combination with ibrutinib in these studies, included BR (bendamustine 
and rituximab), FCR (fludarabine, cyclophosphamide, and rituximab), ofatumumab, and 
R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).  
The most frequently reported TEAEs in subjects receiving ibrutinib in combination therapy 
(N=423): 
Most frequently reported TEAEs 
≥20% a    
Most frequently reported Grade 3 or 
4 TEAEs ≥3% b   
Most frequently reported Serious 
TEAEs ≥2% c   
Neutropenia 
Neutropenia 
Pneumonia  
Diarrhea 
Thrombocytopenia 
Febrile neutropenia  
Nausea 
Febrile neutropenia 
Atrial fibrillation 
Thrombocytopenia 
Pneumonia 
Pyrexia 
Fatigue 
Neutrophil count decreased 
Cellulitis 
Anemia 
Anemia 
 
Pyrexia 
Fatigue 
 
 
Hypertension 
 
 
Diarrhea 
 
a Source is Table 10 of ibrutinib IB (v10), b source is Table 12 of ibrutinib IB (v10), c source is Table 13 of 
ibrutinib IB (v10). 


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1.2.4. 
Risks 
1.2.4.1. 
Bleeding-related Events   
There have been reports of hemorrhagic events in subjects treated with ibrutinib, both with and 
without thrombocytopenia. These include minor hemorrhagic events such as contusion, epistaxis, 
and petechiae; and major hemorrhagic events, some fatal, including gastrointestinal bleeding, 
subdural intracranial hemorrhage, and hematuria. Use of ibrutinib in subjects requiring other 
anticoagulants or medications that inhibit platelet function may increase the risk of bleeding. 
Subjects with congenital bleeding diathesis have not been studied. See Section 6.1.2.4 for 
guidance on concomitant use of anticoagulants, antiplatelet therapy and/or supplements. See 
Section 6.2 for guidance on ibrutinib management with surgeries or procedures. In an in vitro 
platelet function study, inhibitory effects of ibrutinib on collagen-induced platelet aggregation 
were observed, refer to Section 6.1.2.4. 
1.2.4.2. 
Infections 
Infections (including sepsis, bacterial, viral, or fungal infections) were observed in subjects 
treated with ibrutinib therapy. Some of these reported infections have been associated with 
hospitalization and death. Consider prophylaxis according to standard of care in subjects who are 
at increased risk for opportunistic infections (reference Section 5.6 and Section 6.1.1). Although 
causality has not been established, cases of progressive multifocal leukoencephalopathy (PML) 
have occurred in patients treated with ibrutinib. Subjects should be monitored for symptoms 
(fever, chills, weakness, confusion) and appropriate therapy should be instituted as indicated.  
1.2.4.3. 
Cytopenias  
Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and anemia) were 
reported in subjects treated with ibrutinib. Subjects should be monitored for fever, weakness, or 
easy bruising and/or bleeding. 
1.2.4.4. 
Interstitial Lung Disease (ILD) 
Cases of interstitial lung disease (ILD) have been reported in subjects treated with ibrutinib. 
Monitor subjects for pulmonary symptoms indicative of ILD. Should symptoms develop follow 
the protocol dose modification guidelines (see Section 5.3.4). 
1.2.4.5. 
Atrial Fibrillation 
Atrial fibrillation and atrial flutter have been reported in subjects treated with ibrutinib, 
particularly in subjects with cardiac risk factors, hypertension, acute infections, and a previous 
history of atrial fibrillation. Subjects who develop arrhythmic symptoms (eg, palpitations, 
lightheadedness) or new onset of dyspnea should be evaluated clinically, and if indicated, have 
an ECG performed. For atrial fibrillation which persists, consider the risks and benefits of 
ibrutinib treatment and follow the protocol dose modification guidance (see Section 5.3.4). 


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1.2.4.6. 
Non-melanoma Skin Cancer  
Non-melanoma skin cancers have occurred in subjects treated with ibrutinib. Monitor subjects 
for the appearance of non-melanoma skin cancer.  
1.2.4.7. 
Tumor Lysis Syndrome 
There have been reports of tumor lysis syndrome (TLS) events in subjects treated with 
single-agent ibrutinib or in combination with chemotherapy. Subjects at risk of TLS are those 
with comorbidities and/or risk factors such as high tumor burden prior to treatment, increased 
uric acid (hyperuricemia), elevated lactate dehydrogenase (LDH), bulky disease at baseline, and 
pre‐existing kidney abnormalities. 
1.2.4.8. 
Diarrhea 
Diarrhea is the most frequently reported non-hematologic AE with ibrutinib monotherapy and 
combination therapy. Other frequently reported gastrointestinal events include nausea, vomiting, 
and constipation. These events are rarely severe. Should symptoms be severe or prolonged 
follow the protocol dose modification guidelines (see Section 5.3.3).  
1.2.4.9. 
Rash 
Rash has been commonly reported in subjects treated with either single agent ibrutinib or in 
combination with chemotherapy. Most rashes were mild to moderate in severity. Isolated cases 
of severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS) have 
been reported in subjects treated with ibrutinib. Subjects should be closely monitored for signs 
and symptoms suggestive of SCAR including SJS. Subjects receiving ibrutinib should be 
observed closely for rashes and treated symptomatically, including interruption of the suspected 
agent as appropriate. In addition, hypersensitivity-related events including erythema, urticaria, 
and angioedema have been reported. 
1.2.4.10. 
Hypertension 
Hypertension has been commonly reported in subjects treated with ibrutinib. Monitor subjects 
for new onset of hypertension or hypertension that is not adequately controlled after starting 
ibrutinib. Adjust existing anti-hypertensive medications and/or initiate anti-hypertensive 
treatment as appropriate. 
1.2.5. 
Summary of Clinical Data with Ibrutinib in MM 
1.2.5.1. 
PCYC-1111-CA 
PCYC-1111-CA is a multicenter Phase 2 study in subjects with relapsed or relapsed and 
refractory MM. The primary objective of the study is to determine the efficacy of ibrutinib, both 
as a single agent and in combination with dexamethasone by assessing the clinical benefit rate 


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(CBR). The secondary objectives are to evaluate the efficacy of ibrutinib in this population as 
assessed by the duration of clinical benefit (DCB), ORR, duration of response (DOR), and the 
safety and drug PK. The exploratory objectives are PFS, time-to-progression (TTP), and OS. 
Subjects were enrolled to one of four cohorts, with ibrutinib doses ranging from 420 mg/day 
(Cohort 1), 560 mg/day (Cohort 2), to 840 mg/day (Cohorts 3 and 4). Ibrutinib is given in 
combination with weekly dexamethasone (40 mg weekly) in Cohorts 2 and 4; addition of 
dexamethasone was permitted upon disease progression in Cohorts 1 and 3. All cohorts have 
completed Stage 1 enrollment.  
A total of 69 subjects were enrolled in Stage 1: 13 subjects in Cohort 1, 18 subjects in Cohort 2, 
18 subjects in Cohort 3 and 20 subjects in Cohort 4. At the time of the interim analysis, Cohort 4 
(ibrutinib 840 mg/day in combination with weekly dexamethasone) met the Simon 2-stage 
enrollment expansion criteria (≥3 MRs in 18 evaluable subjects) with a CBR of 25% (5/20). 
(Vij 2014). As of 20 September 2014 an additional 23 subjects were enrolled to Cohort 4 
(total n=43) with confirmation of the initial safety and activity seen in Cohort 4 Stage 1 
enrollment.  
As of 09 March 2015, a total of 92 subjects were enrolled across four dosing cohorts (420 mg – 
840 mg). The most common treatment emergent adverse events (>15%) included diarrhea (52%), 
fatigue (41%), nausea (29%), anemia (27%), cough (22%), arthralgia (21%), muscle spasms 
(21%), dizziness (20%), insomnia (17%), upper respiratory tract infection (17%), back pain 
(15%), dyspnea (15%) and epistaxis (15%). The most common Grade 3 and higher TEAEs 
(>5%) included anemia (15%), thrombocytopenia (9%), and pneumonia (7%).  
Forty-three out of 92 subjects were treated with ibrutinib at 840 mg in combination with weekly 
dexamethasone. The observed safety profile at 840 mg and across the tested cohorts in this 
ongoing study did not indicate clinically meaningful differences and the overall obtained safety 
profile with ibrutinib alone or in combination is consistent with the reported treatment-emergent 
AEs detailed in the current version of the ibrutinib IB.  
1.2.5.2. 
PCYC-1119-CA 
PCYC-1119-CA is a multicenter Phase 1/2b study in subjects with relapsed or relapsed and 
refractory MM. The primary objective of Phase 1 is to determine the maximum tolerated dose 
(MTD) of ibrutinib in combination with carfilzomib and with or without dexamethasone as well 
as to describe the toxicities associated with the combination. The secondary objectives of this 
phase are to assess overall ORR and DOR. In Phase 1 subjects are enrolled to one of three dose 
levels (5 cohorts), with ibrutinib doses ranging from 560 mg/day (Dose Levels 1 and 2) to 
840 mg/day (Dose Level 3) and carfilzomib doses ranging from 20/27 mg/m2 (Dose Level 1) to 
20/36 mg/m2 (Dose Levels 2 and 3). Age-adjusted dexamethasone (10-20 mg) is given in 
combination with ibrutinib and carfilzomib in one cohort in Dose Level 2 and one in Dose Level 
3 while the other cohorts are treated without dexamethasone. Thirteen patients were enrolled in 
the dose escalation phase which was completed after 6 evaluable patients were treated at Dose 


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Level 3 (per protocol, the highest planned dose level). No dose limiting toxicities (DLTs) were 
observed at the highest tested dose level, ibrutinib 840 mg/day in combination with carfilzomib 
20/36 mg/m2 and dexamethasone.  
As of 22 July 2015, a total of 43 subjects were enrolled and dosed in Phase 1: 13 subjects in dose 
escalation and 30 subjects in dose expansion cohorts. In the 40 subjects evaluable for safety and 
efficacy the most common treatment-emergent AEs (≥20%) included diarrhea (43%), 
constipation and fatigue (40% each), cough (38%), anemia (33%), thrombocytopenia, nausea and 
pyrexia (30% each), epistaxis and hypertension (28% each), dyspnea and headache (25%), 
hypokalemia (23%), upper respiratory tract infection (23%), insomnia, peripheral edema and 
urinary tract infection (20%). There were 4 cases of renal failure acute reported, 2 occurred in the 
setting of disease progression and 2 occurred in the setting of infection (pneumonia and 
pseudomonal sepsis). Of the two cases occurring in the context of disease progression one 
occurred following the initiation of subsequent anti-cancer treatment. The most common Grade 3 
and higher TEAEs in 3 or more subjects included hypertension (20%), anemia, pneumonia and 
thrombocytopenia (18% each), diarrhea and fatigue (13% each) and acute kidney injury, pyrexia 
and rash maculopapular (8% each). The overall response rate was 62%, including 24% VGPR or 
better, and median DOR has not been reached (Chari 2015).   
The safety was assessed by an independent Data Monitoring Committee (DMC) and the 
observed safety profile across the three tested dose levels in this ongoing study did not indicate 
clinically meaningful differences. The overall obtained safety profile with ibrutinib in 
combination with carfilzomib with and without dexamethasone is consistent with the reported 
treatment-emergent AEs expected for these agents.  
Based upon the encouraging Phase 1 safety and efficacy data, Phase 2b commenced on 
09 February 2016 with the first patient dosed with the recommended Phase 2 dosing as follows: 
ibrutinib 840 mg daily, carfilzomib 20/36 mg/m2 on two consecutive days each week for three 
weeks of a 4-week cycle and dexamethasone (age adjusted dose) on two consecutive days each 
week.  
1.2.5.3. 
PCYC-1139-CA Safety Overview 
In accordance with the safety analyses described in Section 10.5.6, an internal meeting was held 
by the Sponsor on 15 December 2016 to review safety data of the first 8 subjects enrolled in the 
PCYC-1139-CA study to evaluate ibrutinib in combination with bortezomib and dexamethasone 
following the protocol-defined treatment schedule during Cycle 1 (first 21 days) of treatment. At 
that time, it was confirmed that there were no new safety signals identified in this treatment 
combination or schedule and enrollment continued as described in the protocol.  
As the Sponsor reviews AEs and SAEs on an ongoing basis, a review of the first 59 subjects 
enrolled between September 2016 and April 2017 in PCYC-1139-CA was conducted and 
indicated an increased incidence of severe infections compared to other studies in the Multiple 
Myeloma Program (PCYC-1111-CA and PCYC-1119-CA). As of 24 April 2017, preliminary 


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findings from PCYC-1139-CA, indicated that 21 subjects (36%) experienced a severe infection, 
with 8 (14%) resulting in a fatal outcome. 
With limited data currently available, the Sponsor will continue to follow the status of all 
subjects enrolled to determine contributing factors to this increased rate of infection. In the 
interim, the Sponsor has implemented the following modifications for all currently active 
subjects and potential subjects moving forward to further mitigate the risk of infections: 
• 
Reduction of dexamethasone dose administered (refer to revised study schedule 
Section 5.2). 
• 
Enroll subjects with 2 or 3 prior lines of therapy only which may strengthen the 
benefit/risk ratio for subjects with 1 prior line of therapy who have other treatment 
options. 
• 
Modify the inclusion criteria to meet ANC at inclusion from 1 to 1.5 x 109/L. 
• 
Clarification has been added to emphasize adequate management of infections. 
An internal safety review committee will be established in order to evaluate the rate of infections 
for ongoing and new patients approximately every 6 weeks (refer to Section 10.5.6.1).   
1.3. 
Bortezomib (VELCADE®) Description 
Bortezomib is a reversible proteasome inhibitor with antineoplastic activity.  
Full marketing approval in the EU was granted by the EMA for the treatment of adult subjects in 
the following indications: 1) monotherapy or in combination with pegylated liposomal 
doxorubicin or dexamethasone in patients with progressive MM who have received at least one 
prior therapy and who have already undergone or are unsuitable for haematopoietic stem cell 
transplantation 2) in combination with melphalan and prednisone in patients with previously 
untreated MM who are not eligible for high-dose chemotherapy with haematopoietic stem cell 
transplantation, 3) in combination with dexamethasone, or with dexamethasone and thalidomide 
for the induction treatment of patients with previously untreated MM who are eligible for 
high-dose chemotherapy with haematopoietic stem cell transplantation, and 4) in combination 
with rituximab, cyclophosphamide, doxorubicin and prednisone in patients with previously 
untreated mantle cell lymphoma who are unsuitable for haematopoietic stem cell transplantation. 
1.3.1. 
Pharmacokinetics and Product Metabolism 
The total systemic exposure of bortezomib in patients with multiple myeloma after repeat dose 
administration (AUClast) was equivalent for subcutaneous and intravenous administration. The 
Cmax after subcutaneous administration (20.4 ng/mL) was lower than intravenous (223 ng/mL). 
The AUClast geometric mean ratio was 0.99 and 90% confidence intervals were 80.18% - 
122.80%. 
The mean distribution volume of bortezomib ranged from approximately 498 to 1884 L/m2 
following single- or repeat-dose administration of 1 mg/m2 or 1.3 mg/m2 to patients with 


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multiple myeloma. This suggests bortezomib distributes widely to peripheral tissues. The 
binding of bortezomib to human plasma proteins averaged 83% over the concentration range of 
100 to 1000 ng/mL. 
In vitro studies indicate that bortezomib is primarily oxidatively metabolized via cytochrome 
P450 enzymes 3A4, 2C19, and 1A2. Bortezomib metabolism by CYP 2D6 and 2C9 enzymes is 
minor. The major metabolic pathway is deboronation to form 2 inactive deboronated metabolites 
that subsequently undergo hydroxylation to several metabolites. When compared to patients with 
normal hepatic function, mild hepatic impairment did not alter dose-normalized bortezomib 
AUC. However, the dose-normalized mean AUC values were increased by approximately 60% 
in patients with moderate or severe hepatic impairment. Various degrees of renal impairment do 
not affect bortezomib exposure. 
Bortezomib is a poor inhibitor of human liver microsome cytochrome P450 1A2, 2C9, 2D6, and 
3A4, with IC50 values of 30µM (>11.5 µg/mL). Bortezomib may inhibit 2C19 activity 
(IC50 = 18 µM, 6.9 µg/mL) and increase exposure to drugs that are substrates for this enzyme. 
Bortezomib did not induce the activities of cytochrome P450 3A4 and 1A2 in primary cultured 
human hepatocytes. 
1.3.2. 
Summary of Clinical Data for Bortezomib and Dexamethasone in MM 
Bortezomib is approved for subcutaneous injection with a recommended starting dose of 
1.3 mg/m2 administered twice weekly for 2 weeks (Days 1,4,8,11) followed by a 10-day rest 
period (Days 12-21). For extended therapy of more than 8 cycles, bortezomib may be 
administered on the standard schedule, or, for relapsed multiple myeloma, on a maintenance 
schedule (VELCADE® prescribing information). 
A Phase 3 randomized, open label trial evaluated the efficacy and safety of bortezomib 
administered IV vs. high-dose dexamethasone in patients with relapsed or refractory MM who 
had received 1-3 prior lines of therapy. The trial enrolled 669 patients and those treated with 
bortezomib had higher response rates with an ORR of 38% for bortezomib and CR rate of 6% for 
bortezomib, compared to 18% and less than 1% for dexamethasone, respectively. For those 
patients treated with bortezomib, the median time to progression was 6.2 months compared to 
3.5 months with dexamethasone. Both in patients who were refractory to their last prior therapy 
and those who were not refractory, overall survival was significantly longer and response rate 
was significantly higher in those treated with bortezomib (Richardson 2005).  
Bortezomib is also appropriate for retreatment of MM starting at the last tolerated dose. 
A Phase 2, single arm, open label trial evaluated the efficacy and safety of retreatment with 
bortezomib with and without dexamethasone in patients with MM who had relapsed after 
achieving ≥ PR with initial bortezomib-based therapy. The study enrolled 130 patients that 
achieved a complete response (CR) or PR upon completion of prior bortezomib therapy; had 
progressive disease (PD) after previously achieving PR or had relapsed from CR (as defined by 
European Group for Blood and Marrow Transplantation [EBMT] criteria (Blade 1998) and 


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≥ 6 months elapsed since last dose of bortezomib. Bortezomib was administered with or without 
dexamethasone at the investigator’s discretion and per standard of care. The median number of 
prior therapies, including prior bortezomib was 2. Thirty-six patients (28%) received 
single-agent bortezomib, and 94 (72%) received bortezomib with dexamethasone. The outcomes 
for all evaluable patients included an ORR of 40% with a complete response (CR) achieved in 
one patient (1%). The median DOR and TTP in patients who achieved a best confirmed response 
of ≥PR during bortezomib retreatment was 6.5 and 8.4 months, respectively. These outcomes 
were consistent regardless of number of prior therapies (Petrucci 2013).  
1.3.3. 
Summary of Clinical Safety for Bortezomib 
The most common all grade TEAEs (≥ 20%) in patients receiving bortezomib include nausea, 
diarrhea NOS (52% each), fatigue (39%), peripheral neuropathies (35%), thrombocytopenia 
(33%), constipation (30%), vomiting NOS (29%), anorexia (21%) and pyrexia (20%). The most 
common TEAE Grade 3 and 4 was thrombocytopenia (28%). Most common AEs leading to 
discontinuation included peripheral neuropathy (8%), diarrhea (3%), and thrombocytopenia, 
various gastrointestinal disorders, fatigue, hypercalcemia, and spinal cord compression (2% each, 
Richardson 2005). 
Other risks that have been reported in patients receiving bortezomib include hypotension (8%), 
cardiac toxicity (8%) with reactions suggestive of heart failure (≤1%); pulmonary toxicity 
including acute respiratory distress syndrome (ARDS) and acute diffuse infiltrative pulmonary 
disease of unknown etiology, Posterior Reversible Encephalopathy Syndrome (PRES), tumor 
lysis syndrome and hepatic toxicity (VELCADE® prescribing information).  
Clinical studies in MM have shown that herpes zoster reactivation was more common in subjects 
treated with bortezomib (6-11%) compared to control arms (3-4%), and in one study, the 
incidence of herpes zoster reactivation occurred less frequently in subjects receiving prophylactic 
antiviral therapy (3%) compared to subjects who did not receive prophylactic antiviral therapy 
(17%) [VELCADE® prescribing information].  
For the most comprehensive nonclinical and clinical information regarding bortezomib, please 
refer to the current version of VELCADE® Summary of Product Characteristics (SmPC).  
1.4. 
Justification of Study Design and Dose Rationale 
This is a Phase 2 study designed to assess the efficacy and safety of ibrutinib in combination 
with bortezomib and dexamethasone in relapsed or relapsed and refractory subjects with MM. 
Determining the choice of therapy in the relapsed setting is based upon numerous factors 
including age, performance status, comorbidities, efficacy and tolerability of prior treatments, 
number of prior therapies and the interval since the last treatment. 
Ibrutinib alone or in combination with other therapeutic agents (ie, dexamethasone and 
carfilzomib) has demonstrated a favorable safety profile with clinical activity in relapsed or 


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relapsed and refractory MM. In PCYC-1111 the highest clinical activity was seen with ibrutinib 
840 mg in combination with dexamethasone. The CBR was 23% (n=43) in comparison with 6% 
and 8% at lower dose levels and a trend towards improved PFS was observed (refer to 
Section 1.2.5.1). In PCYC-1119, ibrutinib was tested in combination with carfilzomib with and 
without dexamethasone at various dose levels. Initial efficacy data in 39 subjects with relapsed 
or relapsed and refractory MM reported an ORR of 62% and a CBR of 72%. The highest dose 
level (840 mg) has been expanded with an initial ORR of 65% and CBR of 77% seen in 
17 subjects (refer to Section 1.2.5.2).  
The clinical data from both Studies 1111 and 1119 in subjects with relapsed or relapsed/ 
refractory MM indicate that there is an increase in responses and depth of responses with 
increasing doses of ibrutinib, with the highest responses shown at the 840 mg/day dose level. 
In addition, the overall safety profile of ibrutinib in both studies in the setting of relapsed or 
relapsed and refractory MM in combination with other approved therapies revealed no clinically 
significant differences across dose levels of ibrutinib and was generally consistent with the safety 
profile of single agent ibrutinib when dosed at 420 mg/day and 840 mg/day outlined in the 
current version of the ibrutinib IB. There are no unexpected safety findings in either of the 
Studies 1111 and 1119 reported to date in MM (n=132).  
The use of bortezomib in combination with either corticosteroids or corticosteroids and another 
agent is considered a standard of care in Europe in both the elderly (non-transplant eligible) as 
well as the younger, fit patient (<65 or pts in good clinical condition). In addition, based upon the 
rates and depth of response as well as the PFS rates, a 3-drug combination with a bortezomib and 
dexamethasone is considered the standard of care prior to autologous stem cell transplant 
(ASCT). Bortezomib alone or in combination is also approved by the EMA for relapsed and 
refractory MM, although it is most commonly used in combination with dexamethasone in this 
setting (Moreau 2013).  
Despite the frequency of bortezomib use in the front-line setting, numerous studies have shown 
that retreatment with bortezomib either alone or in combination with corticosteroids in those 
patients having had a durable (≥6 months) partial response (PR) to prior bortezomib benefited 
with an overall response rate (ORR) of 40% and 8.4 month time to progression (TTP) (refer to 
Section 1.3.2, Petrucci 2013).  
Although significant advancements have been made, an unmet need still exists for patients with 
MM who progress on bortezomib, highlighting the need for agents with novel mechanisms of 
action. In a recent randomized, double-blind Phase 3 study using a pan-deactylase inhibitor, 
panobinostat (PANORAMA 1) plus bortezomib and dexamethasone in patients who received 
prior bortezomib and IMiDs, a significant increase in PFS compared to placebo plus bortezomib 
and dexamethasone was observed in patients with relapsed or relapsed and refractory MM 
(refer to Section 1.1.1).  


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Bortezomib has been successfully used in other combinations for more than 8 cycles of 
treatment, most recently receiving approval in combination with panobinostat and 
dexamethasone with a dosing schedule including extended bortezomib treatment as demonstrated 
in the current SmPC of panobinostat. Furthermore, the National Comprehensive Cancer Network 
(NCCN) has also recommended the use of extended bortezomib therapy for those patients 
tolerating therapy and receiving clinical benefit (NCCN 2015).  
Overexpression of BTK in myeloma cells compared to normal plasma cells and the ability of 
BTK inhibition to extend survival in mouse models has been reported (Tai 2012, Yang 2015). 
In addition, preclinical data suggest that BTK inhibitors and immunomodulatory agents target 
the clonogenic side populations of CD138neg cells (Jakubikova 2011). Evidence of BTK 
overexpression (BTKOE) has been identified in the CD138neg side population and was associated 
with the marked upregulation of several stem cell genes (ie, NANOG, MYC and SOX2). 
Yang et al, also demonstrated that BTKOE side population cells contributed to blunted responses 
of MM cells when treated with widely used MM drugs (ie, bortezomib, doxorubicin and 
etoposide) as well as a significant survival advantage of BTKOE cells when compared to BTKWT 
(Yang 2015). To better understand how BTK may promote drug resistance in MM, Yang et al 
studied the activity of the ABC transporter efflux and found an increase in activity in BTKOE 
cells as well as an increased expression of the ABCB1 transporter protein. Subsequent inhibition 
of the drug efflux pump led to a restoration of bortezomib sensistivity in BTKOE cells.  
The addition of ibrutinib to the well established regimen of bortezomib and dexamethasone in 
subjects with previously treated MM may represent a regimen that can improve outcomes by 
improving the efficacy and durability of response to this standard therapy.  
2. 
STUDY OBJECTIVE 
2.1. 
Primary Objective 
• 
To evaluate Progression-Free Survival (PFS) according to International Myeloma 
Working Group (IMWG) response criteria (Rajkumar 2011) in subjects with relapsed or 
relapsed and refractory MM. 
2.2. 
Secondary Objective(s) 
• 
Overall Response Rate (≥PR) 
• 
PFS Rate at Landmark Points 
• 
Duration of Response (DOR) 
• 
Overall survival (OS) 
• 
Time to Progression (TTP) 
• 
To evaluate the safety and tolerability of ibrutinib in combination with bortezomib and 
dexamethasone. 


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2.3. 
Exploratory Objectives 
• 
To evaluate the pharmacokinetics of ibrutinib and bortezomib when dosed in 
combination with dexamethasone. 
• 
To evaluate potential prognostic and predictive biomarkers relative to treatment 
outcomes (including gene expression profiles [GEP], secreted proteins, bone turnover 
and/or immunophenotyping) in subjects with relapsed or relapsed and refractory MM. 
• 
To assess the utilization and outcomes of subsequent anti-cancer therapies in subjects 
with relapsed or relapsed and refractory MM. 
3. 
STUDY DESIGN 
3.1. 
Overview of Study Design 
This study will be conducted as a Phase 2, open-label, non-randomized, international multicenter 
study to evaluate the efficacy and safety of ibrutinib in combination with bortezomib and 
dexamethasone in subjects with relapsed or relapsed and refractory MM. 
A total of approximately 125 subjects will be enrolled. 
The Screening Phase assessments will be performed within 30 days prior to the initiation of 
study treatment. Eligible subjects will have relapsed or relapsed and refractory MM, having 
received 2-3 prior lines of therapy, and have demonstrated disease progression following 
completion of most recent treatment regimen (relapsed) or are relapsed and refractory to the most 
recent treatment regimen defined as either non-responsive or disease progression on or within 60 
days of last treatment (Rajkumar 2011). Subjects who satisfy all the inclusion/exclusion criteria 
are eligible to enter the study. 
The Treatment Phase will extend from first dose of study treatment until the End-of-Treatment 
(EOT) visit (which should occur 30 days from last dose of study treatment or prior to the start of 
a new anti-cancer therapy). Initiation of study treatment should occur within 30 days of 
consenting and screening procedures, following approval by the Sponsor’s Medical Monitor. 
All subjects enrolled will receive ibrutinib in combination with bortezomib and dexamethasone 
according to Section 5. All subjects will continue study treatment until confirmed disease 
progression, study treatment is no longer tolerated by the subject or other protocol specified 
reason for discontinuation are met (Section 5.8). Further information on dosing is provided in 
Section 5. Efficacy evaluations will be performed as specified in Section 7.5. Subjects with 
confirmed disease progression must discontinue all study treatment.  
The Post-treatment Follow-up Phase will begin once a subject discontinues study treatment and 
will continue until death, lost to follow up, consent withdrawal, or study end, whichever occurs 
first.  


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• 
The Response Follow-up Phase will occur for subjects who discontinue for reasons other 
than disease progression (ie, for AE or Investigator decision), and will include efficacy 
assessments at a minimum every 4 weeks ±7 days until disease progression. Response 
Follow-up will continue regardless of initiation of subsequent anticancer therapies. 
Subjects with confirmed progression will continue to be followed in the Long-term 
Follow-up Phase. 
• 
The Long-term Follow-up Phase will occur for subjects with disease progression and 
subjects will be followed for survival, first two subsequent anti-cancer therapies and 
other malignancies every 12 weeks ± 14 days until study end.  
 


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Figure 1: 
Study Design Schematic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCREENING  
Within 28 days prior to start of study treatment  
(Refer to Section 8 for detail of  required assessments) 
SCREENING  
Within 28 days prior to start of study treatment  
(Refer to Section 8 for detail of  required assessments) 
SCREENING  
Within 28 days prior to start of study treatment  
(Refer to Section 8 for detail of  required assessments) 
SCREENING  
Within 28 days prior to start of study treatment  
(Refer to Section 8 for detail of  required assessments) 
SCREENING  
Within 28 days prior to start of study treatment  
(Refer to Section 8 for detail of  required assessments) 
SCREENING  
Within 28 days prior to start of study treatment  
(Refer to Section 8 for detail of  required assessments) 
SCREENING  
Within 30 days prior to start of study treatment  
(Refer to Section 8.2 for details of required assessments) 
Treatment Cycles 1-8 (21-day cycle) 
STUDY TREATMENT: 
Ibrutinib 840 mg orally, once daily continuously starting Day 1 of Cycle 1 until confirmed PD, 
unacceptable toxicity or other protocol specified reason for discontinuation 
COMBINATION THERAPY: 
Bortezomib 1.3 mg/m2 SC on Days 1, 4, 8, and 11 of each Cycle 
Dexamethasone 20 mg orally on Days 1, 4, 8, and 11 of each Cycle 
ASSESS ELIGIBILITY/ENROLLMENT 
If subject satisfies all inclusion/exclusion criteria, following review 
of eligibility and confirmation of enrollment from Sponsor, initiate 
study treatment  
Treatment Cycles 9-12 (42-day cycle) 
 
STUDY TREATMENT: 
Ibrutinib 840 mg orally, once daily continuously until confirmed PD, unacceptable toxicity or 
other protocol specified reason for discontinuation 
COMBINATION THERAPY: 
Bortezomib 1.3 mg/m2 SC on Days 1, 8, 22, and 29 of each Cycle 
Dexamethasone 20 mg orally on Days 1, 8, 22, and 29 of each Cycle 
Treatment Cycles 13+ (28-day cycle) 
 
STUDY TREATMENT: 
Ibrutinib orally 840 mg, once daily continuously until confirmed PD, unacceptable toxicity or 
other protocol specified reason for discontinuation 
COMBINATION THERAPY: 
Dexamethasone 40 mg orally once weekly 
TREATMENT DISCONTINUATION 
Due to confirmed PD, unacceptable toxicity or other reason for treatment discontinuation  
(Refer to Section 9.2). Complete EOT visit. 
Response Follow-up 
Prior to confirmed PD. Continue efficacy 
evaluations every 4 weeks until  
confirmed PD. 
Long-Term Follow-up 
Following confirmed PD. Follow-up for survival status 
and record first two subsequent anti-MM therapies and 
other malignancies every 12 weeks. 


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3.2. 
Statement of Compliance 
This study will be conducted in compliance with this protocol, principles of International 
Conference on Harmonisation (ICH), Good Clinical Practice (GCP), Declaration of Helsinki, and 
all applicable national and local regulations governing clinical studies. 
4. 
SUBJECT SELECTION 
The inclusion and exclusion criteria for enrolling subjects on this study are described below. If 
there are any questions about the entry criteria, the Investigator should consult with the Medical 
Monitor before considering a subject for the study. Selected eligibility criteria must be confirmed 
in writing by the Medical Monitor prior to enrollment. 
4.1. 
Inclusion Criteria 
To be enrolled in the study, each potential subject must meet all of the following inclusion 
criteria. 
Disease Related 
1. Subjects with MM who have received 2 or 3 prior lines of therapy (Appendix 4) and have 
demonstrated disease progression since the completion of the most recent treatment regimen.  
• 
Subjects may have received prior bortezomib treatment but must not be refractory or 
non-responsive (see exclusion criteria 5) 
2. Measurable disease defined by at least ONE of the following: 
• 
Serum monoclonal protein (SPEP) ≥1 g/dL (for subjects with IgA, IgD, IgE or IgM 
multiple myeloma SPEP ≥0.5 g/dL) 
• 
Urine monoclonal protein (UPEP) ≥200 mg by 24 hour urine electrophoresis  
Laboratory 
3. Adequate hematologic function for at least 7 days prior to Screening and dosing independent 
of platelet transfusion and growth factor support, with the exception of pegylated G-CSF 
(granulocyte-colony stimulating factor pegfilgrastim) and darbopoeitin which require 
adequate hematologic function at least 14 days prior to Screening and dosing. Adequate 
hematologic function is defined as: 
• 
Absolute neutrophil count ≥1500 cells/mm3 (1.5 x 109/L) 
• 
Platelet count ≥75,000 cells/mm3 (75 x 109/L) 
4. Adequate hepatic and renal function defined as: 
• 
Serum aspartate transaminase (AST) or alanine transaminase (ALT) ≤2.5 x upper limit 
of normal (ULN) 
• 
Creatinine Clearance (CrCl) ≥30 mL/min (by Cockcroft-Gault estimation OR as 
measured by 24 hour urine collection) 
• 
Total Bilirubin ≤1.5 x ULN 


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5. Prothrombin time (PT)/ International normal ratio (INR) ≤1.5 x upper limit of normal (ULN) 
and PTT (activated partial thromboplastin time [aPTT]) ≤1.5 x ULN (unless abnormalities 
are unrelated to coagulopathy or bleeding disorder). When treated with warfarin or other 
vitamin K antagonists, then INR ≤3.0). 
Demographic 
6. Male and female ≥18 years of age 
7. Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 
Ethical/Other 
8. Female subjects who are of non-reproductive potential (ie, post-menopausal by history - no 
menses for ≥1 year; OR history of hysterectomy; OR history of bilateral tubal ligation; OR 
history of bilateral oophorectomy). Female subjects of reproductive potential must have a 
negative serum or urine pregnancy test upon study entry. 
9. Male and female subjects of reproductive potential who agree to use highly effective 
methods of birth control (eg, condoms, implants, injectables, combined oral contraceptives, 
some intrauterine devices [IUDs], complete abstinence1, or sterilized partner) during the 
period of therapy and for 90 days after the last dose of study treatment. 
4.2. 
Exclusion Criteria 
To be enrolled in the study, potential subjects must not have met any of the following exclusion 
criteria: 
Disease-Related 
1. Primary refractory disease defined as nonresponsive in patients who have never achieved a 
minimal response or better with any therapy. 
2. History of plasma cell leukemia, primary amyloidosis, POEMS syndrome within 12 months 
prior to first administration of study treatment. 
Concurrent Conditions 
3. Recent prior chemotherapy: 
a. 
Alkylators (eg, melphalan, cyclophosphamide) and/or anthracyclines <21 days prior to 
first administration of study treatment 
b. High dose corticosteroids, immodulatory agents [IMiDs] or proteasome inhibitors [PIs] 
<14 days prior to first administration of study treatment  
c. 
Monoclonal antibody <2 weeks prior to first administration of study treatment. 
                                                   
1 Complete abstinence is a highly effective method only if defined as refraining from heterosexual intercourse during 
the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject. 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01 About_HMA/Working_Groups/ 
CTFG/2014_09_HMA_CTFG_Contraception.pdf 


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4. Prior exposure to BTK inhibitors 
5. Refractory or non-responsive to prior PI therapy (bortezomib or carfilzomib) 
a. 
Refractory is defined as progression on treatment or within 60 days of completion.  
b. Non-responsive is defined as failure to achieve ≥MR per IMWG response criteria 
(Rajkumar 2011). 
6. History of hypersensitivity reactions to prior bortezomib, to boron, mannitol or nitrogen. 
7. History of other malignancies, except: 
a. 
Malignancy treated with curative intent and with no known active disease present for 
≥3 years before the first administration of study treatment and felt to be at low risk for 
recurrence by treating physician. 
b. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of 
disease. 
c. 
Adequately treated carcinoma in situ without evidence of disease. 
8. Peripheral neuropathy Grade ≥2 or Grade 1 with pain at Screening 
9. Prior allogeneic stem cell transplant 
10. Recent infection requiring systemic treatment that was completed <7 days before the first 
administration of study treatment and/or uncontrolled active systemic infection. 
11. Unresolved toxicities from prior anti-cancer therapy, defined as having an event not resolved 
to CTCAE v 4.03, Grade ≤ 1 or to the levels dictated in the inclusion/exclusion criteria with 
the exception of alopecia. 
12. Known bleeding disorders (eg, von Willebrand’s disease or hemophilia) 
13. History of stroke or intracranial hemorrhage within 6 months prior to enrollment. 
14. Known history of human immunodeficiency virus (HIV) or active with hepatitis C virus 
(HCV) or hepatitis B virus (HBV). Subjects who are positive for hepatitis B core antibody, 
hepatitis B surface antigen (HbsAg), or hepatitis C antibody must have a negative 
polymerase chain reaction (PCR) result before enrollment. Those who are PCR positive will 
be excluded. 
15. Major surgery within 4 weeks of first administration of study treatment. 
16. Any life-threatening illness, medical condition including uncontrolled Diabetes Mellitus, or 
organ system dysfunction that, in the opinion of the investigator, could compromise the 
subject’s safety or put the study outcomes at undue risk. 
17. Currently active, clinically significant hepatic impairment (≥mild hepatic impairment 
according to the Child-Pugh classification [Appendix 8]). 
18. Currently active, clinically significant cardiovascular disease, such as uncontrolled 
arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart 
Association Functional Classification; or a history of myocardial infarction, unstable angina, 
or acute coronary syndrome within 6 months prior to enrollment.  


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19. Unable to swallow capsules, malabsorption syndrome, disease significantly affecting 
gastrointestinal function, resection of the stomach or small bowel, symptomatic inflammatory 
bowel disease or ulcerative colitis, or partial or complete bowel obstruction. 
20. Subjects who received a strong cytochrome P (CYP) 450 3A inhibitor within 7 days prior to 
the first administration of study treatment or subjects who require continuous treatment with 
a strong CYP 3A inhibitor (Appendix 5). 
21. Female subjects who are pregnant, or breastfeeding, or planning to become pregnant while 
enrolled in this study or within 90 days of last dose of study drug. Male subjects who plan to 
father a child while enrolled in this study or within 90 days after the last dose of study drug. 
22. Unwilling or unable to participate in all required study evaluations and procedures. 
23. Unable to understand the purpose and risks of the study and to provide a signed and dated 
informed consent form (ICF) and authorization to use protected health information 
(in accordance with national and local subject privacy regulations). 
5. 
TREATMENT OF SUBJECTS 
5.1. 
Enrollment 
Subjects who satisfy all the inclusion/exclusion criteria are eligible to enter the study. This is an 
open-label, Phase 2 study; there will be no stratification of subjects.  
5.2. 
Study Treatment  
All enrolled subjects will receive ibrutinib in combination with bortezomib and dexamethasone.  
Ibrutinib (PO) 
840 mg once daily on a continuous basis  
Bortezomib (SC) 
1.3 mg/m2 on Days 1, 4, 8 and 11 during Cycles 1-8; Days 1, 8, 22, and 29 during 
Cycles 9-12 
Dexamethasone (PO)† 
20 mg on Days 1, 4, 8, and 11 during Cycles 1-8; 20 mg on Days 1, 8, 22, and 29 during 
Cycles 9-12; and 40 mg once weekly during Cycle 13 and beyond  
† Dose adjustment of dexamethasone is recommended for subjects >75 years of age to 10 mg on days specified in 
the protocol during Cycles 1-12 and to 20 mg on days specified in the protocol for Cycles 13 and beyond, however, 
this will be at investigator’s discretion with dose modification guidelines followed per protocol for toxicity.  
5.3. 
Ibrutinib 
All subjects will receive ibrutinib and will follow guidelines described below for ibrutinib dosing 
and toxicity management.  
5.3.1. 
Formulation, Packaging, and Storage of Ibrutinib 
Ibrutinib capsules are provided as a hard gelatin capsule containing 140 mg of ibrutinib. All 
formulation excipients are compendial and are commonly used in oral formulations. Refer to the 
ibrutinib IB for a list of excipients.  


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The ibrutinib capsules will be packaged in opaque high-density polyethylene plastic bottles with 
labels bearing the appropriate label text to meet the applicable regulatory requirements. All study 
treatment will be dispensed in child-resistant packaging.  
Refer to the Pharmacy Manual for additional guidance on study treatment storage, preparation 
and handling. 
5.3.2. 
Dosage and Administration of Ibrutinib 
Ibrutinib 840 mg (6 x 140 mg capsules) is administered orally once daily with 8 ounces 
(approximately 240 mL) of water at approximately the same time each day. The capsules should 
be swallowed intact and subjects should not attempt to open capsules or dissolve them in water. 
The use of strong CYP3A inhibitors/inducers, and grapefruit and Seville oranges should be 
avoided for the duration of the study (Section 6.1.2.1). 
If a dose is missed, it can be taken as soon as possible on the same day with a return to the 
normal schedule the following day. The subject should not take extra capsules to make up the 
missed dose. 
Ibrutinib will be dispensed to subjects in bottles. Unused ibrutinib capsules dispensed during 
previous visits must be returned and drug accountability records updated at the beginning of the 
next cycle. Returned capsules must not be re-dispensed to anyone. 
The first dose of ibrutinib will be administered orally on Cycle 1 Day 1 during the clinic visit, 
after which ibrutinib will be self-administered daily by the subject on an outpatient basis. 
Ibrutinib dosing is continuous (without interruption) throughout the Treatment Phase and may be 
administered at the same time as bortezomib and dexamethasone.  
If a dose of bortezomib or dexamethasone is held or delayed at any time for toxicity that does not 
require ibrutinib to be held or delayed, dosing of ibrutinib should continue. If a Day 1 (of any 
Cycle) is delayed due to scheduling issues, ibrutinib dosing should continue. 
Treatment will continue until confirmed disease progression or other reason for treatment 
discontinuation as outlined in Section 5.8.  
Dose modifications for toxicity are outlined in Section 5.3.4. 
5.3.3. 
Dose Hold, Reduction or Discontinuation of Ibrutinib 
In order to continue ibrutinib at the start of a new cycle, the subject must not meet any of the 
criteria for ibrutinib dose modification (see Section 5.3.4). 
Treatment with ibrutinib should be withheld for any unmanageable, potentially study treatment-
related non-hematological toxicity that is Grade 3 or higher in severity and any hematologic 
toxicity meeting the criteria in Section 5.3.4. Subjects who require full-dose of anticoagulant 


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treatment (eg, warfarin or heparin) should have ibrutinib held until stable on anticoagulant 
therapy (Section 6.1.2.4). Subjects that require an invasive procedure or surgery must have 
ibrutinib withheld according to the guidance in Section 6.2. Any other clinically important events 
where dose delays may be considered appropriate by the Investigator should be discussed with 
the Medical Monitor. 
Ibrutinib may be withheld for a maximum of 28 consecutive days for toxicity. Ibrutinib should 
be discontinued in the event of an ibrutinib toxicity lasting more than 28 days, unless reviewed 
and approved by the Medical Monitor. 
5.3.4. 
Dose Modification of Ibrutinib 
The dose of ibrutinib must be modified according to the dose modification guidance in Table 1. 
if any of the following toxicities occur:  
• 
Grade 4 neutropenia (ANC <500/µL) for more than 7 days. Refer to Section 6 for 
instruction regarding the use of growth factor support 
• 
Grade 3 thrombocytopenia (platelets <50,000/µL) in the presence of clinically 
significant bleeding events  
• 
Grade 4 thrombocytopenia (platelets <25,000/µL) 
• 
Grade 3 or 4 nausea, vomiting, or diarrhea if persistent, despite optimal anti-emetic 
and/or anti-diarrheal therapy  
• 
Any other Grade 4 or unmanageable Grade 3 toxicity attributed to ibrutinib  
For Grade 3 or 4 atrial fibrillation or persistent atrial fibrillation of any grade, consider the risks 
and benefits of ibrutinib treatment. If clinically indicated, the use of anticoagulants or antiplatelet 
agents may be considered for the thromboprophylaxis of atrial fibrillation (Section 6.1.2.4).  
In the event that the investigator feels deviation from the recommendations above is required, 
please consult the medical monitor to discuss for approval. 


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Table 1: 
Ibrutinib Dose Modification Guidance 
Hematologic Adverse Events 
Occurrence 
Action to be Taken 
First 
Withhold ibrutinib until recovery to an ANC ≥750/µL or platelets >25,000/µL with no 
evidence of Grade ≥2 bleeding; may restart at original dose level 
Subsequenta 
Withhold ibrutinib until recovery to an ANC ≥750/µL or platelets >25,000/µL with no 
evidence of Grade ≥2 bleeding; may restart at 1 dose level lower (refer to Table 2) 
Non-Hematologic Adverse Events 
Occurrence 
Action to be Taken 
First 
Withhold ibrutinib until recovery to Grade ≤1 or baseline; may restart at original dose 
level 
Subsequenta 
Withhold ibrutinib until recovery to Grade ≤1 or baseline; may restart at 1 dose level 
lower (refer to Table 2) 
a Do not dose below 280 mg daily; please refer to guidance provided in Sections 5.3.5 and 6.2.1 for 
exceptions. 
For required dose modification for hepatic impairment refer to Section 5.3.5 and for concomitant 
treatment with CYP3A inhibitors refer to Section 6.1.2.1.  
Table 2: 
Ibrutinib Dose Modifications 
Starting Dose Level 
840 mg 
Dose Reduction Level 1 
700 mg 
Dose Reduction Level 2 
560 mg 
Dose Reduction Level 3 
420 mg 
Dose Reduction Level 4 
280 mg 
Dose Reduction Level 5 
Discontinue 
After a dose reduction, dose escalation of ibrutinib to the previous higher dose (1 level up) may 
be considered after consultation with the Medical Monitor if the event does not recur after at 
least 2 cycles of the reduced dose. 
Dose changes must be recorded in the Dose Administration eCRF. If ibrutinib is discontinued for 
toxicity, subject will end the Treatment Phase of the study. 


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5.3.5. 
Dose Modification for Hepatic Impaired Subjects 
Ibrutinib is metabolized in the liver and therefore subjects with clinically significant chronic 
hepatic impairment at the time of Screening (Child-Pugh class B or C) are excluded from study 
participation. Refer to Appendix 8 for Child-Pugh classification.  
• 
For subjects who develop mild liver impairment (Child-Pugh class A), the recommended 
dose for ibrutinib is 280 mg daily (two capsules) unless lower doses had already been 
implemented.  
• 
For subjects who develop moderate liver impairment (Child-Pugh class B), the 
recommended dose is 140 mg daily (one capsule).  
• 
Subjects who develop severe hepatic impairment (Child-Pugh class C) must hold study 
treatment until resolved to moderate impairment (Child-Pugh class B) or better and 
could be re-treated according to resolved hepatic conditions (ie, 140 mg or 280 mg for 
moderate or mild impairment, respectively). 
Subjects who develop acute hepatic toxicity with liver enzymes Grade 3 or higher while on study 
should be managed per standard dose modification guidelines in Section 5.3.4. 
5.4. 
Bortezomib  
All subjects will receive bortezomib and will follow guidelines for bortezomib dosing and 
toxicity management. 
5.4.1. 
Formulation, Packaging, and Storage of Bortezomib 
Bortezomib (VELCADE®) will be supplied as single-use vials containing 3.5 mg of bortezomib 
as a lyophilized white to off-white powder for subcutaneous administration.  
Unopened vials of bortezomib are stable until the date indicated on the package when stored in 
the original package protected from light. Bortezomib contains no antimicrobial preservative and 
are only intended for single use.  
Bortezomib will be provided by Pharmacyclics and will be relabeled for clinical trial use. 
Refer to the Pharmacy Manual for detailed guidance for bortezomib storage, preparation and 
reconstitution.  
5.4.2. 
Dosage, Preparation and Administration of Bortezomib 
Bortezomib will be administered SC at each clinic visit beginning on Day 1 of Cycle 1. 
Bortezomib dosing during the Treatment Phase occurs on Days 1, 4, 8, and 11 of Cycles 1-8 in a 
21 day cycle. For Cycles 9-12, bortezomib dosing occurs on Days 1, 8, 22, and 29 in a 42 day 
cycle. At least 72 hours should elapse between consecutive doses of bortezomib. The dose is 
calculated using the subject’s body surface area (BSA) on Day 1 of every Cycle.  
Bortezomib may be dosed at the same time as ibrutinib and dexamethasone. 


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Treatment will continue until disease progression or other reason for treatment discontinuation as 
outlined in Section 5.8.  
Dose modifications for toxicity are outlined in Section 5.4.3. 
For instructions regarding drug accountability and disposal/return of unused bortezomib refer to 
the Pharmacy Manual. 
5.4.3. 
Dose Hold, Reduction or Discontinuation of Bortezomib 
In order to initiate a new cycle of therapy with bortezomib, the subject must have an ANC 
≥750/µL and a platelet count ≥25,000/µL and no bortezomib related toxicities requiring dose 
hold as per Section 5.4.4 on Day 1. If these criteria are not met, a repeat assessment is to be 
performed at least weekly or more frequent per the Investigator’s decision. The initiation of 
bortezomib should be delayed until the subject meets the above criteria at which time the subject 
will initiate drug without dose modification. Once a cycle has initiated, if bortezomib must be 
held for toxicity during dosing, omitted doses should not be made up.  
Any other clinically important events where dose delays may be considered appropriate by the 
Investigator should be discussed with the Medical Monitor. 
Bortezomib may be withheld for a maximum of 28 consecutive days for toxicity. Bortezomib 
treatment should be discontinued in the event of a bortezomib related toxicity lasting more than 
28 days, unless reviewed and approved by the Medical Monitor. 
If bortezomib is discontinued prior to protocol-scheduled completion, mid-cycle visits associated 
with bortezomib administration (ie, Day 4, Day 8, Day 11 during Cycles 1-8, or Day 8, Day 22, 
Day 29 during Cycles 9-12), with the exception of efficacy assessments on Day 22, are not 
required. 
5.4.4. 
Dose Modification of Bortezomib  
The dose of bortezomib should be modified according to the dose modification guidelines in 
Table 3 if any of the following toxicities occur: 


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Table 3: 
Dose Modification or Interruption for Bortezomib Toxicity 
Toxicity 
Intervention 
Neutropenia: 
•
ANC <500/µL
•
Febrile neutropenia (ANC <1,000/µL with
an associated temperature of >38.5°C)
•
Hold therapy until ANC resolves to Grade ≤2
•
If only one dose was omitted prior to correction to
these levels, bortezomib should be restarted at the
same dose.
•
If two or more doses were omitted, consecutively,
or within the same cycle, bortezomib should be
restarted with a one level dose reduction.
Thrombocytopenia: 
•
Grade 3 (platelet count <50,000/µL)
associated with Grade ≥2 bleeding, 
•
Grade 4 (platelet count <25,000/µL)
•
Hold therapy until platelet count resolves to Grade
≤2
•
If only one dose was omitted prior to correction to
these levels, bortezomib should be restarted at the
same dose.
•
If two or more doses were omitted, consecutively,
or within the same cycle, bortezomib should be
restarted with a one level dose reduction.
Peripheral Neuropathy: 
•
Grade 1 with pain
•
Grade 2 (moderate symptoms; limiting
instrumental activities of daily living
[ADL*])
•
Reduce bortezomib by one dose level
Peripheral Neuropathy: 
•
Grade 2 with pain
•
Grade 3 (severe symptoms; limiting self
care ADL**)
•
Withhold bortezomib treatment until symptoms of
toxicity have resolved to ≤ Grade 1 without pain.
When toxicity resolves reinitiate bortezomib
treatment and reduce dose to 0.7 mg/m2 once per
week.
Peripheral Neuropathy: 
•
Grade 4 (life threatening consequences;
urgent intervention indicated) and or severe 
autonomic neuropathy 
•
Discontinue bortezomib
Hepatic Impairment: 
Moderate: 
•
Bilirubin >1.5x−3x ULN
•
SGOT(AST) level- Any
Severe: 
•
Bilirubin >3x ULN
•
SGOT(AST) level- Any
•
Reduce dose of bortezomib to 0.7 mg/m2 for one
cycle, if stable or improved at the start of the next
cycle, consider escalation to 1.0 mg/m2 or to 1.3
mg/m2 if resolved to mild. Should this event recur
upon dose escalation, de-escalate to previous level.
Herpes Zoster reactivation any grade 
•
Hold therapy until lesions are dry
•
Restart at the same dose
Other bortezomib related non-hematologic 
toxicity ≥ Grade 3 
•
Determine attribution of toxicity and hold therapy.
If toxicity resolves to Grade ≤2, resume therapy


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Toxicity 
Intervention 
with a one level dose reduction. 
Grading based on NCI Common Toxicity Criteria CTCAE v 4.03. 
*Instrumental ADL: refers to preparing meals, shopping for groceries or clothes, using telephone, managing money, etc;
**Self care ADL: refers to bathing, dressing and undressing, feeding self, using the toilet, taking medicinal products, 
and not bedridden. 
Table 4: 
Dose Reduction of Bortezomib 
Cycles 1-8 
Cycles 9-12 
Starting Dose Level 
1.3 mg/m2 twice per week 
1.3 mg/m2 
Dose Reduction Level 1 
1.3 mg/m2 once per week 
1.0 mg/m2 
Dose Reduction Level 2 
1.0 mg/m2 once per week 
0.7 mg/m2 
Dose Reduction Level 3 
0.7 mg/m2 once per week 
Discontinue 
Dose Reduction Level 4 
Discontinue 
After a dose reduction, dose escalation of bortezomib to the previous higher dose (1 level up) 
may be considered after consultation with the Medical Monitor if the event does not recur after at 
least 2 cycles of the reduced dose. 
Dose changes must be recorded in the Dose Administration eCRF.  
If a dose of ibrutinib or dexamethasone is held or delayed at any time for toxicity that does not 
require bortezomib to be held or delayed, dosing of bortezomib should continue. 
Subjects requiring permanent discontinuation of bortezomib due to toxicity may continue to 
receive ibrutinib and dexamethasone.  
5.5. 
Dexamethasone 
All subjects will receive dexamethasone and will follow guidelines for dexamethasone dosing 
and toxicity management. 
5.5.1. 
Formulation, Packaging, and Storage of Dexamethasone 
Dexamethasone tablets for oral administration are available in multiple strengths. Commercially 
available dexamethasone will be supplied by Pharmacyclics. The commercial material will be 
relabeled for clinical trial use.  
Refer to the Pharmacy Manual for additional guidance on dexamethasone storage, preparation 
and handling. 
5.5.2. 
Dosage and Administration of Dexamethasone 
The first dose of dexamethasone will be administered orally on Day 1 of Cycle 1 during the 
clinic visit after which dexamethasone will be self-administered by the subjects on an outpatient 
basis. Dexamethasone will be administered at 20 mg on the day of each bortezomib dose during 


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Cycles 1-12. Dose adjustment of dexamethasone is recommended for subjects >75 years of age 
to 10 mg on days specified in the protocol during Cycles 1-12, however, this will be at 
investigator’s discretion with dose modification guidelines followed per protocol for toxicity. 
During Cycles 1-8, if there is a dose modification to weekly administration of bortezomib, dose 
of dexamethasone will be administered at the last tolerated cumulative weekly dose (ie, 40 mg of 
dexamethasone on the day of bortezomib administration; 20 mg for subjects >75 years of age). 
During Cycle 13 and beyond, dexamethasone will be administered at 40 mg weekly ±1 day. 
Dose adjustment of dexamethasone is recommended for subjects >75 years of age to 20 mg on 
days specified in the protocol for Cycles 13 and beyond however, this will be at investigator’s 
discretion with dose modification guidelines followed per protocol for toxicity. If a dose 
modification of dexamethasone is required during Cycles 1-12, subjects should continue dosing 
with dexamethasone at the last tolerated cumulative weekly dose beginning with Cycle 13 if this 
is less than 40 mg and maintain this dose throughout the remainder of study treatment. If at any 
time bortezomib is discontinued due to toxicity, dosing with dexamethasone can continue in the 
absence of dexamethasone related toxicity. 
If the subject misses a dose, it can be taken as soon as possible on the same day or the following 
day with a return to the normal schedule. If dexamethasone dosing requires a schedule 
adjustment of more than ±1 day contact the Medical Monitor to discuss. 
Treatment will continue until disease progression or other reason for treatment discontinuation as 
outlined in Section 5.8.  
Dose modifications for toxicity are outlined in Section 5.5.3. 
5.5.3. 
Dose Modification of Dexamethasone 
Treatment with dexamethasone should be withheld for any unmanageable Grade ≥3 
dexamethasone related toxicity and may be reduced for unmanageable Grade 2 toxicity. Refer to 
Table 5 for dexamethasone dose modifications due to toxicity. Any other clinically important 
events where dose delays may be considered appropriate by the Investigator should be discussed 
with the Medical Monitor. Dexamethasone may be withheld for a maximum of 28 consecutive 
days for toxicity. Dexamethasone should be discontinued in the event of a toxicity lasting more 
than 28 days, unless reviewed and approved by the Medical Monitor. 


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Table 5: 
Dose Modification of Dexamethasone 
Starting Dose Level 
Cycles 1-12† 
Cycle 13 and Beyond† 
20 mg 
40 mg 
Dose Reduction Level 1 
12 mg 
20 mg 
Dose Reduction Level 2 
8 mg 
12 mg 
Dose Reduction Level 3 
Discontinue 
8 mg 
Dose Reduction Level 4 
N/A 
Discontinue 
† Dose adjustment of dexamethasone is recommended for subjects >75 years of age to 10 mg on days 
specified in the protocol during Cycles 1-12 with dose reduction level 1 for toxicity to 4 mg, and any 
subsequent reduction would require dexamethasone discontinuation, and 20 mg during Cycles 13 and 
Beyond following the dose reduction levels specified above with starting dose level of 20 mg, however, 
this will be at investigator’s discretion with dose modification guidelines followed per protocol for 
toxicity.  
Subjects unable to tolerate the minimum dose of dexamethasone should discontinue 
dexamethasone dosing and continue treatment with ibrutinib or ibrutinib and bortezomib. 
5.6. 
Prophylaxis and Treatment of Infections in Multiple Myeloma 
Patients with multiple myeloma are at increased risk of infection (Nucci 2009, Billmark 2015). 
The rate of infections is highest in the first three to four months of treatment initiation and in 
the setting of relapsed disease (Billmark 2015, Auguston 2005). Factors that contribute to 
the increased risk of infection include impaired lymphocyte function, suppression of normal 
plasma cell function, hypogammaglobulinemia, and chemotherapy induced neutropenia. 
Pneumonias and urinary tract infections account for the majority infections with Streptococcus 
pneumoniae, Haemophilus influenza, and Escherichia coli being the most common organisms. 
Preventative measures that may decrease the rate of infection among patients with multiple 
myeloma include the use of vaccines, prophylactic antibiotics, antifungals, antivirals, and 
intravenous immunoglobulin. Usage of antimicrobial prophylaxis in accordance with standard 
practice is permitted and should be strongly considered in all patients who are deemed at an 
increased risk for infections (especially the opportunistic infections) particularly in the first few 
months of study treatment (refer to Section 6.1.1).  
Patients suspected of having an infection should be treated promptly (after obtaining appropriate 
cultures of blood, urine, chest x-ray, etc.) and according to institutional guidelines according to 
the flora and resistance patterns seen at the institution (in the absence of an identified pathogen). 
Study treatment should be managed according to the guidance provided in the respective sections 
(refer to Sections 5.3, 5.4, and 5.5). 


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5.7. 
Overdose 
5.7.1. 
Ibrutinib 
There is no specific experience in the management of ibrutinib overdose in patients. There was 
no maximum tolerated dose (MTD) reached in the Phase 1 study in which subjects received up to 
12.5 mg/kg/day (1400 mg/day). Healthy subjects were exposed up to single dose of 1680 mg. 
One healthy subject experienced reversible Grade 4 hepatic enzyme increases (AST and ALT) 
after a dose of 1680 mg. Subjects who ingested more than the recommended dosage should be 
closely monitored and given appropriate supportive treatment. 
Refer to Section 11 for further information regarding special reporting situations as a result of 
overdose.  
5.7.2. 
Bortezomib 
There is no known specific antidote for bortezomib overdosage. In humans, fatal outcomes 
following the administration of more than twice the recommended therapeutic dose have been 
reported, which were associated with the acute onset of symptomatic hypotension and 
thrombocytopenia. In the event of an overdosage, the patient’s vital signs should be monitored 
and appropriate supportive care given.  
5.7.3. 
Dexamethasone 
In the event of an overdose, subjects should be closely monitored and given appropriate 
supportive treatment. In the case of acute overdosage, according to the subject’s condition, 
supportive therapy may include gastric lavage or emesis. 
5.8. 
Criteria for Permanent Discontinuation of Study Treatment 
Investigators are encouraged to keep a subject who is experiencing clinical benefit in the study 
until confirmed disease progression, significant toxicity puts the subject at risk, or routine 
noncompliance puts the study outcomes at risk. For a complete list of criteria for permanent 
discontinuation of study treatment refer to Section 9.2. 
An End-of-Treatment Visit (Section 8.3.12) is required for all subjects except for those subjects 
who have withdrawn full consent (see Section 9.3). 
6. 
CONCOMITANT MEDICATIONS/PROCEDURES 
6.1. 
Concomitant Medications 
6.1.1. 
Permitted Concomitant Medications 
Supportive medications in accordance with standard practice (such as for emesis, diarrhea, etc.) 
are permitted. Use of herpes simplex virus (HSV) prophylaxis (ie, acyclovir) should be 
considered in all subjects and administered in accordance with standard practice. 


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Usage of antimicrobial prophylaxis in accordance with standard practice (eg, ASCO 
guidelines [Flowers 2013]) is permitted and should be considered in subjects who are at 
increased risk for opportunistic infections. 
Erythropoietic growth factors (eg, erythropoietin) and hematopoietic growth factors are allowed 
per institutional policy and in accordance with the ASCO guidelines (Smith 2006). Transfusional 
support (packed red blood cells and platelets) may be given in accordance with institutional 
policy..  
Short courses (≤14 days) of steroid treatment for non-cancer-related medical reasons (eg, joint 
inflammation, asthma exacerbation, rash, antiemetic use and infusion reactions) at doses that are 
clinically indicated are permitted in addition to those assigned per protocol treatment. 
6.1.2. 
Medications to be Used with Caution 
6.1.2.1. 
CYP3A Inhibitors/Inducers 
Ibrutinib 
Ibrutinib is metabolized primarily by CYP3A4. Avoid concomitant use of oral/systemic strong or 
moderate CYP3A inhibitors and consider alternative agents with less CYP3A inhibition.  
• 
If a strong CYP3A inhibitor must be used, reduce ibrutinib dose to 140 mg or withhold 
treatment for the duration of the inhibitor use. Subjects should be monitored for signs of 
ibrutinib toxicity. 
• 
If a moderate CYP3A inhibitor must be used, reduce ibrutinib to 280 mg for those 
subjects receiving 840 mg and to 140 mg for those subjects receiving doses below 
840 mg for the duration of the inhibitor use. Avoid grapefruit and Seville oranges during 
ibrutinib treatment, as these contain moderate inhibitors of CYP3A (see Section 5.3.2). 
• 
No dose adjustment is required in combination with mild inhibitors.  
Avoid concomitant use of oral/systemic strong CYP3A inducers (eg, carbamazepine, rifampin, 
phenytoin, and St. John’s Wort). Consider alternative agents with less CYP3A induction. 
A list of common CYP3A inhibitors and inducers is provided in Appendix 5. For further 
information, please refer to the current version of the IB and examples of inhibitors, inducers, 
and substrates can be found at http://medicine.iupui.edu/clinpharm/ddis/main-table/. This 
website is continually revised and should be checked frequently for updates. 
Bortezomib 
Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2.  
Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure to 
bortezomib by 35% in 12 patients. Monitor patients for signs of bortezomib toxicity and consider 


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a bortezomib dose reduction if bortezomib must be given in combination with strong CYP3A4 
inhibitors (eg, ketoconazole, ritonavir).  
Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure 
of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to 
exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. 
Efficacy may be reduced when bortezomib is used in combination with strong CYP3A4 
inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in subjects 
receiving bortezomib. St. John’s Wort (Hypericum perforatum) may decrease bortezomib 
exposure unpredictably and should be avoided.  
Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of 
bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of 
bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant. 
6.1.2.2. 
Drugs that may Have Their Plasma Concentrations Altered by Ibrutinib 
In vitro studies indicated that ibrutinib is not a substrate of P-glycoprotein (P-gp), but is a mild 
inhibitor. Ibrutinib is not expected to have systemic drug-drug interactions with P-gp substrates. 
However, it cannot be excluded that ibrutinib could inhibit intestinal P-gp after a therapeutic 
dose. There is no clinical data available. Therefore, to avoid a potential interaction in the GI 
tract, narrow therapeutic range P-gp substrates such as digoxin, should be taken at least 6 hours 
before or after ibrutinib.  
6.1.2.3. 
QT Prolonging Agents 
Any medications known to cause QT prolongation should be used with caution; periodic 
electrocardiogram (ECG) and electrolyte monitoring should be considered.  
6.1.2.4. 
Concomitant Use of Antiplatelet Agents and Anticoagulants 
Warfarin or other vitamin K antagonists as well as supplements such as fish oil and vitamin E 
preparations should be avoided when possible. Use ibrutinib with caution in subjects requiring 
anticoagulants or medications that inhibit platelet function. In an in vitro platelet function study, 
inhibitory effects of ibrutinib on collagen-induced platelet aggregation were observed. Bleeding 
events of any grade, including bruising and petechiae, occurred in subjects treated with ibrutinib. 
Subjects with congenital bleeding diathesis have not been studied. Ibrutinib should be held at 
least 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of 
bleeding (see Section 6.2). 
Subjects requiring the initiation of therapeutic anticoagulation therapy (eg, atrial fibrillation), 
should be monitored closely for signs and symptoms of bleeding and the risks and benefits of 
continuing ibrutinib treatment should be considered.  


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6.1.3. 
Prohibited Concomitant Medications 
Any non-study protocol related chemotherapy, anti-cancer immunotherapy or experimental 
therapy is prohibited while the subject is receiving study treatment. Localized, hormonal, or bone 
sparing treatment for non-B-cell malignancies may be considered with approval of the Medical 
Monitor. 
The need for radiation therapy is considered to be a treatment failure. However, an exception 
(that is, subjects allowed to remain in the treatment phase of the study) is made for radiation 
therapy to a pathological fracture site to enhance bone healing or to treat post-fracture pain that is 
refractory to narcotic analgesics because pathologic bone fractures do not by themselves fulfill a 
criterion for disease progression. 
The Sponsor should be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered. 
6.2. 
Guidelines for Ibrutinib Management with Surgeries or Procedures 
Ibrutinib may increase the risk of bleeding with invasive procedures or surgery. The following 
guidance should be applied to the use of ibrutinib in the perioperative period for subjects who 
require surgical intervention or an invasive procedure while receiving ibrutinib:   
6.2.1. 
Minor Procedures 
For minor procedures (such as a central line placement, needle biopsy, lumbar puncture [other 
than shunt reservoir access], thoracentesis, or paracentesis) ibrutinib should be held for at least 
3 days prior to the procedure and should not be restarted for at least 3 days after the procedure. 
For bone marrow biopsies that are performed while the subject is on ibrutinib, it is not necessary 
to hold ibrutinib.  
6.2.2. 
Major Procedures 
For any surgery or invasive procedure requiring sutures or staples for closure, ibrutinib should be 
held at least 7 days prior to the intervention and should be held at least 7 days after the procedure 
and restarted at the discretion of the investigator when the surgical site is reasonably healed 
without serosanguineous drainage or the need for drainage tubes. 
6.2.3. 
Emergency Procedures 
For emergency procedures, ibrutinib should be held as soon as possible and until the surgical site 
is reasonably healed, or for at least 7 days after the urgent surgical procedure, whichever is 
longer. 


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7. 
STUDY EVALUATIONS 
7.1. 
Screening/Administrative 
All clinical screening assessments and routine laboratory must be performed within 30 days of 
the first administration of study treatment. 
7.1.1. 
Informed Consent 
The subject must read, understand, and sign the Research Ethics Board/Independent Ethics 
Committee (REB/IEC) approved ICF confirming his or her willingness to participate in this 
study before any study-specific screening procedures are performed. In addition, subjects must 
sign all approved ICF amendments per the site REB/IEC guidelines during the course of the 
study.  
7.1.2. 
Confirm Eligibility 
All necessary procedures and evaluations must be performed to document that the subject meets 
all of the inclusion criteria and none of the exclusion criteria (Section 4). Study site personnel 
will submit the Eligibility Worksheet to the Medical Monitor or Sponsor designee for approval to 
proceed with enrollment. All protocol required assessments predose on Cycle 1 Day 1 must 
continue to meet eligibility where applicable.  
7.1.3. 
Medical History and Demographics 
The subject’s relevant history through review of medical records and by interview will be 
collected and recorded. Concurrent medical signs and symptoms must be documented to 
establish baseline severities. A disease history, including the date of initial diagnosis and list of 
all prior anti-cancer treatments, dates administered, and responses to these treatments, will be 
recorded. 
7.1.4. 
Prior and Concomitant Medications 
All active medications from the signing of ICF or at least 14 days prior to first dose through 
30 days after the last dose of study treatment will be documented.  
7.1.5. 
Adverse Events 
The accepted regulatory definition for an AE is provided in Section 11.1. The occurrence of an 
AE at the time the ICF is signed until first dose should be recorded under medical history in the 
eCRF form. All medical occurrences after the first dose of study treatment until 30 days after the 
last dose of study treatment or first dose date of subsequent anticancer therapy, whichever occurs 
first, that meet the AE definition must be recorded as AEs in the eCRF. Laboratory abnormalities 
or changes in vital signs designated as clinically significant by the investigator will also be 
documented as AEs. Additional important requirements for AE and SAE reporting are explained 
in Section 11.2.  


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7.2. 
Assessments 
7.2.1. 
Eye-related Symptom Assessment 
The subjects will be asked about eye-related symptoms at Screening and during all subsequent 
physical exams while on treatment. 
If there are any eye-related symptoms of severity Grade ≥2 at Screening or if the subjects 
develop any eye-related symptoms of severity Grade ≥2 while on study treatment, an 
ophthalmologic evaluation/consult must be performed and the outcome must be reported on the 
ophthalmologic eCRF.  
7.2.2. 
Physical Examination, Height, and Weight 
The physical examination for Screening, Day 1 of every Cycle, Suspected PD or CR, and EOT 
visits will include, at a minimum, the general appearance of the subject, height (Screening Visit 
only, may use historical height measurement if available in source documents) and weight, and 
examination of the skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities, 
musculoskeletal system, lymphatic system, and nervous system. A limited symptom-directed 
physical examination, including weight may be performed at all other time points. Refer to 
Schedule of Assessments (Appendix 1). 
7.2.3. 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
The ECOG performance index is found in Appendix 2. The ECOG performance status will be 
assessed at time points specified in the Schedule of Assessments (Appendix 1).  
7.2.4. 
Vital Signs 
Vital signs will include blood pressure, heart rate, and body temperature and will be assessed at 
time points specified in the Schedule of Assessments (Appendix 1).  
7.2.5. 
Follow-up for Other Malignancies 
Occurrences of any new malignant tumors including solid tumors, skin malignancies and 
hematologic malignancies will be reported throughout study participation, including duration of 
study treatment and during any protocol specified follow-up periods including post-progression 
follow-up for overall survival, refer to Section 11.2.3. 
7.3. 
Clinical Laboratory Assessments 
7.3.1. 
Hematology 
Hematology parameters will include a complete blood count: white blood cells, red blood cells, 
hemoglobin, hematocrit, platelets, neutrophils, and, if available, lymphocytes, monocytes, 
eosinophils and basophils. See time points specified in the Schedule of Assessments 
(Appendix 1). All assessments will be performed by the local laboratory.  


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7.3.2. 
Serum Chemistry 
Serum chemistry parameters will include sodium, potassium, chloride, blood urea nitrogen 
(BUN)/urea, creatinine, glucose, calcium, total protein, albumin, AST, ALT, alkaline 
phosphatase, total bilirubin, LDH, phosphate, uric acid, and magnesium. See time points 
specified in the Schedule of Assessments (Appendix 1). All assessments will be performed by 
the local laboratory.  
7.3.3. 
Creatinine Clearance 
Creatinine clearance will be calculated locally by Cockcroft-Gault estimation OR as measured by 
24 hour urine collection. See time points specified in the Schedule of Assessments (Appendix 1).  
7.3.4. 
Coagulation Studies 
Measurement of PT/INR, and aPTT will be performed at Screening by the local laboratory. In 
addition, assessments for those subjects on anticoagulation will be performed per investigator 
discretion according to local standard of care practices and analyzed by the local laboratory. 
7.3.5. 
Hepatitis Serologies 
Hepatitis serologies including hepatitis C antibody, hepatitis B surface antigen, and hepatitis B 
core antibody will be evaluated at Screening. If hepatitis B core antibody, hepatitis B surface 
antigen or hepatitis C antibody is positive, then PCR to quantitate hepatitis B DNA or hepatitis C 
RNA must be performed and must be negative prior to enrollment. Hepatitis serologies will be 
analyzed by the local laboratory. 
7.3.6. 
Pregnancy Test 
Serum or urine pregnancy test will be required at Screening by local laboratory only for females 
of reproductive potential. A serum or urine pregnancy test will also be performed on Day 1 prior 
to first dose. If positive, pregnancy must be ruled out by ultrasound to be eligible. This test may 
be performed more frequently if required by local regulatory authorities. 
7.3.7. 
C-reactive Protein and Serum β2-microglobulin 
Samples will be collected at Cycle 1, Day 1 only. Samples will be analyzed by central 
laboratory. 
7.4. 
Diagnostic/Procedures 
7.4.1. 
Electrocardiogram 
Triplicate 12-lead ECGs will be taken (≥1 minute apart) at Screening only. Any clinically 
significant abnormalities noted at Screening should be included in the medical history. A single 
ECG tracing will be performed at subsequent time points as clinically indicated. 
Electrocardiograms should be performed at the investigator’s discretion, particularly in subjects 
with arrhythmic symptoms (eg, palpitations, lightheadedness) or new onset dyspnea. 


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7.5. 
Efficacy Assessments 
Efficacy assessments will be performed every 3 weeks for Cycles 2-12 (refer to Section 8 for 
investigator assessment visit timepoints) and every 4 weeks for Cycle 13 and beyond (Day 1 of 
every Cycle). Response assessments will be based upon the IMWG Response Criteria 
(Rajkumar 2011, refer to Appendix 6). All assessments will be analyzed by the central 
laboratory. See time points specified in the Schedule of Assessments (Appendix 1). 
All screening and Cycle 1 Day 1 efficacy assessments will include quantitative 
immunoglobulins, serum and urine electrophoresis, serum and urine immunofixation, and serum 
free light chain assay. 
After Cycle 1 Day 1 assessment, SPEP, UPEP and other parameters, as applicable, according to 
the IMWG response criteria will be measured and followed.  
At the Investigator’s discretion additional evaluations may be performed according to standard of 
care but they are not to be used for response assessment. 
If at any time CR is suspected, all assessments including quantitative immunoglobulins, serum 
protein electrophoresis and immunofixation, urine protein electrophoresis and immunofixation, 
serum free light chain, radiographic imaging (if applicable) and bone marrow biopsy 
(see Section 7.5.6) must be performed as per the IMWG response assessment guidelines. 
Any suspected case of disease progression should be reported to the Sponsor within 24 hours of 
awareness. If disease progression is suspected solely based on the results of a single examination 
or a single laboratory parameter (eg, SPEP or UPEP), this finding should be confirmed by a 
subsequent evaluation no later than the next protocol scheduled response assessment following 
the first finding. Additional assessments should be performed at the discretion of the treating 
physician to confirm progressive disease if indicated (eg, radiographic imaging).  
In general, subjects should continue study treatment until progression is confirmed by a 
subsequent examination. When disease progression has been confirmed, study treatment should 
be permanently discontinued. Following confirmed disease progression, subjects should continue 
to adhere to all other study-related procedures.  
If a subject discontinues study treatment for reasons other than confirmed disease progression, 
efficacy assessments will continue every 4 weeks until progression is confirmed during the 
Response Follow-up Phase (refer to Section 8.4.1.).  
Whenever possible, subsequent anti-cancer therapy should be withheld until confirmed disease 
progression.  


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7.5.1. 
Serum and Urine Protein Electrophoresis 
Samples will be collected at Screening, and prior to study treatment administration on Day 1 of 
Cycle 1. Additional sample collection will occur every 3 weeks for Cycles 2-12 and every 
4 weeks for Cycle 13 and beyond. Refer to the Schedule of Assessments for timepoints 
(Appendix 1). Samples will be analyzed by central laboratory. 
7.5.2. 
Serum Free Light Chain Assay 
Samples will be collected at Screening, and prior to study treatment administration on Day 1 of 
Cycle 1. Additional sample collection on study is only required to confirm CR (conducted on the 
first observation that the subject has detectable M-protein) and then repeated at each subsequent 
assessment until disease progression per Section 7.5. Refer to the Schedule of Assessments for 
additional timepoints (Appendix 1). Samples will be analyzed by central laboratory.  
7.5.3. 
Serum and Urine Immunofixation 
Samples will be collected at Screening and prior to treatment administration on Day 1 of 
Cycle 1. Repetitive serum and urine immunofixation on study is only required to confirm CR 
(conducted on the first observation that the subject has no detectable M-protein) and then 
repeated at each subsequent assessment until disease progression. Refer to the Schedule of 
Assessments for additional timepoints (Appendix 1). Samples will be analyzed by central 
laboratory.  
7.5.4. 
Quantitative Serum Immunoglobulins  
Samples for Serum Immunoglobulins IgA, IgG and IgM will be collected at Screening, prior to 
study treatment administration on Day 1 of Cycle 1. Additional sample collection will occur 
every 3 weeks for cycles 2-12 and every 4 weeks for cycle 13 and beyond. If clinically indicated, 
serum immunoglobulins IgD or IgE should also be collected at the timepoints specified above. 
Refer to the Schedule of Assessments for additional timepoints (Appendix 1). Samples will be 
analyzed by central laboratory. 
7.5.5. 
Bone Radiologic Assessment 
Skeletal Survey or Low-Dose Whole-Body CT Scan 
A radiologic assessment for evaluation of bone lesions is required. Either a low-dose whole-body 
CT or a radiologic skeletal survey including a lateral radiograph of the skull, antero-posterior and 
lateral views of the spine, and antero-posterior views of the pelvis, ribs, femora, and humeri will 
be performed. Radiological assessment is to be done within 50 days prior to the first 
administration of study treatment. Additional radiologic assessments may be performed at any 
time during the study, as determined necessary by the investigator.  
For selected sites only (Optional): Low-dose whole-body CT scan will be performed at Cycle 9 
Day 1, Cycle 13 Day 1, and at the time of relapse (if not performed within 6 months of another 
timepoint) for exploratory analysis.  


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Plasmacytoma Evaluation 
Magnetic resonance imaging (MRI), computed tomography (CT) or positron emission 
tomography (PET)/CT scans are to be performed as clinically indicated. If evidence of 
plasmacytoma noted on radiographic imaging at Screening, subsequent response assessments 
must include follow-up studies using the same imaging modality every 3 months. 
7.5.6. 
Bone Marrow Biopsy and/or Aspirate  
A unilateral bone marrow biopsy and/or aspirate will be obtained at Screening and submitted to a 
local laboratory to evaluate for morphology and document bone marrow involvement Subjects 
who have had a bone marrow biopsy and/or aspirate within 90 days of first administration of 
study treatment may use those bone marrow biopsy and/or aspirate results in lieu of performing 
the baseline bone marrow biopsy and/or aspirate required for this study. A bone marrow aspirate 
will be required at Screening to be sent to the central lab.  
Testing will be performed at the study center’s local laboratory or other clinical laboratories, as 
appropriate. Information about the respective laboratories must be provided by the 
investigational sites.  
If the subject’s physical examination findings, laboratory evaluations, and radiographic 
evaluations suggest that CR has been achieved, an additional bone marrow aspirate and/or biopsy 
should be obtained to confirm the CR. Bone marrow for confirmation of CR should include 
staining for CD138 and κ/λ mono-clonality by immunohistochemistry (IHC) or 
immunofluorescence and will be assessed locally.  
Bone marrow aspirate (up to 6 mL) will be collected for biomarkers, fluorescence in-situ 
hybridization (FISH) and other exploratory evaluations and submitted to a central lab at 
Screening and, if performed, at the time of CR and following confirmed PD (may be done at 
EOT or prior to a new anti-cancer therapy). These samples will be tested to determine if there is 
a genomics signature of the CD138+ bone marrow cells that correlate to response to treatment 
(Section 7.6.2.1). 
7.5.7. 
Assessment of Minimal Residual Disease (MRD) 
Subjects who achieve a complete response (CR) after the start of study treatment will be assessed 
for minimal residual disease (MRD). MRD will be assessed by whole exome sequencing in bone 
marrow aspirate samples when CR is confirmed. Following confirmation of CR, MRD 
assessments will be repeated every 12 months until disease progression or study exit. Samples 
will be submitted to a central laboratory.  
7.6. 
Biomarker, Correlative and Special Studies 
7.6.1. 
Pharmacokinetics  
During treatment with ibrutinib in combination with bortezomib and dexamethasone, plasma 
concentrations of ibrutinib, its metabolite PCI-45227, and bortezomib will be determined using 


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validated analytical methods on all patients. Other potential metabolites of ibrutinib may be 
explored.  
Refer to the Pharmacokinetic Sample Schedule (Table 6). 
Table 6: 
Pharmacokinetic Sample Schedule for Ibrutinib and Bortezomib 
Cycle 
Day 
Predoseb 
Time after ibrutinib and bortezomib dosinga 
30 min 
(30 ± 5 min) 
1 hour 
(1h ± 15 min) 
2 hour  
(2 h ± 15 min) 
4 hour  
(4 h ± 30 min) 
6 hour 
(5 h to 8h) 
2 
1 
X 
X 
X 
X 
X 
X 
2 
X 
X = Pharmacokinetics timepoint for ibrutinib and bortezomib 
a. Ibrutinib may be dosed at the same time as bortezomib and dexamethasone.
b. Samples for ibrutinib and bortezomib should be collected approximately 24 (±2 h) hours after previous study
dose and approximately 30-60 minutes before ibrutinib and bortezomib administration.
Refer to the Laboratory Manual for instructions on collecting and processing PK samples. On the 
day of the sampling visit, the clinical staff will instruct the subject to not take ibrutinib, or 
dexamethasone before arrival at the clinic. Study treatment intake will be observed by clinic staff 
and time of last meal prior to administration of study treatment on Cycle 2 Day 1 and Cycle 2 
Day 2 will be recorded. The actual time (versus requested time) that each PK sample is drawn 
must be recorded using a 24 hour format.  
7.6.2. 
Biomarkers 
7.6.2.1. 
Genetic and Molecular Prognostic Markers 
Protein and pharmacogenomic biomarkers will be tested in peripheral blood and bone marrow 
aspirate samples to evaluate potential biomarkers predicting treatment response and mechanisms 
of resistance. Peripheral blood will be collected at Screening, on Day 1 of Cycle 1, and on Day 1 
of every even Cycle, Suspected Disease Progression and EOT. Bone marrow aspirate samples 
will be collected at Screening, CR and Suspected Disease Progression or EOT and submitted to a 
central lab (refer to Appendix 1). Testing of biomarkers will include but not limited to the 
biomarker for secreted proteins, gene expression profiling, targeted sequencing for genomic 
alterations, and intracellular signaling pathway analysis. 
Inhibition of BTK and other related kinases (eg, ITK) may also be explored to demonstrate target 
modulation and biological activity in both peripheral blood and bone marrow aspirate. 
7.6.3. 
Serum Carboxy-terminal Collagen Crosslinks (CTX) 
The blood sample for serum CTX to assess bone resorption requires 12 hour fasting prior to 
collection at Screening and additional time points specified in the Schedule of 
Assessments (Appendix 1).  


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7.7. 
Sample Collection and Handling 
The actual dates and times of sample collection must be recorded in source documents for 
transcription to the eCRF or laboratory requisition form. Refer to the Schedule of 
Assessments (Appendix 1) for the timing and frequency of all sample collections. 
Instructions for the collection, handling, and shipment of samples are found in the Laboratory 
Manual. 
7.8. 
Survival and Subsequent Anti-cancer Therapies 
7.8.1. 
Survival 
After disease progression, subjects will be contacted to assess survival status every 12 weeks 
(± 14 days) from EOT Visit until death, subject withdrawal of full consent, lost to follow-up or 
study termination by Sponsor, whichever comes first. At the time of the analysis and at study 
closure, a survival sweep will be conducted. All subjects who are not known to have died or 
withdrawn consent prior to survival sweep will be contacted at that time. 
7.8.2. 
Subsequent Anti-cancer Therapies 
After study treatment is complete, the following information will be collected for the first two 
subsequent anti-cancer therapies: 
• 
Start and stop dates of first and second subsequent anti-cancer therapies  
• 
Indication for initiation of subsequent anti-cancer therapies  
• 
Agents administered 
• 
Best response and date of progression following the first subsequent anticancer therapy 
Please Note:  If new anti-cancer treatment is initiated prior to confirmed disease progression, 
Response Follow-up visits must continue to occur every 4 weeks following the 
End-of-Treatment visit per protocol. 
8. 
STUDY PROCEDURES 
8.1. 
Overview 
The study is divided into a Screening Phase, a Treatment Phase, and a Follow-up Phase. The 
Schedule of Assessments (Appendix 1) summarizes the frequency and timing of efficacy, PK, 
biomarker, and safety measurements applicable to this study. All subjects enrolled will undergo 
the same study procedures throughout the study unless otherwise noted. 
8.2. 
Screening Phase 
Screening procedures will be performed up to 30 days before Cycle 1, Day 1. All subjects must 
first read, understand, and sign the IRB/IEC-approved ICF before any study-specific screening 


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procedures are performed. After signing the ICF, screening and being deemed eligible for entry, 
subjects will be enrolled into the study. 
8.2.1. 
Screening Visit 
The following procedures will be performed at the Screening Visit within 30 days prior to 
treatment unless otherwise noted: 
• 
Relevant medical history including demographic information 
• 
Record concomitant medication history including over-the-counter drugs, vitamins and 
herbs  
• 
Record AEs since signing of the ICF 
• 
Perform a complete physical examination, including height and weight 
• 
Eye-related symptom assessment  
• 
Evaluation of ECOG performance status 
• 
Obtain vital signs (including blood pressure, heart rate, and body temperature)  
• 
Obtain triplicate 12-lead ECG (≥1 minute apart) 
• 
Imaging by CT, MRI or PET/CT (if applicable) 
• 
Bone radiological assessment (may be performed within 50 days of C1D1) 
• 
Bone marrow biopsy (if not performed within 90 days prior to first dose of study 
treatment)  
• 
Bone marrow aspirate (up to 6 mL) to be sent to central lab for biomarker assessment 
(Section 7.5.6) 
• 
Obtain blood/urine specimens for the following laboratory tests: 
o Hematology 
o Serum chemistry 
o Coagulation studies (PT/INR, aPTT) 
o Creatinine clearance 
o Hepatitis serologies  
o Serum and urine protein electrophoresis (SPEP and UPEP) 
o Serum free light chain assay (sFLC) 
o Serum and urine immunofixation 
o Quantitative serum immunoglobulins (IgA, IgG, IgM and if clinically indicated, 
IgD or IgE) 
o Biomarkers including serum CTX (requires 12 hour fasting) 
• 
Obtain urine or serum pregnancy test for females of reproductive potential  
• 
Review inclusion and exclusion criteria to confirm subject eligibility 


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8.3. 
Treatment Phase 
Subjects must continue to satisfy all eligibility criteria on Day 1 of Cycle 1 in order to begin 
treatment.  
Study treatment with ibrutinib in combination with bortezomib and dexamethasone should be 
continued until confirmed disease progression, unacceptable treatment-related toxicity, or other 
reasons outlined in Section 9.2. Local safety labs will be used to guide all dosing-related 
decisions. In the event of clinically suspected disease progression, the subject may continue to 
receive study medication until disease progression is confirmed, at the discretion of the 
Investigator.  
Refer to the Schedule of Assessments (Appendix 1) for a complete list of procedures to be 
performed at each scheduled study visit. 
8.3.1. 
Cycle 1, Day 1 
Subjects who are deemed eligible will return to the clinic on Cycle 1, Day 1. Safety laboratory 
assessments performed within 48 hours prior to the first dose of study treatment may be used for 
dosing. 
Predose 
• 
Complete physical exam including weight 
• 
Eye-related symptom assessment  
• 
ECOG performance status 
• 
Obtain vital signs (including blood pressure, heart rate, and body temperature)  
• 
Collect blood/urine samples for the following laboratory tests: 
o Hematology (C1D1 testing not required if done within 48 hours prior to the first dose 
of study treatment) 
o Serum chemistry (C1D1 testing not required if done within 48 hours prior to the first 
dose of study treatment) 
o SPEP/UPEP 
o Serum free light chain assay (sFLC) 
o Serum and urine immunofixation 
o Quantitative Immunoglobulins (IgA, IgG and IgM and if clinically indicated,  
IgD or IgE) 
o Biomarkers including Serum CTX (requires 12 hour fasting)  
o C-Reactive Protein and Serum β2-microglobulin 
o Obtain urine or serum pregnancy test for females of reproductive potential  
• 
Review of AEs and concomitant medications 
• 
Review inclusion and exclusion criteria to confirm subject eligibility prior to dosing 


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Dosing and Postdose 
• 
Dispense ibrutinib  
• 
Administration of ibrutinib, bortezomib and dexamethasone   
8.3.2. 
Cycle 1-8, Days 4 and 11 
Predose  
• 
Symptom directed physical exam including weight 
• 
Obtain vital signs (including blood pressure, heart rate, and body temperature)  
• 
Collect blood samples for the following laboratory tests: 
o Hematology  
• 
Review of AEs and concomitant medications  
Dosing and Postdose 
• 
Administration of ibrutinib, bortezomib and dexamethasone 
8.3.3. 
Cycle 1-12, Day 8 
Predose  
• 
Symptom directed physical exam including weight 
• 
Obtain vital signs (including blood pressure, heart rate, and body temperature)  
• 
Collect blood samples for the following laboratory tests: 
o Hematology 
• 
Review of AEs and concomitant medications  
Dosing and Postdose 
• 
Administration of ibrutinib, bortezomib and dexamethasone 
8.3.4. 
Cycle 2, Day 1 
Predose  
• 
Complete physical exam including weight 
• 
Eye-related symptom assessment  
• 
ECOG performance status 
• 
Obtain vital signs (including blood pressure, heart rate, and body temperature)  
• 
Collect blood/urine samples for the following laboratory tests: 
o Hematology 
o Serum chemistry 
o Quantitative immunoglobulins (IgA, IgG and IgM and if clinically indicated,  
IgD or IgE) 
o Efficacy Assessments as applicable per Section 7.5 


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• 
Biomarkers including Serum CTX (requires 12 hour fasting) 
• 
Collect predose PK sample for ibrutinib and bortezomib 
• 
Review of AEs and concomitant medications 
• 
Investigator response assessment  
Dosing and Postdose 
• 
Administration of ibrutinib, bortezomib and dexamethasone   
• 
Blood sample collection for ibrutinib and bortezomib PK  
(times from study treatment dose): 
o 30 minutes ± 5 minutes after dosing (for ibrutinib and bortezomib PK) 
o 1 hour ± 15 minutes after dosing (for ibrutinib and bortezomib PK) 
o 2 hours ± 15 minutes after dosing (for ibrutinib and bortezomib PK) 
o 4 hours ± 30 minutes after dosing (for ibrutinib and bortezomib PK  
o 6 hours (window 5 to 8 hours) after dosing (for ibrutinib and bortezomib PK) 
8.3.5. 
Cycle 2, Day 2 
Predose  
• 
Collect a blood sample for the following laboratory test: 
o Collect predose PK sample for ibrutinib and bortezomib 
• 
Review of AEs and concomitant medications 
Dosing and Postdose 
• 
Administration of ibrutinib  
8.3.6. 
Cycles 3-12, Day 1 (odd cycles)  
Predose  
• 
Complete physical exam including weight 
• 
Eye-related symptom assessment  
• 
ECOG performance status 
• 
Obtain vital signs (including blood pressure, heart rate, and body temperature)  
• 
Collect blood/urine samples for the following laboratory tests: 
o Hematology 
o Serum chemistry 
o Quantitative immunoglobulins (IgA, IgG and IgM and if clinically indicated,  
IgD or IgE) 
o Efficacy Assessments as applicable per Section 7.5 
• 
Review of AEs and concomitant medications  
• 
Investigator response assessment  


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Dosing and Postdose 
• 
Administration of ibrutinib, bortezomib and dexamethasone   
8.3.7. 
Cycles 4-12, Day 1 (even cycles) 
Predose  
• 
Complete physical exam including weight 
• 
Eye-related symptom assessment  
• 
ECOG performance status 
• 
Obtain vital signs (including blood pressure, heart rate, and body temperature)  
• 
Collect blood/urine samples for the following laboratory tests: 
o Hematology 
o Serum chemistry 
o Quantitative immunoglobulins (IgA, IgG and IgM and if clinically indicated,  
IgD or IgE) 
o Efficacy Assessments as applicable per Section 7.5 
o Biomarkers including Serum CTX (requires 12 hours fasting) 
• 
Review of AEs and concomitant medications  
• 
Investigator response assessment  
Dosing and Postdose 
• 
Administration of ibrutinib, bortezomib and dexamethasone   
8.3.8. 
Cycles 9-12, Days 22 and 29 
Predose 
• 
Symptom directed physical exam including weight 
• 
Obtain vital signs (including blood pressure, heart rate, and body temperature)  
• 
Collect  blood/urine samples for the following laboratory test: 
o Hematology 
o Serum chemistry (Day 22 Only) 
o Quantitative immunoglobulins (IgA, IgG and IgM and if clinically indicated,  
IgD or IgE) [Day 22 Only] 
o Efficacy assessments as applicable per Section 7.5 (Day 22 Only) 
• 
Review of AEs and concomitant medications 
• 
Investigator response assessments (Day 22 Only) 
Dosing and Postdose 
• 
Administration of ibrutinib, bortezomib and dexamethasone  


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8.3.9. 
Cycle 13 and Beyond, Day 1 (odd cycles)  
Predose  
• 
Complete physical exam including weight 
• 
Eye-related symptom assessment 
• 
ECOG performance status 
• 
Obtain vital signs (including blood pressure, heart rate, and body temperature) 
• 
Collect blood/urine samples for the following laboratory tests: 
o Hematology 
o Serum chemistry 
o Quantitative immunoglobulins (IgA, IgG and IgM and if clinically indicated,  
IgD or IgE) 
o Efficacy assessments as applicable per Section 7.5 
• 
Review of AEs and concomitant medications  
• 
Investigator response assessment  
Dosing and Postdose 
• 
Administration of ibrutinib and dexamethasone    
8.3.10. 
Cycle 14 and Beyond, Day 1 (even cycles)  
Predose  
• 
Complete physical exam including weight 
• 
Eye-related symptom assessment 
• 
ECOG performance status 
• 
Obtain vital signs (including blood pressure, heart rate, and body temperature) 
• 
Collect blood/urine samples for the following laboratory tests: 
o Hematology 
o Serum chemistry 
o Quantitative immunoglobulins (IgA, IgG and IgM and if clinically indicated,  
IgD or IgE) 
o Efficacy assessments as applicable per Section 7.5 
o Biomarkers including Serum CTX (requires 12 hour fasting) 
• 
Review of AEs and concomitant medications  
• 
Investigator response assessment  
Dosing and Postdose 
• Administration of ibrutinib and dexamethasone 


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8.3.11. 
Suspected PD Visit 
The Suspected PD visit should be performed at any time during the study, if based on clinical 
and/or laboratory evaluation, the Investigator suspects PD. If a suspected PD visit is the first 
observation of PD, the subsequent confirmatory assessment must occur on or before the next 
protocol scheduled response assessment timepoint (refer to Section 7.5 for further details). 
The following procedures will be performed: 
• 
Complete physical exam including weight 
• 
Eye-related symptom assessment  
• 
ECOG performance status 
• 
Obtain vital signs (including blood pressure, heart rate, and body temperature)  
• 
Collect blood/urine samples for the following laboratory tests: 
o Hematology 
o Serum chemistry 
o Quantitative immunoglobulins (IgA, IgG and IgM and if clinically indicated,  
IgD or IgE) 
o Efficacy assessments as applicable per Section 7.5 
o Biomarkers including Serum CTX (requires 12 hour fasting)  
• 
Collect up to 6mL of bone marrow aspirate (if PD has been confirmed) to be sent to 
central lab for biomarker assessment (Section 7.5.6) 
• 
Radiographic imaging; if applicable  
• 
Review of AEs and concomitant medications 
• 
Investigator response assessment  
8.3.12. 
End-of-Treatment Visit 
An EOT visit should occur 30 days (±7 days) from the last dose of study treatment or prior to the 
start of a new anti-cancer treatment, whichever occurs first. If the subject starts a new anti-cancer 
treatment less than 7 days after the Suspected PD visit, only those procedures not conducted at 
the Suspected PD visit should be performed at the EOT visit.  
The following procedures will be performed at the EOT visit: 
• 
Complete physical exam including weight 
• 
Eye-related symptom assessment  
• 
ECOG performance status 
• 
Obtain vital signs (including blood pressure, heart rate, and body temperature)  
• 
Collect blood/urine samples for the following laboratory tests: 
o Hematology 
o Serum chemistry 


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o Quantitative immunoglobulins (IgA, IgG and IgM and if clinically indicated,  
IgD and/or IgE) 
o Efficacy assessments as applicable per Section 7.5 
o Biomarkers including Serum CTX (requires 12 hour fasting) 
• 
Collect up to 6mL of bone marrow aspirate (if not collected at suspected PD visit) to be 
sent to central laboratory for biomarker assessment (may be done prior to the start of 
new anti-cancer therapy after PD is confirmed). 
• 
Review of AEs and concomitant medications 
• 
Collect subject diary and any remaining drug from last cycle 
• 
Investigator response assessment, if applicable  
8.4. 
Follow-up Phase 
Once a subject has completed the EOT visit, he/she will enter the Follow-up Phase. Subjects who 
withdraw from treatment for reasons other than PD will participate in ongoing Response 
Follow-up. 
8.4.1. 
Response Follow-up  
Subjects who discontinue the study for reasons other than PD will be followed at a minimum 
every 4 weeks (±7 days) until PD. During this period, evaluations used for response assessment 
(ie, labs, radiographic imaging, bone marrow biopsy) will be done per Investigator’s discretion. 
• 
Collect blood/urine samples for the following laboratory tests: 
o Hematology 
o Serum chemistry 
o Quantitative immunoglobulins (IgA, IgG and IgM and if clinically indicated,  
IgD or IgE) 
o Efficacy Assessments as applicable per Section 7.5  
• 
Survival status and new anti-cancer therapies (refer to Section 7.8.2) 
• 
Investigator response assessment 
8.4.2. 
Long-Term Follow-up  
Once subjects progress, they will be contacted approximately every 12 weeks (±14 days) from 
EOT by clinic visit or telephone to assess survival. The first two subsequent anti-cancer therapies 
will be collected. Subjects will be contacted until death, subject withdrawal, lost to follow-up, or 
study termination by the Sponsor, whichever occurs first to obtain the following: 
• 
Survival status and new anti-cancer therapies (refer to Section 7.8.2) 
• 
Other malignancies 
At the time of the interim analysis and at study closure, a survival sweep will be conducted. 
All subjects who are on study and not known to have died prior to the survival sweep will be 
contacted at that time. 


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9. 
SUBJECT COMPLETION AND WITHDRAWAL 
9.1. 
Completion 
A subject will be considered to have completed the study if he or she has died before the end of 
the study, has not been lost to follow up, or has not withdrawn consent before the end of study.  
9.2. 
Withdrawal from Study Treatment 
Study treatment will be discontinued in the event of any of the following events: 
• 
Confirmed Progressive disease  
• 
Unacceptable toxicity: an intercurrent illness or an AE that prevents further ibrutinib 
administration  
• 
Withdrawal of consent for treatment by subject 
• 
Investigator decision (such as chronic noncompliance, significant protocol deviation, or 
best interest of the subject) 
• 
Study termination by Sponsor 
• 
Subject becomes pregnant 
All subjects, regardless of reason for discontinuation of study treatment will undergo an EOT 
visit and be followed for progression (if applicable) and survival.  
The Investigator should notify the Sponsor if a subject discontinues treatment due to disease 
progression and should provide documentation of disease progression for review by the 
Sponsor’s Medical Monitor. If a subject shows signs of disease progression, the subject may 
continue study treatment until disease progression is confirmed. These subjects should remain in 
the study to be followed for survival.  
Should there be subjects continuing on study treatment at the time of study closure who are still 
deriving clinical benefit, then study treatment will be made available through either an expanded 
access program, a long-term extension study, a registry, or similar.  
9.3. 
Withdrawal from Study (Study Exit) 
Withdrawal from study (including all follow-up) will occur under the following circumstances: 
• 
Withdrawal of consent for follow-up observation by the subject 
• 
Lost to follow-up 
• 
Study termination by Sponsor 
• 
Death 
If a subject is lost to follow-up, every reasonable effort should be made by the study site 
personnel to contact the subject. The measures taken to follow up should be documented. 


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When a subject withdraws before completing the study, the following information should be 
documented in the source documents: 
• 
Reason for withdrawal 
• 
Whether the subject withdraws full consent (ie, withdraws consent to treatment and all 
further contact) or partial consent (ie, withdraws consent to treatment but agrees to 
participate in follow-up visits) 
10. 
STATISTICAL METHODS 
Statistical analysis will be performed by the Sponsor or under the authority of the Sponsor. 
A general description of the statistical methods for the analysis of the efficacy and safety data is 
outlined below. Specific details will be provided in the Statistical Analysis Plan (SAP). 
10.1. 
Analysis Populations 
10.1.1. 
All-treated Population 
The all-treated population is defined as all eligible subjects who have enrolled into the Phase 2 
study and received any dose of study treatment. Eligible subjects are defined as all subjects who 
signed the ICF, with a confirmed diagnosis of MM who have received 2-3 prior lines of therapy 
and have demonstrated disease progression following the completion of the last line of therapy 
according to IMWG response criteria (Appendix 6), and have a baseline assessment. The 
all-treated population will be the primary population for all efficacy analyses.  
10.1.2. 
Response-evaluable Population 
The response-evaluable population is defined as all enrolled subjects who are in the All-treated 
population, received at least 1 dose of study treatment, and provided at least one post-baseline 
response (or disease) assessment. The response-evaluable population will be used for efficacy 
sensitivity analyses as described in the statistical analysis plan.  
10.1.3. 
Safety Population 
The safety population will consist of all enrolled subjects who received at least one dose of study 
treatment. The safety population will be used for the analysis of safety data. 
10.1.4. 
Additional Analysis Populations 
Additional analysis population, which may be used in sensitivity analyses for primary and 
secondary efficacy objectives or analyses for exploratory objectives, will be defined in the 
statistical analysis plan. 


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10.2. 
Sample Size Determination 
This study will be conducted as an open-label, non-randomized international multicenter study to 
evaluate the efficacy and safety of ibrutinib in combination with bortezomib and dexamethasone 
in subjects with relapsed or relapsed and refractory MM. 
A total of approximately 125 subjects will be enrolled. 
The primary endpoint is mPFS. Assuming that the PFS follows an exponential distribution, a 
sample size of approximately 125 eligible subjects will provide approximately 80% power at a  
1-sided 0.025 significance level to test the null hypothesis of mPFS ≤8 months vs ≥12 months 
under the alternative hypothesis. The 2-sided 95% Brookmeyer-Crowley confidence interval 
with the log-log-transformed Greenwood variance estimate for mPFS will be calculated to test 
the hypotheses. An mPFS of 8.1 months was observed in the PANORAMA-1 Study where a 
similar patient population was treated with bortezomib + dexamethasone (Richardson 2014). 
This hypothesis for mPFS with the revised enrollment to only include 2-3 prior lines of therapy 
without enrollment limitations for prior bortezomib exposure is further supported by recent data 
in the ENDEAVOR Study demonstrating similar outcome (Moreau 2016). The sample size of 
approximately 125 subjects is determined by simulation method assuming that the PFS follows 
an exponential distribution and the mPFS is 12 months with ibrutinib in combination with 
bortezomib and dexamethasone. In addition, an enrollment period of 20 months with an average 
enrollment rate of 6 subjects per month, an exponential censoring process allowing 
approximately 6.5% censored observations, for example, due to non-progression related dropout, 
during the study duration prior to the analysis, and the time of primary analysis at 12 months 
after the last subject enrolled into the study were also assumed in the simulation. Under the 
above assumptions, approximately 83 PFS events would occur prior to the analysis.  
10.3. 
Subject Information 
The distribution of subjects for each of the analysis populations will be provided. The number of 
subjects enrolled by each investigative site and country, dosed, and discontinued will be 
summarized. Treatment discontinuation will be summarized according to the reasons for 
discontinuation. Demographic and baseline vital sign variables will be summarized. Baseline 
disease characteristics will also be summarized. 
10.4. 
Efficacy Analyses 
10.4.1. 
Primary Endpoint 
The primary efficacy endpoint of this study is mPFS. Progression free survival is defined as the 
time from the date of first dose of study treatment to confirmed disease progression or death 
from any cause, whichever occurs first. The mPFS is the time at which the percentage or 
probability of surviving and progression-free is 50%. The mPFS will be assessed according to 
the IMWG response criteria (Appendix 6).  


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10.4.2. 
Secondary Endpoints 
• 
ORR is the proportion of subjects who achieve a PR or better over the course of the 
study but prior to initiation of subsequent anti-cancer therapy. 
• 
PFS rates at landmark points are the percentages or probabilities of surviving and 
progression-free at the landmark time points. The landmark time points will be described 
further in the SAP.  
• 
The DOR is defined as the interval between the date of initial documentation of a 
response and the date of first documented evidence of progressive disease, death, or date 
of censoring if applicable, for responders only. Responders are subjects in the ITT 
population who achieve PR or better according to the IMWG response criteria. Non 
responders (≤PR) will be excluded from the analysis for DOR. 
• 
OS is defined as the time from the date of first dose of study treatment until date of death 
due to any cause.  
• 
TTP is defined as the time from the start of treatment until date of disease progression. 
Subjects who die due to causes other than disease progression will be censored at the 
date of death.  
10.5. 
Analysis Methods 
10.5.1. 
Primary Efficacy Analyses 
The distribution of PFS and the mPFS will be estimated by the Kaplan-Meier method. The null 
hypothesis of mPFS ≤8 months will be tested against ≥12 months under the alternative 
hypothesis. The 2-sided 95% Brookmeyer-Crowley confidence interval with the log-log-
transformed Greenwood variance estimate for mPFS will be calculated to test the hypotheses. 
The null hypothesis will be rejected if the lower bound of the confidence interval is greater than 
8 months. Subjects who withdraw from the study or are considered lost to follow-up without 
prior documentation of disease progression will be censored on the date of the last adequate 
disease assessment. Subjects who are progression-free and alive at the time of clinical cut-off, or 
have unknown status will be censored on the date of the last adequate disease assessment. For 
subjects without an adequate post-baseline disease assessment, PFS will be censored on the date 
of first dose of study treatment. Adequate disease assessment is defined according to the IMWG 
response criteria.  
10.5.2. 
Secondary Efficacy Analysis 
ORR will be estimated and the corresponding 2-sided 95% exact binomial confidence interval 
will be calculated. The ORR will be assessed based on IMWG response criteria. 
The point estimate of the PFS rate at the selected landmark time points will be provided by the 
Kaplan-Meier estimate and the corresponding 2-sided 95% confidence interval will be calculated 
using the log-log-transformed Greenwood variance estimate. The distribution of DOR, PFS, OS 
and TTP will be estimated using the Kaplan-Meier method and further described in the SAP. 


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10.5.3. 
Exploratory Efficacy Analysis 
Exploratory endpoints and their analyses will be described in the SAP and may include a 
summary of time to subsequent anticancer therapies in subjects with relapsed or relapsed and 
refractory MM.  
10.5.4. 
Pharmacokinetic Analyses 
10.5.4.1. 
Ibrutinib 
Non-compartmental analysis of ibrutinib and PCI-45227 plasma concentration-time data will be 
performed using WinNonlin. Descriptive statistics will be used to summarize ibrutinib and 
PCI-45227 concentrations at each sampling time point and PK parameters of ibrutinib and 
PCI-45227 (including, but not limited to: Cmax, Tmax, AUClast, and t1/2). 
Ibrutinib and PCI-45227 data will be listed for all subjects with available plasma concentrations. 
Subjects will be excluded from the PK analysis if their data do not allow for accurate assessment 
of the PK (eg, incomplete administration of the study agent; concentration data not sufficient for 
PK parameter calculation due to missing PK draws at multiple visits; or early discontinuation 
from the study). 
All concentrations below the lowest quantifiable concentration or missing data will be labeled as 
such in the concentration data presentation. Concentrations below the lowest quantifiable 
concentration will be treated as zero in the summary statistics and for the calculation of PK 
parameters. All subjects and samples excluded from the analysis will be clearly documented in 
the study report. 
Derived PK parameters may be subjected to further explore PK/pharmacodynamic correlation 
between exposure with relevant clinical or biomarker information. 
Bioanalytical data from this study may also be combined with data from other studies performed 
with ibrutinib in subjects with hematologic malignancies as part of a population PK analysis 
using nonlinear mixed effects models using NONMEM. Available subject characteristics 
(demographics, laboratory variables, genotypes, etc) will be tested as potential covariates 
affecting PK parameters. The results of the population PK analyses (if performed) will be 
presented in a separate report. 
10.5.4.2. 
Bortezomib 
Individual bortezomib concentrations will be tabulated along with descriptive statistics. 
Individual and mean concentration-time profiles will be generated and included in the report. 
Pharmacokinetic parameters will be determined using standard non-compartmental methods. 
The following PK parameters will be determined: peak concentration (Cmax), time to peak 
concentration (Tmax) and area under the curve (AUC), as data allow. Descriptive statistics of 
non-compartmental PK parameters will be provided. 


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10.5.5. 
Biomarker Analysis Plan 
Samples of whole blood and bone marrow will be collected and may be subjected to biomarker 
assays which will compare the levels of protein expression and the cytogenetic profile of 
subject’s cancer cell genes prior and at the End-of-Treatment. These findings may offer some 
insight to the effects that the study treatment has on multiple myeloma which can help 
researchers identify changes in key biomarkers to monitor disease status of patients and may 
offer a method to better categorize the disease. If there is evidence that study treatment stops 
working, tests will be performed to determine the mechanism of resistance that the tumor cells 
have adapted to prevent response to study treatment. Some of these samples may be stored and 
tested later, as defined in the informed consent, as new and more sensitive assays are developed.  
10.5.6. 
Safety Analyses 
Analysis of safety data will be conducted on the safety population, which includes enrolled 
subjects who receive at least 1 dose of study treatment. The baseline value for safety assessments 
will be defined as the last value on or before the day of the first dose of study treatment if we do 
not specify. The safety analyses will be based on the monitoring of AEs, survival status, ECOG 
performance status, vital signs measurements, and clinical laboratory results. 
The safety variables to be analyzed include exposure of study treatment, AEs, clinical laboratory 
test results (hematology and chemistry), ECOG performance status, physical examination, and 
vital signs measurements. In general, continuous variables will be summarized using descriptive 
statistics (n, mean, median, standard deviation, standard error and range). Categorical variables 
will be summarized using frequencies and percentages. No formal statistical testing is planned.  
The Sponsor or designee will review data on the safety of ibrutinib in combination with 
bortezomib and dexamethasone after approximately 6 subjects have completed at least 1 cycle 
(21 days) of treatment. If a new safety signal is identified with the study treatment combination, 
enrollment will be held pending further evaluation.  
Depending on the outcome of the initial safety review, the Sponsor or designee may recommend 
that the study continue with enrollment, implement an amendment, or terminate the study.  
Adverse Events 
Adverse event parameters to be evaluated are the type, incidence, and intensity of AEs; the 
relationship of AEs to study treatment; and the action taken with respect to study treatment due 
to AEs. 
The verbatim terms used in the eCRF by Investigators to identify AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) and graded according to 
NCI CTCAE v 4.03. Treatment-emergent AEs are those AEs occurring after the first dose of 
study treatment and within 30 days following the last dose of study treatment (ibrutinib, 
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subsequent anticancer therapy whichever occurs first. In addition, TEAEs are any adverse event 
that is considered study treatment-related regardless of the start date of the event; or any adverse 
event that is present at baseline but worsens after the first administration of study treatment in 
severity or is subsequently considered drug-related by the Investigator. All TEAEs will be 
included in the analysis. The number and percent of subjects with TEAEs will be summarized by 
system organ class and preferred term. Drug related AEs, SAEs, Grade ≥3 AEs, AEs leading to 
study treatment discontinuation, dose modification, or death, and events of special interest will 
be summarized and listed. 
Clinical Laboratory Tests 
Laboratory tests will be summarized separately for hematology and serum chemistry. All 
laboratory values will be graded using the NCI CTCAE v 4.03. The worst toxicity grade during 
the study will be tabulated. 
Standard methods for summarizing laboratory variables will be used, including the use of 
summary statistics and shift tables. 
10.5.6.1. 
Sponsor Safety Review Committee 
In addition to standard surveillance activities throughout the conduct of the study, the Sponsor 
will implement an internal safety review committee to review the incidence, severity, and 
outcome of infections on this study as well as any other potential safety signals approximately 
every 6 weeks. The committee will include, at minimum, representatives from Clinical Science, 
Drug Safety, and Biometrics to review all available AE and SAE data. Depending on the 
outcome of the internal safety reviews, the Sponsor may decide to implement an amendment, or 
terminate the study. 
10.5.7. 
Interim Analysis 
An interim analysis is planned after approximately 80% of the subjects have been enrolled or 
2 months before the projected completion of enrollment, whichever comes earlier. At the time of 
the interim analysis, the distribution of 1 and 2 to 3 prior lines of therapy and prior exposure to 
bortezomib will be reassessed to validate the initial hypothesis based on the actual subject 
population enrolled. The final timing of the interim analysis, as well as the responsible party to 
perform the interim analysis, will be specified in the SAP or a separate Interim Analysis Plan. 
The purpose of the interim analysis is to examine the actual distribution of PFS based on the 
interim data, and estimate the probability of success of the study. The outcome of the interim 
analysis may lead to a futility stop of the study, continue the study as planned, or an adaptation 
of the sample size according to the interim analysis plan.  


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10.5.8. 
Primary Analysis 
The primary analysis for the clinical study report is planned to include the data up to 12 months 
after the last subject enrolled or 83 PFS events, whichever occurs earlier. The time of the primary 
analysis may be changed depending on the outcome of the interim analysis. 
10.5.9. 
Subgroup Analysis 
The subgroup analyses for the subgroups of subjects with special interests will be described in 
the SAP.  
11. 
ADVERSE EVENT REPORTING 
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the Sponsor, and are mandated by 
regulatory agencies worldwide. The Sponsor has established Standard Operating 
Procedures (SOPs) in conformity with regulatory requirements worldwide to ensure appropriate 
reporting of safety information; all clinical studies conducted by the Sponsor or its affiliates will 
be conducted in accordance with those procedures. 
11.1. 
Adverse Event Definitions and Classifications 
11.1.1. 
Adverse Events 
An AE is any untoward medical occurrence in a patient administered a pharmaceutical product 
and which does not necessarily have a causal relationship with this treatment. An AE can 
therefore be any unfavorable and unintended sign (including a clinically significant abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of an 
investigational study treatment, whether or not considered related to the study treatment 
(ICH-E2A 1995). 
For the purposes of this clinical study, AEs include events which are either new or represent 
detectable exacerbations of pre-existing conditions. 
The term “disease progression” should not be reported as an AE term. As an example, 
"worsening of underlying disease" or the clinical diagnosis that is associated with disease 
progression should be reported. 
Adverse events may include, but are not limited to: 
• 
Subjective or objective symptoms spontaneously offered by the subject and/or observed 
by the Investigator or study staff including laboratory abnormalities of clinical 
significance. 
• 
Any AEs experienced by the subject through the completion of final study procedures. 


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• 
AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with MM that were not present 
before the AE reporting period  
Complications that occur as a result of protocol-mandated interventions (eg, invasive 
procedures such as biopsies). 
The following are NOT considered AEs: 
• 
Pre-Existing Condition: A pre-existing condition (documented on the medical history 
eCRF) is not considered an AE unless the severity, frequency, or character of the event 
worsens during the study period. 
• 
Pre-Planned or Elective Hospitalization: A hospitalization planned before signing the 
ICF is not considered an SAE, but rather a therapeutic intervention. However, if during 
the pre-planned hospitalization an event occurs, which prolongs the hospitalization or 
meets any other SAE criteria, the event will be considered an SAE. Surgeries or 
interventions that were under consideration, but not performed before enrollment in the 
study, will not be considered serious if they are performed after enrollment in the study 
for a condition that has not changed from its baseline level. Elective hospitalizations for 
social reasons, solely for the administration of chemotherapy, or due to long travel 
distances are also not SAEs. 
• 
Diagnostic Testing and Procedures: Testing and procedures should not to be reported 
as AEs or SAEs, but rather the cause for the test or procedure should be reported. 
11.1.2. 
Serious Adverse Events 
A serious adverse event (SAE) based on International Conference on Harmonisation (ICH) and 
EU Guidelines on Pharmacovigilance for Medicinal Products for Human Use is any untoward 
medical occurrence that at any dose: 
• 
Results in death (ie, the AE actually causes or leads to death). 
• 
Is life-threatening. Life-threatening is defined as an AE in which the patient was at risk 
of death at the time of the event. It does not refer to an event which hypothetically might 
have caused death if it were more severe. If either the Investigator or the Sponsor 
believes that an AE meets the definition of life-threatening, it will be considered 
life-threatening. 
• 
Requires in-patient hospitalization >24 hours or prolongation of existing hospitalization. 
• 
Results in persistent or significant disability/incapacity (ie, the AE results in substantial 
disruption of the patient’s ability to conduct normal life functions). 
• 
Is a congenital anomaly/birth defect. 
• 
Is an important medical event that may not result in death, be immediately 
life-threatening or require hospitalization, but may be considered an SAE when, based 
upon appropriate medical judgment, the event may jeopardize the patient or patient may 
require intervention to prevent one of the other outcomes listed in this definition. 
Examples of such events are intensive treatment in an emergency department or at home 


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for allergic bronchospasm, blood dyscrasias, or convulsion that does not result in 
hospitalization; or development of drug dependency or drug abuse. 
Given that the Investigator’s perspective may be informed by having actually observed the event, 
and the Sponsor is likely to have broader knowledge of the drug and its effects to inform its 
evaluation of the significance of the event, if either the Sponsor or the Investigator believes that 
the event is serious, the event will be considered serious. 
11.1.3. 
Unexpected Adverse Events 
An “unexpected” AE is an AE that is not listed in the IB/package insert or is not listed at the 
specificity or severity that has been observed. For example, hepatic necrosis would be 
“unexpected” (by virtue of greater severity) if the IB referred only to elevated hepatic enzymes 
or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be “unexpected” 
(by virtue of greater specificity) if the IB/package insert listed only cerebral vascular accidents. 
"Unexpected" also refers to AEs that are mentioned in the IB as occurring with a class of drugs 
or as anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the study treatment under investigation. 
11.1.4. 
Severity Criteria (Grade 1-5) 
Definitions found in the Common Terminology Criteria for Adverse Events version 4.03 
(CTCAE v 4.03) will be used for grading the severity (intensity) of AEs. The CTCAE v4.03 
displays Grades 1 through 5 with unique clinical descriptions of severity for each referenced AE. 
Should a subject experience any AE not listed in the CTCAE v 4.03, the following grading 
system should be used to assess severity: 
• 
Grade 1 (Mild AE) – experiences which are usually transient, requiring no special 
treatment, and not interfering with the subject’s daily activities 
• 
Grade 2 (Moderate AE) – experiences which introduce some level of inconvenience or 
concern to the subject, and which may interfere with daily activities, but are usually 
ameliorated by simple therapeutic measures 
• 
Grade 3 (Severe AE) – experiences which are unacceptable or intolerable, significantly 
interrupt the subject’s usual daily activity, and require systemic drug therapy or other 
treatment 
• 
Grade 4 (Life-threatening or disabling AE) – experiences which cause the subject to be 
in imminent danger of death 
• 
Grade 5 (Death related to AE) – experiences which result in subject death 
11.1.5. 
Causality (Attribution) 
The Investigator is to assess the causal relation (ie, whether there is a reasonable possibility that 
the study treatment caused the event) using the following definitions: 


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Not Related: 
Another cause of the AE is more plausible; a temporal sequence 
cannot be established with the onset of the AE and administration of 
the investigational product; or, a causal relationship is considered 
biologically implausible. 
Unlikely Related: 
The current knowledge or information about the AE indicates that a 
relationship to the investigational product is unlikely. 
Possibly Related: 
There is a clinically plausible time sequence between onset of the 
AE and administration of the investigational product, but the AE 
could also be attributed to concurrent or underlying disease, or the 
use of other drugs or procedures. Possibly related should be used 
when the investigational product is one of several biologically 
plausible AE causes. 
Related: 
The AE is clearly related to use of the investigational product. 
11.2. 
Documenting and Reporting of Adverse Events 
The Investigator is responsible for ensuring that all AEs and SAEs observed or reported during 
the study, as outlined in the prior sections, are recorded on the eCRF. All SAEs must also be 
reported on the SAE Report Form and submitted to the Sponsor (see Section 11.2.2.2). 
11.2.1. 
Special Reporting Situations 
Special reporting situations on a Sponsor study treatment that may require expedited reporting 
and/or safety evaluation include, but are not limited to: 
• 
Overdose of any study treatment 
• 
Suspected abuse/misuse of a study treatment 
• 
Inadvertent or accidental exposure to a study treatment 
• 
Medication error involving a product (with or without subject/patient exposure to the 
study treatment, eg, name confusion) 
If any special reporting situation meets the criteria of an AE, it should be reported on the Serious 
Adverse Event Report Form. The Serious Adverse Event Report Form should be sent via email or 
fax to Pharmacyclics Drug Safety or designee within 24 hours of awareness. 
11.2.2. 
Adverse Event Reporting Procedures 
11.2.2.1. 
All Adverse Events 
All AEs whether serious or non-serious, will be recorded in the source documents from the time 
signed and dated ICF is obtained until 30 days following the last dose of study treatment or first 
dose date of subsequent anticancer therapy, whichever occurs first. All SAEs will be reported to 
the Sponsor Drug Safety via an SAE reporting form and will be recorded in the eCRF from the 
time of ICF signing. Non-serious AEs will be recorded in the source documents from the time of 
ICF signing and will be recorded in the eCRF from the first dose of study treatment until 30 days 


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after the last dose of study treatment or first dose date of subsequent anticancer therapy, 
whichever occurs first. 
Serious adverse events occurring more than 30 days following the last dose of study treatment or 
after the first dose date of subsequent anticancer therapy, whichever occurs first, should also be 
reported if considered related to any of the study treatment. Resolution information after 30 days 
should be provided. 
Progressive disease should NOT be reported as an AE, but instead symptoms/clinical signs of 
disease progression may be reported (See Section 11.1.1). 
All AEs, regardless of seriousness, severity, or presumed relationship to study treatment, must be 
recorded using medical terminology in the source document. All records will need to capture the 
details of the duration and the severity of each episode, the action taken with respect to the study 
treatment, Investigator’s evaluation of its relationship to the study treatment, and the event 
outcome. Whenever possible, diagnoses should be given when signs and symptoms are due to a 
common etiology (eg, cough, runny nose, sneezing, sore throat, and head congestion should be 
reported as "upper respiratory infection"). Investigators must record in the eCRF their opinion 
concerning the relationship of the AE to study therapy. All measures required for AE 
management must be recorded in the source document and reported according to Sponsor 
instructions. 
All deaths should be reported with the primary cause of death as the AE term, as death is 
typically the outcome of the event, not the event itself. Autopsy and postmortem reports must be 
forwarded to the Sponsor, or designee, as outlined above, if allowed per local regulatory 
guidelines. 
If a death occurs within 30 days after the last dose of study treatment, the death must be reported 
to the Sponsor as a SAE.  
11.2.2.2. 
Expedited Reporting Requirements for Serious Adverse Events 
All SAEs (initial and follow-up information) will be reported on the Serious Adverse Event 
Report Form and sent to Pharmacyclics Drug Safety, or designee, within 24 hours of the 
discovery of the event or information. Pharmacyclics may request follow-up and other additional 
information from the Investigator (eg, hospital admission/discharge notes and laboratory results). 
The contact information (phone, email and fax) for Pharmacyclics Drug Safety can be found on 
the Serious Adverse Event Report Form and instructions. 
All SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the subject's participation in the study, must be followed until any of the 
following occurs: 
• 
The event resolves 


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• 
The event stabilizes 
• 
The event returns to baseline, if a baseline value/status is available 
• 
The event can be attributed to agents other than the study treatment or to factors 
unrelated to study conduct 
• 
It becomes unlikely that any additional information can be obtained (subject or health 
care practitioner refusal to provide additional information, lost to follow up after 
demonstration of due diligence with follow-up efforts) 
The Sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities 
and governing bodies according to the local regulations. 
The Investigator (or Sponsor where required) must report these events to the appropriate 
Independent Ethics Committee/Institutional Review Board (IEC/IRB) that approved the protocol 
unless otherwise required and documented by the IEC/IRB. 
11.2.3. 
Other Malignancies 
All new malignant tumors including solid tumors, skin malignancies and hematologic 
malignancies will be reported for the duration of study treatment and during any 
protocol-specified follow-up periods including post-progression follow-up for overall survival. If 
observed, enter data in the corresponding eCRF. 
11.2.4. 
Pregnancy 
Before study enrollment, subjects must agree to take appropriate measures to avoid pregnancy. 
However, should a pregnancy occur in a female study subject, consent to provide follow-up 
information regarding the outcome of the pregnancy and the health of the infant until 30 days old 
will be requested. 
A female subject must immediately inform the Investigator if she becomes pregnant from the 
time of consent to 90 days after the last dose of study treatment. A male subject must 
immediately inform the Investigator if his partner becomes pregnant from the time of his consent 
to 90 days after the last dose of study treatment. Any female subjects receiving study treatment 
who become pregnant must immediately discontinue study treatment. The Investigator should 
counsel the subject, discussing any risks of continuing the pregnancy and any possible effects on 
the fetus. 
11.2.4.1. 
Pregnancy Reporting 
Although pregnancy itself is not regarded as an AE, the outcome will need to be documented. 
Any pregnancy occurring in a subject or subject’s partner from the time of first dose up until 90 
days after the last dose of study treatment must be reported. Any occurrence of pregnancy must 
be recorded on the Pregnancy Report Form Part I and submitted to Pharmacyclics Drug Safety, 
or designee, within 24 hours of learning of the event. All pregnancies will be followed for 
outcome, which is defined as elective termination of the pregnancy, miscarriage, or delivery of 


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the fetus. For pregnancies with an outcome of live birth, the newborn infant will be followed 
until 30 days old by completing the Pregnancy Report Form Part II. Any congenital 
anomaly/birth defect noted in the infant must be reported as a SAE. 
11.2.5. 
Eye-Related Adverse Events 
New or worsening eye-related symptoms that are Grade 2 or higher, or a symptom that was 
Grade 2 or higher at baseline worsens, should be evaluated by an ophthalmologist whose 
findings should be reported on the ophthalmologic eCRF. 
11.2.6. 
Adverse Events of Special Interest 
Specific AEs or groups of AEs will be followed as part of standard safety monitoring activities 
by the Sponsor. These events (regardless of seriousness) should be reported on the Serious 
Adverse Event Report Form and sent via email or fax to Pharmacyclics Drug Safety, or designee, 
within 24 hours of awareness.  
11.2.6.1. 
Major Hemorrhage 
Major hemorrhage is defined as any of the following:  
• 
Any treatment-emergent hemorrhagic AEs of Grade 3 or higher* 
• 
Any treatment-emergent serious adverse event of bleeding of any grade 
• 
Any treatment-emergent central nervous system hemorrhage/hematoma of any grade 
* All hemorrhagic events requiring transfusion of red blood cells should be reported as Grade 3 or higher AE per 
CTCAE v 4.03. 
Events meeting the definition of major hemorrhage will be captured as an event of special 
interest according to Section 11.2.6 above. 
12. 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS 
12.1. 
Regulatory and Ethical Compliance 
This clinical study was designed and will be implemented in accordance with the protocol, 
the ICH Harmonized Tripartite Guidelines for Good Clinical Practices, with applicable local 
regulations (including the European Directive 2001/20/EC), and with the ethical principles laid 
down in the Declaration of Helsinki. 
12.2. 
Research Ethics Board (REB) and Independent Ethics Committee (IEC) Approval 
The Investigator will submit this protocol, the ICF, IB, and any other relevant supporting 
information (eg, all advertising materials or materials given to the subject during the study) to the 
appropriate REB/IEC for review and approval before study initiation. Amendments to the 
protocol and ICF must also be approved by the REB/IEC before the implementation of changes 
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The Investigator is responsible for providing the REB/IEC with any required information before 
or during the study, such as SAE expedited reports or study progress reports. 
The REB/IEC must comply with current country-specific national regulations and/or local laws. 
The following documents must be provided to Pharmacyclics or its authorized representative 
before entering subjects in this study: (1) a copy of the REB/IEC letter that grants formal 
approval; and (2) a copy of the REB/IEC-approved ICF. 
12.3. 
Informed Consent 
The ICF and process must comply with country specific national regulations and/or local laws. 
The ICF will document the study-specific information the Investigator or his/her designee 
provides to the subject and the subject’s agreement to participate. 
The Investigator or designee (designee must be listed on the Delegation of Authority log), must 
explain in terms understandable to the subject the purpose and nature of the study, study 
procedures, anticipated benefits, potential risks, possible AEs, and any discomfort participation 
in the study may entail. This process must be documented in the subject’s source record. Each 
subject must provide a signed and dated ICF before any study-related (nonstandard of care) 
activities are performed. The original and any amended signed and dated consent forms must 
remain in each subject’s study file at the study site and be available for verification by study 
monitors at any time. A copy of each signed consent form must be given to the subject at the 
time that it is signed by the subject. 
12.4. 
Quality Control and Quality Assurance 
Sponsor shall implement and maintain quality control and quality assurance procedures to ensure 
that the study is conducted and data are generated, documented and reported in compliance with 
the protocol, GCP, and applicable regulatory requirements. This study shall be conducted in 
accordance with the provisions of the Declaration of Helsinki (October 2008) and all revisions 
thereof, and within the ICH guidelines on GCP (ICH E6). 
12.5. 
Protected Subject Health Information Authorization 
Information on maintaining subject confidentiality in accordance to individual local and national 
subject privacy regulations must be provided to each subject as part of the informed consent 
process (refer to Section 7.1.1), either as part of the ICF or as a separate signed document. 
The Investigator or designee must explain to each subject that for the evaluation of study results, 
the subject’s protected health information obtained during the study may be shared with 
Pharmacyclics and its designees, regulatory agencies, and REBs/IECs. As the study Sponsor, 
Pharmacyclics will not use the subject’s protected health information or disclose it to a third 
party without applicable subject authorization. It is the Investigator’s or designee’s responsibility 
to obtain written permission to use protected health information from each subject. If a subject 


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withdraws permission to use protected health information, it is the Investigator’s responsibility to 
obtain the withdrawal request in writing from the subject and to ensure that no further data will 
be collected from the subject. Any data collected on the subject before withdrawal will be used 
in the analysis of study results. 
During the review of source documents by the monitors or auditors, the confidentiality of the 
subject will be respected with strict adherence to professional standards and regulations. 
12.6. 
Study Files and Record Retention 
The Investigator must keep a record that lists all subjects who have consented to enroll in the 
study. For those subjects subsequently excluded from enrollment, the reason(s) for exclusion is 
to be recorded. 
The Investigator/study staff must maintain adequate and accurate records to enable the conduct 
of the study to be fully documented and the study data to be subsequently verified. Essential 
documentation includes, but is not limited to, the IB, signed protocols and amendments, 
REB/IEC approval letters (dated), signed investigator agreements and Financial Disclosures, 
signed ICFs (including subject confidentiality information), drug dispensing and accountability 
records, shipping records of investigational product and study-related materials, signed 
(electronically), dated and completed electronic case report forms (eCRFs), and documentation 
of eCRF corrections, SAE forms transmitted to Pharmacyclics and notification of SAEs and 
related reports, source documentation, normal laboratory values, decoding procedures for 
blinded studies, curricula vitae for study staff, and all relevant correspondence and other 
documents pertaining to the conduct of the study. 
All essential documentation will be retained by the Investigator for at least 2 years after the date 
the last marketing application is approved for the drug for the indication for which it is being 
investigated and until there are no pending or contemplated marketing applications; or, if no 
application is to be filed or if the application is not approved for such indication, until 2 years 
after formal discontinuation of clinical development of the drug.  
The Investigator must notify Pharmacyclics and obtain written approval from Pharmacyclics 
before destroying any clinical study documents or images (eg, scan, radiograph, ECG tracing) at 
any time. Should an Investigator wish to assign the study records to another party or move them 
to another location, advance written notice will be given to Pharmacyclics. Pharmacyclics will 
inform the Investigator of the date that study records may be destroyed or returned to 
Pharmacyclics. 
Pharmacyclics must be notified in advance of, and Pharmacyclics must provide express written 
approval of, any change in the maintenance of the foregoing documents if the Investigator 
wishes to move study records to another location or assign responsibility for record retention to 
another party. If the Investigator cannot guarantee the archiving requirements set forth herein at 
his or her study site for all such documents, special arrangements must be made between the 


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Investigator and Pharmacyclics to store such documents in sealed containers away from the 
study site so that they can be returned sealed to the Investigator for audit purposes. 
12.7. 
Case Report Forms and Record Maintenance 
Electronic CRFs will be used to collect the clinical study data and must be completed for each 
enrolled subject with all required study data accurately recorded such that the information 
matches the data contained in medical records (eg, physicians’ notes, nurses’ notes, clinic charts 
and other study-specific source documents). Authorized study site personnel (ie, listed on the 
Delegation of Authority log) will complete eCRFs designed for this study according to the 
completion guidelines that will be provided. The Investigator will ensure that the eCRFs are 
accurate, complete, legible, and completed within a reasonable amount of time. At all times, 
the Investigator has final responsibility for the accuracy and authenticity of all clinical data. 
The eCRFs exists within an electronic data capture (EDC) system with controlled access 
managed by Pharmacyclics or its authorized representative for this study. Study staff will be 
appropriately trained in the use of eCRFs and application of electronic signatures before the start 
of the study and before being given access to the EDC system. Original data and any changes of 
data will be recorded using the EDC system, with all changes tracked by the system and recorded 
in an electronic audit trail. The Investigator attests that the information contained in the eCRFs is 
true by providing electronic signature within the EDC system. After database lock, the 
Investigator will receive a copy of the subject data (eg, paper, CD, or other appropriate media) 
for archiving at the study site. 
12.8. 
Investigational Study Drug Accountability 
Ibrutinib and any Pharmacyclics-supplied comparator used must be kept in a locked limited 
access room. The study treatments must not be used outside the context of the protocol. Under no 
circumstances should the Investigator or other site personnel supply ibrutinib, bortezomib and 
dexamethasone to other Investigators, subjects, or clinics or allow supplies to be used other than 
as directed by this protocol without prior authorization from Pharmacyclics. 
Accountability records for ibrutinib, bortezomib and dexamethasone must be maintained and 
readily available for inspection by representatives of Pharmacyclics and are open to regular 
inspections by regulatory authorities at any time.  
An Investigational Drug Accountability Log must be used for drug accountability.  
For additional details on investigational study drug management, please refer to the Pharmacy 
Manual. 
12.9. 
Study Monitoring/Audit Requirements 
Representatives of Pharmacyclics or its designee will monitor this study until completion. 
Monitoring will be conducted through personal visits with the Investigator and site staff, remote 


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monitoring, as well as any appropriate communications by mail, fax, email, or telephone. The 
purpose of monitoring is to ensure that the study is conducted in compliance with the protocol, 
SOPs, and other written instructions and regulatory guidelines, and to ensure the quality and 
integrity of the data. This study is also subject to reviews or audits. 
To assure the accuracy of data collected in the eCRFs, it is mandatory that the monitor/auditor 
have access to all original source documents, including all electronic medical records (EMR) at 
reasonable times and upon reasonable notice. If access to the EMR cannot be granted to the 
monitor, the site must ensure that all certified copies of documents are available during 
monitoring visits for all screened and enrolled subjects. During the review of source documents, 
every effort will be made to maintain the anonymity and confidentiality of all subjects during 
this clinical study. However, because of the experimental nature of this treatment, the 
Investigator agrees to allow the REB/IEC, representatives of Pharmacyclics, its designated 
agents and authorized employees of the appropriate Regulatory Authority to inspect the facilities 
used in this study and, for purposes of verification, allow direct access to the hospital or clinic 
records of all subjects enrolled into this study. A statement to this effect will be included in the 
informed consent and permission form authorizing the use of protected health information. 
Pharmacyclics or its authorized representative may perform an audit at any time during or after 
completion of this study. All study-related documentation must be made available to the 
designated auditor. In addition, a representative of the FDA or other Regulatory Agencies may 
choose to inspect a study site at any time before, during, or after completion of the clinical study. 
In the event of such an inspection, Pharmacyclics will be available to assist in the preparation. 
All pertinent study data should be made available as requested to the Regulatory Authority for 
verification, audit, or inspection purposes. 
12.10. Investigator Responsibilities 
A complete list of Investigator responsibilities are outlined in the clinical trial research 
agreement and the investigator agreements, both of which are signed by the Investigator before 
commencement of the study. In summary, the Investigator will conduct the study according to 
the current protocol; will read and understand the IB; will obtain REB/IEC approval to conduct 
the study; will obtain informed consent from each study participant; will maintain and supply to 
the Sponsor or designee, auditors and regulatory agencies adequate and accurate records of study 
activity and drug accountability for study-related monitoring, audits, REB/IEC reviews and 
regulatory inspections; will report SAEs to the Sponsor or designee and REB/IEC according to 
the specifics outlined in this protocol; will personally conduct or supervise the study; and will 
ensure that colleagues participating in the study are informed about their obligations in meeting 
the above commitments. 
12.11. Sponsor Responsibilities 
A complete list of the Sponsor responsibilities is outlined in the clinical trial research agreement 
and in the laws and regulation of the country in which the research is conducted. In summary, 


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the Sponsor will select qualified Investigators, provide them with the information they need to 
properly conduct the study, ensure adequate monitoring of the study, conduct the study in 
accordance with the general investigational plan and protocols and promptly inform 
Investigators, health and regulatory agencies/authorities as appropriate of significant new 
adverse effects or risks with respect to the drug. 
12.12. Financial Disclosure 
A separate financial agreement will be made between each Principal Investigator and 
Pharmacyclics or its authorized representative before the study drug is delivered. 
For this study, each Investigator and Sub-Investigator (as designated on the investigator 
agreements) will provide a signed Financial Disclosure Form. Each Investigator will notify 
Pharmacyclics or its authorized representative of any relevant changes in financial disclosure 
information during the conduct of the study and for 1 year after the study has been completed. 
12.13. Liability and Clinical Trial Insurance 
In the event of a side effect or injury, appropriate medical care as determined by the 
Investigator/designee will be provided. 
The ICF will include a description of treatment in the event of a study related injury and 
handling of the costs associated therewith, incorporating country-specific national regulations 
and/or local laws. Financial compensation for lost wages, disability or discomfort due to the 
study is not available. 
Clinical trial insurance has been undertaken according to the laws of the countries where the 
study will be conducted. An insurance certificate will be made available to the participating sites 
at the time of study initiation. 
12.14. Protocol Amendments 
Pharmacyclics will initiate any change to the protocol in a protocol amendment document. 
The amendment will be submitted to the REB/IEC together with, if applicable, a revised model 
ICF, unless the changes do not warrant a submission (non-substantial amendments in the EU). 
Written documentation of REB/IEC and required site approval must be received by 
Pharmacyclics before the amendment may take effect at each site. Additionally under this 
circumstance, information on the increased risk and/or change in scope must be provided to 
subjects already actively participating in the study, and they must read, understand and sign any 
revised ICF confirming willingness to remain in the trial. 
No other significant or consistent change in the study procedures, except to eliminate an 
immediate hazard, shall be effected without the mutual agreement of the Investigator and 
Pharmacyclics. 


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12.15. Publication of Study Results 
Pharmacyclics may use the results of this clinical study in registration documents for Regulatory 
Authorities in the US or abroad. The results may also be used for papers, abstracts, posters, or 
other material presented at scientific meetings or published in professional journals or as part of 
an academic thesis by an Investigator. In all cases, to avoid disclosures that could jeopardize 
proprietary rights and to ensure accuracy of the data, Pharmacyclics reserves the right to preview 
all manuscripts and abstracts related to this study, allowing Pharmacyclics sufficient time to 
make appropriate comments before submission for publication. 
In most cases, the Investigators at the sites with the highest accruals of eligible subjects shall be 
listed as lead authors on manuscripts and reports of study results. The Medical Monitor, study 
director and/or lead statistician may also be included in the list of authors. This custom can be 
adjusted upon mutual agreement of the authors and Pharmacyclics and in accordance with 
current standards for authorship as recorded in professional conference and journal submission 
instructions. 
12.16. Study Discontinuation 
The Sponsor reserves the right to terminate the study at any time. Should this be necessary, both 
the Sponsor and the Investigator will arrange discontinuation procedures. In terminating the 
study, the Sponsor and the Investigator will assure that adequate consideration is given to the 
protection of the subjects’ interests. 
12.17. Study Completion 
The study is expected to be completed approximately 2 years from last patient enrolled, the time 
point all subjects have exited the study for any reason, or study termination at the Sponsor’s 
discretion, whichever occurs first. 
 
 


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13. 
REFERENCES 
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2. Altieri, A, Chen B, Bermejo JL, et al. Familial risks and temporal incidence trends of multiple 
myeloma. European Journal of Cancer. 2006;42,1661-70. 
3. Bam R, Ling W, Khan S, et al. Role of Bruton’s tyrosine kinase in myeloma cell migration and 
induction of bone disease. American Journal of Hematology. 2013;88:463-71. 
4. Blade J, Samson D, Reece D, et al. Criteria for evaluating disease response and progression in 
patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell 
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5. Cancer Research UK. Myeloma Incidence Statistics [Internet]. Available from 
www.cancerresearchuk.org, accessed on Sep 2015.  
6. Chari A, Chabra S and Usmani S et al. Combination Treatment of the Bruton’s Tyrosine Kinase 
Inhibitor Ibrutinib and Carfilzomib in Patients with Relapsed or Relapsed and Refractory Multiple 
Myeloma: Initial Results from a Multicenter Phase 1/2b Study. Blood. 2015; 126: Abstract 377.   
7. Child CG, Turcotte JG. “Surgery and portal hypertension”. In Child CG. The liver and portal 
hypertension. Philadelphia:Saunders. 1964 pp. 50-64.  
8. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 
1976;16:31-41. 
9. Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03. Published June 14, 2010 
10. Crocetti E, De Angelis R, Buzzoni C, et al. Cancer prevalence in United States, Nordic Countries, 
Italy, Australia, and France: an analysis of geographic variability. British journal of cancer. 
2013;109(1), 219-28. 
11. Dimopolous MA, Orlowski RZ, Facon T, et al. Retrospective Matched-Pair Analysis Of The Efficacy 
and Safety of Bortezomib Plus Dexamethasone Versus Bortezomib Monotherapy in Patients (Pts) 
With Relapsed Multiple Myeloma. Blood. 2013,122 (21). 
12. Dimopoulos MA, Richardson PG, Moreau P and Anderson KC. Current treatment landscape for 
relapsed and/or refractory multiple myeloma. Nature Reviews Clinical Oncology. 2015;12:42-54. 
13. Dimopoulos, M.A. & Terpos, E. Multiple myeloma. Annals of Oncology. 
2010;21(Suppl. 7), Vii 143-50. 
14. Elias L and Buggy J. Bruton Tyrosine Kinase Expression in Multiple Myeloma. Haematologica 
2013;98(s1):Abstract P211 
15. Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality 
Worldwide: IARC CancerBase No. 11 [Internet].Lyon, France: International Agency for Research on 
Cancer; 2013. Available from: http://globocan.iarc.fr, accessed on Nov 2015. 
16. Flowers CR, Seidenfeld J, Bow EJ, et al. Antimicrobial prophylaxis and outpatient management of 
fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology 
clinical practice guideline. J Clin Oncol. 2013;31:794-810. 
17. Greipp PR, San Miguel J, Durie, BGM, et al. International Stating System for Mulitple 
Myeloma. J Clin Oncol. 2005;23:3212-420. 


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18. Herman SE, Gordon AL, Hertlein E, et al. Bruton tyrosine kinase represents a promising therapeutic 
target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood. 
2011;117:6287-96. 
19. International Conference on Harmonisation (ICH) of Technical Requirements for Registration of 
Pharmaceuticals for Human Use: ICH Harmonised Tripartite Guideline: Guidance for Good Clinical 
Practice (ICH-E6) (R1). June 1996.   
20. Investigator's Brochure. Ibrutinib. Version 10: 29 August 2016. Pharmacyclics LLC; Janssen 
Research & Development, LLC. 
21. Jakubikova J, Adamia S, Kost-Alimova M, et al. Lenalidomide targets clonogenic side population in 
multiple myeloma: pathophysiologic and clinical implications. Blood. 2011;117:4409-19. 
22. Kawano M, Hirano T, Matsuda T, et al. Autocrine generation and requirement of BSF-2/IL-6 for 
human multiple myelomas. Nature. 1988;332:83-85. 
23. King, T. Myeloma-A Comprehensive Guide. 2014. Myeloma Australia.  
24. Moreau P, San Miguel J, Ludwig H, et al. Multiple Myeloma: ESMO Clinical Practice Guidelines. 
Ann Oncol. 2013; 24 (Supplement 6) vi133-7.  
25. National Comprehensive Cancer Network (NCCN) Guidelines for multiple myeloma. Version 5 
2015. 
26. Oken MM, Creech RH, Tormey DC, et al. Toxicity And Response Criteria Of The Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-55. 
27. Pan Z, Scheerens H, Li SJ, et al. Discovery of selective irreversible inhibitors for Bruton's tyrosine 
kinase. ChemMedChem. 2007;2:58-61. 
28. Petrucci MT, Giraldo P, Carradini P, et al. A Prospective, International Phase  Study of Bortezomib 
Retreatment in Patients with Relapsed Multiple Myeloma. Br J Haematol. 2013;160:649-59.  
29. Pugh RN, Murray-Lyon IM, Dawson L, Pietroni MC, Williams R. “Transection of the oesophagus for 
bleeding oesophageal varices”. The British journal of surgery. 1973;60: 646-649. 
30. Rajkumar SV, Harousseau JL, Durie B, et al. Consensus recommendations for the uniform reporting 
of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 
2011;117:4691-5.  
31. Renshaw C, Ketley N, Møller, H., & Davies, E. A. Trends in the incidence and survival of multiple 
myeloma in South East England 1985-2004.BMC cancer. 2010;10(1),74. 
32. Richardson PG., Sonneveld P, Schuster MW, et al. Bortezomib or High-Dose Dexamethasone for 
Relapsed Multiple Myeloma. N Engl J Med. 2005;352:2487-98.  
33. Richardson, PG, Hungria VTM, Yoon S., et al. Panorama 1: A randomized, double-blind, phase 3 
study of panobinostat or placebo plus bortezomib and dexamethasone in relapsed or relapsed and 
refractory multiple myeloma. J Clin Oncol. 2014;32:5s,(suppl; abstr 8510). 
34. Roodman GD, Choi SJ. MIP-1 alpha and myeloma bone disease. Cancer Treat Res. 2004;118:83-100. 
35. Roodman GD. Pathogenesis of myeloma bone disease. J Cell Biochem. 2010a;109:283-91. 
36. Roodman GD. Targeting the bone microenvironment in multiple myeloma. J Bone Miner Metab. 
2010b;28:244-50. 
37. Roodman GD. Osteoblast function in myeloma. Bone. 2011;48:135-40. 


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38. San Miguel JF, Hungria TM, Yoon S, et al. Panobinostat Plus Bortezomib and Dexamethasone in 
Patients With Relapsed or Relapsed and Refractory Multiple Myeloma Who Received Prior 
Bortezomib and IMiDs: A Predefined Subgroup Analysis of PANORAMA 1. J Clin Oncol. 
2015;33,(suppl; abstract 8562).  
39. Smith TJ, Khatcheressian J, Lyman GH, et al. Update of Recommendations for the Use of White 
Blood Cell Growth Factors: An Evidence-Based Clinical Practice Guideline. Journal of Clinical 
Oncology. 2006;24: 3187-205. 
40. Summary of Product Characteristics. VELCADE®. 26 April 2014. Janssen-Cilag International 
Pharmaceutica NV.  
41. Tai Y, Chang B, Kong S, et al. Bruton tyrosine kinase inhibition is a novel therapeutic strategy 
targeting tumor in the bone marrow microenvironment in multiple myeloma. Blood. 
2012;120:1877-87. 
42. US Food & Drug Administration. Guidance for Industry: Clinical Safety Data Management: 
Definitions and Standards for Expedited Reporting. ICH-E2A. March 1995. 
43. VELCADE® prescribing information. Cambridge, MA: Millenium Pharmaceuticals, Inc.; 2015.  
44. Vij R, Huff C and Bensinger W et al. Ibrutinib, Single Agent or in Combination with Dexamethasone, 
in Patients with Relapsed or Relapsed/Refractory Multiple Myeloma (MM): Preliminary Phase 2 
Results. Blood. 2014;124:Abstract 31. 
45. Yang Y, Shi J and Gu Z et al. Bruton Tyrosine Kinase Is a Therapeutic Target in Stem-like Cells from 
Multiple Myeloma. Cancer Research. 2015;75:594-604. 
46. Nucci M, Anaissie E. Infections in patients with multiple myeloma in the era of high-dose therapy 
and novel agents. Clin Infect Dis. 2009;49(8):1211. 
47. Blimark C, Holmberg E, Mellqvist UH, et al. Multiple myeloma and infections: a population-based 
study on 9253 multiple myeloma patients. Haematologica. 2015;100(1):107. Epub 2014 Oct 24. 
48. Augustson BM, Begum G, Dunn JA, et al. Early mortality after diagnosis of multiple myeloma: 
analysis of patients entered onto the United Kingdom Medical Research Council trials between 1980 
and 2002--Medical Research Council Adult Leukaemia Working Party. J Clin Oncol. 
2005;23(36):9219.  
49. Moreau P, Joshua D, Chng W-J, et al. Impact of prior treatment on patients with relapsed multiple 
myeloma treated with carfilzomib and dexamethaseone vs. bortezomib and dexamethasone in the 
phase 3 ENDEAVOR study. Leukemia (2017) 31, 115–22. 


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14. 
APPENDICES 
 


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Appendix 1. Schedule of Assessments 
 
Screening 
Phase 
Treatment Phase 
Follow-up Phase 
Study Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3-8 
Cycle 9-12 
Cycle 13+ 
Suspected 
PD Visit 
EOT 
Response 
Follow-up 
Long-term 
Follow-up 
q 4 weeks 
30-days 
Study Day 
 
1 
4 
8 
11 
1 
2 
4 8 
11 
1 
4 
8 
11 
1 
8 
22 29 
1 
Any time 
 
q 4 weeks 
q 12 weeks 
Visit Window 
-30 days 
 
± 2 days 
 
± 7days 
± 7 days 
± 14 days 
Study Procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm Eligibility 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History and Demographics 
X` 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Assessments 
Physical Exama (Ht. at Screening 
only) 
X 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
 
 
Symptom Directed PE 
 
 
X X 
X 
 
 
X X 
X 
 
X X 
X 
 
X 
X 
X 
 
 
 
 
 
ECOG status 
X 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
 
 
Vital Signsb 
X 
X X X 
X 
X 
 
X X 
X 
X X X 
X 
X X 
X 
X 
X 
X 
X 
 
 
Eye-related Symptom Assessmentc 
X 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
 
 
12-lead ECGd 
X 
Additional tests may be performed if clinically indicated  
(eg subject with palpitations, lightheadedness) 
 
 
 
Imaging by CT, MRI, or PET/CT, if 
applicablee 
X 
Subsequent response assessments must include follow-up studies q 3 months 
 if evidence of plasmacytoma at Screening. 
X 
(If applicable) 
 
Concomitant Medications 
X 
X X X 
X 
X X X X 
X 
X X X 
X 
X X 
X 
X 
X 
X 
X 
 
 
Adverse eventsf 
X 
X X X 
X 
X X X X 
X 
X X X 
X 
X X 
X 
X 
X 
X 
X 
 
 
Study Treatment Administration 
Ibrutinib dosingg 
 
X 
Continuous daily dosing 
 
 
 
Bortezomib dosingh 
 
X X X 
X 
X 
 
X X 
X 
X X X 
X 
X X 
X 
X 
 
 
 
 
 
Dexamethasone dosingi 
 
X X X 
X 
X 
 
X X 
X 
X X X 
X 
X X 
X 
X 
X 
 
 
 
 
Efficacy Assessments - Refer to Section 7.5 
Investigator Response Assessment 
(refer to Appendix 6)j 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
 
Serum and Urine protein 
electrophoresis (SPEP/UPEP)k 
X 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
 
Quantitative Immunoglobulins 
X 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X  
X 
X 
X 
 
Serum free light chain assay (sFLC) 
X 
X 
Additional tests may be performed to confirm CR 
 
 
 
Serum and Urine immunofixationl  
X 
X 
Additional tests may be performed to confirm CR 
 
 
 


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Screening 
Phase 
Treatment Phase 
Follow-up Phase 
Study Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3-8 
Cycle 9-12 
Cycle 13+ 
Suspected 
PD Visit 
EOT 
Response 
Follow-up 
Long-term 
Follow-up 
q 4 weeks 
30-days 
Study Day 
 
1 
4 
8 
11 
1 
2 
4 8 
11 
1 
4 
8 
11 
1 
8 
22 29 
1 
Any time 
 
q 4 weeks 
q 12 weeks 
Visit Window 
-30 days 
 
± 2 days 
 
± 7days 
± 7 days 
± 14 days 
Efficacy Assessments (continued) - Refer to Section 7.5 
Bone Radiologic Assessmentm 
X 
 
 
 
 
Additional tests may be performed, as determined necessary,  
at any time during participation in the study  
 
Bone marrow biopsy and/or 
aspiraten 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
Survival status and new anti-cancer 
therapyo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Clinical Laboratory Assessments 
Hematologyp 
X 
X X X 
X 
X 
 
X X 
X 
X X X 
X 
X X 
X 
X 
X 
X 
X 
X 
 
Chemistryq 
X 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
 
Estimated Creatinine Clearancer 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation (PT/INR, aPTT) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (serum or urine) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis serologiess 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-reactive protein 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
β2-microglobulin 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarkers and Pharmacokinetic Assessments 
PK (see separate schedule)t 
 
 
 
 
 
X X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow aspirate for 
Biomarkersu 
X 
Additional test may be performed to confirm CR 
X 
X  
(If applicable) 
 
Biomarkers: whole blood collection  
X 
X 
 
 
 
X 
 
 
 
 
Day 1 of every even Cycle  
X 
X 
 
 
Biomarkers: serum CTXv 
X 
X 
 
 
 
X 
 
 
 
 
Day 1 of every even Cycle  
X 
X 
 
 
a. At Screening, Day 1 of each Cycle, Suspected PD or CR, and EOT, Physical Exam should include: skin, eyes, ears, nose, throat, lungs, heart, abdomen, 
extremities, musculoskeletal system, lymphatic system, nervous system and weight. At all other time points symptom-directed Physical Exam, including 
weight, is required. Height is required at Screening only. 
b. Vital signs (blood pressure, heart rate, and body temperature)   
c. Refer to Section 11.2.5 for additional information. 
d. Performed at Screening in triplicate. Not required at subsequent cycles unless clinically indicated. 
e. Magnetic resonance imaging (MRI), computed tomography (CT) or PET/CT scans are to be performed as clinically indicated. If evidence of plasmacytoma 
noted on radiographic imaging at Screening, subsequent response assessments must include follow-up studies every 3 months. Refer to Section 7.5.5. 


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f. Adverse events are collected from the time the subject signs the ICF until 30 days following last dose of study treatment or first dose date of subsequent 
anticancer therapy, whichever occurs first. In addition to all routine AE reporting, all new malignant tumors including solid tumors, skin malignancies and 
hematologic malignancies are to be reported as AEs for the duration of the study treatment and during any protocol-specified follow-up periods.  
g. Starting C1D1 subjects will be provided a dosing diary and dispensed ibrutinib to self-administer daily. Subject is to return unused ibrutinib and completed 
diary at day 1 of each subsequent cycle. 
h. Bortezomib will be administered by subcutaneous injection (SC) on Days 1, 4, 8 and 11 of each Cycle during Cycles 1-8 and on Days 1, 8, 22 and 29 of  each 
cycle during Cycles 9-12 until disease progression, unacceptable toxicity, or other protocol specified reason (refer to Section 9). 
i. Dexamethasone will be administered orally at 20 mg on Days 1, 4, 8, and 11 during Cycles 1-8, and Days 1, 8, 22, and 29  during Cycles 9-12. Beginning 
Cycle 13, dexamethasone will be administered orally at 40 mg once weekly. There will be a ± 1 day window for dexamethasone administration. Refer to 
Section 5.5.2.  
j. Beginning C2D1, Investigator response assessments should be performed every 3 weeks through Cycle 12 (refer to Section 8) and every 4 weeks for Cycle 13 
and beyond (Day 1 of every Cycle). 
k. SPEP and UPEP will be collected at Screening, C1D1 and every 3 weeks during Cycles 1-12 and every 4 weeks during Cycles 13 and beyond (Day 1 of every 
cycle). Samples will be submitted to a Central Laboratory. Refer to Section 7.5. If at any time CR is suspected, all assessments must be performed per IMWG 
guidelines. 
l. Required at Screening and Cycle 1 Day 1. Additional test required to confirm CR, conducted at first observation of CR and then repeated at Day 1 of each 
cycle until progression.  
m. Either a low-dose whole-body CT or radiologic skeletal survey including the skull, antero-posterior and lateral views of the spine, and antero-posterior views 
of the pelvis, ribs, femora and humeri will be performed for evaluation of bone lesions. Assessments to be done within 50 days of C1D1. MRI, CT or PET/CT 
scans are to be performed if clinically indicated. If evidence of plasmacytoma is noted on imaging at Screening, subsequent response assessments must include 
follow-up assessments every 3 months. For selected sites only: optional low-dose whole-body CT scan to be performed at Cycle 9 Day 1, Cycle 13 Day 1, and 
at the time of relapse (if not performed within 6 months of another timepoint) for exploratory analysis.  
n. To be submitted at Screening and confirmation of CR to a local laboratory to evaluate for morphology and document bone marrow involvement. If bone 
marrow biopsy and/or aspirate was done within 90 days of first administration of study treatment assessment does not need to be repeated. Bone marrow 
aspirate is required at Screening and sent to a central lab. Refer to Section 7.5.6 for additional information.  
o. After disease progression, subjects will be contacted to assess survival status approximately every 12 weeks (±14 days). After ibrutinib treatment is 
discontinued all information on first and second subsequent anti-cancer therapies will be collected to include: start and stop dates and indication for initiation 
of subsequent anti-cancer therapy. Refer to Section 7.8.2 for additional information.  
p. Hematology (WBC, RBC, Hgb, Hct, platelet count, neutrophils, and, if available, lymphocytes, monocytes, eosinophils and basophils. C1D1 testing not 
required if done within 48 hours prior to the first dose of study treatment. All assessments will be performed by the local laboratory. 
q. Chemistry (sodium, potassium, chloride, BUN/urea, creatinine, glucose, calcium, total protein, albumin, AST, ALT, alkaline phosphatase, total bilirubin, LDH, 
phosphate, and uric acid, and magnesium). C1D1 testing not required if done within 48 hours prior to the first dose of study treatment. All assessments will be 
performed by the local laboratory. 
r. Estimated creatinine clearance is only required during Screening and will be calculated using local laboratory results.  
s. Hepatitis serologies including Hepatitis C antibody, Hepatitis B surface antigen, and Hepatitis B core antibody will be evaluated at Screening. If Hepatitis B 
core antibody, Hepatitis B surface antigen or Hepatitis C antibody is positive, then PCR to quantitate Hepatitis B/C must be performed and must be negative 
prior to enrollment.  


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t. Assessments pre- and post-dose ibrutinib and bortezomib, see Table 6. Ibrutinib will be administered in the treatment center on C2 D1 and C2D2. Time of 
dose is to be recorded in the medical record for PK evaluation. For C2D1 and C2D2, record time of last meal prior to administration of study treatment.  
u. Bone marrow aspirate samples (up to 6 mL) to be collected for biomarker testing and submitted to a central lab at Screening, at the time of CR, and following 
confirmed PD (may be done at EOT or prior to the start of new anti-cancer therapy). Refer to Section 7.5.6 for additional information. MRD assessment will 
be done at the time of CR, repeated every 12 months following confirmed CR, and at the time of disease progression or study exit. Refer to Section 7.5.7 for 
additional information.  
v. Biomarker serum CTX collections require 12 hour fasting prior to collection. 


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Appendix 2. ECOG Status Scores 
Status 
Eastern Cooperative Oncology Group (ECOG) Performance Status** 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, eg, light housework, office work. 
2 
Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and 
about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
5 
Dead. 
**Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity and 
Response Criteria of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. 
Available at: http://www.ecog.org/general/perf_stat.html. Accessed January 4, 2008. 
 
 


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Appendix 3. Cockcroft-Gault Formula for Estimating Creatinine Clearance 
 
Ccr = 
(140 – age) x Body Weight (kg) 
(Serum creatinine mg/dL) x 72 
 
Note: 
• 
Multiply by 0.85 for women 
• 
Use with caution in cirrhosis and muscle wasting 
• 
To convert µmol (micromoles)/L of creatinine to mg/dL, divide by 88.4. 
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31-41. 
 
 


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Appendix 4. Lines of Therapy 
According to the IMWG Consensus panel on uniform reporting criteria in clinical trials 
(Rajkumar 2011), a line of therapy consists of at least 1 or more cycles of a planned treatment 
regimen. This may consist of single-agent or combination therapy or a sequence of treatments 
administered in a planned manner. For example, a planned induction, followed by autologous 
stem cell transplant (ASCT) followed by maintenance is considered one line of therapy. A new 
line of therapy starts when a planned course is modified as a result of progression, relapse or 
toxicity or when a planned period of observation is interrupted by the need for additional 
treatment of the disease. Modification of drug doses or resuming therapy after holding will not 
be considered a new line of therapy provided that there was no evidence of progression of 
disease as defined in the “Response Criteria” section of this document. 
 
 


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Appendix 5. Inhibitors and Inducers of CYP3A 
Inhibitors and inducers of CYP3A are defined as follows. Refer to Section 6.1.2.1 on instructions 
for concomitant use of CYP3A inhibitors and inducers with ibrutinib. Further information can be 
found at the following website: http://medicine.iupui.edu/clinpharm/ddis/main-table/. 
Inhibitors of CYP3A4/5 
Inducers of CYP3A4/5 
Strong inhibitors: 
carbamazepine 
indinavir 
efavirenz 
nelfinavir 
nevirapine 
ritonavir 
barbiturates 
clarithromycin 
glucocorticoids 
itraconazole 
modafinil 
ketoconazole 
oxcarbarzepine 
nefazodone 
phenobarbital 
saquinavir 
phenytoin 
suboxone 
pioglitazone 
telithromycin 
rifabutin 
cobicistat 
rifampin 
boceprevir 
St. John’s Wort 
mibefradil 
troglitazone 
telaprevir 
 
troleandomycin 
 
posaconazolea 
 
Moderate inhibitors: 
 
aprepitant 
 
amprenavir 
 
amiodarone 
 
atazanavir 
 
ciprofloxacin 
 
crizotinib 
 
darunavir 
 
dronedarone 
 
erythromycin 
 
diltiazem  
 
fluconazole 
 
fosamprenavir 
 
grapefruit juice 
 
Seville orange juice 
 
verapamil 
 
voriconazolea 
 
imatinib 
 
Weak inhibitors: 
 
cimetidine 
 
fluvoxamine 
 
All other inhibitors: 
 
chloramphenicol 
 
delaviridine 
 
diethyl-dithiocarbamate 
 
gestodene 
 
mifepristone 
 
norfloxacin 
 
norfluoxetine 
 
star fruit 
 
a.     Classification based on internal data. 
 
 
 
 


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Appendix 6. International Myeloma Working Group Response Criteria (Rajkumar 2011) 
IMWG Response Criteria 
CATEGORY 
RESPONSE CRITERIA a 
Stringent complete 
response (sCR)   
CR as defined below plus all of the following: 
• 
Normal serum FLC ratio  
• 
Absence of clonal cells in bone marrow by IHC or immunofluorescence b 
Complete response 
(CR) 
• 
Negative immunofixation of the serum and urine  
• 
<5% plasma cells in bone marrow  
• 
Disappearance of any soft tissue plasmacytomas  
• 
If at on study, the only measurable non-bone marrow parameter was FLC, 
normalization of FLC ratio 
Very good partial 
response (VGPR) 
• 
PR as defined below plus all of the following: 
• 
Serum and urine M-component detectable by immunofixation but not on 
electrophoresis or 
• 
If at on study, serum measurable, ≥90% or greater reduction in serum M-component 
plus urine M-component <100 mg per 24 h  
Partial Response  
(PR) 
• 
One of the following: 
 If at on study, serum and urine measurable, a ≥50% reduction of serum M-protein 
and reduction in 24-h urinary M-protein by ≥90% or to <200 mg per 24 h  
 If at on study, only serum measurable (but urine not), a ≥ 50% reduction of serum 
M-protein  
 If at on study, urine measurable (but serum not), a reduction in 24-h urinary 
M-protein by ≥90% or to <200 mg per 24 h  
• 
In addition to the above criteria, if a plasmacytoma present at baseline, ≥50% 
reduction in the size of soft tissue plasmacytomas is also required 
Minimal Response 
(MR) 
• 
≥25% but ≤49% reduction of serum M-protein and reduction in 24h urine M-protein 
by 50-89%,  
• 
In addition to the above criteria, if a plasmacytoma present at baseline,  
25-49% reduction in the size of soft tissue plasmacytomas is also required 
• 
No increase in size or number of lytic bone lesions (development of compression 
fracture does not exclude response) 
Stable disease (SD) 
Not meeting criteria for CR, VGPR, PR, MR or progressive disease 
Progressive disease 
(PD) 
Any one or more of the following:  
• 
Increase of 25% from lowest value in d: 
 Serum M-component (absolute increase must be ≥0.5 g/dL)c  
 Serum M-component increase ≥1 g/dL, if starting M component was ≥5 g/dL 
 Urine M-component (absolute increase must be ≥200 mg/24 h) c 
Or any one or more of the following felt related to the underlying clonal plasma cell 
proliferative disorder 
 Development of new soft tissue plasmacytomas or bone lesions 
Hypercalcemia (corrected serum calcium ≥11.5 mg/dL) 
a All response categories require two consecutive assessments made at any time before the institution of any new 
therapy; CR and PR, MR and SD categories also require no known evidence of progressive or new bone lesions if 
radiographic studies were performed. Radiographic studies are not required to satisfy these response 
requirements. Bone marrow assessments need not be confirmed. 
b Presence/absence of clonal cells is based upon the k/λ ratio. An abnormal k/λ ratio by IHC and/or 
immunofluorescence requires a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting presence 
of an abnormal clone is k/λ of >4:1 or <1;2.  
c Positive immunofixation alone in a subject previously classified as CR will not be considered progression. 
d In the case where a value is felt to be a spurious result per physician discretion (for example, a possible lab error), 
that value will not be considered when determining the lowest value. 


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Confirmation of Response Categories  
In order to be classified as a hematologic response, confirmation of serum monoclonal protein, and urine 
monoclonal protein (when primary determinant of response) results must be made by verification on two 
consecutive determinations. Confirmation assessments may be performed at any time after the initial 
assessment.  
• 
Bone marrow aspirate/biopsy is only required to document CR. However, a second confirmatory 
bone marrow is not required to confirm response in any case. 
• 
Radiographic studies are not required to satisfy these response requirements; however, if radiographic 
studies were performed there should be no evidence of progressive or new bone lesions. 
Measurable disease  
o Serum M-protein ≥1 g/dL (for subjects with IgA, IgD, IgE or IgM multiple myeloma SPEP 
≥0.5 g/dL) 
o Urine M-protein ≥ 200 mg/24 h 
 
 
 


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Appendix 7. International Staging System (ISS) for Myeloma Criteria (Greipp 2005) 
Stage 
Criteria 
Stage 1 
β2-microglobulin <3.5 mg/L 
Albumin ≥3.5g/dL 
Stage 2 
Neither 1 or 3 
Stage 3 
β2-microglobulin >5.5 mg/L 
Greipp PR, San Miguel J, Durie, BGM, et al. International Stating System for 
Mulitple Myeloma. J Clin Oncol. 2005;23:3212-420. 


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Appendix 8. Child-Pugh Score for Subjects with Liver Impairment 
Measure 
1 Point 
2 Points 
3 Points 
Total bilirubin, μmol/L 
(mg/dL) 
<34 (<2) 
34-50 (2-3) 
>50 (>3) 
Serum albumin, g/dL 
>3.5 
2.8-3.5 
<2.8 
PT INR 
<1.7 
1.71-2.30 
>2.3 
Ascites 
None 
Mild 
Moderate to Severe 
Hepatic encephalopathy 
None 
Grade I-II  
(or suppressed with medication) 
Grade III-IV  
(or refractory) 
Points 
Class 
5-6 
A 
7-9 
B 
10-15 
C 
Source:  
Child CG, Turcotte JG (1964) “Surgery and portal hypertension”. In Child CG. The liver and portal hypertension. 
Philadelphia:Saunders. pp. 50-64.  
Pugh RN, Murray-Lyon IM, Dawson L, Pietroni MC, Williams R (1973). “Transection of the oesophagus for 
bleeding oesophageal varices”. The British journal of surgery, 60 (8): 646-649. 

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Statistical Analysis Plan 
 
 
An Open-label study of Ibrutinib in Combination with Bortezomib and Dexamethasone in Subjects with 
Relapsed or Relapsed and Refractory Multiple Myeloma  
 
 
PCYC-1139-CA 
 
 
June 20, 2018 
Version 2.0 
 
 
The information in this document is considered privileged and confidential by Pharmacyclics LLC, and 
may not be disclosed to others except to the extent necessary to obtain Institutional Review Board 
approval and informed consent, or as required by Federal and State Laws.  Persons to whom this 
information is disclosed must be informed that this information is privileged and confidential and that it 
should not be further disclosed. 
 
 
 
 
 


 
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TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS ................................................................................. 4 
1 
INTRODUCTION ............................................................................................. 5 
1.1 
Study Design ..................................................................................................................5 
1.2 
Endpoints .......................................................................................................................5 
 
Primary Endpoint(s) ..........................................................................................5 
 
Secondary Endpoints ........................................................................................5 
 
Exploratory Endpoint ........................................................................................6 
 
Safety Assessments ...........................................................................................6 
1.3 
Statistical Hypotheses ....................................................................................................6 
1.4 
Sample Size Determination ............................................................................................6 
1.5 
Planned Analysis ............................................................................................................7 
 
Final Analysis ...................................................................................................7 
2 
GENERAL ANALYSIS CONSIDERATION ................................................. 7 
2.1 
Analysis Sets ..................................................................................................................7 
2.2 
Definition of Subgroups .................................................................................................7 
3 
SUBJECT INFORMATION ............................................................................. 9 
3.1 
Subject Disposition ........................................................................................................9 
3.2 
Demographics and Baseline Characteristics ..................................................................9 
3.3 
Concomitant Medications ..............................................................................................9 
3.4 
Extent of Exposure to Study Treatment .........................................................................9 
3.5 
Subsequent Anti-Cancer Treatment .............................................................................10 
4 
ANALYSIS FOR ENDPOINTS ..................................................................... 11 
5 
SAFETY ASSESSMENTS .............................................................................. 13 
6 
CHANGES IN PROTOCOL PLANNED ANALYSIS ................................ 14 
7 
REFERENCES ................................................................................................. 15 


 
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LIST OF ABBREVIATIONS 
AE 
adverse event 
ATC 
Anatomical Therapeutic Chemical 
CI 
confidence interval 
CR 
complete response 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DOR 
Duration of Overall Response 
Hgb 
hemoglobin 
MedDRA 
Medical Dictionary for Regulatory Activities 
mPFS 
median progression-free survival 
NCI 
National Cancer Institute 
ORR 
overall response rate 
OS 
overall survival 
PCYC 
Pharmacyclics 
PD 
progressive disease 
PFS 
progression-free survival 
PR 
partial response 
PT 
preferred term 
SAP 
statistical analysis plan 
TEAE 
treatment-emergent adverse events 


 
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1 
INTRODUCTION 
This statistical analysis plan (SAP) is based on the protocol Amendment 4 and is to define key 
elements including variable definitions, and statistical methods for analysis of data in evaluation 
of efficacy and safety of the study PCYC-1139-CA.  Analyses of pharmacokinetics data will be 
addressed in a separate document.  Biomarker analysis will not be performed for this study, as 
the Sponsor decided not to pursue the indication of multiple myeloma for ibrutinib. Throughout 
this SAP, “study treatment” and “study drug” are used interchangeably. 
Analysis methods specified in this document take precedence over those described in protocol 
should there be any difference.  
1.1 
Study Design 
The study is an open-label, international, multicenter study of ibrutinib in combination with 
bortezomib and dexamethasone in subjects with MM who have received 2 or 3 prior lines of 
therapy and have demonstrated disease progression following the completion of the last line of 
therapy. 
Approximately 125 subjects were to be enrolled.  Due to early termination of the study per 
sponsor’s decision, enrollment was closed at the time when 74 subjects received at least 1 dose 
of study drug.  The decision to discontinue study was based on the consideration that MM may 
not be the disease area where ibrutinib can provide a significantly better therapeutic benefit for 
the majority of patients compared to other approved drugs currently on the market. Therefore, 
the sponsor decided to focus the future research and development efforts in other disease areas 
where we can provide more benefits to patients. 
1.2 
Endpoints 
 
Primary Endpoint(s) 
o The primary efficacy endpoint is median Progression Free survival (PFS) per the 
International Myeloma Working Group (IMWG) response criteria (Rajkumar 2011) 1,2,3 
in subjects with relapsed or relapsed and refractory MM. 
 
Secondary Endpoints 
o Overall response rate (ORR): partial response (PR) or better, according to the IMWG 
response criteria per investigator assessment 
o PFS rates at landmark points are the percentages or probabilities of surviving and 
progression-free at the landmark time points. 
o Duration of Response (DOR) 


 
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o Overall Survival (OS) 
o Time to Progression (TTP) 
 
Exploratory Endpoint 
o Time to subsequent anticancer therapies in subjects with relapsed or relapsed and 
refractory MM 
 
Safety Assessments 
o Safety and tolerability of ibrutinib in combination with bortezomib and dexamethasone 
1.3 
Statistical Hypotheses 
The null hypothesis is the median PFS (mPFS) ≤8 months and the alternative hypothesis is 
mPFS ≥12 months. A 2-sided 95% confidence interval for the mPFS will be calculated to test the 
hypothesis.    
1.4 
 Sample Size Determination 
The sample size was originally estimated to be approximately 125 to achieve 80% power at a 1-
sided 0.025 significance level to test the null hypothesis of mPFS ≤8 months vs ≥12 months 
under the alternative hypothesis, with the assumption that the PFS follows an exponential 
distribution. The 2-sided 95% Brookmeyer-Crowley confidence interval with the log-log-
transformed Greenwood variance estimate for mPFS will be calculated to test the hypotheses. An 
mPFS of 8.1 months was observed in the PANORAMA-1 Study where a similar patient 
population was treated with bortezomib and dexamethasone4. This hypothesis for mPFS with the 
revised enrollment to only include 2-3 prior lines of therapy without enrollment limitations for 
prior bortezomib exposure is further supported by recent data in the ENDEAVOR Study 
demonstrating similar outcome5. The sample size of approximately 125 subjects is determined by 
simulation method assuming that the PFS follows an exponential distribution and the mPFS is 12 
months with ibrutinib in combination with bortezomib and dexamethasone. In addition, an 
enrollment period of 20 months with an average enrollment rate of 6 subjects per month, an 
exponential censoring process allowing approximately 6.5% censored observations, for example, 
due to non-progression related dropout, during the study duration prior to the analysis, and the 
time of primary analysis at 12 months after the last subject enrolled into the study were also 
assumed in the simulation. Under the above assumptions, approximately 83 PFS events would 
occur prior to the analysis. 


 
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1.5 
Planned Analysis 
 
Final Analysis  
The final analysis for the clinical study report was originally planned to include the data up to 
12 months after the last subject enrolled or 83 PFS events occurred, whichever occurs earlier.  
However, after 74 subjects were enrolled and treated, the sponsor decided to terminate the study 
due to a decision to no longer pursue the indication.  Therefore, the final analysis will be 
conducted when all subjects have exited PCYC-1139-CA study (study termination or subjects 
being rolled over to a long-term extension study, PCYC-1145-LT).  The timing of the primary 
analysis will be approximately 18-20 months after the last subject enrolled.  No interim analysis 
will be conducted.  
2 
GENERAL ANALYSIS CONSIDERATION 
Subjects will be analyzed and summarized for safety and other selected endpoints.   
2.1 
Analysis Sets 
o All-Treated Population 
The all-treated population include subjects who have received any dose of study 
treatment.      
o Response-Evaluable Population 
The response-evaluable population is defined as all-treated subjects who provided at least 
one post-baseline response (or disease) assessment. 
o Safety Population 
The safety population include subjects who have received any dose of study treatment 
which is the same as all-treated population. 
 
2.2 
Definition of Subgroups 
Analyses for the baseline subgroups (hereafter referred as “subgroup” or “subgroups”) will be 
performed for the primary endpoint analysis to assess the internal consistency of any treatment 
benefit.  The baseline subgroup variables (Table 1) and the cutoff values are subject to change if 
warranted to better represent the data.  
Table 1: Baseline Subgroups 


 
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Subgroup 
Definition of Subgroup 
Analysis Type 
Prior bortezomib exposure 
Yes, No  
Efficacy: Progression Free 
Survival 
Number of prior line therapy 
1, >= 2 
Efficacy: Progression Free 
Survival 
 


 
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3 
SUBJECT INFORMATION  
3.1 
Subject Disposition 
The disposition tables will include the following summaries. 
 Analysis population (all-treated subjects) 
 Enrollment by region, country and investigator  
 Study Treatment Disposition and Discontinuation  
 Study Status, Duration of Treatment and Study Exit  
The Kaplan-Meier estimates will be calculated to estimate the time on study using reversed 
censoring from the OS analysis. 
3.2 
Demographics and Baseline Characteristics 
Subject demographics, baseline characteristics and baseline disease characteristics will be 
summarized with descriptive statistics for the all-treated population. 
3.3 
Concomitant Medications 
Medications will be coded to Anatomical Therapeutic Chemical (ATC) class and the preferred 
drug name (hereafter referred as “preferred name”) per World Health Organization drug 
dictionary.  
 
Concomitant medications will be summarized by ATC class and preferred term (PT).  The 
summarization includes all the concomitant medications taken any time while on study treatment 
(i.e., from the date of first dose through the date of last dose of the study treatment). Each subject 
will be counted once for each PT, and each ATC class.  The following concomitant medications 
will be summarized separately.  Details are in the mock-up tables. 
 CYP3A inhibitors and inducers  
 Anticoagulants and antiplatelet agents   
 Prophylaxis for infections 
3.4 
Extent of Exposure to Study Treatment 
Exposure to study treatment will be summarized for the all-treated population.  Descriptive 
statistics will be provided for the following data for each of the 3 drugs unless otherwise 
specified: treatment duration (month), and number (%) of subjects with dose reduction due to 
adverse events (AEs).  Dexamethasone exposure will be analyzed in 2 separate modules (prior to 


 
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12May2017 vs. on/after 12May2017) per the protocol amendment 4 which decreased the 
frequency of dexamethasone dose regimen. 
3.5 
Subsequent Anti-Cancer Treatment 
Subsequent anti-cancer treatment will be summarized for the all-treated population.   


 
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4 
ANALYSIS FOR ENDPOINTS 
Analysis of endpoints (Table 2) will be conducted on the all-treated population.   
Table 2:  Definitions and Analyses for Endpoints 
 
Endpoint 
Definition 
Analysis Method  
Primary Endpoints: 
 
 
PFS assessed by 
investigator 
Progression free survival (PFS) is 
defined as the time from the date of 
first dose of study treatment to 
confirmed disease progression or death 
from any cause, whichever occurs first. 
The PFS will be assessed according to 
the IMWG response criteria. 
 
Primary Analysis: 
Kaplan-Meier (KM) estimates, mPFS 
and its associated 95% confidence 
interval will be displayed.  The 2-
sided 95% Brookmeyer-Crowley 
confidence interval with the log-log-
transformed Greenwood variance 
estimate for mPFS will be calculated 
to test the hypotheses. The null 
hypothesis will be rejected if the 
lower bound of the confidence 
interval is greater than 8 months.   
Subgroup Analysis: 
KM estimates, mPFS and its 
associated 95% CI similar to those for 
the primary analysis will be 
calculated by Number of prior 
systemic therapies (1 vs ≥2 and prior 
bortezomib exposure (yes vs no)  
 
Secondary endpoints: 
 
 
PFS Rates at 
landmark points 
PFS rates at landmark points are the 
proportion of subjects without 
progression (i.e., KM estimates) at the 
landmark time points. 
 
PFS at landmark time points (4, 8, 12, 
16 months from date of first dose of 
study treatment) will be obtained by 
Kaplan-Meier method.  The 95% CI 
for the landmark PFS rates will be 
provided using the log-log-
transformed Greenwood variance 
estimate. 
 
Overall Response 
Rate (ORR) 
 
 
The proportion of subjects achieving a 
best overall response of PR or better 
per investigator assessment per IMWG 
at or prior to initiation of subsequent 
ORR will be estimated and the 
corresponding 2-sided 95% exact 
binomial confidence interval will be 
calculated. 


 
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Endpoint 
Definition 
Analysis Method  
 
anticancer therapy 
 
 
 
Overall Survival 
(OS) 
Time from date of first dose of study 
treatment to the date of death from any 
cause  
Kaplan-Meier estimates, median OS 
(mOS) and its associated 95% 
confidence interval will be displayed. 
 
 
 
Duration of 
Response (DOR) 
The time interval between the date of 
initial documentation of a response 
(PR or better) and the date of first 
documented evidence of PD, death, or 
date of censoring for the subjects not 
progressed/died. The censoring date is 
the last adequate tumor assessment 
date. 
Kaplan Meier estimates, median DOR 
and its associated 95% confidence 
interval will be displayed. 
 
 
 
Time to Progression 
(TTP) 
Time from date of first dose of study 
treatment to the date of first 
documented evidence of PD or date of 
censoring for the subjects not 
progressed. The censoring date is the 
last adequate tumor assessment date. 
Kaplan Meier estimates, median TTP 
and its associated 95% confidence 
interval will be displayed. 
 
 
 
 
Note: PR: partial response; IMWG: International Myeloma Working Group. The primary and secondary 
endpoints will be analyzed for the All-Treated population.
 


 
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SAFETY ASSESSMENTS 
Safety data will be summarized for all-treated population unless otherwise indicated. Table 3 
summarizes the safety analyses to be carried out. AEs will be coded in accordance with the 
Medical Dictionary for Regulatory Activities (MedDRA). Severity of AEs will be graded by the 
investigator according the NCI Common Terminology Criteria for Adverse Events (NCI-
CTCAE) v4.03.  
In general, the treatment-emergent period is defined as the period from the date of the first dose 
of study treatment up to 30 days after the date of the last dose of study treatment or the day 
before initiation of subsequent anticancer therapy, whichever comes first. Treatment emergent 
AEs are those events that occur or worsen during the treatment-emergent period or that are 
related to the study treatment or events with a complete missing onset date but with a resolution 
date during the treatment phase.  
All laboratory values will be converted to and reported as international standard (SI) units. In 
general, only data from the central laboratory will be summarized and analyzed. Laboratory 
parameters will be graded using the NCI CTCAE v4.03.  
Table 3:  Summary of Safety Assessments 
 
Assessment Type 
Definition   
Analysis Methods 
 
AE 
TEAEs, SAEs, grade 3 or worse TEAEs, 
related TEAEs, TEAEs leading to treatment 
discontinuation, TEAEs leading to dose 
reduction, TEAEs leading to death, protocol- 
defined events of special interest and other 
safety observations 
Descriptive summary 
statistics and/or listings 
Lab 
Worst post-baseline toxicity grade for 
selected CTCAE gradable hematology and 
chemistry.  Abnormalities in creatinine 
clearance, uric acid, and liver function  
Descriptive summary 
statistics and/or listings 
Vital Signs and other 
Observations Related to 
Safety 
SBP, DBP, weight, heart rate, new or 
worsened eye-related symptoms 
Descriptive summary 
statistics and/or listings 
TEAE: treatment-emergent adverse event; SAE= serious adverse event; CTCAE= Common Terminology Criteria 
for Adverse Events.  
 


 
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CHANGES IN PROTOCOL PLANNED ANALYSIS 
The following modifications to the protocol “Statistical Methods and Analysis” section are made 
due to the decision by sponsor to terminate the study early. 
1) The interim analysis per Protocol Section 10.5.7 will not be performed. 
2) Biomarker analysis will not be performed.   
3) The study originally planned to have 125 subjects enrolled.  Due to early termination of 
the study per sponsor’s decision, enrollment was closed and 74 subjects received at least 
1 dose of study drug.  The planned statistical power will not be met due to the decrease in 
sample size.   Therefore, the final efficacy analysis will focus only on the primary 
endpoint, as well as PFS, OS and ORR.  The exploratory analysis (time to subsequent 
anticancer therapies) will not be performed.  
4) Safety analyses will be conducted on the all-treated population. 


 
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REFERENCES 
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approvals for myeloma. Leukemia 2008; 22(2):231-239. 
2. Durie BG, Harousseau JL, Miguel JS, et al. International uniform response criteria for 
multiple myeloma. Leukemia 2006; 20(9):1467-1473. 
3. Rajkumar SV, Harousseau JL, Durie B, et al. Consensus recommendations for the uniform 
reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 
1. Blood 2011; 117(18): 4691-4695. 
4. Richardson, PG, Hungria VTM, Yoon S., et al. Panorama 1: A randomized, double-blind, 
phase 3 study of panobinostat or placebo plus bortezomib and dexamethasone in relapsed or 
relapsed and refractory multiple myeloma. J Clin Oncol. 2014;32:5s,(suppl; abstr 8510). 
5. Moreau P, Joshua D, Chng W-J, et al. Impact of prior treatment on patients with relapsed 
multiple myeloma treated with carfilzomib and dexamethasone vs. bortezomib and 
dexamethasone in the phase 3 ENDEAVOR study. Leukemia (2017) 31, 115–22.