A Phase I Study of Ibrutinib (PCI-32765) in Combination With Revlimid/Dexamethasone (Rd) in Relapsed/Refractory Multiple Myeloma
Phase: PHASE1
Conditions: Refractory Multiple Myeloma, Multiple Myeloma in Relapse, Multiple Myeloma
Sponsor: Alliance Foundation Trials, LLC.

Version Date 22-Jan-2024 
CONFIDENTIAL 
Version # 3.0 
1 
ALLIANCE FOUNDATION TRIALS (AFT) 
PROTOCOL NUMBER 
AFT – 15 
A Phase I Study of Ibrutinib (PCI-32765) in Combination with Revlimid/Dexamethasone 
(Rd) in Relapsed/Refractory Multiple Myeloma 
Protocol Version:3.0 
Protocol Version Date: January 22, 2024 
Investigational Product: Ibrutinib (PC-32765) 
IND Sponsor: Alliance Foundation Trials, LLC 
IND#: 140017 
Investigational Product Supplier: Pharmacyclics LLC 
ClinicalTrials.gov Identifier: NCT03702725 
This document contains confidential information of Alliance Foundation Trials, LLC. The information in this document cannot 
be used for any purpose other than the evaluation or conduct of the clinical investigation without the prior written consent of 
Alliance Foundation Trials, LLC. 

Version Date 22-Jan-2024 
CONFIDENTIAL 
Version # 3.0 
4 
 
 
Synopsis and Study Schema 
 
Study Title 
A Phase I Study of Ibrutinib (PCI-32765) in Combination with 
Revlimid/dexamethasone (Rd) in Relapsed/Refractory Multiple 
Myeloma 
Study Number 
AFT-15 
Study Type/Phase 
Phase Ib 
Clinical Indication 
Relapsed/Refractory Multiple Myeloma 
ClinicalTrials.gov 
Identifier 
NCT03702725 
IND Number 
140017 
Number of Study 
Patients 
19-25 (Dose escalation:9-18; Dose expansion: 4-10) 
Estimated 
Duration of Trial 
Approximately 42 to 48 months to enroll 
*Patients are treated until disease progression 
Rationale 
In the last decade, significant progress has been made in the treatment of 
Multiple Myeloma (MM), primarily due to the introduction of 
proteasome inhibitors (PI) and immunomodulatory drugs (IMiDs). 
However, nearly all patients ultimately relapse and require further 
therapy, making the development of new compounds for MM therapy an 
important priority. 
Preclinical studies suggest synergism between lenalidomide and 
ibrutinib in MM. The anti-myeloma effects of lenalidomide have been 
previously described and include caspase-8-dependent apoptosis of 
MM cells, inhibition of angiogenesis, and activation of NK and T 
effector cells. Both ibrutinib and lenalidomide downregulate IRF4, a 
master transcriptional factor that mediates myeloma cell survival, and 
both exert effects on the BM microenvironment with overlapping yet 
distinct targets that influence MM cell growth and survival. The 
combination of lenalidomide and ibrutinib is thus an attractive 
therapeutic strategy not only as a potent anti-MM regimen but also in 
terms of positively impacting bone disease. 

Version Date 22-Jan-2024 
CONFIDENTIAL 
Version # 3.0 
5 
 
 
 
Primary Objective 
1. To determine the maximum tolerated dose (MTD) in phase I 
and recommended dose in extension cohort of ibrutinib in 
combination with lenalidomide and dexamethasone 
2. To examine the safety profile of ibrutinib in combination with 
lenalidomide and dexamethasone 
Secondary 
Objectives 
To determine the following: 
1. Progression-free survival (PFS): Time from registration to 
disease progression or death due to any cause. 
2. Overall survival (OS): Time from registration to death due to 
any cause. 
3. Overall Response Rate: Time from start of treatment to 
objective response 
4. Duration of response: Time from documented response to 
disease progression among those patients whose disease meets 
the IMWG criteria for disease response 
Correlative Science 
Objectives 
To perform select immunologic studies with this combination therapy. 
Study Design 
Part 1: Dose Escalation 
Patients in the dose escalation phase will receive oral treatment with: 
Ibrutinib: Days 1-28 of every 28-day cycle 
Lenalidomide: Days 1-21 of every 28-day cycle 
Dexamethasone: 40 mg for patients <75 at the time of registration 
20 mg for patients ≥75 at registration on Days 1, 8,15 and 22 of every 
Cycle. One cycle is 28 days. 
Starting doses of ibrutinib and lenalidomide will be assigned at the time 
of registration. A minimum of 2 or a maximum of 6 patients will be 
accrued to a given dose level. Doses will not be escalated in any 
individual patient. If none of the first 3 patients treated at a given dose 
level develops a DLT during the first cycle of treatment, enrollment to 
the dose level will be closed and enrollment will reopen at next higher 
dose level. If there are no other higher dose levels to be tested, three 
additional patients will be enrolled at the current dose level to confirm 
MTD. If one of the first 3 patients treated at a given dose level 
develops a DLT during the first cycle of treatment, three additional 
patients will be enrolled onto the current dose level. If, at any time in 
the enrollment of these 3 additional patients, a patient develops a DLT, 
enrollment will be closed to this dose level. Enrollment will be re- 
opened to the next lower dose level if fewer than 6 patients have been 
treated at that dose level. If none of these 3 additional patients develops 
a DLT during the first cycle of treatment, enrollment to this dose level 
will be closed and enrollment will reopen at next higher dose level. If

Version Date 22-Jan-2024 
CONFIDENTIAL 
Version # 3.0 
6 
 
 
 
 
there are no other higher dose levels to be tested, this will be 
considered the MTD. 
Patients will return to the clinic every 28 days for physical exams, 
laboratory assessments and review of side effects. 
Patients who do not have disease progression and have not experienced 
unacceptable toxicities will be eligible to continue protocol treatment at 
their current dose level until disease progression, unacceptable toxicity, 
or refusal. Those patients who have not experienced progression of 
disease but have unacceptable toxicity may be eligible for re-treatment 
at a lower dose. 
Part 2: Dose Expansion Once the MTD has been established or 
determined, 4-10 additional patients will be treated at the MTD of 
lenalidomide and ibrutinib at the same schedule as above. 
Dexamethasone will be given at the same dose as in the dose escalation 
portion of the study. 
Patients who have not had disease progression and have experienced 
acceptable toxicity will be eligible to continue protocol treatment at 
their current dose level until disease progression, unacceptable toxicity, 
or refusal. Those patients who have not progressed and who have 
experienced unacceptable toxicity may be eligible for re-treatment at a 
lower dose. A maximum of 2 reductions are allowed. 
Criteria for discontinuation of protocol therapy include: 
 Tumor progression 
 Request by the patient to withdraw 
 Unacceptable adverse events 
 Treatment delay of >4weeks 
 Intercurrent illness which would, in the judgment of the 
investigator, affect assessments of clinical status to a significant 
degree that require discontinuation of drug 
 Non-protocol chemotherapy, or an experimental drug during the 
trial 
Patients who discontinue treatment for any of the above reasons will go 
to survival follow-up. Once a patient has entered the survival follow-up 
phase of the trial, his/her therapy is at the discretion of the treating 
physician. Patients’ charts will be reviewed for progression and survival 
endpoints during visits with treating physicians. 
Bone marrow aspirate will be collected at pre-treatment and at end of 
cycle 1 for micro-RNA profiling and gene expression for correlative 
studies. 
Peripheral blood will be collected at pre-treatment, after cycles 1, 3, 6 
and 12 for immunome correlative studies. 

Version Date 22-Jan-2024 
CONFIDENTIAL 
Version # 3.0 
7 
 
 
 
Inclusion Criteria 
1. Men and women ≥ 18 years 
2. Eastern Cooperative Oncology Group (ECOG) performance 
status of 0–1. 
3. Symptomatic MM (as defined by revised IMWG criteria) with 
measurable disease, defined here as having at least one of the 
following: 
 Serum monoclonal protein  0.5 g/dL 
 ≥200 mg of monoclonal protein in the urine on 24 hour 
electrophoresis 
 Serum immunoglobulin free light chain: involved FLC 
≥ 10 mg/dL (≥ 100 mg/L) AND abnormal serum 
immunoglobulin kappa to lambda free light chain ratio 
4. At least 1 prior line of therapy with demonstrated disease 
progression following the most recent line of treatment 
(induction followed by maintenance or autologous transplant 
and maintenance, will be considered a line of therapy. Each 
subsequent change of regimen will be considered a line of 
therapy) 
5. Progression of disease within 60 days of completion of last 
therapeutic regimen or the failure to achieve minimal response 
while on last treatment (according to IMWG). 
6. Patients should not have progressed on lenalidomide at a dose 
of more than 10 mg. 
7. No prior treatment with ibrutinib or any other protein kinase 
inhibitory drug or drug targeting the BCR signal transduction 
pathway. 
8. Patients with prior Daratumumab and allogeneic stem cell 
transplant are included. 
9. PT/INR <1.5 x ULN and PTT (aPTT) <1.5 x ULN except if on 
anticoagulation for medical reasons in which case INR should 
be ≤3 
10. Adequate hematologic function independent of transfusion and 
growth factor support for at least 7 days prior to registration, 
with the exception of pegylated G-CSF (pegfilgrastim) and 
darbopoeitin (which require at least 14 days prior to screening 
and enrollment) defined as: 
 Absolute neutrophil count (ANC) 1000/mm3 
independent of growth factor support. 
 Transfusion independent platelet counts 75,000/mm3 
(or 50,000/mm3 if bone marrow involvement is ≥50%). 

Version Date 22-Jan-2024 
CONFIDENTIAL 
Version # 3.0 
8 
 
 
 
 
 Hemoglobin level 8 g/dL, independent of transfusion 
support. 
11. Biochemical values must be within the following limits within 7 
days prior to registration 
 Alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST) 2.5 x upper limit of normal 
(ULN). 
 Total bilirubin 1.5 x ULN (unless bilirubin rise is due 
to Gilbert’s syndrome or of non-hepatic origin). 
 Serum creatinine 2 x ULN or GFR ≥ 30 ml/min based 
on either the estimated Glomerular Filtration Rate 
(Crockcoft-Gault) or measured GFR from 24-hour urine 
sample. Study participants with 30 < GFR < 60 will be 
treated according to manufacturer’s instruction with 
lenalidomide 10mg rather than 25 mg. 
12. Ability to understand and willingness to sign a written informed 
consent from (ICF). 
13. Ability to adhere with the study visit schedule and other 
protocol procedures. 
14. A negative pregnancy test will be required for all women of 
child bearing potential within 7 days prior to study treatment 
start. Breast feeding is not permitted. 
15. Fertility requirements 
 Female patients with child bearing potential must have a 
negative pregnancy test at least 7 days before starting 
treatment drugs. 
 Male subject must use an effective barrier method of 
contraception during the study and for 3 months 
following the last dose if sexually active with a female 
of childbearing potential. 
 Female patients must be either post-menopausal, free 
from menses ≥2 yrs, surgically sterilized, willing to use 
two adequate barrier methods of contraception to 
prevent pregnancy or agree to abstain from sexual 
activity starting from screening and for 90 days 
afterwards. 
 Female patients of child bearing potential must agree to 
comply with the fertility and pregnancy test 
requirements dictated by the Rev-Assist program. 
16. Willingness to provide blood and tissue samples for correlative 
research purposes 

Version Date 22-Jan-2024 
CONFIDENTIAL 
Version # 3.0 
9 
 
 
 
Exclusion Criteria 
1. Prior history of Polyneuropathy, organomegaly, 
endocrinopathy, M-protein, and skin changes (POEMS) 
syndrome, osteosclerotic myeloma, Crow-Fukase syndrome, 
primary amyloidosis or plasma cell leukemia. 
2. Radiotherapy within 21 days of registration. However, if the 
radiation portal was localized to single lesion or fracture site 
and covered by ≤ 5% of the bone marrow reserve 
(by investigator estimate), the subject may be enrolled 
irrespective of the end date of radiotherapy. 
3. Prior chemotherapy: 
 Alkylators (e.g. melphalan, cyclophosphamide) 21 
days prior to registration and/or monoclonal antibody ≤ 
6 weeks prior to first administration of study treatment. 
 Anthracyclines 21 days prior to registration. 
 High dose corticosteroids, immune modulatory drugs 
(thalidomide), or proteasome inhibitors (bortezomib or 
carfilzomib) 14 days prior to registration. 
o If patient is on current lenalidomide treatment, 
they may continue on current dose until starting 
protocol treatment. 
4. No concomitant high dose corticosteroids (concurrent use of 
corticosteroids). EXCEPTION: Patients may be on chronic 
steroids (maximum dose 10 mg/day prednisone equivalent) if 
they are being given for disorders other than myeloma, i.e., 
adrenal insufficiency, rheumatoid arthritis, etc. 
5. Currently active, clinically significant cardiovascular disease 
such as uncontrolled or symptomatic arrhythmias, congestive 
heart failure, or myocardial infarction within 6 months of 
registration, or any Class 3 or 4 cardiac disease as defined by 
the New York Heart Association Functional Classification 
(QTcF> 470 msec). 
6. Unable to swallow capsules or disease significantly affecting 
gastrointestinal function, such as malabsorption syndrome, 
resection of the stomach or small bowel, or complete bowel 
obstruction. 
7. History of prior malignancy, with the exception of the 
following: 
 Malignancy treated with curative intent and with no 
known active disease present for more than 3 years prior 
to registration and felt to be at low risk for recurrence by 
treating physician; 

Version Date 22-Jan-2024 
CONFIDENTIAL 
Version # 3.0 
10
 
 
 
 
 Adequately treated non-melanoma skin cancer or lentigo 
maligna without current evidence of disease; or 
 Adequately treated breast or cervical carcinoma in situ 
without current evidence of disease. 
8. Peripheral neuropathy Grade > 2 on clinical examination within 
14 days prior to registration. 
9. Uncontrolled diabetes mellitus. 
10. Currently active systemic fungal, bacterial, viral, or other 
infection not controlled (defined as exhibiting ongoing 
signs/symptoms related to the infection and without 
improvement, despite appropriate antibiotics or other 
treatment). 
11. Use of antibiotics for treatment of infection within 14 days prior 
to registration. 
12. Recent infection requiring systemic treatment that was 
completed within 14 days of registration. 
13. Known infection with human immunodeficiency virus (HIV) or 
active infection with hepatitis C virus (HCV) or hepatitis B 
virus (HBV) or any uncontrolled active systemic infection. 
Note: Subjects with known history positive for hepatitis B core 
antibody, hepatitis B surface antigen, or hepatitis C antibody 
must have a negative polymerase chain reaction (PCR) result 
within 14 days prior to registration. 
14. History of stroke or intracranial hemorrhage within 6 months 
prior to registration. 
15. Subjects who received a strong cytochrome P450 (CYP3A) 
inhibitor within 7 days prior to the first dose of ibrutinib or 
subjects who require continuous treatment with a strong 
CYP3A inhibitor see (Appendix II) 
16. Currently active, clinically significant hepatic impairment. 
Child-Pugh class B or C according to the Child Pugh 
classification (Appendix III). 
17. Lactating or pregnant. 
18. Major surgery within 4 weeks prior to registration. 
19. Known bleeding disorders (eg, von Willebrand’s disease or 
hemophilia). 
20. Allergies and adverse drug reactions: history of allergy to study 
drug components. 

Version Date 22-Jan-2024 
CONFIDENTIAL 
Version # 3.0 
11
 
 
 
 
21. Vaccinated with live, attenuated vaccines within 4 weeks of 
first dose of study drug. 
22. Any life-threatening illness, medical condition, or organ system 
dysfunction that, in the investigator’s opinion, could 
compromise the subject’s safety or put the study outcomes at 
undue risk. 
23. Unresolved toxicities from prior anti-cancer therapy, defined as 
having not resolved to Common Terminology Criteria for 
Adverse Event (CTCAE, version 5.0), Grade 0 or 1, or to the 
levels dictated in the inclusion/exclusion criteria with the 
exception of alopecia. 

Version Date 22-Jan-2024 
CONFIDENTIAL 
Version # 3.0 
12
 
 
Schema 
 
 
 

Version Date 22-Jan-2024 
CONFIDENTIAL 
Version # 3.0 
13
 
 
Table of Contents 
Protocol Contacts .......................................................................................................................................... 2 
Study Resources ............................................................................................................................................ 3 
Synopsis and Study Schema .......................................................................................................................... 4 
Schema ........................................................................................................................................................ 12 
Table of Contents ........................................................................................................................................ 13 
Table of Tables ............................................................................................................................................ 18 
1. 
Background Information ..................................................................................................................... 19 
1.1. 
Overview of Disease and Patient Population ........................................................................... 19 
1.1.1 
Overview of Disease ........................................................................................................... 19 
1.1.2 
Lenalidomide ....................................................................................................................... 19 
1.1.3 
Study Rationale ................................................................................................................... 22 
1.2. 
Study Design ........................................................................................................................... 22 
1.3. 
Study Design Rationale ........................................................................................................... 24 
1.4. 
Study Agents ........................................................................................................................... 25 
1.4.1 
Ibrutinib ............................................................................................................................... 25 
1.4.2 
Risks .................................................................................................................................... 28 
1.4.3 
Lenalidomide (Revlimid) .................................................................................................... 30 
2. 
Objectives and Endpoints .................................................................................................................... 30 
2.1. 
Primary Objectives .................................................................................................................. 30 
2.2. 
Secondary Objectives .............................................................................................................. 30 
2.3. 
Exploratory Objectives ............................................................................................................ 30 
2.4. 
Endpoints ................................................................................................................................. 31 
2.4.1 
Primary and Secondary........................................................................................................ 31 
2.4.2 
Correlative ........................................................................................................................... 31 
3. 
Patient Selection / Population .............................................................................................................. 31 
3.1. 
Inclusion Criteria ..................................................................................................................... 31 
3.2. 
Exclusion Criteria .................................................................................................................... 33 
3.3. 
Inclusion of Women and Minorities ........................................................................................ 34 
4. 
Site Enrollment Requirements ............................................................................................................. 34 
5. 
Patient Enrollment ............................................................................................................................... 35 
6. 
Treatment Plan .................................................................................................................................... 35 
6.1. 
Treatment Regimen ................................................................................................................. 35 
6.2. 
Pre-Treatment Criteria ............................................................................................................. 36 
6.2.1 
Cycle 1 Day 1 ...................................................................................................................... 36 
6.2.2 
Subsequent Cycles ............................................................................................................... 36 

Version Date 22-Jan-2024 
CONFIDENTIAL 
Version # 3.0 
14
 
 
6.3. 
Agent Administration .............................................................................................................. 37 
6.3.1 
Ibrutinib ............................................................................................................................... 37 
6.3.2 
Lenalidomide ....................................................................................................................... 37 
6.3.3 
Dexamethasone.................................................................................................................... 37 
6.3.4 
Compliance .......................................................................................................................... 37 
6.4. 
Supportive Care and Concomitant Medications ...................................................................... 38 
6.4.1 
Permitted Concomitant Medications ................................................................................... 38 
6.4.2 
Medications to be Used with Caution .................................................................................. 38 
6.4.3 
Prohibited Concomitant Medications .................................................................................. 40 
6.4.4 
Guidelines for Ibrutinib Management with Surgeries or Procedure .................................... 40 
7. 
Dose De-Escalation ............................................................................................................................. 40 
7.1. 
Definition of Dose-Limiting Toxicity (DLT) .......................................................................... 40 
7.2. 
Determination of Maximum Tolerated Dose (MTD) .............................................................. 41 
7.3. 
Enrollment and determination of MTD ................................................................................... 41 
8. 
Dose and Treatment Modifications ..................................................................................................... 42 
8.1. 
Ibrutinib Dose/Delays Modifications ....................................................................................... 42 
8.1.1 
Dose Modification for Adverse Reactions........................................................................... 42 
8.1.2 
Dose Modification for Hepatic Impaired Subjects .............................................................. 44 
8.2. 
Lenalidomide, ibrutinib, and dexamethasone dose delay modifications .................................. 45 
8.2.1 
Ibrutinib Dose Modifications for Use with CYP3A Inhibitors ............................................ 46 
8.3. 
Criteria for Discontinuation of Protocol treatment .................................................................. 47 
9. 
Study Assessments and Procedures ..................................................................................................... 47 
9.1. 
Assessment Types ................................................................................................................... 47 
9.1.1 
Imaging Assessments .......................................................................................................... 47 
9.1.2 
Safety and Tolerability Assessments ................................................................................... 48 
9.1.3 
Electrocardiogram ............................................................................................................... 49 
9.1.4 
Biomarkers/Correlative Studies ........................................................................................... 49 
9.1.5 
Follow-up for Other Malignancies ...................................................................................... 49 
10. 
Adverse Events ................................................................................................................................ 52 
10.1. 
Definitions ............................................................................................................................... 52 
10.1.1 
Adverse Events .................................................................................................................... 52 
10.1.2 
Serious Adverse Events ....................................................................................................... 52 
10.1.3 
Suspected Unexpected Serious Adverse Reaction (SUSAR) .............................................. 52 
10.1.4 
Events of Clinical Interest ................................................................................................... 52 
10.2. 
Expected Adverse Events ........................................................................................................ 52 
10.3. 
Adverse Events of Special Interest (AESIs) ............................................................................ 53 

Version Date 22-Jan-2024 
CONFIDENTIAL 
Version # 3.0 
15
 
 
10.3.1 
Major Hemorrhage .............................................................................................................. 53 
10.4. 
Adverse Event Reporting Exceptions ...................................................................................... 53 
10.5. 
Adverse Event Reporting ........................................................................................................ 54 
10.5.1 
Serious Adverse Event Reporting ........................................................................................ 54 
10.5.2 
Pregnancy Reporting ........................................................................................................... 54 
10.5.3 
Other Malignancies ............................................................................................................. 55 
10.5.4 
Adverse Events of Special Interest (AESI) ......................................................................... 55 
10.5.5 
Expedited Reporting for Serious Adverse Events and AESIs ............................................. 55 
10.5.6 
Special Reporting Situations ............................................................................................... 56 
10.6. 
Assessment of Adverse Events ................................................................................................ 56 
10.6.1 
Assessment of Severity of Adverse Events ......................................................................... 56 
10.6.2 
Assessment of Causality of Adverse Events ....................................................................... 57 
10.7. 
Expedited Safety Reporting to Regulatory Agencies and Pharmacyclics ................................ 58 
11. 
Drug Information ............................................................................................................................. 58 
11.1. 
Ibrutinib ................................................................................................................................... 58 
11.1.1 
Form .................................................................................................................................... 58 
11.1.2 
Storage and Stability ........................................................................................................... 58 
11.1.3 
Handling .............................................................................................................................. 59 
11.1.4 
Availability .......................................................................................................................... 59 
11.1.5 
Preparation ........................................................................................................................... 59 
11.1.6 
Administration ..................................................................................................................... 59 
11.1.7 
Ordering .............................................................................................................................. 59 
11.1.8 
Accountability ..................................................................................................................... 59 
11.1.9 
Destruction and Return ........................................................................................................ 59 
11.2. 
Lenalidomide (REVLIMID®) .................................................................................................. 60 
11.2.1 
Description .......................................................................................................................... 60 
11.2.2 
Form .................................................................................................................................... 60 
11.2.3 
Storage and Stability ........................................................................................................... 60 
11.2.4 
Handling .............................................................................................................................. 60 
11.2.5 
Availability .......................................................................................................................... 60 
11.2.6 
Ordering .............................................................................................................................. 60 
11.2.7 
Accountability ..................................................................................................................... 60 
11.2.8 
Destruction and Return ........................................................................................................ 61 
11.3. 
Dexamethasone........................................................................................................................ 61 
11.3.1 
Description .......................................................................................................................... 61 
11.3.2 
Form .................................................................................................................................... 61 
11.3.3 
Storage and Stability ........................................................................................................... 61 
11.3.4 
Handling .............................................................................................................................. 61 

Version Date 22-Jan-2024 
CONFIDENTIAL 
Version # 3.0 
16
 
 
11.3.5 
Availability .......................................................................................................................... 61 
11.3.6 
Preparation ........................................................................................................................... 61 
11.3.7 
Ordering .............................................................................................................................. 61 
11.3.8 
Accountability ..................................................................................................................... 61 
11.3.9 
Destruction and Return ........................................................................................................ 62 
12. 
Data Collection and Management/ Data and Specimen Submission ............................................... 62 
12.1. 
Data Collection and Submission .............................................................................................. 62 
12.2. 
Specimen Collection and Submission ..................................................................................... 62 
13. 
Correlative Studies .......................................................................................................................... 62 
13.1. 
Peripheral Blood and Bone Marrow Samples ......................................................................... 63 
13.2. 
Immunome .............................................................................................................................. 63 
13.3. 
Immunohistochemistry analysis (IHC) in bone marrow biopsies ............................................ 63 
13.4. 
Measurement of Effect ............................................................................................................ 63 
13.5. 
Methods for Evaluation of Measurable Disease ...................................................................... 64 
13.6. 
Response Criteria .................................................................................................................... 64 
13.6.1 
International Myeloma Working Group Response Criteria ................................................. 64 
13.6.2 
FreeLite™ Disease Response Criteria ................................................................................. 65 
14. 
Statistical Considerations................................................................................................................. 66 
14.1. 
Overview of the Study Design ................................................................................................ 66 
14.2. 
Sample Size, Accrual Time and Study Duration ..................................................................... 67 
14.3. 
Definitions of Endpoints and Analysis Plan ............................................................................ 67 
14.3.1 
Patient Evaluability ............................................................................................................. 67 
14.3.2 
Statement for Primary Endpoint .......................................................................................... 67 
14.3.1 
Statement for Secondary Endpoints ..................................................................................... 67 
14.4. 
Data and Safety Monitoring .................................................................................................... 68 
15. 
General Regulatory Considerations and Administrative Procedures ............................................... 68 
15.1. 
Compliance with Study Enrollment and Results Posting Requirements ................................. 68 
15.2. 
Regulatory and Ethical Compliance ........................................................................................ 68 
15.3. 
Informed Consent .................................................................................................................... 68 
15.4. 
Responsibilities of the Investigator/IRB/IEC/REB .................................................................. 69 
15.5. 
Financial Disclosures ............................................................................................................... 69 
15.6. 
Protocol Deviations ................................................................................................................. 69 
15.7. 
Protocol Amendments ............................................................................................................. 69 
15.8. 
Retention of Records (Study Documentation, record keeping, and retention of records) ........ 70 
15.9. 
Data Confidentiality ................................................................................................................ 70 
15.10. 
Database Management and Quality Control ............................................................................ 71 
15.11. 
Site Monitoring ........................................................................................................................ 71 
15.12. 
Data and Safety Monitoring Board (DSMB) ........................................................................... 71 
15.13. 
Regulatory Reporting .............................................................................................................. 71 

Version Date 22-Jan-2024 
CONFIDENTIAL 
Version # 3.0 
17
 
 
15.14. 
Audits and Inspections ............................................................................................................ 71 
15.15. 
Early Discontinuation of the Study ......................................................................................... 71 
15.16. 
Publication of study protocol and results................................................................................. 72 
References ................................................................................................................................................... 73 
Appendices .................................................................................................................................................. 76 
Appendix I: ECOG Performance Status ...................................................................................................... 77 
Appendix II: Inhibitors and Inducers of CYP3A ......................................................................................... 78 
Appendix III: Child-Pugh Score ................................................................................................................. 80 

Version Date 22-Jan-2024 
CONFIDENTIAL 
Version # 3.0 
18
 
 
Table of Tables 
 
Table 1 
Response Rates in Phase III Trials of Relapse refractory MM ..................................................... 20 
Table 2 
DVT & PE Risks in Phase III Trials of Relapse refractory MM ....................................................... 20 
Table 3 
Dose Level .................................................................................................................................... 23 
Table 4 
Dosing Schedule .......................................................................................................................... 23 
Table 5 
Most frequently reported treatment-emergent adverse events (TEAEs) ................................... 27 
Table 6 
Most frequently reported TEAEs in subjects receiving ibrutinib in combination therapy (N=423) 
. ................................................................................................................................................... 28 
Table 7 
Dose levels for Ibrutinib, Lenalidomide and Dexamethasone ..................................................... 35 
Table 8 
Treatment Plan ............................................................................................................................ 36 
Table 9 
Dose limiting toxicities (DLT) ....................................................................................................... 40 
Table 10 
Hematologic and Non-Hematologic Adverse Events ............................................................... 43 
Table 11 
Ibrutinib Dose Reduction Levels .............................................................................................. 44 
Table 12 
Dose Modification Guidelines for Hepatic Toxicity ................................................................. 44 
Table 13 
Lenalidomide, ibrutinib, and dexamethasone dose delay modifications ................................ 45 
Table 14 
Recommended dose modifications for ibrutinib ..................................................................... 46 
Table 15 
Schedule of Assessment .......................................................................................................... 50 

Version Date 22-Jan-2024 
CONFIDENTIAL 
Version # 3.0 
19
 
 
1. 
Background Information 
 
1.1. Overview of Disease and Patient Population 
 
1.1.1 Overview of Disease 
Multiple myeloma (MM) is the second most common hematological malignancy with 
approximately 22,000 new cases diagnosed each year in the United States. Prior to the 
availability of carfilzomib and pomalidomide, MM patients refractory to both lenalidomide and 
bortezomib had an event free survival of approximately 5 months and an estimated median 
overall survival of 9 months1. The median overall survival (OS) has been extended with the use 
of pomalidomide and carfilzomib to over 15 months2. However, all MM patients will eventually 
become resistant and new mechanisms of action are important to study and develop in order to 
continue to improve the OS of relapsed and refractory (RR) patients. 
1.1.2 Lenalidomide 
Lenalidomide (Revlimid®), a thalidomide analogue, is an immunomodulatory agent with 
antiangiogenic properties. Its mechanism of action remains to be fully characterized. 
Lenalidomide inhibited the secretion of pro-inflammatory cytokines and increased the secretion 
of anti-inflammatory cytokines from peripheral blood mononuclear cells. Of cell lines tested, 
lenalidomide was effective in inhibiting growth of Namalwa cells (a human B cell lymphoma 
cell line with a deletion of one chromosome 5) but was much less effective in inhibiting growth 
of KG-1 cells (human myeloblastic cell line, also with a deletion of one chromosome 5) and 
other cell lines without chromosome 5 deletions. Lenalidomide inhibited the expression of 
cyclooxygenase-2 (COX-2) but not COX-1 in vitro. Lenalidomide is indicated for the treatment 
of patients with transfusion-dependent anemia due to Low- or Intermediate-1-risk 
myelodysplastic syndromes associated with a deletion 5q cytogenetic abnormality with or 
without additional cytogenetic abnormalities. Lenalidomide in combination with dexamethasone 
is indicated for the treatment of newly diagnosed multiple myeloma patients and those who have 
received at least one prior therapy. 
1.1.2.1 Clinical Experience in Relapsed Multiple Myeloma 
A multicenter, open-label, randomized phase 2 study evaluated 2 doses of lenalidomide for 
relapsed, refractory multiple myeloma patients. Seventy patients were randomized to receive 
oral lenalidomide either 30 mg once-daily or 15 mg twice-daily for 21 days of every 28-day 
cycle. Patients with progressive or stable disease after 2 cycles received dexamethasone. 
Analysis showed an increased grade 3/4 myelosuppression in patients receiving 15 mg twice 
daily as compared to those receiving 30mg daily (41% versus 13%, P= .03). Responses were 
evaluated according to European Group for Blood and Marrow Transplantation (EBMT) criteria. 
Overall response rate (complete, partial, or minor) to lenalidomide alone was 25% (24% for once 
daily and 29% for twice-daily lenalidomide). Median overall survival (OS) in the 30-mg once- 
daily and twice-daily groups was 28 and 27 months, respectively. Median progression free 
survival was 7.7 months on once-daily versus 3.9 months on twice-daily lenalidomide (P = 0.2). 
Dexamethasone was added in 68 patients and 29% responded. Time to first occurrence of 
clinically significant grade 3 / 4 myelosuppression was shorter in the twice daily group (1.8 vs 
5.5 months, P = .05). Significant peripheral neuropathy and deep vein thrombosis each occurred 

Version Date 22-Jan-2024 
CONFIDENTIAL 
Version # 3.0 
20
 
 
in only 3%. Lenalidomide was active and well tolerated in relapsed, refractory myeloma, with 
the 30-mg once-daily regimen providing the basis for future studies as monotherapy and with 
dexamethasone3. 
In a safety and efficacy study of single agent lenalidomide in relapsed and refractory multiple 
myeloma patients, lenalidomide 30 mg (days 1-21 of 28-day cycle) was given to 222 patients 
who had relapsed or progressed after 1 or more prior therapies4. Sixty-seven percent of patients 
had received three or more prior therapies, and 45% had received one or more autologous stem 
cell transplant. Eighty and 43% of patients had received thalidomide and bortezomib based 
therapies respectively. The median dose of lenalidomide was 25 mg (5-30mg) and the median 
duration of treatment was 4.2 months (0.06-38). The overall response rate (complete and partial) 
was 26% with 2% complete response4. 
Two phase III trials comparing lenalidomide + dexamethasone to single agent dexamethasone in 
patients with relapsed and/or refractory multiple myeloma were published5, 6. Patients who had 
received 1-3 prior therapies, and progressed on their last therapy were randomized to receive 
lenalidomide 25 mg daily on days 1-21, placebo on days 22-28, plus dexamethasone, 40 mg, 
days 1-4, 9-12, and 17-20 of every 28 day cycle, or placebo daily for 28 days plus 
dexamethasone, 40 mg, days 1-4, 9-12, 17-20, every 28 days. The responses reported are 
summarized in Table 1 while the incidence of DVT and pulmonary embolism are summarized in 
Table 2. Anemia, thrombocytopenia, neutropenia, fatigue, neuropathy, and constipation were 
observed more often in the lenalidomide + dexamethasone group compared to the 
dexamethasone only group; however, these events were generally manageable. 
Table 1 
Response Rates in Phase III Trials of Relapse refractory MM 
 
 
Weber et al (NEJM 2007) 
Dimopoulos et al (NEJM 2007) 
 
Lenalidomide + 
Dexa (n=177)
Dexa 
Alone 
(n=176) 
 
P Value
Lenalidomide + 
Dexa (n=176) 
Dexa Alone 
(n=175) 
 
P Value
Overall Response 
Rate (%) 
108 (61) 
35 (20) 
<0.001
106 (60.2) 
42 (24) 
<0.001
Complete 
Response 
14.1% 
0.6% 
<0.001
15.9% 
3.4% 
<0.001
Median TTP 
(mo.) 
11.1 
4.7 
<0.001
11.3 
4.7 
<0.001
Median OS (mo.)
29.6 
20.2 
<0.001
Not Reached 
20.6 
0.03 
 
 
 
 
Table 2 
DVT & PE Risks in Phase III Trials of Relapse refractory MM 
 
 
Weber et al 
Dimopoulos et al 

Version Date 22-Jan-2024 
CONFIDENTIAL 
Version # 3.0 
21
 
 
 
 
Lenalidomide + 
Dexamethasone
Dexamethasone 
Alone 
Lenalidomide + 
Dexamethasone
Dexamethasone 
Alone 
Deep Vein Thrombosis 
(%) 
11.9 
3.4 
4.0 
3.5 
Pulmonary Embolism (%)
3.4 
0.6 
4.4 
1.2 
The dexamethasone used in the above two studies is considered high dose. A phase III study 
compared lenalidomide plus high-dose dexamethasone (doses and schedule as described above) 
to lenalidomide (dose and regimen as above) plus low-dose dexamethasone (40 mg given on 
days 1, 8, 15, 22 of 28-day cycles) in newly diagnosed multiple myeloma patients. Overall 
survival at 1 year was 96% for the low-dose dexamethasone compared to 87% for the high-dose 
dexamethasone (P=0.0002). As a result, the trial was stopped and patients on the high-dose 
therapy were crossed over to the low-dose therapy7. Subsequently, most therapies involving 
dexamethasone use low-dose. 
1.1.2.2 Ibrutinib and Multiple Myeloma 
Ibrutinib is a Bruton’s tyrosine kinase (Btk) inhibitor. Btk is a member of the Tec family of 
tyrosine kinases, whose activation regulates B-cell development and plays an important role in 
antibody production and has been shown to be a therapeutic target in MM8, 9. Treatment of 
myeloma cells directly with ibrutinib results in a modest reduction in cell viability and induction 
of apoptosis in vitro. In addition, ibrutinib directly inhibits osteoclastic bone resorption, prevents 
release of multiple osteoclast-derived tumor growth factors, prevents adhesion of MM cells to 
bone marrow stromal cells (BMSCs), and inhibits migration of SDF-1-induced MM cells10,11. In 
addition, Ibrutinib has been shown to inhibit BTK-driven NK-kB p65 activity to overcome 
bortezomib-resistance8, 11. Dysregulation of osteoclast activity plays a critical role in MM 
pathogenesis. Btk regulates osteoclast differentiation through RANK signaling, and indeed in 
pre-clinical studies involving MM cells lines, inhibition of Btk decreased OC function. A phase 
II study of Ibrutinib single agent or in combination with dexamethasone in relapsed or 
relapsed/refractory MM showed a clinical benefit across all dose levels but the highest activity of 
25% at the highest dose of 840 mg with or without 40mg dexamethasone without the occurrence 
of new safety signals12. The number of median prior therapies was 4 (range, 2-14), 41% had ≥ 5 
prior therapies and 80% had undergone autologous stem cell transplants. Sixty-two percent of 
patients were refractory to their last line of therapy including 45% to both an immunomodulatory 
agent and a proteasome inhibitor. Overall, 57% experienced a Grade 3 or higher adverse 
event. The most commonly reported non-hematologic toxicities (any grade) were diarrhea 
(51%), fatigue (41%), nausea (35%), dizziness (25%), and muscle spasms (23%). The majority 
were Grade 1 and 2. Hematologic toxicity of any grade was anemia (29%), thrombocytopenia 
(23%), and neutropenia (7%) with 16%, 9% and 4% being Grade 3, respectively. There were no 
clinically meaningful differences among dose levels. At least one dose modification occurred in 
22% of patients, with 6 discontinuing due to an adverse event12. 
1.1.2.3 Ibrutinib and Lenalidomide 
The combination of Ibrutinib and lenalidomide have been studied in patients with relapsed and 
refractory lymphoma and chronic lymphocytic leukemia in a phase 1 and 2 clinical trials. The 

Version Date 22-Jan-2024 
CONFIDENTIAL 
Version # 3.0 
22
 
 
phase 2 study in mantle cell lymphoma, a B-cell malignancy, as in MM was well tolerated with 
the most common grade 3-4 adverse events being neutropenia (38%), infection (22%) and 
cutaneous toxicity. The preclinical study in MM suggest synergism between lenalidomide and 
ibrutinib in MM11. A phase 1 / 2b clinical trial of Ibrutinib and pomalidomide (a third generation 
Imid) is currently ongoing (NCT02548962). The anti-myeloma effects of lenalidomide have 
been previously described and include caspase-8-dependent apoptosis of MM cells, inhibition of 
angiogenesis, and activation of NK and T effector cells. Both ibrutinib and lenalidomide 
downregulate IRF4, a master transcriptional factor that mediates myeloma cell survival, and both 
exert effects on the BM microenvironment with overlapping yet distinct targets that influence 
MM cell growth and survival. The combination of lenalidomide and ibrutinib is thus an 
attractive therapeutic strategy not only as a potent anti-MM regimen but also in terms of 
positively impacting bone disease. 
1.1.3 Study Rationale 
MM patients refractory to both lenalidomide and bortezomib have an event free survival of 
approximately 5 months and an estimated median overall survival of 9 months1. While this has 
improved with pomalidomide and carfilzomib to a median of 15 months, all MM patients will 
eventually become resistant and new mechanisms of action are important to study and develop in 
order to continue to improve the OS of relapsed and refractory (RR) patients. Ibrutinib, a Btk 
inhibitor, has shown efficacy as a single agent and in combination with dexamethasone. Pre- 
clinical studies suggest synergism between Ibrutinib and lenalidomide in MM cell lines. 
We seek to determine the response in relapse/refractory multiple myeloma patients using 
Ibrutinib in combination with lenalidomide and dexamethasone with the primary endpoint of 
determining safety, tolerability and the maximum tolerated dose (MTD), and secondary 
endpoints of progression-free survival, overall survival, duration of response, and 
pharmacokinetic and pharmacodynamics of Ibrutinib in combination with lenalidomide and 
dexamethasone. 
1.2. Study Design 
 
This is a single-arm, open label, phase Ib study of Ibrutinib in combination with lenalidomide 
and dexamethasone in adult (age 18 years and older) patients with relapsed/refractory MM. A 
dose-escalation will be completed with the primary endpoint of determining safety, tolerability 
and maximum tolerated dose (MTDs) in a standard 3+3 design over 3 dose levels of 560, 560 
and 840 mg of Ibrutinib given orally daily, lenalidomide given at 15 mg, 25 mg and 25 mg orally 
daily on days 1-21 of a 28-day cycle and dexamethasone 40 mg given orally weekly (patients 75 
yrs and older will start with Dexamethasone20 mg) (Table 3 and 4). Patients with GFR 30-60 
ml/min will receive lenalidomide 10 mg daily, days 1 – 21 of 28 according to manufacturer’s 
recommendation. A minimum of 6 and a maximum of 18 patients will be recruited in the phase I 
portion. Upon identification of the MTD for the dose level combination of Ibrutinib and 
lenalidomide/dexamethasone, a 10-patient expansion cohort will commence. Secondary 
endpoints of progression-free survival, overall survival, duration of response, and 
pharmacokinetic and pharmacodynamics of Ibrutinib in combination with lenalidomide and 
dexamethasone will be assessed. 
 
Please see Section 7 for dexamethasone dose modification guidelines. 

Version Date 22-Jan-2024 
CONFIDENTIAL 
Version # 3.0 
24
 
 
6 patients have been treated at that dose level. If none of these 3 additional patients develops a 
DLT during the first cycle of treatment, enrollment to this dose level will be closed and 
enrollment will reopen at next higher dose level. If there are no other higher dose levels to be 
tested, this will be considered the MTD. 
For this protocol, the patient must return to their registration institution for evaluation and 
continuation of treatment (at least every 28 ± 3 days) according to the test schedule. Patients who 
have not had disease progression and have experienced acceptable toxicity will be eligible to 
continue protocol retreatment at their current dose level until disease progression, unacceptable 
toxicity, or refusal. Those patients who have not progressed and who have experienced 
unacceptable toxicity may be eligible to continue protocol retreatment at a lower dose. 
Criteria for discontinuation of all protocol therapy include: 
 Tumor progression 
 Request by the patient to withdraw 
 Unacceptable adverse events 
 Treatment delay of >4weeks 
 Intercurrent illness which would, in the judgment of the investigator, affect assessments 
of clinical status to a significant degree of require discontinuation of drug 
 Non-protocol chemotherapy, or an experimental drug during the trial 
Patients who discontinue treatment for any of the above reasons will go to survival follow-up. 
Once a patient has entered the survival follow-up phase of the trial, his/her therapy is at the 
discretion of the treating physician. The sponsor would like to collect that information, if the 
patient agrees. 
Patients who discontinue treatment due to toxicity should be monitored until resolution or 
stabilization of adverse event. 
Expansion cohort 
Once the MTD has been established or determined, 10 additional patients will be treated at the 
MTD. The total number of patients to be enrolled in the study will be 28. 
1.3. Study Design Rationale 
In the last decade, significant progress has been made in the treatment of Multiple Myeloma 
(MM), primarily due to the introduction of proteasome inhibitors (PI) and immunomodulatory 
drugs (IMiDs). However, nearly all patients ultimately relapse and require further therapy, 
making the development of new compounds for MM therapy an important priority. 
Preclinical studies suggest synergism between lenalidomide and ibrutinib in MM. The 
anti-myeloma effects of lenalidomide have been previously described and include caspase-8- 
dependent apoptosis of MM cells, inhibition of angiogenesis, and activation of NK and T 
effector cells. Both ibrutinib and lenalidomide downregulate IRF4, a master transcriptional 
factor that mediates myeloma cell survival, and both exert effects on the BM microenvironment 
with overlapping yet distinct targets that influence MM cell growth and survival. The 
combination of lenalidomide and ibrutinib is thus an attractive therapeutic strategy not only as a 
potent anti-MM regimen, but also in terms of positively impacting bone disease. 
Based on these preliminary results, we propose a phase Ib study to determine the dosing schedule 

Version Date 22-Jan-2024 
CONFIDENTIAL 
Version # 3.0 
25
 
 
of Ibrutinib in combination with lenalidomide and dexamethasone, and to assess the clinical 
efficacy of this combination. 
1.4. Study Agents 
 
1.4.1 Ibrutinib 
Ibrutinib (Imbruvica®) is a first-in-class, potent, orally administered, covalently binding 
inhibitor of Bruton’s tyrosine kinase (BTK) co-developed by Pharmacyclics LLC and Janssen 
Research & Development, LLC for the treatment of B-cell malignancies. 
Ibrutinib has been approved in many regions, including the US and EU, for patients with mantle 
cell lymphoma (MCL) who have received one prior line of therapy and first-line treatment for 
chronic lymphocytic leukemia (CLL), first-line treatment of patients with CLL with a deletion of 
the short arm of chromosome 17 (del17p) or a TP53 mutation, and patients with Waldenström’s 
macroglobulinemia. Ibrutinib is currently under investigation in various indications as a single 
agent and in combinations. 
B cells are lymphocytes with multiple functions in the immune response, including antigen 
presentation, antibody production, and cytokine release. B-cells express cell surface 
immunoglobulins comprising the B-cell receptor (BCR), which is activated by binding to 
antigens. Antigen binding induces receptor aggregation and the clustering and activation of 
multiple tyrosine kinases, which in turn activate further downstream signaling pathways20. 
For the most comprehensive nonclinical and clinical information regarding ibrutinib background, 
safety, efficacy, and in vitro and in vivo preclinical activity and toxicology of ibrutinib, refer to 
the latest version of the ibrutinib Investigator's Brochure. 
1.4.1.1 Summary of Nonclinical Data 
Pharmacology 
Ibrutinib was designed as a selective and covalent inhibitor of the Btk27. 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 expression24. 
For more detailed and comprehensive information regarding nonclinical pharmacology, refer to 
the current ibrutinib Investigator’s Brochure. 
Toxicology 
In safety pharmacology assessments, 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 

Version Date 22-Jan-2024 
CONFIDENTIAL 
Version # 3.0 
26
 
 
(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 20 times the 
exposure (area under the concentration-time curve [AUC]) in patients administered the dose of 
560 mg daily and 420 mg, respectively. Fetal loss and reduced fetal body weights were also seen 
in treated pregnant animals. 
For the most comprehensive information regarding nonclinical safety pharmacology and 
toxicology, please refer to the current IB. 
Carcinogenesis, Mutagenesis, Impairment of Fertility 
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. 
1.4.1.2 Summary of Clinical Data 
For the most comprehensive clinical information regarding ibrutinib, refer to the current version 
of the Investigator's Brochure. 
Pharmacokinetics and Product Metabolism 
Following oral administration of ibrutinib at doses ranging from 420 to 840 mg/day, exposure to 
ibrutinib increased as doses increased 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 in 
the urine. 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 IB. 
Summary of Clinical Safety 
A brief summary of safety data from monotherapy and combination therapy studies is provided 

Version Date 22-Jan-2024 
CONFIDENTIAL 
Version # 3.0 
27
 
 
in below. For the most up to date and most comprehensive safety information regarding 
ibrutinib, please refer to the current version of the IB. Additional safety information may be 
available for approved indications in regional prescribing labels where the study is conducted 
(eg, USPI, SmPC). 
Pooled safety data for 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 IB update in B-cell malignancies are summarized below. 
Table 5 
Most frequently reported treatment-emergent adverse events (TEAEs) 
 
Most frequently reported 
TEAEs >15% 
Most frequently reported 
Grade 3 or 4 TEAEs >3% 
Most frequently reported 
Serious TEAEs >2% 
Diarrhea 
Neutropenia 
Pneumonia 
Fatigue 
Pneumonia 
Atrial fibrillation 
Nausea 
Thrombocytopenia 
Febrile neutropenia 
Cough 
Anemia 
Pyrexia 
Anemia 
Hypertension 
Diarrhea 
 
Pyrexia 
Atrial fibrillation 
 
Neutropenia 
Upper respiratory tract 
infection 
Thrombocytopenia 
Edema peripheral 
 
 
 
For more detailed information refer to the current version of the IB. 
 
Pooled safety data for a total of 423 subjects treated with various therapies in combination with 
ibrutinib from 4 studies conducted in 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). 

Version Date 22-Jan-2024 
CONFIDENTIAL 
Version # 3.0 
28
 
 
Table 6 
Most frequently reported TEAEs in subjects receiving ibrutinib in 
combination therapy (N=423) 
 
Most frequently reported 
TEAEs >20% 
Most frequently reported 
Grade 3 or 4 TEAEs >3% 
Most frequently reported 
Serious TEAEs >2% 
Neutropenia 
Neutropenia 
Pneumonia 
Diarrhea 
Thrombocytopenia 
Febrile neutropenia 
Nausea 
Febrile neutropenia 
Atrial fibrillation 
Thrombocytopenia 
Pneumonia 
Pyrexia 
Fatigue 
Anemia 
Pyrexia 
Neutrophil count decreased 
Hypertension 
Anemia 
Fatigue 
Diarrhea 
Cellulitis 
For more detailed information refer to the current version of the IB. 
1.4.2 Risks 
 
1.4.2.1 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 6.4.2 for guidance 
on concomitant use of anticoagulants, antiplatelet therapy and/or supplements. See Section 6.4.4 
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. 
 
1.4.2.2 Lymphocytosis and Leukostasis 
Leukostasis 
There were isolated cases of leukostasis reported in subjects treated with ibrutinib. A high 
number of circulating lymphocytes (>400,000/µL) may confer increased risk. For subject and 
ibrutinib management guidance, refer to Section 5. 
Lymphocytosis 
Upon initiation of treatment, a reversible increase in lymphocyte counts (ie, ≥50% increase from 
baseline and an absolute count >5000/µL), often associated with reduction of lymphadenopathy, 
has been observed in most subjects with chronic lymphocytic leukemia (CLL)/small lymphocytic 
lymphoma (SLL) treated with ibrutinib. This effect has also been observed in some subjects with 
MCL treated with ibrutinib. This observed lymphocytosis (increase in the number of circulating 

Version Date 22-Jan-2024 
CONFIDENTIAL 
Version # 3.0 
29
 
 
lymphocytes eg, >400,000/µL) is a pharmacodynamic effect and should not be considered 
progressive disease in the absence of other clinical findings. In both disease types, lymphocytosis 
typically occurs during the first few weeks of ibrutinib therapy and typically resolves within a 
median of 8.0 weeks in subjects with MCL and 14 weeks in subjects with CLL/SLL. This 
pharmacodynamic effect was less prominent or not observed in other indications. 
1.4.2.3 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 6.4.1). (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. 
1.4.2.4 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. 
1.4.2.5 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 guidelines (see Section 7). 
1.4.2.6 Non-Melanoma Skin Cancer 
Non-melanoma skin cancers have occurred in patients treated with ibrutinib. Patients should be 
monitored for the appearance of non-melanoma skin cancer. 
1.4.2.7 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 tumor lysis syndrome 
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. 
1.4.2.8 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. Dose modification guidelines for severe or 
prolonged symptoms related to diarrhea can be found in Section 8. 

Version Date 22-Jan-2024 
CONFIDENTIAL 
Version # 3.0 
30
 
 
1.4.2.9 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 erythema, urticaria, and 
angioedema have been reported. 
1.4.2.10 Interstitial Lung Disease (ILD) 
Cases of interstitial lung disease (ILD) have been reported in patients treated with ibrutinib. 
Monitor patients for pulmonary symptoms indicative of ILD. Should symptoms develop follow 
the protocol dose modification guidelines (see Section 8). 
1.4.2.11 Hypertension 
Hypertension has been commonly reported in subjects treated with ibrutinib. Monitor patients for 
new onset of hypertension that is not adequately controlled after starting ibrutinib. Adjust 
existing anti-hypertensive medications and/or initiate anti-hypertensive treatment as appropriate. 
1.4.3 Lenalidomide (Revlimid) 
Lenalidomide is approved for use in MM and its toxicity profile is well known. Please refer to 
the current version of the IB. 
2. 
Objectives and Endpoints 
 
2.1. Primary Objectives 
The primary objectives of this study are: 
1. To determine the maximum tolerated dose (MTD)-recommended phase II doses of 
ibrutinib in combination with lenalidomide and dexamethasone 
2. To examine the safety profile of ibrutinib in combination with lenalidomide and 
dexamethasone 
2.2. Secondary Objectives 
The secondary objectives of this study are: 
1. To determine progression-free survival (PFS) 
2. To determine overall survival (OS) 
3. To determine duration of response 
4. To determine overall response rate (ORR) 
 
2.3. Exploratory Objectives 
The correlative objective of this study is to: 

Version Date 22-Jan-2024 
CONFIDENTIAL 
Version # 3.0 
31
 
 
1.  To perform select immunologic studies with this combination 
 
2.4. Endpoints 
 
2.4.1 Primary and Secondary 
Primary: 
1. Maximum tolerated dose (MTD): The maximum tolerated dose (MTD) is defined as the 
highest dose level among those under consideration where at most 1 of 6 patients 
develops a dose limiting toxicity and 2 or more of the 3-6 patients treated at the next 
higher dose level develop a dose limiting toxicity. 
2. Safety profile: The maximum grade of each type of toxicity will be recorded for each 
patient. For each toxicity reported by dose level, the percentage of patients developing 
any degree of that toxicity as well as the percentage of patients developing a severe 
degree (Grade 3 or higher) due to treatment will be determined. 
Secondary: 
1. Progression free survival (PFS) defined as the time from study entry to the 
documentation of disease progression using IMWG criteria or death due to any cause. 
2. Overall survival (OS) is defined as time from registration to death due to any cause. 
3. Overall Response rate(ORR) 
4. Duration of response, defined as the time from documented response to disease 
progression among those patients whose disease meets the IMWG criteria for disease 
response. 
5. Safety Profile: CTCAE v5.0 will be used to grade and assign attribution to each adverse 
event reported. 
2.4.2 Correlative 
1. Immunologic studies: bone marrow aspirate and peripheral blood samples will be 
collected from patients for immunome studies. See Protocol Section 13 for more 
information. 
3. 
Patient Selection / Population 
19-25 patients (9-18 dose escalation; 4-10 dose expansion) with symptomatic multiple myeloma 
(as defined by IMWG criteria) will be enrolled across multiple investigational sites in the United 
States. Screening labs must be performed within 7 days prior to registration. Complete body CT 
scan if clinically indicated at screening must be performed within 14 days prior to registration. 
3.1. Inclusion Criteria 
1. Men and women ≥ 18 years 
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0–1 (Appendix I). 
3. Symptomatic MM (as defined by revised IMWG criteria) with measurable disease, 
defined here as having at least one of the following: 
 Serum monoclonal protein  0.5 g/dL 
 ≥200 mg of monoclonal protein in the urine on 24 hour electrophoresis 

Version Date 22-Jan-2024 
CONFIDENTIAL 
Version # 3.0 
32
 
 
 Serum immunoglobulin free light chain: involved FLC ≥ 10 mg/dL (≥ 100 mg/L) 
AND abnormal serum immunoglobulin kappa to lambda free light chain ratio. 
4. At least 1 prior therapy with demonstrated disease progression following the most recent 
line of treatment. 
5. Progression of disease within 60 days of completion of last therapeutic regimen or the 
failure to achieve minimal response while on last treatment (according to IMWG). 
 Patients should not have progressed on lenalidomide at a dose of more than 10 
mg. 
6. No prior treatment with ibrutinib or any other protein kinase inhibitory drug or drug 
targeting the BCR signal transduction pathway. 
7. Patients with prior daratumumab and allogeneic stem cell transplant are included. 
8. PT/INR <1.5 x ULN and PTT (aPTT) <1.5 x ULN, except if on anticoagulation for 
medical reasons in which case INR should be ≤ 3 
9. Adequate hematologic function independent of transfusion and growth factor support for 
at least 7 days prior to registration, with the exception of pegylated G-CSF 
(pegfilgrastim) and darbopoeitin which require at least 14 days prior to screen and 
enrollment defined as: 
 Absolute neutrophil count (ANC) 1000/mm3 independent of growth factor 
support. 
 Transfusion independent platelet counts 75,000/mm3 (or 50,000/mm3 if bone 
marrow involvement is ≥50%). 
 Hemoglobin level 8 g/dL, independent of transfusion support. 
10. Biochemical values must be within the following limits within 7 days prior to registration 
 Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 2.5 x 
upper limit of normal (ULN). 
 Total bilirubin 1.5 x ULN (unless bilirubin rise is due to Gilbert’s syndrome or 
of non-hepatic origin). 
 Serum creatinine 2 x ULN or GFR > 30 ml/min based on either the estimated 
Glomerular Filtration Rate (Crockcoft-Gault) or measured GFR from 24-hour 
urine sample. Study participants with GFR 30-50 ml/min will be treated 
according to manufacturer’s instruction with lenalidomide 10mg rather than 25 
mg. 
11. Ability to understand and willingness to sign a written informed consent form (ICF). 
12. Ability to adhere with the study visit schedule and other protocol procedures. 
13. A negative pregnancy test will be required for all women of child bearing potential within 
7 days prior to registration. Breast feeding is not permitted. 
14. Fertility requirements 
 Female patients with child bearing potential must have a negative pregnancy test 
at least 7 days before starting treatment drugs. 
 Male subject must use an effective barrier method of contraception during the 
study and for 3 months following the last dose if sexually active with a female of 
childbearing potential. 

Version Date 22-Jan-2024 
CONFIDENTIAL 
Version # 3.0 
33
 
 
 Female patients must be either post-menopausal, free from menses ≥ 2yrs, 
surgically sterilized, willing to use two adequate barrier methods of contraception 
to prevent pregnancy, or agree to abstain from sexual activity starting from 
screening and for 90 days after lenalidomide treatment 
 Female patients of childbearing potential must agree to comply with the fertility 
and pregnancy test requirements dictated by the Rev-Assist program. 
15. Willingness to provide blood and tissue samples for correlative research purposes 
3.2. Exclusion Criteria 
1. Prior history of: Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin 
changes (POEMS) syndrome, osteosclerotic myeloma, Crow-Fukase syndrome, primary 
amyloidosis or plasma cell leukemia. 
2. Radiotherapy within 21 days of registration. However, if the radiation portal was 
localized to single lesion or fracture site and covered by ≤ 5% of the bone marrow reserve 
(by investigator estimate), the subject may be enrolled irrespective of the end date of 
radiotherapy. 
3. Prior chemotherapy: 
 Alkylators (e.g. melphalan, cyclophosphamide) 21 days prior to registration 
and/or monoclonal antibody ≤ 6 weeks prior to first administration of study 
treatment. 
 Anthracyclines 21 days prior to registration. 
 High dose corticosteroids, immune modulatory drugs (thalidomide), or 
proteasome inhibitors (bortezomib or carfilzomib) 14 days prior to registration. 
 If patient is on current lenalidomide treatment, they may continue on 
current dose until starting protocol treatment. 
4. No concomitant high dose corticosteroids (concurrent use of corticosteroids). 
EXCEPTION: Patients may be on chronic steroids (maximum dose 10 mg/day 
prednisone equivalent) if they are being given for disorders other than myeloma, i.e., 
adrenal insufficiency, rheumatoid arthritis, etc. 
5. Currently active, clinically significant cardiovascular disease such as uncontrolled or 
symptomatic arrhythmias 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 registration or 
baseline QTcF of > 470. 
6. Unable to swallow capsules or disease significantly affecting gastrointestinal function, 
such as malabsorption syndrome, resection of the stomach or small bowel, or complete 
bowel obstruction. 
7. History of prior malignancy, with the exception of the following: 
 Malignancy treated with curative intent and with no known active disease present 
for more than 3 years prior to registration and felt to be at low risk for recurrence 
by treating physician; 
 Adequately treated non-melanoma skin cancer or lentigo maligna without current 
evidence of disease; or 

Version Date 22-Jan-2024 
CONFIDENTIAL 
Version # 3.0 
34
 
 
 Adequately treated breast or cervical carcinoma in situ without current evidence 
of disease. 
8. Peripheral neuropathy Grade > 2 on clinical examination within 14 days prior to 
registration. 
9. Uncontrolled diabetes mellitus. 
10. Currently active systemic fungal, bacterial, viral, or other infection not controlled 
(defined as exhibiting ongoing signs/symptoms related to the infection and without 
improvement, despite appropriate antibiotics or other treatment). 
11. Use of antibiotics for treatment of infection within 14 days prior to registration 
12. Recent infection requiring systemic treatment that was completed within 14 days of 
registration. 
13. Known infection with human immunodeficiency virus (HIV) or active infection with 
hepatitis C virus (HCV) or hepatitis B virus (HBV) or any uncontrolled active systemic 
infection. 
Note: Subjects who are positive for hepatitis B core antibody, hepatitis B surface antigen, 
or hepatitis C antibody must have a negative polymerase chain reaction (PCR) result 
within 14 days prior to registration. 
14. History of stroke or intracranial hemorrhage within 6 months prior to registration. 
15. Patients who received a strong cytochrome P450 (CYP) 3A inhibitor within 7 days prior 
to the first dose of ibrutinib or patient who requires continuous treatment with a strong 
CYP3A inhibitor (Appendix II). 
16. Currently active, clinically significant hepatic impairment (Child-Pugh class B or C) 
according to the Child Pugh classification (Appendix III). 
17. Lactating or pregnant 
18. Major surgery within 4 weeks prior to registration 
19. Known bleeding disorders (e.g. von Willebrand’s disease or hemophilia). 
20. Allergies and adverse drug reactions: history of allergy to study drug components 
21. Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug. 
22. Any life-threatening illness, medical condition, or organ systemic dysfunction that, in the 
investigator’s opinion, could compromise the subject’s safety or put the study outcomes 
at undue risk. 
23. Unresolved toxicities from prior anti-cancer therapy, defined as not having resolved to 
CTCAE Version 5.0, Grade 0 or 1, with the exception of alopecia. 
3.3. Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for this trial. 
4. 
Site Enrollment Requirements 
Site must submit all required essential documents including: 
 IRB/Regulatory Approval of protocol, informed consent document and study participant 
materials obtained in one of two ways: 
o Option 1: use the Alliance Foundation Trials (AFT) Central IRB as the study 
site’s IRB of record for this study [AFT will be using Quorum as the CIRB 
vendor for this study] –OR- 

Version Date 22-Jan-2024 
CONFIDENTIAL 
Version # 3.0 
37
 
 
6.3. Agent Administration 
 
6.3.1 Ibrutinib 
Ibrutinib is administered orally once daily. The capsules are to be taken around the same time 
each day with 8 ounces (approximately 240 mL) of water. 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. 
If a dose is not taken at the scheduled time, it can be taken as soon as possible on the same day 
with a return to the normal schedule the following day. The patient should not take extra 
capsules to make up the missed dose. 
The first dose of ibrutinib will be delivered in the clinic on Day 1, after which subsequent dosing 
is typically on an outpatient basis. Ibrutinib will be dispensed to subjects in bottles at each visit. 
Study drug may not be shipped to the subject without approval from PCYC and may not be 
dispensed to anyone other than the subject. Unused ibrutinib dispensed during previous visits 
must be returned to the site and drug accountability records updated at each visit. Returned 
capsules must not be redispensed to anyone. 
6.3.1.1 Overdose 
There is no specific experience in the management of ibrutinib overdose in patients. No 
maximum tolerated dose (MTD) was 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 11for further information regarding AE reporting. 
6.3.2 Lenalidomide 
Lenalidomide is a commercially available agent that is FDA approved for this indication. 
Administration of lenalidomide may be per package insert, institutional standard, or investigator 
discretion. 
6.3.3 Dexamethasone 
Dexamethasone is a commercially available agent that is FDA approved for this indication. 
Administration of dexamethasone may be per package insert, institutional standard, or 
investigator discretion. 
6.3.4 Compliance 
Patients should be instructed to record daily administration of the study drugs in a drug or 
medication diary. 

Version Date 22-Jan-2024 
CONFIDENTIAL 
Version # 3.0 
38
 
 
6.4. Supportive Care and Concomitant Medications 
 
6.4.1 Permitted Concomitant Medications 
 Anti-diarrheal medications: Diarrhea can be managed conservatively with loperamide. 
The recommended dose of loperamide is 4 mg at first onset, followed by 2 mg every 2-4 
hours until diarrhea free (maximum 16 mg/day). 
o In the event of grade 3 or 4 diarrhea, the following supportive measures are 
allowed: hydration, octreotide, and antidiarrheals. 
o If diarrhea is severe (requiring intravenous rehydration) and/or associated fever or 
severe neutropenia (grade 3 or 4), broad-spectrum antibiotics must be prescribed. 
Patients with severe diarrhea or any diarrhea associated with severe nausea or 
vomiting should be hospitalized for intravenous hydration and correction of 
electrolyte imbalances. 
 Transfusions of blood products may be given in accordance with institutional policy. 
 DVT prophylaxis: patients will be required to be on some form of anticoagulation with at 
least aspirin 81 mg daily while on lenalidomide. 
 Low dose oral corticosteroid of short courses (14 days) of treatment for non-cancer 
related medical reasons (e.g. joint inflammation, asthma exacerbation, rash, antiemetic 
use and infusion reactions) at doses that do not exceed 10 mg per day of prednisone or 
equivalent are permitted. 
 Usage of antimicrobial prophylaxis in accordance with standard practice (eg, ASCO 
guidelines [Flower 2013]) is permitted and should be considered in subjects who are at 
increased risk for opportunistic infections. 
 Corticosteroid for treatment of autoimmune cytopenias for <14 days at doses that do not 
exceed 100 mg per day of prednisone or equivalent are permitted. 
 Localized palliative radiation therapy may be given for pain control. This will however 
need to be approved by study chairs. In addition, if there is any other situation in which 
radiation is required in the course of study therapy for an event that does not constitute 
disease progression, radiation may be administered as long as lenalidomide and ibrutinib 
are restarted immediately following radiation therapy. 
 Neutrophil growth factors: 
o The use of filgrastim and pegfilgrastim or red blood cell growth factors 
(erythropoietin) is permitted per institutional policy and in accordance with the 
ASCO guidelines (Smith 2006). Neutrophil growth factors are not allowed during 
cycle 1 in the course of DLT assessment. 
6.4.2 Medications to be Used with Caution 
 
6.4.2.1 CYP3A – Inhibitors/Inducers 
Ibrutinib is metabolized primarily by CYP3A4. Concomitant use of ibrutinib and drugs that 
strongly or moderately inhibit CYP3A can increase ibrutinib exposure and therefore strong 

Version Date 22-Jan-2024 
CONFIDENTIAL 
Version # 3.0 
39
 
 
CYP3A inhibitors should be avoided. 
 If a strong CYP3A inhibitor (eg, ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, 
clarithromycin, telithromycin, itraconazole, nefazadone, cobicistat and posaconazole) 
must be used, reduce ibrutinib dose to 140 mg for the duration of the inhibitor use or 
withhold ibrutinib treatment temporarily (for 7 days or less). Subjects should be 
monitored for signs of ibrutinib toxicity. 
 If a moderate CYP3A inhibitor (eg, voriconazole, erythromycin, amprenavir, aprepitant, 
atazanavir, ciprofloxacin, crizotinib, diltiazem, fluconazole, fosamprenavir, imatinib, 
verapamil, amiodarone, and dronedarone) is indicated, reduce ibrutinib to 140 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 6.3.1). 
 No dose adjustment is required in combination with mild inhibitors. 
 Avoid concomitant use of 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 II. A comprehensive 
list of inhibitors, inducers and substrates may be found at 
http://medicine.iupui.edu/clinpharm/ddis/main-table/. 
This website is continually revised and should be checked frequently for updates. 
For the most comprehensive effect of CYP3A inhibitors or inducers of ibrutinib exposure, please 
refer to the current version of the IB. 
6.4.2.2 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. 
6.4.2.3 Antiplatelet Agents and Anticoagulants 
Use ibrutinib with caution in subjects requiring other 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. Supplements such as fish oil and vitamin E 
preparations should be avoided during treatment with ibrutinib. Bleeding events of any grade, 
including bruising and petechiae, occurred in subjects 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 on the type of surgery and the risk of bleeding. 
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 

Version Date 22-Jan-2024 
CONFIDENTIAL 
Version # 3.0 
40
 
 
continuing ibrutinib treatment. 
6.4.3 Prohibited Concomitant Medications 
Any non-study protocol related chemotherapy, anticancer immunotherapy, experimental therapy 
are prohibited while the subject is receiving protocol treatment. Radiation given for palliation of 
pain is allowed and is not considered protocol therapy violation. However, approval should be 
given by the chairpersons of the study. 
Erythropoietic growth factors (eg, erythropoietin and darbepoetin) and neutrophil growth factors 
(eg, filgrastim and peg-filgrastim) are also prohibited during initial treatment, DLT assessment 
period. 
Warfarin or vitamin K antagonists should not be administered concomitantly with ibrutinib. 
6.4.4 Guidelines for Ibrutinib Management with Surgeries or Procedure 
Ibrutinib may increase 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. 
6.4.4.1 Minor Surgical Procedures 
For minor procedures (such as a central line placement, skin or 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 for these procedures. 
6.4.4.2 Major Surgical 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 (except for emergency procedures) 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. 
7. 
Dose De-Escalation 
 
7.1. Definition of Dose-Limiting Toxicity (DLT) 
 
Attributions should be made as possibly, probably, or definite. 
Table 9 
Dose limiting toxicities (DLT) 
 
Toxicity 
DLT Definition 
Hematologic 
Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with 
bleeding or requirement for platelet transfusion. 

Version Date 22-Jan-2024 
CONFIDENTIAL 
Version # 3.0 
41
 
 
 
 
Grade 4 neutropenia lasting more than 5 days. 
Other nonhematologic* 
 grade 3 as per NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0* 
 
Grade 4 febrile neutropenia 
 
 grade 3 hyperglycemia due to dexamethasone if it cannot be 
controlled with appropriate therapy 
 
Treatment delays ≥ 21 days for any non-hematologic or 
hematological toxicity 
 
Treatment related death 
 
Grade ≥ 3 thrombotic/embolic events including DVT 
 
Grade 4 nausea, vomiting and diarrhea 
*except grade 3 nausea, vomiting, diarrhea that does not require tube feeding, total parenteral 
nutrition or prolonged hospitalization, diarrhea responsive to medical treatment, nausea or 
vomiting controlled with antiemetics, or transient electrolyte abnormalities that resolve < grade 1 
within 48 hours 
7.2. Determination of Maximum Tolerated Dose (MTD) 
The maximum tolerated dose is defined as the highest dose level among those tested where at 
most one out of 6 patients develops a DLT prior to the start of their second cycle of treatment 
and the next highest dose level is such that 2 out of a maximum of 6 patients treated at this dose 
level developed a DLT prior to the start of their second cycle of treatment. 
7.3. Enrollment and determination of MTD 
A minimum of 2 or a maximum of 6 patients will be accrued to a given dose level. Enrollment 
will begin with 3 patients accrued to dose level 1. 
Dose de/escalation scheme for Dose 1: 
- If none of the first 3 patients treated at dose level 1develops a DLT during the first 
cycle of treatment, then the next cohort of 3 patients will be enrolled at dose level 2. 
- If one of the first 3 patients treated at dose level 1develops a DLT during the first 
cycle of treatment, then an additional cohort of 3 patients will be enrolled at the 
current dose level. 
- If at most 1 of the 6 patients enrolled at dose level 1 develops a DLT during the first 
cycle of treatment, the next cohort of 3 patients will be treated at dose level 2. 
- If 2 or more of the 6 patients enrolled at level 1 develops a DLT during the first cycle 
of treatment, enrollment will be halted, and the study team will discuss whether to 

Version Date 22-Jan-2024 
CONFIDENTIAL 
Version # 3.0 
42
 
 
submit an amendment to reopen enrollment to a lower dose level. 
As of October 7, 2021, 3 patients have been enrolled onto dose level 2. 
 
Dose de/escalation scheme for Dose 2: 
- If none of the first 3 patients treated at dose level 2 develops a DLT during the first 
cycle of treatment, then the next cohort of 3 patients will be enrolled onto dose level 
3. 
- If one of the 3 patients treated at dose level 2 develops a DLT during the first cycle of 
treatment, then the next cohort of 3 patients will be enrolled at dose level 2. 
- If 2 or more of the 6 patients treated at dose level 2 develops a DLT then 
an additional 10 patients will be enrolled onto dose level 1 before 
completing enrollment. 
- If 2 or more of 3 patients treated at dose level 2 develops a DLT during the first cycle 
of treatment, an additional 10 patients will be enrolled onto dose level 1 to further 
assess safety before completing enrollment. 
Dose de/escalation scheme for Dose 3 (if applicable): 
- If at most 1 of 6 patients treated at dose level 2 develops a DLT during the first cycle 
of treatment and 1 or fewer of the 6 patients treated at dose level 3 develops a DLT in 
the first cycle of treatment, then an additional 4 patients will be treated on dose level 
3 before completing enrollment. 
- If at most 1 of 6 patients treated at dose level 2 develops a DLT during the first cycle 
of treatment and 2 or more of the 3-6 patients treated at dose level 3 develops a DLT 
during the first cycle of treatment, then an additional 7 patients will be enrolled onto 
dose level 2 before completing enrollment. 
- If at most 1 of 6 patients treated at dose level 3 develops a DLT during the first cycle 
of treatment then an additional 4 patients will be enrolled onto dose level 3 before 
completing enrollment. 
- If 2 or more of the 3-6 patients treated at dose level 3 develops a DLT during the first 
cycle of treatment then an additional 7 patients will be enrolled onto dose level 2 
before completing enrollment. 
8. 
Dose and Treatment Modifications 
 
8.1. Ibrutinib Dose/Delays Modifications 
 
8.1.1 Dose Modification for Adverse Reactions 
The dose of ibrutinib must be modified according to the dose modification guidelines in the 
tables below if any of the following toxicities occur: 
 Grade 4 neutropenia (ANC <500/ µL) for more than 7 days. See Section 5.4 for 
instructions regarding the use of growth factor support. 
 Grade 3 thrombocytopenia (platelets <50,000/ µL) in the presence of clinically 

Version Date 22-Jan-2024 
CONFIDENTIAL 
Version # 3.0 
43
 
 
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. 
For grade 3 and above cardiac arrhythmias, ibrutinib should be held. For grade 2 and above heart 
failure, ibrutinib should be held. If clinically indicated, the use of anticoagulants or antiplatelet 
agents may be considered for the thromboprophylaxis of atrial fibrillation. 
If the dose of ibrutinib is reduced, at the investigator’s discretion, the dose of ibrutinib may be 
re-escalated after 2 cycles of a dose reduction in the absence of a recurrence of the toxicity that 
led to the reduction. Dose changes must be recorded in the dose administration eCRF. 
Dose delays and modifications will be made as indicated in the following table(s). The 
descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0 will be utilized for dose delays and dose modifications. A 
copy of the CTCAE version 5.0 can be downloaded from the CTEP website 
 
Table 10 
Hematologic and Non-Hematologic Adverse Events 
 
Occurrence Action to be Taken 
First 
Hold Ibrutinib for Grade ≥3 neutropenia with infection/fever, or any Grade 4 
hematological toxicities. Once the symptoms of the toxicity have resolved to 
Grade 1 or baseline, ibrutinib may be reinitiated. If these toxicities persist or 
recur following two dose reductions, ibrutinib will be discontinued 
Non-Hematologic Adverse Events 
Occurrence Action to be Taken 
 
Hold ibrutinib for Grade 2 cardiac failure. Hold Ibrutinib for any Grade 3 or 
greater non-hematological toxicities. Once the symptoms of the toxicity have 
resolved to Grade 1 or baseline, ibrutinib may be reinitiated. If these toxicities 
persist or recur following two dose reductions, ibrutinib will be discontinued 

Version Date 22-Jan-2024 
CONFIDENTIAL 
Version # 3.0 
44
 
 
Table 11 
Ibrutinib Dose Reduction Levels 
 
Starting Dose Level
840 mg
560 mg
420 mg
Dose Reduction Level 1
560 mg
420 mg
280 mg
Dose Reduction Level 2
420 mg
280 mg
140 mg
Dose Reduction Level 3
280 mg
140 mg
Discontinue
Dose Reduction Level 4
140 mg
Discontinue
N/A
8.1.1.1 Leukocytosis/Leukostasis (Optional for ibrutinib Monotherapy study) 
A high number of circulating white blood cells (> 400,000/µL) may confer increased risk of 
leukostasis; these subjects should be closely monitored. Administer supportive care such as 
hydration and/or leukophoresis as indicated. Ibrutinib may be temporarily held, and medical 
monitor should be contacted. 
8.1.2 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. 
 
For subjects with existing chronic mild hepatic impairment (Child-Pugh class A) at 
enrollment, the starting dose has to be adjusted to a level of 280 mg daily. 
 
For subjects who develop mild hepatic impairment while on study (Child-Pugh class A), 
the recommended dose reduction for ibrutinib/placebo is to a level of 280 mg daily. 
 
For subjects who develop moderate to severe hepatic impairment while on study (Child- 
Pugh class B and C) 
 
Study drug will be held until resolved to mild impairment (Child-Pugh class A) 
Subjects who develop acute hepatic toxicity with liver enzymes Grade 3 or higher while on study 
should be managed per standard dose modification guidelines. 
Table 12 
Dose Modification Guidelines for Hepatic Toxicity 
 
Measure 
1 point 
2 points 
3 points 
Total bilirubin, μmol/L (mg/dL
<34 (<2) 
34-50 (2-3) 
>50 (>3) 
Serum albumin, g/L (g/dL) 
>35 (>3.5) 
28-35 (2.8-3.5) 
<28 (<2.8) 
PT INR 
<1.7 
1.71-2.30 
>2.30 
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 

Version Date 22-Jan-2024 
CONFIDENTIAL 
Version # 3.0 
45
 
 
 
10-15 
C 
Source: 
1. 
Child CG, Turcotte JG. “Surgery and portal hypertension”. In Child CG. The liver and portal hypertension. 
Philadelphia:Saunders. 1964. pp. 50-64. 
2. 
Pugh RN, Murray-Lyon IM, Dawson L, Pietroni MC, Williams R . “Transection of te oesophagus for bleeding 
oesophageal varices”. The British journal of surgery, 1973;60: 646-9. 
 
8.2. Lenalidomide, ibrutinib, and dexamethasone dose delay modifications 
If treatment is held for more than 28 days, then all study treatment will be discontinued 
 
Table 13 
Lenalidomide, ibrutinib, and dexamethasone dose delay modifications 
 
Neutropenia 
Grade 3 or greater on day 1 of cycle: hold lenalidomide and monitor 
CBC weekly; if resolves to ≤ grade 2 within 4 weeks, resume 
lenalidomide with 5mg dose reduction. During treatment, G-CSF or 
GM-CSF may be used after completion of cycle 1 for neutropenia at 
the discretion of as needed by the treating physician. 
Febrile Neutropenia 
Hold lenalidomide for the remainder of the cycle. Following 
completion of cycle 1, consider G-CSF administration until there is 
adequate count recovery ANC≥1000/µL + absence of fever.  If 
neutropenia resolves ≤ grade 2, resume with lenalidomide at 5 mg 
dose reduction for subsequent cycles 
Thrombocytopenia 
If grade 3 or greater, hold lenalidomide the remainder of the cycle 
and until platelets ≥ 50,000/µL. Then resume lenalidomide at 5 mg 
dose reduction for subsequent cycles Platelet transfusion may be 
given following completion of cycle 1. Platelet transfusion for severe 
thrombocytopenia may be administered in cycle 1 at investigator 
discretion following discussion with Principal Investigators. 
Anemia 
For grade 3 or greater, hold lenalidomide for the remainder of the 
cycle and until hemoglobin recovers to ≤ grade 2. Red cell 
transfusion may be given. 
Fatigue (asthenia, malaise)
For intolerable grade 2 or grade 3-4, hold protocol therapy thought 
to be probable or definitely related to the reaction until resolves to ≤ 
grade 1, then resume protocol therapy with dose reduction of 
implicated  protocol  therapy  by  one  dose  level  (5  mg  for 
lenalidomide, 1 dose level below for Ibrutinib and/or 50% for 
dexamethasone).
Rash 
If grade 3 hold lenalidomide and ibrutinib until resolves to ≤ grade 
2, then resume protocol therapy. Antihistamine (Benadryl, Claritin, 
zyrtec) may be given. If grade > 3 rash recurs, hold therapy until rash 
resolves to < grade 2, resume with one level dose reduction of 
agent(s) believed to be responsible for rash. For grade 4 rash, 
exfoliative or bullous rash, Stevens-Johnson Syndrome, toxic 
epidermal necrolysis, drug reaction with eosinophilia and systemic 
symptoms (DRESS), permanently discontinue lenalidomide
Renal insufficiency
For patients with calculated or measured GFR <30ml/min, 
lenalidomide should be omit until creatinine returns to baseline 
Hepatic Toxicity
If Grade ≥ 2, hold lenalidomide. After return to baseline, restart at 1 
dose level below.

Version Date 22-Jan-2024 
CONFIDENTIAL 
Version # 3.0 
46
 
 
 
Venous Thromboembolism 
All protocol treatment should be held until the patient is adequately 
anti-coagulated. Patients with recurrent thrombosis despite adequate 
anti-coagulation should be removed from protocol therapy. 
Suspected Pregnancy 
Protocol therapy should be held until pregnancy is ruled out. 
Discontinue all protocol therapy if pregnancy is positive 
Dyspepsia, gastric or 
duodenal ulcer, gastritis 
Grade 1-2 (requiring medical 
management) 
Treat with H2 blockers, sucralfate, or omeprazole. If symptoms 
persist despite above measures, decrease dexamethasone dose by 
50% 
Acute pancreatitis 
Hold all study therapy until resolution. Do not resume 
dexamethasone. Consider one level dose reduction of either 
lenalidomide and/or ibrutinib. 
Edema > Grade 3 (limiting 
function and unresponsive to 
therapy or anasarca) 
Diuretics as needed and decrease dexamethasone dose by 50%; if 
edema persists despite above measures, decrease dose another dose 
level. Discontinue dexamethasone and do not resume if symptoms 
persist 
despite 
second 
reduction. 
Permanently 
discontinue 
lenalidomide for any episode of Angioedema 
Confusion or mood alteration 
> Grade 2 (interfering with 
function ± interfering with 
activities of daily living) 
Hold all study therapy until symptoms resolve. Restart with 50% 
reduction of dexamethasone. If symptoms persist despite above 
measures, permanently discontinue dexamethasone. Consider one 
level dose reduction of lenalidomide and/or ibrutinib if either agent 
is felt to be contributing.
Muscle weakness > Grade 2 
(symptomatic and 
interfering with function 
±interfering with activities of 
daily living) 
Hold all study therapy. Restart with 50% dose reduction of 
dexamethasone dose. If weakness persists despite above measures 
decrease dose by another 50%. Discontinue dexamethasone and do 
not resume if symptoms persist. Consider one level dose reduction 
of lenalidomide and/or ibrutinib if either agent is felt to contributing. 
Hyperglycemia > Grade 3 or 
higher 
Hold dexamethasone. Treat with insulin or oral hypoglycemics as 
needed. If uncontrolled despite above measures, decrease dose by 
50%. 
 
 
8.2.1 Ibrutinib Dose Modifications for Use with CYP3A Inhibitors 
The coadministration of ibrutinib with a strong or moderate CYP3A inhibitor may increase ibrutinib 
plasma concentrations. Increased ibrutinib concentrations may increase the risk of drug-related 
toxicity. Dose modifications of ibrutinib are recommended when used concomitantly with 
posaconazole, voriconazole and moderate CYP3A inhibitors. 
 
Table 14 
Recommended dose modifications for ibrutinib 
 
 
Patient Population
Coadministered Drug
Recommended Ibrutinib Dose
B-Cell Malignancies 
• Moderate CYP3A inhibitors 
280 mg once daily 
 
Interrupt dose as recommended 
(see label) 

Version Date 22-Jan-2024 
CONFIDENTIAL 
Version # 3.0 
47
 
 
• Voriconazole 200 mg twice 
daily 
• Posaconazole suspension 
100 mg once daily, 100 mg 
twice daily, or 200 mg twice 
daily
140 mg once daily 
 
Interrupt dose as recommended 
(see label) 
 
B-Cell Malignancies 
• Posaconazole suspension 200 
mg three times daily or 400 mg 
twice daily 
• Posaconazole IV injection 300 
mg once daily 
• Posaconazole delayed-
release tablets 300 mg once 
daily
70 mg once daily 
 
Interrupt dose as recommended 
(see label) 
 
• Other strong CYP3A 
inhibitors 
Avoid concomitant use. 
If these inhibitors will be used 
short-term (such as anti- 
infectives for seven days or less), 
interrupt ibrutinib 
 
8.3. Criteria for Discontinuation of Protocol treatment 
Patients are continued on treatment until any of the criteria for discontinuation of protocol 
therapy is met, which includes: 
 Tumor progression 
 Request by the patient to withdraw 
 Unacceptable adverse events 
 Treatment delay of >4weeks 
 Intercurrent illness which would, in the judgment of the investigator, affect assessments 
of clinical status to a significant degree of require discontinuation of drug 
Administration of non-protocol anti-tumor drug during the trial. Patients who discontinue 
treatment for any of the above reasons will go to survival follow-up where late toxicities and 
clinical outcome information will be collected every 6 months for a maximum of 2 years post 
registration. Once a patient has entered the survival follow-up phase of the trial, his/her therapy 
is at the discretion of the treating physician. 
9. 
Study Assessments and Procedures 
 
9.1. Assessment Types 
 
9.1.1 Imaging Assessments 
A CT/MRI scan will be collected if clinically indicated for all participants at screening (within 
14 days prior to registration). A repeat scan will be collected if clinically indicated at completion 
of cycle 6 for patients with extramedullary disease indicated on the baseline scan. 

Version Date 22-Jan-2024 
CONFIDENTIAL 
Version # 3.0 
48
 
 
9.1.1.1 Central Imaging Review 
Scans should be submitted to Imaging Core Lab (ICL) at Ohio State University for central 
review within 3 days of acquisition. 
The complete CT scans will be submitted to the Imaging Core Laboratory in digital DICOM 
format; BMP files, JPG files, or hard copies (films) are not acceptable. 
The entire imaging data in DICOM format must be submitted to the ICL within no more than 30 
business days once the image acquisition is completed at site. 
De-identify the patient data using institutional procedures to remove patient name and medical 
record number while preserving the patient ID number and protocol number of the AFT trial. 
The de-identified digital images may be burned to a CD or transferred to a PC based system for 
further electronic data transfer purposes. 
Data can be electronically transferred to the Imaging Core Lab by 1) Web Transfer; 2) FTP 
transfer: 
1. Web Transfer: 
Any PCs with internet access and web browser (e.g., Internet Explorer, Mozilla Firefox) can be 
used to transfer DICOM images and other required files to the ICL through website 
upload.imagingcorelab.com. The standard Web Transfer information will be provided separately 
through the specific trial e-mail, per the request by participating sites before their first data 
submission. 
2. FTP Transfer: 
Any FTP software can be used to initiate access to the secure FTP Server of the ICL. The 
standard FTP access information will be provided separately through the specific trial e-mail, per 
the request by participating sites before their first data submission. 
Send an e-mail notification to inform the Imaging Core Lab at the specific trial email of the data 
submission once the data transfer is completed. 
3. Shipment/Mail (not preferred but accepted): 
If the above electronic data transfers cannot be achieved, the de-identified images in DICOM 
format can be burned to a CD, labeled with info of patient ID, study date, baseline/follow-ups on 
the CD cover, and mailed to the ICL at: 
 
 
 
 
 
 
 
Phone: 
 
Fax: 
 
Any questions or problems about the data transfer to the Imaging Core Lab, email the ICL 
at the specific trial email 
, or call the ICL IT group at 
 
 or 
 for help. 
9.1.2 Safety and Tolerability Assessments 

Version Date 22-Jan-2024 
CONFIDENTIAL 
Version # 3.0 
49
 
 
Hematology and chemistry assessments (WBC, ANC, Hgb, PLT, SGOT AST, total bilirubin, 
alkaline phosphatase, creatinine, potassium, sodium albumin) and LDH/Uric acid levels will be 
reviewed at screening and monitored throughout the study. Patients will visit the clinic monthly 
for laboratory assessments, physical examination, concomitant medication review, and adverse 
event assessment. Refer to the study table assessment table in Section 9 for details on study 
assessments and procedures performed for this trial. 
9.1.3 Electrocardiogram 
ECG will be performed at screening and at end of study treatment. As there are rare events of 
arrhythmia/afibrillation associated with ibrutinib, ECGs may also be performed during the course 
of the study as deemed needed by the investigator. 
9.1.4 Biomarkers/Correlative Studies 
Bone marrow aspirates will be collected at pre-treatment and end of cycle 1 MicroRNA- 
profiling. 
Peripheral blood will be collected at pretreatment and after cycles 1, 3, and 6 for immunome 
studies. Refer to Section 13 for detailed correlative studies information. 
9.1.5 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. 

Version Date 07-OCT-2021 
CONFIDENTIAL 
Version # 2.0
50
 
 
Table 15 
Schedule of Assessment 
 
 
 
Treatment Day → 
Assessments and Procedures ↓ 
≤ 14 days prior 
to registration 
Day 1 
(all 
cycles) 
Day 15 
± 2 days (all 
cycles) 
End of 
Cycle 
1 
End of 
Cycle 
3 
End of 
Cycle 6 
At end of treatment 
or treatment 
discontinuation 
History and exam, weighta 
X 
X 
X 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
ECOG Performance Status 
X 
X 
X 
 
 
 
X 
Adverse event assessment 
X 
X 
X 
 
 
 
X 
Concomitant Medications 
X 
 
 
 
 
 
X 
Hematology group: WBC, ANC, ALC, Hgb, and 
PLTb 
X 
X 
X 
 
 
 
X 
Chemistry group SGOT AST, total bili, Alk 
Phos, Creatinine, potassium, calcium, 
magnesium, phosphorus, sodium, albumin), 
blood glucoseb 
 
X 
 
X 
 
X 
 
 
 
 
X 
TSH, Free T4cc 
X 
 
 
 
 
 
 
LDH, Uric Acidb 
X 
X 
X 
 
 
 
X 
Serum pregnancy testd 
X 
 
 
 
 
 
 
Complete body CT 
X 
Xe 
 
 
 
Xe 
Xe 
Bone Marrow Biopsyf 
X 
 
 
X 
 
 
 
Mandatory blood specimensg 
X 
Xg 
 
Xg 
Xg 
Xg 
 
ECGh 
X 
 
 
 
 
 
X 

Version Date 07-OCT-2021 
CONFIDENTIAL 
Version # 2.0
51
 
 
 
Treatment Day → 
Assessments and Procedures ↓ 
≤ 14 days prior 
to registration 
Day 1 
(all 
cycles) 
Day 15 
± 2 days (all 
cycles) 
End of 
Cycle 
1 
End of 
Cycle 
3 
End of 
Cycle 6 
At end of treatment 
or treatment 
discontinuation 
Serum Immunoglobulins, monoclonal protein 
and free light chain; beta 2 microglobulini 
X 
 
 
 
 
 
X 
a. History, exam, and weigh will be done on day 1 of subsequent cycles after cycle 2 
b. Labs will be done weekly for the first 2 cycles, then on day 1 of subsequent cycles 
c. TSH and Free T4 at screening and every 2 cycles 
d. To be performed within 7 days of receiving drug. 
e. If clinically indicated for those with extramedullary disease indicated on baseline CT at completion of cycle 6 (cycle 6 day 28 
±3 days) or to confirm CR 
f. 2 tubes of 5 ml each of bone marrow aspirates in green tube (2) to be collected pre-treatment (prior to start of cycle 1) and at 
end of cycle 1 (prior to start of cycle 2). 
g. 15 ml peripheral blood to be collected prior to start of treatment and at end of cycles 1, 3, and 6 for the immunome correlate 
h. ECG should be performed within 14 days prior to registration and end of treatment, and as needed during the course of the 
study. 
i. Immunoglobulins, serum free light chains (kappa and Lambda), serum monoclonal protein, beta 2 microglobulin ≤ 14 days 
prior to registration and day 1 of each cycle. 24-hour Urine Protein and immunofixation ≤ 14 days prior to registration, and 
every 3 months. 

Version Date 07-OCT-2021 
CONFIDENTIAL 
Version # 2.0
52
 
 
 
 
10. Adverse Events 
 
10.1. Definitions 
 
10.1.1 Adverse Events 
Per the International Conference of Harmonisation (ICH) guidelines, an adverse event (AE) is 
any untoward medical occurrence in a subject is 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 drug, whether or not considered related to the study drug. 
10.1.2 Serious Adverse Events 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of 
either the investigator or sponsor, it results in any of the following outcomes: Death, a life- 
threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a 
persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions, or a congenital anomaly/birth defect. Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
10.1.3 Suspected Unexpected Serious Adverse Reaction (SUSAR) 
 An adverse reaction that is both unexpected (not consistent with the applicable product 
information) and also meets the definition of an SAE/Reaction 
 Qualifies for expedited IND safety reporting to the FDA, Competent Authorities and 
other regulatory bodies by meeting all three definitions of suspected adverse reaction, 
serious, and unexpected. 
 Expected adverse reactions and related serious adverse reactions to study drugs are listed 
in the IB/package insert(s). A serious adverse reaction that is not included in the 
IB/package insert(s) should be evaluated and reporting on the study specific SAE form by 
the site investigator as a SUSAR within 24 hours after learning of the event. 
10.1.4 Events of Clinical Interest 
Adverse Events of special interest are events that the drug manufacturer or the Sponsor of the 
study, AFT, are actively monitoring as a result of a previously identified signal (even if non- 
serious). 
10.2. Expected Adverse Events 
Expected toxicities for ibrutinib combination therapy are summarized above in Section 1.4.1.2. 

Version Date 07-OCT-2021 
CONFIDENTIAL 
Version # 2.0
53
 
 
For more detailed information refer to the current version of the IB. 
10.3. Adverse Events of Special Interest (AESIs) 
Specific adverse events, or groups of adverse events, will be followed as part of standard safety 
monitoring activities. These events (regardless of seriousness) will be reported to AFT into the 
Rave EDC system within 24 hours of becoming aware of the event(s). AFT will also report to 
Pharmacyclics Drug Safety, or designee, on the Serious Adverse Event Report Form via email or 
fax within the 15 days of awareness. 
10.3.1 Major Hemorrhage 
Major hemorrhage is defined as any of the following: 
 Any treatment-emergent hemorrhagic adverse events of Grade 3 or higher*. 
 Any treatment-emergent serious adverse events 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 5.0. 
Events meeting the definition of major hemorrhage will be captured as an event of special 
interest according to Section 11.5.4. 
10.4. Adverse Event Reporting Exceptions 
The following are NOT considered AEs: 
 Disease progression: The term disease progression should not be reported as an adverse 
event term. As an example, “worsening of underlying disease” or the clinical diagnosis 
that is associated with disease progression should be reported. 
 Baseline condition: A pre-existing condition (documented on the medical history CRF) 
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 
informed consent form 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. 
Deaths occurring outside of the serious adverse event reporting period that are clearly due 
to progressive disease should be reported via routine reporting methods in the Rave data 

Version Date 07-OCT-2021 
CONFIDENTIAL 
Version # 2.0
54
 
 
capture system. Deaths occurring within the reporting window, even if considered to be 
related to disease progression as the cause of death should be reported as a Serious Adverse 
Event with death noted as the outcome of the event. 
 Asymptomatic Treatment-related Lymphocytosis: This event should also not be 
considered an AE. Subjects with treatment-related lymphocytosis should remain on study 
treatment and continue with all study-related procedures 
10.5. Adverse Event Reporting 
Adverse event data collection and reporting, which are required as part of every clinical study are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents. All AEs whether serious or non-serious, will be captured 
from the time of first study related procedure until 30 days following cessation of treatment. Any 
increase of a documented baseline condition from screening/history will be reported as an 
adverse event. Adverse events are entered into the eCRF in Rave Electronic Data Capture 
(EDC) system. 
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. 
10.5.1 Serious Adverse Event Reporting 
Serious adverse events reported after 30 days following the last dose of study drug should also be 
reported if considered related to study drug. Resolution information after 30 days should be 
provided. 
All serious adverse events that occur more than 30 days after the last administration of 
investigational agent/intervention, through 90 days following cessation of treatment, whether or 
not related to the investigational product, require reporting into Rave EDC within 24 hours of 
awareness of the event. 
If a death occurs within 30 days after the last dose of study drug, the death must be reported as a 
serious adverse event. 
NOTE: Deaths occurring outside of the serious adverse event reporting period that are clearly 
due to progressive disease should be reported via routine reporting methods in the Rave EDC 
system. Deaths occurring within the reporting window, even if considered to be related to 
disease progression as the cause of death should be reported within Rave EDC system with death 
noted as the outcome of the event. 
10.5.2 Pregnancy Reporting 
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 or female partner of a male subject must immediately inform the Investigator if 
she becomes pregnant from the time of consent to 90 days after the last dose of study drug Any 
female subjects receiving study drug(s) who become pregnant must immediately discontinue 

Version Date 07-OCT-2021 
CONFIDENTIAL 
Version # 2.0
55
 
 
study drug. The Investigator should counsel the subject, discussing any risks of continuing the 
pregnancy and any possible effects on the fetus. 
Although pregnancy itself is not regarded as an adverse event, the outcome will need to be 
documented. Any pregnancy occurring in a female subject or female partner of a male subject 
must be reported from the time of first dose to 90 days after the last dose of study drug must be 
reported. 
All pregnancies will be followed for outcome, which is defined as elective termination of the 
pregnancy, miscarriage, or delivery of the fetus. In pregnancies with an outcome of live birth, the 
newborn infant will be followed until 30 days old. Pregnancies should be reported to AFT as 
serious in the Rave EDC system on the pregnancy form within 24 hours of becoming aware of 
the event(s). AFT will submit SAE pregnancy reports to Pharmacyclics per SAE reporting 
timelines. Any congenital anomaly/birth defect noted in the infant must be reported as a serious 
adverse event. 
10.5.3 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 in Rave EDC. 
10.5.4 Adverse Events of Special Interest (AESI) 
Adverse events of Special Interest (AESI) will be followed as part of standard safety monitoring 
activities. These events (regardless of seriousness) will be reported to AFT into the Rave EDC 
system within 24 hours of becoming aware of the event(s). AFT will report to Pharmacyclics per 
SAE reporting timelines. 
10.5.5 Expedited Reporting for Serious Adverse Events and AESIs 
All serious adverse events and AESIs (initial and follow-up information) will be reported to AFT 
in the Rave EDC system within 24 hours of becoming aware of the event(s). AFT will report to 
Pharmacyclics per regulatory reporting timelines. AFT may request follow-up and other 
additional information from the Investigator. 
All serious adverse events 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 
 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 drug 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) 

Version Date 07-OCT-2021 
CONFIDENTIAL 
Version # 2.0
56
 
 
Expedited AE reporting timelines are defined as: 
 
 “All Grade 3, 4 and 5 AEs: 24-Hour; 4 Calendar Days” – The AE must initially be 
reported via Rave EDC System ≤ 24 hours of learning of the AE, followed by a complete 
expedited report ≤ 4 calendar days of the initial 24-hour report. 
 “All Grade 1 and 2 AEs resulting in hospitalization or prolonged hospitalization: 24- 
Hour; 10 Calendar Days” – The AE must initially be reported via Rave EDC System ≤ 24 
hours of learning of the AE, followed by a complete expedited report ≤ 10 calendar days 
of the initial 24-hour report. 
10.5.6 Special Reporting Situations 
Special reporting situations on a study may require expedited reporting and/or safety evaluation 
include, but are not limited to: 
 Overdose of any study drug 
 Suspected abuse/misuse of a study drug 
 Inadvertent or accidental exposure to a study drug 
 Medication error involving a product (with or without subject exposure to the study 
drug, eg, name confusion) 
Occurrence of any special reporting situations should be recorded in the eCRF. If any special 
reporting situation meets the criteria of an AE, it should be recorded on the AEs eCRF. If the AE 
is considered serious, it should be recorded on the AEs eCRF as serious within Rave EDC. The 
serious adverse event should also be reported on the Serious Adverse Event Report Form which 
should be sent via email or fax to Pharmacyclics Drug Safety or designee within 15 calendar 
days. 
10.6. Assessment of Adverse Events 
Investigators will assess the occurrence of adverse events and serious adverse events at all 
subject evaluation time points during the study. All adverse events and serious adverse events 
whether volunteered by the subject, discovered by study personnel during questioning, detected 
through physical examination, clinically significant laboratory test, or other means, will be 
recorded in the subject’s medical record and entered into the eCRF in Medidata® Rave 
Electronic Data Capture (EDC) system (Rave EDC). 
All adverse events, regardless of seriousness, severity, or presumed relationship to study drug, 
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 drug, the investigator’s evaluation of its relationship to the study drug, 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"). 
10.6.1 Assessment of Severity of Adverse Events 
Definitions found in the Common Terminology Criteria for Adverse Events Version 4.0 
(CTCAE v 5.0) will be used for grading the severity (intensity) of non-hematologic AEs. The 
CTCAE v5.0 displays Grades 1 through 5 with unique clinical descriptions of severity for each 

Version Date 07-OCT-2021 
CONFIDENTIAL 
Version # 2.0
57
 
 
referenced AE. Should a subject experience any AE not listed in the CTCAE v5.0, 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 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to AFT (or designee) 
using the same procedure used for transmitting the initial SAE report. 
10.6.2 Assessment of Causality of Adverse Events 
The investigator is to assess the causal relation (ie, whether there is a reasonable possibility that 
the study drug caused the event) using the following definitions: 
 
Unrelated:
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:
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 
Probably Related:
when there is high suspicion, but not clearly, related to 
investigational product 
Definitely Related: 
The AE is clearly related to use of the investigational product. 

Version Date 07-OCT-2021 
CONFIDENTIAL 
Version # 2.0
58
 
 
10.7. Expedited Safety Reporting to Regulatory Agencies and Pharmacyclics 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
 An adverse reaction that is both unexpected (not consistent with the applicable product 
information) and also meets the definition of an SAE/Reaction 
 Qualifies for expedited IND safety reporting to the FDA, Competent Authorities and 
other regulatory bodies by meeting all three definitions of suspected adverse reaction, 
serious, and unexpected. 
 Expected adverse reactions and related serious adverse reactions to study drugs are listed 
in the IB/package insert(s). A serious adverse reaction that is not included in the 
IB/package insert(s) should be evaluated and reporting on the study specific SAE form by 
the site investigator as a SUSAR within 24 hours after learning of the event. 
The Safety Management group at AFT will complete and submit expedited regulatory safety 
reports (MedWatch, CIOMS, etc.) of SUSARs to the relevant regulatory/competent authorities 
within the required reporting timelines. In general, AFT is required to report all non-fatal or non- 
life threatening SUSARs to the FDA within 15 calendar days of investigator awareness of the 
event and all SUSARs resulting in hospitalization, prolongation of hospitalization, or death 
within 7 calendar days of AFT awareness. AFT will submit safety reports to Pharmacyclics in 
parallel to regulatory agency submission and no later than 15 calendar days from AFT’s first 
awareness date. 
 
11. Drug Information 
 
11.1. Ibrutinib 
Ibrutinib is an inhibitor of Brutin’s tyrosine kinase (BTK) with the empirical formula 
C25H24N6O2 and a molecular weight of 440.50 Daltons. Ibrutinib is also known as 
IMBRUVICA and is distributed and manufactured by several manufacturers. 
11.1.1 Form 
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 Investigator's Brochure for a list of excipients. 
The ibrutinib capsules will be packaged in opaque high-density polyethylene plastic bottles with 
labels bearing the appropriate label text as required by governing regulatory agencies. All study 
drug will be dispensed in child-resistant packaging. 
Study drug labels will contain information to meet the applicable regulatory requirements. 
11.1.2 Storage and Stability 
Bottles of ibrutinib should be stored at room temperature 20°C to 25°C (68°F to 77°F). 
Excursions are permitted between 15°C and 30°C (59°F to 86°F). Capsules should be retained in 
original package until dispensing. 

Version Date 07-OCT-2021 
CONFIDENTIAL 
Version # 2.0
59
 
 
11.1.3 Handling 
Bottles of ibrutinib should be stored in conditions specified in Section 11.1.2 above, per package 
insert, or according to institutional standards. 
11.1.4 Availability 
Ibrutinib is not approved for this indication and will be supplied free of charge by Pharmacyclics 
LLC. 
 
11.1.5 Preparation 
A supply sufficient for one cycle (28 days) will be provided to the patient at the beginning of 
each cycle. 
11.1.6 Administration 
Ibrutinib is administered orally once daily. The capsules are to be taken around the same time 
each day with 8 ounces (approximately 240 mL) of water. The capsules should be swallowed 
intact and the patient 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. 
If a dose is not taken at the scheduled time, it can be taken as soon as possible on the same day 
with a return to the normal schedule the following day. The patient should not take extra 
capsules to make up the missed dose. The first dose will be delivered in the clinic on Day 1, after 
which subsequent dosing is typically on an outpatient basis. 
11.1.7 Ordering 
Initial and re-supply of ibrutinib should be requested using the PCYC drug order system. 
Additional instructions will be provided to sites under separate cover. 
11.1.8 Accountability 
Site investigators or designated responsible parties must maintain a record of the inventory of 
distribution of ibrutinib using the appropriate documentation method (e.g. drug accountability 
log). 
The investigator is responsible for keeping accurate records of the clinical supplies received from 
AFT or designee, the amount dispensed to patients and the amount remaining at the conclusion 
of the study. 
11.1.9 Destruction and Return 
Sites may destroy unused study drug according to their institutional policies. If any study drug is 
lost or damaged, its disposition should be documented in the source documents. Patients will be 
instructed to return empty containers (if applicable) and unused investigational product to the 
clinic site. 

Version Date 07-OCT-2021 
CONFIDENTIAL 
Version # 2.0
60
 
 
11.2. Lenalidomide (REVLIMID®) 
 
11.2.1 Description 
Lenalidomide (REVLIMID®), a thalidomide analogue, is an immunomodulatory agent with 
antiangiogenic properties. The chemical name is 3-(4-amino-1-oxo 1,3-dihydro -2H-isoindol-2- 
yl) piperidine-2,6-dione. The empirical formula for lenalidomide is C13H13N3O3, and the gram 
molecular weight is 259.3. 
11.2.2 Form 
Lenalidomide is off-white to pale-yellow solid powder. Lenalidomide is soluble in organic 
solvent/water mixtures and buffered aqueous solvents. It is more soluble in organic solvents and 
low pH solutions. 
Solubility was significantly lower in less acidic buffers, ranging from about 0.4 to 0.5 mg/ml. 
Lenalidomide has an asymmetric carbon atom and can exist as the optically active forms S(-) and 
R(+), and is produced as a racemic mixture with a net optical rotation of zero. 
11.2.3 Storage and Stability 
Lenalidomide is commercially available and will be dispensed by a pharmacist registered in the 
Revlimid REMS® program. Lenalidomide should be stored at room temperature away from 
direct sunlight and protected from excessive heat and cold. 
11.2.4 Handling 
Females of childbearing potential should not handle or administer lenalidomide unless they are 
wearing gloves. 
11.2.5 Availability 
Lenalidomide is commercially available and will be dispensed by a pharmacist registered in the 
Revlimid REMS® program. 
11.2.6 Ordering 
Lenalidomide will be provided as commercial supply in accordance with the Revlimid REMS® 
program of Celgene Corporation. Per standard Revlimid REMS® requirements all physicians 
who prescribe lenalidomide for research subjects enrolled into this trial, and all research subjects 
enrolled into this trial, must be registered in and must comply with all requirements of the 
Revlimid REMS® program. Prescriptions must be filled within 14 days, unless the patient is a 
female of childbearing potential, in which case the prescription must be filled within 7 days. 
Only enough lenalidomide for one cycle of therapy will be supplied to the patient each cycle. 
11.2.7 Accountability 
Lenalidomide is commercially available therefore, no drug accountability records are required. 
The investigator is responsible for monitoring patient compliance by monitoring patient diary 
and or pill count. 

11.2.61 Destruction and 
Version Date 07-OCT-2021 
CONFIDENTIAL 
Version # 2.0
61
 
 
Participants will be instructed to return empty bottles or unused capsules via the Revlimid 
REMS® program. 
11.3. Dexamethasone 
 
11.3.1 Description 
The molecular weight for dexamethasone is 392.47. It is designated chemically as 9-fluoro- 
11β,17, 21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione. Dexamethasone is stable in air 
and almost insoluble in water. The empirical formula is C22H29FO5 
11.3.2 Form 
Dexamethasone is a white to practically white, odorless, crystalline powder. It is available in 4 
mg tablets for oral administration. Each tablet contains dexamethasone as the active ingredient, 
and the following inactive ingredients: calcium phosphate, lactose, magnesium stearate, and 
starch. The tablet shell may contain the following: D&C Yellow 10, FD&C Yellow 6, and/or 
FD&C Blue 1. 
11.3.3 Storage and Stability 
At the study site, all study drugs will be stored in a locked, safe area to prevent unauthorized 
access. 
Dexamethasone should be stored at controlled room temperature, 68-77◦F (20-25◦C) and not 
frozen, and according to label requirements. 
11.3.4 Handling 
Dexamethasone should be handled by trained pharmacy staff. The use of gloves and other 
appropriate protective clothing is recommended as necessary. 
11.3.5 Availability 
Dexamethasone supply will be obtained through commercial supply. 
11.3.6 Preparation 
Dexamethasone is an oral drug and does not require specific preparation details. 
11.3.7 Ordering 
The investigator or designee will order drug supply from commercial supply. 
11.3.8 Accountability 
The investigator is responsible for keeping accurate records of the clinical supplies received from 
AFT or designee, the amount dispensed to patients and the amount remaining at the conclusion 
of the study. 

11.3.62 Destruction and 
Version Date 07-OCT-2021 
CONFIDENTIAL 
Version # 2.0
62
 
 
Sites may destroy unused study drug according to their institutional policies. If any study drug is 
lost or damaged, its disposition should be documented in the source documents. Patients will be 
instructed to return empty containers (if applicable) and unused investigational product to the 
clinic site. 
12. Data Collection and Management/ Data and Specimen Submission 
 
12.1. Data Collection and Submission 
Data collection for this study will be done through the Medidata® Rave clinical data 
management system. Access to the study in Rave EDC is granted through the iMedidata 
application to all persons with the appropriate roles assigned in AFT CTMS System. See Data 
Entry Guidelines for additional instructions. 
12.2. Specimen Collection and Submission 
Bone marrow aspirates will be collected at a pre-treatment and end of cycle 1 correlatives. Two 
2 ml tubes will be collected at each time point. 
Peripheral blood will be collected at pretreatment and after cycles 1, 3, and 6 for immunome 
studies. 15 ml of blood will be collected at each time point. 
Table 16 
Research Blood and Body Fluid to be Collected 
 
Correlative Study 
(Section 13 for more 
information) 
Mandatory or 
Optional 
Blood or 
Body Fluid 
being 
Collected 
After 
registration, 
prior to start of 
treatment 
At completion 
of Cycle 1, 3, 
and 6 
 
 
immunome studies 
Mandatory 
Peripheral 
blood 
X 
X 
Mandatory 
Peripheral 
blood 
X 
X 
bone marrow aspirates 
mandatory 
Bone marrow 
fluid 
X 
X* 
*at the end of Cycle 1 only 
 
Details for processing and shipping of specimens can be found in the study specific correlative 
science manual. 
13. Correlative Studies 
To be performed in 
 

Version Date 07-OCT-2021 
CONFIDENTIAL 
Version # 2.0
63
 
 
13.1. Peripheral Blood and Bone Marrow Samples 
Peripheral blood samples and bone marrow samples will be sent to the Alliance Foundation 
Biorepository, who will process the samples before sending them to City of Hope. Peripheral 
blood and bone marrow aspirates will be used to analyze Th1/Th2 response in treated patients 
and the bone marrow aspirates will be used to isolate CD-138+ myeloma cells for the analysis of 
Btk, microRNA (miR) and mRNA expression for correlation with outcomes. 
13.2. Immunome 
The immunome correlative will be completed in the expansion phase only. Peripheral blood will 
be collected at pre-treatment, after cycles 1, 3, and 6, and the PBMC fraction will be used to 
quantify immune subset changes over the course of treatment including B cells, cytotoxic T cells, 
T regulatory cells, T central memory cells, NK cells, NKT cells, and B-cell subsets by flow 
cytometry to assess for any changes that may correlate with outcome. Specifically, 5x106 PBMC 
will be stained using Maxpar® Direct™ Immune Profiling System and detect by mass cytometry 
analysis. We are planning to collect at least 40 longitudinal samples for the analysis. 
At Pre-treatment and end of cycle 1 (before start of cycle 2) bone marrow aspirates will be 
collected for total RNA sequencing. Specifically, CD138+ plasma cells will be purified from 
total marrow cells of patients by Human Whole Blood CD138+ Selection Kit (Cat#18387, Stem 
Cell Technologies), as described in section 13.3. We are planning to perform RNA sequencing in 
total 10 longitudinal samples isolated from 5 patients. 
13.3. Immunohistochemistry analysis (IHC) in bone marrow biopsies 
Bone marrow core biopsies collected at the same time of the bone marrow aspirates (Pre- 
treatment and end of cycle 1) will be used to perform IHC staining to determine levels of B-cell 
receptor signaling and Btk activation in the bone marrow of the myeloma patients after 
treatment. Phosphorylated and total Btk, phosphorylated and total PLCγ and phosphorylated and 
total ERK will be assessed by IHC and coexpression with CD-138+ MM cells will be also 
assessed. Furthermore, by RT-PCR we will evaluate the variation in BTK mRNA levels 
associated to the treatment as previously described. 
13.4. Measurement of Effect 
Patients enrolled onto this trial must have measurable disease defined as disease that can be 
measured either by serum or urinary evaluation of the monoclonal component or by serum assay 
of FLC and is defined by at least one of the following three measurements: 
 Serum M-protein > (0.5 g/dl) g/dl 
 Urine M-protein > 200 mg/24 h 
 Serum FLC assay: Involved FLC level > 10 mg/dl (> 100 mg/l) provided serum FLC 
ratio is abnormal. 
The disease response will be assessed using criteria based on the International Working Group 
Uniform Response Criteria in Section 15.3.1. If the only measurable parameter is serum 
immunoglobulins free light chain (FLC), the participant will be followed by FreeLite™ Disease 
Response Criteria provided in Section 15.3.2. 
The same method of assessment and technique should be used for disease measurement 

Version Date 07-OCT-2021 
CONFIDENTIAL 
Version # 2.0
64
 
 
throughout the study. Disease response should be confirmed by two consecutive assessments at a 
minimum of 6 weeks apart. 
13.5. Methods for Evaluation of Measurable Disease 
All baseline evaluations should be performed on Cycle 1, Day 1 of therapy. Response will be 
assessed by M-protein quantification, protein electrophoresis and immunofixation from serum, a 
24-hour urine collection and serum free light chain. In addition, bone marrow aspiration and 
biopsy will be performed confirm CR and differentiate between CR and stringent CR. 
13.6. Response Criteria 
 
13.6.1 International Myeloma Working Group Response Criteria 
Table 17 
Response
IMWG criteria
sCR
CR as defined below plus normal FLC ratio and absence of clonal cells in 
bone marrow by immunohistochemistry or 2 – 4 color flow cytometry 
CR
Negative immunofixation on the serum and urine and disappearance of 
any soft tissue plasmacytomas and < 5% plasma cells in bone marrow. 
In patients with only FLC disease, a normal FLC ratio of 0.26–1.65 is 
required. 
VGPR 
Serum and urine M-protein detectable by immunofixation but not on 
electrophoresis 
or 
≥ 90% reduction in serum M-protein plus urine M-protein level < 100 mg/24 h 
In patients with only FLC disease, >90% decrease in the difference between 
involved and uninvolved FLC levels is required. 
PR
≥ 50% reduction of serum M-protein and reduction in 24 hours urinary M- 
protein by ≥90% or to < 200 mg/24 h 
If the serum and urine M-protein are unmeasurable, a ≥ 50% decrease in the 
difference between involved and uninvolved FLC levels is required in place 
of the M-protein criteria 
Stable disease
Not meeting criteria for CR, VGPR, PR, or progressive disease

Version Date 07-OCT-2021 
CONFIDENTIAL 
Version # 2.0
65
 
 
 
Progressive 
disease 
Increase of ≥ 25% from lowest response value in any one or more of the 
following: 
Serum M-component and/or (the absolute increase must be ≥ 0.5 g/dL) Urine 
M-component and/or (the absolute increase must be ≥200 mg/24 h) Only in 
patients without measurable serum and urine M-protein levels; the difference 
between involved and uninvolved FLC levels. The absolute increase must be > 
10 mg/dL 
Definite development of new bone lesions or soft tissue plasmacytomas or 
definite increase in the size of existing bone lesions or soft tissue 
plasmacytomas Development of hypercalcaemia (corrected serum calcium > 
11.5 mg/dL or 2.65 mmol/L) that can be attributed solely to the plasma cell 
proliferative disorder 
Additional response criteria for specific disease states 
Minor response in patients with relapsed and refractory myeloma adapted from the EMBT 
Criteria ≥ 25% but < 49% reduction of serum M protein and reduction in 24-hour urine M 
protein by 50 – 89%, which still exceeds 200 mg/24hrs. In addition to above; if present at 
baseline, 25-49% reduction in the size of soft tissue plasmacytomas is also required No increase 
in size or number of lytic bone lesions (development of compression fractures does not exclude 
response). 
13.6.2 FreeLite™ Disease Response Criteria 
Table 18 
 
Response
FreeLite™criteria
CR
For those patients being followed by serum free light chain (and NO 
measurable serum or urine M-spike), which were immunofixation 
negative at enrollment, normalization of serum free light chain ratio. 
Normalization is defined as the serum free light chain ratio being within 
the normal range. If the serum free light chain ratio is not within the 
normal range, but the individual kappa and lambda light chain values are 
within normal range, this may be considered CR. 
PR
If only measurable parameter is serum immunoglobulins free light chain 
(FLC), EITHER of the following changes quality as partial response: 
- A 50% decrease in the difference between involved and uninvolved FLC 
levels; OR 
- A 50% decrease in the level of involved FLC AND a 50% decrease (or 
normalization) in the ratio of involved/uninvolved FLC 
Progressive 
Disease 
If only measurable parameter is serum immunoglobulins free light (FLC), 
either of the following qualify as progression: 
- 50% increase in the difference between involved and uninvolved FLC levels 
from the lowest response level, which must also be an absolute increase of at 
least 10 mg/dL; OR 
- 50% increase in the level of involved FLC AND a 50% increase in the ratio 
of involved/uninvolved FLC from the lowest response level. 

Version Date 07-OCT-2021 
CONFIDENTIAL 
Version # 2.0
66
 
 
14. Statistical Considerations 
 
14.1. Overview of the Study Design 
This is a single-arm, open label, phase Ib study of Ibrutinib in combination with lenalidomide 
and dexamethasone in adult (age 18 years and older) patients with relapsed/refractory MM. A 
3+3 phase I clinical trial design as described in Section 6.0 was chosen to determine the MTD of 
Ibrutinib in combination with lenalidomide given on days 1-21 of a 28-day cycle and 
dexamethasone given orally weekly. An expansion cohort of 10 patients will be treated at the 
MTD to gather additional safety and anti-tumor activity data. 
As of April 15, 2021, 2 patients have been enrolled onto dose level 2. 
- 
If none of the first 3 patients treated at dose level 2 develops a DLT, then the next cohort 
of 3 patients will be enrolled onto dose level 3 and biospecimen collection will begin for 
all subsequent patients enrolled. 
- 
If one of the 3 patients treated at dose level 2 develops a DLT, then the next cohort of 3 
patients will be enrolled at dose level 2 and correlatives biospecimens will be collected 
from these patients. 
o If 2 or more of the 6 patients treated at dose level 2 develops a DLT then an 
additional 10 patients will be enrolled onto dose level 1 so that a total of 10 
patients will have provided biospecimens at the MTD. (Note: Total sample size 
will be 6 [from dose level 1] + 6 [ from dose level 2] + 10 [for dose expansion] = 
22. Biospecimens will be available for 10 patients treated at the MTD.) 
- 
If 2 or more of 3 patients treated at dose level 2 has an DLT, an additional 10 patients 
will be enrolled onto dose level 1 to further assess safety and collect specimens for 
correlative aims. (Note: Total sample size will be 6 [from dose level 1] + 3 [from dose 
level 2] + 10 [for dose expansion] = 19. Biospecimens will be available for 10 patients 
treated at the MTD.) 
- 
If at most 1 of 6 patients treated at dose level 2 develops a DLT and 2 or more of the 3-6 
patients treated at dose level 3 develops a DLT, then an additional 7 patients will be 
enrolled onto dose level 2 so that a total of 10 patients will have provided biospecimens 
at the MTD. (Note: Total sample size will be 6 [from dose level 1] + 6 [from dose level 
2] + 6 [maximum number anticipated on dose level 3] + 7 [for dose expansion] = 25. 
Biospecimens will be available for 10 patients treated at the MTD.) 
- 
If at most 1 of 6 patients treated at dose level 2 develops a DLT and 1 or fewer of the 6 
patients treated at dose level 3 develops a DLT, then an additional 4 patients will be onto 
dose level 3 so that a total of 10 patients will have provided biospecimens at the MTD. 
(Note: Total sample size will be 6 [from dose level 1] + 6 [from dose level 2] + 6 
[maximum number anticipated on dose level 3 to establish it as MTD] + 4 [for dose 
expansion] = 22. Biospecimens will be available for 10 patients treated at the MTD.) 
- 
If at most 1 of 6 patients treated at dose level 3 develops a DLT then an additional 4 
patients will be enrolled onto dose level 3 so that a total of 10 patients will have provided 
biospecimens at the MTD. (Note: Total sample size will be 6 [from dose level 1] + 3 

Version Date 07-OCT-2021 
CONFIDENTIAL 
Version # 2.0
67
 
 
[from dose level 2] + 6 [maximum number anticipated on dose level 3] + 4 [for dose 
expansion] = 19. Biospecimens will be available for 10 patients treated at the MTD.) 
- 
If 2 or more of the 3-6 patients treated at dose level 3 develops a DLT then an additional 
7 patients will be enrolled onto dose level 2 so that a total of 10 patients will have 
provided biospecimens at the MTD. (Note: Total sample size will be 6 [from dose level 
1] + 3 [ from dose level 2] + 6 [ maximum number anticipated on dose level 3] + 7 [for 
dose expansion] = 22. Biospecimens will be available for 10 patients treated at the 
MTD.) 
14.2. Sample Size, Accrual Time and Study Duration 
A minimum of 6 and a maximum of 25 patients will be accrued. We anticipate that 3 patients 
will be enrolled and followed for the development of a DLT every 4-6 months, the time between 
determination of MTD and opening of the expansion cohort to be 2 months, and 1 patient per 
month would be enrolled during the expansion phase of the study. Thus, the enrollment period 
would be approximately 42 to 48 months. 
14.3. Definitions of Endpoints and Analysis Plan 
14.3.1 Patient Evaluability 
All patients meeting the eligibility criteria who have signed a consent form and have begun 
treatment will be included in the analysis of the safety and clinical outcome data. 
14.3.2 Statement for Primary Endpoint 
The primary endpoint of the dose escalation portion of this phase I study is the MTD. The 
maximum tolerated dose is defined as the highest dose level among those tested where at most 
one out of 6 patients develops a DLT prior to the start of their second cycle of treatment and the 
next highest dose level is such that 2 or more patients among the maximum of 6 patients treated 
at that dose level developed a DLT prior to the start of their second cycle of treatment. 
The primary endpoint of the expansion portion of this phase I study is the objective response 
rate. The objective response rate is the percent of patients who meet the International Myeloma 
Working Group Response Criteria for sCR, CR, VGPR, or PR on two consecutive evaluations at 
least 4 weeks apart among the patients who began study treatment. A 90% binomial confidence 
interval will be constructed for the overall objective response rate. 
14.3.1 Statement for Secondary Endpoints 
Secondary Endpoints include: 
Maximum Toxicity Grade: 
The maximum grade of each type of toxicity will be recorded for each patient. For each toxicity 
reported by dose level, the percentage of patients developing any degree of that toxicity as well 
as the percentage of patients developing a severe degree (Grade 3 or higher) will be determined. 
Number/Duration of Response: 
For each dose level, the number of response and the duration of response will be tabulated. The 
duration of response is the time from initiation of first response to first documentation of disease 

Version Date 07-OCT-2021 
CONFIDENTIAL 
Version # 2.0
68
 
 
progression or death. Patients who have not progressed will be censored at the date of their last 
disease evaluation. 
Progression-free Survival (PFS)/ Overall Survival (OS) 
Secondary endpoints for the expansion cohort include progression-free survival (PFS) and 
overall survival (OS) time. 
Survival time is defined as the time from study entry to death due to any cause. 
Progression-free survival time is the time from study entry to the documentation of disease 
progression or death due to any cause. 
If a patient dies without a recurrence documented, the patient will be censored at the date of last 
disease evaluation. The distribution of response times, progression-free survival times and 
survival times will be estimated using the Kaplan-Meier method. 
14.4. Data and Safety Monitoring 
Interim reports from the statistical team will be generated for the Data and Safety Monitoring 
Board (DSMB). 
 
15. General Regulatory Considerations and Administrative Procedures 
 
15.1. Compliance with Study Enrollment and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the study is solely 
responsible for determining whether the study and its results are subject to the requirements for 
submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. Information posted 
will allow patients to identify potentially appropriate trials for their disease conditions and 
pursue participation by calling a central contact number for further information on appropriate 
study locations and study site contact information. 
15.2. Regulatory and Ethical Compliance 
 
This study will be conducted in compliance with the study protocol, subsequent amendment(s) 
and with the study-specific manuals/guidelines, if applicable. These documents ensure that the 
ICH E6 guideline for Good Clinical Practice is maintained as well as compliance with the 
principles of the Declaration of Helsinki (World Medical Association), or the laws and 
regulations of the country in which the research is conducted, whichever afford the greater 
protection to the individual. 
Studies conducted in the United States or under a U.S. Investigational New Drug (IND) 
application will comply with U.S. FDA regulation and applicable local, state and federal laws. 
15.3. Informed Consent 
It is the responsibility of the Investigator, or a person designated by the Investigator (if 
acceptable by local regulations), to obtain written Informed Consent from each patient 
participating in this study, after adequate explanation of the aims, methods, anticipated benefits, 
and potential hazards of the study. This information must be provided to the patient prior to 
undertaking any trial-related procedure which is not part of the routine clinical management of 

Version Date 07-OCT-2021 
CONFIDENTIAL 
Version # 2.0
69
 
 
the patient (i.e. would not be indicated outside the study). The proposed Informed Consent Form 
and consenting process must comply with the GCP guidelines, regulatory requirements and be 
consistent with IRB/institutional policies. 
15.4. Responsibilities of the Investigator/IRB/IEC/REB 
The regulatory requirements for the Investigator can be found in Subpart D of 21CFR312 
(21CFR 312.60: General Responsibilities of Investigators) and in ICH E6 Section 4. 
 
Additional requirements are also outlined in the Statement of Investigator Responsibilities (Form 
FDA 1572) and the Site Services Agreement. Alliance Foundation Trials, LLC (AFT) will 
supply the protocol and subsequent amendments. 
 
The Investigator is responsible for the overall study compliance, execution, oversight and 
management of the study at their site, and satellites if applicable. 
 
As specified in 21CFR 312.62(Investigator Record Keeping and Record Retention) and ICH E6 
Sections 4.9 and 8, the Investigator is responsible for ensuring that their study staff maintains 
and retains all study related documentation, including but not limited to: signed Informed 
Consent forms, protocol documents, Institutional Review Board (IRB) approvals, relevant IRB 
and Sponsor correspondence, and assorted regulatory documents. The Investigator is responsible 
for retaining and keeping safe all patient related documentation. In order to do this, the site staff 
will complete electronic case report forms (eCRFs) in a timely manner. 
15.5. Financial Disclosures 
Investigators will provide AFT with adequate and accurate financial information in accordance 
with local regulations and laws in order to allow AFT to submit complete and accurate financial 
certification or disclosure statements to the appropriate health authorities. Investigators are 
responsible for providing updated information on financial interests during the course of the 
study as well as for 1 year after completion of the study. 
15.6. Protocol Deviations 
The investigator is responsible to document and explain any deviations from the approved 
protocol. The investigator should promptly report any deviations that might impact patient safety 
and data integrity to AFT and if locally applicable, to the respective IRB in accordance with 
local IRB policies and procedures. 
 
A deviation is a departure from the protocol. If deviations are discovered by the monitor or data 
manager, other member of study staff or otherwise, they will be discussed with the Investigator 
and study staff. AFT does not provide waivers for protocol deviations. 
15.7. Protocol Amendments 
Any modifications to the protocol or the Informed Consent Form which may impact the conduct 
of the study, potential benefit of the study, or may affect patient safety, including changes of 
study objectives, study design, patient population, sample sizes, study procedures, or significant 
administrative aspects will require a formal amendment to the protocol. Such amendment will be 
released by AFT, agreed by the investigator(s) and approved by relevant IRBs prior to 

Version Date 07-OCT-2021 
CONFIDENTIAL 
Version # 2.0
70
 
 
implementation. A signed and dated statement that the protocol, any subsequent relevant 
amended documents and the Informed Consent Form have been approved by relevant IRBs must 
be provided to AFT before the study is initiated. Because administrative processing of 
amendments may take time which could impact study conduct, AFT may release operational 
memos to allow such changes to the protocol conduct to occur prior to the formal amendment 
review without being considered a protocol deviation. This is particularly true for changes which 
impact patient safety. Such memos should be processed per local IRB/institutional standard. 
Per the IST Agreement, any amendments to the Protocol or Informed Consent Form must be sent 
to Pharmacyclics for review and approval prior to submission to the IRB. 
Administrative changes of the protocol are minor corrections and/or clarifications that have no 
effect on the way the study is to be conducted. These administrative changes will be released by 
the AFT, agreed by the investigator(s) and notified to the IRB as per institutional guidelines. 
15.8. Retention of Records (Study Documentation, record keeping, and retention of 
records) 
Any records and documents relating to the conduct of this study and the distribution of 
investigational product, must be retained by the investigator until notification by AFT, or for the 
length of time required by relevant national or local health authorities, whichever is longer. After 
that period of time, the documents may be destroyed, subject to local regulations. No records 
may be disposed of without the written approval of AFT. Written notification should be provided 
to AFT prior to transferring any records to another party or moving them to another location. 
 
If the Investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), AFT should be prospectively notified. The study 
records must be transferred to a designee acceptable to AFT, such as another investigator, 
another institution, or to AFT itself. 
15.9. Data Confidentiality 
Patient medical information both, associated with biologic specimens or not, is confidential and 
may only be disclosed to third parties as permitted by the ICF (or separate authorization for use 
and disclosure of personal health information) which has been signed by the patient, unless 
permitted or required by law. Data derived from biologic specimen analysis on individual 
patients will in generally not be provided to study investigators unless a request for research use 
is granted. The overall results of any research conducted using biologic specimens will be 
available in accordance with the effective AFT policy on study data publication. 
 
Data collected during this study may be used to support the development, registration or 
marketing of an investigational product. All data collected during the study will be controlled by 
the sponsor, AFT. AFT will abide by all relevant data protection laws. After a patient has 
consented to take part in the study, their medical records and the data collected during the study 
will be reviewed by representatives of the sponsor and the manufacturer to confirm that the data 
collected are accurate and for the purpose of analyzing the results. These records and data may 
be additionally reviewed by auditors or by regulatory authorities. 

Version Date 07-OCT-2021 
CONFIDENTIAL 
Version # 2.0
71
 
 
15.10. Database Management and Quality Control 
The Site Principal Investigator and/or his/her designee will prepare and maintain adequate and 
accurate participant case histories with observations and data pertinent to the study. 
 
Medidata® Rave electronic data capture (EDC) system will be used for this study. The study 
data will be entered by study-site personnel from the source documents onto an eCRF in Rave 
EDC. eCRFs will be completed in a timely manner. 
 
In accordance with federal regulations, the Investigator is responsible for the accuracy and 
authenticity of all clinical and laboratory data entered onto eCRFs. At study completion, when 
the database has been declared to be complete and accurate, the database will be locked. 
15.11. Site Monitoring 
Monitoring visits will be conducted by representatives of the Alliance Foundation according to 
the US CFR Title 21 Parts 50, 56, and 312 and ICH Guidelines for GCP (E6). 
15.12. Data and Safety Monitoring Board (DSMB) 
The Alliance Foundation Trials Data Safety Monitoring Board will be monitoring this study to 
ensure objectivity and the safety of participants. The DSMB will meet twice a year either at a 
face-to-face meeting or by teleconference. At each meeting, the study will be reviewed for safety 
and progress toward completion. 
15.13. Regulatory Reporting 
Serious adverse events will be forwarded to FDA by the IND Sponsor according to 21 CFR 
312.32. 
 
It is the responsibility of the investigator and the research team to ensure that serious adverse 
events are reported according to the Code of Federal Regulations, Good Clinical Practices 
(GCP), the protocol guidelines, AFT’s guidelines, and Institutional Review Board (IRB) policy. 
15.14. Audits and Inspections 
To enable evaluations and/or audits from health authorities or AFT, the Investigator agrees to 
keep records, including the identity of all participating subjects (sufficient information to link 
records, e.g., eCRFs and hospital records), all original signed informed consent forms, copies of 
all eCRFs, safety reporting forms, source documents, and detailed records of treatment 
disposition, and adequate documentation of relevant correspondence (e.g., letters, meeting 
minutes, telephone calls reports). In the event that the investigator or other site personnel are 
notified of a Health Authority’s intent to inspect the site(s), notification will be sent to 
 immediately upon awareness. 
15.15. Early Discontinuation of the Study 
Early study termination will be the result of the criteria specified below: 
 
 Poor adherence to protocol and regulatory requirements 
 Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects 

Version Date 07-OCT-2021 
CONFIDENTIAL 
Version # 2.0
72
 
 
 Plans to modify or discontinue the development of the study drug 
15.16. Publication of study protocol and results 
Alliance Foundation Trials, LLC prioritizes the timely presentation and publication of study 
results. Publications and any kind of presentations of results from the study shall be in 
accordance with accepted scientific practice, academic standards and customs and must be 
approved in writing by AFT as the sponsor of this trial. No investigator may present or publish 
any portion of this study without written approval from AFT. 

Version Date 07-OCT-2021 
CONFIDENTIAL 
Version # 2.0
73
 
 
References 
Kumar SK, Lee JH, Lahuerta JJ, Morgan G, Richardson PG, Crowley J, et al. Risk of 
progression and survival in multiple myeloma relapsing after therapy with IMiDs and 
bortezomib: a multicenter international myeloma working group study. Leukemia. 
2012;26(1):149-57. 
 
Siegel DS, Martin T, Wang M, Vij R, Jakubowiak AJ, Lonial S, et al. A phase 2 study of single- 
agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. 
Blood. 2012;120(14):2817-25. 
 
Richardson PG, Blood E, Mitsiades CS, Jagannath S, Zeldenrust SR, Alsina M, et al. A 
randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and 
refractory multiple myeloma. Blood. 2006;108(10):3458-64. 
 
Richardson P, Jagannath S, Hussein M, Berenson J, Singhal S, Irwin D, et al. Safety and efficacy 
of single-agent lenalidomide in patients with relapsed and refractory multiple myeloma. Blood. 
2009;114(4):772-8. 
 
Weber DM, Chen C, Niesvizky R, Wang M, Belch A, Stadtmauer EA, et al. Lenalidomide plus 
dexamethasone for relapsed multiple myeloma in North America. N Engl J Med. 
2007;357(21):2133-42. 
 
Dimopoulos M, Spencer A, Attal M, Prince HM, Harousseau JL, Dmoszynska A, et al. 
Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med. 
2007;357(21):2123-32. 
 
Rajkumar SV, Jacobus S, Callander NS, Fonseca R, Vesole DH, Williams ME, et al. 
Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone 
as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled 
trial. Lancet Oncol. 2009;11(1):29-37. 
 
Murray MY, Zaitseva L, Auger MJ, Craig JI, MacEwan DJ, Rushworth SA, et al. Ibrutinib 
inhibits BTK-driven NF-kappaB p65 activity to overcome bortezomib-resistance in multiple 
myeloma. Cell cycle. 2015;14(14):2367-75. 
 
Yang Y, Shi J, Gu Z, Salama ME, Das S, Wendlandt E, et al. Bruton tyrosine kinase is a 
therapeutic target in stem-like cells from multiple myeloma. Cancer Res. 2015;75(3):594-604. 
 
Bam R, Ling W, Khan S, Pennisi A, Venkateshaiah SU, Li X, et al. Role of Bruton's tyrosine 
kinase in myeloma cell migration and induction of bone disease. Am J Hematol. 2013;88(6):463- 
71. 
 
Rushworth SA, Bowles KM, Barrera LN, Murray MY, Zaitseva L, MacEwan DJ. BTK inhibitor 
ibrutinib is cytotoxic to myeloma and potently enhances bortezomib and lenalidomide activities 
through NF-kappaB. Cell Signal. 2013;25(1):106-12. 

Version Date 07-OCT-2021 
CONFIDENTIAL 
Version # 2.0
74
 
 
Vij R, Huff CA, Bensinger WI, Siegel DS, Jagannath S, Berdeja J, 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(21):31-. 
 
Geiss GK, Bumgarner RE, Birditt B, Dahl T, Dowidar N, Dunaway DL, et al. Direct multiplexed 
measurement of gene expression with color-coded probe pairs. Nat Biotechnol. 2008;26(3):317- 
25. 
 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. 
Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe, 
J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST guideline (version 
1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
 
Bam R, Ling W, Khan S, et al. Role of Bruton’s tyrosine kinase in myeloma cell migration and 
induction of bone disease. Am J Hematol. 2013;88:463-71. 
 
Rushworth SA, Bowles KM, Barrera LN, Murray MY, Zaitseva L, MacEwan DJ. BTK inhibitor 
ibrutinib is cytotoxic to myeloma and potently enhances bortezomib and lenalidomide activities 
through NF-κB. Cell Signal. 2013;25:106-12. 
 
Weber, D.M., et al., Lenalidomide plus Dexamethasone for Relapsed Multiple Myeloma in 
NorthAmerica. N Engl J Med 2007; 357:2133-2142. 
 
Yang, Y. et al., Exploiting Synthetic Lethality for the Therapy of ABC Diffuse Large B Cell 
Lymphoma. Cancer Cell 2012; 21, 723 
 
Durie, BGM et al., International uniform response criteria for multiple myeloma. Leukemia 
2006; 20: 1467 – 1473. 
 
Bishop GA, Haxhinasto SA, Stunz LL, et al. Antigen-specific B-lymphocyte activation. Crit 
Rev Immunol 2003;23:165–197. 
 
Chang BY, Francesco M, De Rooij MF, et al. Egress of CD19+CD5+ cells into peripheral blood 
following treatment with the Bruton tyrosine kinase inhibitor ibrutinib in mantle cell lymphoma 
patients. Blood. 2013a;122:2412-24. 
 
Chang BY, Francesco M, Steggerda S, et al. Ibrutinib Inhibits Malignant Cell Adhesion and 
Migration and Reduces Tumor Burden in Lymph Node and Bone Marrow in a Murine Model of 
Mantle Cell Dissemination and Progression. 2013b AACR: Abstract 923. 
 
Child CG, Turcotte JG. “Surgery and portal hypertension”. In Child CG. The liver and portal 
hypertension. Philadelphia:Saunders. 1964. pp. 50-64. 
 
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. 

Version Date 07-OCT-2021 
CONFIDENTIAL 
Version # 2.0
75
 
 
International Conference on Harmonization (ICH) Guideline for Industry: Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting (ICH-E2A). March 1995 
 
Oken, MM, Creech RH, Tormey DC, et al.: Toxicity And Response Criteria Of The Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 5:649-55, 1982. 
 
Pan Z, Scheerens H, Li SJ, et al. Discovery of selective irreversible inhibitors for Bruton's 
tyrosine kinase. ChemMedChem 2007;2:58-61. 
 
Pugh RN, Murray-Lyon IM, Dawson L, et al. “Transection of the oesophagus for bleeding 
oesophageal varices”. The British journal of surgery. 1973;60: 646-9. 
 
Satterthwaite AB, Witte ON. The role of Bruton's tyrosine kinase in B cell development and 
function: a genetic perspective. Immunol Rev 2000;175:120-127. 
 
Shaffer AL, Rosenwald A, Staudt LM. Lymphoid malignancies: The dark side of B-cell 
differentiation. Nat Rev Immunol 2002;2:920–932. 
 
Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the use of 
white blood cell growth factors: An evidence-based clinical practice guideline. J Clin Oncol 
2006;24:3187-205. 
 
Stevenson FK, Krysov S, Davies AJ, et al. B-cell receptor signaling in chronic lymphocytic 
leukemia. Blood 2011;118: 4313-4320. 

Version Date 07-OCT-2021 
CONFIDENTIAL 
Version # 2.0
76
 
 
Appendices 
Appendix I: ECOG Performance Status 
Appendix II: Inhibitors and Inducers of CYP3A 
Appendix III: Child-Pugh score 

Version Date 07-OCT-2021 
CONFIDENTIAL 
Version # 2.0
77
 
 
Appendix I: ECOG Performance Status 
 
 
Grade
Description
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction.
 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, 
but ambulatory and able to carry out work of a light or sedentary nature 
(e.g., light housework, office work). 
 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% of 
waking hours.
3 
In bed >50% of the time. Capable of only limited self-care, confined to 
bed or chair more than 50% of waking hours.
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair.
5 
Dead. 
* As published in Am. J. Clin. Oncol.: 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. The Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair.

Version Date 07-OCT-2021 
CONFIDENTIAL 
Version #2
78
 
 
 
 
Appendix II: Inhibitors and Inducers of CYP3A 
Inhibitors of CYP3A are defined as follows. A comprehensive list of inhibitors can be found at 
the following website: http://medicine.iupui.edu/clinpharm/ddis/table.aspx. The general 
categorization into strong, moderate, and weak inhibitors according to the website is displayed 
below. Refer to Section 5.4 on instructions for concomitant use of CYP3A inhibitors and 
inducers with ibrutinib. 
Inhibitors of CYP3A
Inducers of CYP3A
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
 
posaconazole
 
Moderate inhibitors:
 
aprepitant
 
amprenavir
 
amiodarone
 
atazanavir
 
ciprofloxacin
 
crizotinib
 
darunavir/ritonavir
 
dronedarone
 
erythromycin
 
diltiazem
 
fluconazole
 
fosamprenavir
 
grapefruit juice
 
Seville orange juice
 
verapamil
 
voriconazole
 
imatinib
 
Weak inhibitors:
 

Version Date 07-OCT-2021 
CONFIDENTIAL 
Version #2
79
 
 
 
cimetidine
 
fluvoxamine
 
All other inhibitors:
 
chloramphenicol
 
delaviridine
 
diethyl-dithiocarbamate
 
gestodene
 
mifepristone
 
norfloxacin
 
norfluoxetine
 
star fruit
 
Source: 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx. 

Version Date 07-OCT-2021 
CONFIDENTIAL 
Version #2
80
 
 
Appendix III: Child-Pugh Score 
 
 
Measure 
1 point 
2 points 
3 points 
Total bilirubin, μmol/L (mg/dL
<34 (<2) 
34-50 (2-3) 
>50 (>3) 
Serum albumin, g/L (g/dL) 
>35 (>3.5) 
28-35 (2.8-3.5) 
<28 (<2.8) 
PT INR 
<1.7 
1.71-2.30 
>2.30 
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: 
 
1. Child CG, Turcotte JG. “Surgery and portal hypertension”. In Child CG. The liver and 
portal hypertension. Philadelphia:Saunders. 1964. pp. 50-64. 
2. Pugh RN, Murray-Lyon IM, Dawson L, Pietroni MC, Williams R . “Transection of te 
oesophagus for bleeding oesophageal varices”. The British journal of surgery, 1973;60: 
646-9.