Phase I/II Trial of Ibrutinib, Dexamethasone, and Lenalidomide as Initial Therapy for Transplant Ineligible Multiple Myeloma Patients
Phase: PHASE1
Conditions: Recurrent Plasma Cell Myeloma, Refractory Plasma Cell Myeloma
Sponsor: Mayo Clinic

M C 1 4 8 A / 1 6- 0 0 4 1 7 9 
P h a s e I/II Tri al of I br uti ni b, D e x a m et h a s o n e, a n d L e n ali d o mi d e a s 
I niti al T h era p y f or Tr a n s pl a nt I n eli gi bl e M ulti pl e M y el o m a P ati e nt s 
N C T 0 3 0 1 5 7 9 2 
D o c u m e nt D at e: 0 2/ 0 8 / 2 0 2 2 

MC148A 
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Mayo Clinic Cancer Center 
 
Phase I/II Trial of Ibrutinib, Dexamethasone, and Lenalidomide as Initial Therapy for Transplant 
Ineligible Multiple Myeloma Patients 
 
 
 
 
Study Chairs: 
Sikander Ailawadhi, MD 
Mayo Clinic 
4500 San Pablo Rd 
Jacksonville, FL 32256 
904 953 2607 
 
 
Study Co-chairs: 
Asher A Chanan-Khan, MD 
 
 
Vivek Roy, MD 
 
 
Taimur Sher, MD 
 
 
Statistician: 
Betsy R LaPlant MS√ 
 
 
√Study contributor(s) not responsible for patient care 
 
 
Drug Availability 
Commercial Agents: Lenalidomide, Dexamethasone 
Drug Company Supplied: Ibrutinib IND#132492 
 
 
 
 
Document History 
(Effective Date) 
Activation 
Amendment 1 
Amendment 2 
Amendment 3 
Amendment 4 
November 7, 2016 
November 20, 2017 
February 1, 2018 
September 11, 2018 
Pending Approval 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Protocol Resources 
Questions: 
Contact Name: 
Patient eligibility*, test schedule, 
treatment delays/interruptions/adjustments, 
dose modifications, adverse events, 
forms completion and submission 
Patricia A Koenig RN, Quality Assurance Specialist  
Phone: 507-284-4642  
Email: koenig.patricia@mayo.edu  
Drug administration, infusion pumps,  
nursing guidelines 
Lisa Kottschade, RN 
Phone: 507-284-0207 
Email: kottschade.lisa@mayo.edu 
 
Forms completion and submission 
Dustin Chapin, CCRP 
Phone: 904-953-3768  
Email: Chapin.Dustin@mayo.edu  
 
Protocol document, consent form, 
regulatory issues 
Nichole Plouffe, Protocol Development Coordinator 
Phone: 904-953-0314 
Email: Plouffe.Nichole@mayo.edu  
 
Serious Adverse Events  
Patricia G McNamara, SAE Coordinator 
Phone: 507-266-3028 
E-mail: mcnamara.patricia@mayo.edu 
 
*No waivers of eligibility 
 

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Table of Contents 
Phase I/II Trial of Ibrutinib, Dexamethasone, and Lenalidomide as Initial Therapy for Transplant 
Ineligible Multiple Myeloma Patients 
1 
Protocol Resources 
 
2 
Table of Contents 
 
3 
Schema – Phase 1 (1-3 prior lines of therapy) 
4 
Schema – Phase II (previously untreated multiple myeloma) 
5 
1.0 
Background 
6 
2.0 
Goals  
13 
3.0 
Patient Eligibility 
14 
4.0 
Test Schedule 
17 
5.0 
Grouping Factor: 
20 
6.0  
Registration/Randomization Procedures 
20 
7.0 
Protocol Treatment 
22 
8.0 
Dosage Modification Based on Adverse Events 
24 
9.0 
Ancillary Treatment/Supportive Care 
32 
10.0 
Adverse Event (AE) Reporting and Monitoring 
34 
11.0 
Treatment Evaluation 
44 
12.0 
Descriptive Factors 
49 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient 
49 
14.0 
Body Fluid Biospecimens 
51 
15.0 
Drug Information 
55 
16.0  
Statistical Considerations and Methodology 
65 
17.0 
Pathology Considerations/Tissue Biospecimens: None. 
74 
18.0 
Records and Data Collection Procedures 
75 
19.0  
Budget  
76 
20.0 
References 
77 
Appendix I 
Myeloma Frailty Score 
79 
Appendix II 
Activities of Daily Living (ADL) and Instrumental Activities of Daily 
Living (IADL) 
80 
Appendix III 
Charlson Comorbidity Index 
81 
Appendix IV 
ECOG Performance Status Scale 
82 
Appendix V 
Creatinine Clearance (CrCl) Calculation 
83 
Appendix VI 
New York Heart Association Classification of Congestive Heart Failure 84 
Appendix VII 
Mayo Risk Stratification 
85 
Appendix VIIIa 
Patient Medication Diary (Phase I/Phase II) 
87 
Appendix VIIIb 
Patient Medication Diary (Phase II, Cycle 1 Only) 
89 
Appendix IX 
MDASI-MM Questionnaire 
91 
Appendix X 
Inhibitors and Inducers of CYP3A 
93 
Appendix XI 
Serum Calcium Corrected for Albumin 
95 
Appendix XII 
Child-Pugh Score 
96 
Appendix XIII 
Patient Information Sheet 
97 

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Schema – Phase 1 (1-3 prior lines of therapy) 
 
Phase I only: Prior to discussing protocol entry with the patient,  
call the MCCC Registration Office (507-284-2753) for dose level and  
to insure that a place on the protocol is open to the patient. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 Cycle length=28 days 
2 Cycle length = 84 days 
3  Repeat every 28 days x 3 for each cycle  
 
 
 
Generic name: Ibrutinib  
Brand name(s): Imbruvica® 
Mayo Abbreviation: PCI-32765  
Availability: Provided by 
Pharmacyclics 
Generic name:    Lenalidomide 
Brand name(s): Revlimid® 
Mayo Abbreviation: REVLIMID 
Availability: Commercial 
Generic name: Dexamethasone 
Brand name(s): Decadron® 
Mayo Abbreviation: DXM  
Availability: Commercial 
Treatment1  
Ibrutinib Days 1-28 
Lenalidomide Days 1-21 
Dexamethasone Days 1, 8, 15, 22 
x 24 cycles 
Registration 
Event 
Monitoring 
Treatment2,3 
Lenalidomide Days 1-21 
Dexamethasone Days 1, 8, 15, 22 
PD at any time 
Unacceptable adverse   
Event 
 
events 
 
 
Monitoring 
Patient refusal 
Subsequent treatment 

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Schema – Phase II (previously untreated multiple myeloma) 
NOTE: Phase II will not be initiated until after FDA review of Phase I data  
and approval to continue 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 Cycle length = 28 Days 
2 Cycle length = 84 days 
3  Repeat every 28 days x 3 for each cycle  
 
 
Generic name: Ibrutinib  
Brand name(s): Imbruvica® 
Mayo Abbreviation: PCI-32765  
Availability: Provided by  
Pharmacyclics 
Generic name:    Lenalidomide 
Brand name(s): Revlimid® 
Mayo Abbreviation: REVLIMID 
Availability: Commercial 
Generic name: Dexamethasone 
Brand name(s): Decadron® 
Mayo Abbreviation: DXM  
Availability: Commercial 
 
PD at any time 
Unacceptable adverse   
Event 
events  
 
Monitoring 
Patient refusal 
Subsequent treatment 
Registration 
Treatment1 
Ibrutinib Days 1-28 and  
Dexamethasone Days 1,8,15, 22  
x 1 cycle 
Treatment1 
Ibrutinib Days 1-28 
Lenalidomide Days 1-21 
Dexamethasone Days 1, 8, 15, 22 
x 23 cycles  
Treatment2,3 
Lenalidomide Days 1-21 
Dexamethasone Days 1, 8, 15, 22 
Event Monitoring 

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1.0 
Background 
1.1 
Multiple Myeloma 
Multiple myeloma is a malignant disorder of the plasma cells, characterized by 
uncontrolled and progressive proliferation of a plasma cell clone. The disease leads to 
progressive morbidity and eventual mortality by lowering resistance to infection and 
causing significant skeletal destruction (with bone pain, pathological fractures, and 
hypercalcemia), anemia, renal failure, neurological complications and hyper viscosity 
syndrome. 
 
The majority of patients with multiple myeloma produce a monoclonal protein, also 
called paraprotein, M-protein or M-component, which is an immunoglobulin (Ig) or a 
fragment of one that has lost its function1,2. Normal immunoglobulin levels are 
compromised, leading to susceptibility of infections. The proliferating multiple myeloma 
cells displace the normal bone marrow leading to dysfunction in normal hematopoietic 
tissue and destruction of the normal bone marrow architecture, which is reflected by 
clinical findings such as anemia, paraprotein in serum or urine, and bone resorption seen 
as diffuse osteoporosis or lytic lesions shown in radiographs 3. Furthermore, 
hypercalcemia, renal insufficiency or failure, and neurological complications are 
frequently seen4.  A small minority of patients with multiple myeloma are non-secretory. 
 
At the time of diagnosis, multiple myeloma is a heterogeneous disease, with a course that 
varies on the basis of both disease- and host-related factors (e.g., age, renal function, 
stage, chromosomal abnormalities). Multiple myeloma causes significant morbidity and 
mortality. It accounts for approximately 1% of all malignancies and 13% of hematologic 
cancers. Approximately 50,000 patients per year are diagnosed with multiple myeloma in 
the EU and US, and 30,000 patients per year die due to multiple myeloma. 
 
1.2 
Treatment for Multiple Myeloma 
Treatment choices for multiple myeloma vary with age, performance status, comorbidity, 
the aggressiveness of the disease, and related prognostic factors4. Newly diagnosed 
patients with multiple myeloma are typically categorized into 2 subpopulations usually 
defined by their age and suitability for the subsequent approach to treatment. Younger 
patients will typically receive an induction regimen followed by consolidation treatment 
with high-dose chemotherapy and autologous stem cell transplantation (ASCT). For those 
not considered suitable for high-dose chemotherapy and ASCT, longer-term treatment 
with multi-agent combinations including alkylators, high-dose steroids, and novel agents 
are currently considered as standards of care. 
 
Over the past few years several novel treatments (immunomodulatory drugs; IMiDs and 
proteasome inhibitors) have become available for patients with MM. Although higher 
percentages of patients are achieving remission, all patients eventually relapse and 
become resistant to therapy. Novel agents and new combinations regimens are needed for 
improved outcome in this disease. There is an increasing body of evidence suggesting 
that clinical or laboratory parameters may be important in selecting specific treatment 
options for patients with MM5-7. This is further important since the novel agents being 
used for the treatment of MM have their own inherent side effect profiles that are unique 
and need specific management as against the more expected adverse events from 
conventional chemotherapeutic agents. This is especially true in elderly patients who may 

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have other comorbidities, since the median age at diagnosis for MM is 70 years. Thus, 
there is a constant need to develop newer, better tolerated agents/regimens that can keep 
the disease controlled for prolonged durations as well as be safe with respect to low 
cumulative toxicities. A recently developed tool based on geriatric assessment has been 
validated in a pooled analysis by the International Myeloma Working Group and is 
recommended to be used prospectively in trials focusing on non-transplant eligible newly 
diagnosed MM patients, which is the target population for this proposed clinical trial.8 
This tool will be utilized in the said protocol to address patient eligibility. 
 
1.3 
Lenalidomide (len) and Dexamethsone (dex) in Treatment Naive MM Patients 
The combination of len and dex is widely used as an initial regimen for elderly patients 
and those considered ineligible for ASCT)9. Although IMiDs are a relatively safe and 
convenient oral option for MM patients, they have their own set of adverse events 
including cytopenias, risk of thrombosis, necessitating the use of thromboprophylaxis, 
and more recently noted potential risk of second primary malignancies (SPM). 
Furthermore, len use in patients with renal insufficiency (seen in up to 20% patients with 
MM at the time of initial diagnosis) is difficult due to an amplified adverse event profile 
seen as a result of prolonged half-life of the drug in these patients. Newer agents that may 
be oral and free of such potential adverse events need to be tested in this MM population, 
where ASCT may not be an option due to age and comorbidities. 
 
1.4 
BTK Inhibition 
One such novel agent is ibrutinib (ibr), a small-molecular inhibitor of Bruton’s Tyrosine 
Kinase (BTK), administered by mouth once daily. In normal B-cell development the 
receptor for B-cell activating factor (BAFF) of the TNF family (BAFF-R) is coupled to 
the NF-κB pathway by BTK10. Loss of BTK results in defective BAFF-mediated 
activation of both canonical and non-canonical NF-κB pathways. Thus, BAFF-induced 
signaling to NF-κB via BTK serves to promote B-cell survival. These findings are in 
keeping with the clinical observations that genetic defects in BTK are associated with a 
profound deficiency of B-cells,11 and that the BTK inhibitor ibr is cytotoxic to chronic 
lymphocytic leukemia (CLL) cells 12,13. As the NF-κB pathway is central to myeloma cell 
survival, and BTK couples cell survival surface signals to the NF-κB pathway in B-cell 
development, as well as the BTK inhibitor, ibr being highly effective in killing CLL cells, 
further investigation of the efficacy of ibr in MM is warranted. 
 
1.5 
BTK Inhibition in B-cell Malignancies Including MM 
Ibrutinib is approved by the FDA for the treatment of certain B-cell malignancies 
including CLL, Waldenstrom’s macroglobulinemia (WM) and relapsed/refractory mantle 
cell lymphoma (MCL). Ongoing clinical trials are exploring the efficacy of ibrutinib, 
alone or in combination regimens in patients with MM. One of these, an open label phase 
2 dose escalation study in patients with relapsed and/or refractory MM (n=69) with a 
median of 4 prior lines of therapy has shown that at Ibr doses higher than those used in 
CLL and MCL (840 mg vs. 420 mg and 560 mg, respectively), the clinical benefit rate 
(≥minor response) was 25% and another 25% achieved stable disease (SD), leading to a 
median progression free survival (PFS) of 5.6 months.14 Patients in this clinical trial were 
relatively heavily pre-treated with median 4 prior lines of therapy. Another phase 1 
clinical trial of Ibr (560-840 mg) in combination with carfilzomib (20/27-20/36 mg/m2) 
and dexamethasone is underway and preliminary results have shown that at these doses 

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and in this combination, Ibr did not cause any dose-limiting toxicities (DLT) and the dose 
escalation is currently underway. Patients (n=39) in this trial had a median of 3 prior lines 
of therapy and all were refractory to their most recent therapy (presented at American 
Society of Hematology Annual Meeting, 2015). The overall response rate (ORR) noted 
was 58% with a clinical benefit rate of 67%. Of note, 25% of the patients enrolled had 
previous exposure to carfilzomib and pomalidomide. Other clinical trials of Ibr with anti-
MM agents including pomalidomide are planned. Using it earlier on in the clinical course 
of MM patients may show a clearer signal of the efficacy of ibr in MM. Furthermore, 
long-term follow up data from patients treated with ibr for CLL, MCL and 
Waldenstrom’s macroglobulinemia (WM) have shown an excellent tolerability of ibr, 
without any major or cumulative adverse events. 
 
1.6 
Rationale for Combining Ibrutinib with Lenalidomide 
The exact mechanism of action for len is not fully understood. Efficacy of len is in part 
by augmenting interferon-β (IFNβ) production. In a cereblon-dependent fashion, len 
down regulates IRF4 and SPIB, transcription factors that together prevent IFNβ 
production by repressing IRF7 and amplify prosurvival NF-κB signaling by 
transactivating CARD11. Blockade of B cell receptor signaling by BTK inhibition using 
ibr also down regulates IRF4 and consequently synergizes with len in cell death, 
suggesting attractive combination therapeutic strategies15. Furthermore, we have 
performed apoptosis assays in resistant (CD20-) and sensitive (CD20+) WM (a plasma 
cell disorder related to MM) cell lines (BCWM1 and RPCIWM1), showing potential 
synergy for the combination of ibr and len (Figure 1; unpublished data). Two ongoing 
phase 1 trials of the combination of ibr and len in B-cell malignancies have recently been 
presented with initial reports. These include one in relapsed and/or refractory CLL16, and 
the other in relapsed and/or refractory 
NHL17. Both these trials are currently 
undergoing dose escalations but are 
different from the proposed trial in 
MM since the patients in these trials 
were relatively heavily pre-treated. 
Since the dose of this combination, 
especially with dexamethasone which 
is an integral part of MM treatment is 
not yet determined, a formal phase 1 
component of the trial is proposed and 
necessary. 
 
Thus, it is rational to test the efficacy of ibr in MM as a single-agent as well as in 
combination with len+dex, especially in treatment-naive elderly or transplant ineligible 
patients, where a more favorable adverse event profile is desirable. Since such a 
combination has not been previously tested in MM, an initial phase 1 trial component 
with a recommended phase 2 dose (RP2D) strategy for the combination of ibr with len 
and dex is being proposed. After the RP2D of this combination has been determined, 
subsequent enrollment would be with patients initially treated with ibr and dex and after 
completing the first cycle of treatment with this (1 cycle=28days), len will be added. This 
will help provide important correlative data to explore the biological activity as well as 
pharmacodynamics of ibrutinib in myeloma, for which concrete data is so far lacking 
despite clinical trials showing efficacy. 
Figure 1. In vitro data showing potential synergy of Len+Ibr in 
MM and WM cell lines  

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1.7 
Correlative Research 
1.71 
To determine the role of members of the BTK signalosome in achievement or lack 
thereof of response to ibrutinib: The variability in extent of response to a 
therapeutic agent may suggest underlying adaptability of the MM clone through 
components of the BTK signalosome. Patients with B-cell malignancies treated 
with ibr demonstrate upregulation of p-Akt and p-Erk (downstream mediators of 
BTK) in some (but not all) cases, suggesting that these pathways may contribute 
to survival of the malignant clone.18 It was also concluded in this work that these 
cells might not be dependent upon the proximal BTK pathways mediated 
apoptosis and thus, resistant to killing by ibr. To address this question we will 
establish the profile of BTK signalosome for each patient through determination 
of the mRNA (RT-PCR/nanostring assay; whole exome sequencing (WES), 
transcriptom analysis) and protein expression (western blot analysis) of members 
of the BTK signaling pathway and look for associations between this and 
eventual response (or lack thereof) to the treatment. The said tests will be done 
analyzing the CD138+ cells enriched from the bone marrow samples collected at 
baseline, after 1 month of treatment with ibr alone and then at the time of disease 
progression. This will help explore mechanisms of acquired resistance to ibr. In 
MM. We will also look for pAKT, pS6 and pERK as indirect pharmacodynamic 
biomarkers analyzed in patient’s PBMC collected as a peripheral blood sample at 
baseline and then after 1 cycle of treatment with ibr, prior to adding the len/ dex. 
 
1.72 
To explore biologic effects of ibrutinib on microenvironment in MM and 
correlate with response to treatment: In cancer redirection of host immunity 
from a predominant Th2 to Th1 response can deliver antitumor response. Ibr can 
bind to ITK, a member of the TEC-kinase family, which mediates TCR signaling 
through PLCg, NFAT, NF-kappaB and MAPK.19 This results in activation and 
proliferation of CD8+ cells. Our hypothesis is that ibr alters the Th2:Th1 balance 
in the blood and bone marrow microenvironment, skewing towards a more Th1 
profile and this may translate into its clinical efficacy. We further hypothesize 
that the robustness of the Th1 response will direct ibr’s depth of response. We 
will assess this in bone marrow samples comparing the baseline sample to one 
collected after 1 cycle of treatment with ibr using the MultiOmyx Tumor 
Infiltrating Lymphocytes panel for T helper (CD4+), Treg (FOXP3+), T 
cytotoxic (CD8+), B cells (CD20+), macrophage (CD68+), NK cells (CD56+), 
immunosuppression (PD-L1), CD138+, CD38+, ITK and BTK. Furthermore, 
BTK/ITK occupancy by ibr has been associated with response rates in other B-
cell malignancies where this is an effective agent (CLL) but this has never been 
tested in MM. This assay will be performed to assess target coverage in bone 
marrow samples obtained from patients at the end of 1 cycle of treatment with 
ibr. In addition, PBMC samples (2 ml of whole blood with heparin) from 
baseline and after 1 cycle of treatment with ibr will be assessed for: 
Th1 cells (live+, CD19-, CD3+, CD4+, CD8-, IFNg+) 
Th2 cells (live+, CD19-, CD3+, CD4+, CD8-, IL4+) 
Th17 cells (live+, CD19-, CD3+, CD4+, CD8-, IL17+) 
Treg cells (live+, CD19-, CD14-, CD3+, CD4+, CD25+, CD127-, FOXP3, 
CCR4+) 
 
1.73 
To explore compliance to treatment: The proposed regimen in this clinical trial is 
all-oral. Data from other malignant and non-malignant diagnoses (e.g., CML, 

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hypertension) where oral therapeutic agents are utilized have shown that patient 
adherence to treatment is significantly associated with a likelihood of achieving 
better disease control.20-22 This has not been established yet in MM, where oral 
therapeutic agents are being used increasingly, especially in elderly patients 
where there may be a higher medication-burden. Patient compliance to ibr with 
len+dex will be assessed by means of self-reported and healthcare staff assessed 
pill count/diary. Correlation between medication adherence and disease response 
will be assessed. 
 
1.74 
To assess effects of treatment on patient reported Quality of Life (QoL) 
measures: Although orally available therapeutic agents may be more convenient, 
majority of them have to be taken on an ongoing basis as long as there is disease 
response and no “unacceptable” toxicities. This concept with long duration of 
therapy as well as the symptom complex from the disease and the therapeutic 
agents can significantly affect the patient’s QoL, especially in patients with 
advanced age at the time of MM diagnosis.23 In the proposed trial, patient-
reported QoL will be measured with the MD Anderson Symptom Inventory – 
Multiple Myeloma (MDASI-MM), which has been a validated tool.24 The 
MDASI-MM consists of 13 core items, 7 MM-specific symptom severity items 
and 6 interference items; the time frame for addressing symptom severity and 
interference is the last 24 hours. From these items, mean subscale scores have 
been derived: mean Core (13 core items), mean Severity (13 core items + 7 MM-
specific items), and mean Interference (6 interference items); an exploratory 
analysis in this study will examine a 4th score, the mean Severity score for the 7 
MM symptoms. Response options range from 0 (“not present”) to 10 (“as bad as 
you can imagine”) for the severity items and from 0 (“did not interfere”) to 10 
(“interfered completely”) for the interference items. These will be completed by 
patients in a paper or electronic entry as per the following schedule: 
• 
At baseline (within 14 days prior to starting treatment) 
• 
At the end of 1 cycle of treatment 
• 
At six months 
• 
At one year of treatment 
• 
At any time the patient is removed from the study protocol (due to 
disease progression or adverse events; within 14 days of removal from 
the study)  
The primary outcome of interest for this trial is the difference in the change of 
the mean Symptom Severity score for the Core plus 7 MM symptom items from 
baseline to various time points noted above with this treatment regimen. 
 
1.75 
To assess effects of treatment on bone turnover: Bone turnover can be assessed 
by measuring serum levels of RNAKL, RNAK, NFκB, BAP, RUNX2, CBfa1, 
OPG, DKK1, MMP1, MMP2, sFRP-2 protein biomarkers. These will be checked 
at baseline and after 1 month of treatment with ibr alone in order to assess 
whether ibr suppresses osteoclast activation since bone resorption activity is an 
independent risk factor for overall survival in MM. 
 
 

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1.8 
Trial Design 
This will be a phase I/II non-randomized, open label, prospective clinical trial in patients 
with treatment naïve MM, who are considered ineligible for or otherwise refuse to 
undergo an ASCT. Since so far there have not been any clinical trials to determine the 
recommended dose of the combination of ibr with len and dex in MM, a phase I trial of 
this combination in patients with relapsed MM is planned. The reason to limit this trial to 
patients with relapsed MM is to establish safety as well as get an initial signal of efficacy 
of this combination in MM patients prior to introducing this in patients with newly 
diagnosed MM, where the proposed regimen of ibr+len+dex has never been studied 
before. Furthermore, the signal of efficacy in patients with relapsed disease would 
provide a more compelling justification to explore BTK inhibition in patients with newly 
diagnosed MM. In the phase I portion, the dose of len and dex would be fixed at the 
standard dose and the ibr dose would be adjusted to find the RP2D of this combination 
regimen. 
 
1.9 
Ibrutinib Summary of Clinical Safety 
 
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, which 
included 1 randomized-control study, are 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). Most 
frequently reported TEAEs in subjects receiving ibrutinib in combination therapy 
(N=423): 
Most frequently reported TEAEs 
>10%   
Most frequently reported Grade 3 
or 4 TEAEs >2%  
Most frequently reported Serious 
TEAEs >1%  
Neutropenia 
Neutropenia 
Febrile neutropenia 
Diarrhea 
Thrombocytopenia 
Pneumonia 
Nausea 
Febrile neutropenia 
Atrial fibrillation 
Thrombocytopenia 
Pneumonia 
Pyrexia 
Fatigue 
Hypertension  
 
For more detailed information refer to the current version of the IB. 
1.91 
Ibrutinib: Risks 
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, 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 
15.20 for guidance on concomitant use of anticoagulants, antiplatelet therapy 
and/or supplements and ibrutinib management with surgeries or procedures. 

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1.92 
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. For atrial fibrillation which 
persists, consider the risks and benefits of ibrutinib treatment and follow the 
protocol dose modification guidelines (see Section 8). 
1.93 
Cytopenias 
Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, 
and anemia) were reported in subjects treated with ibrutinib. 
1.94 
Diarrhea 
Diarrhea is the most frequently reported non-hematologic AE with ibrutinib 
monotherapy and combination therapy. Other frequently reported gastrointestinal 
events include nausea, vomiting, and constipation. These events are rarely severe. 
Should symptoms be severe or prolonged follow the protocol dose modification 
guidelines (see Section 8). 
1.95 
Infections 
Fatal and non-fatal infections have occurred with ibrutinib therapy. At least 25% 
of subjects with MCL and 35% of subjects with CLL had Grade 3 or greater 
infections per NCI Common Terminology Criteria for Adverse Events 
(CTCAE v4.0). The most commonly reported infections include pneumonia, 
cellulitis, urinary tract infection and sepsis. Although causality has not been 
established, cases of progressive multifocal leukoencephalopathy (PML) have 
occurred in patients treated with ibrutinib. 
1.96 
Non-melanoma skin cancer 
 Non melanoma skin cancers have occurred in subjects treated with Ibrutinib. 
Monitor subjects for the appearance of non melanoma skin cancer. 
1.97 
Rash 
Rash has been commonly reported in subjects treated with either single agent 
ibrutinib or in combination with chemotherapy.  In a randomized Phase 3 study 
(PCYC-1112-CA), rash occurred at a higher rate in the ibrutinib arm than in the 
control arm. Most rashes were mild to moderate in severity. 
1.98 
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 LDH, bulky disease at baseline, and pre-existing kidney abnormalities. 
1.99 
Interstitial Lund 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). 
 
 

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2.0 
Goals 
2.1 
Primary Objective: 
2.11 
Phase 1: To determine the maximum tolerated dose (MTD) of ibrutinib that can 
be combined with lenalidomide and dexamethasone in relapsed MM patients. 
2.12 
Phase 2: To estimate the overall response rate (ORR) including partial response 
(PR) or better of the combination of ibrutinib, lenalidomide, and dexamethasone 
in subjects with newly diagnosed MM who are not candidates for high dose 
chemotherapy and ASCT. 
2.2 
Secondary Objectives: 
Phase I 
2.21 
To evaluate the safety profile of this regimen in relapsed MM patients. 
Phase II 
2.22 
To evaluate the progression free survival (PFS) of the combination of ibrutinib, 
lenalidomide, and dexamethasone in MM patients  
2.23 
To evaluate the safety profile of this regimen in untreated MM patients. 
2.24 
To evaluate the duration of response for patients treated with this 3-drug 
regimen. 
2.25 
To evaluate overall survival (OS) for patients treated with this 3-drug regimen 
2.3 
Exploratory Objective: 
2.31 
To explore compliance to treatment. 
2.32 
To assess effects of treatment on patient-reported quality of life (QoL) measures 
2.4 
Correlative Research Objective: 
2.41 
To determine the role of members of the BTK signalosome in achievement or 
lack thereof of response to ibrutinib. 
2.42 
To explore biologic effects of ibrutinib on microenvironment in MM and 
correlate with response to treatment. 
2.43 
To evaluate pharmacodynamic measures including receptor occupancy for BTK 
prior to introducing lenalidomide in patients treated with ibrutinib and 
dexamethasone. 
2.44  
To evaluate the impact of ibrutinib on platelet aggregation. 
 

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3.0 
Patient Eligibility 
Phase I only: Prior to discussing protocol entry with the patient, call the MCCC 
Registration Office (507-284-2753) for dose level and to insure that a place on the protocol is 
open to the patient.  
3.1 
Inclusion Criteria 
3.11 
Age ≥18 years. 
3.12 
Diagnosis: 
3.121 Phase I: Confirmed diagnosis of relapsed or refractory multiple myeloma 
3.122 Phase II: Confirmed diagnosis of active multiple myeloma and must be 
newly diagnosed.  
NOTE: All tests for establishing disease status must be completed ≤28 
days prior to registration. 
3.13 
Measurable disease ≤28 days prior to registration, defined by at least one of the 
following: 
• 
Serum monoclonal protein ≥1.0 g/dL (see Section 11.1 for definition) 
• 
>200 mg of monoclonal protein in the urine on 24-hour electrophoresis  
• 
Serum immunoglobulin free light chain >10 mg/dL AND abnormal serum 
immunoglobulin kappa to lambda free light chain ratio. 
• 
Monoclonal bone marrow plasmacytosis >30% (evaluable disease). 
3.14 
Prior treatment: 
3.141 Phase I: Exposure to 2-3 prior lines of therapy or no therapeutic options 
3.142 Phase II: Previously untreated for symptomatic MM.  
EXCEPTION: ≤7 days with pulse steroids or localized radiation 
therapy, without curative intent, for a myeloma-related complication 
prior to registration is allowed, as considered necessary by the treating 
physician. 
3.15 
Myeloma Frailty Score: 
NOTE: This will include calculating a frailty score [Appendix I; based on age, 
activities of daily living, instrumental activities of daily living (Appendix II) and 
Charlson comorbidity index (Appendix III)]. 
3.151  Phase I: “Intermediate fitness” or “Frail” 
NOTE: No “fit” patients will be included in the phase 1 portion of the 
trial which is being done to determine the MTD of the 3-drug 
combination. 
3.152 Phase II: Transplant-ineligible as per their treating physician.  
NOTE: All the patients with “intermediate fitness” or “frail” status will 
be considered transplant-ineligible. Other reasons to consider transplant 
ineligibility may include, but are not limited to: financial constraints or 
patient preference. In case such patients have a frailty score of “fit”, it 
should be duly noted by the treating physician. 
3.16 
ECOG Performance Status 0, 1, or 2 (Appendix IV). 
 
 

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3.17 
The following laboratory values obtained ≤14 days prior to registration: 
• 
Absolute neutrophil count (ANC) ≥1,000 cell/mm3 without growth factor 
support 
• 
Platelets ≥50,000 cells/mm3 for patients who have bone marrow 
plasmacytosis <50% or ≥30,000 cells/mm3 for patients who have bone 
marrow plasmacytosis of ≥50% 
• 
Calculated or measured creatinine clearance ≥30 ml/min (see Appendix V) 
• 
Total bilirubin ≤1.5 x upper limit of normal (ULN) unless due to Gilbert’s 
syndrome.  
• 
 Aspartate aminotransferase (AST)/SGOT and alanine aminotransferase 
(ALT)/SGPT ≤3 x ULN 
• 
PT/INR ≤1.5 X ULN 
3.18 
Provide informed written consent. 
3.19a 
Willing to return to enrolling institution for follow-up (during the Active 
Monitoring Phase of the study). 
3.19b Persons able to become pregnant must be willing to adhere to the scheduled 
pregnancy testing as required in the REVLIMID REMS™ program. 
3.19c 
Willing to be registered into the mandatory REVLIMID REMS™ program, and 
willing and able to comply with the requirements of the REVLIMID REMS™ 
program. 
3.19d Ability to complete study-related (QoL, pill diary) questionnaire(s) by 
themselves or with assistance. 
3.19e 
Willing to provide bone marrow aspirate and core, and blood samples for 
correlative research purposes (see Sections 6.31, 14.0). 
 
3.2 
Exclusion Criteria 
3.21 
Non-secretory MM or known AL amyloidosis. 
3.22 
Clinically significant active infection requiring intravenous antibiotics ≤14 days 
prior to registration. 
3.23 
≥Grade 3 neuropathy and/or POEMS syndrome (plasma cell dyscrasia with 
polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin 
changes). 
3.24 
Other prior malignancy. 
EXCEPTIONS:  
• 
Adequately treated basal cell or squamous cell skin cancer 
• 
Any in situ cancer 
• 
Adequately treated Stage I or II cancer from which the patient is currently in 
complete remission, or 
• 
Any other cancer from which the patient has been disease-free for ≥at least 
three years prior to registration 
3.25 
Concurrent therapy considered to be investigational.  
NOTE: Patients must not be planning to receive any radiation therapy (except 
localized radiation for palliative care that must be completed prior to starting 
Cycle 1, Day 1). 

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3.26 
Any of the following because this study involves an investigational agent whose 
genotoxic, mutagenic and teratogenic effects on the developing fetus and 
newborn are unknown:  
• 
Pregnant women 
• 
Nursing women (lactating females are eligible provided that they agree not to 
breast feed while taking lenalidomide) 
• 
Men or women of childbearing potential who are unwilling to employ 
adequate contraception  
3.27 
Requires treatment with a strong cytochrome (CYP) 3A4/5 inhibitor (as outlined 
in Appendix X). 
3.28 
Major surgery ≤4 weeks prior to registration. 
3.29a 
History of stroke/intracranial hemorrhage ≤6 months prior to registration. 
3.29b Requires use of therapeutic anticoagulation prior to registration  
NOTE: thromboprophylaxis with any agent is permitted. 
3.29c 
History of clinically significant bleeding or known platelet or coagulation 
disorder. 
3.29d Clinically significant cardiac illness including New York Heart Association 
(NYHA) Class III or Class IV heart failure (Appendix VI), unstable angina 
pectoris, myocardial infarction within the past 6 months, or ≥Grade 3 cardiac 
arrhythmias noted ≤14 days prior to registration.  
3.29e 
Hepatic impairment 
3.29e1 
Phase I 
Any currently active, clinically significant hepatic impairment (Child-
Pugh class A, B, or C according to the Child Pugh classification see 
Appendix XII). 
3.29e2 
Phase II 
Currently active, clinically significant hepatic impairment Child-Pugh 
class B or C according to the Child Pugh classification (see Appendix 
XII). 
3.29f 
Known HIV+ patients  
EXCEPTION: If they meet the following additional criteria ≤28 days  prior to 
registration: 
• 
CD4 cells ≥500/mm3 
• 
Viral load of <50 copies HIV mRNA/mm3 if on cART or <10,000 copies 
HIV mRNA if not on cART 
• 
No zidovudine or stavudine as part of cART 
3.29g Known Hepatitis B or Hepatitis C infection 
EXCEPTION: If viral load <800,000 IU/L.  
 
3.29h  Phase I : Active dermatologic disease ≥ Grade 3.  
 

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4.0 
Test Schedule  
4.1 
Test schedule Phase I and II 
 
Prior to Registration 
Active Monitoring Phase 
Tests and Procedures 
≤28 days 
prior to 
registration 
≤14 days 
prior to 
registration 
Every 
14 days 
during 1st 
2 cyclesa 
Cycles 1-24: 
Every 28 days  
(Day 1 of every cycle) 
pre-treatmenta,b 
Cycles 25 and after: 
Every 84 days  
(Day 1 of every cycle) 
pre-treatmenta,b 
End of 
treatmenta 
Informed Consent 
X 
 
 
 
 
 
Complete medical and disease history 
 
X 
X 
X 
X 
X 
Physical examination including skin examc 
 
X 
X 
X 
X 
X 
Height 
 
X 
 
 
 
 
Vital signsc 
 
X 
X 
X 
X 
X 
Performance status (ECOG scale)(Appendix IV)  
 
X 
 
X 
X 
X 
Registered in the REVLIMID REMS™ programo 
 
X 
 
X 
X 
 
Hematologyd 
 
X 
X 
X 
X 
X 
Coagulatione 
 
X 
 
X 
X 
 
Blood chemistriesf 
 
X 
X 
X 
X 
X 
Bone marrow aspirate and biopsy with standard clinical 
testing (including but not limited to myeloma FISH and 
flow cytometry) 
X 
 
 
Xg 
Xg 
Xg 
Electrophoresis of serum and urine (SPEP/UPEP) 
X 
 
 
X  
X  
X  
Affected immunoglobulin  
X 
 
 
Xr 
Xr 
Xr 
Immunofixation serum and urine (IF)  
X 
 
 
X  
X  
X  
Immunoglobulin free light chain (FLC) 
X 
 
 
X  
X  
X  
Serum β2-microglobulin, CRP 
 
X 
 
 
 
 
ECGp 
 
X 
 
Xp 
Xp 
 
Skeletal bone survey 
X 
 
 
Xh 
Xh 
Xh 
PET scan 
X 
 
 
Xh 
Xh 
Xh 
Research blood sample (Section 14.0)R 
 
Xq 
 
X 
X 
X 
Research bone marrow (Section 14.0)i,R 
Xq 
 
 
X 
X 
X 
Concomitant medicationsj 
 
X 
 
 
 
 
Adverse Event monitoringk 
 
X 
X 
X 
X 
X 
Pregnancy testl 
 
X 
 
X 
X 
X 
Patient Medication Diary (Appendix VIII)m 
 
 
 
X 
X 
X 

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Prior to Registration 
Active Monitoring Phase 
Tests and Procedures 
≤28 days 
prior to 
registration 
≤14 days 
prior to 
registration 
Every 
14 days 
during 1st 
2 cyclesa 
Cycles 1-24: 
Every 28 days  
(Day 1 of every cycle) 
pre-treatmenta,b 
Cycles 25 and after: 
Every 84 days  
(Day 1 of every cycle) 
pre-treatmenta,b 
End of 
treatmenta 
Patient Questionnaire Booklets, (Appendix IX)n 
 
X 
 
X 
X 
X 
 
Cycle length = 28 days Cycles 1-24; Cycle length = 84 days Cycles 25 and beyond 
a) All scheduled visits will have a window of ±3 days unless otherwise stated, all procedures to be completed ≤3 days prior to commencing 
subsequent treatment cycle 
b) Does not need to be repeated on Cycle 1, Day 1, if completed ≤14 days prior to registration 
c) To include blood pressure, pulse rate, temperature, weight. Screening for second primary malignancies and especially dermatologic cancers is 
recommended per standard clinical practice. All patients must have documentation at baseline for any skin lesions considered at risk of a 
melanoma or non-melanomatous skin cancer. If any such lesion is identified, it should be addressed immediately. During the conduct of the 
clinical trial, please monitor for any potential skin malignancy lesions, as considered clinically necessary. All male patients at risk for prostate 
cancer recommended to undergo screening including a serum PSA level if not done ≤6 months prior to registration. 
d) Hematology: CBC with differential, including hemoglobin and platelet count 
e) Coagulation: prothrombin time (PT) and international normalized ratio (INR) 
f) Blood chemistries: sodium, chloride, potassium, magnesium, phosphate, uric acid, BUN, glucose, ALT/AST (SGPT/SGOT), alkaline 
phosphatase, total protein, total bilirubin, albumin, serum creatinine, and estimated creatinine clearance (Appendix V), calcium and lactate 
dehydrogenase (LDH).  
g) Standard of care procedure ≤28 days prior to registration, and to document CR, sCR or PD while on treatment (whether PD noted to single-
agent ibr or the combination of ibr with len+dex). NOTE: For Phase II, an additional bone marrow biopsy and aspirate will be collected after 
completion of Cycle 1 of treatment for correlative sample collection in order to evaluate the exploratory endpoints of the study. 
h) Skeletal bone survey and PET scan for extramedullary disease assessment ≤28 days prior to registration and then at any time when disease 
progression is noted, clinically or on laboratory assessment. 
i) Per Section 14, to coincide with the timing of all standard-of-care bone marrow aspirate/biopsy collections in addition to a mandatory 
collection done prior to starting second cycle in Phase 2. 
j) Concomitant medications: all on-going medications and those taken ≤14 days prior to first dose until 30 days after the last dose.  Recorded in 
medical record only after baseline. Prior to every cycle, all patient medications must be reviewed and recorded in the medical record (see 
Appendix X for a list of contraindicated medications).   
k) During treatment period, at end of treatment visit. The patient should be contacted by a nurse 30 days after the last dose of study treatment (or 
at the time of initiation of subsequent treatment if started before 30 days) to check if the patient has experienced any late adverse events. Grade 
3 or higher adverse events at least possibly related to study treatment and deaths due to any cause should be reported as a late adverse event on 
the event monitoring form if they were not already reported on the Adverse Event  form for the last cycle and they occurred prior to any 
subsequent treatment. and 30 days post-end of treatment 

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l) For persons of childbearing potential, a negative pregnancy test (urine or serum) must be documented. A person of childbearing potential is a 
sexually mature human with an intact uterus who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally 
postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). Frequency of 
testing as required by REMS® program or as clinically indicated. 
m) To be collected on day 1 of every cycle starting cycle 2 and at end of treatment, in order to document patient compliance to treatment. 
Separate records to be collected for ibrutinib, lenalidomide and dexamethasone 
n) MDASI-MM questionnaire to be completed at baseline (≤14 days prior to starting treatment), at the end of Cycle 1 (± 3 days), at the end of 
Cycle 6 (±3 days) and at completion of Cycle 12 of treatment (±3 days), at any time the patient progresses while on the 3-drug regimen and is 
removed from the study treatment (≤14 days after removal from the study) 
o) All unused lenalidomide must be returned as instructed through the REVLIMID REMS™ program. 
p) To be performed at screening and as clinically indicated throughout the study. Check ECG at any time if the patient’s vital signs suggest an 
issue or if the patient has complaints that could be related to atrial fibrillation including subtle findings such as otherwise unexplained fatigue 
or nausea.  
q) Collected after registration but prior to treatment. 
r) Serum immunoglobulins to include IgA, IgG, IgM in all cases and IgD, IgE as clinically indicated.  
 
R Research test (see Sections 14.0 and 19.0). 
 
4.2 
Event Monitoring/Survival Follow-up 
 
Event Monitoring Phase1 
q. 3 months 
until PD or 
subsequent 
treatment  
At PD 
or 
subsequent 
therapy 
After PD or 
subsequent 
therapy  
q. 6 months 
Death 
New Primary 
Event Monitoring 
X 
X 
X 
X 
At each 
occurrence 
1. If a patient is still alive 3 years after registration, no further follow-up is required. 
 

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5.0 
Grouping Factor: 
5.1 
Phase I vs. Phase II 
6.0  
Registration/Randomization Procedures 
6.1 
Phase I 
Prior to discussing protocol entry with the patient, call the MCCC Registration 
Office (507-284-2753) for dose level and to insure that a place on the protocol is 
open to the patient.  
6.11 
Registration Procedures 
6.111 To register a patient, fax (507-284-0885) a completed eligibility checklist 
to the Mayo Clinic Cancer Center (MCCC) Registration Office between 
8 a.m. and 4:30 p.m. central time Monday through Friday. 
6.2 
Phase II  
6.21 
Registration Procedures 
6.211 To register a patient, access the Mayo Clinic Cancer Center (MCCC) 
web page and enter the registration/randomization application. The 
registration/randomization application is available 24 hours a day, 7 days 
a week. Back up and/or system support contact information is available 
on the Web site. If unable to access the Web site, call the MCCC 
Registration Office at (507) 284-2753 between the hours of 8 a.m. and 
4:30 p.m. Central Time (Monday through Friday). 
The instructions for the registration/randomization application are 
available on the MCCC web page (http://ccswww.mayo.edu/training/) 
and detail the process for completing and confirming patient registration.  
Prior to initiation of protocol treatment, this process must be completed 
in its entirety and a MCCC subject ID number must be available as noted 
in the instructions.  It is the responsibility of the individual and 
institution registering the patient to confirm the process has been 
successfully completed prior to release of the study agent. Patient 
registration via the registration/randomization application can be 
confirmed in any of the following ways: 
• 
Contact the MCCC Registration Office (507) 284-2753. If the patient 
was fully registered, the MCCC Registration Office staff can access 
the information from the centralized database and confirm the 
registration. 
• 
Refer to “Instructions for Remote Registration” in section 
“Finding/Displaying Information about A Registered Subject.” 
6.3 
Phase I and II 
6.31 
Correlative Research: 
A mandatory correlative research component is part of this study, the patient 
will be automatically registered onto this component (see Sections 3.19e and 
14.1). 
6.32 
Prior to accepting the registration, registration/randomization application will 
verify the following: 
• 
IRB approval at the registering institution 

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Protocol Version Date: 08Feb2022 
 
• 
Patient eligibility 
• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected health 
information  
 
6.33 
Documentation of IRB approval must be on file in the Registration Office before 
an investigator may register any patients.  
 
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Registration Office 
(fax: 507-284-0885).  If the necessary documentation is not submitted in advance 
of attempting patient registration, the registration will not be accepted and the 
patient may not be enrolled in the protocol until the situation is resolved. 
 
When the study has been permanently closed to patient enrollment, submission of 
annual IRB approvals to the Registration Office is no longer necessary. 
 
6.34 
At the time of registration, the following will be recorded: 
• 
Patient has/has not given permission to store and use his/her sample(s) for 
future research of multiple myeloma at Mayo. 
• 
Patient has/has not given permission to store and use his/her sample(s) for 
future research to learn, prevent, or treat other health problems. 
• 
Patient has/has not given permission for MCCC to give his/her sample(s) to 
researchers at other institutions. 
 
6.35 
Treatment on this protocol must commence at Mayo Clinic under the supervision 
of a medical oncologist/hematologist. 
 
6.36 
Treatment cannot begin prior to registration and must begin ≤ 28 days after 
registration. 
 
6.37 
Pretreatment tests/procedures (see Section 4.0) must be completed within the 
guidelines specified on the test schedule. 
 
6.38 
All required baseline symptoms (see Section 10.6) must be documented and 
graded. 
 
6.39a 
Study drug is available on site.  
 
6.39b Patient questionnaire booklet is available on site; copies are not acceptable for 
this submission. 
 
 

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7.0 
Protocol Treatment 
7.1 
Treatment Schedule 
7.11 
Phase I Treatment Schedule 
Cycles 1-24 
Agent 
Dose Level 
Route 
Day 
Cycles 
Ibrutinib 
As assigned by 
MCCC Registration 
Office 
PO 
1-28 
Cycle 1-24 
Lenalidomide 
25 mg 
PO 
1-21 
Cycle 1-24 
Dexamethasone 
40 mg* 
PO 
1, 8, 15, 22 
Cycle 1-24 
Cycle length = 28 days 
*Starting dose level of dexamethasone for patients ≥75 years old will be 20mg 
Cycles 25 and beyond 
Agent 
Dose Level Route 
Day 
 
Cycles 
Lenalidomide 
25 mg 
PO 
1-21 
Repeat every 
28 days x 3 for 
each cycle 
Cycles 25 and 
beyond 
Dexamethasone 
40 mg* 
PO 
1, 8, 15, 22 
Cycles 25 and 
beyond 
Cycle length = 84 days 
*Starting dose level of dexamethasone for patients ≥75 years old will be 20mg 
Treatment schedule will follow the study schema outlined above. All patients will start 
with ibrutinib as assigned by the registration office, lenalidomide 25 mg PO days 1-21, 
and dexamethasone 40 mg PO weekly. EXCEPTION: Lenalidomide will be adjusted per 
guidelines for renal dysfunction with CrCl between 30-60 ml/min (see Table 8.32). 
Treatment will be continued until disease progression as long as the patient continues to 
respond and does not have any unacceptable toxicity. All the patients enrolled in the trial 
will have a follow up for at least 3 years after registration to capture the secondary 
endpoints of the study. 
Note: Thromboprophylaxis is required as standard of care (see Section 9.3). 
7.12 
Phase II Treatment Schedule (To be implemented after FDA review of 
Phase I) 
Cycles 1-24 
Agent 
Dose Level 
Route 
Day 
Cycles 
Ibrutinib 
As determined 
in Phase I 
PO 
1-28 
Cycle 1 and beyond 
Lenalidomide 
25 mg 
PO 
1-21 
Cycle 2 and beyond (Not 
given in Cycle 1) 
Dexamethasone 
40 mg* 
PO 
1, 8, 15, 22 
Cycle 1 and beyond 
Cycle length = 28 days 
*Starting dose level of dexamethasone for patients ≥75 years old will be 20mg 
Cycles 25 and beyond 
Agent 
Dose Level 
Route 
Day 
 
Cycles 
Lenalidomide 
25 mg 
PO 
1-21 
Repeat 
every 28 
days x 3 for 
each cycle 
Cycles 25 
and beyond 
Dexamethasone 
40 mg* 
PO 
1, 8, 15, 22 
Cycles 25 
and beyond 

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Protocol Version Date: 08Feb2022 
 
Cycle length = 84 days 
*Starting dose level of dexamethasone for patients ≥75 years old will be 20mg 
Treatment schedule will follow the study schema outlined above. All patients will start 
with ibrutinib at the dose level determined by the phase I portion and dexamethasone 
40 mg PO weekly. Lenalidomide 25 mg PO Days 1-21 will be added Cycle 2. 
Treatment will be continued until disease progression as long as the patient continues to 
respond and does not have any unacceptable toxicity. All the patients enrolled in the trial 
will have a follow up for at least 3 years after registration to capture the secondary 
endpoints of the study. 
7.2 
Treatment by a local medical doctor (LMD) is not allowed. 
7.3 
Phase I – determination of Maximum Tolerated Dose (MTD) 
7.31 
Dose Escalation (Phase I): 
Dose level escalations/de-escalations will be done during the Phase I portion for 
Ibrutinib. In case any dose modifications to ibrutinib and/or dexamethasone are 
required during the Phase I portion due to specific adverse events requiring dose 
modifications (as outlined in Section 8 below), a specific discussion should be 
done with the study PI and appropriately documented. A patient on the Phase I 
portion of the study who develops a DLT should have treatment omitted until the 
toxicity resolves to Grade 1 or better or baseline, and then may be restarted at the 
next lower dose level for the DLT portion only.  .  
Only DLTs occurring in the first cycle and at the patient’s first Dose Level of 
treatment will be used to guide dose determination for the Phase II portion of the 
trial per Section 16.22. 
 
 
 
 
 
 
 
*Starting dose level 
**Starting dose level of dexamethasone for patients ≥75 years old will be 20mg 
7.311  Three patients will be treated at each dose level and observed for a 
minimum of 28 days, to assess toxicities, before new patients are treated. 
Doses will not be escalated in any individual patient. 
7.312 Investigators are to contact the Study Chair as soon as any dose-limiting 
toxicity (DLT) occurs. 
 
7.32 
Definitions of DLT: For this protocol, dose-limiting toxicity (DLT) will be 
defined as an adverse event attributed (definitely, probably, or possibly) in the 
first cycle to the study treatment and meeting the following criteria (as per 
CTCAE V4.0): 
a) Any Grade 3 or greater non-hematological toxicity will be a DLT, with the 
exception of: fatigue, inadequately treated nausea, vomiting, or diarrhea; 
inadequately treated hyperglycemia; or hypersensitivity reaction. A rash 
considered associated with immune activation phenomenon secondary to 
Dose level 
Ibrutinib 
Lenalidomide 
Dexamethasone** 
-1 
280 mg 
25 mg 
40 mg 
1* 
420 mg 
25 mg 
40 mg 
2 
560 mg 
25 mg  
40 mg  
3 
700 mg  
25 mg  
40 mg 
4 
840 mg 
 25 mg 
40 mg  

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Protocol Version Date: 08Feb2022 
 
lenalidomide and/or ibrutinib will not be considered a DLT and may be 
treated concurrent to study treatment with solumedrol (Recommended 
treatment would be with a Medrol Dose Pak®)For a baseline abnormality 
prior to drug therapy, a worsening by at least 2 CTCAE grades and of clinical 
significance will be considered a DLT. 
b) Grade 3 nausea, vomiting or diarrhea will be a DLT if it occurs despite 
appropriate maximal anti-emetic and/or antidiarrheal therapy. 
c) Grade 3 hyperglycemia will be a DLT if the patient is symptomatic or 
glucose level is >300 mg/ml despite appropriate administration of insulin 
and/or oral antidiabetic agents. 
d) Grade 4 neutrophil count decreased lasting >7 days or Grade 3 or 4 febrile 
neutropenia associated with fever (≥38.5℃). 
e) Grade 4 platelet count decreased. Grade 3 platelet count decreased lasting 
>7 days or associated with Grade 2 or higher hemorrhage. 
f) Delay of treatment with ANY agent for ≥14 days due to possibly, probably 
or definitely treatment-related toxicity during Cycle 1.  
7.4 
Overdose 
Any dose of study drug in excess of that specified in this protocol is considered to be an 
overdose.  Signs and symptoms of an overdose that meet any Serious Adverse Event 
criterion must be reported as a Serious Adverse Event in the appropriate time frame and 
documented as clinical sequelae to an 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 10 for further information regarding AE reporting. 
 
8.0 
Dosage Modification Based on Adverse Events 
Strictly follow the modifications in this table for the first cycle of combination treatment with 
ibrutinib, lenalidomide and dexamethasone, until individual treatment tolerance can be 
ascertained (not including the treatment period where MTD of the combination is being 
determined as per Section 7.31). Thereafter, these modifications should be regarded as 
guidelines to produce mild-to-moderate, but not debilitating, side effects. Reductions apply to 
treatment given in the preceding cycle and are based on adverse events observed since the prior 
dose. 
ALERT: 
ADR reporting may be required for some adverse events (See Section 10) 
8.1 
General Considerations: 
a) Missed doses are to be omitted rather than made up, unless the dose of one of the study 
drugs was forgotten and remembered on the same day, in which case the dose can be 
taken that day. Any doses missed on a particular day are not to be made up the next day. 

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Protocol Version Date: 08Feb2022 
 
Doses that are considered to be vomited are not to be made up and a mention about the 
time of dose and time of vomiting episode should be made in the pill diary. 
b) If multiple toxicities are experienced, dose modifications will be based on the toxicity 
requiring the largest dose reduction. 
c) Reductions are based on the dose given in the preceding cycle and are based on 
toxicities with an attribution of possible, probable, or definite that were observed since 
the prior toxicity evaluation. 
d) If either ibrutinib or lenalidomide must be permanently discontinued, the patient will be 
removed from the protocol therapy. 
e) If a drug is omitted due to specific adverse events and the patient is on combination 
therapy, the other agents, considered unrelated to the adverse event may be continued. 
f) A dose omission of >28 days for ibrutinib or lenalidomide is not allowed. If a patient 
cannot be administered a dose for >28 days due to adverse events or any other reason, 
the patient should be removed from the study treatment and go to event monitoring. 
g) Patients will be removed from the study if we are unable to manage the adverse events 
they experience, and it is therefore necessary to permanently discontinue ibrutinib or 
lenalidomide. These events are listed in the tables in Section 8.3 and 8.5. 
 
8.2 
Dose Reductions for Phase I cycles 2 and beyond and Phase II portion (based on Adverse 
Events in Tables below): 
8.21 
The following recommended dose modifications will be utilized for ibrutinib, 
lenalidomide and/or dexamethasone separately as per the best judgment of which 
drug was most likely to have caused the toxicity: 
8.22 
Dose level tables 
8.221 
Lenalidomide 
Dose Level 
Lenalidomide* 
Starting Dose 25 mg 
1st dose reduction 
20 mg 
2nd dose reduction 
15 mg 
3rd dose reduction 
10 mg 
4th dose reduction 
Discontinue 
*Other than lenalidomide dose adjusted for renal dysfunction 
 
8.222 
Dexamethasone 
Dose Level 
Dexamethasone 
Starting Dose 40 mg* 
1st dose reduction 
20 mg 
2nd dose reduction 
12 mg 
3rd dose reduction 
8 mg 
4th dose reduction 
Discontinue 
*Starting dose level of dexamethasone for patients ≥75 years old will be 20mg so 
those patients will start with the 2nd dose reduction row.  
 
 

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8.223 
Ibrutinib 
Ibrutinib 
Starting Dose 
840 mg 
Starting Dose 
700 mg 
Starting Dose 
560 mg 
Starting Dose 
420 mg 
Starting Dose 
280 mg 
1st dose reduction 
700 mg 
560 mg 
420 mg 
280 mg 
Discontinue 
2nd dose reduction 
560 mg 
420 mg 
280mg 
Discontinue 
 
3rd dose reduction 
420 mg 
280mg 
Discontinue 
 
 
4th dose reduction 
280 mg 
Discontinue 
 
 
 
5th dose reduction 
Discontinue 
 
 
 
 
 
8.3 
Lenalidomide Dose Modifications 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* 
unless otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT 
ACTION** 
Investigations 
Platelet count 
decreased 
Grade 4  
Lenalidomide 
*Omit dose until AE has resolved to 
Grade 1 or better 
• Follow CBC weekly 
• If thrombocytopenia <30,000/mm3 
recurs, reduce dose by one dose level 
(by 5 mg) and continue therapy when 
platelet count ≥30,000/mm3 
 
If, after lenalidomide has been 
omitted, and the AE does not return to 
≤Grade 1 within 4 weeks, then the 
patient must be removed from 
protocol treatment and proceed to 
Event Monitoring 
 
Neutrophil count 
decreased 
Grade 4  
 
*Omit dose until AE has resolved to 
Grade 1 or better 
• Follow CBC weekly 
* If neutropenia has resolved to 
≤Grade 2, resume dose at one level 
lower 
*If, after lenalidomide has been 
omitted, and the AE does not return to 
≤Grade 1 within 4 weeks, then the 
patient must be removed from 
protocol treatment and proceed to 
Event Monitoring 

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CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT 
ACTION** 
Blood and lymphatic 
system disorders 
Anemia  
Grade 4 
 
*Omit dose until AE has resolved to 
Grade 2 or better 
• Follow CBC weekly 
* If anemia has resolved to ≤Grade 2, 
resume dose at one level lower 
*If, after lenalidomide has been 
omitted, and the AE does not return to 
≤Grade 2 within 4 weeks, then the 
patient must be removed from 
protocol treatment and proceed to 
Event Monitoring 
 
Febrile neutropenia 
≥Grade 3 
 
• Omit dose and follow CBC weekly 
• If neutropenia has resolved to 
≤Grade 2, resume dose at same level 
with GCSF support (See Section 9.7) 
Cardiac disorders 
Sinus bradycardia/ 
other cardiac 
arrhythmia 
Grade 2 
Lenalidomide 
Omit dose and follow at least weekly 
until resolution 
• If AE resolves to ≤Grade 1, reduce 
dose by one dose level (by 5mg) and 
continue therapy 
 
≥ Grade 3 
 
• Discontinue study treatment and go 
to event monitoring 
Vascular disorders 
Thromboembolic event 
≥ Grade 3 
 
• Omit dose and start anticoagulation; 
restart at investigator’s discretion 
(maintain dose level) 
Immune system 
disorders 
Allergic reaction 
Grade 2-3 
 
• Omit dose and follow at least 
weekly until resolution 
• If AE resolves to ≤Grade 1, reduce 
dose by 5 mg and continue therapy 
 
Anaphylaxis 
Grade 4 
 
• Discontinue study treatment and go 
to event monitoring 
Skin and 
subcutaneous tissue 
disorders 
Erythema multiforme 
≥Grade 3 
 
Discontinue study treatment and go to 
event monitoring 
 
Skin ulceration  
≥Grade 2 
 
Discontinue study treatment and go to 
event monitoring 
 
Other: Non-blistering 
rash Grade 3 
 
• If Grade 3 omit dose and follow 
weekly until resolution 
• If AE resolves to ≤Grade 2 continue 
therapy 
 
Other: Non-blistering 
rash Grade 4 
 
• Discontinue study treatment and go 
to event monitoring 
Other AEs 
Non-hematologic AE 
assessed as related to 
lenalidomide  
≥Grade 3 
 
• Omit dose and follow at least 
weekly until resolution 
• If the AE resolves to ≤Grade 2, 
implement one dose reduction step 
and continue therapy (per Table 8.2) 

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* 
Located at http:/ctep.cancer.gov/protocolDevelopment/electronic_applications.ctc.htm 
**  Use the following to describe actions in the Action column: 
 Omit = The current dose(s) for the specified drug(s) during a cycle is skipped.  The patient does not 
make up the omitted dose(s) at a later time 
 Hold/Delay = The current dose(s) of all drugs during a cycle is delayed.  The patient does make up 
the delayed dose(s) when the patient meets the protocol criteria to restart drugs. 
 Discontinue = The specified drug(s) are totally stopped.    
 
If lenalidomide has been omitted and the toxicity does not return to ≤Grade 2 within 28 days,  the patient 
must be removed from protocol treatment and proceed to Event Monitoring. 
 
8.31 
Lenalidomide dose adjustment for renal function 
Lenalidomide dose will be adjusted as per standard of care guidelines in the 
prescribing information of lenalidomide for multiple myeloma patients. Patients 
with creatinine clearance (CrCl) <30 ml/min noted while on treatment and not 
considered secondary to disease progression will have dose modifications as per 
the following guidelines. Patients with baseline CrCl <30 ml/minute are not 
eligible for this study. 
 
Table 8.32: Lenalidomide dose adjustment for baseline renal dysfunction 
Creatinine Clearance (CrCl) 
Lenalidomide Dose 
CrCl >60 ml/minute 
No adjustment required* 
CrCl 30-60 ml/minute 
10 mg once daily (may increase to 15 mg once daily 
after 2 cycles if nonresponsive but tolerating treatment)   
CrCl <30 ml/minute (non-dialysis 
dependent) 
15 mg every 48 hours 
*The starting dose would be as determined by the phase 1 of the trial. MTD will be utilized for 
phase 2 as long as the CrCl >60 ml/minute and dose adjustments needed as per the table if CrCl 
<60 ml/minute. 
 
8.4 
Dexamethasone Dose Modifications 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0* unless otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT 
ACTION** 
Metabolism and 
nutrition disorders 
Hyperglycemia 
(despite adequate anti-
hyperglycemic 
management) 
Grade 2 
Dexameth
asone 
Treatment with insulin or oral 
hypoglycemics as needed  
 
Grade 3 or 4 
 
• Discontinue dexamethasone 
* Can continue lenalidomide and 
ibrutinib as per protocol 

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CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT 
ACTION** 
Gastrointestinal 
disorders 
Upper gastrointestinal 
hemorrhage 
Grade 3 or 4 
OR 
Lower gastrointestinal 
hemorrhage 
Grade 3 or 4 
 
•  Discontinue dexamethasone 
* Can continue lenalidomide and 
ibrutinib as per protocol 
 
Pancreatitis 
≥ Grade 3 (Severe 
pain; vomiting; 
medical intervention 
indicated (e.g., 
analgesia, nutritional 
support)) 
 
Discontinue dexamethasone and do not 
resume 
* Can continue lenalidomide and 
ibrutinib as per protocol 
Gastrointestinal 
disorders 
Dyspepsia, gastric or 
duodenal ulcer, 
gastritis ≥Grade 3 
(Severely altered GI 
function; TPN 
indicated; elective 
operative or 
endoscopic 
intervention indicated; 
limiting self-care 
ADL; disabling) 
Dexameth
asone 
Omit dexamethasone until symptoms 
adequately controlled 
Restart one dose level below along with 
concurrent therapy with H2 blockers, 
sucralfate, or omeprazole 
If symptoms persist despite above 
measures, discontinue dexamethasone 
and do not resume 
 
Can continue lenalidomide and ibrutinib 
per protocol 
Cardiac Disorders 
Sinus bradycardia/ 
other cardiac 
Arrhythmia 
Grade 3 or 4 
Omit dose and follow at least weekly 
If the AE resolves to ≤Grade 2, 
implement one dose reduction step and 
continue therapy 
General disorders and 
administration site 
conditions 
Edema 
≥Grade 3 (limiting 
function and 
unresponsive to 
therapy or anasarca) 
 
Diuretics as needed, and decrease 
dexamethasone dose by 1 dose level 
If edema persists despite above 
measures, decrease dose another dose 
level 
Discontinue dexamethasone and do not 
resume if symptoms persist despite 
second reduction 
Ibrutinib and lenalidomide should be 
continued. 
Psychiatric disorders 
Confusion or Mood 
alteration 
≥ Grade 2 (Severe 
disorientation; limiting 
selfcare ADL) 
Omit dexamethasone until symptoms 
resolve 
Restart with one dose level reduction  
If symptoms persist despite above 
measures, discontinue dexamethasone 
and do not resume 
Ibrutinib and lenalidomide should be 
continued. 

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CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT 
ACTION** 
Other 
Non-hematologic AE 
assessed as 
lenalidomide related 
≥Grade 3 
Omit dose and follow at least weekly 
If the AE resolves to ≤Grade 2, 
implement one dose reduction step and 
continue therapy 
 
 
 

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8.5 
Ibrutinib Dose Modifications 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* 
unless otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT 
ACTION** 
Investigations 
Neutrophil count 
decreased  
Grade 4 lasting >7 days 
 
Platelet count decreased 
Grade ≥3 
Ibrutinib 
Omit ibrutinib** until recovery to Grade ≤1 
or baseline 
May restart at same dose for first 
occurrence 
Each subsequent occurrence may restart at 
next lower dose after recovery to Grade ≤1 
or baseline  
If AE occurs at lowest dose discontinue 
treatment and go to event monitoring 
 
Blood and lymphatic 
system disorders 
Febrile neutropenia 
≥Grade 3 
 
Omit ibrutinib** until fever resolves and 
ANC ≥1000/µL, then resume ibrutinib at 
the previous dose 
Gastrointestinal 
disorders 
Nausea ≥Grade 3 (if 
persistent despite optimal 
antiemetic therapy) 
Vomiting ≥Grade 3 (if 
persistent despite optimal 
antiemetic therapy) 
Diarrhea ≥Grade 3 (if 
persistent despite optimal 
anti-diarrheal therapy) 
 
Omit ibrutinib** until recovery to Grade ≤1 
or baseline 
May restart at same dose for first 
occurrence 
Each subsequent occurrence may restart at 
next lower dose after recovery to Grade ≤ 1 
or baseline  
If AE occurs at lowest dose discontinue 
treatment and go to event monitoring 
Other (Non-
hematologic)**** 
Any other Grade 4 AE or 
any unmanageable 
Grade 3 AE 
 
Omit ibrutinib** until recovery to Grade ≤1 
or baseline 
May restart at same dose for first 
occurrence 
Each subsequent occurrence may restart at 
next lower dose after recovery to Grade ≤1 
or baseline 
If AE occurs at lowest dose discontinue 
treatment and go to event monitoring 
Additional Adverse Events: 
** If ibrutinib is omitted in the middle of the cycle and the toxicity resolves, patient can 
re-start the drug but the days of drug treatment missed do not need to be caught-up and 
can be omitted in order to maintain the cycle schedule. 
• 
Dose omission: Ibrutinib may be omitted for adverse event considerations for a 
maximum of 28 consecutive days. Study medication should be discontinued 
permanently in the event of AE lasting more than 28 days. 
 
• 
If multiple adverse events are seen, administer dose based on the greatest 
reduction required by any single adverse event observed.  
• 
Dose modifications are for adverse events attributed to study treatment only.  
Dose modifications are not required for adverse events if they are deemed 
unrelated and/or unlikely related to study treatment. 

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• 
Reductions apply to treatment given in the preceding cycle and are based on 
adverse events observed since the prior dose. 
**** If cough, dyspnea, and other pulmonary symptoms occur, a chest x-ray and high-
resolution chest CT scan should be obtained. Incentive spirometry studies (to include 
DLCO) should be considered.  Consider Pneumocystis pneumonia or viral pneumonitis. 
Patients who experience a deep vein thrombosis (DVT), pulmonary embolus (PE), or 
other clotting event should have all study drugs temporarily omitted while full-dose 
anticoagulation is initiated (other than warfarin or other Vitamin K antagonist). There 
should not be a delay of more than 28 days in reinitiating the study treatment.  
 
NOTE: If the patient experiences a significant adverse event requiring a dose reduction 
at the start of the next cycle, then the dose will remain lowered for that entire remaining 
length of the study treatment. 
NOTE: Adverse events requiring a dose-reduction step for any or all drugs beyond 
the two dose-reduction steps (levels –1 and –2) (per Table 8.2) will be at the 
discretion of the treating physician, if the decision is made for the patient to be kept 
on study. These dose reductions must be clearly recorded in reported clinical data.  
NOTE: For a dose omission of ibrutinib or lenalidomide of more than 28 days 
beyond the scheduled date of retreatment, the patient should discontinue protocol 
treatment and go to the event monitoring phase per Section 4.2. In the event patient 
is benefitting from treatment and the delay was unrelated to treatment toxicity, 
patient may remain on study with approval of study PI. 
8.51 
Dose Modification for Hepatic Impaired Subjects 
Ibrutinib is metabolized in the liver and therefore subjects with clinically 
significant hepatic impairment at the time of screening (Child- Pugh class B or 
C) are excluded from study participation. For subjects who develop mild liver 
impairment while on study (Child-Pugh class A), the recommended dose 
reduction for ibrutinib is to a level of 280 mg daily (two capsules). For subjects 
who develop moderate liver impairment while on study (Child-Pugh class B), the 
recommended dose reduction is to a level of 140 mg daily (one capsule). Subjects 
who develop severe hepatic impairment (Child-Pugh class C) must omit ibrutinib 
until resolved to moderate impairment (Child-Pugh class B) or better. Monitor 
subjects for signs of toxicity and follow dose modification guidance as needed 
(Refer to Appendix XII). 
9.0 
Ancillary Treatment/Supportive Care 
9.1 
Full Supportive Care 
Patients should receive full supportive care while on this study.  This includes blood 
product support, antibiotic treatment, and treatment of other newly diagnosed or 
concurrent medical conditions.  All blood products and concomitant medications such as 
antidiarrheals, analgesics, and/or antiemetics received from the first day of study 
treatment administration until 30 days after the final dose will be recorded in the medical 
records. 
9.2 
Bisphosphonates 
Patients may receive concurrent treatment with a bisphosphonate. 
 
 

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9.3 
Thrombophylaxis 
Due to the increased risk of deep vein thrombosis (DVT) for multiple myeloma patients, 
thromboprophylaxis is to be used as standard of care on this regimen according to the 
International Myeloma Working Group guidelines 
(http://jco.ascopubs.org/content/32/6/587.full).26 
9.4 
Steroids 
Patients may continue on low level/stable steroid doses for replacement or inhalation 
therapy if they were on these prior to initiating the study treatment, provided that the 
chronic, stable steroid replacement dose is < 10 mg of prednisone daily or its equivalent. 
9.5 
Prohibited medications 
The following medications are not permitted during the trial: 
• 
Any other investigational treatment  
• 
Any cytotoxic chemotherapy 
• 
Any other systemic anti-neoplastic therapy including, but not limited to, 
immunotherapy, hormonal therapy or monoclonal antibody therapy. 
• 
Any external beam radiotherapy 
9.6 
Anti-emetics 
Anti-emetics may be used at the discretion of the attending physician 
9.7 
Blood products and growth factors 
Blood products and growth factors should be utilized as clinically warranted and 
following institutional policies and recommendations.  The use of growth factors should 
follow published guidelines of the American Society of Clinical Oncology (42) Update of 
Recommendations for the Use of Hematopoietic Colony-Stimulating Factors: Evidence-
Based, Clinical Practice Guidelines.27  
9.8 
Diarrhea 
Diarrhea could 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). 
In the event of Grade 3 or 4 diarrhea, the following supportive measures are allowed: 
hydration, octreotide, and antidiarrheals. 
If diarrhea is severe (requiring intravenous rehydration) and/or associated with 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. 
9.9a 
Concomitant medications 
Any systemic, anti-myeloma therapy or steroids other than those prescribed by the 
protocol are prohibited while on protocol therapy. Guidelines for selection and use of 
other concomitant medications should be derived from the lenalidomide, ibrutinib and 
dexamethasone prescribing information. Other than study medications, administration of 
any therapeutic or diagnostic investigational agent (for any indication) is prohibited while 
on study (see Section 15.0 for a complete list). 
9.9b 
Patients at high risk for tumor lysis syndrome 

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Patients considered by the treating physician to be at a high risk of tumor lysis syndrome 
should be started on appropriate tumor lysis prophylaxis such as allopurinol. 
 
10.0 
Adverse Event (AE) Reporting and Monitoring 
The site principal investigator is responsible for reporting any/all serious adverse events to the 
sponsor as described within the protocol, regardless of attribution to study agent or treatment 
procedure. 
The sponsor/sponsor-investigator is responsible for notifying FDA and all participating 
investigators in a written safety report of any of the following: 
• 
Any suspected adverse reaction that is both serious and unexpected. 
• 
Any findings from laboratory animal or in vitro testing that suggest a significant risk for 
human subjects, including reports of mutagenicity, teratogenicity, or carcinogenicity. 
• 
Any findings from epidemiological studies, pooled analysis of multiple studies, or 
clinical studies, whether or not conducted under an IND and whether or not conducted by 
the sponsor, that suggest a significant risk in humans exposed to the drug 
• 
Any clinically important increase in the rate of a serious suspected adverse reaction over 
the rate stated in the protocol or Investigator’s Brochure (IB). 
Summary of SAE Reporting for this study  
(please read entire section for specific instructions): 
  
WHO: 
WHAT form: 
WHERE to send: 
All sites 
Pregnancy Reporting 
http://ctep.cancer.gov/protocolDevelopment/electronic
_applications/docs/PregnancyReportFormUpdated.p
df 
Mayo Sites – attach to MCCC 
Electronic SAE Reporting Form 
  
Mayo Clinic 
Sites 
Mayo Clinic Cancer Center SAE Reporting Form 
http://livecycle2.mayo.edu/workspace/?startEndpoin
t=MC4158-56/Processes/MC4158-56-
Process.MC4158-56  
AND attach 
MedWatch 3500A: 
http://www.fda.gov/downloads/AboutFDA/ReportsM
anualsForms/Forms/UCM048334.pdf 
Will automatically be sent to 
CANCERCROSAFETYIN@mayo.edu 
 
 
 

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Definitions 
Adverse Event 
Any untoward medical occurrence associated with the use of a drug in humans, whether or 
not considered drug related.  
Suspected Adverse Reaction 
Any adverse event for which there is a reasonable possibility that the drug caused the adverse 
event. 
Expedited Reporting 
Events reported to sponsor within 24 hours, 5 days or 10 days of study team becoming aware 
of the event. 
Routine Reporting 
Events reported to sponsor via case report forms 
Events of Interest 
Events that would not typically be considered to meet the criteria for expedited reporting, but 
that for a specific protocol are being reported via expedited means in order to facilitate the 
review of safety data (may be requested by the FDA or the sponsor).  
Unanticipated Adverse Device Event (UADE) 
Any serious adverse effect on health or safety or any life-threatening problem or death caused 
by, or associated with, a device, if that effect, problem, or death was not previously identified 
in nature, severity, or degree of incidence in the investigational plan or application (including 
a supplementary plan or application), or any other unanticipated serious problem associated 
with a device that relates to the rights, safety, or welfare of subjects 
10.1 
Adverse Event Characteristics 
CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site: 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm) 
a. Identify the grade and severity of the event using the CTCAE version 4.0. 
b. Determine whether the event is expected or unexpected (see Section 10.2). 
c. Determine if the adverse event is related to the study intervention (agent, treatment or 
procedure) (see Section 10.3). 
d. Determine whether the event must be reported as an expedited report. If yes, 
determine the timeframe/mechanism (see Section 10.4).  
e. Determine if other reporting is required (see Section 10.5). 
f. Note: All AEs reported via expedited mechanisms must also be reported via the 
routine data reporting mechanisms defined by the protocol (see Sections 10.6 and 
18.0). 
NOTE: A severe AE is NOT the same as a serious AE, which is defined in Section 10.4. 

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10.2 
Expected vs. Unexpected Events  
Expected events - are those described within the Section 15.0 of the protocol, the study 
specific consent form, package insert (if applicable), and/or the investigator brochure, (if 
an investigator brochure is not required, otherwise described in the general 
investigational plan).  
Unexpected adverse events or suspected adverse reactions are those not listed in Section 
15.0 of the protocol, the study specific consent form, package insert (if applicable), or in 
the investigator brochure (or are not listed at the specificity or severity that has been 
observed); if an investigator brochure is not required or available, is not consistent with 
the risk information described in the general investigational plan. 
Unexpected also refers to adverse events or suspected adverse reactions that are 
mentioned in the investigator brochure as occurring with a class of drugs but have not 
been observed with the drug under investigation. 
An investigational agent/intervention might exacerbate the expected AEs associated with a 
commercial agent. Therefore, if an expected AE (for the commercial agent) occurs with a 
higher degree of severity or specificity, expedited reporting is required. 
NOTE: *The consent form may contain study specific information at the discretion of the 
Principal Investigator; it is possible that this information may NOT be included in the 
protocol or the investigator brochure. Refer to protocol or IB for reporting needs. 
10.3 
Attribution to agent(s) or procedure 
When assessing whether an adverse event (AE) is related to a medical agent(s) medical or 
procedure, the following attribution categories are utilized: 
Definite - The AE is clearly related to the agent(s)/procedure. 
Probable - The AE is likely related to the agent(s)/procedure. 
Possible - The AE may be related to the agent(s)/procedure. 
Unlikely - The AE is doubtfully related to the agent(s)/procedure. 
Unrelated - The AE is clearly NOT related to the agent(s)/procedure. 
 
10.31 AEs Experienced Utilizing Investigational Agents and Commercial Agent(s) on 
the SAME (Combination) Arm 
NOTE: When a commercial agent(s) is (are) used on the same treatment arm as 
the investigational agent/intervention (also, investigational drug, biologic, 
cellular product, or other investigational therapy under an IND), the entire 
combination (arm) is then considered an investigational intervention for 
reporting. 
• An AE that occurs on a combination study must be assessed in accordance with the 
guidelines for investigational agents/interventions.  
• An AE that occurs prior to administration of the investigational agent/intervention 
must be assessed as specified in the protocol. In general, only Grade 4 and 5 AEs 
that are unexpected with at least possible attribution to the commercial agent require 
an expedited report, unless hospitalization is required. Refer to Section 10.4 for 
specific AE reporting requirements or exceptions. 
An investigational agent/intervention might exacerbate the expected AEs associated 
with a commercial agent. Therefore, if an expected AE (for the commercial agent) 

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occurs with a higher degree of severity or specificity, expedited reporting is 
required. 
• An increased incidence of an expected adverse event (AE) is based on the 
patients treated for this study at their site. A list of known/expected AEs is 
reported in the package insert or the literature, including AEs resulting from a 
drug overdose. 
• Commercial agent expedited reports must be submitted to the FDA via MedWatch 
3500A for Health Professionals (complete all three pages of the form). 
http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM0
48334.pdf 
or 
http://www.fda.gov/AboutFDA/ReportsManualsForms/Forms/ListFormsAlphabe
tically/default.htm 
Instructions for completing the MedWatch 3500A: 
http://www.fda.gov/downloads/Safety/MedWatch/HowToReport/DownloadFor
ms/UCM387002.pdf 
 
10.32 EXPECTED Serious Adverse Events: Protocol Specific Exceptions to 
Expedited Reporting 
For this protocol only, the following Adverse Events/Grades are expected to occur 
within this population and do not require Expedited Reporting. These events must still 
be reported via Routine Reporting (see Section 10.6).* 
*Report any clinically important increase in the rate of a serious suspected 
adverse reaction (at your study site) over that which is listed in the protocol or 
investigator brochure as an expedited event.  
*Report an expected event that is greater in severity or specificity than expected 
as an expedited event. 
 
System Organ Class 
(SOC) 
Adverse event/ Symptoms 
CTCAE Grade at which the event 
will not be expeditedly reported1 
Blood and lymphatic 
system disorders 
Anemia 
≤Grade 4 
Gastrointestinal Disorders  
Diarrhea  
≤Grade 3 
Nausea 
≤Grade 3 
Vomiting  
≤Grade 4 
General disorders and 
administration site 
conditions 
Fatigue 
≤Grade 4 
Investigations 
Lymphocyte count decreased 
≤Grade 4 
Neutrophil count decreased 
≤Grade 4 

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System Organ Class 
(SOC) 
Adverse event/ Symptoms 
CTCAE Grade at which the event 
will not be expeditedly reported1 
Platelet count decreased 
≤Grade 4 
 
White blood cell count 
decreased 
 
≤Grade 4 
1 These exceptions only apply if the adverse event does not result in hospitalization. If the adverse 
event results in hospitalization, then the standard expedited adverse events reporting 
requirements must be followed.  
Specific protocol exceptions to expedited reporting should be reported expeditiously by 
investigators ONLY if they exceed the expected grade of the event. 
The following hospitalizations are not considered to be SAEs because there is no “adverse event” 
(i.e., there is no untoward medical occurrence) associated with the hospitalization: 
● Hospitalizations for respite care 
● Planned hospitalizations required by the protocol 
● Hospitalization planned before informed consent (where the condition requiring the hospitalization 
has not changed post study drug administration) 
● Hospitalization for elective procedures unrelated to the current disease and/or treatment on this trial 
● Hospitalization for administration of study drug or insertion of access for administration of study 
drug 
● Hospitalization for routine maintenance of a device (e.g., battery replacement) that was in place 
before study entry 
● Hospitalization, or other serious outcomes for signs and symptoms of progression of the cancer.] 
 
10.4 
Expedited Reporting Requirements for IND/IDE Agents  
10.41 Phase 1 and Early Phase 2 Studies: Expedited Reporting Requirements for 
Adverse Events that Occur on Studies under an IND/IDE within 30 Days of 
the Last Administration of the Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or not they 
are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:  
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 
21 CFR 312.32; ICH E2A and ICH E6). 

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ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the sponsor within 
the timeframes detailed in the table below.  
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization 
≥24 hrs 
7 Calendar Days 
24-Hour 3 Calendar 
Days 
Not resulting in 
Hospitalization 
≥24 hrs 
Not required 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 3 Calendar Days” - The AE must initially be reported within 24 hours of learning of the AE, 
followed by a complete expedited report within 3 calendar days of the initial 24-hour report. 
o “7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar days 
of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 3 calendar days for: 
• All Grade 3, 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
• Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered. Footnote “1” above 
applies after this reporting period. 
Effective Date: May 5, 2011 
NOTE: Refer to Section 10.32 for exceptions to Expedited Reporting 
10.42 General reporting instructions 
The Mayo IND Coordinator will assist the sponsor-investigator in the processing 
of expedited adverse events and forwarding of suspected unexpected serious 
adverse reactions (SUSARs) to the FDA and IRB. 
Submit the Medwatch form and the CIOMS 1 form via email  
AEintakeCT@pcyc.com  or fax ((408) 215-3500) to Pharmacyclics Drug 
Safety, or designee, within 15 days of the event. Pharmacyclics may request 
follow-up and other additional information from the Sponsor Investigator. 
10.43 Reporting of re-occurring SAEs 
ALL SERIOUS adverse events that meet the criteria outlined in table10.41 
MUST be immediately reported to the sponsor within the timeframes detailed in 
the corresponding table. This reporting includes, but is not limited to SAEs that 
re-occur again after resolution. 
10.5 
Other Required Reporting 
10.51 Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSOS) 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSOS) in 
general, include any incident, experience, or outcome that meets all of the 
following criteria: 

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1. Unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
2. Related or possibly related to participation in the research (in this guidance 
document, possibly related means there is a reasonable possibility that the 
incident, experience, or outcome may have been caused by the procedures 
involved in the research); and 
3. Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
Some unanticipated problems involve social or economic harm instead of the 
physical or psychological harm associated with adverse events. In other cases, 
unanticipated problems place subjects or others at increased risk of harm, but no 
harm occurs. 
Note: If there is no language in the protocol indicating that pregnancy is not 
considered an adverse experience for this trial, and if the consent form does not 
indicate that subjects should not get pregnant/impregnate others, then any 
pregnancy in a subject/patient or a male patient’s partner (spontaneously 
reported) which occurs during the study or within 120 days of completing the 
study should be reported as a UPIRTSO. 
Mayo Clinic Cancer Center (MCCC) Institutions: 
If the event meets the criteria for IRB submission as a Reportable 
Event/UPIRTSO, provide the Reportable Event coversheet and appropriate 
documentation to CANCERCROSAFETYIN@mayo.edu. The Mayo Regulatory 
Affairs Office will review and process the submission to the Mayo Clinic IRB. 
10.52 Death 
Note: A death on study requires both routine and expedited reporting 
regardless of causality, unless as noted below. Attribution to treatment or 
other cause must be provided. 
Any death occurring within 30 days of the last dose, regardless of attribution to 
an agent/intervention under an IND/IDE requires expedited reporting within 
24-hours. 
Any death occurring greater than 30 days with an attribution of possible, 
probable, or definite to an agent/intervention under an IND/IDE requires 
expedited reporting within 24-hours. 
Reportable categories of Death  
• 
Death attributable to a CTCAE term. 
• 
Death Neonatal: A disorder characterized by cessation of life during the 
first 28 days of life.  
• 
Death NOS: A cessation of life that cannot be attributed to a CTCAE term 
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• 
Sudden death NOS: A sudden (defined as instant or within one hour of the 
onset of symptoms) or an unobserved cessation of life that cannot be 
attributed to a CTCAE term associated with Grade 5. 
• 
Death due to progressive disease should be reported as Grade 5 
“Neoplasms benign, malignant and unspecified (including cysts and 
polyps) – Other (Progressive Disease)” under the system organ class 
(SOC) of the same name. Evidence that the death was a manifestation of 
underlying disease (e.g., radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a disease process) 
should be submitted. 
10.53 Secondary Malignancy 
• 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, radiation 
or chemotherapy). A secondary malignancy is not considered a metastasis of 
the initial neoplasm. 
• 
All secondary malignancies that occur following treatment with an agent under 
an IND/IDE will be reported. Three options are available to describe the event: 
o Leukemia secondary to oncology chemotherapy (e.g., Acute Myeloctyic 
Leukemia [AML]) 
o Myelodysplastic syndrome (MDS) 
o Treatment-related secondary malignancy 
• 
Any malignancy possibly related to cancer treatment (including AML/MDS) 
should also be reported via the routine reporting mechanisms outlined in each 
protocol. 
10.54 Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is 
NOT a metastasis from the initial malignancy). Second malignancies require ONLY 
routine reporting unless otherwise specified. 
 
10.55 Pregnancy, Fetal Death, and Death Neonatal  
If a female subject (or female partner of a male subject) taking investigational 
product becomes pregnant, the subject taking should notify the Investigator, and 
the pregnant female should be advised to call her healthcare provider 
immediately. The patient should have appropriate follow-up as deemed necessary 
by her physician. If the baby is born with a birth defect or anomaly, a second 
expedited report is required. 
Prior to obtaining private information about a pregnant woman and her infant, the 
investigator must obtain consent from the pregnant woman and the newborn 
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form will need to be submitted to the IRB for these subjects if a pregnancy 
occurs. If informed consent is not obtained, no information may be collected. 
In cases of fetal death, miscarriage or abortion, the mother is the patient. In cases 
where the child/fetus experiences a serious adverse event other than fetal death, 
the child/fetus is the patient. 
NOTE: When submitting Mayo Expedited Adverse Event Report reports for 
“Pregnancy”, “Pregnancy loss”, or “Neonatal loss”, the potential risk of exposure 
of the fetus to the investigational agent(s) or chemotherapy agent(s) should be 
documented in the “Description of Event” section. Include any available medical 
documentation. Include this form: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/Pregna
ncyReportFormUpdated.pdf 
10.551 
Pregnancy 
Pregnancy should be reported in an expedited manner as Grade 3 
“Pregnancy, puerperium and perinatal conditions - Other 
(pregnancy)” under the Pregnancy, puerperium and perinatal 
conditions SOC. Pregnancy should be followed until the outcome is 
known. 
10.552 
Fetal Death 
Fetal death is defined in CTCAE as “A disorder characterized by death 
in utero; failure of the product of conception to show evidence of 
respiration, heartbeat, or definite movement of a voluntary muscle after 
expulsion from the uterus, without possibility of resuscitation.” 
Any fetal death should be reported expeditiously, as Grade 4 
“Pregnancy, puerperium and perinatal conditions - Other 
(pregnancy loss)” under the Pregnancy, puerperium and perinatal 
conditions SOC. 
10.553 
Death Neonatal 
Neonatal death, defined in CTCAE as “A disorder characterized by 
cessation of life occurring during the first 28 days of life” that is felt by 
the investigator to be at least possibly due to the investigational 
agent/intervention, should be reported expeditiously.  
A neonatal death should be reported expeditiously as Grade 4 
“General disorders and administration - Other (neonatal loss)” 
under the General disorders and administration SOC.  
 
 

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10.6 
Required Routine Reporting  
10.61 Baseline and Adverse Events Evaluations 
Pretreatment symptoms/conditions to be graded at baseline and adverse events to 
be graded at each evaluation.  
Grading is per CTCAE v4.0 unless alternate grading is indicated in the table 
below: 
System Organ Class 
(SOC) 
Adverse event/Symptoms 
Baseline 
Each 
evaluation 
Blood and lymphatic 
system disorders 
Anemia 
 
X 
Gastrointestinal disorders 
# of stools 
X 
 
Diarrhea 
 
X 
Nausea 
 
X 
General disorders and 
administration site 
conditions 
Fatigue 
X 
X 
Investigations 
Neutrophil count decreased 
 
X 
Platelet count decreased 
 
X 
Nervous system disorders Peripheral motor neuropathy 
X 
X 
Peripheral sensory neuropathy 
X 
X 
10.62 Submit via appropriate MCCC Case Report Forms (i.e., paper or electronic, as 
applicable) the following AEs experienced by a patient and not specified in 
Section 10.6: 
10.621 Grade 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
10.622 Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure. 
10.623 Grade 5 AEs (Deaths) 
10.6231 
Any death within 30 days of the patient’s last study 
treatment or procedure regardless of attribution to the study 
treatment or procedure. 
10.6232 
Any death more than 30 days after the patient’s last study 
treatment or procedure that is felt to be at least possibly 
treatment related must also be submitted as a Grade 5 AE, 
with a CTCAE type and attribution assigned. 
 
10.7 
Late Occurring Adverse Events 
Refer to the instructions in the Forms Packet (or electronic data entry screens, as 
applicable) regarding the submission of late occurring AEs following completion of the 
Active Monitoring Phase (i.e., compliance with Test Schedule in Section 4.0). 
 
 

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10.8 
Adverse Events of Special Interest (AESI) 
 
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 
Pharmacyclics Drug Safety per SAE reporting timelines.   
10.81 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 v4.0. 
Events meeting the definition of major hemorrhage will be captured as an event of special 
interest according to Section 10.8 above. 
 
11.0 
Treatment Evaluation 
The International Myeloma Working Group (IMWG) uniform response criteria will be used to 
assess response to therapy.28 
11.1  
Terms and definitions 
• 
Monoclonal protein: synonyms include M-spike, M-protein and myeloma protein, 
paraprotein, M-component. 
 
Serum Monoclonal protein level is quantitated using densitometry on SPEP except in 
cases where the SPEP is felt to be unreliable.   
• Monoclonal protein migrating in the β-region (usually IgA Monoclonal 
protein)  
• Cases in which the Monoclonal protein is so large and narrow on agarose 
(some specimens >4 g/dL) that they underestimate the actual immunoglobulin 
level (by greater than 1500 mg/dL) due to technical staining properties of the 
agarose gel. 
• Cases in which there are multiple peaks of same Monoclonal protein 
(aggregates or dimers) 
 
If SPEP is not available or felt to be unreliable (above examples) for routine 
Monoclonal protein quantitation, then quantitative immunoglobulin levels derived 
from nephelometry or turbidometry can be accepted.  However, this must be 
explicitly reported at baseline, and only nephelometry can be used for that patient to 
assess response. SPEP derived Monoclonal protein values and quantitative 
nephelometric immunoglobulin values cannot be used interchangeably.   
 
Urine Monoclonal protein measurement is estimated using 24-h UPEP only.  
Random or 24 h urine tests measuring kappa and lambda light chain levels are not 
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FLC estimation is currently carried out using the serum FLC assay (Freelite, The 
Binding Site Limited, UK).  Patients with kappa/lambda FLC ratio <0.26 are defined 
as having monoclonal lambda FLC and those with ratios >1.65 as having a 
monoclonal kappa FLC.  The monoclonal light chain isotype is considered the 
involved FLC isotype, and the opposite light chain type as the uninvolved FLC type.  
 
• 
Response terms: The following response terms will be used: stringent Complete 
Response (sCR), complete response (CR), very good partial response (VGPR), partial 
response (PR), Minimal Response (MR), stable disease (SD), and progressive disease 
(PD).  
 
In addition, for each response category, there will be an “unconfirmed” response 
category, which will be for internal use, for the purpose of guiding decision making 
and test ordering. These designations will applied at the time of the first measurement 
at which the quantitative aspect of the response category has been satisfied without 
the confirmation step having been satisfied. The designation “u” will precede the 
standard abbreviations, and will include usCR, uCR, uVGPR, uPR, uMR, uPD.  
 
• 
Measurable disease: Patients who have a measurable serum or urine Monoclonal 
proteinrotein.  
 
o Serum Monoclonal protein ≥1 g/dl  
o Urine Monoclonal protein ≥ 200 mg/24 h 
o Serum FLC assay: Involved FLC level ≥  10 mg/dl provided serum FLC ratio is 
abnormal 
o Bone marrow plasma cells ≥ 30% 
 
The serum free light chain (FLC) assay is of particular use in monitoring response to 
therapy in patients who have oligo-secretory or non-secretory disease and should be used 
in assessing response only if the baseline serum and/or urine M proteins are not 
“measurable” as above, and the baseline level of the involved FLC is “measurable.”  
When using this assay, it is important to note that the FLC levels vary considerably with 
changes in renal function and in patients with renal insufficiency, the levels of both the 
kappa and lambda may remain elevated, but the ratio normalizes with achievement of 
CR.  Thus, both the level of the involved and the uninvolved FLC isotype (i.e., the 
involved/uninvolved ratio or involved-uninvolved difference) should be considered in 
assessing response.  Patients included on the study on the basis of FLC alone (i.e., no 
measurable serum/urine Monoclonal protein) should be the only ones who are 
evaluated using FLC response criteria.  The others should follow usual criteria and 
ignore FLC results with the exception of defining stringent complete response. 
 
• 
Evaluable disease: Patients who do not have a “measurable” serum Monoclonal 
protein, serum free light chain, or urine Monoclonal protein. 
 
• 
Oligosecretory myeloma: Patient with multiple myeloma who has NEVER had 
“measurable” serum Monoclonal protein or urine Monoclonal protein, but has had a 
detectable Monoclonal protein in his/her serum and/or urine and/or measurable serum 
free light chain.  
 

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• 
Non-secretory myeloma: Patient with multiple myeloma who has NEVER had a 
detectable Monoclonal protein in his/her serum and/or urine. 
 
11.2  
Clarification of test indications 
Listed below are the minimal required tests required to assess response based on the 
characteristics of their disease at on study. 
Table 11.2 
Tests  Required To Assess Response (Must Be Done At Each Disease Measurement Visit 
except as indicated1,2) 
On Study Baseline Value 
SPEP4 
24 hr 
UPEP2 
Ig 
FLC 
BM Bx 
Serum Monoclonal protein ≥1 g/dl, and urine 
Monoclonal protein ≥200 mg/24 hrs 
X 
X 
 
 
Serum Monoclonal protein ≥1 g/dl, but urine 
Monoclonal protein <200 mg/24 hrs 
X 
 
 
 
Serum Monoclonal protein <1 g/dl, and urine 
Monoclonal protein ≥200 mg/24 hrs 
 
X 
 
 
Serum Monoclonal protein <1 g/dl, urine 
Monoclonal protein <200 mg/24 hrs, but involved 
Ig FLC is ≥10 mg/dL 
 
 
X 
 
Serum Monoclonal protein <1 g/dl, urine 
Monoclonal protein <200 mg/24 hrs, involved Ig 
FLC is <10 mg/dL, bone marrow ≥30% plasma 
cells 
 
 
 
X3 
1  SPEP, UPEP, Immunofixation studies of both serum and urine, and Bone marrow 
biopsy are required to document CR regardless of registration values, and in addition 
FLC measurement and bone marrow immunophenotyping is required to document 
sCR.  SPEP and UPEP are required to document VGPR regardless of registration 
values. 
2  For serum measurable patients, 24 hour urine does not need to be confirmed (i.e. 
repeated after documented response) for any response category 
3  At a minimum, a bone marrow biopsy should be repeated every 3 months until 
documented response. Bone marrow biopsy results do not need to be repeated after 
documented response. 
4    If serum Monoclonal proteinrotein is being followed by quantitative immunoglobulin 
levels derived from nephelometry or turbidometry, quantitative immunoglobulins are 
required. SPEP is only required to document CR or VGPR.  
 
11.3 
Confirmed response  
In order to be classified as a hematologic response, confirmation of serum M- protein, 
serum immunoglobulin free light chain (when primary determinant of response) and 
urine M- protein (when primary determinant of response) results must be made by 
verification on two consecutive determinations.   
• 
Bone marrow aspirate and biopsy are only required to document CR or sCR, 
except for patients with evaluable disease only, where a bone marrow is required 
to document all response categories including progression. However, a second 
confirmatory bone marrow is not required to confirm response in any case. 
• 
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however, if radiographic studies were performed there should be no evidence of 
progressive or new bone lesions. 
Appropriate tests required to document and confirm response are listed in Table 11.2 
11.4 
Bone progression  
Caution must be exercised to avoid rating progression on the basis of variation of 
radiologic technique alone.  Compression fracture does not exclude continued response 
and may not indicate progression.  When progression is based on skeletal disease alone, it 
should be discussed with the Study Chair before removing the patient from the study.  
11.5 
 Response and Progression 
Criteria for response and progression are listed in Table 11.5. Progressive disease for all 
patients as defined in Table 11.5.  
NOTE: For patients that have progressive disease on ibrutinib and dexamethasone during 
cycle 1, baseline values for the assessment of response to the combination of ibrutinib, 
dexamethasone, and lenalidomide will be defined as the values at the end of cycle 1.     
 
Table 11.5 
CATEGORY 
RESPONSE CATEGORY a 
Stringent Complete 
Response (sCR) b 
• 
CR as defined plus 
• 
Normal FLC ratio and 
• 
Absence of clonal PCs by immunohistochemistry or 2- to 4- color 
flow cytometry i 
Complete Response 
(CR) b 
• Negative immunofixation of serum and urine c and 
• Disappearance of any soft tissue plasmacytoma and 
• <5% PCs in Bone Marrow and 
• If the only measurable disease is FLC, a normal FLC ratio d  
Very Good Partial 
Response (VGPR)  
• Serum and urine Monoclonal protein  detectable by 
immunofixation but not on electrophoresis c or 
• ≥90% reduction in serum Monoclonal protein  and urine 
Monoclonal protein <100 mg/24 h c  
• If the only measurable disease is FLC, a >90% reduction in the 
difference between involved and uninvolved FLC levels 
Partial Response (PR) 
• If present at baseline, ≥50% reduction of serum Monoclonal 
protein and reduction in 24-hour urinary Monoclonal protein by 
≥90% or to <200 mg/24hrs c 
• If the only measurable disease is FLC, a ≥50% reduction in the 
difference between involved and uninvolved FLC levels 
• If the only measurable disease is BM, a ≥50% reduction in BM 
PCs (provided the baseline PCs was ≥30%) 
• If present at baseline, ≥50% reduction in the size of soft tissue 
plasmacytomas 
Minor Response (MR)  
• If present at baseline, ≥25% but ≤49% reduction of serum M 
protein and reduction in 24-hour urine Monoclonal protein by 50-
89% which still exceeds 200mg/24 hours c and 
• If present at baseline, 25-49% reduction in the size of soft tissue 
plasmacytoma and 
• No increase in the size or number of lytic bone lesions 
(development of compression fracture does not exclude response) 
Progressive Disease 
Increase of 25% from lowest value in any of the following f, g: 

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Table 11.5 
CATEGORY 
RESPONSE CATEGORY a 
(PD) b, h 
 
• Serum Monoclonal protein (absolute increase must be ≥ 0.5 g/dL) 
and/or 
• Urine Monoclonal protein (absolute increase must be ≥200 mg/24 
hrs) and/or 
• If the only measurable disease is FLC, the difference between 
involved and uninvolved FLC levels (absolute increase must be 
>10 mg/dL)  and/or 
• If the only measurable disease is BM, bone marrow PC percentage 
(absolute increase must be ≥10%) e  
 
Or any one or more of the following: 
• Development of new bone lesion or soft tissue plasmacytoma or 
definite increase in the size of existing bone lesions or soft tissue 
plasmacytoma 
• Development of hypercalcemia (corrected serum calcium 
>11.5mg/dL) that can be attributed solely to the PC proliferative 
disorder 
Stable Disease (SD) 
Not meeting criteria for sCR, CR, VGPR, PR, MR or PD 
 
a All response categories require two consecutive assessments (sCR, CR, VGPR, PR, MR, PD) made at 
any time before the institution of any new therapy; sCR, CR, VGPR, PR, MR and SD categories also 
require no known evidence of progressive or new bone lesions if radiographic studies were performed. 
Radiographic studies are not required to satisfy these response requirements. Bone marrow assessments 
need not be confirmed. Each category, except for stable disease, will have a working subcategory of 
“unconfirmed” [prefix ‘u”] to designate first time point at which response category MAY have been 
achieved if confirmed. 
 
b CR patient will need to progress at the same level as VGPR and PR patients to be considered a PD.  A 
positive immunofixation alone is not sufficient. 
 
c If more than one M protein spike meets the criteria for measurable disease at baseline, then both need to 
be followed for response.  Otherwise, only follow the measurable M protein spike for response.   
 
d In patients in whom the only measurable disease is by serum FLC levels: CR in such patients indicates a 
normal FLC ratio of 0.26-1.65 in addition to the CR criteria listed above. 
 
e Bone marrow criteria for PD are only to be used in patients without measurable disease by M protein and 
by FLC;  
 
f A "25% increase" refers to M protein, FLC and bone marrow results and does not refer to bone lesions, 
soft tissue plasmacytoma or hypercalcemia.  The lowest value does not need to be a confirmed value.  If 
the lowest serum Monoclonal protein is ≥ 5 g/dL, an increase in serum Monoclonal protein of ≥ 1 g/dL is 
sufficient to define disease progression. 
 
g In the case where a value is felt to be a spurious result per physician discretion (for example, a possible 
lab error), that value will not be considered when determining the lowest value. 
 

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h Progressive disease should be confirmed.  However, treatment may be discontinued for progressive 
disease that is unconfirmed per physician discretion.  In this case, an objective status of PD should be 
entered on the measurement form and progressive disease should be reported on the event monitoring 
form. 
 
i Presence/absence of clonal cells is based upon the k/l ratio. An abnormal k/l ratio by 
immunohistochemistry requires a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting 
presence of an abnormal clone is k/l of 4:1 or 1:2. 
 
12.0 
Descriptive Factors  
12.1 
Parameters followed for hematologic response (pick one): serum monoclonal protein ≥1 
g/dL and urine monoclonal protein ≥200 mg/24 hours vs. serum monoclonal protein 
≥1g/dL only vs. urine monoclonal protein ≥200 mg/24 hours only vs. serum 
immunoglobulin free light chain ≥10 mg/dL with an abnormal free light chain ratio vs. 
bone marrow plasma cells >30%. Distinguish between SPEP measurements versus 
quantitative IgA measurements for serum monoclonal protein. 
 
12.2 
MM risk categories (As per Appendix VII): High vs. standard/intermediate 
 
12.3 
MM patient frailty patient status (per Appendix I):  fit vs. intermediate fitness vs. frail 
 
12.4  
 Phase I only:   Dose Level (to be assigned by Registration Office):   
-1 vs. 1 vs. 2 vs. 3 vs. 4  
 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient   
13.1 
Patients who are responding 
Patients who are sCR, CR, VGPR, PR, MR, or SD (or usCR, uCR, uVGPR, uPR, uMR) 
will continue treatment per protocol.   Treatment may continue until disease progression 
as long as the patient continues to respond and does not have any unacceptable toxicity. 
13.3 
Criteria for Initiation of Event Monitoring  
Patients who go off protocol treatment for the following reasons will go to the event 
monitoring phase per Section 4.2: 
 
• 
Progressive multiple myeloma while on combination treatment with ibrutinib, 
lenalidomide and dexamethasone 
• 
Patient requests to discontinue study treatment 
• 
Patient develops an intercurrent illness that precludes further participation, or 
requires a prohibited concomitant treatment 
• 
The Investigator withdraws the patient in the patient’s best interests 
• 
Patient is lost to follow-up (defined as the inability to contact the patient for more 
than 2 years 
• 
Administrative reasons (e.g., the patient is transferred to hospice care) 
• 
An adverse event, which in the opinion of the Investigator, precludes further trial 
participation  
• 
A dose omission of more than 28 days beyond the scheduled date of retreatment for 
ibrutinib or lenalidomide 
 

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All attempts should be made to complete the End of Study procedures if a patient goes 
off treatment early. 
13.4 
Criteria for Study Discontinuation 
The study may be temporarily or permanently discontinued at any site and at any time.  
Reasons for study discontinuation may include, but are not limited to, the following: 
• 
Safety concerns 
• 
Poor enrollment 
• 
Non-compliance with the protocol, Good Clinical Practice guidances or other 
regulatory requirements by the Investigator(s) 
• 
Request to discontinue the trial by a regulatory or health authority or an IRB 
• 
Manufacturing difficulties/concerns 
 
All Investigators and the requisite regulatory authorities will be notified if the study is 
suspended or terminated for safety reasons.  In the case of such termination, the 
Investigator will notify the IRB. 
13.5 
Failure to complete Cycle 1 
Phase I Only:  If a patient fails to complete the first cycle (each cycle=28 days) of the 
treatment for reasons other than toxicity, the patient will be regarded as inevaluable and 
will be replaced.    
13.6 
Ineligibles 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry.  
The patient may continue treatment off-protocol at the discretion of the physician as long 
as there are no safety concerns, and the patient was properly registered. The patient will 
go directly to the event-monitoring phase of the study (or off study, if applicable).  
• 
If the patient received treatment, all data up until the point of confirmation of 
ineligibility must be submitted.  Event monitoring will be required per Section 18.0 
of the protocol.  
• 
If the patient never received treatment, on-study material and the End of Active 
Treatment/Cancel Notification Form must be submitted. No further data submission 
is necessary. 
13.7 
Major violation 
A patient is deemed a major violation, if protocol requirements regarding treatment in 
cycle 1 of the initial therapy are severely violated that evaluability for primary end point 
is questionable.  All data up until the point of confirmation of a major violation must be 
submitted.  The patient will go directly to the event-monitoring phase of the study.  The 
patient may continue treatment off-protocol at the discretion of the physician as long as 
there are no safety concerns, and the patient was properly registered.  Event monitoring 
will be required per Section 4.2 of the protocol. 
13.8 
Cancel 
A patient is deemed a cancel if he/she is removed from the study for any reason before 
any study treatment is given. On-study material and the End of Active Treatment/Cancel 
Notification Form must be submitted. No further data submission is necessary. 
 

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14.0 
Body Fluid Biospecimens  
14.1 
Summary Table of Research Blood and Body Fluid Specimens to be collected for this Protocol 
Correlative Study 
(Section for more 
information) 
Mandatory 
or Optional 
Blood or 
Body 
Fluid 
being 
Collected 
Type of 
Collection 
Tube 
(color of 
tube top) 
Volume to 
collect per 
tube (# of 
tubes to be 
collected) 
  
Baseline  
  
Every cycle  
  
End of 
treatment  
Process 
at site? 
Temperature 
Conditions 
for Storage 
/Shipping 
BTK Signalosome 
Mandatory 
Bone 
marrow 
aspirate 
Green Top 
tube 
5 mL 
(2) 
Baseline/ 
\after 
registration 
but prior to 
treatment    
Prior to 
addition of 
len to ibr-
dex* and as 
clinically 
indicated***  
Confirmed 
disease 
progression   
No 
On dry ice 
Effect of Ibr on 
microenvironment 
Mandatory 
Bone 
marrow 
aspirate 
Green Top 
tube 
5 mL 
(1) 
Baseline/  
 after 
registration 
but prior to 
treatment 
Prior to 
addition of 
len to ibr-
dex* and as 
clinically 
indicated***  
Confirmed 
disease 
progression   
No 
At room 
temperature 
Effect of Ibr on 
microenvironment 
Mandatory 
Peripheral 
Blood 
Green Top 
tube 
5 mL 
(2) 
Baseline/  
after 
registration 
but prior to 
treatment  
Every 3 
cycles while 
patient 
continues on 
treatment** 
 
No 
At room 
temperature 
Effect of Ibr on 
platelet 
aggregation 
(Platelet surface 
glycoprotein by 
flow cytometry, 
blood) 
Mandatory  
Peripheral 
Blood 
Yellow 
Top tube 
5 ml 
Baseline/  
after 
registration 
but prior to 
treatment 
Every cycle 
for first 3 
cycles; 
 then every 3 
cycles while 
patient 
continues on 
treatment for 
up to 12 
cycles  
Confirmed 
disease 
progression 
Yes  
At room 
temperature 

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Correlative Study 
(Section for more 
information) 
Mandatory 
or Optional 
Blood or 
Body 
Fluid 
being 
Collected 
Type of 
Collection 
Tube 
(color of 
tube top) 
Volume to 
collect per 
tube (# of 
tubes to be 
collected) 
  
Baseline  
  
Every cycle  
  
End of 
treatment  
Process 
at site? 
Temperature 
Conditions 
for Storage 
/Shipping 
Effect of Ibr on 
platelet 
aggregation 
Platelet 
aggregation study 
(functional) 
Mandatory  
Peripheral 
Blood 
Special 
tubes to be 
supplied by 
heme lab 
 
9 ml 
(4) 
Baseline/  
after 
registration 
but prior to 
treatment 
Every 3 
cycles while 
patient 
continues on 
treatment for 
up to 12 
cycles  
Confirmed 
disease 
progression 
Yes  
At room 
temperature 
*Phase II only  
**Additional samples to be drawn in-between every 3 cycles in case there is confirmed disease progression  
*** Additional samples to be drawn if a bone marrow is done for confirmation of response or as otherwise clinically indicated. 
ibr=ibrutinib, len=lenalidomide, dex=dexamethasone

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Protocol Version Date: April 23, 2015 
14.2 
Collection and Processing 
No specific instructions other than outlined in table 14.1 
 
14.3 
Shipping and Handling 
14.31 Kits will not be used for this study. 
 
14.32 Shipping Specimens 
Samples will be transported/shipped to Mayo Clinic in Florida at the following 
address: 
Chanan-Khan laboratory 
Attn:  Aneel Paulus, M.D. 
Griffin  Building 164 
4500 San Pablo Rd. 
Jacksonville, FL 32224 
 
14.33 Handling Specimens 
Samples should be transported same day (if from Mayo Clinic, Florida) or 
shipped by overnight mail (if from Mayo Clinic in Arizona or Minnesota) on dry 
ice and dispatched only on Monday-Thursday for a receipt in Jacksonville on 
Tuesday-Friday. 
14.4 
Background and Methodology 
14.41 BTK signalosome: The variability in the extent of clinical response may suggest 
underlying adaptability of the MM clone mediated through components of the 
BTK signalosome. Patients with B-cell malignancies treated with ibrutinib 
demonstrate upregulation of p-Akt and p-Erk (downstream mediators of BTK) in 
some (but not all) patients and suggest that these downstream pathways may 
contribute to the survival of the malignant clone.18 They also concluded that these 
cells might not be dependent upon the proximal BTK pathways mediated 
apoptosis and thus resistant to killing by ibrutinib. To address this question we 
will establish the profile of BTK signalosome for each patient through 
determination of the mRNA (RT-PCR/ nanostring assay) and protein expression 
(western blot analysis) of members of the BTK signaling pathway. Samples: 
Bone marrow samples (2 x 5ml green top tubes) will be collected at prior to 
initiating the ibrutinib therapy, at the time of disease progression while on ibr 
therapy or if there is a lack of response noted to single-agent ibr at the time points 
specified in the study schema. In the form of expected results, we anticipate (a) 
variability in the expression and phosphorylation status of various members of 
BTK pathway (Syk, Lyn CD79 FYN) and their targets (ERK, AKT, NFKB and 
Bcl-2, Mcl-1, XIAP, MYC, CD40 and CFLAR) (b) and predict correlation of this 
variability with the depth of response achieved in that patient. Furthermore, this 
will also help identify the signalosome pattern that may suggest lack of 
response/progression to single-agent ibr in MM patients. 
 
14.42 Effect of ibrutinib on MM microenvironment: In cancer redirection of host 
immunity from a predominant Th2 to Th1 response can deliver antitumor 
response. Ibr can bind to ITK, a member of the TEC-kinase family mediates TCR 
signaling through PLCg, NFAT, NF-kappaB and MAPK.19 This results in 
activation and proliferation of CD8+ cells. Our hypothesis is that ibr alters the 

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Th2:Th1 balance in the blood and bone marrow microenvironment skewing 
towards a more Th1 profile and this may translate into its clinical efficacy. We 
further hypothesize that the robustness of the Th1 response will direct ibrutinib's 
depth of response. Blood and bone marrow will be evaluated/quantified for Th1 
and Th2 cells (by flow cytometry). Changes in the cellular profile as well as 
respective cytokine (such as IL2, IL12, INFg and IL4, IL5, IL13 and IL10, 
respectively) will be measured (for cytokine we will use the multiplex assay). 
Blood (2 x 5ml green top tubes) and bone marrow samples (1 x 5ml green top 
tubes) will be collected at any time prior to initiating the ibrutinib therapy. Serial 
bone marrow samples will be collected at the time of disease progression while 
on ibr therapy or if there is a lack of response noted to single-agent ibr at the time 
points specified in the study schema. Furthermore, serial blood samples will be 
collected every 3 months while the patient remains on study treatment and 
additionally at the time of disease progression while on ibr therapy or if there is a 
lack of response noted to single-agent ibr at the time points specified in the study 
schema. 
 
We anticipate that ibr treatment (a) will results in increase in Th1 cells both in 
the blood and the bone marrow with bone marrow demonstrating a higher 
percentage of Th1 cell activity and that (b) extent of immune cellular response 
will correlate with the robustness of the clinical response and that (c) the 
cytokine profile will mimic this cellular pattern and can be used to predict 
immune cellular response to ibrutinib. Identification / validation of immune 
restoration ability of ibr and its correlation with disease response will be a highly 
novel observation and will define a unique role and mechanism of ibrutinib in 
MM. 
 
14.43 Effect of ibrutinib on platelet aggregation: While it is known that ibrutinib causes 
platelet dysfunction, the mechanistic pathway is not clearly understood. In-vitro 
studies have shown possible interaction with collagen receptor GPVI and also 
affect platelet adhesion on von Willebrand factor. To further characterize the 
bleeding events in ibrutinib-treated patients, we will investigate the effect of 
ibrutinib on platelet aggregation ex vivo. Platelet flow cytometric analysis is the 
preferred method to assess quantitative surface glycoprotein (GP) deficiencies. 
GP expression levels can be measured by using fluorescent-conjugated GP-
specific antibodies and their fluorescent intensities can be compared to normal 
ranges of various glycoproteins. Platelet aggregometry uses a combination of 
laser light scattering to monitor the continuous formation of platelet 
microaggregates. The test is sensitive enough to detect aggregates containing 
only two or three platelets. The method uses of a panel of platelet agonists (eg, 
collagen, ADP, epinephrine, ristocetin) at a range of concentrations that triggers 
classical platelet responses, including shape change as well as primary and 
secondary aggregation. The recorded response depends upon the normal 
functioning of the platelet, the presence of inhibitors of platelet function, as well 
as the concentration of agonist, facilitating detection of classical platelet 
disorders based upon the pattern of aggregation.  
 

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15.0 
Drug Information 
15.1 
Ibrutinib (Imbruvica™, PCI-32765) 
 
15.11 Background: Ibrutinib is an antineoplastic agent that is an inhibitor of  
Bruton’s tyrosine kinase. 
 
15.12 Formulation: Ibrutinib comes in a different dosage forms.   
• 
Capsules: either size 0, gray 140 mg capsules or size 2, yellow 
immediate-release 70 mg capsules.  The capsules also contain the 
following compendial excipients: microcrystalline cellulose, 
croscarmellose sodium, sodium lauryl sulfate, and magnesium stearate.  
Capsules are packaged in high-density polyethylene bottles with an 
induction seal and a child resistant screw-top cap. 
 
15.13 Preparation and storage:  
• 
Ibrutinib capsules: 70 mg and 140 mg. store at 15°C to 25°C (59°F to 
77°F) with excursions permitted to 30°C (86°F).  
 
15.14 Administration:  Administer orally with water at approximately the same time 
every day.  Ibrutinib can be taken with or without food. Swallow capsules whole; 
do not open, break, or chew the capsules.  Hazardous agent; use appropriate 
precautions for handling and disposal. 
 
 
15.15 Pharmacokinetic information: 
a)  Absorption – Current data indicates bioavailability is low and displays high 
inter-subject variability.  The median time to reach maximum plasma 
concentration (Tmax) is approximately 2 hours.  Administration of ibrutinib in a 
fasted condition resulted in approximately 60% of exposure as compared to 
administration either in fed condition (30 minutes after a high-fat breakfast), or 
when drug was taken 30 minutes before or 2 hours after a meal. Based on data 
for the effects of food, ibrutinib could be taken with or without food at 
approximately the same time each day. The effect of food on the PK of ibrutinib 
560 mg tablets was similar to that observed for ibrutinib capsules.   
b)  Distribution: The plasma protein binding of ibrutinib and its metabolite PCI 
45227 in human plasma is 97.3% and 91%, respectively.  The apparent steady 
state volume of distribution is approximately 10,000 L. 
c)  Metabolism – Ibrutinib is extensively metabolized by CYP3A4/5 
(major) and CYP2D6 (minor).  Ibrutinib is metabolized in the liver.   
d)  Elimination –The excretion of ibrutinib is predominantly via the feces 
with approximately 80% recovered mostly within 2 days, whereas ~8% is 
excreted in urine. Approximately 1% of the ibrutinib is recovered as 
unchanged drug, all in feces. The half-life elimination is 4-6 hours.  
Overall, these PK characteristics resulted in minimal accumulation of both 
parent compound and metabolite PCI-45227 on repeated daily dosing of 
ibrutinib. 
e) Special populations: a small increase in bioavailability was estimated 
with increasing age. Exposure is predicted to increase approximately 14% 
and decrease approximately 20% in subjects of 81 and 49 years of age, 
compared to a typical 67-year old subject. No statistically significant 

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Protocol Version Date: 08Feb2022 
 
effects were observed for the other covariates tested, i.e., sex, race, mild 
and moderate renal impairment, mild hepatic impairment and B-cell 
histology. The recommended doses for patients with mild and moderate 
liver impairment are 280 mg/day and 140 mg/day (Child-Pugh Class A 
and B, respectively). It is not recommended to administer ibrutinib to 
subjects with severe hepatic impairment (Child-Pugh Class C). Pediatric 
studies are still ongoing. 
 
15.16   Potential Drug Interactions:  Ibrutinib is primarily metabolized by 
cytochrome P450 enzyme 3A4/5.   Voriconazole and posaconazole can be 
used concomitantly with ibrutinib as per the dosing guidance described in 
the specific clinical study protocol. All other strong inhibitors of CYP3A 
(eg, ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, 
clarithromycin, telithromycin, itraconazole, nefazodone, and cobicistat) 
should be avoided, and an alternative with less CYP3A inhibitory potential 
should be considered. If the benefit outweighs the risk and a strong 
CYP3A inhibitor must be used, see the recommended dose modifications 
described in the specific clinical study protocol. 
 
If a moderate CYP3A inhibitor (eg, fluconazole, erythromycin,  
amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, diltiazem, 
fosamprenavir, imatinib, verapamil, amiodarone, dronedarone) is indicated 
in patients with B-cell malignancies, reduce the ibrutinib dose to 280 mg 
for the duration of the inhibitor use or as per recommended dose 
modifications described in the specific clinical study protocol. No ibrutinib 
dose modifications for moderate inhibitors are required in patients with 
cGVHD dosed with ibrutinib 420 mg. 
 
No dose adjustment is required in combination with mild inhibitors. 
Monitor patient closely for toxicity and follow dose modification guidance 
as needed. Avoid grapefruit and Seville oranges during ibrutinib treatment 
as these contain moderate inhibitors of CYP3A. 
 
Administration of ibrutinib with strong inducers of CYP3A decreases 
ibrutinib plasma concentrations by up to 90%. Avoid concomitant use of 
strong CYP3A inducers (eg, carbamazepine, rifampin, phenytoin and St. 
John’s Wort). Consider alternative agents with less CYP3A induction. 
 
To minimize the potential for an interaction in the GI tract, narrow 
therapeutic range P-gp or BCRP substrates such as digoxin or 
methotrexate should be taken at least 6 hours before or after ibrutinib. 
Ibrutinib may also inhibit BCRP systemically and increase the exposure of 
drugs that undergo BCRP-mediated hepatic efflux, such as rosuvastatin. 
 
There have been reports of bleeding-related events in subjects treated with 
ibrutinib. Warfarin or other vitamin K antagonists should not be 
administered concomitantly with ibrutinib unless specified in the protocol. 
Supplements such as fish oil and vitamin E preparations should be 
avoided. 
 

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Based on preliminary data from the combination studies of ibrutinib and 
venetoclax, venetoclax exposure (area under the concentration-time curve 
[AUC]) at 400 mg QD appears to be approximately 1.7 to 1.8-fold higher 
with 420 mg ibrutinib and approximately 3-fold higher with 560 mg 
compared with venetoclax single agent exposure. To date, no new safety 
signals have been identified in these ongoing combination therapy studies 
Patients should be closely monitored for signs of toxicity. 
 
Evaluation of the effect of repeated administration of ibrutinib on the PK 
of oral contraceptives (OC), showed that the maximal daily dose of 560 
mg did not lead to a decreased exposure of OC drugs 
ethinylestradiol(EE)/levonorgestrel in female subjects, suggesting that the 
OCs remain efficacious when used during ibrutinib therapy. 
 
15.17 Known potential toxicities:   
• 
Very Common (≥10%): neutropenia, thrombocytopenia, anemia, 
diarrhea, nausea, constipation, vomiting, decreased appetite, 
fatigue, peripheral edema, pyrexia, pneumonia, upper respiratory 
tract infection, arthralgia, back pain, headache, cough, dyspnea, 
rash 
• 
Common (1 to <10%): febrile neutropenia, leukocytosis, 
lymphocytosis, atrial fibrillation, vision blurred, stomatitis, 
gastritis, asthenia, bronchitis, lung infection, sinusitis, urinary tract 
infection, neutrophil count decreased, platelet count decreased, 
dehydration, hyperuricemia, myalgia, extremity pain, dizziness, 
hematuria, epistaxis, erythematous rash, maculo-papular rash, 
hematoma, hypertension, cellulitis, infection, lower respiratory 
tract infection, sepsis, skin infection, arthritis, bone pain, flank 
pain, basil cell carcinoma, squamous cell carcinoma, syncope, 
acute kidney injury, pleural effusion, respiratory failure, macular 
rash, hypotension, respiratory tract infection, cardiac failure 
• 
Rare (<1%): leukostasis syndrome, pancytopenia, atrial flutter, , 
myocardial infarction, colitis, intestinal obstruction, oral mucosal 
blistering, systemic inflammatory response syndrome, atypical 
pneumonia, bacteremia, infectious enterocolitis, neutropenic 
sepsis, periorbital cellulitis, pneumonia (pneumocystis jirovecii, 
bacterial, cryptococcal, fungal, haemophilus, influenzal, viral, 
pseudomonal klebsiella, legionella, parainfluenzae viral, 
streptococcal, organising), septic shock, urosepsis, post procedural 
hemorrhage, subdural hematoma, tumor lysis syndrome, pain 
(pelvic, groin), hemorrhage intracranial, lung infiltration, 
pneumonitis, pustular rash, breast cellulitis, bronchopulmonary 
aspergillosis, Escherichia sepsis, viral lower respiratory tract 
infection, pneumococcal sepsis, fungal sinusitis, staphylococcal 
infection, staphylococcal skin infection, interstitial lung disease, 
angioedema, hypertensive crisis , chronic sinusitis bacteroides 
bacteremia, orbital cellulitis, staphylococcal cellulitis, Escherichia 
bacteremia, alveolitis allergic, Stevens-Johnson syndrome, 
Haemophilus bacteremia/sepsis, pseudomonal lung infection, 
bacterial sepsis, herpes zoster disseminated, muscle hemorrhage, 
cerebral hemorrhage, deep vein thrombosis, squamous cell 

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carcinoma of the skin, basosquamous carcinoma of the skin, 
hepatic failure, ventricular tachyarrhythmia, basal cell carcinoma, 
neutrophilic dermatoses 
• 
Cardiac Arrhythmias: Atrial fibrillation, atrial flutter, and cases 
of ventricular tachyarrhythmia including some fatal events, have 
been reported in subjects treated with ibrutinib, particularly in 
subjects with cardiac risk factors, hypertension, acute infections, 
and a previous history of cardiac arrhythmia. Periodically monitor 
subjects clinically for cardiac arrhythmia. Subjects who develop 
arrhythmic symptoms (eg, palpitations, lightheadedness, syncope, 
chest discomfort or new onset of dyspnea) should be evaluated 
clinically, and if indicated, have an ECG performed. For cardiac 
arrhythmias which persist, consider the risks and benefits of 
ibrutinib treatment, and follow the dose modification guidelines 
• 
Cerebrovascular accidents:  Cases of cerebrovascular accident, 
transient ischemic attack, and ischemic stroke including fatalities 
have been reported with the use of ibrutinib in the post-marketing 
setting, with and without concomitant atrial fibrillation and/or 
hypertension.  Regular monitoring and appropriate treatment of 
conditions that can contribute to the occurrence of these events is 
recommended.  
 
Please refer to the prescribing information or Investigator’s Brochure for a more 
complete comprehensive list of treatment- 
 
15.18 Drug procurement:  Drug will be provided free of charge to study participants 
by Pharmacyclics, Inc. 
 
15.19a Nursing Guidelines:  
• 
There are numerous drug to drug interactions. Record all of patient’s 
medications including OTC, and herbal use. Avoid concomitant use with 
agents as listed in section 15.16. 
• 
Patients should be instructed to avoid eating grapefruit (including juice) and 
Seville oranges while on ibrutinib. 
• 
Peripheral edema is common. Instruct patients to report this to the study 
team. 
• 
Gastrointestinal side effects are common (diarrhea, nausea, constipation, 
abdominal pain, vomiting, etc). Treat symptomatically and monitor for 
effectiveness of intervention. 
• 
Monitor CBC w/diff. Instruct patients in energy conserving lifestyle (anemia) 
and to report any unusual bruising or bleeding and/or signs or symptoms of 
infection to study team. 
• 
Arthralgias, Myalgias, and muscle spasm can be seen. Treat symptomatically 
and monitor for effectiveness. 
• 
Monitor renal function/uric acid levels, especially in patients who may be 
experiencing dehydration. 
• 
Respiratory symptoms may include, cough, SOB, and URI. Instruct patients 
to report these symptoms to the study team. 
• 
Rarely patients can experience secondary skin cancers. Instruct patients to 
report any new skin lesions to the study team. 

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• 
Rash can be seen. Instruct patient to report to study team.  
• 
Cardiac arrhythmias have been seen with this agent including a-fib, atrial 
flutter and ventricular tachyarrhythmia’s, some of which have led to death.  
Instruct patients who experience any palpitations, lightheadedness, syncope, 
or SOB to see medical care immediately.  This is especially important in 
patients who have pre-existing cardiac issues. 
• 
Warn patients of the risk of bleeding. Patients should not take warfarin or 
other vitamin K antagonists while on ibrutinib, unless the protocol allows for 
it. Additionally, patients should be cautioned to avoid fish oil and vitamin E 
supplements. 
• 
Patients who are concurrently on ibrutinib and ventoclax should be 
monitored closely for excess toxicity. 
• 
Ibrutinib should be held at least 3-7 days pre and post-surgery, depending on 
type of surgery. 
• There have been reports of CVA and TIA in patients on ibrutinib. 
Instruct patients to report any headaches and/or neurologic changes 
immediately or seek out emergency care. 
• Patients may experience dry eyes, blurred vision or decreases in 
vision. Instruct patients to report this to the study team.  
 
15.19b Medications to be Used with Caution with Ibrutinib 
CYP3A-Inhibitors/Inducers 
Ibrutinib is metabolized primarily by CYP3A. Avoid co-administration with 
strong CYP3A4 or moderate CYP3A inhibitors and consider alternative agents 
with less CYP3A inhibition. 
• 
If a strong CYP3A inhibitor (eg, ketoconazole, indinavir, nelfinavir, 
ritonavir, saquinavir, clarithromycin, telithromycin, itraconazole, nefazadone, 
or cobicistat) must be used, reduce ibrutinib dose to 140 mg or withhold 
treatment for the duration of inhibitor use. Subjects should be monitored for 
signs of ibrutinib toxicity.  
• 
If a moderate CYP3A inhibitor (eg, voriconazole, erythromycin, amprenavir, 
aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, 
diltiazem, fluconazole, fosamprenavir, imatinib, verapamil, amiodarone, or 
dronedarone) must be used, reduce ibrutinib to 140 mg (for 840 mg/day dose, 
reduce to 280 mg) for the duration of the inhibitor use. Avoid grapefruit and 
Seville oranges during ibrutinib/placebo treatment, as these contain moderate 
inhibitors of CYP3A. 
• 
No dose adjustment is required in combination with mild inhibitors.  
Avoid concomitant use of 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 10.  A 
comprehensive list of inhibitors, inducers, and substrates may be found at 

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Protocol Version Date: 08Feb2022 
 
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 on ibrutinib 
exposure, please refer to the current version of the IB. 
 
QT Prolonging Agents 
Any medications known to cause QT prolongation should be used with caution; 
periodic ECG and electrolyte monitoring should be considered. 
Antiplatelet Agents and Anticoagulants 
Warfarin or vitamin K antagonists should not be administered concomitantly 
with ibrutinib.  Supplements such as fish oil and vitamin E preparations should 
be avoided.  Use ibrutinib with caution in subjects requiring other anticoagulants 
or medications that inhibit platelet function.  Subjects with congenital bleeding 
diathesis have not been studied.  For guidance on ibrutinib and the use of 
anticoagulants during procedures/surgeries see Section X. 
Subjects requiring the initiation of therapeutic anticoagulation therapy (eg, atrial 
fibrillation), consider the risks and benefits of continuing ibrutinib treatment.  If 
therapeutic anticoagulation is clinically indicated, treatment with ibrutinib should 
be held and not be restarted until the subject is clinically stable and has no signs 
of bleeding. Subjects should be observed closely for signs and symptoms of 
bleeding. No dose reduction is required when study drug is restarted. 
 
Guidelines for Ibrutinib Management with Surgeries or Procedures 
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. 
 
Minor Surgical Procedures 
For minor procedures (such as a central line placement, needle biopsy, 
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. 
 
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 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. 
 
Emergency Procedures 
For emergency procedures, ibrutinib should be held after the procedure until the 
surgical site is reasonably healed, for at least 7 days after the urgent surgical 
procedure. 

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15.2 
Lenalidomide for Oral Administration (Revlimid®) 
15.21 Background: Lenalidomide has antineoplastic, immunomodulatory and 
antiangiogenic characteristics via multiple mechanisms. Lenalidomide selectively 
inhibits secretion of proinflammatory cytokines (potent inhibitor of tumor 
necrosis factor-alpha secretion); enhances cell-mediated immunity by stimulating 
proliferation of anti-CD3 stimulated T cells (resulting in increased IL-2 and 
interferon gamma secretion); inhibits trophic signals to angiogenic factors in 
cells. Lenalidomide inhibits the growth of myeloma cells by inducing cell cycle 
arrest and cell death. 
 
15.22 Formulation and Dispensing: Commercially available for oral administration 
as: Capsules: 5 mg, 10 mg, 15 mg and 25 mg  
Lenalidomide is approved for marketing only under a FDA approved, restricted 
distribution program called Revlimid REMS. Physicians, pharmacies, and 
patients must be registered; a maximum 28-day supply may be dispensed; a new 
prescription is required each time it is filled; pregnancy testing is required for 
females of childbearing potential. 
 
15.23 Preparation, storage, and stability: Store oral capsules at controlled 
room temperature between 15ºC and 30ºC (59 ºF and 86 ºF). Refer to 
labeling on the bottle for expiration date of the commercial tablets. 
  
15.24 Administration:  Refer to the treatment section for specific administration 
instructions. Administer with water. Swallow capsule whole; do not break, open, 
or chew. 
 
15.25 Pharmacokinetic information: 
Absorption: Rapid 
Metabolism: Approximately two-thirds of Lenalidomide is eliminated 
unchanged through urinary excretion.  
Protein binding: ~30% 
Time to peak, plasma: Healthy volunteers: 0.6-1.5 hours; Myeloma 
patients: 0.5-4 hours 
Half-life elimination: ~3 hours 
Excretion: Urine (~67% as unchanged drug) 
 
15.26 Potential Drug Interactions: 
Increased Effect/Toxicity: Abatacept and Anakinra may increase the risk 
of serious infection when used in combination with Lenalidomide. 
Lenalidomide may increase the risk of infections associated with vaccines 
(live organism). 
Decreased Effect: Lenalidomide may decrease the effect of vaccines 
(dead organisms). 
Herb/Nutraceutical Interactions: Avoid echinacea (has 
immunostimulant properties; consider therapy modifications). 
 
15.27 Known potential adverse events: Consult the package insert for the most 
current and complete information.  

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Boxed Warnings:  
1. Potential for human birth defects 
2. Hematologic toxicity (neutropenia and thrombocytopenia) 
3. Deep Venous Thrombosis and Pulmonary Embolism 
Common known potential toxicities, >10%:   
Cardiovascular: Peripheral edema  
Central nervous system: Fatigue, pyrexia, dizziness, headache 
Dermatologic: Pruritus, rash, dry skin 
Endocrine & metabolic: Hyperglycemia, hypokalemia 
Gastrointestinal: Diarrhea, constipation, nausea, weight loss, dyspepsia, 
anorexia, taste perversion, abdominal pain 
Genitourinary: Urinary tract infection 
Hematologic: Thrombocytopenia, neutropenia, anemia, myelosuppression 
is dose-dependent and reversible with treatment interruption and/or dose 
reduction 
Infection, especially when white blood cell count is low 
Neuromuscular & skeletal: Muscle cramp, arthralgia, back pain, tremor, 
weakness, paresthesia, limb pain, muscle spasms 
Ocular: Blurred vision 
Respiratory: Nasopharyngitis, cough, dyspnea, pharyngitis, epistaxis, 
upper respiratory infection, pneumonia, shortness of breath 
Less common known potential toxicities, 1% - 10%:  
Cardiovascular: Edema, deep vein thrombosis, hypertension, chest pain, 
palpitation, atrial fibrillation, syncope 
Central nervous system: Insomnia, hypoesthesia, pain, depression 
Dermatologic: Brusing, cellulitis, erythema 
Endocrine & metabolic: Hypothyroidism, hypomagnesemia, hypocalcemia 
Gastrointestinal: Vomiting, xerostomia, loose stools 
Genitourinary: Dysuria 
Hematologic: Leukopenia, febrile neutropenia, Lymphopenia 
Hepatic: ALT increased 
Neuromuscular & skeletal: Myalgia, rigors, neuropathy 
Respiratory: Sinusitis, rhinitis, bronchitis, pulmonary embolism 
Miscellaneous: Night sweats, diaphoresis 
Rare known potential toxicities, <1% (Limited to important or life-
threatening):  
Angioedema, Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis 
Tumor Lysis Syndrome, Graft vs. Host Disease, rhabdomyolysis, Kidney 
damage which may require dialysis 
 
15.28 Drug procurement:  As a requirement of the REMS program, access to 
Lenalidomide is restricted. Lenalidomide is approved for marketing only under a 
FDA approved, restricted distribution program called REVLIMID REMS  
(www.REVLIMIDREMS.com) formerly known as the RevAssist program. 
Physicians, pharmacies, and patients must be registered; a maximum 28-day 
supply may be dispensed; a new prescription is required each time it is filled; 
pregnancy testing is required for females of childbearing potential. 
 
15.29 Nursing Guidelines:  

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• 
Myelosuppression is dose-dependent and reversible with treatment 
interruption and/or dose reduction. Monitor CBC w/diff regularly. Instruct 
patient to report any unusual bruising or bleeding (thrombocytopenia); signs 
and symptoms of infection (neutropenia); and energy conserving lifestyle 
(anemia). 
• 
Lenalidomide can have thrombotic adverse events (i.e DVT and PE). Instruct 
patient to report any limb swelling or pain, and to seek medical attention for 
shortness of breath or chest pain. 
• 
Because of the potential for birth defects patients should be instructed in 
effective methods of birth control. Female patients should use 2 forms of 
birth control during treatment and for 4 weeks after discontinuing therapy. 
Males must be instructed to use a latex condom during any sexual contact 
with a woman of child bearing potential (even if they have had a vasectomy), 
because it is unknown if lenalidomide is present in semen. 
• 
Patents may experience pruritus, rash and dry skin. Because of the rare risk 
of Steven’s Johnson Syndrome, patients should immediately report any rash 
to their provider. 
• 
Drug may cause hyperglycemia. Patients with diabetes or impaired fasting 
glucose may need to have their glucose levels monitored more closely. 
• 
Gastrointestinal side effects (diarrhea, constipation, nausea, dyspepsia, 
anorexia, etc) are commonly seen. Manage patent symptomatically and 
monitor for effectiveness. 
• 
Patients may experience myalgias, arthralgias, parasthesias, and other 
generalized pain. Administer analgesics as ordered and monitor for their 
effectiveness. Rarely infective bursitis and arthritis have been reported. 
Instruct patients to report any joint pain or redness to study immediately. 
• 
Upper respiratory symptoms (nasopharyngitis, cough, epistaxis, etc.) can be 
seen. Manage symptomatically and monitor for effectiveness. 
• 
Agent may cause fatigue, dizziness, vertigo or blurred vision. Instruct patient 
to report abdominal pain and/or jaundice to the study team. 
• 
All prescribers and patients must be enrolled into the REVLIMID REMS 
program. Only enough lenalidomide for one cycle of therapy will be supplied 
to the patient each cycle. 
• 
Rarely secondary malignancies have been seen after lenalidomide therapy, 
including MDS, squamous/basal cell carcinomas of the skin, T-cell type 
acute leukemia. 
• 
Monitor Renal function, renal failure has been reported. 
15.3 
Dexamethasone for Oral Administration (DXM) 
15.31 Background: Dexamethasone is an adrenal corticosteroid compound. 
Dexamethasone decreases inflammation by suppression of neutrophil migration, 
decreased production of inflammatory mediators, and reversal of increased 
capillary permeability; suppresses normal immune response. Dexamethasone’s 
mechanism of antiemetic activity is unknown. 
 
15.32 Formulation: Commercially available for oral administration as:  
Tablets [scored]: 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 4 mg, and 6 mg 
Solution, oral: 0.5 mg/mL (500 mL) 
Solution, oral concentrate: Dexamethasone Intensol: 1 mg/mL (30 mL) 
 

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15.33 Preparation, storage, and stability: Refer to package insert for complete 
preparation and dispensing instructions. Store oral tablets at room 
temperature between 20ºC to 25ºC (60ºF to 77ºF). Protect from moisture. 
Dispense in a well-closed, light-resistant container as defined in the 
USP/NF. Store oral liquid at room temperature, do not freeze. Do not use 
if solution contains a precipitate. Refer to commercial package for drug 
expiration date. 
 
15.34 Administration:  Refer to the treatment section for specific administration 
instructions. May be taken with meals to decrease GI upset.  
 
15.35 Pharmacokinetic information: 
Onset of action: Prompt 
Duration of metabolic effect: 72 hours 
Metabolism: Hepatic 
Half-life elimination: Normal renal function: 1.8-3.5 hours; Biological 
half-life: 36-54 hours 
Time to peak, serum: Oral: 1-2 hours 
Excretion: Urine and feces 
 
15.36 Potential Drug Interactions: 
Cytochrome P450 Effect: Substrate of CYP3A4 (major); Induces 
CYP2A6 (weak), 2B6 (weak), 2C8 (weak), 2C9 (weak), 3A4 (strong) 
Increased Effect/Toxicity: Aprepitant, azole antifungals, calcium channel 
blockers, cyclosporine, estrogens, and macrolides may increase the serum 
levels of corticosteroids. Corticosteroids may increase the hypokalemic 
effects of amphotericin B or potassium-wasting diuretics (loop or 
thiazide); monitor. Refer to the package insert for a listing of other drugs. 
Decreased Effect: Antacids and bile acid sequestrants may reduce the 
absorption of corticosteroids; may reduce the absorption of corticosteroids; 
separate administration by 2 hours. Aminoglutethimide, barbiturates, and 
CYP3A4 inducers may reduce the serum levels/effects of dexamethasone 
and dexamethasone may decrease the levels/effects of other CYP3A4 
substrates. Serum concentrations of isoniazid may be decreased by 
corticosteroids. Corticosteroids may lead to a reduction in warfarin effect. 
Corticosteroids may suppress the response to vaccinations. 
Ethanol/Nutrition/Herb Interactions:  
Ethanol: Avoid ethanol (may enhance gastric mucosal irritation). 
Food: Dexamethasone interferes with calcium absorption. Limit caffeine. 
Herb/Nutraceutical: Avoid cat’s claw, Echinacea (have immunostimulant 
properties) 
 
15.37 Known potential adverse events: Consult the package insert for the most 
current and complete information.  
Common known potential toxicities, frequency not defined:   
Fluid and electrolyte disturbances, congestive heart failure in susceptible 
persons, hypertension, euphoria, personality changes, insomnia, 
exacerbation of infection, exacerbation or symptoms of diabetes, 
psychosis, muscle weakness, osteoporosis, vertebral compression 
fractures, pancreatitis, esophagitis, peptic ulcer, dermatologic disturbances, 

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convulsions, vertigo and headache, endocrine abnormalities, ophthalmic 
changes, and metabolic changes. Some patients have experienced itching 
and other allergic, anaphylactic or hypersensitivity reactions. Withdrawal 
from prolonged therapy may result in symptoms including fever, myalgia 
and arthralgia. 
 
15.38 Drug procurement:  Commercial supplies. Pharmacies or clinics shall obtain 
supplies from normal commercial supply chain or wholesaler. 
 
15.39 Nursing Guidelines:  
• 
Monitor regularly for hypertension, CHF and other evidence of fluid 
retention. 
• 
Advise patient of possible mood or behavioral changes, i.e., depression, 
euphoria, insomnia, even psychosis.  Instruct patient to report any suspected 
changes to healthcare team. 
• 
Assess for symptoms of gastric ulcer, heartburn, or gastritis.  Suggest 
antacids.  Instruct patient to report symptoms to healthcare team if unable to 
control. 
• 
Evaluate signs of infection, particularly local candidal infections and treat 
appropriately. 
• 
Monitor blood glucose frequently. 
• 
Instruct patient to report frequent, unrelenting headaches or visual changes to 
healthcare team. 
• 
Advise patient that easy bruising is a side effect. 
16.0  
Statistical Considerations and Methodology 
16.1 
Overview 
This is a phase I/II study of a novel regimen of Ibrutinib, dexamethasone , and 
lenalidomide in patients with MM.  The phase I portion is designed to determine the 
maximum tolerated dose (MTD) of ibrutinib that can be combined with lenalidomide and 
dexamethasone in patients with relapsed MM.  The phase II portion is designed to assess 
the confirmed response rate of Ibrutinib, dexamethasone, and lenalidomide using a one 
stage phase II study design with an interim analysis in patients with transplant ineligible 
newly diagnosed MM.  
 
Note:  Phase II will not be initiated until after FDA review of Phase I data and approval 
to continue. 
 
16.11 Primary Endpoint: The primary endpoint of the phase I portion of this trial is to 
assess the maximum tolerated dose (MTD).  The primary endpoint of the phase II 
portion of this trial is the rate of confirmed response.  A confirmed response is 
defined as a patient who has achieved an sCR, CR, VGPR, or PR on two 
consecutive evaluations at any time during treatment.   Confirmed response will 
be evaluated using all cycles. All patients meeting the eligibility criteria, who 
have signed a consent form and have begun treatment will be evaluable for 
response, unless they are determined to be a major violation. 
 
16.12 Sample Size:  This phase I portion of this study is expected to require a minimum 
of 6 and a maximum of 24 evaluable patients. For the phase II portion, the one 
stage study design with an interim analysis to be used is fully described below.  

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A minimum of 15 and a maximum of 34 evaluable patients will be accrued total 
onto this phase II study unless undue toxicity is encountered.  We anticipate 
accruing an additional 5 patients  (2 phase I, 3 phase II) to account for 
ineligibility, cancellation, major treatment violation, or other reasons for a total 
of 63 patients overall. 
 
16.13 Accrual Rate and Study Duration:  The anticipated accrual rate is 2 evaluable 
multiple myeloma patients per month.  At this rate, it will likely take about 3 
months to enroll, treat, and evaluate each cohort of 3 patients in the dose 
escalation portion.  We expect to evaluate a maximum of 4 dose levels, for a total 
duration of approximately 1.5 years  in the dose escalation portion.  The phase II 
patients are expected to accrue in the subsequent 1.5 years.  The maximum total 
study duration is expected to be approximately 3.5 years, or until the last patient 
accrued has been observed for at least 6 months. 
 
16.2 
Phase I Portion Study Design: 
This portion of the study will consist of a phase I trial to determine the MTD of ibrutinib 
in combination with lenalidomide and dexamethasone. A standard cohort of 3 phase I 
design will be utilized as described below.  Three patients will be treated at each dose 
level and observed for a minimum of four weeks (i.e. one full cycle) before new patients 
are treated.  Doses will not be escalated in any individual patient. 
 
16.21 MTD Definition: MTD is defined as the dose level below the lowest dose that 
induces dose-limiting toxicity (DLT) in at least one-third of patients (at least 2 of 
a maximum of 6 new patients). A total of 6 patients treated at the MTD will be 
sufficient to identify common toxicities at the MTD. For instance, those toxicities 
with an incidence of at least 25% will be observed with a probability of at least 
82% (1-(1-0.25)6). 
 
Refer to section 7.32 for determination of dose-limiting toxicity (DLT) 
 
16.22 Dose Escalation: The dose escalation portion of this study will utilize a standard 
cohort of three design. The dose levels to which patients will be assigned in 
sequential cohorts are described in Section 7.3. The first cohort of three patients 
will be treated at dose level 1.  Decisions on when and how to dose escalate are 
described below. 
 
16.221  Three patients will be treated at a given dose level combination and 
observed for 1 cycle to assess toxicity.  
 
16.222  If DLT is not seen in any of the 3 patients, 3 new patients will be 
accrued and treated at the next higher dose level. If DLT is seen in 2 or 
3 of 3 patients treated at a given dose level, then the next 3 patients 
will be treated at the next lower dose level, if only 3 patients were 
enrolled and treated at this lower dose level.  
 
16.223  If DLT is seen in 1 of 3 patients treated at a given dose level, up to 3 
additional patients will be enrolled and treated at the same dose level. 
If DLT is seen in at least one of these additional three patients (≥2 of 
6), the MTD will have been exceeded and further accrual will cease to 

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this cohort. If dose-limiting toxicity (DLT) is not seen in any of the 
three additional patients, 3 new patients will be accrued and treated at 
the next higher dose level.  
 
16.224  After enrolling 6 patients on a specific dose level, if DLT is observed 
in at least 2 of 6 patients, then the MTD will have been exceeded and 
defined as the previous dose unless only 3 patients were treated at the 
lower dose level. In that case, 3 additional patients will be treated at 
this lower dose level such that a total of 6 patients are treated at the 
MTD to more fully assess the toxicities associated with the MTD. 
 
16.225  Dose de-escalation: If dose-limiting toxicity meets the stopping 
boundaries set by the above dose escalation algorithm at dose level 1 
(for example, more than 1 out of 3 patients or more than 1 out of 6 
patients), the next cohort of three patients will be entered at a dose 
level of -1. Further dose re-escalation will depend on the toxicity 
profile observed at these dose levels, and re-evaluation of the regimen 
by the study team may be done. 
 
16.226 If a patient fails to complete the first cycle of treatment for reasons other 
than toxicity, the patient will be regarded as inevaluable and will be 
replaced. 
 
16.227  Operating Characteristics for standard cohort of 3 design: The following 
table gives the probability of dose escalation at a single dose level as a 
function of the true probability of DLT at that level using the cohorts of 3 
design described above. 
 
True Rate 
of DLT (%) 
 
Probability of Dose Escalation 
10 
0.91 
20 
0.71 
30 
0.49 
40 
0.31 
50 
0.17 
 
16.23 Analysis Plans: All the relevant results pertaining to toxicity, MTD, response, 
timed endpoints and laboratory correlates will be examined in an exploratory and 
hypothesis-generating fashion. The small sample size and the heterogeneous 
patient population associated with phase I studies restricts the generalizability of 
the results. Any notable statistical result should only be viewed as preliminary 
evidence for further study in Phase II trials rather than a definitive finding in and 
of itself. 
 
16.231 Adverse Event Profile 
 
The number and severity of all adverse events (overall and by dose-level) 
will be tabulated and summarized in this patient population. The Grade 
3+ adverse events will also be described and summarized in a similar 

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fashion. This will provide an indication of the level of tolerance for this 
treatment combination in this patient group. 
 
16.232 Toxicity Profile 
 
The term toxicity is defined as adverse events that are classified as either 
possibly, probably, or definitely related to study treatment.  Non-
hematologic toxicities will be evaluated via the ordinal CTC standard 
toxicity grading. Hematologic toxicity measures of thrombocytopenia, 
neutropenia, and leukopenia will be assessed using continuous variables 
as the outcome measures (primarily nadir) as well as categorization via 
CTC standard toxicity grading. 
  
Overall toxicity incidence as well as toxicity profiles by dose level and 
patient will be explored and summarized. Frequency distributions, 
graphical techniques and other descriptive measures will form the basis 
of these analyses. 
 
16.233 Response Profile 
A response is defined to be a sCR, CR, VGPR, or PR noted as the 
objective status. Response will be evaluated using all cycles of treatment. 
All patients meeting the eligibility criteria who have signed a consent 
form and have begun treatment will be evaluable for response.  
Responses will be summarized by simple descriptive summary statistics 
delineating depth of response as well as stable and progressive disease in 
this patient population 
16.3 
Phase II Statistical Design: 
16.31 Decision Rule: 
In a previous study of lenalidomide and dexamethasone in patients with 
transplant ineligible newly diagnosed multiple myeloma, 1076 patients were 
treated and evaluated for response.29  The overall response rate in 541 patients 
treated with 18 cycles of lenalidomide and dexamethasone was 73%. In 535 
patients who received continuous dosing of lenalidomide and dexamethasone 
until disease progression, the overall response rate was 75%. An increase in 
overall response rate for ibrutinib, dexamethasone, and lenalidomide would be of 
interest. 
The largest success proportion where the proposed treatment regimen would be 
considered ineffective in this population is 65%, and the smallest success 
proportion that would warrant subsequent studies with the proposed regimen in 
this patient population is 85%. The following one–stage design with an interim 
analysis is based on a two-stage Simon optimum design30 and requires 34 
evaluable patients to test the null hypothesis that the true success proportion in 
this patient population is at most 65% 
 
16.311 Interim Analysis: Enter 15 evaluable patients into the study. If 10 or 
fewer successes are observed in the first 15 evaluable patients, we will 
consider this regimen ineffective in this patient population and terminate 
the study.  Otherwise, if the number of successes is at least 11, we will 
continue accrual. 

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16.312 Final Decision Rule:  Enter an additional 19 evaluable patients into the 
study.  If 25 or fewer successes are observed in the first 34 evaluable 
patients, we will consider this regimen ineffective in this patient 
population and terminate this study. Otherwise, if the number of 
successes is at least 26, this will be considered evidence of promising 
activity and the treatment may be recommended for further testing in 
subsequent studies in this population. 
 
16.313 Over Accrual: If more than the target number of patients are accrued, the 
additional patients will not be used to evaluate the stopping rule or used 
in any decision making process. 
 
16.314 NOTE:  We will not suspend accrual at the interim analysis to allow the 
first 15 patients to become evaluable, unless undue toxicity is observed. 
Given the limited overall sample size and the inclusion of an adverse 
events stopping rule, we feel it is ethical to not halt accrual for the 
interim analysis. However, if accrual is extremely rapid, we may 
temporarily suspend accrual in order to obtain safety data on these 
patients before re-opening accrual to further patients. 
 
16.32 Power and Significance Level: Assuming that the number of successes is 
binomially distributed, the significance level is .09, i.e. there is a 9% chance of 
finding the drug to be effective when it truly is not.  The probability of declaring 
that this regimen warrants further study (i.e. statistical power) and the probability 
of stopping at the interim analysis under various success proportions can be 
tabulated as a function of the true success proportion as shown in the following 
table. 
 
If the true success proportion is... 
0.65 
0.70 
0.75 
0.80 
0.85 
Then the probability of declaring 
that the regimen warrants further 
study is… 
0.092 
0.233 
0.459 
0.715 
0.904 
And the probability of stopping at 
the interim analysis is… 
0.648 
0.485 
0.314 
0.164 
0.062 
 
16.33 Other considerations:  Adverse events, quality/duration of response, and patterns 
of treatment failure observed in this study, as well as scientific discoveries or 
changes in standard care will be taken into account in any decision to terminate 
the study. 
 
16.4 
Analysis Plan 
The analysis for this trial will commence at planned time points (see 16.3) and at the time 
the patients have become evaluable for the primary endpoint. The Statistician and Study 
Chair will make the decision, in accord with CCS Standard Operating Procedures, 
availability of data for secondary endpoints (e.g., laboratory correlates), and the level of 
data maturity. It is anticipated that the earliest date in which the results will be made 
available via manuscript, abstract, or presentation format is when last patient has been 
followed for at least 6 months. 
 

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16.41 Primary Outcome Analysis: 
16.411 Definition: The primary endpoint of this trial is the confirmed response 
rate. A success is defined as a sCR, CR, VGPR, or PR noted as the 
objective status on two consecutive evaluations at any time.  All patients 
meeting the eligibility criteria who have signed a consent form and have 
begun treatment will be evaluable for response, unless they are 
determined to be a major violation. 
16.412 Estimation:  The proportion of successes will be estimated by the number 
of successes divided by the total number of evaluable patients. Ninety-
five percent confidence intervals for the true success proportion will be 
calculated according to the approach of Duffy and Santner. 
16.413 Over Accrual: If more than the target number of patients are accrued, the 
additional patients will not be used to evaluate the stopping rule or used 
in any decision making processes; however, they will be included in final 
point estimates and confidence intervals 
16.42 Secondary Outcome Analyses 
16.421 Progression-free survival time is defined as the time from registration to 
the time of progression or death due to any cause. A progression that 
occurs during cycle 1 of the phase II portion prior to the addition of 
lenalidomide will not be considered an event. Patients who are alive and 
progression-free will be censored on the date of their last disease 
assessment. Patients who receive subsequent treatment for myeloma 
before disease progression will be censored on the date of their last 
disease assessment prior to initiation of the subsequent treatment. The 
distribution of progression-free survival will be estimated using the 
method of Kaplan-Meier. 
16.422 Survival time is defined as the time from registration to death due to any 
cause. The distribution of survival time will be estimated using the 
method of Kaplan-Meier. 
16.423 Duration of response is defined for all evaluable patients who have 
achieved a confirmed response as the date at which the patient’s 
objective status is first noted to be a sCR, CR, VGPR, or PR to the 
earliest date progression is documented. The distribution of duration of 
response will be estimated using the method of Kaplan-Meier. 
16.424 Adverse Events: All eligible patients that have initiated treatment will be 
considered evaluable for assessing adverse event rate(s). The maximum 
grade for each type of adverse event will be recorded for each patient, 
and frequency tables will be reviewed to determine patterns. 
Additionally, the relationship of the adverse event(s) to the study 
treatment will be taken into consideration. 
16.43 Exploratory Outcomes Analyses 
16.431 Compliance to Treatment: Patient compliance to ibrutinib, 
dexamethasone, and lenalidomide will be assessed by means of self-
reported and healthcare staff assessed pill count/diary. Correlation 
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16.432 Quality of Life (QoL): In the proposed trial, patient-reported QoL will be 
measured with the MD Anderson Symptom Inventory – Multiple 
Myeloma (MDASI-MM), which has been a validated tool.24 The 
MDASI-MM consists of 13 core items, 7 MM-specific symptom severity 
items and 6 interference items; the time frame for addressing symptom 
severity and interference is the last 24 hours. From these items, mean 
subscale scores have been derived: mean Core (13 core items), mean 
Severity (13 core items + 7 MM-specific items), and mean Interference 
(6 interference items); an exploratory analysis in this study will examine 
a 4th score, the mean Severity score for the 7 MM symptoms. Response 
options range from 0 (“not present”) to 10 (“as bad as you can imagine”) 
for the severity items and from 0 (“did not interfere”) to 10 (“interfered 
completely”) for the interference items. These will be completed by 
patients in a paper or electronic entry at baseline (within 14 days of 
starting treatment), at the end of cycle 1 (± 3 days), at the end of cycle 6 
(±3 days) and at completion of cycle 12 of treatment (±3 days), at any 
time the patient progresses while on the 3-drug regimen and is removed 
from the study protocol (within 14 days of removal from the study). The 
primary outcome of interest for this trial is the difference in the change 
of the mean Symptom Severity score for the Core plus 7 MM symptom 
items from baseline to the end of 6 cycles of therapy, and any variation 
reported in the MDASI-MM score at one year. 
16.44 Exploratory Correlative Outcomes Analyses 
16.441 BTK signalosome members (BTK, PLCy2, Lyn, Fyn, Syk, BLNK, 
BCAP, PI3K, NFkB, NFAT, pAKT and pS6) will be profiled by MSD-
based mesoscale assay (or phospho-flow) at baseline before treatment, 
after cycle 1 (phase II patients only), and at the time of response 
assessment or disease progression. BTK signalosome component 
expression levels will be determined from BM and/or peripheral blood.  
Each measure will be summarized descriptively at each time point and 
changes across time will be evaluated.   Correlation with response to 
overall therapy will be assessed using Wilcoxon’s rank sum tests. 
16.442 Ibrutinib has been shown to modulate T-cells populations (Th1, Th2 and 
T-Regs). Similarly, the combination of lenalidomide and dexamethasone 
is also known to act on these cell types. To understand the impact of this 
combination, we will conduct flow cytometry/FACS analysis to identify 
percentages of the immune cell populations (T-cells, NK cells, 
macrophages) in the bone marrow and peripheral blood at baseline 
before treatment, after cycle 1 (phase II patients only) and at the time of 
response assessment or disease progression. Each measure will be 
summarized descriptively at each time point and changes across time will 
be evaluated. Correlation with response to overall therapy will be 
assessed using Wilcoxon’s rank sum tests. 
16.5 
Data and Safety Monitoring: 
16.51 The principal investigator(s) and the study statistician will review the study at 
least twice a year to identify accrual, adverse event, and any endpoint problems 
that might be developing. The Mayo Clinic Cancer Center (MCCC) Data Safety 
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for this trial at least twice a year, based on reports provided by the MCCC 
Statistical Office. 
16.52 Adverse Event Stopping Rules: 
The stopping rules specified below are based on the knowledge available at study 
development. We note that the Adverse Event Stopping Rule may be adjusted in 
the event of either (1) the study re-opening to accrual or (2) at any time during 
the conduct of the trial and in consideration of newly acquired information 
regarding the adverse event profile of the treatment(s) under investigation. The 
study team may choose to suspend accrual because of unexpected adverse event 
profiles that have not crossed the specified rule below. 
Phase I: By the nature of the “cohorts of three” phase I study design, toxicity 
(i.e., adverse events that are possibly, probably or definitely related to study 
treatment) stopping rules are in place for each dose level. Specifically, if 2 or 
more dose-limiting toxicities (DLTs) are observed during Cycle 1 at any given 
dose level, accrual to that dose level will be stopped, and patients will be accrued 
to the next lower dose level until a maximum of 6 patients are treated at the lower 
level. Note that a DLT that affects dose escalation is only that which is observed 
in the first cycle of treatment. However, adverse events for all cycles will be 
reviewed and the study team will determine whether the dose level needs to be 
adjusted for future patients. Specifically, if one of the following occurs, then 
enrollment should stop and the trial should be re-evaluated whether to continue 
or close the trial permanently to accrual. The study team will evaluate all 
toxicities on all dose levels before determining how to proceed. 
• 
if ≥1 in the first 3 patients experience a Grade 4 or higher non-
hematologic adverse event at least possibly related to treatment over all 
cycles at any dose level 
• 
≥2 in the first 6 patients experience a Grade 4 or higher non-hematologic 
adverse event at least possibly related to treatment over all cycles at any 
dose level 
Phase II: Accrual will be temporarily suspended to this study if at any time we 
observe events considered at least possibly related to study treatment (i.e. an 
adverse event with attribute specified as  “possible,” “probable,” or “definite”) 
that satisfy one of the following: 
• 
if 5 or more patients in the first 15 treated patients experience a Grade 4 or 
higher non-hematologic adverse event at least possibly related to treatment. 
• 
if after the first 15 patients have been treated, 30% of all patients experience 
a Grade 4 or higher non-hematologic adverse event at least possibly related 
to treatment.  
We note that we will review Grade 4 and 5 adverse events deemed “unrelated” or 
“unlikely to be related”, to verify their attribution and to monitor the emergence 
of a previously unrecognized treatment-related adverse event. 
 
16.6 
Results Reporting on ClinicalTrials.gov 
At study activation, this study will have been registered within the “ClincialTrials.gov” 
website. The Primary and Secondary Endpoints along with other required information for 
this study will be reported on www.ClinicalTrials.gov. For purposes of timing of the 
Results Reporting, the initial estimated completion date for the Primary Endpoint of this 
study is 3.5 years after the study opens to accrual. The definition of “Primary Endpoint 

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Completion Date” (PECD) for this study is at the time the last patient registered has been 
followed for at least 6 months. 
16.7 
Inclusion of Women and Minorities: 
16.71 This study will be available to all eligible patients, regardless of race, gender, or 
ethnic origin. 
16.72 There is no information currently available regarding differential effects of this 
regimen in subsets defined by race, gender, or ethnicity, and there is no reason to 
expect such differences to exist. Therefore, although the planned analysis will, as 
always, look for differences in treatment effect based on racial and gender 
groupings, the sample size is not increased in order to provide additional power 
for subset analyses. 
16.73 The geographical region served by MCCC has a population which includes 
approximately 3% minorities. Based on prior MCCC studies involving similar 
disease sites, we expect about 3-5% of patients will be classified as minorities by 
race and about 33% of patients will be women. Expected sizes of racial by 
gender subsets are shown in the following table: 
Accrual Estimates by Gender/Ethnicity/Race 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
0 
1 
1 
Not Hispanic or Latino 
21 
41 
62 
Ethnic Category: Total of all subjects 
21 
42 
63 
Racial Category 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
0 
0 
0 
Black or African American 
1 
1 
2 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
20 
41 
61 
Racial Category: Total of all subjects 
21 
42 
63 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 

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Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, 
India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and 
Vietnam. (Note: Individuals from the Philippine Islands have been recorded as Pacific 
Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial 
groups of Africa. Terms such as “Haitian” or “Negro” can be used in addition to 
“Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 
17.0 
Pathology Considerations/Tissue Biospecimens: None.  
 

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18.0 
Records and Data Collection Procedures 
18.1 
Submission Timetable 
Data submission instructions for this study can be found in the Case Report Form packet. 
18.2 
Event monitoring 
See Section 4.2 and data submission table in the case report form packet for the event 
monitoring schedule. 
18.3 
CRF completion 
This study will use Medidata Rave for remote data capture (rdc) of all study data. 
18.4 
Site responsibilities 
Each site will be responsible for insuring that all materials contain the patient’s initials, 
MCCC registration number, and MCCC protocol number. Patient’s name must be 
removed. 
18.5 
Supporting documentation 
This study requires supporting documentation for diagnosis prior to study entry as well as 
for evidence of response to study therapy and progression after study therapy. Supporting 
documentation for diagnosis will include either a pathology report or a laboratory report 
demonstrating multiple myeloma (including SPEP, UPEP, FLC, Serum and Urine 
Immunofixation, Bone Marrow Biopsy and Aspirate, skeletal bone survey, PET scan, 
Plasma Cell Proliferation and Assessment and FISH). These reports should be uploaded 
into the Supporting Documentation: Baseline form within 14 days of registration. 
 
For progression of disease prior to study entry, supporting documentation includes the 
evidence needed to determine the patient’s progression prior to enrollment. These 
documents should be uploaded into the Supporting Documentation: Baseline form within 
14 days of registration. 
 
For response to treatment, supporting documentation may include SPEP, UPEP, FLC, 
Serum and Urine Immunofixation, Bone Marrow Biopsy and aspirate, skeletal bone 
survey, and PET scan. These documents should be uploaded into the Supporting 
Documentation form. 
  
For patients who progress after study therapy supporting documentation may include any 
of the following: SPEP, UPEP, FLC, serum and urine immunofixation, bone marrow 
biopsy and aspirate, skeletal bone survey, and PET scan. These documents should be 
uploaded into the Supporting Documentation form. 
 
18.6 
Labelling of materials 
Each site will be responsible for insuring that all materials contain the patient’s initials, 
MCCC registration number, and MCCC protocol number. Patient’s name must be 
removed. 
18.7 
Incomplete materials 
Any materials deemed incomplete by the MCCC Operations Office will be considered 
“not received” and will not be edited or otherwise processed until the missing 

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information is received. A list of the missing documents will be made available to the 
appropriate co-sponsor/participant. 
18.8 
Overdue lists 
A list of overdue materials and forms for study patients will be generated monthly. The 
listings will be sorted by location and will include the patient study registration number. 
The appropriate co-sponsor/participant will be responsible to obtain the overdue material. 
 
 
19.0  
Budget 
19.1 
Costs charged to patient:  All routine clinical care.  Ibrutinib will be provided free of 
charge by Pharmacyclics (an AbbVie company). 
19.2 
Tests to be research funded:  Correlative studies outlined in Sections 14.0.   
19.3 
Other budget concerns: Protocol administration, study coordinator time, data 
management, and statistical analysis efforts will be funded by Pharmacyclics (an AbbVie 
company). 
 
 

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20.0 
References 
1. Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of 
multiple myeloma. Leukemia. 2009;23(1):3-9. 10.1038/leu.2008.291. 
2. Palumbo A, Sezer O, Kyle R, et al. International Myeloma Working Group guidelines for the 
management of multiple myeloma patients ineligible for standard high-dose chemotherapy with 
autologous stem cell transplantation. Leukemia. 2009;23(10):1716-1730. 10.1038/leu.2009.122. 
3. Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed multiple 
myeloma. Mayo Clinic Proceedings. 2003;78(1):21-33. 
4. Palumbo A, Anderson K. Multiple myeloma. New England Journal of Medicine. 2011;364(11):1046-
1060. 
5. Chanan-Khan AA, Kaufman JL, Mehta J, et al. Activity and safety of bortezomib in multiple 
myeloma patients with advanced renal failure: A multicenter retrospective study. Blood. 
2007;109(6):2604-2606. 
6. Jagannath S, Richardson PG, Sonneveld P, et al. Bortezomib appears to overcome the poor prognosis 
conferred by chromosome 13 deletion in phase 2 and 3 trials. Leukemia. 2007;21(1):151-157. 
7. Richardson PG, Barlogie B, Berenson J, et al. Extended follow-up of a Phase II trial in relapsed, 
refractory multiple myeloma: Final time-to-event results from the SUMMIT trial. Cancer. 
2006;106(6):1316-1319. 
8. Palumbo A, Bringhen S, Mateos MV, et al. Geriatric assessment predicts survival and toxicities in 
elderly myeloma patients: an International Myeloma Working Group report. Blood. 
2015;125(13):2068-2074. Prepublished on 2015/01/30 as DOI 10.1182/blood-2014-12-615187. 
9. Rajkumar SV, Jacobus S, Callander NS, 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. The Lancet Oncology. 2010;11(1):29-37. 
10. Shinners NP, Carlesso G, Castro I, et al. Bruton's tyrosine kinase mediates NF-κB activation and B 
cell survival by B cell-activating factor receptor of the TNF-R family. Journal of Immunology. 
2007;179(6):3872-3880. 
11. Mohamed AJ, Yu L, Bäckesjö CM, et al. Bruton's tyrosine kinase (Btk): Function, regulation, and 
transformation with special emphasis on the PH domain. Immunological Reviews. 2009;228(1):58-73. 
12. Herman SEM, 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(23):6287-6296. 
13. Ponader S, Chen SS, Buggy JJ, et al. The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic 
lymphocytic leukemia cell survival and tissue homing in vitro and in vivo. Blood. 2012;119(5):1182-
1189. 
14. Vij R, Huff CA, Bensinger WI, 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 (Abstract). 
15. Yang Y, Shaffer AL, Emre NCT, et al. Exploiting Synthetic Lethality for the Therapy of ABC 
Diffuse Large B Cell Lymphoma. Cancer Cell. 2012;21(6):723-737. 
16. Pollyea DA, Coutre S, Gore L, et al. A Dose Escalation Study of Ibrutinib with Lenalidomide for 
Relapsed and Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Blood. 
2014;124(21):1987 (Abstract). 
17. Christian B, Kuruvilla J, Smith S, et al. A Phase I Study of Ibrutinib and Lenalidomide in Patients 
with Relapsed and Refractory B-Cell Non-Hodgkin's Lymphoma. Blood. 2014;124(21):4476 
(Abstract). 
18. Woyach JA, Bojnik E, Ruppert AS, et al. Bruton's tyrosine kinase (BTK) function is important to the 
development and expansion of chronic lymphocytic leukemia (CLL). Blood. 2014;123(8):1207-1213. 
10.1182/blood-2013-07-515361. 

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19. Dubovsky JA, Beckwith KA, Natarajan G, et al. Ibrutinib is an irreversible molecular inhibitor of ITK 
driving a Th1-selective pressure in T lymphocytes. Blood. 2013;122(15):2539-2549. 10.1182/blood-
2013-06-507947. 
20. Kuwabara A, Babb A, Ibrahim A, et al. Poor outcome after reintroduction of imatinib in patients with 
chronic myeloid leukemia who interrupt therapy on account of pregnancy without having achieved an 
optimal response. Blood. 2010;116(6):1014-1016. 10.1182/blood-2010-04-280206. 
21. Marin D, Bazeos A, Mahon FX, et al. Adherence is the critical factor for achieving molecular 
responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on 
imatinib. J Clin Oncol. 2010;28(14):2381-2388. 10.1200/JCO.2009.26.3087. 
22. Nuesch R, Schroeder K, Dieterle T, Martina B, Battegay E. Relation between insufficient response to 
antihypertensive treatment and poor compliance with treatment: a prospective case-control study. 
BMJ. 2001;323(7305):142-146. 
23. Sonneveld P, Verelst SG, Lewis P, et al. Review of health-related quality of life data in multiple 
myeloma patients treated with novel agents. Leukemia. 2013;27(10):1959-1969. 
10.1038/leu.2013.185. 
24. Jones D, Vichaya EG, Wang XS, et al. Validation of the M. D. Anderson Symptom Inventory 
multiple myeloma module. J Hematol Oncol. 2013;6:13. 10.1186/1756-8722-6-13. 
25. Chen N, Lau H, Kong L, et al. Pharmacokinetics of lenalidomide in subjects with various degrees of 
renal impairment and in subjects on hemodialysis. Journal of clinical pharmacology. 
2007;47(12):1466-1475. Prepublished on 2007/10/24 as DOI 10.1177/0091270007309563. 
26. Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide- and lenalidomide-
associated thrombosis in myeloma. Leukemia. 2008;22(2):414-423. Prepublished on 2007/12/21 as 
DOI 10.1038/sj.leu.2405062. 
27. Ozer H, Armitage JO, Bennett CL, et al. 2000 update of recommendations for the use of 
hematopoietic colony-stimulating factors: evidence-based, clinical practice guidelines. American 
Society of Clinical Oncology Growth Factors Expert Panel. Journal of clinical oncology : official 
journal of the American Society of Clinical Oncology. 2000;18(20):3558-3585. Prepublished on 
2000/10/14 as DOI. 
28. Rajkumar SV, Harousseau JL, Durie B, et al. Consensus recommendations for the uniform reporting 
of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 
2011;117(18):4691-4695. Prepublished on 2011/02/05 as DOI 10.1182/blood-2010-10-299487. 
29. Benboubker L, Dimopoulos MA, Dispenzieri A, et al. Lenalidomide and dexamethasone in 
transplant-ineligible patients with myeloma. The New England journal of medicine. 
2014;371(10):906-917. Prepublished on 2014/09/04 as DOI 10.1056/NEJMoa1402551. 
30. Simon R. Optimal two-stage designs for phase II clinical trials. Controlled clinical trials. 
1989;10(1):1-10. Prepublished on 1989/03/01 as DOI. 
 
 
 

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Appendix I 
Myeloma Frailty Score 
 
Variable 
Patient Category 
Score 
Age 
≤75 years 
0 
76-80 years 
1 
>80 years 
2 
Charlson Index (See Appendix 
III) 
Charlson ≤1 
0 
Charlson ≥2 
1 
Activities of Daily Living 
(ADL) Score  (See Appendix II) 
ADL >4 
0 
ADL ≤4 
1 
Instrumental Activities of Daily 
Living (IADL) Score (see 
Appendix II) 
IADL >5 
0 
IADL ≤5 
1 
 
Additive Total Score 
Patient Status 
0 
Fit 
1 
Intermediate fitness  
≥2 
Frail 
 

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Appendix II 
Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) 
 
Score 
ADL 
IADL 
0-1 
Bathing (tub bath, shower, sponge bath) 
Ability to use the telephone 
0-1 
Dressing (taking clothes from the wardrobe/drawers and getting 
dressed) 
Shopping 
0-1 
Toileting (going to the toilet room, using toilet, arranging 
clothes) 
Food preparation 
0-1 
Transferring 
Housekeeping 
0-1 
Continence 
Laundry 
0-1 
Feeding 
Mode of transportation 
0-1 
- 
Responsibility for own 
medications 
0-1 
- 
Ability to handle finances 
For each category, the patient receives a score of 1 if they can complete the activity and a score of 0 if 
they cannot complete the activity. The sum of each column is computed to get total scores for ADL and 
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Appendix III Charlson Comorbidity Index 
http://www.uroweb.org/fileadmin/livesurgery/Charlson_Comorbidity_Index.pdf 
AKA: Charlson Comorbidity Index, Comorbidity‐Adjusted Life Expectancy 
1.  Indication 
1.  Assess whether a patient will live long enough to benefit from a specific screening measure or 
medical intervention 
2.  Scoring: Comorbidity Component (Apply 1 point to each unless otherwise noted) 
1.  Myocardial Infarction 
2.  Congestive Heart Failure 
3. Peripheral Vascular Disease 
4.  Cerebrovascular Disease 
5.  Dementia 
6.  COPD 
7.  Connective Tissue Disease 
8.  Peptic Ulcer Disease 
9.  Diabetes Mellitus (1 point uncomplicated, 2 points if end‐organ damage) 
10.  Moderate to Severe Chronic Kidney Disease (2 points) 
11.  Hemiplegia (2 points) 
12.  Leukemia (2 points) 
13.  Malignant Lymphoma (2 points) 
14.  Solid Tumor (2 points, 6 points if metastatic) 
15.  Liver Disease (1 point mild, 3 points if moderate to severe) 
16.  AIDS (6 points) 
3.  Scoring: Age 
1.  Age <40 years: 0 points 
2.  Age 41‐50 years: 1 points 
3.  Age 51‐60 years: 2 points 
4.  Age 61‐70 years: 3 points 
5.  Age 71‐80 years: 4 points 
4.  Interpretation 
1.  Calculate Charlson Score or Index (i) 
1.  Add Comorbidity score to age score 
2.  Total denoted as 'i' below 
2.  Calculate Charlson Probablity (10 year mortality) 
1.  Calculate Y = e^(i * 0.9) 
2.  Calculate Z = 0.983^Y 
3.  where Z is the 10 year survival 
5.  References 
1.  Charlson (1987) J Chron Dis 40: 373–83 
2.  Gold (1994) J Clin Epidemiol 47: 1245–51 

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Appendix IV ECOG Performance Status Scale 
 
ECOG PERFORMANCE STATUS* 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled. Cannot carry on any selfcare. 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 ECOG Performance Status is in the public domain therefore available for public use. To duplicate the 
scale, please cite the reference above and credit the Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
From http://www.ecog.org/general/perf_stat.html 
 
 

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Appendix V 
Creatinine Clearance (CrCl) Calculation 
 
 
Cockcroft-Gault Equation: 
Creatinine clearance for males =  (140 - age)(weight in kg) 
 
(72)(serum creatinine in mg/dL) 
 
Creatinine clearance for females =  (140 - age)(weight in kg)(0.85) 
 
(72)(serum creatinine in mg/dL) 
 
 

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Appendix VI New York Heart Association Classification of Congestive Heart Failure 
 
NYHA 
Class 
Symptoms 
I 
Cardiac disease, but no symptoms and no limitation in ordinary physical activity, e.g. 
no shortness of breath when walking, climbing stairs etc. 
II 
Mild symptoms (mild shortness of breath and/or angina) and slight limitation during 
ordinary activity. 
III 
Marked limitation in activity due to symptoms, even during less-than-ordinary activity, 
e.g. walking short distances (20–100 m). Comfortable only at rest. 
IV 
Severe limitations. Experiences symptoms even while at rest. Mostly bedbound 
patients. 
 
Adapted from Dolgin M, Association NYH, Fox AC, Gorlin R, Levin RI, New York Heart 
Association. Criteria Committee. Nomenclature and criteria for diagnosis of diseases of the 
heart and great vessels. 9th ed. Boston, MA: Lippincott Williams and Wilkins; March 1, 1994. 
Original source: Criteria Committee, New York Heart Association , Inc.  Diseases of the Heart 
and Blood Vessels. Nomenclature and Criteria for diagnosis, 6th edition  Boston, Little, Brown 
and Co. 1964, p 114. 
 

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Appendix VII Mayo Risk Stratification 
 
 
High Risk 
FISH deletion 17p 
FISH t(14; 16) 
FISH t(14; 20) 
GEP (if done) High-risk signature 
 
 
Intermediate Risk 
 
FISH t(4:14) 
Metaphase cytogenetic del 13 
Hypodiploidy 
 
 
Standard Risk 
 
All others including: 
 
FISH t(11; 14) 
 
FISH t(6; 14) 
 

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Appendix VIIIa 
Patient Medication Diary (Phase I/Phase II) 
(Phase I, all cycles and Phase II Cycle 2 and beyond) 
 PATIENT MEDICATION DIARY 
Please complete this diary on a daily basis. Write in the amount of the dose of ibrutinib, 
lenalidomide and dexamethasone that you took in the appropriate “Day” box. 
On the days that you do not take any study drug, please write in “0”. If you forget to take your 
daily dose, please write in “0”, but remember to take your prescribed dose at the next regularly 
scheduled time. 
If you experience any health/medical complaints or take any medication other than ibrutinib, 
lenalidomide or dexamethasone, please record this information. 
Take the ibrutinib with water at about the same time every day (with or without food). Swallow 
the capsules whole; do not open, break, or chew the capsules. Please do not eat grapefruits or 
Seville oranges, or drink grapefruit juice while taking the ibrutinib.   
Please take the dexamethasone with food.   
 
Week of: _________________________ 
Study Drug 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Ibrutinib 
 
 
 
 
 
 
 
Lenalidomide 
 
 
 
 
 
 
 
Dexamethasone 
 
 
 
 
 
 
 
 
Week of: _________________________ 
Study Drug 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Ibrutinib 
 
 
 
 
 
 
 
Lenalidomide 
 
 
 
 
 
 
 
Dexamethasone 
 
 
 
 
 
 
 
 
Week of: _________________________ 
Study Drug 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
Ibrutinib 
 
 
 
 
 
 
 
Lenalidomide 
 
 
 
 
 
 
 
Dexamethasone 
 
 
 
 
 
 
 
 
Week of: _________________________ 
Study Drug 
Day 22 
Day 23 
Day 24 
Day 25 
Day 26 
Day 27 
Day 28 
Ibrutinib 
 
 
 
 
 
 
 
Lenalidomide 
 
 
 
 
 
 
 
Dexamethasone 
 
 
 
 
 
 
 
Patient Signature: ___________________________________________ 
My next scheduled visit is: _______________________________ 
If you have any questions, please call:  ______________________ 
 

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HEALTH/MEDICAL COMPLAINTS 
Please record all health/medical complaints you may have experienced below. 
 
Please describe what you experienced 
Date started 
Date stopped 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
OTHER MEDICATION 
Record only medication (prescription and/or over-the-counter, including herbal medications and vitamins) 
taken other than ___________________________. 
 
Name of Medication 
Why did you take the 
medication? 
Dose 
Frequency 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Coordinator Use Only 
Verified by ____________________________ 
Date_______________ 
 
 
 

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Appendix VIIIb 
Patient Medication Diary (Phase II, Cycle 1 Only) 
PATIENT MEDICATION DIARY 
Please complete this diary on a daily basis. Write in the amount of the dose of ibrutinib and 
dexamethasone that you took in the appropriate “Day” box. 
On the days that you do not take any study drug, please write in “0”. If you forget to take your 
daily dose, please write in “0”, but remember to take your prescribed dose at the next regularly 
scheduled time. 
If you experience any health/medical complaints or take any medication other than ibrutinib or 
dexamethasone, please record this information. 
 
Take your ibrutinib with water at about the same time every day (with or without food). Swallow 
the capsules whole; do not open, break, or chew the capsules.  Please do not eat grapefruits or 
Seville oranges, or drink grapefruit juice while taking the ibrutinib.   
 
Please take the dexamethasone with food.   
 
Week of: _________________________ 
Study Drug 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Ibrutinib 
 
 
 
 
 
 
 
Dexamethasone 
 
 
 
 
 
 
 
 
Week of: _________________________ 
Study Drug 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Ibrutinib 
 
 
 
 
 
 
 
Dexamethasone 
 
 
 
 
 
 
 
 
Week of: _________________________ 
Study Drug 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
Ibrutinib 
 
 
 
 
 
 
 
Dexamethasone 
 
 
 
 
 
 
 
 
Week of: _________________________ 
Study Drug 
Day 22 
Day 23 
Day 24 
Day 25 
Day 26 
Day 27 
Day 28 
Ibrutinib 
 
 
 
 
 
 
 
Dexamethasone 
 
 
 
 
 
 
 
Patient Signature: ___________________________________________ 
My next scheduled visit is: _______________________________ 
If you have any questions, please call:  ______________________ 
 
 

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HEALTH/MEDICAL COMPLAINTS 
Please record all health/medical complaints you may have experienced below. 
 
Please describe what you experienced 
Date started 
Date stopped 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
OTHER MEDICATION 
Record only medication (prescription and/or over-the-counter, including herbal medications and vitamins) 
taken other than ___________________________. 
 
Name of Medication 
Why did you take the 
medication? 
Dose 
Frequency 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Coordinator Use Only 
Verified by ____________________________ 
Date_______________ 

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Appendix IX MDASI-MM Questionnaire 
 
 

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Appendix X 
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. 
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 
 
Bitter or Seville orange juice** 
 
verapamil 
 
voriconazole 
 
imatinib 
 
Weak inhibitors: 
 
cimetidine 
 
Fluvoxamine 
 
 

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Inhibitors of CYP3A 
Inducers of CYP3A 
All other inhibitors: 
 
chloramphenicol 
 
delaviridine 
 
diethyl-dithiocarbamate 
 
gestodene 
 
mifepristone 
 
norfloxacin 
 
norfluoxetine 
 
star fruit 
 
**Herbal weight loss supplements and/or dietary supplements containing bitter orange are also 
prohibited 
 
Source: 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx. 

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Appendix XI Serum Calcium Corrected for Albumin 
 
If calcium is expressed in mg/dL and albumin is expressed in g/dL: 
Corrected calcium (mg/dL) = serum calcium (mg/dL) + 0.8 × (4 - serum albumin [g/dL]) 
 
If calcium is expressed in mmol/L and albumin is expressed in g/L: 
Corrected calcium (mmol/L) = serum calcium (mmol/L) + 0.02 × (40 - serum albumin [g/L]) 
 
Source: Burtis 1999 
 
 
 
 
 

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Appendix XII 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 the 
oesophagus for bleeding oesophageal varices”.  The British journal of surgery, 1973;60: 646-9. 
 
 

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Appendix XIII Patient Information Sheet 
You have been given a booklet to complete for this study.  The booklet contains some 
questions about your ‘quality of life’ as a patient receiving treatment for cancer.  You 
answers will help us to better understand how the treatment you are receiving is affecting 
the way you feel. 
 
 
1. The booklet contains one set of questions: 
MDASI-MM Questionnaire (26 questions) 
 
2. Please select one answer for each question. 
 
3.  Please complete the booklet during your scheduled clinical visit and return it to your 
nurse or your physician 
 
 
 
Thank you for taking the time to help us