Clinical trial NCT03567616
Conditions: Multiple Myeloma
Keywords: Cancer Multiple Myeloma (MM) Relapsed or Refractory (R/R) Venetoclax Pomalidomide Dexamethasone
Sponsor: AbbVie
Start date: 2018-10-18; Completion date: 2020-06-18
Enrollment: 8 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This was an open-label, multicenter study designed to evaluate the safety and preliminary efficacy of venetoclax combined with pomalidomide and dexamethasone in participants with relapsed or refractory (R/R) multiple myeloma (MM) who received at least 1 prior line of therapy with documented evidence of progression during or after the participant's last treatment regimen. The study was designed to consist of 2 parts: Part 1 (dose escalation) and Part 2 (dose expansion). For Part 2 the participants were to be divided into 2 cohorts, participants positive for t(11;14) translocation and participants negative for t(11;14) translocation.

Detailed description:
Following communication of the results of the primary progression-free survival (PFS) analysis from the Phase 3 BELLINI study (Study M14-031; NCT02755597), the company-sponsored MM studies were placed on partial clinical hold (PCH) in March 2019 by the United States (US) Food and Drug Administration and enrollment was halted. The sponsor did not pursue release of the PCH for this study; therefore, enrollment was not re-opened. In accordance with the terms of the PCH, participants who were deriving clinical benefit were allowed to continue to receive treatment. One participant was still active in Part 1 of the study when the sponsor decided not to pursue release of the PCH (in January 2020) and, therefore, continued to receive treatment and have regular assessments until disease progression. The study was discontinued when the last participant completed study treatment. No participants were enrolled in Part 2 of the study.

Arms: arm 1: Venetoclax (400 mg oral \[PO\], once daily \[QD\]) administered with pomalidomide (4 mg PO, QD) and dexamethasone (40 mg once weekly \[qw\]) in 28-day cycles until documented disease progression, documented unacceptable toxicity, withdrawal of consent, or the participant met other criteria for discontinuation per study protocol arm 2: Participants positive for t(11;14) translocation were to receive the venetoclax dose determined to be safe in Part 1 as well as pomalidomide (4 mg oral \[PO\], once daily \[QD\]) and dexamethasone (40 mg once weekly \[qw\]) arm 3: Participants negative for t(11;14) translocation were to receive the venetoclax dose determined to be safe in Part 1 as well as pomalidomide (4 mg oral \[PO\], once daily \[QD\]) and dexamethasone (40 mg once weekly \[qw\])
Interventions: intervention 1: Venetoclax intervention 2: Pomalidomide intervention 3: Dexamethasone
Intervention descriptions: intervention 1: Tablet; oral intervention 2: Capsule; oral intervention 3: Administered orally; for participants over 75 years of age, dexamethasone could have been administered at a 20 mg dose \[qw\]

Protocol documents:
Prot_000.pdf: 
NCT03567616


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TABLE OF CONTENTS
1
SYNOPSIS
6
2
INTRODUCTION
11
2.1
BACKGROUND AND RATIONALE
11
2.2
BENEFITS AND RISKS TO PATIENTS
13
3
STUDY OBJECTIVES AND ENDPOINTS
14
3.1
OBJECTIVES
14
3.2
PRIMARY EFFICACY ENDPOINT
14
3.3
SECONDARY EFFICACY ENDPOINTS
14
3.4
SAFETY ENDPOINTS
15
3.5
PHARMACOKINETIC ENDPOINTS
15
3.6
BIOMARKER RESEARCH ENDPOINTS
15
4
INVESTIGATIONAL PLAN
15
4.1
OVERALL STUDY DESIGN AND PLAN
15
4.2
DISCUSSION OF STUDY DESIGN
18
5
STUDY ACTIVITIES
19
5.1
ELIGIBILITY CRITERIA
19
5.2
CONTRACEPTION RECOMMENDATIONS
23
5.3
PROHIBITED MEDICATIONS AND THERAPY
24
5.4
PRIOR AND CONCOMITANT THERAPY
24
5.5
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY
27
5.6
FOLLOW-UP FOR SUBJECT WITHDRAWAL FROM STUDY
28
5.7
STUDY DRUGS
28
5.8
RANDOMIZATION/DRUG ASSIGNMENT
29
5.9
PROTOCOL DEVIATIONS
29
6
SAFETY CONSIDERATIONS
30
6.1
COMPLAINTS AND ADVERSE EVENTS
30
6.2
RECORDING DATA AND ANALYSES OF SAFETY FINDINGS
34
6.3
REPORTING ADVERSE EVENTS AND INTERCURRENT ILLNESSES
34


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6.4
TOXICITY MANAGEMENT
34
6.5
DOSE-LIMITING TOXICITY
37
6.6
PRODUCT COMPLAINTS
39
7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
39
7.1
STATISTICAL AND ANALYTICAL PLANS
39
7.2
DETERMINATION OF SAMPLE SIZE
39
7.3
DEFINITION FOR ANALYSIS POPULATIONS
40
7.4
STATISTICAL ANALYSES FOR EFFICACY
40
7.5
STATISTICAL ANALYSES FOR SAFETY
40
7.6
STATISTICAL ANALYSES FOR PHARMACOKINETICS
40
7.7
STUDY INTERIM ANALYSIS
40
7.8
SAFETY REVIEW COMMITTEE
41
8
ETHICS
41
8.1
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD
41
8.2
ETHICAL CONDUCT OF THE STUDY
41
8.3
SUBJECT CONFIDENTIALITY
41
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
41
10 DATA QUALITY ASSURANCE
42
11 COMPLETION OF THE STUDY
42
12 REFERENCES
42
LIST OF TABLES
TABLE 1.
DOSE-ESCALATION DECISION RULE
16
TABLE 2.
STUDY DRUG INFORMATION
29
TABLE 3.
CLINICAL LABORATORY TESTS
58
TABLE 4.
ASSESSMENTS FOR IMWG RESPONSE CRITERIA
64
TABLE 5.
SCHEDULE OF BIOMARKER RESEARCH SAMPLE COLLECTIONS
69


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TABLE 6.
PHARMACOKINETIC SAMPLING TIMES
70
TABLE 7.
DOSE MODIFICATIONS FOR VENETOCLAX WITH CONCOMITANT MODERATE AND STRONG CYP3A 
INHIBITOR USE
80
TABLE 8.
DOSE MODIFICATIONS FOR POMALIDOMIDE WITH CONCOMITANT STRONG CYP1A2 INHIBITOR 
USE
80
TABLE 9.
STUDY DRUG DOSE LEVELS
80
TABLE 10.
TOXICITIES RELATED TO VENETOCLAX
81
TABLE 11.
TOXICITIES RELATED TO POMALIDOMIDE
82
TABLE 12.
TOXICITIES RELATED TO DEXAMETHASONE
83
LIST OF FIGURES
FIGURE 1.
STUDY DESIGN
17
LIST OF APPENDICES
APPENDIX A.
STUDY SPECIFIC ABBREVIATIONS AND TERMS
44
APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
47
APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
48
APPENDIX D.
ACTIVITY SCHEDULE
49
APPENDIX E.
STUDY PROCEDURES
55
APPENDIX F.
IMWG RESPONSE CRITERIA FOR MULTIPLE MYELOMA (2016)
72
APPENDIX G.
TUMOR LYSIS SYNDROME CLASSIFICATION
75
APPENDIX H.
RECOMMENDATIONS FOR INITIAL MANAGEMENT OF ELECTROLYTE IMBALANCES AND 
PREVENTION OF TUMOR LYSIS SYNDROME IN MULTIPLE MYELOMA SUBJECTS
76
APPENDIX I.
RECOMMENDED DOSE REDUCTIONS RELATED TO DRUG TOXICITIES AND USE WITH 
CONCOMITANT MEDICATIONS
79


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APPENDIX J.
SAMPLE LIST OF PROHIBITED AND CAUTIONARY MEDICATIONS THAT MAY INTERACT WITH 
STUDY DRUGS
84
APPENDIX K.
CORTICOSTEROID CONVERSION TABLE
86
APPENDIX L.
SAFETY REPORTING CONTACT INFORMATION
87
APPENDIX M. PROTOCOL AMENDMENT SUMMARY OF CHANGES
88












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2 INTRODUCTION
2.1 Background and Rationale
Why Is This Study Being Conducted
Venetoclax, an inhibitor of the anti-apoptotic protein B-cell lymphoma (BCL)-2, is currently being 
evaluated for the treatment of patients with chronic lymphocytic leukemia (CLL), small lymphocytic 
lymphoma (SLL), acute myeloid leukemia (AML), multiple myeloma (MM), and non-Hodgkin's lymphoma 
(NHL).
Overexpression of BCL-2 is a major contributor to the pathogenesis of some lymphoid malignancies 
including MM.  Current treatment paradigms for relapsed or refractory (R/R) MM clearly demonstrate 
that new treatments are needed for patients with MM.  Plasma cells are typically geared towards long-
term survival and have low apoptotic rates associated with high levels of anti-apoptotic proteins such as 
BCL-2 and myeloid-cell leukemia (MCL)-1.  Dysregulation of apoptotic pathways in these cells, often 
from aberrant BCL-2 and/or MCL-1 overexpression, is thought to play a major role in the development 
and progression of MM.  Antagonizing BCL-2 and MCL-1 function to induce apoptosis is a compelling 
therapeutic approach in MM.
Venetoclax (also referred to as ABT-199, A-1195425.0, GDC-0199, RO5537382, Venclexta,® and 
Venclyxto®) is a selective, potent, orally bioavailable, small molecule, BCL-2 inhibitor that restores 
programmed cell death (apoptosis) in cancer cells.  Venetoclax binds with high affinity (inhibition rate 
constant [Ki] < 0.010 nM) to antiapoptotic protein BCL-2 and with lower affinity to other antiapoptotic 
BCL-2 family proteins, like BCL-extra large (BCL-XL) and BCL-Walter and Eliza Hall Institute (BCL-w) 
(> 4,000-fold and > 2,000- to > 20,000-fold lower affinity than to BCL-2, respectively).  The anticipated 
and observed venetoclax-associated toxicities are also mechanism based; in particular, BCL-2-mediated 
effects on lymphocytes.1,2  Venetoclax, as a BCL-2-selective (BCL-XL-sparing) inhibitor, is projected to 
yield an improved therapeutic profile compared to dual BCL-2/BCL-XL inhibitors.  Because the survival of 
platelets depends on BCL-XL,3 thrombocytopenia, a major dose-limiting toxicity (DLT) caused by 
inhibition of BCL-XL in the clinic,4 is not expected to be dose limiting for venetoclax.
Venetoclax has demonstrated potent killing of MM cell lines and primary tumor samples bearing the 
t(11;14) translocation, which tend to express high levels of BCL-2 relative to MCL-1.  Additionally, in 
Study M12-901, subjects with tumor cells determined to express high levels of BCL-2 had better 
reduction in M-protein and overall clinical response to venetoclax in combination with bortezomib, a 
proteasome inhibitor that upregulates expression of the MCL-1 inhibitor, Noxa, and dexamethasone.
Pomalidomide, a thalidomide analog, is a potent immunomodulatory drug (IMiD) that displays 
antiangiogenic, antiproliferative, and immunomodulatory activity.  Pomalidomide is also shown to 
stimulate antibody-dependent cytotoxic T-cell activity.  In addition, dexamethasone promotes 
BCL-2-dependence in MM through increased expression of BCL-2 and BIM potentially increasing 
sensitivity to venetoclax.  Venetoclax, dexamethasone, and pomalidomide have all demonstrated 
significant activity in MM.  Therefore, the combination of a potent BCL-2 inhibitor (venetoclax) with a 
potent IMiD (pomalidomide), and low-dose dexamethasone in subjects with R/R MM may lead to 
additive antitumor effects because of multiple complementary mechanisms of action.


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As of 28 November 2016, 4 Phase 1/2 studies are ongoing in the MM indication with venetoclax.  Overall 
for MM, when treated with venetoclax as a single agent or in combination with other therapies, most 
subjects experience at least 1 adverse event (AE) with the most common being nausea, diarrhea, and 
fatigue in monotherapy studies; and diarrhea, constipation, thrombocytopenia, neuropathy peripheral, 
and insomnia in combination studies.  Approximately half of the subjects in MM clinical trials experience 
≥ Grade 3 AEs with the most common being anemia, platelet count decreased, neutrophil count 
decreased, and thrombocytopenia.  Approximately 30% of subjects experienced serious adverse events 
(SAEs).  All of the AEs reported in the current MM studies are consistent with underlying disease or 
concomitant medical conditions, as well as other combination agents used to treat MM patients.  
Neutropenia and infections are consistent with the expected safety profile of venetoclax based on 
expected on-target effects of BCL-2 inhibition.
The BELLINI study (Study M14-031), a global, Phase 3, multicenter, randomized, double-blind study of 
bortezomib and dexamethasone in combination with either venetoclax or placebo in subjects with R/R
MM who are sensitive or naïve to proteasome inhibitors, was unblinded as per protocol for the final 
analysis of the primary efficacy endpoint. As of the data cutoff date of 26 November 2018, 194 subjects
were randomized to the venetoclax arm and 97 subjects to the placebo arm (2:1 randomization). The 
BELLINI study met its primary endpoint of progression-free survival (PFS; 22.4 versus 11.5 months, 
hazard ratio [HR] 0.63, 95% confidence interval [CI]: 0.44 - 0.90) and showed statistically significant 
improvements in overall response rate (ORR; 82% versus 68%) and very good partial response (VGPR) or 
better (59% versus 36%) in the venetoclax arm compared to the control arm. However, there were 
51 deaths in the safety analysis set, 40 (20.7%) in the venetoclax arm and 11 (11.5%) in the placebo arm 
(the median overall survival [OS] has not been reached in either arm). The imbalance was 
predominantly seen in the treatment-emergent deaths which are those occurring on-therapy or within 
30 days after the last dose of therapy. Among the 14 treatment-emergent deaths reported, 13 (6.7%) 
were in the venetoclax arm and 1 (1.0 %) in placebo arm. Of the 13 treatment-emergent deaths in the 
venetoclax arm, 8 were attributed by investigator to an event of infection; more than half of the deaths
were also in the setting of refractory or progressive disease (PD). Although the majority of infection-
related deaths occurred within 180 days of starting study treatment, some have occurred later, even 
after a year or more on treatment. A higher rate of Grade 3 or 4 neutropenia was seen in the venetoclax 
arm compared to placebo but an association of infection-related deaths with neutropenia has not been 
established at this point. Among the 37 nontreatment-emergent deaths (those occurring more than 
30 days after the last dose of study treatment), 27 (14.0%) were in the venetoclax arm (6 deaths
attributed to infection, 3.1%), and 10 (10.4%) in the placebo arm (2 deaths attributed to infection, 2.1%). 
After the data cutoff of 26 November 2018, additional deaths were reported in the BELLINI trial. As of 
01 March 2019, there were 65 deaths in the safety analysis set, 48 (24.7%) in venetoclax arm and 
17 (17.5%) in the placebo arm.
This is the first study of venetoclax in combination with pomalidomide and dexamethasone.  This study 
will determine if venetoclax and pomalidomide can be safely combined for treatment of subjects with 
R/R MM and produce potentially meaningful clinical activity.
Clinical Hypothesis
Overall, MM accounts for more than 10% of all hematologic malignancies and 1% of all malignancies.  It 
is the most prevalent hematologic malignancy in patients older than 65 years of age.  Approximately 
114,000 new cases of MM were diagnosed worldwide in 2012.5


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The treatment paradigms and outcomes for patients with MM have markedly changed in the past 
decade with the introduction of several new, more effective, and less toxic therapies, doubling the 
median OS from 3 years to 6 years.6,7  Nevertheless, significant unmet needs remain for the treatment of 
MM, as this disease has no cure to date and current therapies can only slow disease progression, 
prolong survival, and minimize symptoms.  In fact, the majority of patients with MM will relapse or 
become refractory, regardless of the line of therapy, which is associated with high morbidity and 
mortality.  Additionally, the remission duration in relapsed myeloma decreases with each regimen.
Various treatment options are available in case of relapse ranging from conventional cytostatic agents 
such as melphalan or cyclophosphamide and steroids to novel classes of drugs, including IMiDs, 
proteasome inhibitors (PIs), histone deacetylase (HDAC) inhibitors, and monoclonal antibodies (anti-CS1, 
anti-CD38) with and without corticosteroids.  Most recommended treatment protocols comprise 
variable combinations of these drugs.
The mechanisms of action of venetoclax (BCL-2 inhibitor) and pomalidomide (IMiD) are independent and 
have the potential to provide additive clinical benefit relative to the individual agents alone in subjects 
with R/R MM.
2.2 Benefits and Risks to Patients
Despite recent therapeutic advances, MM remains incurable and is associated with high morbidity and 
mortality; even with the best available approved agents, all subjects will eventually relapse.  
Furthermore, the remission duration in R/R MM decreases with each subsequent regimen.8
Based on supportive safety and efficacy data from ongoing Phase 1/2 studies of venetoclax as a single 
agent or in combination with other therapies (see above), subjects enrolled in this study are anticipated 
to benefit from the combined treatment with pomalidomide based on the pro-apoptotic effects in 
myeloma cells.
Since the antitumorigenic effects of venetoclax and pomalidomide on myeloma cells are via distinctive 
mechanisms of action, the combination of these 2 drugs is anticipated to result in an enhanced 
therapeutic effect that could potentially benefit patients with relapsed MM.  The goal of this study is to 
determine the safety profile, tolerability, and the potential efficacy of venetoclax combined with 
pomalidomide and dexamethasone in patients with R/R MM.
Following the analysis of the BELLINI study (see Section 2.1), guidance for dose interruption/reduction 
following a Grade ≥ 3 infection or any serious infection in subjects receiving venetoclax have been 
implemented (see Section 6.4 and Appendix I).
For further details, please see findings from completed studies including safety data in the venetoclax 
Investigator Brochure9 and the pomalidomide package insert.10


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3 STUDY OBJECTIVES AND ENDPOINTS
3.1 Objectives
Primary
The primary objective of this study is:
!
To characterize the safety and tolerability profiles of venetoclax combined with pomalidomide 
and dexamethasone when co-administered in subjects with R/R MM
Secondary
The secondary objectives of this study are:
!
To evaluate the anti-MM activity of co-administered venetoclax combined with pomalidomide 
and dexamethasone therapy
!
To characterize the plasma pharmacokinetics (PK) of venetoclax and pomalidomide when 
co-administered in subjects with R/R MM
Exploratory
The exploratory objectives of this study are:
!
To evaluate correlative biomarkers of co-administered venetoclax combined with pomalidomide 
and dexamethasone therapy including, but not limited to, BCL-2 family member expression and 
chromosomal abnormalities
!
To assess minimal residual disease (MRD) negativity in the bone marrow by next generation 
sequencing
3.2 Primary Efficacy Endpoint
The primary efficacy endpoint is the ORR which is defined as all responses greater than or equal to 
partial response (PR).
3.3 Secondary Efficacy Endpoints
Key Secondary Endpoints
The secondary endpoints are as follows:
!
PFS
!
Duration of response (DOR)


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!
Time-to-progression (TTP)
The definitions of key secondary endpoints are specified in the Statistical Analysis Plan (SAP).
3.4 Safety Endpoints
Safety evaluations include AE monitoring, physical examinations, vital sign measurements, 
electrocardiograms (ECGs), and clinical laboratory testing (hematology and chemistry) as a measure of 
safety and tolerability for the entire study duration.
3.5 Pharmacokinetic Endpoints
PK samples will be collected and analyzed for venetoclax and pomalidomide concentrations.  The PK 
parameters of maximum observed plasma concentration (Cmax), the time to Cmax (Tmax), and the area 
under the plasma concentration versus time curve (AUC) from time 0 to 24 hours postdose (AUC0-24) will 
be determined, as appropriate, using noncompartmental methods.  Additional parameters may also be 
calculated if appropriate.
3.6 Biomarker Research Endpoints
Biospecimens (blood, serum, plasma, bone marrow aspirate, and bone marrow core biopsy tissue) will 
be collected at specified time points (Appendix D) throughout the study to evaluate known and/or novel 
disease-related or drug-related biomarkers.  Types of biomarkers analyzed may include nucleic acids, 
proteins, lipids, and/or metabolites.  The analyses may include BCL-2 family member expression, 
immune cell phenotyping and quantification, T-cell clonality, chromosomal abnormalities 
(immunoglobulin [Ig]H translocations, amplifications, or deletions), and/or MRD negativity.  Baseline 
t(11;14) status will be determined for all subjects and guide subject enrollment in the dose-expansion 
phase (Part 2), as detailed in Section 5.1.  The biomarker research may be exploratory in nature and 
results may not be included with the clinical study report.  Further details regarding the biomarker 
research rationale and collection time points are located in Appendix D and Appendix E.
4 INVESTIGATIONAL PLAN
4.1 Overall Study Design and Plan
The schematic of the study is shown in Figure 1.  Further details regarding study procedures are located 
in Appendix E.
This is an open-label, multicenter study designed to evaluate the safety and preliminary efficacy of 
venetoclax combined with pomalidomide and dexamethasone in subjects with R/R MM who have 
received at least 1 prior line of therapy.  The study will consist of 2 parts:  Part 1 (dose escalation) and 
Part 2 (dose expansion).


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Part 1:  Dose Escalation
The dose-escalation phase of the study will evaluate the safety, tolerability, and PK profile of 
combination therapy with venetoclax, pomalidomide, and dexamethasone in 6 to 12 subjects who will 
be enrolled in 2 cohorts of at least 3 subjects per cohort.  In the first cohort, a low dose of venetoclax 
(400 mg oral [PO], once daily [QD]) will be administered with the approved dose of pomalidomide (4 mg 
PO, QD) and dexamethasone (40 mg once weekly [qw]).  If acceptable safety and tolerability are 
observed at the completion of Cycle 1 with at least 3 dose-limiting toxicity (DLT)-evaluable subjects, the 
dose of venetoclax will be escalated to 800 mg QD (Cohort 2), which has been identified as the target 
dose; the dose of pomalidomide and dexamethasone will not change.  The decision to escalate to the 
higher dose of venetoclax will be made according to the Bayesian optimal interval (BOIN) design and 
based on the cumulative number of subjects who experience a DLT at the current combination dose.
Table 1 displays the dose-escalation decision rule for the BOIN design with target toxicity rate of 30% 
and optimal interval of (23.6%, 35.9%).
Table 1.
Dose-Escalation Decision Rule
Action
Number of DLT-Evaluable Subjects Treated at 
Current Combination
3
4
5
6
7
8
9
10
Escalate if number of subjects with DLT ≤
0
0
1
1
1
1
2
2
Stay at current combination if number of subjects with DLT =
1
1
-
2
2
2
3
3
De-escalate if number of subjects with DLT ≥
2
2
2
3
3
3
4
4
Eliminatea if number of subjects with DLT ≥
3
3
4
4
5
5
5
6
DLT = dose-limiting toxicity
a.
Eliminate current combination and higher combinations (i.e., venetoclax dose and pomalidomide dose ≥ current dose 
level).
Subjects must complete at least 80% of pomalidomide dosing and at least 80% of venetoclax dosing in 
Cycle 1 or experience a DLT to be considered evaluable for dose-escalation decisions.  Subjects not 
DLT-evaluable may be replaced as necessary to meet minimum requirement for dose escalation.  DLTs 
are defined in Section 6.5.
Additional information regarding the BOIN design will be provided in the SAP.
During Part 1, dose review meetings will be conducted at the completion of Cycle 1 in at least 
3 evaluable subjects in each cohort.
All subjects who participate in the dose-escalation phase of the study will undergo bone marrow 
aspirate collection for cytogenetic determination at baseline.
Part 2:  Dose Expansion
The dose-expansion phase of the study will consist of 2 arms.  Arm A will further evaluate the safety and 
efficacy profile of the combination therapy with venetoclax, pomalidomide, and dexamethasone in 
approximately 23 subjects positive for t(11;14) translocation.  Arm B will further evaluate the safety and 


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efficacy profile of the combination therapy with venetoclax, pomalidomide, and dexamethasone in 
approximately 27 subjects negative for t(11;14) translocation.  Subjects will receive the venetoclax dose 
that is determined to be safe in Part 1 + pomalidomide (4 mg PO, QD) + dexamethasone (40 mg qw).  All 
subjects who participate in the dose-expansion phase of the study are required to undergo bone 
marrow aspirate collection at screening for determination of t(11;14) status before enrollment.
See Section 5.1 for information regarding eligibility criteria.
Review of the efficacy and safety data will be completed on an ongoing basis.  During Part 1, dose 
review meetings will be conducted at the completion of Cycle 1 with at least 3 evaluable subjects in each 
cohort.  Additional reviews will be held as deemed necessary based on study events or data.
Figure 1.
Study Design
Dex = dexamethasone; Pom = pomalidomide; QD = once daily; qw = once weekly; Ven = venetoclax
Note:
Venetoclax will be administered once daily from Day 1 through Day 28 of each cycle.  Pomalidomide will be 
administered once daily from Day 1 through Day 21 of each cycle.
Hematology must be completed before the initiation of each subsequent cycle of combination therapy.  
Subjects must meet the following minimum criteria to continue combination therapy:
!
absolute neutrophil count (ANC) ≥ 500/μL; growth factor support is allowed after Cycle 1
!
platelets ≥ 50,000/mm3
!
all other AEs should resolve to ≤Grade 2
Subjects will receive venetoclax and pomalidomide until documented disease progression, documented 
unacceptable toxicity, withdrawal of consent, or the subject meets other criteria for discontinuation per 
study protocol (Section 5.5).  Subjects will remain on study treatment as long as venetoclax or 
pomalidomide/dexamethasone is being administered.  Subjects may discontinue pomalidomide/ 
dexamethasone but may continue receiving venetoclax QD as monotherapy for up to 2 years following
the date of the last subject enrolled on study provided the subject completed venetoclax plus 
pomalidomide and dexamethasone dosing in Cycle 1, continue to tolerate venetoclax, have no evidence 
of disease progression, and do not meet any criteria for treatment discontinuation.  For subjects that 


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continue to derive benefit after 2 years of treatment following the date of the last subject enrolled, 
AbbVie will work with the investigator to evaluate options for continuation of venetoclax therapy.
4.2 Discussion of Study Design
Choice of Control Group
Not applicable.
Appropriateness of Measurements
Standard statistical, clinical, and laboratory procedures will be utilized in this study.  All efficacy 
measurements in this study are standard for assessing disease activity in subjects with R/R MM.  All 
clinical and laboratory procedures in this study are standard and generally accepted.
Suitability of Subject Population
Venetoclax has demonstrated potent killing of MM cell lines and primary tumor samples bearing the 
t(11;14) translocation, which tend to express high levels of BCL-2 relative to MCL-1.  Pomalidomide is a 
potent IMiD that displays antiangiogenic, antiproliferative, and immunomodulatory activity.  
Additionally, dexamethasone promotes BCL-2-depenedence in MM through increased expression of 
BCL-2 and BIM potentially increasing sensitivity to venetoclax.  Venetoclax, dexamethasone, and 
pomalidomide have all demonstrated significant activity in MM.  Therefore, a potent BCL-2 inhibitor 
(venetoclax) with a potent IMiD (pomalidomide), and low-dose dexamethasone in subjects with R/R MM 
might be combined safely and with potentially meaningful clinical activity in this subject population.
Selection of Doses in the Study
The selected dosage regimen of pomalidomide (4 mg QD on Days 1 to 21 of each 28-day cycle) and 
dexamethasone (40 mg, qw) is the approved dosage regimen for this combination therapy in subjects 
with MM that have received at least 2 prior therapies, as specified on the US package insert.10
The selected dosage regimen of venetoclax is based on the results from a Phase 1b study 
(Study M12-901) of venetoclax plus bortezomib and dexamethasone in R/R MM subjects.  An exposure-
response analysis of the efficacy (best response) and safety (Grade ≥ 3 anemia, thrombocytopenia, and 
neutropenia) from the study indicated that a venetoclax dosage regimen of 600 mg QD or higher in 
combination with bortezomib and dexamethasone would likely result in a substantial VGPR or better 
response rate with these response rates increasing through 1200 mg QD.  No relationship was observed 
between venetoclax exposure and anemia or thrombocytopenia but the neutropenia (Grade ≥ 3) rates 
began to increase at doses greater than 800 mg QD.  Based on these efficacy and safety results and 
treatment compliance considerations, a (maximum) venetoclax dose of 800 mg QD was selected.  The 
first subjects (Cohort 1) who administer the combination of venetoclax with pomalidomide and 
dexamethasone will receive a lower dose of venetoclax (400 mg) to evaluate safety of this specific 
combination before escalation to the 800 mg dose of venetoclax (if appropriate).


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5 STUDY ACTIVITIES
5.1 Eligibility Criteria
Subjects must meet all of the following criteria to be included in the study.  Anything other than a 
positive response to the questions below will result in exclusion from study participation.
Consent
1. Subjects must voluntarily sign and date an informed consent, approved by an Independent 
Ethics Committee (IEC)/Institutional Review Board (IRB), before the initiation of any screening or 
study-specific procedures.
2. All subjects enrolled in this trial must be registered and must comply with all requirements of 
the pomalidomide risk evaluation and mitigation strategies (REMS) program or local equivalent.
Demographic and Laboratory Assessments
3. Adult male or female, at least 18 years old.
4. Laboratory values meeting the following criteria within the screening period before the 
first dose of study drug:
!
serum alanine aminotransferase (ALT) ≤ 3 × the upper limit of normal (ULN)
!
aspartate aminotransferase (AST) ≤ 3 × ULN
!
total bilirubin ≤ 1.5 × ULN (subject with documented Gilbert's syndrome may be allowed 
total bilirubin > 1.5 × ULN)
!
creatinine clearance (CrCL) ≥ 30 mL/min, measured by 24-hour urine collection or calculated 
using the Cockcroft-Gault formula
!
prothrombin/international normalized ratio (INR) and/or activated partial thromboplastin 
time (aPTT) ≤1.5 × normal limits
!
ANC > 1,000/μL (growth factor support is allowed to achieve eligibility criteria)
!
platelet count
!
≥ 75,000/mm3 for subjects with ≤ 50% myeloma involvement in the bone marrow
!
≥ 50,000/mm3 for subjects with > 50% myeloma involvement in the bone marrow
!
no platelet transfusion ≤ 72 hours before screening platelet count
!
hemoglobin ≥ 8.0 g/dL (subject must not receive a blood transfusion within 72 hours before 
screening hemoglobin)
5. Are willing or able to comply with procedures required in this protocol.


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Disease Activity
6. R/R MM with documented evidence of progression during or after the subject's last 
treatment regimen based on the investigator's determination of the International Myeloma 
Working Group (IMWG) criteria.
7. Measurable disease, defined by at least 1 of the following disease activity criteria:
!
serum M-protein ≥ 1.0 g/dL (≥ 10 g/L) for IgG MM
!
serum M-protein ≥0.5 g/dL (≥5 g/L) for IgA, IgD, IgE, and IgM MM
!
urine M-protein ≥ 200 mg/24 hours
!
serum free-light chain (FLC) ≥ 10 mg/dL provided serum FLC ratio is abnormal
8. Has received at least 1 prior line of therapy.
!
A line of therapy consists of > 1 complete cycle of a single agent, a regimen consisting of a 
combination of several drugs, or a planned sequential therapy of various regimens
9. Must meet all of the following prior antimyeloma treatment parameters:
!
subject must have received at least 2 consecutive cycles of lenalidomide or a lenalidomide-
containing regimen
!
subject must be refractory to lenalidomide
!
subject must have documented evidence of PD based on the investigator's 
determination of response as defined by the modified IMWG criteria on or after the last 
regimen
!
subject who received only 1 line of prior treatment must have demonstrated PD on or 
within 60 days of completion of the lenalidomide-containing regimen
!
subject must have been exposed to a PI alone or in combination with another agent
!
subject must have had a response of PR or better to prior therapy based on the 
investigator's determination of response as defined by IMWG criteria
10. Has t(11;14) status determined by an analytically validated fluorescent in situ hybridization 
(FISH) assay per central laboratory testing of a bone marrow aspirate sample and meets the 
following criteria:
!
For Part 1:  MM subjects independent of cytogenetic profile
!
For Part 2, Arm A:  subject must be t(11;14) positive
!
For Part 2, Arm B:  subject must be t(11;14) negative
11. An Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
Subject History
12. No history of clinically significant medical conditions within the last 6 months that, in the 
investigator's opinion, would adversely affect the subject's participation in the study.


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13. No history of any active malignancies, including myelodysplastic syndromes, within the past 
3 years except for the following:
!
adequately treated in situ carcinoma of the cervix uteri or the breast;
!
basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin;
!
prostate cancer Gleason Grade 6 or lower AND with stable prostate-specific antigen levels 
off treatment; or
!
previous malignancy with no current evidence of disease, and which was confined and 
surgically resected (or treated with other modalities) with curative intent and unlikely to 
impact survival during the duration of the study.
14. None of the following conditions:
!
Nonsecretory myeloma, active plasma cell leukemia, Waldenström's macroglobulinemia, 
primary amyloidosis, central nervous syndrome myeloma, and POEMS syndrome 
(polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin 
changes [POEMS])
!
positive human immunodeficiency virus infection or active hepatitis B or C infection
!
major surgery within 4 weeks before first dose of study drug or planned during study 
participation
!
acute infections within 14 days before first dose of study drug requiring antibiotic, 
antifungal, or antiviral therapy
!
significant cardiovascular disease, including uncontrolled angina, arrhythmia, recent 
myocardial infarction (within 6 months of first dose), and congestive heart failure (New York 
Heart Association Functional Class ≥ 3)
!
uncontrolled diabetes or hypertension within 14 days before first dose of study drug
!
peripheral neuropathy ≥ Grade 3 or ≥ Grade 2 with pain within 2 weeks before the first dose 
of study drug
15. No known sensitivity to any IMiDs.
16. No allogenic or syngeneic stem cell transplant within 6 months before the first dose of study 
drug or active ongoing graft versus host disease.
17. No autologous stem cell transplant within 12 weeks before the first dose of study drug.
18. No known meningeal involvement of MM.
19. No previous treatment with venetoclax or other BCL-2 inhibitors, or previous treatment with 
pomalidomide.
Contraception
20. A negative serum pregnancy test for all female subjects of childbearing potential during the 
screening period (within 10 to 14 days before initiating treatment with study drugs) and a 
negative urine pregnancy test for all female subjects within 24 hours before the first dose of 
study drugs.


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21. If female, subject must be either postmenopausal OR permanently surgically sterile OR for 
women of childbearing potential practicing at least 2 protocol-specified methods of birth 
control that are effective from at least 30 days before starting study drugs through at least 
30 days after the last dose of any study drug (refer to Section 5.2).
22. If male, and subject is sexually active with female partner(s) of childbearing potential, he 
must agree, from Study Day 1 through 30 days after the last dose of pomalidomide, to practice 
the protocol-specified contraception (refer to Section 5.2).
23. Female who is not pregnant, breastfeeding, or considering becoming pregnant during the 
study and for approximately 30 days after the last dose of any study drug.
24. Male who is not considering fathering a child or donating sperm during the study and for 
approximately 30 days after the last dose of pomalidomide.
Concomitant Medications
25. Subject must not have been treated with anti-myeloma therapy (other than monoclonal 
antibodies) including:  chemotherapy, radiotherapy, biological therapy, immunotherapy, 
targeted small molecule therapy, or investigational therapy within 5 half-lives (or 2 weeks if 
half-life is unknown or not applicable) before the first dose of study drugs and through the last 
dose of any study drug.
26. Subject must not have been treated with anti-myeloma monoclonal antibodies within 
6 weeks before the first dose of study drugs and through the last dose of any study drug.
27. Subject must not have received corticosteroid therapy at a cumulative dose equivalent of 
≥140 mg of prednisone or a single-dose equivalent to ≥ 40 mg/day of dexamethasone within 
2 weeks before the first dose of study drug.
28. Subject must not have used systemic strong or moderate inhibitor or inducer of cytochrome 
P450 (CYP)3A within 1 week before the first dose of study drugs.
29. Subject must not have used systemic strong inhibitor of CYP1A2 within 1 week before the 
first dose of study drugs.
30. Subject must not have consumed grapefruit, grapefruit products, Seville oranges (including 
marmalade containing Seville oranges), or star fruit within 3 days before the first dose of study 
drugs administrations and through the last dose of any study drug.
31. Subject must not have received any live vaccines within 8 weeks before the first dose of 
study drugs, or have an expected need of live vaccination during study participation including at 
least 4 weeks after the last dose of any study drug.
32. Subject must not anticipate the use of prohibited medications or foods during study 
participation (see Section 5.3 for additional prohibited medications or foods).


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5.2 Contraception Recommendations
Subjects must follow the contraceptive guidelines as specified below (minimum requirements for 
venetoclax and pomalidomide; local guidelines and pomalidomide REMS program may differ and should 
be followed, when applicable).
If female, subject must be either:
!
Postmenopausal defined as:
!
age > 55 years with no menses for at least 24 or more consecutive months without an 
alternative medical cause; or
!
age ≤ 55 years with no menses for 24 or more consecutive months without an alternative 
medical cause and a follicle-stimulating hormone level > 40 IU/L
or
!
Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy, or 
hysterectomy)
or
!
Women of childbearing potential must use 2 reliable forms of contraception simultaneously 
from at least 30 days before initiating treatment with study drugs through at least 30 days after 
the last dose of any study drug.  The 2 methods of reliable contraception must include 1 highly 
effective method and 1 additional effective (barrier) method.  The following are examples of 
highly effective and additional effective methods of contraception:
!
Highly Effective Methods
!
hormonal (birth control pills, injections, levonorgesterel-releasing intrauterine system, 
medroxyprogesterone acetate depot injections, ovulation inhibitory progesterone-only 
pill [e.g., desogestrel])
!
bilateral tubal occlusion/ligation at least 1 month before study Day 1
!
bilateral tubal occlusion via hysteroscopy (i.e., Essure), provided a hysterosalpingogram 
confirms success of the procedure at least 1 month before study Day 1
!
vasectomized partner, provided the vasectomized partner verbally confirms receipt of 
medical assessment of the surgical success and is the sole sexual partner of the female 
subject;
!
intrauterine device
!
Additional Effective Methods
!
male condom
!
diaphragm
!
cervical cap


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or
!
true abstinence which is defined as refraining from heterosexual intercourse if this is in line with 
the preferred and usual lifestyle of the subject (periodic abstinence [e.g., calendar, ovulation, 
symptothermal, postovulation methods] and withdrawal are not acceptable)
There is an increased risk of venous thromboembolism in subjects with MM taking pomalidomide and 
dexamethasone; combined oral contraceptive pills are not recommended.  If a subject is currently using 
combined oral contraception, the subject should switch to another highly effective method.  The risk of 
venous thromboembolism continues for 4 to 6 weeks after discontinuing combined oral contraception.  
The efficacy of contraceptive steroids may be reduced during co-treatment with dexamethasone.
Implants and levonorgestrel-releasing intrauterine systems are associated with an increased risk of 
infection at the time of insertion and irregular vaginal bleeding.  Prophylactic antibiotics should be 
considered, particularly in subjects with neutropenia.
For male subjects, pomalidomide is present in the semen of subjects receiving the drug.  Therefore, 
male subjects must practice complete abstinence or always use a latex or synthetic condom during any 
sexual contact with females of reproductive potential while taking pomalidomide and for up to 4 weeks 
after discontinuing pomalidomide, even if they have undergone a successful vasectomy.  Male subjects 
taking pomalidomide must not donate sperm during study participation and for up to 30 days after 
discontinuing any study drug.
5.3 Prohibited Medications and Therapy
In addition to the medications and therapy listed in the eligibility criteria (Section 5.1, Concomitant 
Medications), the following medications are prohibited during Part 1, Cycle 1:
!
Strong and moderate CYP3A inhibitors
!
Strong CYP1A2 inhibitors
!
Strong and moderate CYP3A inducers
Subjects must be consented for the study before discontinuing any prohibited medications for the 
purpose of meeting study eligibility.  A sample list of prohibited and cautionary medications is listed in 
Appendix J.
5.4 Prior and Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, and/or 
herbal supplements) that the subject is receiving from 30 days before and throughout screening or 
receives during the study and up to 30 days after last dose of study drug must be recorded in the 
electronic case report form (eCRF).  Any prior transfusions (blood or platelet) must be recorded in the 
eCRF and the investigator must ensure that this data is consistent with the subject's medical history.


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The following medications are allowed after Part 1, Cycle 1 and for Part 2 (dose expansion) to use with 
caution if no appropriate therapeutic alternative exists (additional guidance noted):
!
Strong and moderate CYP3A inhibitors (venetoclax dose reductions)
!
Strong CYP1A2 inhibitors (pomalidomide dose reductions)
!
Strong and moderate CYP3A inducers (avoid)
Recommended venetoclax and pomalidomide dose modifications when administered concomitantly 
with strong or moderate CYP3A inhibitors and strong CYP1A2 inhibitors are provided in Appendix I.
The following medications to use with caution include:
!
warfarin (closely monitor international normalized ratio)
!
P-glycoprotein (P-gp) substrates
!
breast cancer resistance protein (BCRP) substrates
!
organic anion-transporting polypeptide (OATP)1B1/1B3 substrates
!
P-gp inhibitors
!
BCRP inhibitors
!
high-dose corticosteroids
Specific examples of prohibited and cautionary medications that fall into these categories can be found 
in Appendix J.
Subjects should be advised that cigarette smoking reduces pomalidomide exposure because of CYP1A2 
induction and therefore may reduce efficacy.
Herbal and natural remedies are to be avoided while on study drug.
Any questions regarding prior or concomitant therapy should be raised to the AbbVie emergency 
contact.  Information regarding potential drug interactions with venetoclax or pomalidomide can be 
located in the Investigator's Brochure or package insert, respectively.
While on study, unless prohibited by the protocol, subjects should receive best supportive care per 
investigator discretion.  Supportive care and medications that may be required for venetoclax and/or 
pomalidomide during the study include the following:
!
allopurinol or other appropriate tumor lysis syndrome (TLS) risk-reducing agent
!
adequate fluids to ensure dehydration prevention (note:  per institutional standards while using 
medical judgment)
!
enteric-coated aspirin 81 mg PO, QD or low molecular weight heparin if history of prior 
thrombotic disease according to local practice


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Allowed Concomitant Therapies
The following concomitant medications are allowed during the study:
!
Bisphosphonates intravenous or PO as indicated per institutional guidelines.  Note:  institution 
of bisphosphonates after Cycle 2 if not already in use is prohibited.
!
Only low-dose corticosteroids (e.g., prednisone ≤ 10 mg PO, QD or its equivalent), inhaled 
steroids, and topical preparations for reasons other than MM (e.g., asthma) are allowed during 
the study.  Systemic corticosteroids > 10 mg PO QD of prednisone (or its equivalent) should not 
be given on the same day as dexamethasone administration.  Systemic corticosteroids > 10 mg 
PO QD of prednisone (or its equivalent) are allowed when the dose of prednisone (or its 
equivalent) is given for less than 7 days and the cumulative dose is < 120 mg.  For additional 
guidance and to determine the equivalent dose of systemic corticosteroid, refer to Appendix K.
!
Surgery and radiation:
!
Localized radiation therapy to a site of pre-existing disease may be permitted while on 
study.  Following approval by the AbbVie Therapeutic Area Medical Director (TA MD) or 
designee, the subject may initiate or continue with protocol therapy without interruption 
during the course of palliative radiation therapy if the risk of excessive bone marrow 
suppression or other toxicity is acceptable, per the investigator's opinion, and the treatment 
is in the best interest of the subject.
!
If the subject develops a definite increase in the size of existing bone lesions or soft tissue 
plasmacytomas that meet the criteria for PD, treatment must be discontinued for PD 
regardless of whether radiation therapy is initiated.
!
Kyphoplasty, vertebroplasty, or emergency orthopedic surgery is permitted.
!
Use of radiotherapy or surgical intervention must be recorded on the eCRF.
Pretreatment Guidance
Anti-Infective Prophylaxis
It is recommended that subjects should receive anti-infective prophylaxis (e.g., amoxicillin/clavulanic 
acid, levofloxacin, or equivalent per institutional guidelines) at least during the first 90 days of study, 
when Grade 4 neutropenia develops (ANC < 500 cells/μL) and continued until the neutropenia improves 
to Grade 3 or better (ANC > 500 cells/μL), and upon disease progression for at least 30 days, unless 
contraindicated per investigator discretion.  Furthermore, it is recommended that subjects deemed at 
high risk of infection receive immunoglobulin replacement therapy (i.e., intravenous immunoglobulin 
[IVIG]) per institutional guidelines or at the Investigator's discretion.  Pneumocystis prophylaxis is 
allowed per institutional guidelines or at the investigator's discretion.
!
The use of antibiotics that are moderate or strong CYP3A4 inhibitors should be avoided or used 
with caution and with the appropriate venetoclax dose modification (Appendix I) as per 
protocol.


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Pneumococcal and Influenza Vaccination
Pneumococcal vaccination may be considered during the initiation of screening procedures for all 
subjects who have not previously received the vaccine.  At the investigator's discretion, influenza 
vaccination may also be considered (live attenuated vaccines are not allowed) during the initiation of 
screening procedures and while on study treatment.
Tumor Lysis Syndrome Prophylaxis
There is a potential for TLS in subjects affected by hematologic malignancies.  Refer to Section 6.4 for 
required TLS prophylaxis.
5.5 Withdrawal of Subjects and Discontinuation of Study
A subject may voluntarily withdraw or be withdrawn from the study at any time for reasons including, 
but not limited to, the following:
!
clinically significant abnormal laboratory results or AEs, which rule out continuation of the study 
drug, as determined by the investigator or the AbbVie TA MD;
!
investigator's opinion that discontinuation is in the best interest of the subject;
!
subject requests withdrawal from the study;
!
eligibility criteria violation was noted after the subject started study drug and continuation of 
the study drug would place the subject at risk;
!
introduction of prohibited medications or dosages and continuation of the study drug would 
place the subject at risk;
!
subject becomes pregnant while on study drug;
!
subject is significantly noncompliant with study procedures which would put the subject at risk 
for continued participation in the trial.
Each subject must be withdrawn if any of the following occur:
!
disease progression confirmed with IMWG criteria
!
drug-related toxicities that lead to dose interruption of > 28 days (subjects may remain in the 
study if only 1 treatment is discontinued)
!
use of antimyeloma treatment not specified in the protocol or operations manual and before 
documented disease progression
For subjects to be considered lost to follow-up, reasonable attempts must be made to obtain 
information on the final status of the subject.  At a minimum, 2 telephone calls must be made and 
1 certified letter must be sent and documented in the subject's source documentation.


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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
AbbVie may terminate this study prematurely, either in its entirety or at any site.  The investigator may 
also stop the study at his/her site if he/she has safety concerns.  If AbbVie terminates the study for 
safety reasons, AbbVie will promptly notify the investigator.
In the event a subject withdraws consent to participate in the clinical study and AbbVie is notified in 
writing, no new biomarker data will be collected from the withdrawn subject or added to the existing 
data or database(s).  A subject may withdraw consent for optional research at any time and remain in 
the clinical study.  Data generated from biomarker research samples collected before subject 
withdrawal of consent will remain part of the study results.
5.6 Follow-Up for Subject Withdrawal from Study
To minimize missing data for efficacy and safety assessments, subjects who prematurely discontinue 
study drug treatment should continue to be followed for all regularly scheduled visits, unless subjects 
have decided to discontinue the study participation entirely (withdrawal of informed consent).  Subjects 
should be advised on the continued scientific importance of their data even if they discontinue 
treatment early.
If a subject discontinues study participation (withdrawal of informed consent), the procedures outlined 
for the end-of-treatment visit should be completed as soon as possible, preferably within 2 weeks.  In 
addition, if subject is willing, a 30-day follow-up phone call after the last dose of study drug may be 
completed to ensure all treatment-emergent AEs/SAEs have been resolved to a ≤ Grade 1 or baseline 
level or, in the opinion of the investigator, the event is unlikely to resolve.
All attempts must be made to determine the date of the last study drug dose and the primary reason for 
the discontinuation of the study drugs or study participation.  The information will be recorded on the 
appropriate eCRF page.  However, these procedures should not interfere with the initiation of any new 
treatments or therapeutic modalities that the investigator feels are necessary to treat the subject's 
condition.  Following the discontinuation of the study drugs, the subject will be treated in accordance 
with the investigator's clinical judgment, irrespective of whether or not the subject decides to continue 
participation in the study.
5.7 Study Drugs
Venetoclax manufactured by AbbVie will be administered PO, QD for each 28-day cycle beginning on 
Day 1 and should be taken at approximately the same time each day.  Subjects will be trained to self-
administer venetoclax (refer to Operations Manual Section 4.1).
Pomalidomide will be administered PO, QD on Days 1 to 21 for each repeated 28-day cycle.  Subjects will 
be trained to self-administer pomalidomide (refer to Operations Manual Section 4.1).
Subject dosing will be recorded in a subject dosing diary.  The subject will be instructed to return all drug 
containers (even if empty) to the study site personnel at each study visit.  The study site personnel will 
document compliance.
AbbVie will not supply drugs other than venetoclax and pomalidomide, if applicable.  Dexamethasone 
and any other noninvestigational medicinal products (standard of care) must be obtained commercially.


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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Pomalidomide will be dispensed as noninvestigational medical product in the US under the Pomalyst 
REMS program.  Further information can be found at:  www.CelgeneRiskManagement.com.
Study drug information is presented in Table 2.
Table 2.
Study Drug Information
Investigational 
Product
Manufacturer
Mode of 
Administration
Dosage Form
Strength
Venetoclax
AbbVie
Oral
Film-coated tablet
100 mg
Pomalidomide
Celgene
Oral
Capsules
1, 3, and/or 4 mg
Venetoclax will be packaged in bottles with quantities sufficient to accommodate study design.  
Pomalidomide will be packaged in bottles or blisters in cartons (local marketed product or overlabeled 
product with a clinical study label).  Each kit will be labeled per local requirements and this label must 
remain affixed to the kit.  Upon receipt, study drugs should be stored as specified on the label and kept 
in a secure location.  Each kit will contain a unique kit number.  This kit number is assigned to a subject 
via Interactive Response Technology (IRT) and encodes the appropriate study drugs to be dispensed at 
the subject's corresponding study visit.  Study drugs must not be dispensed without contacting the IRT 
system.  Study drugs will only be used for the conduct of this study.
Information on the investigational products is provided in Operations Manual Section 4.
5.8 Randomization/Drug Assignment
This is an open-label study.  There is no randomization for this study.  All subjects will be assigned a 
unique identification number by the IRT at the screening visit following signed consent and completion 
of at least 1 study-required procedure.  For subjects who rescreen, the screening number assigned by 
the IRT at the initial screening visit should be used.
5.9 Protocol Deviations
The investigator is responsible for complying with all protocol requirements, written instructions, and 
applicable laws regarding protocol deviations.  Protocol deviations are prohibited except when 
necessary to eliminate an immediate hazard to study subjects.  If a protocol deviation occurs (or is 
identified), the investigator is responsible for notifying IEC/IRB, regulatory authorities (as applicable), 
and AbbVie.


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6 SAFETY CONSIDERATIONS
6.1 Complaints and Adverse Events
Complaints
A complaint is any written, electronic, or oral communication that alleges deficiencies related to the 
physical characteristics, identity, quality, purity, potency, durability, reliability, safety, effectiveness, or 
performance of a product.  Complaints associated with any component of this investigational product 
must be reported to AbbVie.
Medical Complaints/Adverse Events and Serious Adverse Events
An AE is defined as any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship with 
this treatment.  An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not the event is considered causally related to the use of the 
product.
An AE can result from use of the drug as stipulated in the protocol or labeling, as well as from accidental 
or intentional overdose, drug abuse, or drug withdrawal.  Any worsening of a pre-existing condition or 
illness is considered an AE.  Worsening in severity of an AE should be reported as a new AE.  Laboratory 
abnormalities and changes in vital signs are considered to be AEs only if they result in discontinuation 
from the study, necessitate therapeutic medical intervention, meet protocol-specified criteria (see 
Section 6.4 regarding toxicity management), and/or if the investigator considers them to be AEs.
The investigators will monitor each subject for clinical and laboratory evidence of AEs on a routine basis 
throughout the study.  The investigator will assess and record any AE in detail including the date of 
onset, event diagnosis (if known), or sign/symptom, severity, time course (end date, ongoing, 
intermittent), relationship of the AE to study drug, and any action(s) taken.  For SAEs considered as 
having "no reasonable possibility" of being associated with study drug, the investigator will assign 
"other" as the cause of the event.  For AEs to be considered intermittent, the events must be of similar 
nature and severity.  AEs, whether in response to a query, observed by site personnel, or reported 
spontaneously by the subject, will be recorded.
All AEs will be followed to a satisfactory conclusion.
An elective surgery/procedure scheduled to occur during a study will not be considered an AE if the 
surgery/procedure is being performed for a pre-existing condition and the surgery/procedure was 
preplanned before study entry.  However, if the pre-existing condition deteriorates unexpectedly during 
the study (e.g., surgery performed earlier than planned) then the deterioration of the condition for 
which the elective surgery/procedure being done will be considered an AE.
If an AE meets any of the following criteria, it is to be reported to AbbVie or contract research 
organization (as appropriate) as an SAE within 24 hours of the site being made aware of the SAE:


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Death of Subject
An event that results in the death of a subject.
Life Threatening
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had not been 
taken.  This does not include an event that would have been fatal if 
it had occurred in a more severe form.
Hospitalization or 
Prolongation of Hospitalization
An event that results in an admission to the hospital for any length 
of time or prolongs the subject's hospital stay.  This does not 
include an emergency room visit or admission to an outpatient 
facility.
Congenital Anomaly
An anomaly detected at or after birth or any anomaly that results in 
fetal loss.
Persistent or Significant 
Disability/Incapacity
An event that results in a condition that substantially interferes 
with the activities of daily living of a subject.  Disability is not 
intended to include experiences of relatively minor medical 
significance such as headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle).
Important Medical Event 
Requiring Medical or Surgical 
Intervention to Prevent 
Serious Outcome
An important medical event that may not be immediately life-
threatening or result in death or hospitalization but, based on 
medical judgment, may jeopardize the subject and may require 
medical or surgical intervention to prevent any of the outcomes 
listed above (i.e., death of subject, life threatening, hospitalization, 
prolongation of hospitalization, congenital anomaly, or persistent 
or significant disability/incapacity).  Additionally, any elective or 
spontaneous abortion or stillbirth is considered an important 
medical event.  Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency room 
or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency 
or drug abuse.
Hospitalization of a subject to allow observation and management (e.g., intravenous [IV] hydration) for 
the purpose of TLS prophylaxis will not be captured as an SAE unless there is an additional reason for 
hospitalization or an additional criterion for seriousness other than hospitalization (e.g., abnormal 
postdose TLS laboratories that necessitate therapeutic medical intervention, etc.).
All AEs reported from the time the study drugs are administered until 30 days after discontinuation of 
any study drug will be collected whether solicited or spontaneously reported by the subject.  In addition, 
protocol-related SAEs and nonserious AEs will be collected from the time the subject signed the study-
specific informed consent.
All AEs should be followed until resolution, return to baseline, or determined to be stable per the 
investigator.


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AE = adverse event; SAE = serious adverse event
*
Only if considered by the investigator to be causally related to study-required procedures.
a.
30 Days after the last dose of venetoclax.
Adverse Event Severity and Relationship to the Study Drugs
The investigators will rate the severity of each AE according to the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.  If a reported AE increases in 
severity, the initial AE should be given an outcome date and a new AE must be reported on a different 
onset date than the end date of the previous AE to reflect the change in severity.  The dates on the AEs 
cannot overlap.  For all reported SAEs that increase in severity, the supplemental eCRFs also need to be 
updated to reflect any changes due to the increase in severity.
For AEs not captured by the NCI CTCAE, the following should be used:
Grade 1
The AE is transient and easily tolerated by the subject (mild).
Grade 2
The AE causes the subject discomfort and interrupts the subject's usual activities 
(moderate).
Grade 3
The AE causes considerable interference with the subject's usual activities and may 
be incapacitating (moderate to severe).
Grade 4
The AE is life-threatening and requires urgent intervention (severe).
Grade 5
The AE resulted in death of the subject (severe).
The investigators will use the following definition to assess the relationship of each AE to the use of the 
study drugs:


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Reasonable Possibility
After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there is 
sufficient evidence (information) to suggest a causal relationship.
No Reasonable 
Possibility
After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there is no 
evidence (information) to suggest a causal relationship.
For causality assessments, events assessed as having a reasonable possibility of being related to the 
study drug will be considered "associated."  Events assessed as having no reasonable possibility of being 
related to study drug will be considered "not associated."  In addition, when the investigator has not 
reported causality or deemed it not assessable, AbbVie will consider the event associated.
If an SAE is assessed as having no reasonable possibility of being related to study drug per the 
investigator's opinion, an "other" cause of event must be provided by the investigator for the SAE.
Adverse Events of Special Interest
AEs will be monitored throughout the study to identify any of special interest that may indicate a trend 
or risk to subjects.  The following AEs of special interest (serious and nonserious) are to be entered into 
the electronic data capture system immediately (i.e., no more than 24 hours after the site becoming 
aware of the event):
!
TLS
Dose-Limiting Toxicity
DLTs (as defined Section 6.5) will be assessed during the first cycle of venetoclax and pomalidomide 
dosing.  Toxicities occurring after the first cycle of dosing will also be evaluated by the investigator and 
the AbbVie TA MD and taken into consideration for dose-escalation decisions.
Pregnancy
While not an AE, pregnancy in a study subject must be reported to AbbVie within 1 working day of the 
site becoming aware of the pregnancy.  If a pregnancy occurs in a study subject or in the partner of a 
study subject, information regarding the pregnancy and the outcome will be collected.  In the event of 
pregnancy occurring in a subject's partner during the study, written informed consent from the partner 
must be obtained before collection of any such information.  A separate consent will be provided by 
AbbVie for this purpose.  Pregnancies in study subject's partners will be collected from the date of the 
first dose through 30 days following the last dose of study drug.
The pregnancy outcome of an elective or spontaneous abortion, stillbirth, or congenital anomaly is 
considered an SAE and must be reported to AbbVie within 24 hours of the site becoming aware of the 
event.
Deaths
Deaths that occur during the protocol-specified AE reporting period that are attributed by the 
investigator solely to progression of MM should be recorded only on the study completion eCRF with 


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disease progression as the reason for discontinuation and not on the AE eCRF.  All other on-study 
deaths, regardless of relationship to study drug, must be recorded on the AE eCRF and immediately 
reported to the sponsor.
Death should be considered an outcome and not a distinct event.  The event or condition that caused or 
contributed to the fatal outcome should be recorded as the single medical concept on the AE eCRF.  
Generally, only 1 such event should be reported.  The term "sudden death" should be used only for the 
occurrence of an abrupt and unexpected death because of presumed cardiac causes in a subject with or 
without pre-existing heart disease within 1 hour after the onset of acute symptoms or, in the case of an 
unwitnessed death, within 24 hours after the subject was last seen alive and stable.  If the cause of 
death is unknown and cannot be ascertained at the time of reporting, "unexplained death" should be 
recorded on the AE eCRF.  If the cause of death later becomes available (e.g., after autopsy), 
"unexplained death" should be replaced by the established cause of death.
Lack of Efficacy or Worsening of Disease
Events that are clearly consistent with the expected pattern of progression of the underlying disease, 
including transformation to a more aggressive histology, are also considered an expected outcome for 
this study and will NOT be recorded as AEs.  These data will be captured as efficacy assessment data 
only.  If there is any uncertainty as to whether an event is due to disease progression, the event should 
be reported as an AE.
6.2 Recording Data and Analyses of Safety Findings
AEs will be coded using the Medical Dictionary for Regulatory Activities.  Details on the statistical 
analyses for safety will be provided in the SAP.
6.3 Reporting Adverse Events and Intercurrent Illnesses
In the event of an SAE, whether associated with study drug or not, the investigator will notify clinical 
pharmacovigilance within 24 hours of the site being made aware of the SAE by entering the SAE data 
into the electronic data capture system.  SAEs that occur before the site has access to the RAVE® system, 
or if RAVE is not operable, should be documented on the SAE nonCRF forms and emailed (preferred 
route) or faxed to clinical pharmacovigilance within 24 hours of the site being made aware of the SAE 
(refer to Appendix L for safety reporting contact information).
6.4 Toxicity Management
Venetoclax:  Venetoclax could lead to suppression of lymphocytes.  In addition, clinically significant 
neutropenia may also be observed.  Both lymphopenia and neutropenia could increase the risk for 
infections, including opportunistic infections.  Venetoclax treatment can also lead to TLS.  Subjects will 
be managed based on their TLS risk factors as detailed below.
Pomalidomide:  Pomalidomide could lead to neutropenia, anemia, and thrombocytopenia.  Among the 
nonhematologic toxicities, venous and arterial thromboembolism, hepatotoxicity, hypersensitivity 
reactions, dizziness and confusional state, and neuropathy have been reported with pomalidomide.


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Dexamethasone:  Dose modifications or discontinuation may be necessary for gastrointestinal events, 
acute pancreatitis, neurologic disorders or muscle weakness, and edema or hyperglycemia.
Subjects will be monitored for these events throughout the study and treatment may be discontinued or 
adjusted as appropriate.  Dose modifications and treatment guidelines for drug-related toxicities 
(venetoclax, pomalidomide, or dexamethasone) are provided in Appendix I.  If an investigator considers 
it necessary, subjects who interrupt study therapy for longer than 28 days may be discontinued from 
further study therapy.
Prophylaxis and Management of Tumor Lysis Syndrome
Venetoclax and pomalidomide can cause rapid reduction in tumor and thus poses a risk for TLS.  
Changes in electrolytes consistent with TLS that require prompt management can occur as early as 6 to 
8 hours following the first dose of venetoclax (Appendix H).  Definitions of laboratory TLS and clinical TLS 
are provided in the Appendix G (Howard grading classification).
There is a potential for TLS in subjects affected by hematologic malignancies.  Depending on the specific 
tumor type, risk factors may include one or more of the following:  bulky disease or high tumor burden, 
elevated pretreatment lactate dehydrogenase levels, elevated leukocyte count, renal insufficiency, and 
dehydration.
MM subjects with high tumor burden (e.g., high bone marrow plasma cell infiltration, plasma cell 
leukemia, or bulky plasmacytomas), rapidly increasing M-protein or light chains or high proliferative 
activity, plasmablastic morphology, or compromised renal function (CrCL < 50 mL/minute) may be at 
higher risk of developing TLS.11  Additionally, subjects with t(11;14) and high bone marrow plasma cell 
infiltration or a significant number of circulating plasma cells appear to have an increased risk for TLS 
when treated with venetoclax.
Consider TLS prophylaxis with oral hydration (at least 1 to 2 L, as tolerable) in all subjects at least 
72 hours before the first day of dosing with venetoclax and pomalidomide.  Prophylaxis with uric acid 
reducing agents may be required for subjects with high uric acid levels.  Monitor for clinical and 
laboratory evidence of TLS during treatment (Appendix G) and manage abnormalities in serum 
creatinine, uric acid, and electrolytes promptly according to institutional guidelines (guidance also 
available in Appendix H).
For subjects with t(11;14) and > 50% bone marrow plasma cell infiltration or CrCL < 50 mL/minute, oral 
hydration as aforementioned is required and chemistry laboratory tests (phosphate, potassium, calcium, 
uric acid, creatinine, lactate dehydrogenase, and AST at a minimum) should be done at approximately 
6 hours after the first dose with venetoclax.  Consider uric acid-lowering drugs in subjects at higher risk 
for TLS.  More intensive measures (e.g., IV hydration, frequent monitoring of laboratory values, 
hospitalization, etc.) should be considered at the investigator's discretion or in accordance with 
institutional guidelines.  All TLS prophylaxis measures should be appropriately recorded in the eCRF.
In case of evidence of TLS, dosing with venetoclax should be interrupted.  Drug interruption for up to 
72 hours following transient (i.e., lasting < 48 hours) chemical changes and laboratory TLS will not 
require a dose reduction.  If the TLS has not resolved within 72 hours, then a dose reduction should be 
considered.  The subject may be allowed to re-escalate to the final dose based on a risk assessment 
(including tumor burden status).  If active correction of electrolytes was performed, the first dose of 


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venetoclax should only be given when electrolytes have been stable without additional treatment for at 
least 24 hours.
If a subject meets criteria for clinically significant laboratory or clinical TLS, the subject must dose reduce 
(refer to the Appendix I, as applicable).  The subject may be allowed to re-escalate to the intended 
cohort dose based on a risk assessment (including tumor burden status) after discussion between the 
investigator and the TA MD.
Additional TLS prophylaxis and monitoring (more frequent laboratory sample collection, IV hydration, 
dose ramp-up requirements, etc.) can be implemented as needed based upon review of safety data 
(e.g., if a higher than expected rate of laboratory TLS is observed or cases of clinical TLS are identified).
Management of Neutropenia and Other Cytopenias
Venetoclax and pomalidomide can cause cytopenias including clinically significant neutropenia and 
lymphopenia that can increase risk for serious infection including opportunistic infections.  Subjects with 
a history of neutropenia who have received multiple prior therapies and/or have significant bone 
marrow involvement may be at a particularly high risk.  Grade 3 or 4 neutropenia has been reported in 
subjects treated with venetoclax and pomalidomide.
Complete blood counts should be monitored throughout the treatment period.  Anti-infective 
prophylaxis and granulocyte-colony stimulating factor (G-CSF) for management of neutropenia should 
be considered per institutional guidelines.  Subjects should receive anti-infective prophylaxis 
(e.g., amoxicillin/clavulanic acid or levofloxacin or equivalent per institutional guidelines) when Grade 4 
neutropenia develops (ANC < 500 cells/μL) and continued until the neutropenia improves to Grade 3 or 
better (ANC > 500 cells/μL).  Please refer to the Appendix I for guidance on dose reductions or 
interruptions related to venetoclax or pomalidomide toxicities.
Management of Decrease in Spermatogenesis
Venetoclax may cause a decrease in spermatogenesis.  Male subjects considering preservation of 
fertility should bank sperm before initiating treatment with venetoclax.
Embryo-Fetal Toxicity
Pomalidomide is contraindicated in pregnancy.  Pomalidomide is a thalidomide analog; thalidomide is a
known human teratogen that causes severe life-threatening birth defects.  Refer to the pomalidomide 
package insert for details.10
Venous and Arterial Thromboembolism
Deep venous thrombosis, pulmonary embolism, myocardial infarction, and stroke occur in subjects with 
multiple myeloma treated with pomalidomide.  Antithrombotic prophylaxis is recommended for 
subjects with a history of cardiovascular disease or per investigator discretion.  Refer to the 
pomalidomide package insert for details.10
Management of Infection
Subjects should receive anti-infective prophylaxis (e.g., amoxicillin/clavulanic acid or levofloxacin or 
equivalent per institutional guidelines) at least during the first 90 days of study and upon disease 


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progression for at least 30 days unless contraindicated per investigator discretion.  Furthermore, 
subjects deemed at high risk of infection should receive immunoglobulin replacement therapy (i.e., IVIG) 
per institutional guidelines or at the investigator's discretion.
The use of antibiotics that are moderate or strong CYP3A inhibitors should be avoided or used with 
caution and with appropriate venetoclax dose modification (refer to Appendix I) as per protocol.
All subjects receiving venetoclax should be closely monitored for infections and in the event of a 
Grade ≥3 or serious infection, treatment with venetoclax should be interrupted and upon resolution, 
treatment can be either resumed at a reduced dose or discontinued, depending on investigator's clinical 
judgment.
Please refer to Table 9 and Table 10 for guidance on dose interruptions and/or reductions related to 
venetoclax toxicities.
Potential for drug-drug interactions should be considered.  Please refer to Appendix J for a description of 
prohibited and cautionary medications.
Management of Other Toxicities
If other events occur that are related to venetoclax or pomalidomide, the investigator may interrupt or 
dose reduce venetoclax and/or pomalidomide, as appropriate (refer to Appendix I).
Pomalidomide must be permanently discontinued for angioedema, skin exfoliation, bullae, or any other 
severe dermatologic reaction.
All subjects should be monitored for new onset hematologic, hepatic, and renal toxicities with dose 
delay or reduction as appropriate.  Please follow local, approved product label or applicable summary of 
product characteristics12 for monitoring guidelines for pomalidomide or Appendix I for venetoclax.
Dexamethasone dose modifications or discontinuation may be necessary for Grades 1 to 2 
gastrointestinal disorders that do not respond to appropriate treatment, > Grade 3 gastrointestinal 
events, acute pancreatitis, > Grade 2 neurologic disorders or muscle weakness, and ≥ Grade 3 edema or 
hyperglycemia (refer to Appendix I).
6.5 Dose-Limiting Toxicity
DLTs for dose-escalation purposes will be determined during the first cycle (28 days) of study drug 
administration at the designated cohort dose.  AEs occurring following Cycle 1 will also be evaluated by 
the investigator and the AbbVie TA MD and may be considered as dose limiting.  Any of the following 
events that concur with the administration of venetoclax, pomalidomide, or dexamethasone, which 
cannot be attributed by the investigator to a clearly identifiable cause such as disease progression, 
concurrent illness, or concomitant medication, will be considered a DLT:
!
Grade 4 neutropenia lasting more than 7 days
!
Grade 3 or Grade 4 neutropenia with fever
!
Grade 4 thrombocytopenia that has not recovered before the start of the next cycle of therapy


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!
Grade 2 or higher bleeding associated with Grade ≥ 3 thrombocytopenia
!
Unexpected Grade 2 or higher toxicity which requires dose modification or delay of ≥ 1 week
!
Clinical TLS
!
Laboratory TLS if the metabolic abnormalities are deemed clinically significant by the 
investigator
!
All other Grades 3, 4, or 5 AEs with the exception of the following:
!
Grades 3, 4 afebrile neutropenia
!
Grade 3 thrombocytopenia that does not result in bleeding
!
Grades 3, 4 lymphopenia
!
Grades 3, 4 leukopenia
!
Grade 3 or 4 hyperuricemia or hypocalcemia or Grade 3 hyperkalemia, if transient (i.e., 
lasting < 48 hours) and without manifestations of clinical TLS (i.e., creatinine ≥ 1.5 × ULN, 
cardiac arrhythmias, sudden death, or seizures)
!
Grade 3 fatigue
!
Grade 3 peripheral neuropathy
!
Grade 3 nausea, vomiting, and/or diarrhea that are responsive to treatment
!
Grade 3 hyperglycemia that is controllable with insulin or oral hyperglycemic agents within 
24 hours
!
Grade 3 hypertension that is reversible within 24 hours
!
Grade 3 confusion that is reversible within 24 hours
!
Grade 3 or higher local reaction to subcutaneous injections that does not resolve within 
24 hours
!
Grade 3 insomnia that is managed with a sedative or reversible within 24 hours
!
Grade 3 edema that is controlled with diuretics or reversible within 24 hours
!
Grade 3 dyspepsia that is managed with histamine 2 blockers/proton pump inhibitors or 
reversible within 24 hours
Any DLTs observed during the designated cohort dosing period will require a modification of the 
designated cohort dose as directed per the dose-escalation guidelines (Section 4.1).
Any DLT will require an interruption and possible discontinuation of venetoclax, pomalidomide, and/or 
dexamethasone.  Venetoclax, pomalidomide, and/or dexamethasone may be reintroduced at a reduced 
dose if the toxicity grade returns to ≤ Grade 1 or to baseline if Grade 2 at study entry.
Drug interruption for up to 72 hours following transient (i.e., lasting < 48 hours) chemical changes and 
laboratory TLS may be allowed and may not be considered a DLT or require a dose reduction.  If the TLS 


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has not resolved within 72 hours, then a dose reduction should be considered.  The subject may be 
allowed to re-escalate to the final dose based on a risk assessment (including tumor burden status).
Any reduced dose level of venetoclax, pomalidomide, and/or dexamethasone will be defined by AbbVie 
after discussion between the investigator and the AbbVie TA MD.  The dose of venetoclax, 
pomalidomide, and/or dexamethasone may be increased thereafter as defined by AbbVie after 
discussion between the investigator and the AbbVie TA MD.  The venetoclax dose is not to exceed the 
highest tolerated dose level.  All decisions regarding continued dosing for individual subjects will be 
medically managed by the investigator, in conjunction with the AbbVie TA MD, as appropriate.  These 
decisions will be driven by the definition of DLTs as described above.
6.6 Product Complaints
A product complaint is any complaint related to the biologic or drug component of the product or to the 
medical device component(s).
For a product, this may include, but is not limited to, damaged/broken product or packaging, product 
appearance whose color/markings do not match the labeling, labeling discrepancies/inadequacies in the 
labeling/instructions (e.g., printing illegible), missing components/product, device not working properly, 
or packaging issues.
Product complaints concerning the investigational product and/or device must be reported to AbbVie 
within 24 hours of the study site's knowledge of the event.  Product complaints occurring during the 
study will be followed up to a satisfactory conclusion.
7 STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
7.1 Statistical and Analytical Plans
Complete and specific details of the statistical analysis will be described and fully documented in the 
SAP.  All statistical analyses will be performed using SAS version 9.4 or newer (SAS Institute Inc., Cary, 
North Carolina, USA).
7.2 Determination of Sample Size
Approximately 60 subjects will be enrolled into this 2-part study.
Part 1, Dose Escalation
Part 1 will enroll approximately 3 to 6 subjects per cohort using a BOIN design, resulting in a total of 6 to 
12 subjects.
Part 2, Dose Expansion
Part 2 will enroll approximately 50 subjects.


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Arm A:  t(11;14)-Positive
The historical ORR for pomalidomide + dexamethasone is 35%.13,14  By adding venetoclax to this 
combination, an ORR of 70% is clinically meaningful for t(11;14)-positive subjects.  The sample size for 
Arm A will be approximately 23 subjects.  Allowing for a maximum 1-sided type 1 error rate of 0.025 and 
assuming an ORR of 35% from the historical data, 23 subjects will provide 90% power if the true ORR for 
t(11;14)-positive subjects treated with venetoclax + pomalidomide + dexamethasone is 70%.
Arm B:  t(11;14)-Negative
The historical ORR for pomalidomide + dexamethasone is 35%.  By adding venetoclax to this 
combination, an ORR of 60% is clinically meaningful for t(11;14)-negative subjects.  The sample size for 
Arm B will be approximately 27 subjects.  Allowing for a maximum 1-sided type 1 error rate of 0.1 and 
assuming an ORR of 35% from the historical data, 27 subjects will provide 90% power if the true ORR for 
t(11;14)-negative subjects treated with venetoclax + pomalidomide + dexamethasone is 60%.
7.3 Definition for Analysis Populations
The Full Analysis Set (FAS) includes all subjects who received at least 1 dose of study drug.  The FAS will 
be used for all safety, PK, efficacy and baseline analyses.
7.4 Statistical Analyses for Efficacy
Exact tests for H0:  ORR ≤ 35% and H1:  ORR > 35% with 1-sided significance levels 0.025 and 0.1 for 
Arms A and B, respectively, will be performed.  Point estimates and exact 95% confidence intervals of 
ORR for each of the 2 arms (Arms A and B) will be calculated.  Details of the analysis methods for all 
efficacy endpoints will be provided in the SAP.
7.5 Statistical Analyses for Safety
Details pertaining to the safety analyses can be found in the SAP.
7.6 Statistical Analyses for Pharmacokinetics
Details pertaining to the PK analyses can be found in the SAP.
7.7 Study Interim Analysis
Interim analyses may be conducted when adequate data from approximately 10 and 16 subjects are 
available from Arms A and B, respectively. Details pertaining to the safety analyses can be found in the 
SAP.


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7.8 Safety Review Committee
A Safety Review Committee (SRC) will periodically review safety data across all studies with venetoclax 
in MM that do not have a study-specific independent monitoring committee.  This review committee 
will be responsible for periodic, regular reviews to assess the safety of the interventions during the 
study.  A separate charter will be prepared outside of the protocol outlining the SRC member 
responsibilities, frequency of data reviews, and relevant data to be assessed.
8 ETHICS
8.1 Independent Ethics Committee/Institutional Review Board
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the IEC/IRB for review and approval.  Approval of both the protocol and the informed 
consent form(s) must be obtained before any participant is enrolled.  Any amendment to the protocol 
will require review and approval by the IEC/IRB before the changes are implemented to the study.  In 
addition, all changes to the consent form(s) will be IEC-/IRB-approved.
8.2 Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, operations manual, International Council 
for Harmonisation (ICH) guidelines, applicable regulations and guidelines governing clinical study 
conduct, and the ethical principles that have their origin in the Declaration of Helsinki.  Responsibilities 
of the investigator are specified in Appendix B.
8.3 Subject Confidentiality
To protect subjects' confidentiality, all subjects and their associated samples will be assigned numerical 
study identifiers or "codes."  No identifiable information will be provided to AbbVie.
9 SOURCE DOCUMENTS AND CASE REPORT FORM 
COMPLETION
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported.  All source documents should be attributable, legible, contemporaneous, original, 
accurate, and complete to ensure accurate interpretation of data.  Clinical site monitoring is conducted 
to ensure that the rights and well-being of human subjects are protected, that the reported trial data 
are accurate, complete, and verifiable, and that the conduct of the trial is in compliance with the 
currently approved protocol, ICH Good Clinical Practice (GCP), and applicable local regulatory 
requirement(s).


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10 DATA QUALITY ASSURANCE
AbbVie will ensure that the clinical trial is conducted and data are generated, documented, and reported 
in compliance with the protocol, ICH GCP, and applicable regulatory requirements.
11 COMPLETION OF THE STUDY
The end-of-study is defined as the date of the last subject's last visit or date of the last follow-up 
contact, whichever is later.
12 REFERENCES
1.
Nakayama K, Nakayama K, Negishi I, et al.  Targeted disruption of Bcl-2 alpha beta in mice:  
occurrence of grey hair, polycystic kidney disease, and lymphocytopenia.  Proc Natl Acad Sci 
USA.  1994;91(9):3700-4.
2.
Yamamura K, Kamada S, Ito S, et al.  Accelerated disappearance of melanocytes in bcl-2-
deficient mice.  Cancer Res.  1996;56(15):3546-50.
3.
Mason KD, Carpinelli MR, Fletcher JI, et al.  Programmed anuclear cell death delimits platelet life 
span.  Cell.  2007;128(6):1173-86.
4.
Roberts AW, Wilson W, Gandhi L, et al.  Ongoing Phase I studies of ABT-263:  mitigating Bcl-XL 
induced thrombocytopenia with lead-in and continuous dosing.  J Clin Oncol.  
2009;27(15S):3505.
5.
Ferlay J, Soerjomataram I, Ervik M, et al.  GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality 
Worldwide:  IARC Cancer Base No 11.  [Internet] Lyon, France:  International Agency for 
Research on Cancer; 2013.  Available from:  
http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx.
6.
Röllig C, Knop S, Bornhäuser M.  Multiple myeloma.  Lancet.  2015;385(9983):2197-208.
7.
Kumar SK, Dispenzieri A, Lacy MQ, et al.  Continued improvement in survival in multiple 
myeloma:  changes in early mortality and outcomes in older patients.  Leukemia.  
2014;28(5):1122-8.
8.
Kumar SK, Therneau T, Gertz M, et al.  Clinical course of patients with relapsed multiple 
myeloma.  Mayo Clin Proc.  2004;79(7):867-74.
9.
Venetoclax (ABT-199) Investigator's Brochure.  Current version.
10. Pomalidomide [package insert].  Summit, NJ; Celgene Corporation. Current version.
11. Fassas AB, Desikan KR, Siegel D, et al.  Tumour lysis syndrome complicating high-dose treatment 
in patients with multiple myeloma.  Br J Haematol.  1999;105(4):938-41.
12. Pomalidomide [Summary of Product Characteristics].  Uxbridge, United Kingdom; Celgene 
Corporation Europe Ltd.  Current version.


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13. Richardson PG, Siegel DS, Vij R, et al.  Pomalidomide alone or in combination with low-dose 
dexamethasone in relapsed and refractory multiple myeloma:  a randomized Phase 2 study. 
Blood.  2014;123(12):1826-32.
14. San Miguel J, Weisel K, Moreau P, et al.  Pomalidomide plus low-dose dexamethasone versus 
high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma 
(MM-003):  a randomised, open-label, Phase 3 trial.  Lancet.  2013;14(11):1055-66.
15. Kumar S, Paiva B, Anderson KC, et al.  International Myeloma Working Group consensus criteria 
for response and minimal residual disease assessment in multiple myeloma.  Lancet Oncol.  
2016;17(8):e328-e46.


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APPENDIX A. STUDY SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
AE
adverse event
ALT
alanine aminotransferase
AML
acute myeloid leukemia
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the plasma concentration versus time curve (AUC)
AUC0-24
AUC from time 0 to 24 hours postdose
BCL
B-cell lymphoma
BCL-w
B-cell lymphoma-Walter and Eliza Hall Institute
BCL-XL
B-cell lymphoma – extra large
BCRP
breast cancer resistance protein
BOIN
Bayesian optimal interval
CDK
cyclin-dependent kinase
CLL
chronic lymphocytic leukemia
Cmax
maximum concentration
CR
complete remission
CrCL
creatinine clearance
CRF
Case Report Form
CRi
complete remission with incomplete blood count recovery
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
DOR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
FAS
Full Analysis Set


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FFPE
fixed formalin paraffin embedded
FISH
fluorescent in situ hybridization
FLC
free-light chain
GCP
Good Clinical Practice
G-CSF
granulocyte-colony stimulating factor
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HDAC
histone deacetylase
HR
hazard ratio
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
Ig
immunoglobulin
IHC
immunohistochemistry
IMiD
immunomodulatory drug
IMWG
International Myeloma Working Group
INR
international normalized ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
IV
intravenous
IVIG
intravenous immunoglobulin
Ki
inhibition rate constant
MCL
myeloid-cell leukemia
MM
multiple myeloma
M-protein
monoclonal-protein
MR
minimal response
MRD
minimal residual disease
MRI
magnetic resonance imaging
NCI
National Cancer Institute
NHL
non-Hodgkin's lymphoma
OATP
organic anion-transporting polypeptide
ORR
overall response rate
OS
overall survival
PD
progressive disease
PET
positron emission tomography


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PFS
progression-free survival
P-gp
P-glycoprotein
PI
proteasome inhibitor
PK
pharmacokinetic(s)
PO
oral
POEMS
polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin 
changes
PR
partial response
PT
prothrombin time
QD
once daily
qPCR
quantitative polymerase chain reaction
qw
once weekly
REMS
risk evaluation and mitigation strategies
RNA
ribonucleic acid
R/R
relapsed or refractory
SAE
serious adverse event
SAP
Statistical Analysis Plan
sCR
stringent complete response
SD
stable disease
SLL
small lymphocytic lymphoma
SRC
Safety Review Committee
SUSAR
Suspected Unexpected Serious Adverse Reaction
TA MD
Therapeutic Area Medical Director
TLS
tumor lysis syndrome
Tmax
time to maximum concentration
TTP
time-to-progression
ULN
upper limit of normal
VGPR
very good partial response


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APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M16-085:  Venetoclax and Pomalidomide
Protocol Date:  24 June 2020
Clinical research studies sponsored by AbbVie are subject to the International Council for Harmonisation 
(ICH) Good Clinical Practices (GCP) and local regulations and guidelines governing the study at the site 
location.  In signing the Investigator Agreement, the investigator is agreeing to the following:
1.
Conducting the study in accordance with ICH GCP, the applicable regulatory requirements, 
current protocol and operations manual, and making changes to a protocol only after notifying 
AbbVie and the appropriate Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC), except when necessary to protect the subject from immediate harm.
1.
Personally conducting or supervising the described investigation(s).
2.
Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed consent and 
ethics committees (e.g., IEC or IRB) review and approval of the protocol and its amendments.
3.
Reporting complaints that occur in the course of the investigation(s) to AbbVie.
4.
Reading the information in the Investigator's Brochure/safety material provided, including the 
instructions for use and the potential risks and side effects of the investigational product(s).
5.
Informing all associates, colleagues, and employees assisting in the conduct of the study about 
their obligations in meeting the above commitments.
6.
Maintaining adequate and accurate records of the conduct of the study, making those records 
available for inspection by representatives of AbbVie and/or the appropriate regulatory agency, 
and retaining all study-related documents until notification from AbbVie.
7.
Maintaining records demonstrating that an ethics committee reviewed and approved the initial 
clinical protocol and all of its amendments.
8.
Reporting promptly, all changes in the research activity and all unanticipated problems involving 
risks to human subjects or others, to the appropriate individuals (e.g., coordinating investigator, 
institution director) and/or directly to the ethics committees and AbbVie.
9.
Providing direct access to source data documents for study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s).
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


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APPENDIX C. LIST OF PROTOCOL SIGNATORIES
Name
Title
Functional Area
Medical Writing
Clinical Hematology Oncology
Statistics
Clinical Pharmacology and Pharmacometrics
Clinical Program Development


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APPENDIX D. ACTIVITY SCHEDULE
The following table shows the required activities for this study.  The individual activities are described in 
detail in Appendix E.










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j.
Pomalidomide education and counseling guidance document for each gender as well as pomalidomide information sheet must be completed and signed before starting 
pomalidomide and each time the subject receives a new supply of pomalidomide.


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APPENDIX E. STUDY PROCEDURES
Subject Information and Informed Consent
The investigator or his/her representative will explain the nature of the study to the subject and answer 
all questions regarding the study.  Prior to any study-related screening procedures being performed on 
the subject or any medications being discontinued by the subject in order to participate in this study, 
the informed consent statement will be reviewed, signed, and dated by the subject, the person who 
administered the informed consent, and any other signatories according to local requirements.  Subjects 
may need to sign an assent document or other simplified version of the informed consent form where 
required by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB) and/or local laws 
and regulations.  A copy of the signed informed consent will be given to the subject and the original will 
be placed in the subject's medical record.  An entry must also be made in the subject's dated source 
documents folder to confirm that informed consent was obtained before any study-related procedures 
were performed and that the subject received a signed copy.
Information regarding benefits for subjects and information regarding provisions for treating and/or 
compensating subjects who are harmed as a consequence of participation in the study can be found in 
the informed consent form.
Samples for optional pharmacogenetic analyses will only be collected if the subject has voluntarily 
signed and dated a separate written consent form for pharmacogenetic testing that has been approved 
by an IRB/IEC after the nature of the testing has been explained and the subject has had an opportunity 
to ask questions.  The separate written consent may be part of the main consent form.  If the subject 
does not consent to the pharmacogenetic testing, the subject will still be allowed to participate in the 
study.
Medical History
A complete medical history including history of tobacco, alcohol, and drug use will be taken at screening.  
The subject's medical history will be updated before the first dose of study drug (Cycle 1, Day 1).  This 
updated medical history will serve as the baseline for clinical assessment.  A detailed oncology history 
will also be collected including:  histology, date of diagnosis of multiple myeloma (MM), any surgical 
procedures, and treatments administered (including dates and type of modality).
On Cycle 1, Day 1, any additional medical history observed after signing of the informed consent but 
before initial study drug administration and not considered related to study-required procedures will be 
recorded in the subject's medical history.
Eastern Cooperative Oncology Group Performance Status
For all subjects, the Eastern Cooperative Oncology Group (ECOG) performance status will be performed 
as outlined in Appendix D.  Post-screening assessments may be done ≤ 3 days before the scheduled visit.
It is recommended, when possible, a subject's performance status will be assessed by the same person 
throughout the study.  ECOG performance status will be assessed as follows:


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Grade
Description
0
Fully active, able to carry on all predisease 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 housework, office work.
2
Ambulatory and capable of all self-care but unable to carry out any work activities.  Up and 
about more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.
4
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair.
5
Dead
Adverse Event Assessment
Please refer to Appendix D.
Physical Examination
A complete physical examination will be performed at screening.  The screening physical examination 
will serve as the baseline for the entire study.  Any significant physical examination findings or clinically 
significant changes from baseline after the first dose will be recorded as adverse events (AEs).  All 
findings, whether related to an AE or part of each subject's medical history, will be captured on the 
appropriate electronic case report form (eCRF) page.
Symptom-directed physical examinations will be performed as specified in Appendix D; however, at any 
visit, a symptom-directed physical examination may be performed as deemed necessary by the 
investigator.  The Cycle 1, Day 1 examination is optional if the screening examination is conducted 
within ≤ 7 days.  For other time points, the symptom-directed physical examinations may be done 
≤3 days before a scheduled visit.
Height and Weight
Height will be measured at the screening visit only.  Body weight will be measured at scheduled visits as 
specified in Appendix D.  The subject should wear lightweight clothing and no shoes during weighing.
Vital Signs
Vital sign determinations of systolic and diastolic blood pressure, pulse rate, respiratory rate, and body 
temperature will be obtained at visits as specified in Appendix D.  In addition, vital signs will be 
measured as clinically indicated.  Blood pressure and pulse rate should be measured after the subject 
has been sitting for at least 3 minutes and before study drug administration.
12-Lead Electrocardiogram
A 12-lead electrocardiogram (ECG) will be performed at the designated study visits as specified in 
Appendix D.  The ECG should be performed before blood collection.  The ECG may be performed up to 
7 days before study drug administration on Day 1.


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The ECGs will be evaluated by an appropriately trained physician at the site ("local reader").  The local 
reader from the site will sign and date all ECG tracings and will provide his/her global interpretation as a 
written comment on the tracing using the following categories:
!
Normal ECG
!
Abnormal ECG – not clinically significant
!
Abnormal ECG – clinically significant
Only the local reader's evaluation of the ECG will be collected and documented in the subject's source 
folder.  The automatic machine reading (i.e., machine-generated measurements and interpretation that 
are automatically printed on the ECG tracing) will not be collected.  Clinically significant findings should 
be documented on the eCRF.
Clinical Laboratory Tests
Historical results may be used for screening laboratory tests if they are obtained within 21 days before 
the first dose.
All laboratory testing will be performed by the central or local laboratories.  Required tests are listed in 
Table 3.
Local laboratories will be utilized to process and provide results for clinical laboratory tests allowing for 
immediate subject medical management.  The principal investigator or subinvestigator will review, 
initial, and date all laboratory results after receipt from the local laboratory.  Local laboratory values will 
be entered by the site directly onto the appropriate eCRF and laboratory normal ranges and certification 
for the laboratory that is used will be provided to the AbbVie clinical team if the result is clinically 
significant (i.e., necessitating an immediate treatment or treatment modification).
The blood samples for serum chemistry tests will be collected before study drug intake as specified in 
Appendix D.  The Cycle 1, Day 1 tests are optional if the screening collection was within ≤ 7 days.  For 
other time points, tests may be completed ≤ 7 days before the scheduled visit and must be reviewed 
before dosing.  The baseline laboratory test results for clinical assessment for a particular test will be 
defined as the last measurement before the initial dose of study drug.
For chemistry laboratory tests performed for tumor lysis syndrome (TLS) prophylaxis and monitoring, 
refer to Table 3.
For subjects receiving intravenous (IV) hydration for TLS prophylaxis before the first dose, the baseline 
value will be the last laboratory value before the subject receives IV hydration for TLS prophylaxis.  For 
subjects without IV hydration for TLS prophylaxis before the first dose, the baseline value will be the last 
laboratory value taken before the first dose of venetoclax.
For cycles with bone marrow assessments, hematology and chemistry laboratory tests should be 
performed on the same day as the bone marrow assessment whenever possible.  If the assessment 
occurs outside of the hematology and chemistry visit window, then the laboratory tests should be 
repeated before dosing.


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If a laboratory test value is outside the reference range and the investigator considers the laboratory 
result to be clinically significant, the investigator will:
!
repeat the test to verify the out-of-range value;
!
follow the out-of-range value to a satisfactory clinical resolution;
!
reduce the dose or temporary interruption of study drug; or
!
discontinue the subject from the study or require the subject to receive treatment; in this case, 
the laboratory result will be recorded as an AE.
Table 3.
Clinical Laboratory Tests
Hematology
Clinical Chemistry
Other Tests
Hematocrit
Hemoglobin
White blood cell count
Neutrophils
Lymphocytes
Monocytes
Platelet count (estimate not 
acceptable)
Blood urea nitrogen
Creatinine
Total bilirubin
Direct and indirect bilirubin
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Alkaline phosphatase
Sodium
Potassium
Calcium
Inorganic phosphorus
Total protein
Glucose
Albumin
Chloride
Bicarbonate
Creatinine clearance (Cockcroft-
Gault calculation)
Uric acidb
Lactate dehydrogenase
Urine and seruma pregnancy
human chorionic gonadotropinc,d
Follicle-stimulating hormonea,c,e
Viral serologiesa
hepatitis B surface antigen (HBsAg)
hepatitis C virus (HCV) antibody 
(and RNA if HCV antibody is positive)
Amylasea,f
Lipasea,f
Serum β2 microglobulina
Coagulation
Prothrombin time (PT)
International normalized ratio 
(INR)
Activated partial 
thromboplastin time (aPTT)
TLS Chemistry Panelg
Creatinine
Potassium
Calcium
Inorganic phosphorus
Lactate dehydrogenase
Uric acidb
RNA = ribonucleic acid; TLS = tumor lysis syndrome
a.
Performed only at screening.
b.
At room temperature, rasburicase causes enzymatic degradation of the uric acid in blood/plasma/serum samples 
potentially resulting in spuriously low plasma uric acid assay readings.  The following special sample handling procedure 
must be followed to avoid ex vivo uric acid degradation.  Uric acid must be analyzed in plasma.  Blood must be collected 
into prechilled tubes containing heparin anticoagulant.  Immediately immerse plasma samples for uric acid measurement 
in an ice water bath.  Plasma samples must be prepared by centrifugation in a precooled centrifuge (4°C).  Finally, the 
plasma must be maintained in an ice water bath and analyzed for uric acid within 4 hours of collection.
c.
Females only.
d.
Pregnancy testing is not required for females of nonchildbearing potential.
e.
If needed to determine postmenopausal status.
f.
Repeat if clinically indicated. 
g.
For subjects with t(11;14) and > 50% bone marrow plasma cell infiltration or creatinine clearance < 50 mL/minute, TLS 
laboratory samples should be collected at approximately 6 hours after the first dose with venetoclax.


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Serum Pregnancy Test
Women of childbearing potential must have 2 negative pregnancy tests before initiating therapy.  The 
first serum pregnancy test should be completed 10 to 14 days before the first dose of study drug and 
confirmed within 24 hours before the first dose.  The subject may not receive study drug until the results 
have been verified as negative.  If the first serum pregnancy test is positive, the subject is considered a 
screen failure.  If the first serum pregnancy test is negative, the subject should complete a urine 
pregnancy test to determine eligibility.
If the repeat serum pregnancy test is:
!
positive, the subject is considered a screen failure;
!
negative, the subject can be enrolled into the trial; or
!
borderline, the AbbVie Therapeutic Area Medical Director (TA MD) will be consulted.
If the first serum pregnancy test is borderline, the subject should repeat the test to determine eligibility.
If the repeat serum pregnancy test is:
!
positive, the subject is considered a screen failure;
!
negative, the subject can repeat the serum pregnancy test; or
!
borderline, the AbbVie TA MD will be consulted.
Pregnancy testing is not required for females of nonchildbearing potential.  Determination of 
postmenopausal status will be made during the screening period based on the subject's history.
A pregnant or breastfeeding female will not be eligible for participation or continuation in this study.
Urine Pregnancy Test
Urine pregnancy tests for all women of childbearing potential will be performed at visits indicated in 
Appendix D per recommendations in the pomalidomide package insert10 and venetoclax IB.9  Once on 
treatment, subjects receiving pomalidomide will have subsequent pregnancy tests weekly during the 
first month then monthly thereafter in females with regular menstrual cycles.  For females with irregular 
menstrual cycles, weekly urine pregnancy testing is required for the first month and then every 14 days 
while on pomalidomide, at end-of-treatment, and 14 and 28 days following the last dose of 
pomalidomide.  Additional urine pregnancy tests can be done at any visit, as needed.
If the urine pregnancy test (which is performed at the site) is negative, begin or continue dosing.  If urine 
pregnancy test is positive or indeterminate, withhold dosing and perform a serum pregnancy test.  
Pregnant subjects must discontinue from the study.
Sensitivity of urine test must be ≥ 25 IU/L.  Additional measures may be required per local prescribing 
information.


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Coagulation
Prothrombin time (PT) and activated partial thromboplastin time (aPTT)/international normalized ratio 
(INR) samples will be collected as specified in Appendix D.  The coagulation panel should be repeated on 
Day 1 of each cycle only for subjects taking Vitamin K antagonists or if otherwise clinically indicated.
Viral Serology
Samples will be collected to identify hepatitis B virus (hepatitis B surface antigen [HBsAg]), and hepatitis 
C virus (HCV) (HCV antibody and ribonucleic acid [RNA] if HCV antibody is positive) as listed in Table 3.
Viral serology samples are to be collected and sent to the central laboratory for testing.
Disease Assessment
For all subjects, disease assessments will be performed as outlined in Appendix D.  Disease assessments 
may be performed approximately 7 days before the scheduled visit.
Analysis of serum protein immunofixation, serum protein electrophoresis, serum quantitative 
immunoglobulins, serum free-light chains (FLCs), urine protein immunofixation, urine protein 
electrophoresis, plasmacytoma evaluation (if applicable), skeletal survey, and bone marrow aspirate and 
biopsy will be utilized for disease assessment.  Subjects will be evaluated using the International 
Myeloma Working Group (IMWG) 2016 criteria for disease response and progression.15  All local 
laboratory results must be entered into the eCRF.
Laboratory Tests for Multiple Myeloma
All serum and urine laboratory tests for IMWG assessments must be sent to a certified central 
laboratory and may also be collected and sent to the local laboratory per the investigator's discretion.  
IMWG assessments per protocol should not be made using local laboratory values (except for bone 
marrow and imaging).
Serum protein immunofixation, serum protein electrophoresis, serum quantitative immunoglobulins, 
serum FLCs, urine protein immunofixation, and urine protein electrophoresis may be performed 
approximately 7 days before the scheduled visit day.
Serum Protein Electrophoresis, Serum Protein Immunofixation, Serum Quantitative Immunoglobulins
Blood samples for serum protein electrophoresis, serum protein immunofixation, and serum 
quantitative immunoglobulin testing will be collected as outlined in Table 4.  Serum protein 
electrophoresis and serum immunofixation will be collected for all subjects at baseline and throughout 
the study until progressive disease (PD) or withdrawal of consent, regardless of serum protein 
electrophoresis being measurable or monoclonal-protein (M-protein) presence at baseline.
Importantly, the assessment of serum protein electrophoresis M-protein and serum immunofixation at 
the time of possible VGPR or complete response (CR)/stringent complete response (sCR) is mandatory, 
even in subjects without measurable values at baseline.


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Serum Free Light Chains
Blood samples for serum FLC testing will be collected for all subjects as outlined in Table 4.
Subjects with measurable disease in either serum protein electrophoresis and/or urine protein 
electrophoresis will be assessed for response only based on these 2 tests and not by the FLC assay.  FLC 
response criteria are only applicable to subjects without measurable disease in the serum or urine 
protein electrophoresis and to fulfill the requirements of sCR or CR per IMWG criteria.15
Urine Protein Immunofixation and Urine Protein Electrophoresis, 24-Hour Urine
Urine samples (24-hour) for urine protein immunofixation and urine protein electrophoresis for 
M-protein testing will be collected for all subjects as outlined in Table 4.  Urine protein electrophoresis 
and urine immunofixation will be collected for all subjects at baseline and throughout the study until PD 
or withdrawal of consent, regardless of urine protein electrophoresis being measurable or M-protein 
presence at baseline.
Importantly, assessment of urine protein electrophoresis M-protein and urine immunofixation at the 
time of possible very good partial response (VGPR) or CR/sCR is mandatory, even in subjects without 
measurable values at baseline.
Subjects with measurable disease at baseline by serum protein electrophoresis and urine protein 
electrophoresis must be followed by both serum protein electrophoresis and urine protein 
electrophoresis assessment of M-protein for response assessment.
Skeletal Survey
Skeletal survey using conventional radiography will be done at screening.  Historical skeletal survey 
results obtained within 30 days before the first dose may be used for screening. A skeletal survey will be 
comprised of the following:
!
lateral radiograph of skull
!
antero-posterior and lateral views of the spine
!
antero-posterior views of pelvis, ribs, femora, tibiae, fibulae, humeri, ulnae, and radii
Skeletal surveys should be completed as outlined in Table 4.  The same radiological method should be 
used throughout the study (x-ray, conventional or low dose computed tomography [CT] scan, positron 
emission tomography [PET]-CT [CT component only], or magnetic resonance imaging [MRI]).  After the 
screening procedure, the skeletal survey should be done while on study only if clinically indicated.  The 
number and location of skeletal and lytic lesions should be recorded on the eCRF.  While the subject is 
on treatment, survey (if done) should record any changes to the number or size of lytic lesions as well as 
the number and location of any new skeletal or lytic lesions.  Changes in measurable lesions over the 
course of therapy will be assessed using IMWG criteria (Appendix F).15


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Plasmacytoma Evaluation
Plasmacytoma evaluation via physical examination or imaging (if clinically indicated) should be 
completed as outlined in Table 4.
CT, PET-CT (CT component only), or MRI (same radiological method should be used throughout study if 
possible) should be performed in all subjects if clinically indicated at baseline to assess for the presence 
of extramedullary plasmacytoma.  To minimize unnecessary radiation in myeloma subjects where 
progression is primarily based on serum and urine M-protein, on-study assessments should only be 
performed if clinically indicated (e.g., pain, concern for disease progression), whether or not present at 
baseline, to confirm minimal response (MR) or better if plasmacytoma present at baseline, and at the 
time of CR/sCR assessment.
A sum of the products of the longest diameters and longest perpendicular diameter for all measurable 
lesions will be calculated at baseline.  This sum will be used as the reference for on-study assessments 
by which to characterize the objective tumor response.
All documented measurable lesions are to be followed throughout the trial.  All assessments to be used 
for tumor response evaluation, including the baseline assessment, must be performed using the same 
method for repeat assessment.  CT and MRI scanning are the preferable methods of assessment.  
Conventional CT and MRI should be performed with contiguous cuts of 10 mm or less or with cuts of 
5 (or 10) mm if spiral CT scanning is used.  Imaging-based evaluation is preferred to evaluation by clinical 
examination.  Evaluation by chest x-ray is less preferable than CT or MRI, and should only be used for 
well-defined lesions surrounded by aerated lung.  Clinical examination is only acceptable when lesions 
are superficial such as a skin nodule or palpable lymph node and the measurements must be properly 
documented.  Ultrasound is not acceptable for documentation of measurable disease.
Duplicate copies of all imaging studies used for tumor response evaluation will be made available for 
review by AbbVie or designee upon request.
Measurable disease are lesions that can be accurately measured in 2 dimensions and both diameters 
must be ≥ 20 mm when evaluated by standard CT scanning or ≥ 10 mm when evaluated by spiral CT 
scanning.  Nonmeasurable disease are all other lesions (or sites of disease), including those that are too 
small (i.e., do not meet above criteria), occur within a previously irradiated area (unless they are 
documented as new lesions since the completion of radiation therapy), bone lesions, leptomeningeal 
disease, ascites, pleural or pericardial effusion (exception for effusions documented by cytology as not 
malignant or present at baseline without progression), lymphangitis cutis/pulmonis, abdominal masses 
that are not pathologically/cytologically confirmed and followed by imaging techniques, and cystic 
lesions.
Bone Marrow Aspirate and Biopsy
Bone marrow aspirate and biopsy should be completed as outlined in Table 4.  Bone marrow aspirates 
and biopsies performed as standard of care throughout the study should also be captured on an eCRF.
A sufficient bone marrow aspirate or biopsy must be collected for clinical assessment (pathology) 
performed by central laboratory as well as for shipment of a portion to AbbVie (or designee) for the 
biomarker analyses.  Samples should be assessed for IWMG first, then split for biomarker analysis.


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Assessment of bone marrow for percentage plasma cells is required within 21 days before the first dose 
for baseline assessment (screening visit) and while on study to confirm CR (i.e., subjects who become 
immunofixation negative) or at time of suspected disease progression, if clinically indicated.
Bone marrow plasma cell clonality must also be evaluated at the time of CR (< 5% plasma cells) to assess 
for sCR, if applicable.  Flow cytometry is preferred over immunohistochemistry (IHC) for assessment of 
clonality by κ and λ staining.  Flow cytometry will be performed only to assess for sCR locally per 
institution standard practice.  If local flow cytometry to assess clonality is not available at the time of CR, 
a core biopsy and/or clot section should be evaluated by IHC staining for κ or λ or light chain restriction.  
To confirm a CR, a second confirmation bone marrow analysis for CR is not needed.
A bone marrow aspirate collection is mandatory at screening and to confirm sCR/CR.  At screening, fresh 
samples should be obtained within 21 days before first dose of study drug and, when possible, should be 
obtained after all other eligibility criteria have been met.  A bone marrow aspirate is optional at time of 
treatment completion or disease progression.
Bone marrow core biopsy (fixed formalin paraffin embedded [FFPE] core) should be also collected, 
unless not recommended per institutional guidelines.  However, a bone marrow biopsy is mandatory in 
the circumstance that an aspirate sample is not available (e.g., due to a dry tap).  Fresh biopsies are 
preferred but archived tissue is acceptable if representative of current disease and if collected within 
the previous 12 weeks without intervening treatment.  Core block or tissue slides are acceptable.  Bone 
marrow core biopsies are optional to confirm sCR, CR, or at the time of treatment completion or disease 
progression.


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Table 4.
Assessments for IMWG Response Criteria
Screening
Cycle 1, Day 1a
Day 1 of each 
Subsequent 
Cycle
Response 
Confirmation (sCR, 
CR, or VGPR)
End-of-
Treatment
Serum protein 
electrophoresis
X
X
X
X
X
Serum protein 
immunofixation
X
X
X
X
X
Serum quantitative 
immunoglobulins
X
X
X
X
Serum free light chain
X
Xb
Xb
X (CR/sCR only)
Xb
Urine protein 
immunofixation
X
X
X
Xc
Xc
Urine protein 
electrophoresis
X
X
X
Xc
Xc
Skeletal survey
X
If clinically indicated.
Plasmacytoma evaluation
If clinically
indicated.
Performed during treatment only to confirm a minimal response or 
better, or to confirm progressive disease, or as clinically indicated.
Bone marrow aspirate and 
biopsy
X
X (sCR or CR only)
Xd
CR = complete response; sCR = stringent complete response; IMWG = International Myeloma Working Group; 
M-protein = monoclonal-protein; VGPR = very good partial response
a.
For Cycle 1, Day 1, screening results or assessments may be used if done within 7 days of Cycle 1, Day 1.
b.
Collect only for subjects without measurable M-protein in screening serum or urine.
c.
Urine protein electrophoresis and urine immunofixation collection is mandatory for confirmation of VGPR, CR, and sCR, 
regardless of whether urine M-protein was measurable at baseline.
d.
Collection of bone marrow sample at progressive disease or end of treatment visit is optional.
Note:
Samples will be collected on the days indicated with a window of approximately 7 days before the scheduled visit.
Source:  Kumar 2016.15
IMWG Criteria for Response and Progression
Subjects will be assessed for response using the 2016 IMWG response criteria (Appendix F).15  Disease 
status categories include sCR, CR, VGPR, partial response (PR), MR, stable disease (SD), and PD.
All response categories (i.e., sCR, CR, VGPR, PR, MR, and PD) require 2 consecutive assessments for 
confirmation and can be made at any time before the institution of any new therapy (no minimum 
interval is required and assessments can be done the same day).  However, to confirm response or PD, 
2 discrete samples are required and testing cannot be based on the splitting of a single sample.  Only 
1 bone marrow assessment is required.  All response categories sCR, CR, VGPR, PR, MR, and SD 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, unless plasmacytoma is 


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present at baseline.  Any soft tissue plasmacytoma documented at baseline must undergo serial 
monitoring as per Table 4.
Subjects with measurable disease in both serum and urine at study entry are required to meet response 
criteria in both serum and urine to qualify for an MR or better.  The overall assigned level of response is 
determined by the lowest level of response.  However, criteria for PD only need to be met and 
confirmed in 1 parameter (serum or urine).
Additional Notes on Specific Response Categories
Stringent Complete Response:  Serum and urine M-protein testing is required to fulfill requirements of 
sCR regardless of whether disease at baseline was measurable on serum, urine, both, or neither.
Complete Response:  Serum and urine M-protein testing is required to fulfill requirements of CR 
regardless of whether disease at baseline was measurable on serum, urine, both, or neither.
It is not essential to perform a bone marrow core biopsy, but if a core biopsy is performed this must also 
contain < 5% plasma cells.
Very Good Partial Response:  Serum and urine M-protein testing is required to fulfill requirements of 
VGPR regardless of whether disease at baseline was measurable on serum, urine, both, or neither.
Minimal Response:  The MR category does not apply for subjects whose disease is only measurable by 
FLC.
Stable Disease:  Subjects should be categorized as SD until they meet the criteria for any response 
category (sCR, CR, VGPR, and PR) or have PD.
Progressive Disease:  Two consecutive assessments for confirmation of PD made at any time before the 
start of new therapy are required per IMWG criteria (Appendix F).  The second assessment may be taken 
immediately if PD is suspected.  If PD is suspected by rising serum or urine M-protein (or FLC in subjects 
without measurable disease), 2 consecutive assessments from central laboratory readings should be 
obtained.
If PD is suspected by clinical symptoms, a plasmacytoma evaluation and/or skeletal survey should be 
obtained, as clinically indicated, and compared with baseline assessments to determine whether a new 
bone lesion or plasmacytoma has developed or an existing lesion or plasmacytoma has worsened.  
Serum and urine protein electrophoresis are also required.
The following assessments are not sufficient to determine PD:
!
Rising serum FLC if disease is measurable in the serum, urine, or both.
!
Serum FLC can be used to determine PD according to the IMWG criteria only for subjects 
without measurable serum and urine M-protein.
!
Clinical relapse based on indicators that are not part of the IMWG criteria for PD (e.g., decrease 
in hemoglobin, hypercalcemia, increase in serum creatinine, hyperviscosity), and relapse from 
clinical relapse categories should not be considered PD.


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!
General worsening of the subject's condition.  If a subject's condition has deteriorated to a point 
that remaining on protocol therapy is not an option, every effort should be made to document 
PD by at least one of the following assessments prior to the initiation of new therapy:  serum 
protein electrophoresis, urine protein electrophoresis, bone marrow biopsy, plasmacytoma 
evaluation, or skeletal survey.
Investigators are requested not to discontinue subjects from treatment for presumed lack of response 
after only 1 cycle of study treatment.
Clinical Relapse:  Clinical relapse is defined per IMWG criteria (Appendix F) and cannot be used to 
determine PD.
Evaluation of Disease
IMWG assessments will be reviewed by the investigator per the IMWG criteria (Appendix F).  If the 
investigator confirms that the subject meets the criteria for PD by 2 consecutive assessments, the 
subject will be deemed as having met an event of disease progression.  For the purposes of this study, 
the date of progression will be the date on which the IMWG assessments were obtained.
Biomarker Sampling
Biospecimens (blood, plasma, serum, bone marrow aspirates, and bone marrow core biopsies) will be 
collected to support the biomarker research objectives of the study.  Refer to Table 5 for the schedule of 
mandatory and optional biomarker research sample collections.  Assessments may include, but are not 
limited to, biomarkers related to the pathway(s) targeted by the study drug or those believed to be 
related to the disease(s) being studied.  The information learned from analyzing these samples may be 
used to investigate factors influencing response to treatment, scientific questions related to MM, and/or 
in the development of new therapies and diagnostic tests.
Evaluations may include B-cell lymphoma (BCL)-2 family member expression, immune cell phenotyping 
and quantification, T-cell clonality, chromosomal abnormalities (immunoglobulin [Ig]H translocations, 
amplifications, or deletions), and/or minimal residual disease (MRD) negativity.  Plasma and serum 
samples may be analyzed for mutational status of circulating tumor deoxyribonucleic acid (DNA) and 
measurement of relevant cytokine, chemokine, matrix metalloproteinases, and markers of bone 
turnover (formation/resorption).  The analyses of tumor tissue/cells may include but are not limited to 
IHC- and quantitative polymerase chain reaction (qPCR)-based assays for BCL-2 family members or other 
nucleic acids or proteins that may regulate the expression of these molecules.  Gene sequencing- and 
hybridization-based techniques may also be used on any of the above specimens for exploratory 
research.  MRD negativity in bone marrow aspirates will be defined at 10–5 threshold as assessed by 
next-generation sequencing in subjects at the time of suspected CR/sCR, and at 6 and 12 months post-
confirmation of CR/sCR for subjects who maintained this response.  Additionally, exploratory analysis of 
MRD negativity at the 10–4 and 10–6 thresholds may be performed.  The samples may be analyzed as part 
of a multistudy assessment of factors influencing the subjects' response to the study drugs (or drugs of 
the same or similar class) and/or progression of the subjects' disease-related conditions.  The 
information obtained from analyzing these samples may be used to investigate factors influencing 
response to treatment, scientific questions related to MM, and/or the development of new therapies 


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and diagnostic tests, or technologies.  The results from these analyses may not be included with the 
clinical study report.
Blood samples may also be sequenced and data analyzed for genetic factors contributing to the disease 
or to the subject's response to venetoclax, pomalidomide, or other study treatment in terms of 
pharmacokinetics (PK), efficacy, tolerability, and safety.  Such genetic factors may include genes for drug 
metabolizing enzymes, drug transport proteins, genes within the target pathway, genes believed to be 
related to the disease or to drug response.  Some genes currently insufficiently characterized or 
unknown may be understood to be important at the time of analysis.  The results are exploratory in 
nature and may not be included with the clinical study report.
All biomarker samples should be labeled and shipped as outlined in the study-specific laboratory 
manual.  AbbVie (companies working with AbbVie) will store these samples in a secure storage space 
with adequate measures to protect confidentiality.  The samples may be retained while research on 
venetoclax/pomalidomide, or drugs in these classes, or MM and related conditions continues, but for no 
longer than 20 years after study completion, or per local requirement.
Bone Marrow Aspirate Collection
A sufficient bone marrow aspirate must be collected for clinical assessment as well as for biomarker 
analyses.  Priority of the aspirate sample split is as follows:
!
assessment of disease response by IMWG criteria (except at screening)
!
fluorescent in situ hybridization (FISH)
!
gene expression analysis
!
MRD assessment
For all subjects in the study who consent to optional biomarker research, optional bone marrow aspirate 
samples may be collected at end-of-treatment if deemed feasible by the investigator.
Priority of the bone marrow aspirate sample split is as follows:
!
gene expression analysis
!
FISH
Bone Marrow Core Biopsy Tissue Collection
One of the following forms of pretherapy tumor tissue (newly collected tissue or archived tissue) will be 
collected at screening to enable biomarker assessments as outlined in the study objectives:
!
Fresh tumor tissue:  Fresh bone marrow core biopsies performed during screening are preferred 
unless not recommended per institution guidelines.  Tissue should be fixed, decalcified, and 
embedded in paraffin according to institutional procedures.  While sending FFPE blocks is 
preferred, slides prepared by the local pathology laboratory are acceptable and should be 
prepared as described in the study-specific laboratory manual.  In addition, a pathology report 


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with the subject identifying information redacted should be submitted along with the tissue 
sample.
!
Archived bone marrow core biopsy tissue:  The most recent archived diagnostic specimen is 
acceptable provided the sample is representative of the subject's current disease state at the 
time of study entry and within 12 weeks before the first dose of study drug.  While sending FFPE 
blocks is preferred, slides prepared by the local pathology laboratory are acceptable and should 
be prepared and stored as described in the study-specific laboratory manual.  In addition, a 
pathology report with the subject identifying information redacted should be submitted along 
with the tissue sample.
For all subjects in the study who consent to optional biomarker research, optional bone marrow core 
biopsy samples may be collected at end-of-treatment (prior to the initiation of a new antimyeloma 
treatment) if deemed feasible by the investigator.  While sending FFPE blocks is preferred, slides 
prepared by the local pathology laboratory are acceptable and should be prepared and stored as 
described in the study-specific laboratory manual.  In addition, a pathology report with the subject 
identifying information redacted should be submitted along with the tissue samples.
Optional Biomarker Research Sample
Optional whole blood samples for pharmacogenetics (DNA and RNA) will be collected on Cycle 1 (Day 1), 
Cycle 3 (Day 1), and end-of-treatment from each subject who consents to optional biomarker analysis.


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Table 5.
Schedule of Biomarker Research Sample Collections
Samples
Biomarker
Screen
Cycle 1, 
Day 1
Cycles 2 
– 5 and 
9, Day 1
Response 
Confirm of 
sCR/CR
6 Months 
Post Confirm 
of sCR/CR
12 Months 
Post Confirm 
of sCR/CR
End-of-
Treatment
Mandatory Peripheral Blood Collections
Peripheral 
Blood
Immuno-
phenotyping 
(4 mL)
Predose Predose
X
Peripheral 
Blood
Immuno-
sequencing (4 mL)
Predose Predose
X
Peripheral 
Blood
Serum markers 
(3.5 mL)
Predose Predose
X
Peripheral 
Blood
Plasma markers 
(3 mL)
Predose Predose
X
Mandatory and Optional Bone Marrow Collections
Bone 
marrow 
aspirate
Gene expression 
(12 mL)
X
X 
(optional)
Bone 
marrow 
aspirate
MRD assessment 
(3 mL)
X
Xa
Xb
Xb
Bone 
marrow 
aspirate
FISH 
(3 mL)
X
X 
(optional)
Bone 
marrow 
core biopsyc
IHC (FFPE blocks 
or slides)
X
X
X 
(optional)
Optional Peripheral Blood Collections (Expansion Phase only)
Peripheral 
blood
PGx DNA/RNA 
(6.5 mL)
X
X 
(Cycle 3 
only)
X
CR = complete response; DNA = deoxyribonucleic acid; FFPE = formalin fixed parafin embedded; FISH = fluorescent in situ 
hybridization; IHC = immunohistochemistry; MRD = minimal residual disease; PGx = pharmacogenetics; RNA = ribonucleic acid; 
sCR = stringent complete response
a.
Only for subjects who are suspected to have a CR/sCR.
b.
For subjects who achieve a CR/sCR and continue to have this response, a bone marrow aspirate will be collected at 
6 months and 12 months post-confirmed CR/sCR.
c.
Unless not recommended per institutional guidelines.  A bone marrow biopsy is mandatory in the circumstance that an 
aspirate sample is not available (e.g., due to a dry tap).




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Venetoclax Samples
Disposition of Samples
Whole blood will be collected into appropriately labeled tubes and processed as outlined in the most 
current version of Study M16-085 laboratory manual.  An inventory of the samples included will 
accompany the package.  Arrangements will be made with AbbVie for the transfer of samples to:
Attn:  AbbVie Sample Receiving
c/o:  Delivery Services
1150 S Northpoint Blvd
Waukegan, IL 60085
Phone:
Fax:
Email:
Measurement Method
Plasma concentrations of venetoclax will be determined by the bioanalysis department at AbbVie using 
a validated method.  Plasma concentration of possible venetoclax metabolite(s) may be determined 
with validated or nonvalidated methods.
Pomalidomide Samples
Disposition of Samples
Whole blood will be collected into appropriately labeled tubes and processed as outlined in the most 
current version of Study M16-085 laboratory manual.  An inventory of the samples included will 
accompany the package.  Arrangements will be made with inVentiv Health Clinique, Inc. for the transfer 
of samples to:
Attn:  Sample Receiving
inVentiv Health Clinique, Inc.
2500 Rue Einstein
Québec (Québec), Canada G1P 0A2
Phone:
(418) 527-4000
Fax:
Email:
Measurement Method
Plasma concentrations of pomalidomide will be determined using a validated method under the 
supervision of bioanalysis department at AbbVie.


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APPENDIX F. IMWG RESPONSE CRITERIA FOR MULTIPLE 
MYELOMA (2016)
Response Subcategory
Response Criteriaa
Stringent complete 
response*
!
Negative immunofixation on the serum and urine (regardless of whether disease 
at baseline was measurable in serum, urine, both, or neither) and
!
Disappearance of any soft tissue plasmacytomas and
!
< 5% plasma cells in bone marrowb and
!
Normal FLC ratio** and
!
Absence of clonal cells in bone marrowb by immunohistochemistry (κ/λ ratio 
≤4:1 or ≥ 1:2 for κ and λ patients, respectively, after counting ≥ 100 plasma cells)c
Complete response*,c
!
Negative immunofixation on the serum and urine (regardless of whether disease 
at baseline was measurable on serum, urine, both, or neither) and
!
Disappearance of any soft tissue plasmacytomas and
!
< 5% plasma cells in bone marrowb and
!
For subjects in whom the only measurable disease is by serum FLC levels, a 
normal FLC ratio** is also required
Very good partial 
response*
!
Serum and urine M-protein detectable by immunofixation but not on 
electrophoresis or
!
≥ 90% reduction in serum M-protein plus urine M-protein < 100 mg per 24 hours
!
For subjects in whom the only measurable disease is by serum FLC levels, VGPR is 
defined as:
!
≥ 90% decrease in the difference between involved and uninvolved FLC 
levels
Partial response
!
≥ 50% reduction of serum M-protein and
!
Reduction in 24-hour urinary M-protein by ≥ 90% or to < 200 mg per 24 hours
!
If the serum and urine M-protein are unmeasurable,d a ≥ 50% decrease in 
the difference between involved and uninvolved FLC levels is required in 
place of the M-protein criteria
!
If the serum and urine M-protein are unmeasurable,d and serum-free light 
assay is also unmeasurable, a ≥ 50% reduction in plasma cells is required in 
place of M-protein provided baseline bone marrow plasma-cell percentage 
was ≥ 30%
!
≥ 50% reduction in the size of soft tissue plasmacytomas is also required, if 
present at baseline
Minimal response
!
25% – 49% reduction of serum M-protein and
!
50% – 89% reduction in 24-hour urinary M-protein and
!
≥ 50% reduction in the size (SPD)f of soft tissue plasmacytomas if present at 
baseline


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Response Subcategory
Response Criteriaa
Stable diseasee
!
Not meeting criteria for CR, VGPR, PR, MR or progressive disease
Progressive disease
!
Any one or more of the following criteria:
!
Increase of 25% from lowest confirmed response value in one or more of the 
following criteria:
!
Serum M-protein (absolute increase must be ≥ 0·5 g/dL);
!
Serum M-protein increase ≥ 1 g/dL, if the lowest M-component was 
≥5 g/dL;
!
Urine M-protein (absolute increase must be ≥ 200 mg/24 hr);
!
In patients without measurable serum and urine M-protein levels, the 
difference between involved and uninvolved FLC levels (absolute increase 
must be > 10 mg/dL);
!
In patients without measurable serum and urine M-protein levels and 
without measurable involved FLC levels, bone marrow plasma-cell 
percentage irrespective of baseline status (absolute increase must be 
≥10%);
!
Appearance of a new lesion(s), ≥ 50% increase from nadir in SPDf of 
> 1 lesion, or ≥ 50% increase in the longest diameter of a previous lesion 
> 1 cm in short axis;
!
≥ 50% increase in circulating plasma cells (minimum of 200 cells/μL) if this is the 
only measure of disease
Clinical relapse
!
Clinical relapse requires one or more of the following criteria: 
!
Direct indicators of increasing disease and/or end organ dysfunction (CRAB 
features) related to the underlying clonal plasma-cell proliferative disorder.  
It is not used in calculation of time-to-progression or progression-free 
survival but is listed as something that can be reported optionally or for use 
in clinical practice;
!
Development of new soft tissue plasmacytomas or bone lesions 
(osteoporotic fractures do not constitute progression);
!
Definite increase in the size of existing plasmacytomas or bone lesions.  A 
definite increase is defined as a 50% (and ≥ 1 cm) increase as measured 
serially by the SPDf of the measurable lesion;
!
Hypercalcemia (> 11 mg/dL);
!
Decrease in hemoglobin of ≥ 2 g/dL not related to therapy or other non-
myeloma-related conditions;
!
Rise in serum creatinine by 2 mg/dL or more from the start of the therapy 
and attributable to myeloma;
!
Hyperviscosity related to serum paraprotein
CR = complete response; CRAB = calcium elevation, renal failure, anemia, lytic bone lesions; CT = computed tomography; 
FLC = free-light chain; IMWG = International Myeloma Working Group; M-protein = monoclonal-protein; MR = minimal 
response; MRI = magnetic resonance imaging; PET = positron emission tomography; PR = partial response; SPD = sum of the 
products of the maximal perpendicular diameters of measured lesions; VGPR = very good partial response


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a.
All response categories require 2 consecutive assessments made at any time before the institution of any new therapy; all 
categories also require no known evidence of progressive or new bone lesions or extramedullary plasmacytomas if 
radiographic studies were performed.  Radiographic studies are not required to satisfy these response requirements.
b.
Confirmation with repeat bone marrow biopsy not needed.
c.
Presence/absence of clonal cells on immunohistochemistry is based upon the k/λ ratio.  An abnormal k/λ ratio by 
immunohistochemistry requires a minimum of 100 plasma cells for analysis.  An abnormal ratio reflecting presence of an 
abnormal clone is k/λ of > 4:1 or < 1:2.
d.
Measurable disease is defined as meeting at least one of the following 3 measurements:  serum M-protein ≥ 1 g/dL 
(≥10 g/L) or urine M-protein ≥ 200 mg/24 hours or serum FLC assay with an involved FLC level ≥ 10 mg/dL (≥ 100 mg/L) 
provided serum FLC ration is abnormal.
e.
Not recommended for use as an indicator of response; stability of disease is best described by providing the time to 
progression estimates.
f.
Plasmacytoma measurements should be taken from the CT portion of the PET/CT, or MRI scans, or dedicated CT scans 
where applicable.  For patients with only skin involvement, skin lesions should be measured with a ruler.  Measurement of 
tumor size will be determined by the SPD.
Notes:
*
Clarification to IMWG criteria for coding CR and VGPR in subjects whom the only measurable disease is by serum FLC 
levels.  In these subjects, CR is defined as a normal FLC ratio of 0.26 to 1.65 in addition to CR criteria listed above, and 
VGPR is defined as a ≥ 90% decrease in the difference between involved and uninvolved FLC levels.
**
Serum and urine M-protein testing is required to fulfill requirements of VGPR and CR categories regardless of whether 
disease at baseline was measurable in serum, urine, both, or neither.


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APPENDIX G. TUMOR LYSIS SYNDROME CLASSIFICATION
Metabolic 
Abnormality
Criteria for Classification of Laboratory 
Tumor Lysis Syndrome*
Criteria for Classification of Clinical 
Tumor Lysis Syndrome**
Hyperuricemia
Uric acid > 8.0 mg/dL (475.8 μmol/L)
Not applicable
Hyperphosphatemia
Phosphorus > 4.5 mg/dL (1.5 mmol/L)
Not applicable
Hyperkalemia
Potassium > 6.0 mmol/L
Cardiac dysrhythmia or sudden death 
probably or definitely caused by 
hyperkalemia
Hypocalcemia
Corrected calcium < 7.0 mg/dL 
(1.75 mmol/L) or ionized calcium 
< 1.12 mg/dL (0.3 mmol/L)#
Cardiac dysrhythmia, sudden death, 
seizure, neuromuscular irritability 
(tetany, paresthesias, muscle twitching, 
carpopedal spasm, Trousseau's sign, 
Chvostek's sign, laryngospasm, or 
bronchospasm), hypotension, or heart 
failure probably or definitely caused by 
hypocalcemia
Acute kidney injury!
Not applicable
Increase in the serum creatinine level of 
0.3 mg/dL (26.5 μmol/L) or the presence 
of oliguria (average urine output 
< 0.5 mL/kg/hr for a 6-hour period)
*
Laboratory TLS requires 2 or more metabolic abnormalities must be present during the same 24-hour period within 3 days 
before the start of therapy or up to 7 days afterward.
**
Clinical TLS requires the presence of laboratory TLS plus one or more findings from the clinical TLS list.
#
Corrected calcium = measured calcium level in mg/dL + 0.8 × (4 – albumin in g/dL).
!
Acute kidney injury, unless attributable to another cause, represents clinical TLS even if criteria for laboratory TLS are not 
satisfied.
*
Not directly or probably attributable to the therapeutic agent.
Source:  Howard SC, Jones DP, Pui CH.  The tumor lysis syndrome.  N Engl J Med.  2011;364(19):1844-54.








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APPENDIX I.
RECOMMENDED DOSE REDUCTIONS RELATED 
TO DRUG TOXICITIES AND USE WITH 
CONCOMITANT MEDICATIONS
If a subject reports taking any over-the-counter or prescription medications, vitamins and/or herbal 
supplements or if administration of any medication becomes necessary from 30 days before the 
screening visit through 30 days after last dose of study drug, the name of the medication, dosage 
information including dose, route, and frequency, date(s) of administration including start and end 
dates, and reason for use must be recorded on the appropriate electronic Case Report Form (eCRF).
Subjects should receive full supportive care during study participation, including transfusion of blood 
products, fluid and electrolyte replacement, and antibiotics when appropriate.  Subjects who use oral 
contraceptives, hormone-replacement therapy, or other maintenance therapy should continue their 
use.  For guidance regarding medications for management of tumor lysis syndrome (TLS) and 
neutropenia, refer to Section 6.4.
General guidelines regarding prohibited, cautionary, and allowed medications are summarized in 
Section 5.3 and Section 5.4.  A sample list of prohibited and cautionary medications that that may 
interact with study drugs is provided in Appendix J.  It is not possible to produce a complete list of 
medications that fall into these categories; if in question, please refer to the appropriate product label.
Concomitant administration of moderate or strong cytochrome P450 (CYP)3A and strong CYP1A2 
inhibitors is prohibited during Part 1 (dose escalation), Cycle 1.  Use of strong or moderate CYP3A 
inhibitors and strong CYP1A2 inhibitors is allowed (with appropriate venetoclax and pomalidomide dose 
reductions, respectively) after Part 1 (dose escalation), Cycle 1 and throughout the study for subjects 
enrolled in Part 2 (dose expansion) if no appropriate therapeutic alternative exists.  Venetoclax dose 
reductions for concomitant administration with moderate or strong CYP3A inhibitors are presented in 
Table 7.  Subjects should be monitored more closely for signs of toxicities and the venetoclax dose may 
need to be further reduced.  Pomalidomide dose reductions for concomitant use with strong CYP1A2 
inhibitors are presented in Table 8.  Subjects should be monitored more closely for signs of toxicities and 
the venetoclax dose may need to be further reduced.  After discontinuation of the CYP3A inhibitor, wait 
for 3 days before venetoclax dose is increased back to the target dose.
Concomitant administration of moderate or strong CYP3A inducers is prohibited during Cycle 1 (dose 
escalation), Part 1.  After completion of Cycle 1 (dose escalation), Part 1, and throughout the study for 
subjects enrolled in Part 2 (dose expansion), concomitant use of moderate or strong CYP3A inducers 
should still be avoided.  Alternative treatments with less CYP3A induction should be considered.
Study drug dose levels are presented in Table 9.  Toxicities related to venetoclax, pomalidomide, and 
dexamethasone are presented in Table 10, Table 11, and Table 12, respectively.


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Table 7.
Dose Modifications for Venetoclax with Concomitant Moderate and Strong 
CYP3A Inhibitor Use
Venetoclax Dose with No 
Moderate or Strong CYP3A 
Inhibitor
Venetoclax Dose if 
Co-Administered with a Moderate 
CYP3A Inhibitor
Venetoclax Dose if 
Co-Administered with a Strong 
CYP3A Inhibitor
400 mg
200 mg
100 mg
600 mg
300 mg
100 mg
800 mg
400 mg
200 mg
CYP = cytochrome P450
Table 8.
Dose Modifications for Pomalidomide with Concomitant Strong CYP1A2 
Inhibitor Use
Assigned Pomalidomide Dose
Pomalidomide Dose if Co-Administered with a Strong CYP1A2 Inhibitor
4 mg
2 mg
CYP = cytochrome P450
The AbbVie Therapeutic Area Medical Director (TA MD) identified in Appendix L should be contacted if 
there are any questions regarding concomitant or prior therapy(ies) and venetoclax or pomalidomide 
dose reductions.
Table 9.
Study Drug Dose Levels
Dose
Venetoclax
Pomalidomide
Dexamethasone
(< 75 years of age)
Dexamethasone 
(≥ 75 years of age)
Starting dose
800 mg
4 mg
40 mg
20 mg
Dose level –1
600 mg
3 mg
20 mg
12 mg
Dose level –2
400 mg
2 mg
12 mg
8 mg
Dose level –3
200 mg
1 mg
8 mg
4 mg


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Table 10.
Toxicities Related to Venetoclax
Toxicities
Recommended Action
Grade 3 or Grade 4 neutropenia with 
infection or fever; or Grade 4 
hematologic toxicities (except for 
lymphopenia)
!
G-CSF or growth factors for neutropenia should be administered 
with venetoclax if clinically indicated.
!
For Grade 4 neutropenia (ANC < 500 cells/μL) without infection, 
anti-infective prophylaxis (e.g., amoxicillin/clavulanic acid or 
levofloxacin or equivalent per institutional guidelines) is 
recommended until the neutropenia improves to Grade 3 or better 
(ANC > 500 cells/μL).
!
First episode:  Interrupt venetoclax and once the toxicity has 
resolved to Grade 1 or baseline level, venetoclax may be resumed 
at the same dose.
!
For subsequent episodes:  Interrupt venetoclax.  Consider using 
G-CSF as clinically indicated.  Follow dose reduction guidelines 
when resuming treatment with venetoclax after resolution.  A 
larger dose reduction may occur at the discretion of the 
investigator and according to the dose reduction guidelines.
Grade ≥3 or serious infections
!
Interrupt venetoclax and upon resolution, treatment can either be 
resumed at a reduced dose (see Table 9) or discontinued, at the 
discretion of the investigator.
Grade 3 or 4 non-hematologic events
!
First episode:  Interrupt venetoclax.  Once toxicity has resolved to 
Grade ≤ 1 or baseline, venetoclax may be resumed at the same 
dose.  No dose modification is required.
!
For subsequent episodes:  Interrupt venetoclax.  Follow dose 
reduction guidelines when resuming treatment with venetoclax 
after resolution.  A larger dose reduction may occur at the 
discretion of the investigator and according to the dose reduction 
guidelines.
Blood chemistry changes or 
symptoms suggestive of TLS
!
Withhold the next day's dose.  If resolved within 24 – 48 hours of 
last dose, resume at the same dose.
!
For any blood chemistry changes requiring more than 48 hours to 
resolve, resume at a reduced dose.
!
For any events of clinical TLS, resume at a reduced dose following 
resolution.
ANC = absolute neutrophil count; G-CSF = granulocyte-colony stimulating factor; TLS = tumor lysis syndrome


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Table 11.
Toxicities Related to Pomalidomide
Toxicity
Recommended Action
Neutropenia:
ANC < 0.5 × 109/L, or febrile 
neutropenia (fever ≥38.5°C and ANC < 
1 × 109/L)
!
Interrupt pomalidomide treatment, follow complete blood 
counts weekly.  Add G-CSF (at discretion of the treating 
physician).
!
ANC returns to ≥ 0.5 × 109/L (or per local guidelines), resume 
pomalidomide treatment at 3 mg/day.
!
For each subsequent drop to < 0.5 × 109/L, interrupt 
pomalidomide treatment.
!
ANC returns to ≥ 1 × 109/L, resume pomalidomide treatment at 
1 mg less than the previous dose.a
Thrombocytopenia:
Platelet count < 25 × 109/L
!
Interrupt pomalidomide treatment for remainder of cycle.
!
Platelet count returns to ≥ 50 × 109/L, resume pomalidomide 
treatment at 1 dose level lower.
Angioedema:
Grade 4 rash, exfoliative or bullous rash
!
Permanently discontinue pomalidomide.
Other Grade 3/4 toxicities judged to be 
related to pomalidomide
!
Interrupt pomalidomide treatment.
!
Restart treatment at 1 dose level lower than the previous dose 
when toxicity has resolved to ≤ Grade 2 at the physician's 
discretion.
ANC = absolute neutrophil count; G-CSF = granulocyte-colony stimulating factor
a.
If adverse reactions occur after dose reductions to 1 mg, then study drug should be discontinued.


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Table 12.
Toxicities Related to Dexamethasone
Toxicity
Recommended Action
Dyspepsia = Grades 1 – 2
Maintain dose and treat with histamine (H2) blockers or 
equivalent.  Decrease by 1 dose level if symptoms persist.
Dyspepsia ≥ Grade 3
Interrupt dose until symptoms are controlled.  Add H2 blocker or 
equivalent and decrease 1 dose level when dose restarted.
Edema ≥ Grade 3
Use diuretics as needed and decrease dose by 1 dose level.
Confusion or mood alteration ≥ Grade 2
Interrupt dose until symptoms resolve.  When dose restarted, 
decrease dose by 1 dose level.
Muscle weakness ≥ Grade 2
Interrupt dose until muscle weakness ≤ Grade 1.  Restart with dose 
decreased by 1 level.
Hyperglycemia ≥ Grade 3
Decrease dose by 1 dose level.  Treat with insulin or oral 
hypoglycemic agents as needed.
Acute pancreatitis
Discontinue dexamethasone treatment regimen.
Other ≥ Grade 3 dexamethasone-related 
adverse events
Stop dexamethasone dosing until adverse event resolves to 
≤Grade 2.  Resume with dose reduced by 1 dose level.




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In addition to the medications listed in this table, subjects receiving venetoclax should not consume 
grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges), or Star 
fruits.  Herbal and natural remedies are to be avoided.


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APPENDIX K. CORTICOSTEROID CONVERSION TABLE
Corticosteroid Conversion Table
Glucocorticoid
Approximate Equivalent Dose (mg)
Short-Acting
Cortisone
25
Hydrocortisone
20
Intermediate-Acting
Methylprednisolone
4
Prednisolone
5
Prednisone
5
Triamcinolone
4
Long-Acting
Betamethasone
0.6 - 0.75
Dexamethasone
0.75
References: 
Dixon JS.  Second-line Agents in the Treatment of Rheumatic Diseases.  Informa Health Care.  1991;456.
Meikle AW, Tyler FH.  Potency and duration of action of glucocorticoids.  Am J of Med.  1977;63(2):200-7.
Webb R, Singer M.  Oxford Handbook of Critical Care.  Oxford; New York:  Oxford University Press, 2005.




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APPENDIX M. PROTOCOL AMENDMENT SUMMARY OF 
CHANGES
Previous Protocol Versions
Protocol
Date
Version 1.0
02 February 2018
Version 2.0
11 June 2018
Version 3.0
15 March 2019
Version 4.0
02 October 2019
The purpose of this amendment is to correct minor clerical errors for consistency and other 
administrative changes throughout the protocol in addition to the following:
!
Rationale:  To update pneumococcal and influenza vaccination requirements in Section 5.4.
!
Updated pneumococcal influenza vaccination requirements to remove requirement for 
re-vaccination if subjects were already vaccinated.
!
Rationale:  To update the list of signatories in Appendix C per current standard operating 
procedure.
!
Replaced 
 and 
 
 with 
 
.
!
Removed 
 as a 
signatory.
!
Rationale:  To delete the progression-free survival follow-up visits.
!
Removed progression-free survival follow-up visits to the Schedule of Activities, Appendix D.
!
Removed the subject criteria for progression-free survival follow-up and the frequency of 
the visits in Appendix E.
!
Rationale:  To delete the survival follow-up assessments.
!
Removed survival follow-up visits to the Schedule of Activities, Appendix D.
!
Removed the survival status activity row to the Schedule of Activities, Appendix D.
!
Removed the summary of the data collected and the frequency for the survival follow-up 
visits in Appendix E.

SAP_001.pdf: 
ABT-199
M16-085 – Statistical Analysis Plan
Version 1.0 – 06 Feb 2018
1
1.0
Title Page
Statistical Analysis Plan
Study M16-085
A Phase 2, Open-Label, Multicenter, Dose-Escalation 
and Expansion Study of Venetoclax and 
Pomalidomide Combination Therapy with 
Dexamethasone in Subjects with Relapsed or 
Refractory Multiple Myeloma
Date:  06 Feb 2018
Version 1.0
NCT03567616


ABT-199
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2.0
Table of Contents
1.0
Title Page ...............................................................................1
2.0
Table of Contents ..................................................................2
3.0
Introduction...........................................................................4
4.0
Study Background.................................................................4
4.1
Objective................................................................................................ 4
4.2
Study Design and Design Diagram ......................................................... 4
4.3
Endpoints ............................................................................................... 6
4.3.1
Primary Efficacy Endpoint ..................................................................... 6
4.3.2
Secondary Efficacy Endpoint ................................................................. 6
4.3.3
Safety Endpoint...................................................................................... 8
4.3.4
Pharmacokinetic Endpoints .................................................................... 8
4.3.5
Biomarker Research Endpoints............................................................... 8
4.4
Sample Size Justification........................................................................ 9
4.5
Interim Analysis................................................................................... 10
5.0
Analysis Populations and Baseline Characteristics...........11
5.1
Analysis Populations ............................................................................ 11
6.0
Efficacy Analyses................................................................. 11
6.1
Primary Efficacy Analysis.................................................................... 11
6.2
Efficacy Analysis ................................................................................. 12
7.0
Safety Analyses.................................................................... 12
7.1
Analysis of Adverse Events.................................................................. 12
7.2
Analysis of Laboratory Data................................................................. 12
7.3
Analysis of Vital Signs and Weight ...................................................... 13
8.0
References............................................................................13
List of Tables
Table 1.
Event and Censoring Dates Used in PFS................................................. 6
Table 2.
Event and Censoring Date Used in TTP.................................................. 7
Table 3.
Event and Censoring Date Used in DOR ................................................ 8
Table 4.
Baseline Characteristics........................................................................ 11


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Table 5.
Dose-Escalation Decision Rules ........................................................... 16
List of Figures
Figure 1.
Study Design Diagram............................................................................ 5
Figure 2.
Interim Analysis Guidelines ................................................................. 10
List of Appendices
Appendix A.
Bayesian Optimal Interval Design ........................................................ 14


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3.0
Introduction
This statistical analysis plan (SAP) serves as a guide for the analysis of the efficacy and 
safety endpoints pertaining to ABT-199 Study M16-085.
Unless noted otherwise, all analyses will be performed using SAS version 9.4 or higher 
(SAS Institute Inc., Cary, NC 27513) in the UNIX operating system.
This SAP will not be updated unless a proposed protocol amendment is expected to 
impact the data analysis.
4.0
Study Background
4.1
Objective
The objective of this study is to determine the safety profile, tolerability, preliminary 
efficacy, recommended Phase 2 dose, and pharmacokinetics (PK) of venetoclax and 
pomalidomide combination therapy with dexamethasone (ven/pom/dex) in subjects with 
relapsed or refractory (R/R) multiple myeloma (MM) who have received ≥ 3 prior lines of 
therapy, including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), or 
who are double-refractory to a PI and an IMiD.
4.2
Study Design and Design Diagram
This is an open-label, multicenter study with two phases, diagrammed in Figure 1.
1.
Dose escalation will consider 6 – 12 subjects confirmed to be t(11;14)+ by an 
analytically-validated FISH assay per central laboratory testing before enrollment.  
Dose escalation will be guided by a Bayesian optimal interval (BOIN) design, 
based on the cumulative number of subjects who experience a DLT at the current 
combination dose.  The subjects will be enrolled in cohorts of at least 3 subjects.  
The first cohort will be administered a 400 mg dose of venetoclax orally, once 
daily (QD).  If acceptable safety and tolerability are observed at the completion of 
Cycle 1 in at least 3 DLT-evaluable subjects, the dose of venetoclax will be 


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5
escalated to 800 mg QD (the target dose).  All subjects will be administered the 
approved dose of pomalidomide (oral 4 mg QD) and dexamethasone (40 mg once 
weekly (qw)).  To be considered DLT-evaluable, subjects must complete at least 
80% of pomalidomide and venetoclax dosing (or experience a DLT) during 
Cycle 1.  DLTs are defined in the operations manual.  Additional information 
regarding the BOIN design is provided in Appendix A.
2.
Dose expansion will consist of 2 independent arms.  Arm A will consider 
t(11;14)+ subjects, and Arm B will consider non-t(11;14) subjects.  All subjects 
who participate in this phase must be screened for t(11;14) translocation status 
before enrollment.  Arm A will feature around 23 subjects and Arm B will feature 
around 27 subjects.  All subjects will receive the ven/pom/dex combination until 
documented PD, unacceptable toxicity, withdrawal of consent, or they meet 
another criteria for discontinuation (see study protocol).  Subjects may discontinue 
pomalidomide but continue receiving venetoclax QD for up to 2 years following 
the date of the last subject enrolled, provided they completed Cycle 1 of 
ven/pom/dex, continue to tolerate venetoclax, do not exhibit PD, and do not meet 
any criteria for discontinuation.  AbbVie will work with the investigator to evaluate 
options for continued venetoclax therapy for subjects that continue to derive benefit 
after 2 years of treatment.
Figure 1.
Study Design Diagram


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4.3
Endpoints
4.3.1
Primary Efficacy Endpoint
The primary efficacy endpoint is the overall response rate (ORR), which is defined as the 
proportion of subjects experiencing a stringent complete response (sCR), complete 
response (CR), very good partial response (VGPR), or partial response (PR).
4.3.2
Secondary Efficacy Endpoint
Key secondary efficacy endpoints include progression-free survival (PFS), duration of 
response (DOR), and time to progression (TTP).  PFS for a given subject is defined as the 
number of days from the date of first dose until the date of the first documented PD or 
death due to any cause, whichever occurs first.  All events of PD will be included, 
regardless of whether the event occurred while the subject was still taking study drug or 
had previously discontinued study drug.  If the subject does not experience PD or death, 
the subject's data will be censored.  See Table 1 for details.
Table 1.
Event and Censoring Dates Used in PFS
Situation
Option for End-Date
Outcome
No baseline assessment
Date of first dose
Censor
PD or death at scheduled 
assessment date or before the next 
scheduled assessment
Date of PD or death (whichever occurs first)
Event
PD or death after exactly one 
missing assessment
Date of PD or death (whichever occurs first)
Event
PD or death after two or more 
missing assessments
Date of first dose (if no adequate assessment is 
available prior to PD/death) or date of the last 
adequate assessment prior to PD/death
Censor
No PD and no death
Date of first dose (if no adequate assessment is 
available) or date of last adequate assessment
Censor
Time to Disease Progression (TTP) for a given subject is defined as the number of days 
from the date of first dose to the date of first documented PD or death due to MM, 


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whichever occurs first.  If the subject does not have an event of PD and the subject has not 
died due to MM, the subject's data will be censored.  See Table 2 for details.
Table 2.
Event and Censoring Date Used in TTP
Situation
Option for End-Date
Outcome
No baseline assessment
Date of first dose
Censor
PD or death due to multiple 
myeloma at scheduled assessment 
date or before the next scheduled 
assessment
Date of PD or death (whichever occurs first)
Event
PD or death due to multiple 
myeloma after exactly one missing 
assessment
Date of PD or death (whichever occurs first)
Event
PD or death due to multiple 
myeloma after two or more missing 
assessments
Date of first dose (if no adequate assessment is 
available prior to PD/death) or date of the last 
adequate assessment prior to PD/death
Censor
No PD and no death due to multiple 
myeloma
Date of first dose (if no adequate assessment is 
available) or date of last adequate assessment
Censor
Duration of Response (DOR) for a given subject is defined as the number of days from 
the date of that subject's first documented response (PR or better) to the date of 
first documented PD or death due to multiple myeloma, whichever occurs first.  If the 
subject with a documented response does not have an event of PD and the subject has not 
died due to MM, the subject's data will be censored.  See Table 3 for details.  Subjects 
who never achieve a documented response will not be included in the analysis of DOR.


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Table 3.
Event and Censoring Date Used in DOR
Situation
Option for End-Date
Outcome
No baseline assessment
Date of first dose
Censor
PD or death due to multiple 
myeloma at scheduled assessment 
date or before the next scheduled 
assessment
Date of PD or death (whichever occurs first)
Event
PD or death due to multiple 
myeloma after exactly one missing 
assessment
Date of PD or death (whichever occurs first)
Event
PD or death due to multiple 
myeloma after two or more missing 
assessments
Date of the last adequate assessment prior to 
PD/death
Censor
No PD and no death due to multiple 
myeloma
Date of the last adequate assessment
Censor
4.3.3
Safety Endpoint
Safety evaluations include adverse event (AE) monitoring, physical examinations, vital 
sign measurements, electrocardiogram (ECG) variables, and clinical laboratory testing 
(hematology, chemistry, and urinalysis) as a measure of safety and tolerability for the 
entire study duration.
4.3.4
Pharmacokinetic Endpoints
PK samples will be collected and analyzed for venetoclax and pomalidomide 
concentrations.  The maximum observed plasma concentration (Cmax), time to Cmax (Tmax), 
and the area under the plasma concentration vs time curve (AUC) will be determined 
using noncompartmental methods.
4.3.5
Biomarker Research Endpoints
Biospecimens (blood, serum, plasma, bone marrow aspirate, and bone marrow core 
biopsy tissue) will be collected at specified time points throughout the study to evaluate 
known or novel disease-related or drug-related biomarkers.  Types of biomarkers 
analyzed may include nucleic acids, proteins, lipids, or metabolites.  Some biomarkers of 


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potential interest can be found in Section 3.2 of this SAP, and any noteworthy results may 
be included in the clinical study report.  Details pertaining to biomarker research 
endpoints can be found in the operations manual.
4.4
Sample Size Justification
Approximately 60 subjects will be enrolled into this two-part study.  Dose escalation will 
enroll around 10 subjects, and dose expansion will enroll around 50 subjects.
1.
Dose Escalation will enroll at least 3 subjects per cohort according to a BOIN 
design, for a total of 6 – 12 subjects. 
2.
Dose Expansion will enroll around 23 subjects in Arm A, and 27 subjects in 
Arm B.
a.
Arm A:  t(11;14)+:  The historical ORR for pom/dex is 35%.1,2  By adding 
venetoclax to this combination, an ORR of 70% is clinically meaningful for 
t(11;14)+ subjects.  Allowing for a maximum one-sided type 1 error rate of 
0.025, and assuming an ORR of 35% from the historical data, 23 subjects will 
provide 90% power if the true ORR for t(11;14)+ subjects treated with 
ven/pom/dex is 70%. 
b. Arm B:  Non-t(11;14):  The historical ORR for pom/dex is 35%.  By adding 
venetoclax to this combination, an ORR of 60% is clinically meaningful for 
non-t(11;14) subjects.  The sample size for Arm B will be approximately 
27 subjects.  Allowing for a maximum one-sided type 1 error rate of 0.1, and 
assuming an ORR of 35% from the historical data, 27 subjects will provide 
90% power if the true ORR for non-t(11;14) subjects treated with ven/pom/dex 
is 60%.


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4.5
Interim Analysis
During the dose escalation phase, review meetings will be conducted at the completion of 
Cycle 1 in at least 3 evaluable subjects per cohort.
Since this is an open-label study, both arms of the dose-expansion phase will be 
continuously monitored.  Interim analysis (IA) may be conducted when adequate data 
from approximately 10 and 16 subjects are available from Arms A and B, respectively.  
Figure 2 displays some guidelines for go/no-go decisions for the IA, broken down by arm. 
Observed ORRs in the green region may be used as evidence to accelerate studies of 
venetoclax in combination with IMiDs to earlier lines of therapy.  Results in the yellow 
region suggest evaluating the depth and duration of response for more guidance.
Arm A:  the probability of making the wrong "go" decision is 2.6%, given a true ORR of 
35%, and the probability of making the wrong "no-go" decision is 1.1%, given a true 
ORR of 70%.  The final analysis for Arm A will include the subjects from the escalation 
portion of the study, resulting in a grand total of around 29 t(11;14)+ subjects.
Arm B:  the probability of making the wrong "go" decision is 2.3%, given a true ORR of 
35%, and the probability of making the wrong "no-go" decision is 1.9%, given a true 
ORR of 60%.
The final go/no-go decision will be based on totality of efficacy and safety data.
Figure 2.
Interim Analysis Guidelines


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5.0
Analysis Populations and Baseline Characteristics
5.1
Analysis Populations
The full analysis set (FAS) includes all subjects who received at least 1 dose of study 
drug.  The FAS will be used for all safety, efficacy, and baseline analyses.
Table 4.
Baseline Characteristics
Variable
Levels
Age
< 65, ≥ 65
Sex
male, female
Race
white, black, Asian, other
Ethnicity
Hispanic, non-Hispanic
Type of myeloma
IgG, IgA, IgD, light chain
Prior lines of therapy
1 – 3, 3 – 6, > 6
Prior therapy with:
!
PI + IMiD
!
PI (bortezomib, carfilzomib, ixazomib)
!
IMiD (thalidomide, lenalidomide, pomalidomide),
!
monoclonal antibody (daratumumab, elotuzumab)
!
stem cell transplant
BCL-2
low, high
ISS stage
I, II, III
ECOG
0, 1, 2, > 2
t(11;14)
positive, negative
t(4;14)
positive, negative
17p deletion
yes, no
13q deletion
yes, no
Hyperdiploid
yes, no
6.0
Efficacy Analyses
6.1
Primary Efficacy Analysis
For ORR, exact (binomial) one-sided tests of H0:  ORR ≤ 35% vs H1:  ORR > 35% at 
significance levels of 0.025 and 0.1 will be performed for Arms A and B, respectively.  


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Point estimates and exact (Clopper-Pearson) 95% confidence intervals of ORR for each of 
the two arms will be calculated.
6.2
Efficacy Analysis
PFS, DOR, and TTP will be analyzed with Kaplan-Meier methodology.  Median PFS, 
DOR, and TTP will be estimated, along with corresponding 95% CIs.
7.0
Safety Analyses
7.1
Analysis of Adverse Events
AE analysis will only include treatment-emergent events (those that have an onset on or 
after the day of the first dose of any study drug), and will not include AEs that have an 
onset of more than 30 days after the last dose of any study drug.
Treatment-emergent AEs will be coded and summarized by system organ class and 
preferred term according to the Medical Dictionary for Regulatory Activities (MedDRA) 
AE coding dictionary.  The percentage of subjects experiencing an AE at a given severity 
will be provided along with the NCI CTCAE version 4.03 toxicity grade and relationship 
to the study drugs.  Serious AEs, AEs leading to discontinuation of treatment, and AEs 
leading to death will be summarized.  All summaries will be done by dose.  For the study 
as a whole, AEs will be evaluated and summarized.
7.2
Analysis of Laboratory Data
Where applicable, laboratory values will be categorized according to the NCI CTCAE 
version 4.03 grades.  Changes from baseline to maximum grades, as well as final post-
baseline grades will be assessed.  The baseline and final grades will be defined as:  the 
grade of the last measurement collected prior to the first dose of any study drug, and the 
grade of the last post-baseline measurement collected no more than 30 days after the last 
dose of any study drug, respectively.  If multiple values are available for a post-baseline 
measurement, then the value with the highest NCI CTCAE grade will be used.


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Detailed listings of data for subjects experiencing NCI CTCAE Grade 3 – 4 blood 
chemistry and hematology values will be provided.  All collected measurements may be 
included in these listings, regardless of the number of days after the last dose of any study 
drug.
7.3
Analysis of Vital Signs and Weight
Detailed listings of data for subjects experiencing potentially clinically significant vital 
sign values (according to the AbbVie-defined criteria) will be provided.  All collected 
measurements may be included in these listings, regardless of the number of days after the 
last dose of any study drug.
8.0
References
1.
Liu S, Yuan Y.  Bayesian optimal interval designs for phase I clinical trials.  
Journal of the Royal Statistical Society:  Series C (Applied Statistics).  
(2015);64(3):507-23.
2.
Richardson PG, Siegel DS, Vij R, et al.  (2014).  Pomalidomide alone or in 
combination with low-dose dexamethasone in relapsed and refractory multiple
myeloma:  a randomized phase 2 study.  Blood.  123(12)1826-32.
3.
San Miguel J, Weisel K, Moreau P, et al.  (2013).  Pomalidomide plus low-dose 
dexamethasone versus high-dose dexamethasone alone for patients with relapsed 
and refractory multiple myeloma (MM-003):  a randomised, open-label, phase 3 
trial.  The Lancet Oncology.  14(11)1055-66.


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Appendix A.
Bayesian Optimal Interval Design
A.1 Methodology
Let ∀denote the pre-specified target toxicity rate.  Let ∆L > 0 and ∆U > 0 be pre-specified 
lower and upper cutoffs, respectively, which satisfy 0 < ∀– ∆L < ∀+ ∆U < 1.  The BOIN 
design consists of determining ∆L and ∆U such that the interval (∀– ∆L, ∀+ ∆U) minimizes 
the probability of incorrect dose assignment decisions.  To determine ∆L and ∆U, consider 
three hypotheses at dose level j: 
H0j:  pj = ∀,  H1j: pj = ∀1,  H2j: pj = ∀2
where pjdenotes the true toxicity rate at dose level j, ∀1 denotes the highest toxicity rate 
that is deemed subtherapeutic such that dose escalation should be made and ∀2 denotes the 
lowest toxicity rate that is deemed overly toxic such that dose de-escalation should be 
made.  Thus, the correct dose assignment decisions under H0j, H1j and H2j are retainment 
(i.e., stay at current dose), escalation and de-escalation, respectively.  
Assuming an equal prior probability of the three hypotheses being true 
(i.e., = Pr(H0j) = Pr(H1j) = Pr(H2j) = 1/3), the optimal interval (∀– ∆L, ∀+ ∆U) which 
minimizes the probability of incorrect dose assignment decisions is given by:
 −Δ =
	
 
 
	
 ()
()  and   + Δ =
	
  

	
 ()
()
Suppose the current dose is j where j = 1, …,J.  Let ̂ =  
⁄
 denote the estimated 
toxicity rate based on the accumulated information on dose combination j with yj toxicities 
and nj subjects.  Define an admissible dose escalation set as AE = {(j+1))} and an 
admissible dose de-escalation set as AD = {(j–1)}.  Dose assignment decisions under the 
BOIN design proceeds as follows:
1.
Treat the first cohort at the starting dose combination.


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2.
Suppose the current cohort is treated at dose combination j; then for the next cohort 
of patients:
a.
If ̂ ≤ −Δ, escalate to the next higher dose combination that belongs to  .  
If j = J, the current dose combination is retained.
b. If ̂ ≥ + Δ, de-escalate to the next lower dose combination that belongs to 
".  If j = 1, the current dose combination is retained.
c.
Otherwise, if  −Δ < ̂ <  + ∆, the current dose combination is retained.
3.
This process continues until the total sample size is exhausted or the study is 
terminated early due to excess toxicity (as described below).
The BOIN design also imposes the following safety rule: dose combinations which satisfy 
%&' > |* ≥+ are eliminated, where # is a pre-specified threshold probability.  
A.2 Application to Study M16-085
If possible, only the venetoclax dose will be increased.  The pomalidomide and 
dexamethasone doses will be fixed in both available cohorts during the dose escalation 
part of the study.
For Study M16-085, the toxicity rates and safety threshold are pre-specified as follows:
∀= 0.30 (target toxicity rate)
∀1 = 0.6∀(highest toxicity rate which is subtherapeutic)
∀2 = 1.4∀(lowest toxicity rate which is overly toxic)
# = 0.95 (safety threshold for dose combination elimination)
The above pre-specified values yield an optimal interval of (0.236, 0.359).  
Approximately 6 – 12 subjects may be enrolled in cohorts of at least 3.  The 


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corresponding BOIN design decision rules (based on the cumulative number of patients 
who experience a DLT at the current dose combination) are presented in Table 5.
Table 5.
Dose-Escalation Decision Rules
Action
Number of DLT-Evaluable Subjects Treated at Current Combination
3
4
5
6
7
8
9
10
Escalate if number of 
subjects with DLT ≤
0
0
1
1
1
1
2
2
Stay at current 
combination if number 
of subjects with DLT =
1
1
-
2
2
2
3
3
De-escalate if number of 
subjects with DLT ≥
2
2
2
3
3
3
4
4
Eliminatea if number of 
subjects with DLT ≥
3
3
4
4
5
5
5
6
DLT = dose-limiting toxicity
a.
Eliminate current and higher combinations (i.e., venetoclax dose and pomalidomide dose ≥ current dose level).