Conditions: Relapsed/Refractory Multiple Myeloma
Keywords: Relapsed/refractory multiple myeloma Relapsed multiple myeloma Refractory multiple myeloma Multiple myeloma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 291
Healthy volunteers: no

Brief summary:
This was a Phase 3, multicenter, randomized, double blind, placebo-controlled study evaluating the efficacy and safety of venetoclax plus bortezomib and dexamethasone in participants with relapsed or refractory multiple myeloma who are considered sensitive or naïve to proteasome inhibitors and received 1 to 3 prior lines of therapy for multiple myeloma.

Detailed description:

Arms:
arm 1: Cycles 1-8: Venetoclax 800 mg orally every day (QD) on Days 1 - 21 plus bortezomib 1.3 mg/m\^2 subcutaneously or IV on Days 1, 4, 8 \& 11 and dexamethasone 20 mg orally on Days 1, 2, 4, 5, 8, 9, 11 \& 12; Cycles 9 and beyond: Venetoclax 800 mg orally every day (QD) on Days 1 - 35 plus bortezomib 1.3 mg/m\^2 subcutaneously or IV on Days 1, 8, 15 and 22 and dexamethasone 20 mg orally on Days 1, 2, 8, 9, 15, 16, 22 and 23 arm 2: Cycles 1-8: Placebo (to match venetoclax 100 mg tablet) 800 mg orally every day (QD) on Days 1 - 21 plus bortezomib 1.3 mg/m\^2 subcutaneously or IV on Days 1, 4, 8 \& 11 and dexamethasone 20 mg orally on Days 1, 2, 4, 5, 8, 9, 11 \& 12; Cycles 9 and beyond: Placebo (to match venetoclax 100 mg tablet) 800 mg orally every day (QD) on Days 1 - 35 plus bortezomib 1.3 mg/m\^2 subcutaneously or IV on Days 1, 8, 15 and 22 and dexamethasone 20 mg orally on Days 1, 2, 8, 9, 15, 16, 22 \& 23

Interventions: intervention 1: Venetoclax intervention 2: Bortezomib intervention 3: Dexamethasone intervention 4: Placebo for venetoclax
Intervention descriptions: intervention 1: Participants self-administered venetoclax tablets by mouth QD in combination with bortezomib. Venetoclax was to be given before other agents administered on the same day, if applicable. Each venetoclax dose was to be taken all at one time with approximately 240 mL of water within 30 minutes after completion of breakfast or the subject's first meal of the day. Tablets were to be swallowed whole and must not have been broken, chewed, or crushed. On days that pre-dose PK sampling was required, dosing occurred at the clinic to facilitate PK sampling. intervention 2: Bortezomib (subcutaneous injection \[preferred\] or IV) was given following administration of venetoclax or placebo in Cycles 1 -8 on Days 1, 4, 8 and 11, and for Cycles 9 and beyond, on Days 1, 8, 15 and 22 and was to be administered per the prescribing information. The route of administration was to stay the same during the study. intervention 3: Dexamethasone was to be given orally, administered per the prescribing information, the day of bortezomib dosing and the following day, given the protocol-defined dosing window (bortezomib dosing window is ± 1 day) is maintained. If bortezomib was interrupted or a dose is skipped, dexamethasone was to be administered as scheduled per protocol (unless dexamethasone was interrupted due to toxicity). intervention 4: Participants self-administered placebo tablets by mouth QD in combination with bortezomib. Placebo was to be given before other agents administered on the same day, if applicable. Each placebo dose was to be taken all at one time with approximately 240 mL of water within 30 minutes after completion of breakfast or the subject's first meal of the day. Tablets were to be swallowed whole and must not have been broken, chewed, or crushed. On days that pre-dose PK sampling was required, dosing occurred at the clinic to facilitate PK sampling.

Protocol document:
Prot_000.pdf: 
Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
1
1.0
Title Page
Clinical Study Protocol M14-031
A Phase 3, Multicenter, Randomized, Double Blind 
Study of Bortezomib and Dexamethasone in 
Combination with Either Venetoclax or Placebo in 
Subjects with Relapsed or Refractory Multiple 
Myeloma Who are Sensitive or Naïve to Proteasome 
Inhibitors
Incorporating Administrative Change 1 and 
Amendment 0.01 (France Only), Japan Local 
Amendment 1, Global Amendments 1, 2, 3, 4, 5, 6, 7, 
and 8
AbbVie Investigational
  Product:
Venetoclax (ABT-199)
Date:
16 December 2020
Development Phase:
3
Study Design:
This is a Phase 3, multicenter, randomized, double blind, 
placebo-controlled study evaluating the efficacy and safety of 
venetoclax plus bortezomib and dexamethasone in subjects with 
relapsed or refractory multiple myeloma who are considered 
sensitive or naïve to proteasome inhibitors and received 1 to 
3 prior lines of therapy for multiple myeloma.
EudraCT Number:
2015-004411-20
Investigators:
Multicenter Study:  Site Investigator information is on file at 
AbbVie.
Sponsor:
AbbVie*
Collaborative Partners:  Genentech/Roche.
 
NCT02755597




Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
3
1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol 
Date
Original
05 February 2016
Amendment 0.01 (France Only)
24 June 2016
Japan Local Amendment 1
27 May 2016
Global Amendment 1
16 June 2017
Global Amendment 2
15 December 2017
Global Amendment 3
09 March 2018
Global Amendment 4
09 January 2019 
Protocol Administrative Change 1
23 January 2019
Global Amendment 5
15 March 2019
Global Amendment 6
24 September 2019
Global Amendment 7
20 April 2020
The purpose of this amendment is to incorporate necessary protocol modifications due to 
the COVID-19 pandemic, as well as the following:
●
Update Section 1.2, Synopsis; Section 2.0, Table of Contents:
Rationale:  to ensure consistency with information throughout the protocol.
●
Update Section 1.3, List of Abbreviations and Definition of Terms:
Rationale: to add COVID-19, DSUR, DTP, and SARS-CoV-2 abbreviations.
●
Update Section 3.5, Benefits and Risks:
Rationale: to include information on the re-evaluation of the benefit and risk 
to subjects participating in the study related to COVID-19 infection.  Based on 
the population and disease being studied and the anticipation that COVID-19 
related risks are not expected to differ substantially between study subjects and 
the broader population of subjects receiving treatment for multiple myeloma, 
no change to the benefit/risk balance for subjects in this study is expected.
●
Update Section 5.1, Overall Study Design and Plan; Section 5.2.4.1, 
Pretreatment Requirements; Section 5.3.1, Efficacy and Safety Measurements 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
4
Assessed; Section 5.3.1.1, Study Procedures; Section 5.3.1.1.1, Screening and 
Treatment Assessments; Section 5.3.1.1.1, Screening and Treatment 
Assessments – Table 3. Clinical Laboratory Tests; Section 5.3.1.1.2, Follow-
up; Section 5.3.1.3, Collection and Handling of Biomarker and Exploratory 
Research Samples; Section 5.3.7.1, Disease Assessments; Section 5.3.7.3, 
Evaluation of Disease; Section 5.4.1, Discontinuation of Individual Subjects 
from Treatment; Section 5.4.2, Withdrawal from Study Visits; Section 5.5.1, 
Treatments Administered; Section 6.1.5, Adverse Event Reporting; Section 6.2, 
Guidelines for Dose Modifications and Treatment; Section 7.0, Protocol 
Deviations; Section 9.2, Ethical Conduct of the Study; Section 10.1, Source 
Documents; Section 11.0, Data Quality Assurance:
Rationale: to provide COVID-19 pandemic-related acceptable protocol 
modifications.
●
Update Section 5.1, Overall Study Design and Plan: Description; 
Section 5.3.1.1.1, Screening and Treatment Assessments; Section 5.3.1.1.2, 
Follow-up; Section 5.3.7.1, Disease Assessments; Section 5.3.7.1, Disease 
Assessments, Table 4. Assessments for IMWG Response Criteria; 
Section 5.4.1, Discontinuation of Individual Subjects from Treatment; 
Section 5.4.3, Withdrawal from Follow-Up:
Rationale:  the final OS analysis is planned for when approximately 116 OS 
events occur. All objectives specified in the protocol will be completed with the 
final OS analysis and therefore from a statistics/scientific perspective: 1) 
maintaining the study blind is not required 2) all data considered for analysis 
per protocol can be considered mature.
●
Update Section 5.1, Overall Study Design and Plan: Description; Section 5.4.1, 
Discontinuation of Individual Subjects from Treatment; Section 5.5.1, 
Treatments Administered:
Rationale:  to provide treatment flexibility with bortezomib and dexamethasone 
dosing per investigator decision once subjects are unblinded.
●
Update Section 5.1, Overall Study Design and Plan: Description; 
Section 5.3.1.1.1, Screening and Treatment Assessments; Section 5.5.1, 
Treatments Administered; Section 6.1.7.1, Management of Cytopenias and 
Infection; Section 6.2.1, Dose Modifications or Delays for Venetoclax/Placebo 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
5
Toxicities; Section 6.2.2, Dose Modifications for Moderate or Strong CYP3A 
Inhibitors Used with Venetoclax/Placebo:
Rationale:  to provide flexibility and simplify study-related procedures for 
subjects in Arm 2 (Placebo + Bd) at the time of unblinding, as these measures 
may no longer be applicable to them.
●
Update Section 5.1, Overall Study Design and Plan: Description; 
Section 5.5.5.2, Blinding of Data for Independent Data Monitoring Committee 
(IDMC):
Rationale:  once subjects are unblinded and the final OS analysis is complete, 
the IDMC supervision will be complete.  AbbVie will continue to monitor 
subjects' safety.
●
Update Section 5.1, Overall Study Design and Plan; Section 5.3.1.1.2, Follow-
up; Section 5.4.1, Discontinuation of Individual Subjects from Treatment; 
Section 5.4.2, Withdrawal from Study Visits:
Rationale: to provide an updated end of study guidance once the number of 
events required for the final OS analysis is reached, as all protocol specified 
objectives will be complete after the final OS analysis.
●
Update Section 5.1, Overall Study Design and Plan: Description, Figure 1. 
Study Schema:
Rationale: to align with the updated end of study guidance.
●
Update Section 5.3.1.1.1, Screening and Treatment Assessments; Appendix E, 
Schedule of Assessments – Treatment: Cycles 1 – 8:
Rationale: administrative changes.
●
Update Section 5.3.7.1, Disease Assessments; Section 5.3.7.2, IMWG Criteria 
for Response and Progression; Section 5.4.1, Discontinuation of Individual 
Subjects from Treatment:
Rationale: after the unblinding, study subjects who are benefiting from study
treatment will be able to continue in the study as, due to the partial clinical 
hold, they are not able to be rolled over into an extension study.
●
Update Section 5.3.7.1, Disease Assessments:
Rationale: to inform that imaging scans are no longer required to be sent to 
an independent central imaging vendor because 1) the planned primary 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
6
progression free survival analysis was completed at the first interim analysis; 
2) the primary progression free survival/response data is considered mature 
with no further changes expected.
●
Update Section 5.5.5.3, Unblinding Process:
Rationale: since objectives specified in the protocol will be completed with the 
final OS analysis and, from a statistics/scientific perspective, keeping the study 
blinded following the final OS analysis is not needed, the study can be 
unblinded once final OS analysis is complete.
●
Update Section 6.1.5, Adverse Event Reporting; Section 10.1, Source 
Documents; Section 11.0, Data Quality Assurance; Appendix N, Protocol 
Amendment:  List of Changes:
Rationale:  to align with the current templated standard language.
●
Update Section 13.0, Completion of the Study:
Rationale:  to define Last Subject Last Visit at the time the number of OS events 
required for the final OS analysis is reached.
●
Update Appendix B, List of Protocol Signatories:
Rationale:  to reflect current list of protocol signatories.
●
Update Appendix E, Schedule of Assessments – Treatment: Cycles 1 – 8; 
Appendix F, Schedule of Assessments – Treatment: Cycles 9 and Beyond 
Through Treatment Completion Visit; Appendix G, Schedule of Assessments –
Follow-up; Appendix I, Sample List of Excluded and Cautionary Medication:
Rationale:  to align with protocol changes and intended study visits.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
7
1.2
Synopsis
AbbVie Inc.
Protocol Number:  M14-031
Name of Study Drug:  Venetoclax (ABT-199)
Phase of Development:  3
Name of Active Ingredient:  Not available 
Date of Protocol Synopsis:  16 December 2020
Protocol Title:  A Phase 3, Multicenter, Randomized, Double Blind, Study of Bortezomib and 
Dexamethasone in Combination with Either Venetoclax or Placebo in Subjects with Relapsed or
Refractory Multiple Myeloma Who are Sensitive or Naïve to Proteasome Inhibitors
Objectives:  
The primary objective of the study is to compare the progression-free survival (PFS) between treatment 
arms in subjects with relapsed or refractory multiple myeloma who are considered sensitive or naïve to 
proteasome inhibitors and received 1 to 3 prior lines of therapy for multiple myeloma.
The secondary objectives are to compare, between treatment arms, the following:  Very Good Partial 
Response (VGPR) or better response rate; PFS in subjects with high BCL-2 expression; duration of 
response (DOR); Patient Reported Outcomes (PRO) including Worst Pain (Brief Pain Inventory – Short 
Form [BPI-SF]), Physical Functioning and Global Health Status/Quality of Life (GHS/QoL) (European 
Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core [EORTC 
QLQ-C30]), and Fatigue (Patient Reported Outcomes Measurement Information System [PROMIS] 
Cancer Fatigue Short Form [SF]); overall survival (OS); time to disease progression (TTP); objective 
response rate (ORR); minimal residual disease (MRD) negativity rate; and safety.
Investigators:  Multicenter
Study Sites:  Approximately 120 sites
Study Population:  Adult male and female subjects with relapsed or refractory multiple myeloma who 
are considered sensitive or naïve to proteasome inhibitors, have received 1 to 3 prior lines of therapy for 
multiple myeloma, and have measurable disease per International Myeloma Working Group (IMWG) 
criteria.  
Number of Subjects to be Enrolled:  Approximately 280
Methodology:  
This is a Phase 3, multicenter, randomized, double blind, placebo-controlled, parallel group study.  This 
study is designed to evaluate the efficacy and safety of venetoclax plus bortezomib and dexamethasone 
(Bd) in subjects with relapsed or refractory multiple myeloma who are considered sensitive or naïve to 
proteasome inhibitors and have received 1 to 3 prior lines of therapy for multiple myeloma.  The study 
will consist of three phases:  Screening, Treatment, and Follow-Up.
Serum, plasma, bone marrow aspirate and bone marrow core biopsy tissue will be collected for 
biomarker analysis and exploratory research at designated time points throughout the study.
Screening
Unless otherwise specified, screening procedures must be performed within 21 days prior to 
randomization, including disease assessments per the IMWG criteria.  Procedures that are completed as 
standard of care within 7 days prior to consent may be considered for screening.  Laboratory tests not 
meeting eligibility criteria can be repeated during the screening period to confirm eligibility.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
8
Methodology (Continued):
Screening (Continued)
Subjects who do not randomize within 21 days of screening will be screen-failed.
Subjects who are screen-failed may be re-screened one additional time.  Subjects who are re-screened 
will be re-consented.  Re-screened subjects will keep their original screening number and will begin the 
screening period once again.  
Once screening procedures are complete and eligibility is confirmed, subjects will be randomized 2:1 to 
one of the following two arms:

Arm 1:  Venetoclax plus Bd

Arm 2:  Placebo plus Bd
Subjects will be stratified based on prior exposure to bortezomib or other proteasome inhibitors 
(proteasome inhibitor-naïve versus proteasome inhibitor-sensitive) and the number of prior lines of 
therapy (1 versus 2 or 3).
Treatment
During Treatment, all subjects will receive venetoclax/placebo orally (PO) once daily (QD) plus Bd as
follows beginning on Cycle 1 Day 1.  Venetoclax/Placebo and dexamethasone should be taken at the site 
on days when bortezomib is administered (Days 1, 4, 8 and 11 of Cycles 1 – 8, and Days 1, 8, 15 and 22 
of Cycles 9 and beyond).  On all other days, subjects can self-administer venetoclax/placebo QD.  
Dexamethasone can be self-administered on Days 2, 5, 9 and 12 of Cycles 1 – 8 and Days 2, 9, 16 and 23 
of Cycles 9 and beyond.  Delays of up to 7 days in the initiation of a cycle due to toxicity or scheduling 
issues will be allowed.  Unless otherwise noted, cycle visits may be completed within a window of 
± 1 day provided the 72-hour bortezomib requirement is kept.   
Cycles 1 – 8, 21-Day Cycle Length

Venetoclax 800 milligram (mg)/Placebo QD on Days 1 – 21

Bortezomib 1.3 mg/meter (m)2 on Days 1, 4, 8 and 11

Dexamethasone 20 mg on Days 1, 2, 4, 5, 8, 9, 11 and 12
Cycles 9 and Beyond, 35-Day Cycle Length

Venetoclax 800 mg/Placebo QD on Days 1 – 35*

Bortezomib 1.3 mg/m2 on Days 1, 8, 15 and 22**

Dexamethasone 20 mg on Days 1, 2, 8, 9, 15, 16, 22 and 23***
*
Placebo tablet administration will be discontinued for subjects in Arm 2 (Placebo + Bd) once subjects are 
unblinded.
**
Bortezomib dosing frequency may be reduced or discontinued per investigator's decision and institutional 
guidelines once subjects are unblinded.
*** Dexamethasone dosing (frequency and/or dose) may be reduced or discontinued per investigator's decision and 
institutional guidelines once subjects are unblinded.
When unblinding occurs, if subjects from Arm 1 (Venetoclax + Bd) and Arm 2 (Placebo + Bd) are on
dexamethasone monotherapy, they must be discontinued from the study treatment and from the study 
once the Safety Follow-Up Visit is completed.
Study visits will occur on Days 1, 4, 8, and 11 of Cycles 1 – 8.  Study visits during Cycle 9 and beyond 
will occur on Days 1, 8, 15 and 22.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
9
Methodology (Continued):
Treatment (Continued)
Subjects will continue their treatment assignment until documented disease progression per Investigator 
assessment, unacceptable toxicity, withdrawal of consent, or the subject meets other protocol criteria for 
discontinuation (whichever occurs first).  All subjects will have a Treatment Completion Visit (TCV) 
performed when treatment is discontinued unless subject has withdrawn consent to participate in the 
study.
Baseline IMWG assessments will be obtained at Cycle 1 Day 1 prior to first dose of study treatment, 
unless the Screening IMWG assessments were completed within 7 days of Cycle 1 Day 1.  Post-baseline 
IMWG assessments will be performed throughout the study on Day 1 (± 1 week) of every cycle starting 
on Cycle 2 Day 1 and continuing until disease progression per the IMWG criteria, or the subject 
withdraws consent.
In addition to being reviewed by the Investigator and/or qualified site staff, all disease assessment 
information will be sent to an Independent Review Committee (IRC).  Interpretations from the IRC will 
not be sent to the site.
With the completion of the PFS analysis, post-baseline IMWG assessments are no longer required to be 
sent to the IRC and will be reviewed only by the Investigator and/or qualified medical site staff.
Follow-Up
All subjects should have one Safety Follow-Up Visit approximately 30 days after the last dose of study 
treatment.
Subjects who discontinue study treatment for reasons other than progressive disease (e.g., toxicity, 
non-compliance, etc.) or subjects who receive an off protocol new anti-multiple myeloma therapy will 
remain on study and continue to be followed for disease progression per the IMWG criteria every 
4 weeks (± 1 week) following last dose of treatment for the first year, and then every 12 weeks 
(± 1 week) thereafter, until progressive disease (PD) or until the number of Overall Survival (OS) events 
required for the final OS analysis is reached, whichever occurs first.  Subjects who experience an event of 
disease progression or withdraw from study will continue to be followed for survival and post treatment 
information until the number of OS events required for the final OS analysis is reached.
Survival information and post treatment information will be collected approximately every 12 weeks (or 
as needed to allow for more frequent data collection) until death, the subject is lost to follow-up, the 
subject withdraws consent, the number of OS events required for the final OS analysis is reached, or the 
study is terminated by AbbVie, whichever occurs first.  Non-treatment emergent death (those occurring 
30 days after the final dose of study drug) information will also be collected until the number of OS 
events required for the final OS analysis is reached.  Subject must request to be withdrawn specifically 
from survival follow-up.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
10
Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:
1.
Eastern Collaborative Oncology Group (ECOG) performance score of ≤ 2.
2.
Subjects has documented relapsed or progressive multiple myeloma on or after any regimen or is 
refractory to the most recent line of therapy.

Relapsed myeloma is defined as previously treated myeloma that progresses and requires 
initiation of salvage therapy, but does not meet criteria for refractory myeloma.

Refractory myeloma is defined as disease that is nonresponsive (failure to achieve minimal 
response or development of PD) while on primary or salvage therapy, or progresses within 
60 days of last therapy.
3.
Subject must have received prior treatment with at least one, but no more than three, prior lines of 
therapy for multiple myeloma.

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.
4.
Prior treatment with bortezomib or other proteasome inhibitor is allowed, provided:  ALL of the 
following criteria are met:

Disease is NOT refractory to any proteasome inhibitor, defined as no disease progression 
(i.e., PD, per IMWG or European Society for Blood and Marrow Transplantation [EBMT] 
criteria) while receiving proteasome inhibitor therapy or within 60 days after the last dose, AND

Best response achieved with any proteasome inhibitor therapy (alone or in combination) was at 
least a Partial Response (PR), AND

Subject did not discontinue any proteasome inhibitor due to intolerance or ≥ Grade 3 related 
toxicity.
5.
Subject has measurable disease at Screening, defined as at least one of the following:

Serum M-protein ≥ 0.5 gram (g)/deciliter (dL), OR

Urine M-protein ≥ 200 mg in 24 hours, OR

Serum immunoglobulin free light chain (FLC) ≥ 10 mg/dL provided serum FLC ratio is 
abnormal.
6.
Subjects must meet the following laboratory parameters, per laboratory reference range:

Absolute neutrophil count (ANC) ≥ 1000/microliter (µL) within 2 weeks prior to randomization; 
subjects may use growth factor support to achieve ANC eligibility criteria.

Platelet count ≥ 50,000/millimeter (mm)3, within 2 weeks prior to randomization.  For subjects 
with > 50% myeloma involvement in the bone marrow, a platelet count of ≥ 30,000/mm3, within 
2 weeks prior to randomization is allowed.  Subjects may not have received a platelet 
transfusion within 72 hours prior to the platelet count used for eligibility.

Hemoglobin ≥ 8.0 g/dL, within 2 weeks prior to randomization.  Subjects may receive red blood 
cell (RBC) transfusions in accordance with institutional guidelines to meet this criteria.

AST and ALT ≤ 3 × upper limit of normal (ULN).

Total bilirubin ≤ 1.5 × ULN.  Subjects with documented Gilbert's syndrome may have bilirubin 
> 1.5 × ULN with the approval of the Primary Therapeutic Area Medical Director (TA MD).

Creatinine clearance (CrCl) ≥ 30 milliliter (mL)/minute (min) measured by 24-hour urine 
collection or calculated using the Cockcroft-Gault formula.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
11
Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion:
1.
Subject is refractory to any proteasome inhibitor, defined as progression on or within 60 days of the 
last dose of a proteasome inhibitor-containing regimen.
2.
Subject has had prior treatment with proteasome inhibitor within 60 days prior to first dose of study 
drug.
3.
Subject has any of the following conditions:

Non-secretory multiple myeloma

Active plasma cell leukemia, i.e., either 20% of peripheral white blood cells or > 2.0 × 109/Liter 
(L) circulating plasma cells by standard differential

Waldenström's macroglobulinemia

Amyloidosis

Polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes 
(POEMS syndrome)

Known Human Immunodeficiency Viral (HIV) infection

Active hepatitis B or C infection based on blood screen tests

Significant cardiovascular disease, including uncontrolled angina, hypertension, arrhythmia, 
recent myocardial infarction within 6 months of randomization, congestive heart failure New 
York Heart Association (NYHA) Class ≥ 3

Major surgery within 4 weeks prior to randomization

Acute infections requiring parenteral therapy (antibiotic, antifungal or antiviral) within 14 days 
prior to randomization

Peripheral neuropathy ≥ Grade 3 or ≥ Grade 2 with pain within 2 weeks prior to randomization

Uncontrolled diabetes or uncontrolled hypertension within 14 days prior to randomization

Any other medical condition that, in the opinion of the Investigator, would adversely affect the 
subject's participation in the study
4.
Subject has a history of other active malignancies, including myelodysplastic syndrome (MDS), 
within the past 3 years prior to study entry, with the following exceptions:

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 (PSA) 
levels off treatment,

Previous malignancy with no evidence of disease confined and surgically resected (or treated 
with other modalities) with curative intent and unlikely to impact survival during the duration of 
the study.
5.
If subject had prior stem cell transplant (SCT), subject has evidence of ongoing graft-versus-host 
disease (GvHD).
Investigational Product:
Venetoclax, 100 mg tablet
Doses:
800 mg QD
Mode of Administration:
Oral
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
12
Reference Therapy:
Placebo (to match venetoclax 100 mg tablet)
Doses:
Placebo QD
Mode of Administration:
Oral
Reference Therapy:
Bortezomib powder for solution for injection
Doses:
Cycles 1 – 8:  1.3 mg/m2 on Days 1, 4, 8 and 11
Cycle 9 and beyond:  1.3 mg/m2 on Days 1, 8, 15 and 22
Mode of Administration:
Subcutaneous (preferred) or Intravenous
Reference Therapy:
Dexamethasone tablet
Doses:
Cycles 1 – 8:  20 mg on Days 1, 2, 4, 5, 8, 9, 11 and 12
Cycle 9 and beyond:  20 mg on Days 1, 2, 8, 9, 15, 16, 22 and 23
Mode of Administration:
Oral
Duration of Treatment:  Subjects will receive venetoclax/placebo plus Bd until documented disease 
progression, unacceptable toxicity, withdrawal of consent, or the subject meets other criteria for 
discontinuation per study protocol.
Criteria for Evaluation:
Efficacy:
IMWG assessments for clinical response and progressive disease will be done per IMWG criteria, and 
will be used to assess PFS, VGPR or better response rate, DOR, TTP, and ORR.
OS will be evaluated according to survival information (i.e., alive or deceased, and if deceased, date and 
cause of death) and post treatment information (including therapy, dates of therapy and response).
PROs will be evaluated using BPI-SF, EORTC QLQ-C30, European Organization for Research and 
Treatment of Cancer Quality of Life Questionnaire Multiple Myeloma Module (EORTC QLQ-MY20), 
PROMIS Cancer Fatigue SF, and EuroQoL EQ-5D-5L (EQ-5D-5L).
Pharmacokinetic:
Pharmacokinetic (PK) samples will be collected and analyzed for venetoclax and bortezomib (and 
dexamethasone, in subjects enrolled in Japan only).  Venetoclax results may be incorporated into a 
population PK analysis to estimate parameters such as clearance.
Biomarkers:
Biospecimens (serum, plasma, bone marrow aspirate and bone marrow core biopsy tissue) will be 
collected to investigate biomarkers.  Types of biomarkers analyzed may include:  BCL-2 family member 
expression, chromosomal abnormalities (Immunoglobulin [Ig] H translocations, amplifications, or 
deletions), and MRD negativity.  Additional biomarkers analyzed may include nucleic acids, proteins, 
lipids or metabolites.  The samples may be analyzed as part of a multi-study assessment of factors 
involved in the response to therapy or the disease state.
Pharmacogenetics:
Deoxyribonucleic Acid (DNA) samples may be analyzed for genetic factors contributing to the response 
to venetoclax in terms of pharmacokinetics, efficacy, tolerability, and safety.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
13
Criteria for Evaluation (Continued):
Safety:
AbbVie will assess adverse events, laboratory data, electrocardiograms (ECG) and vital signs throughout 
the study.  Adverse events intensity and laboratory evaluation changes will be assessed by utilizing 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
Version 4.03.
Statistical Methods:
Efficacy:
Primary Efficacy Endpoint:
The primary efficacy endpoint is PFS.  PFS is defined as the time from randomization to the 
first documented PD or death due to any cause, whichever occurs first.  The primary analysis of PFS will 
be based on data from the IRC's assessment of disease progression.  
A stratified two-sided log-rank test will be used to test PFS.  Two-sided significance level of this test is 
0.05.  The hazards ratio for treatment effect will be estimated and its two-sided 95% confidence interval 
will be provided.  In addition, survivorship functions will be estimated by using Kaplan-Meier product-
limit method.  If reached, median PFS time and its two-sided 95% confidence intervals will be presented 
by treatment group.
Secondary Efficacy Endpoints:
Secondary efficacy endpoints are as follows:  VGPR or better response rate; PROs:  Worst Pain (BPI-
SF), Physical Functioning (EORTC QLQ-C30); OS; PFS in subjects with high BCL-2 expression; DOR; 
TTP; ORR; MRD negativity rate; PROs GHS/QoL (EORTC QLQ-C30), and Fatigue (PROMIS Cancer 
Fatigue SF).
OS is defined as time from randomization to death due to any cause.
VGPR or better response rate is defined as the proportion of subjects with documented Complete 
Response (CR), stringent Complete Response (sCR), or VGPR.
DOR is defined as the time from first documented response (PR or better) to the date of first documented 
PD or death due to multiple myeloma, whichever occurs first.  TTP is defined as the time from 
randomization to the date of first documented PD or death due to multiple myeloma, whichever occurs 
first.  ORR is defined as the proportion of subjects with documented PR or better.
A stratified two-sided (cumulative two-sided α = 0.05) 3-look group sequential log-rank test will be used 
to test OS.  The hazards ratio (HR) for treatment effect will be estimated and its two-sided 95% 
confidence interval will be provided.
VGPR or better response rate and ORR will be analyzed by using Cochran-Mantel-Haenszel test.  
Estimated rates along with corresponding 95% confidence intervals will be presented.
PFS in subjects with high BCL-2 expression, DOR, and TTP will be analyzed by using stratified log-rank 
test.  The hazards ratios for treatment effect will be estimated and two-sided 95% confidence intervals 
will be provided.
For MRD negativity, estimated rates along with corresponding 95% confidence intervals will be 
presented.
Patient-Reported Outcomes:
Worst Pain (BPI-SF), Physical Functioning and GHS/QoL (EORTC QLQ-C30), and Fatigue (PROMIS 
Cancer Fatigue SF) will be analyzed by treatment groups.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
14
Statistical Methods (Continued):
Efficacy (Continued):
Secondary Efficacy Endpoints (Continued):
Statistical Analyses:
The primary analysis of PFS will be performed when approximately 136 PFS events are observed.
Pharmacokinetics:
An analysis of venetoclax plasma concentrations may be performed using a nonlinear mixed effect 
population PK modeling approach.
Biomarkers:
A pre-defined threshold for BCL-2 expression will be utilized to compare median PFS between treatment 
arms in subjects with High BCL-2 expression.  Additionally, biomarker analyses may be explored based 
upon the available data and may not be included in the clinical study report.  Summary tabulations may 
be produced if data from a sufficient number of subjects are collected.
Safety:
Safety will be assessed by evaluating study treatment exposure, adverse events, serious adverse events, 
deaths, and changes in laboratory determinations and vital sign parameters.  Subjects who are 
randomized, but do not receive study drug, will not be included in the analyses of safety.
Sample Size:
For sample size estimation, the median PFS of placebo plus Bd and venetoclax plus Bd is assumed to be 
9 months and 16.25 months, respectively (HR = 0.554, under the assumption of proportionality).  
Two-sided log-rank test with a two-sided type I error rate of α = 0.05 and a power of ≥ 90% is used.  
Under the assumptions above and using a 2:1 randomization ratio to the two arms (venetoclax plus Bd 
versus placebo plus Bd) a total of 136 PFS events per IRC assessment are required.  To observe 136 PFS 
events per IRC assessment, approximately 280 subjects will be randomized.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
15
1.3
List of Abbreviations and Definition of Terms
Abbreviations
ADL
Activities of Daily Living
AE
Adverse Event
ALT
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
aPTT
Activated Partial Thromboplastin Time
ASCO
American Society of Clinical Oncology
AST
Aspartate Aminotransferase
Bd
Bortezomib and dexamethasone
BCL-2
B-cell Lymphoma 2
BMC
Bone Marrow Core
BPI-SF
Brief Pain Inventory – Short Form
BCRP
Breast Cancer Resistance Protein
BUN
Blood Urea Nitrogen
C
Cycle
CBC
Complete Blood Count
CBR
Clinical Benefit Rate
CFR
Code of Federal Regulations
CLL
Chronic Lymphocytic Leukemia
cm
Centimeter
CNS
Central Nervous System
COVID-19
Coronavirus Disease – 2019
CR
Complete Response
CrCl
Creatinine Clearance
CRM
Continual Reassessment Method
CRP
C-Reactive protein
CS
Clinically Significant
CSF
Colony Stimulating Factors
CT
Computerized tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
Cytochrome P450
CYP1A2
Cytochrome P450 1A2
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
16
CYP2B6
Cytochrome P450 2B6
CYP2C8
Cytochrome P450 2C8
CYP2C9
Cytochrome P450 2C9
CYP2C19
Cytochrome P450 2C19
CYP2D6
Cytochrome P450 2D6
CYP3A
Cytochrome P450 3A
D
Day
DCR
Disease Control Rate
DDI
Drug Drug interaction
DE
Dose Escalation
dL
Deciliter
DNA
Deoxyribonucleic Acid
DOR
Duration of Response
DSUR
Drug Safety Update Report
DTP
Direct-to-patient
EBMT
European Society for Blood and Marrow Transplantation
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDC
Electronic Data Capture
eCRF
Electronic Case Report Form
EORTC QLQ-C30
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire Core
EORTC QLQ-MY20
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire Multiple Myeloma Module
EQ-5D-5L
EuroQol EQ-5D-5L
FFPE
Formalin-Fixed, Paraffin-Embedded
FISH
Fluorescent In Situ Hybridization
FLC
Free Light Chain
g
Gram
GCP
Good Clinical Practice
G-CSF
Granulocyte colony-stimulating factor
GHS
Global Health Status
GM-CSF
Granulocyte-macrophage colony-stimulating factor
GVHD
Graft-Versus-Host Disease
HBsAg
Hepatitis B Surface Antigen
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
17
HCV Ab
Hepatitis C Virus Antibody
HDAC
Histone deacetylase
HDPE
High Density Polyethylene
HIV
Human Immunodeficiency Virus
Hr
Hour
HR
Hazards Ratio
HRQoL
Heath-related Quality of Life
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
Ig
Immunoglobulin
IHC
Immunohistochemistry
IMiD®
Immunomodulatory Thalidomide Derivative Compound
IMP
Investigational Medicinal Product
IMWG
International Myeloma Working Group
INR
International Normalized Ratio
IRB
Institutional Review Board
IRC
Independent Review Committee
IRT
Interactive Response Technology
ISS
International Staging System
ITT
Intent To Treat
IUD
Intrauterine Device
IV
Intravenous
Kg
Kilogram
L
Liter
LD50
Lethal Dose 50%
LDH
Lactate Dehydrogenase
MedDRA
Medical Dictionary for Regulatory Activities
m
Meter
µg
Microgram
µL
Microliter
MDS
Myelodysplastic Syndrome
Mg
Milligram
Min
Minute
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
18
mL
Milliliter
mm
Millimeter
MM
Multiple Myeloma
mmHg
Millimeter mercury
mmol
Millimole
MR
Minimal Response
MRI
Magnetic resonance imaging
MRD
Minimal Residual Disease
mRNA
Messenger Ribonucleic Acid
ms
Milliseconds
MTD
Maximum Tolerated Dose
NCI
National Cancer Institute
NCS
Not Clinically Significant
NHL
Non-Hodgkin Lymphoma
nM
Nanomolar
NOAEL
No observed adverse effect level
NYHA
New York Heart Association
OATP
Organic anion transporting polypeptide
ORR
Objective Response Rate
OS
Overall Survival
PD
Progressive Disease
PET
Positron Emission Tomography
PFS
Progression Free Survival
P-gp
P-glycoprotein
PG
Pharmacogenetic
PI
Principal Investigator
PK
Pharmacokinetic
PO
Orally
POEMS
Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal Protein, and 
Skin Changes
PR
Partial Response
PRO
Patient Reported Outcomes
PROMIS
Patient Reported Outcomes Measurement Information System
PSA
Prostate Specific Antigen
PT
Prothrombin Time
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
19
QD
Once Daily
QoL
Quality of Life
qPCR
Quantitative polymerase chain reaction
QTc
QT Interval Corrected for Heart Rate
QTcB
QT Interval Corrected for Heart Rate by Bazett's Formula
QTcF
QT Interval Corrected for Heart Rate by Fridericia's Formula
RBC
Red Blood Cell
RNA
Ribonucleic Acid
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
sβ2M
Serum β2 microglobulin
sCR
Stringent Complete Response
SCT
Stem Cell Transplant
SD
Stable Disease
SE
Safety Expansion
SF
Short Form
sFLC
Serum Free Light Chains
SGOT
Serum glutamic-oxaloacetic transaminase
SGPT
Serum glutamic-pyruvic transaminase 
SPEP
Serum Protein Electrophoresis
sQI
Serum Quantitative Immunoglobulins
SmPC
Summary of Product Characteristics 
SUSAR
Suspected Unexpected Serious Adverse Reaction
TA MD
Therapeutic Area Medical Director
TCV
Treatment Completion Visit
TLS
Tumor Lysis Syndrome
TNT
Time to Next Treatment
TTP
Time to Disease Progression
TTR
Time to Response
UGTs
UDP-glucuronosyltransferases
ULN
Upper Limit of Normal Range
UPEP
Urine Protein Electrophoresis
VAS
Visual Analog Scale
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
20
VGPR
Very Good Partial Response
WBC
White Blood Cell
Pharmacokinetic and Statistical Abbreviations
AUC
Area Under the Plasma Concentration-Time Curve
AUC∞
Area Under the Plasma Concentration-Time Curve from Time Zero to Infinity
CL/F
Apparent Clearance
Cmax
Maximum Observed Plasma Concentration
Other Clarifications
References to "Study Drug" and "IMP" (Investigational Medicinal Product) are defined as 
Venetoclax/Placebo and not Bortezomib and/or Dexamethasone.
References to "Study Treatment" are defined as Venetoclax/Placebo, Bortezomib and 
Dexamethasone.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
21
2.0
Table of Contents
1.0
Title Page..................................................................................1
1.1
Protocol Amendment:  Summary of Changes ...........................................3
1.2
Synopsis .....................................................................................................7
1.3
List of Abbreviations and Definition of Terms........................................15
2.0
Table of Contents...................................................................21
3.0
Introduction ...........................................................................27
3.1
Multiple Myeloma (MM).........................................................................27
3.2
BCL-2 Family of Proteins in Multiple Myeloma.....................................28
3.3
Nonclinical Pharmacology and Clinical Data..........................................28
3.4
Differences Statement..............................................................................36
3.5
Benefits and Risks....................................................................................36
4.0
Study Objectives....................................................................38
5.0
Investigational Plan...............................................................39
5.1
Overall Study Design and Plan:  Description ..........................................39
5.2
Selection of Study Population..................................................................44
5.2.1
Inclusion Criteria .....................................................................................45
5.2.2
Exclusion Criteria ....................................................................................48
5.2.3
Determination of the Number of Prior Lines of Therapy ........................51
5.2.4
Prior and Concomitant Therapy...............................................................52
5.2.4.1
Pretreatment Requirements......................................................................52
5.2.4.2
Allowed Treatments.................................................................................54
5.2.4.3
Excluded and Cautionary Medications ....................................................55
5.3
Efficacy, Pharmacokinetic, Biomarker, Exploratory Research and 
Safety Assessments/Variables..................................................................57
5.3.1
Efficacy and Safety Measurements Assessed ..........................................57
5.3.1.1
Study Procedures .....................................................................................57
5.3.1.1.1
Screening and Treatment Assessments....................................................59
5.3.1.1.2
Follow-Up................................................................................................72
5.3.1.2
Meals and Dietary Requirements.............................................................74
5.3.1.3
Collection and Handling of Biomarker and Exploratory Research 
Samples....................................................................................................74
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
22
5.3.1.3.1
Samples for Mandatory Biomarker Analysis...........................................75
5.3.1.3.2
Samples for Exploratory Research...........................................................77
5.3.2
Drug Concentration Measurements .........................................................78
5.3.2.1
Collection of Samples for Analysis .........................................................78
5.3.2.2
Measurement Methods.............................................................................80
5.3.3
Efficacy Variables....................................................................................80
5.3.4
Safety Variables.......................................................................................81
5.3.5
Pharmacokinetic Variables ......................................................................81
5.3.6
Biomarker and Exploratory Research Variables......................................81
5.3.7
Disease Assessments and IMWG Criteria for Response and 
Progression...............................................................................................83
5.3.7.1
Disease Assessments................................................................................83
5.3.7.2
IMWG Criteria for Response and Progression ........................................92
5.3.7.3
Evaluation of Disease ..............................................................................98
5.4
Removal of Subjects from Therapy or Assessment.................................99
5.4.1
Discontinuation of Individual Subjects from Treatment..........................99
5.4.2
Withdrawal from Study Visits ...............................................................101
5.4.3
Withdrawal from Follow-Up .................................................................101
5.4.4
Discontinuation of Entire Study.............................................................102
5.5
Treatments..............................................................................................103
5.5.1
Treatments Administered.......................................................................103
5.5.2
Identity of Investigational Products.......................................................106
5.5.2.1
Packaging and Labeling.........................................................................107
5.5.2.2
Storage and Disposition of Study Drug and Non-Investigational 
Products..................................................................................................108
5.5.3
Method of Assigning Subjects to Treatment Groups.............................108
5.5.4
Selection and Timing of Dose for Each Subject....................................109
5.5.5
Blinding..................................................................................................109
5.5.5.1
Blinding of Investigational Product.......................................................109
5.5.5.2
Blinding of Data for Independent Data Monitoring Committee 
(IDMC) ..................................................................................................110
5.5.5.3
Unblinding Process ................................................................................110
5.5.6
Treatment Compliance...........................................................................110
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
23
5.5.7
Drug Accountability...............................................................................111
5.6
Discussion and Justification of Study Design........................................111
5.6.1
Discussion of Study Design and Choice of Control Groups..................111
5.6.2
Appropriateness of Measurements.........................................................112
5.6.3
Suitability of Subject Population ...........................................................112
5.6.4
Selection of Doses in the Study .............................................................112
6.0
Complaints ...........................................................................113
6.1
Medical Complaints...............................................................................114
6.1.1
Definitions..............................................................................................114
6.1.1.1
Adverse Event........................................................................................114
6.1.1.2
Serious Adverse Events .........................................................................115
6.1.1.3
Adverse Events Expected Due to Study Related Endpoints..................116
6.1.1.3.1
Deaths ....................................................................................................116
6.1.1.3.2
Lack of Efficacy or Worsening of Disease ............................................117
6.1.2
Adverse Event Severity..........................................................................117
6.1.3
Relationship to Study Treatment ...........................................................118
6.1.4
Adverse Event Collection Period...........................................................118
6.1.5
Adverse Event Reporting.......................................................................119
6.1.6
Pregnancy...............................................................................................122
6.1.7
Toxicity Management ............................................................................123
6.1.7.1
Management of Cytopenias and Infection .............................................123
6.1.7.2
Management of Tumor Lysis Syndrome ...............................................124
6.2
Guidelines for Dose Modifications and Treatment................................125
6.2.1
Dose Modifications or Delays for Venetoclax/Placebo Toxicities........128
6.2.2
Dose Modifications for Moderate or Strong CYP3A Inhibitors 
Used with Venetoclax/Placebo ..............................................................130
6.2.3
Toxicities Related to Bortezomib/Dexamethasone................................130
6.3
Product Complaint .................................................................................134
6.3.1
Definition ...............................................................................................134
6.3.2
Reporting................................................................................................134
7.0
Protocol Deviations..............................................................135
8.0
Statistical Methods and Determination of Sample 
Size ........................................................................................136
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
24
8.1
Statistical and Analytical Plans..............................................................137
8.1.1
Definition for Analysis Populations.......................................................137
8.1.2
Baseline Characteristics.........................................................................137
8.1.3
Efficacy Endpoints.................................................................................138
8.1.3.1
Primary Efficacy Endpoint ....................................................................138
8.1.3.2
Secondary Efficacy Endpoints...............................................................139
8.1.3.3
Tertiary Efficacy Endpoints...................................................................141
8.1.4
Timing of Efficacy Analyses and Safety Evaluations ...........................143
8.1.5
Statistical Analyses of Efficacy .............................................................143
8.1.5.1
Primary Analysis of Efficacy.................................................................143
8.1.5.2
Secondary Analyses of Efficacy ............................................................143
8.1.5.3
Tertiary Analyses of Efficacy ................................................................145
8.1.5.4
Additional Sensitivity and Supportive Efficacy Analyses.....................146
8.1.5.5
Interim Analysis.....................................................................................146
8.1.5.5.1
Progression Free Survival......................................................................146
8.1.5.5.2
Overall Survival.....................................................................................146
8.1.5.6
Multiplicity Adjustments .......................................................................147
8.1.6
Safety Assessments................................................................................147
8.1.7
Statistical Analyses of Safety.................................................................147
8.1.7.1
Duration of Study Treatment .................................................................147
8.1.7.2
Adverse Events ......................................................................................147
8.1.7.3
Serious Adverse Events .........................................................................148
8.1.7.4
Deaths ....................................................................................................148
8.1.7.5
Longitudinal Analyses of Laboratory and Vital Signs Data..................148
8.1.7.6
Analyses of Laboratory Data Using NCI CTCAE.................................148
8.1.7.7
Analyses of Vital Signs Using Criteria for Potentially Clinically 
Significant Vital Sign Values.................................................................149
8.1.7.8
Pharmacokinetics ...................................................................................149
8.2
Determination of Sample Size ...............................................................149
9.0
Ethics.....................................................................................151
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ...........................................................................................151
9.2
Ethical Conduct of the Study.................................................................152
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
25
9.3
Subject Information and Consent...........................................................153
9.3.1
Informed Consent Form and Explanatory Material ...............................154
9.3.2
Revision of the Consent Form and Explanatory Material .....................154
10.0
Source Documents and Case Report Form 
Completion ...........................................................................154
10.1
Source Documents .................................................................................154
10.2
Case Report Forms.................................................................................155
11.0
Data Quality Assurance ......................................................157
12.0
Use of Information...............................................................158
13.0
Completion of the Study .....................................................159
14.0
Investigator's Agreement....................................................161
15.0
Reference List ......................................................................162
List of Tables
Table 1.
Excluded and Cautionary Medications ....................................................56
Table 2.
Patient-Reported Outcome Assessments .................................................65
Table 3.
Clinical Laboratory Tests.........................................................................70
Table 4.
Assessments for IMWG Response Criteria .............................................91
Table 5.
Identity of Investigational Product.........................................................107
Table 6.
Identity of Non-Investigational Products...............................................107
Table 7.
Venetoclax/Placebo* Dose Levels.........................................................128
Table 8.
Hematological and Non-Hematological Toxicities Related to 
Venetoclax/Placebo*..............................................................................129
Table 9.
Dose Modifications for Venetoclax/Placebo:*  Moderate or 
Strong CYP3A Inhibitor Use.................................................................130
Table 10.
Dose Reductions and Treatment Guidelines for Toxicity Related 
to Bortezomib.........................................................................................132
Table 11.
Dose Reductions for Dexamethasone ....................................................133
Table 12.
Treatment Guidelines for Toxicity Related to Dexamethasone.............133
Table 13.
Event and Censoring Date Used in PFS ................................................139
Table 14.
Event and Censoring Date Used in DOR...............................................140
Table 15.
Event and Censoring Date Used in TTP................................................141
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
26
Table 16.
Event and Censoring Date Used in TTR................................................142
Table 17.
Accrual Information...............................................................................150
Table 18.
Power Calculation..................................................................................151
List of Figures
Figure 1.
Study Schema...........................................................................................44
Figure 2.
Adverse Event Collection ......................................................................119
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator ..........................................167
Appendix B.
List of Protocol Signatories....................................................................169
Appendix C.
Revised International Myeloma Working Group Diagnostic 
Criteria for Multiple Myeloma...............................................................170
Appendix D.
Schedule of Assessments – Screening ...................................................172
Appendix E.
Schedule of Assessments – Treatment:  Cycles 1 – 8............................175
Appendix F.
Schedule of Assessments – Treatment:  Cycles 9 and Beyond 
Through Treatment Completion Visit....................................................179
Appendix G.
Schedule of Assessments – Follow-Up..................................................184
Appendix H.
Pharmacokinetic, Pharmacogenetic, and Biomarker Collection............189
Appendix I.
Sample List of Excluded and Cautionary Medication ...........................192
Appendix J.
IMWG Response Criteria for Multiple Myeloma..................................194
Appendix K.
Tumor Lysis Syndrome Classification...................................................197
Appendix L.
Japan Specific Information ....................................................................198
Appendix M.
Corticosteroid Conversion Table ...........................................................200
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
27
3.0
Introduction
3.1
Multiple Myeloma (MM)
Multiple myeloma (MM) represents 1% of all cancers and about 13% of all hematologic 
malignancies.  Approximately 86,000 new cases of MM occur annually worldwide.1  The 
incidence of MM is 6.7 cases per 100,000 in the United States and 6.0 cases per 
100,000 per year in Europe, with an age-adjusted mortality rate of 3.4 cases per 
100,000 per year.2,3  For 2014, it has been estimated that 24,000 new cases of MM would 
be diagnosed and 11,000 deaths would occur in the United States alone.4
Patients with MM experience a number of disease-related symptoms and effects, such as 
bone destruction and bone pain, bone marrow failure, renal failure, and 
immunodeficiency, leading to deterioration in health-related quality of life (HRQoL).5  In 
a study comparing HRQoL data from survivors of 13 uncommon cancers from individuals 
without cancer, survivors of MM and pancreatic cancer were among those with the lowest 
HRQoL scores.6
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 overall survival from 3 years to 6 years.3,7  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 myeloma 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 Immunomodulatory Thalidomide Derivative Compounds (IMiDs), 
proteasome inhibitors, histone deacetylase (HDAC) inhibitors, and monoclonal antibodies 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
28
(anti-CS1, anti-CD38).  Most recommended treatment protocols comprise variable 
combinations of these drugs.  The proteasome inhibitor bortezomib combined with 
dexamethasone (Bd) has proven therapeutic value and is considered to be one of the 
standards of care in the treatment of relapsed multiple myeloma.3,8
3.2
BCL-2 Family of Proteins in Multiple Myeloma
There are two main pathways of apoptosis or programmed cell death, namely the 
extrinsic, or death receptor-mediated pathway, and the intrinsic or mitochondrial pathway.  
The intrinsic pathway is regulated by a delicate balance between anti-apoptotic (BCL-2, 
BCL-XL, BCL-W, BFL-1/A1, and MCL-1) and pro-apoptotic (BAX, BAK, BID, 
BCL-xS, BAD, BIK, BIM, HRK, and NOXA) BCL-2 family proteins.  Normally, BAX 
and BAK are sequestered by the anti-apoptotic proteins BCL-2, BCL-XL, and/or MCL-1 
and prevented from interacting with mitochondria.  
Plasma cells are typically geared towards long-term survival and have low apoptotic rates, 
likely due to high levels of anti-apoptotic proteins such as BCL-2 and MCL-1.  
Dysregulation of apoptotic pathways in these cells, often via aberrant BCL-2 and/or 
MCL-1 overexpression, is thought to play a major role in the development and 
progression of multiple myeloma.  Antagonizing BCL-2 and MCL-1 function to induce 
apoptosis is thus a compelling therapeutic approach in multiple myeloma, and can be 
achieved by combining the BCL-2-selective inhibitor venetoclax with the proteasome 
inhibitor bortezomib, which has been demonstrated to upregulate the MCL-1-neutralizing
protein NOXA.
3.3
Nonclinical Pharmacology and Clinical Data
Venetoclax Activity
Venetoclax is a novel, orally bioavailable small molecule inhibitor of BCL-2 (Ki
< 0.010 nanomolar [nM]) with much lower affinity for BCL-XL and BCL-W (> 480-fold 
and > 2,000-fold lower affinity, respectively).  In vitro, venetoclax has demonstrated cell 
killing activity against MM cell lines and primary patient samples.  The sensitivity of MM 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
29
cell lines correlated most closely with their BCL2/MCL1 messenger ribonucleic acid 
(mRNA) expression ratio, with the most sensitive cell lines expressing high levels of 
BCL2 relative to MCL1.  MM cell lines bearing the t(11;14) translocation were 
particularly sensitive to venetoclax (6 of 8 cell lines with a lethal dose 50% [LD50] 
< 100 nM, median LD50 = 10 nM).  Similar trends were observed for MM primary 
samples treated ex vivo with venetoclax, with four of five t(11;14)-positive samples being 
especially sensitive (LD50 < 100 nM).9
Venetoclax has also shown efficacy in multiple xenograft models of MM when combined 
with bortezomib.  This combination was clearly more efficacious than either agent alone 
in the t(14;16) model RPMI-8226 and the t(4;14) models H929, KMS-11 and OPM-2, 
with improved tumor growth inhibition and tumor growth delay observed in each case.  
Combination efficacy correlated with an ability of bortezomib to upregulate the 
MCL-1-inhibiting protein NOXA.
Additional information on venetoclax clinical pharmacology and clinical data (including 
clinical data with venetoclax in multiple myeloma) can be found in the most current 
version of the Investigator's Brochure.12
Venetoclax Nonclinical Toxicology and Pharmacology
Primary venetoclax-related toxicities were effects on the hematologic system (decreased 
lymphocytes and red blood cell mass in mice, rats and dogs), the male reproductive 
system (testicular germ cell depletion in dogs), and embryo-fetal toxicity in mice.
Decreases in lymphocytes and red blood cell (RBC) mass were dose-related and 
reversible.  Lymphocyte decreases are consistent with the expected pharmacology of 
venetoclax (a selective Bcl-2 inhibitor)10 and, when sustained over periods of 6 to 
9 months in chronic toxicology studies, were not associated with opportunistic infections.  
B-cells were the most sensitive lymphocyte subtype based on the magnitude of decrease 
(> 90%) and/or the length of time required for recovery (up to 18 weeks).  Decreased 
RBC mass, typified by decreased hemoglobin, was adverse only at the high dosages 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
30
administered (–21% in mice at 600 milligram [mg]/kilogram [kg]/day and –23% in dogs 
at 150 mg/kg/day).  Thrombocytopenia has not been observed in toxicology studies in 
mice and dogs.  These findings are consistent with venetoclax as a BCL-2 specific 
(BCL-XL sparing) inhibitor.  Venetoclax produced adverse, non-dose-related microscopic 
findings of testicular germ cell loss in dogs at all dosages tested and did not demonstrate 
reversibility.  In the mouse embryo-fetal development study, increased post-implantation 
loss and decreased fetal body weights occurred at the highest dosage administered 
(150 mg/kg/day); the no-observed-adverse-effect-level (NOAEL) was defined at the 
mid-dose of 50 mg/kg/day.  Venetoclax was not teratogenic in mice or rabbits, and there 
were no other effects on development or fertility.
Other noteworthy findings with venetoclax were epithelial single cell necrosis in multiple 
tissues and hair coat color change, both in dogs.  Single cell necrosis was observed in the 
gallbladder, exocrine pancreas, epididymides, prostate, and stomach.  These findings were 
not adverse based on minimal to mild severity and no microscopic evidence of loss of 
mucosal integrity.  Partial to complete reversibility was observed.
Venetoclax was tested in a battery of safety pharmacology assays, and produced no 
effects in the central nervous system (CNS)/neurobehavioral or respiratory studies in mice 
at oral doses up to and including the highest oral dose of 600 mg/kg.  In conscious dogs, 
venetoclax did not produce any cardiovascular effects up to and including the highest oral 
dose of 150 mg/kg (maximum observed plasma concentration [Cmax] = 16 microgram 
[µg]/milliliter [mL]).  At higher plasma concentrations in anesthetized dogs, mild 
decreases in cardiac contractility and cardiac output, and a small increase in QT Interval 
Corrected for Heart Rate (QTc) (8 milliseconds [ms]), were observed.  These effects 
occurred at concentrations > 3- to 5-fold above peak clinical concentrations at the 
maximum dose and were not considered to be clinically relevant due to their small 
magnitude and lack of a dose-dependent relationship.  On the basis of nonclinical safety 
pharmacology and toxicology evaluations of venetoclax, and on the basis of nonclinical 
and human studies of related anti-apoptotic BCL-2 family protein inhibitors, potential 
mechanism-based toxicities may include lymphopenia and neutropenia,11 signs of tumor 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
31
lysis, reduction in red cell mass, decreased spermatogenesis, skin swelling, and hair 
hypopigmentation.
A detailed discussion of the preclinical toxicology, metabolism, and pharmacology can be 
found in the most current version of the Investigator's Brochure.12
Clinical Pharmacology
Following oral administration, the maximum plasma concentration of venetoclax is 
generally obtained by 5 to 8 hours.  The harmonic mean terminal half-life ranges from 
17 to 41 hours following a single oral dose of venetoclax, which supports the proposed 
daily dosing.  In patients with Chronic Lymphocytic Leukemia (CLL), venetoclax showed 
minimal accumulation, and steady-state Area Under the Plasma Concentration-Time 
Curve (AUC) increased proportionally over the dose range of 150 to 800 mg.
Venetoclax has been administered with food in all clinical studies, as food increased the 
bioavailability of venetoclax.  In Non-Hodgkin Lymphoma (NHL) patients, 
administration of venetoclax with low- and high-fat meals increased the venetoclax area 
under the plasma concentration – time curve from time zero to infinity (AUC∞) by 4.3-
and 4.4-fold, respectively, compared to fasting conditions.  Similarly, in healthy subjects, 
venetoclax administration following low-fat and high-fat meals increased venetoclax 
exposure by approximately 3.4- and 5.1- to 5.3-fold, respectively, compared to fasting 
conditions.  Therefore, venetoclax should be administered with food to ensure adequate 
bioavailability.
Venetoclax is highly bound to plasma proteins with unbound fraction < 0.01, and it is 
primarily eliminated as metabolites in feces with negligible renal elimination (< 0.1%).  
M27 was identified as a major metabolite with an inhibitory activity against Bcl-2 that is 
at least 58-fold lower than venetoclax in vitro.  Venetoclax and M27 are predominantly 
metabolized by cytochrome P450 (CYP) 3A4 (CYP3A4) in vitro; 
UDP-glucuronosyltransferases (UGTs) are not involved in the metabolism of venetoclax.  
Venetoclax is also substrate for P-glycoprotein (P-gp) and breast cancer resistance protein 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
32
(BCRP) transporters.  No active uptake of venetoclax was observed in cells 
overexpressing organic anion transporting polypeptide (OATP) 1B1 or OATP1B3.
The effect of ketoconazole, a potent CYP3A inhibitor, on venetoclax pharmacokinetics 
(PK) was evaluated in 12 patients with relapsed or refractory NHL.  Co-administration of 
ketoconazole with venetoclax resulted in a 2.3-fold increase in venetoclax maximum 
observed plasma concentration (Cmax) and a 6.4-fold increase in AUC∞.  The effect of the 
strong CYP3A inducer rifampin on venetoclax PK was evaluated in 12 female patients of 
non-childbearing potential.  Following co-administration of venetoclax with multiple 
doses of rifampin when CYP3A induction effects dominate, venetoclax Cmax and AUC∞
decreased by approximately 42% and 71%, respectively, compared to venetoclax 
administered alone.  Comparing the venetoclax exposure following multiple doses of 
rifampin to that following the first dose of rifampin, venetoclax Cmax and AUC∞decreased 
by approximately 72% and 84%, respectively.  This comparison isolates the effects of 
rifampin CYP3A induction effects from its transporter inhibition effects.
Based on in vitro results, venetoclax was a P-gp, BCRP, and OATP1B1 inhibitor.  It was 
not a potent in vitro inhibitor of CYP3A4, CYP1A2, CYP2B6, or CYP2D6 (IC50
> 30 µM); and it did not induce CYP3A4 or CYP1A2 at concentrations up to 10 µM.  
Venetoclax is also not predicted to cause inhibition of CYP2C19, CYP2C8, CYP2C9, and 
UGT1A1 at clinically relevant concentrations.  It is not an inhibitor of UGT1A4, 
UGT1A6, UGT1A9 and UGT2B7.
Following co-administration of a single dose of venetoclax with warfarin, R- and 
S-warfarin Cmax and AUC∞increased by approximately 18% to 28%.  Relatively low 
variability was observed in warfarin PK.  
No specific clinical trials have been conducted in the subjects with hepatic or renal 
impairment.  No dose adjustment is recommended in patients with mild or moderate 
hepatic or renal (creatinine clearance [CrCl] ≥ 30 mL/min) impairment based on results of 
the population pharmacokinetic analysis.  The analysis indicated no relationship between 
apparent clearance or apparent volume of distribution and hepatic function.  The 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
33
contribution of renal processes to the elimination of venetoclax is negligible, with < 0.1% 
of the dose being recovered in urine.  Additionally, the population PK analysis showed no 
relationship between venetoclax apparent clearance and baseline renal function.  Based on 
the population PK analysis, age, sex, race and weight also do not have an effect on 
venetoclax clearance.
The potential for venetoclax to affect electrocardiogram parameters was evaluated in 
patients with relapsed or refractory CLL or relapsed or refractory NHL.  Results from this 
study showed that at doses through 1200 mg once daily (QD), venetoclax had no effect on 
the QT interval corrected for heart rate using QT Interval Corrected for Heart Rate by 
Fridericia's formula (QTcF), and there was no relationship between venetoclax exposure 
and change in QTcF interval.
Venetoclax Clinical Data
As of 17 September 2015, a total of 102 subjects were dosed in two AbbVie oncology 
Phase 1 studies in multiple myeloma, at doses ranging from 50 mg to 1200 mg.
Study M13-367 is an open-label, multicenter study evaluating the safety, PK and efficacy 
of venetoclax monotherapy given once daily in subjects with relapsed or refractory MM.  
In the dose-escalation (DE) cohorts (3 + 3 design), venetoclax was given orally daily at 
300, 600, 900, or 1200 mg after a 2-week dose ramp-up.  Subjects in the ongoing safety 
expansion (SE) cohort receive 1200 mg daily after ramp-up.  As of 17 September 2015, 
57 subjects were dosed with venetoclax in Study M13-367:  30 from DE cohorts and 
27 from the SE.  
Study M12-901 is an open-label, multicenter study evaluating the safety, PK and efficacy 
of venetoclax when dosed once daily in combination with bortezomib and dexamethasone 
in subjects with relapsed or refractory MM.  As of 17 September 2015, 45 patients were 
dosed with venetoclax in the DE cohorts at doses ranging from 50 mg to 1000 mg.  Dose 
escalation followed a continual reassessment method (CRM) design.  There is no dose 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
34
ramp-up or lead-in period in this study.  Subjects (N ~ 12) in the planned SE cohort 
receive the recommended Phase 3 dose.
Patients in both studies have been heavily pre-treated, with a median (range) number of 
prior lines of therapy of 4 (1 – 13) and 5 (1 – 13) in Studies M12-901 and M13-367, 
respectively.
Additionally, a small (n ~ 24) Phase 1 clinical trial is also being conducted in Japan to 
evaluate the safety and pharmacokinetic profile of venetoclax monotherapy in Japanese 
subjects with hematological malignancies including multiple myeloma (Study M13-834).
As of 17 September 2015, clinical activity has been observed in both Phase 1 studies 
using the International Myeloma Working Group (IMWG) criteria.13,14  In the venetoclax 
monotherapy Study M13-367, objective responses (partial response [PR] or better) were 
observed in 5 out of 43 evaluable subjects (11.6%).  These responses included 2 complete 
responses [CR] and 3 very good partial responses [VGPR].  Also, 4 of these responses 
were observed in subjects with the t(11;14), who comprised 17 of the evaluable subjects.  
In Study M12-901, objective responses were reported in 21 of 41 evaluable subjects 
(51.2%).  Importantly, the objective response rate (ORR) was 17% (3/18) in subjects 
considered refractory to prior bortezomib therapy, but increased to 71% (12/17) in 
bortezomib-sensitive subjects and 100% (6/6) in bortezomib-naïve subjects, respectively.  
Furthermore, whereas no VGPR or better responses were reported in 
bortezomib-refractory patients, 35% and 83% of the bortezomib-sensitive and 
bortezomib-naïve patients, respectively, experienced VGPR or better responses.  
Preliminary results also indicate that subjects who had received 1 to 3 prior lines of 
therapy had higher ORR (83.3%) and VGPR or better (56%), compared to patients who 
had received 4 – 6 (38.5% ORR) or at least 7 (10% ORR) prior lines of therapy.
As of 17 September 2015, discontinuations in the Phase 1 studies (Studies M13-367 and 
M12-901) were between 67% – 69%, and mostly related to progressive disease (PD) 
(61% – 77% of discontinuations).  Few discontinuations occurred due to adverse events 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
35
(AE) not related to PD (7% – 12% of discontinuations).  In Study M12-901, 
treatment-emergent AEs occurring in ≥ 20% of the subjects were constipation (40%), 
diarrhea (38%), thrombocytopenia (33%), insomnia (29%), asthenia (27%), peripheral 
neuropathy (27%), anemia (24%), nausea (24%), dyspnea (22%), peripheral edema 
(22%), and fatigue (20%).  Grade 3 or 4 AEs in ≥ 10% of subjects in Study M12-901 were 
thrombocytopenia (22%), and anemia (16%).  Serious Adverse Events (SAEs) occurred in 
19 subjects (42%), none considered related to venetoclax.  In ≥ 2 patients, the following 
SAEs were noted:  pneumonia (n = 3), cardiac failure, embolism, pyrexia, sepsis, 
respiratory failure, and thrombocytopenia (n = 2 each).  The safety profile in 
Study M13-367 was similar, but with fewer sensory peripheral neuropathy (6.3%) and no 
AE of insomnia reported.  In Study M13-367, SAEs occurred in 14 subjects (29%).  SAEs 
in ≥ 2 pts were sepsis (n = 3), cough, pyrexia, pneumonia, and malignant neoplasm 
progression (2 each).  The SAEs of anemia, supraventricular tachycardia and upper 
abdominal pain (1 of each) were considered possibly related to venetoclax.  
Tumor Lysis Syndrome (TLS) was identified as an important risk when initiating 
venetoclax in CLL patients even with initial doses of 20 and 50 mg doses.  To-date, in the 
dose-finding Phase 1 study, TLS has not been observed in MM patients receiving 
venetoclax at initial doses of 50 to 1200 mg.  
In addition, due to potential mechanism-based toxicities of lymphopenia and neutropenia, 
serious infections are a potential risk with venetoclax therapy.
All information related to the venetoclax clinical pharmacology and clinical data 
(including clinical data with venetoclax in multiple myeloma) can be found in the most 
current version of the Investigator's Brochure.12
Rationale for Studying Venetoclax with Bortezomib and Dexamethasone in Multiple 
Myeloma Subjects 
It is hypothesized that multiple myeloma cells expressing high levels of BCL-2 and low 
levels of MCL-1 would be more susceptible to BCL-inhibition and induction of cell death 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
36
by venetoclax.  High MCL-1 expression may drive resistance to BCL-inhibition in 
myeloma cells, as MCL-1 is also an important anti-apoptotic molecule.  In this study, the 
addition of bortezomib is especially attractive due to its ability to upregulate the MCL-1 
inhibitor NOXA.  Combination efficacy in the nonclinical setting corresponded with 
bortezomib-mediated NOXA upregulation and disruption of BCL-2-BIM complexes 
driven by venetoclax.  Clinical efficacy data from the Phase 1 combination therapy study 
of venetoclax plus Bd support the hypothesis, with high rates of PR and better in subjects 
that are sensitive or naïve to bortezomib therapy.  
Additional information on venetoclax clinical pharmacology and clinical data can be 
found in the most current version of the Investigator's Brochure.12
3.4
Differences Statement
The current study is the first randomized, double-blind, multicenter Phase 3 study 
comparing venetoclax plus Bd versus placebo plus Bd in relapsed or refractory multiple 
myeloma subjects.
3.5
Benefits and Risks
Despite therapeutic advances, MM remains essentially incurable, associated with high 
morbidity and mortality, and even with the best available approved agents, all patients 
will eventually relapse.  Furthermore, the remission duration in relapsed myeloma 
decreases with each regimen.
Based on evidence of clinically meaningful activity observed in Phase 1 studies with 
venetoclax given as a single agent and when it is combined with the Bd regimen, it is 
anticipated subjects in the investigational arm may benefit from the combined treatment.
Additionally, all subjects randomized in this trial have already progressed on between 1 to 
3 prior lines of therapy and will receive an anti-myeloma regimen of Bd that has proven 
therapeutic value and is a worldwide standard of care.  The safety and efficacy profile of 
Bd has been established in multiple Phase 3 clinical trials.15-18
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
37
Guidance on dose management of Bd is based on the bortezomib prescribing information 
and current standard of care.  
As of 17 September 2015, the safety profile of venetoclax as a monotherapy or plus Bd in 
subjects with relapsed or refractory MM has been consistent with its mechanism of action 
and the background disease in this population.  Based on nonclinical toxicology and 
clinical studies with venetoclax, toxicities may include lymphopenia, neutropenia, anemia 
and gastrointestinal adverse events.  The rate of peripheral neuropathy in Study M12-901 
is in the expected range of a bortezomib-based regimen.  Additionally, no cases of TLS 
have been reported in the Phase 1 studies with venetoclax in MM.  An independent data 
monitoring committee (IDMC) will regularly review safety and efficacy data of treated 
subjects in this study.
The safety and efficacy data to date of venetoclax plus Bd from the Phase 1 study 
supports further evaluation of this combination in subjects with relapsed or refractory 
multiple myeloma.  
Following the study's primary analysis, recommendations for antibiotic prophylaxis and 
dose interruption/reduction for subjects receiving venetoclax/placebo in combination with 
proteasome inhibitors have been implemented (see Section 5.2.4.1, Section 6.1.7.1 and 
Section 6.2.1 - Table 8).  Additionally, recommendations for pneumococcal and influenza 
vaccinations applicable for subjects on study treatment have been implemented (see 
Section 5.2.4.1).
Additional information on venetoclax clinical pharmacology and clinical data (including 
clinical data with venetoclax in multiple myeloma) can be found in the most current 
version of the Investigator's Brochure.12
Considering the coronavirus (COVID-19) pandemic, the benefit and risk to subjects 
participating in this study has been re-evaluated.  Subjects receiving venetoclax, 
bortezomib, and dexamethasone may be at an increased risk for COVID-19 infection or 
experience serious illness if infected.  Management of these adverse events will be made 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
38
on a case-by-case basis with consideration of benefit/risk.  However, based on the 
population and disease being studied and the anticipation that COVID-19 related risks are 
not expected to differ substantially between study subjects and the broader population of 
subjects receiving treatment for multiple myeloma, no change to the benefit/risk balance 
for subjects in this study is expected.
4.0
Study Objectives
The primary objective of the study is to compare PFS based on the IMWG Criteria,13,14 as 
determined by an Independent Review Committee (IRC) between treatment arms in 
subjects with relapsed or refractory multiple myeloma who are considered sensitive or 
naïve to proteasome inhibitors and received 1 to 3 prior lines of therapy for multiple 
myeloma.
The secondary objectives are to compare, between treatment arms, the following:  VGPR 
or better response rate; progression free survival (PFS) in subjects with high BCL-2 
expression; duration of response (DOR); patient reported outcomes (PRO) including 
Worst Pain (Brief Pain Inventory – Short Form [BPI-SF]), Physical Functioning and 
Global Health Status (GHS)/Quality of Life (QoL) (European Organization for Research 
and Treatment of Cancer Quality of Life Questionnaire Core [EORTC QLQ-C30]), and 
Fatigue (Patient Reported Outcomes Measurement Information System [PROMIS] Cancer 
Fatigue Short Form [SF]); overall survival (OS); time to progression (TTP); ORR; 
minimal residual disease (MRD) negativity rate; and safety.
The tertiary objectives of the study are to assess clinical benefit rate (CBR), disease 
control rate (DCR), time to response (TTR), time to next treatment (TNT), other PRO 
endpoints (remaining subscales/items from BPI-SF, EORTC QLQ-C30, European 
Organization for Research and Treatment of Cancer Quality of Life Questionnaire 
Multiple Myeloma Module [EORTC QLQ-MY20], and Euroqol EQ-5D-5L), and a 
preliminary assessment of potential biomarkers for association with PK, safety and 
efficacy.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
39
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This is a Phase 3, multicenter, randomized, double blind, placebo-controlled, parallel 
group study.  This study is designed to evaluate the efficacy and safety of venetoclax plus 
Bd in subjects with relapsed or refractory multiple myeloma who are considered sensitive 
or naïve to proteasome inhibitors and received 1 to 3 prior lines of therapy for MM.  
Approximately 280 subjects at approximately 120 sites will be randomized in a 2:1 ratio 
to receive an oral daily dose of either venetoclax 800 mg or placebo plus Bd, respectively.  
The study is designed to meet scientific and regulatory objectives without enrolling an 
undue number of subjects in alignment with ethical considerations.  Therefore, if the 
target number of subjects has been enrolled, there is a possibility that additional subjects 
in screening will not be enrolled.
The study will consist of the following three phases:
●
Screening:  Study assessments performed prior to randomization, including 
randomization;
●
Treatment:  Study assessments performed from first dose through the 
Treatment Completion Visit (TCV);
●
Follow-Up:  Includes the 30 Day Safety Follow-Up Visit.  Also includes 
IMWG assessments performed after the TCV and survival and post-treatment 
information collected from the date of disease progression until death, subject 
is lost to follow-up, the number of OS events required for the final OS analysis 
is reached, or until study termination by AbbVie.
Screening
Unless otherwise specified, screening assessments must be performed within 21 days 
prior to randomization (see Appendix D and Appendix H for all screening assessments).  
Procedures that are completed as standard of care within 7 days prior to consent may be 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
40
considered for screening.  Laboratory tests not meeting eligibility criteria can be repeated 
during the screening period to confirm eligibility.
Subjects who do not randomize within 21 days of screening will be screen-failed. 
Subjects who are screen-failed may be re-screened one additional time.  Subjects who are 
re-screened will be re-consented.  Re-screened subjects will keep their original screening 
number and will begin the screening period once again.  
Once screening procedures are completed and eligibility is confirmed, subjects will be 
randomized 2:1 to one of the following two arms:
●
Arm 1:  Venetoclax plus Bd;
●
Arm 2:  Placebo plus Bd.
Subjects will be stratified based on prior exposure to bortezomib or other proteasome 
inhibitors (proteasome inhibitor-naïve versus proteasome inhibitor-sensitive) and the 
number of prior lines of therapy (1 versus 2 or 3).
Treatment
Subject treatment must start within 5 days after randomization.  Unless otherwise noted, 
cycle visits may be completed within a window of ± 1 day provided the 72-hour 
bortezomib requirement is kept.  If unable to dose with bortezomib within this allowed 
window, then the cycle visit must be skipped.  A delay of up to 7 days is acceptable for 
Cycle X Day 1 visits, beginning at Cycle 2 Day 1, due to toxicity or scheduling issues.
During Treatment, all assessments must be performed on the day of the specified visit 
unless a time window is specified in the schedule of assessments (Appendix E, 
Appendix F, and Appendix H).  Allowed modifications due to COVID-19 are detailed in 
Section 5.3.1.1.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
41
All eligible subjects will receive venetoclax/placebo orally (PO) once daily (QD) plus Bd 
as follows beginning on Cycle 1 Day 1.  Subjects will be provided with dosing diaries to 
document Venetoclax/Placebo and Dexamethasone dosing compliance beginning at 
Cycle 1 and continuing until discontinuation.  Subjects in Arm 2 (Placebo + Bd) who 
remain on study after being unblinded, will only need to document Dexamethasone 
dosing compliance in their subject dosing diaries.  The subject dosing diaries should be 
reviewed by the Investigator at each clinic visit to assess compliance.  Compliance is 
defined as adhering to the study treatment dosing at least 80% of the time.  Subjects who 
are noncompliant will need to be re-educated by the Investigator and documentation of the 
re-education added to the source documents.
Due to the COVID-19 pandemic, subject visits may be conducted via phone or video 
conference.  In these situations, subject diaries can be couriered to subjects along with 
study drug. Adverse events, concomitant medications and dosing compliance listed in the 
diaries shall be verbally shared with site if a phone or video conference visit occurs 
Diaries should be returned to the study site when the subject is able to visit the site next, 
and appropriately filed with the subject's source documents for this study.
Cycles 1 – 8, 21-day cycle length
●
Venetoclax 800 mg/Placebo QD on Days 1 – 21
●
Bortezomib 1.3 mg/meter (m)2 on Days 1, 4, 8, and 11
●
Dexamethasone 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12
Cycles 9 and beyond, 35-day cycle length
●
Venetoclax 800 mg/Placebo QD on Days 1 – 35*
●
Bortezomib 1.3 mg/m2 on Days 1, 8, 15, and 22**
●
Dexamethasone 20 mg on Days 1, 2, 8, 9, 15, 16, 22 and 23***
*
Placebo tablet administration will be discontinued for subjects in Arm 2 (Placebo + Bd) once subjects are 
unblinded.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
42
**
Bortezomib dosing frequency may be reduced or discontinued per investigator's decision and institutional 
guidelines once subjects are unblinded.
*** Dexamethasone dosing (frequency and/or dose) may be reduced or discontinued per investigator's decision and 
institutional guidelines once subjects are unblinded.
When unblinding occurs, if subjects from Arm 1 (Venetoclax + Bd) and Arm 2 (Placebo + 
Bd) are on dexamethasone monotherapy, they must be discontinued from the study
treatment and from the study once the Safety Follow-Up Visit is completed.
Venetoclax/Placebo will be administered as described in Section 5.5.1.  Note:  Consider 
TLS prophylaxis with oral hydration (at least 1 – 2 liters, as tolerable, each day) in all 
subjects at least 72 hours prior to the first day of dosing with venetoclax/placebo plus Bd 
and continue as appropriate (refer to Section 6.1.7.2).
Venetoclax/Placebo dose modifications guidelines are provided in Section 6.2.1 and 
Section 6.2.2, Table 8, and Table 9.
Bortezomib will be administered as described in Section 5.5.1.  Bortezomib dose 
modifications guidelines are provided in Section 6.2.3 and Table 10.
Dexamethasone will be administered as described in Section 5.5.1.  Dexamethasone dose 
modifications guidelines are provided in Section 6.2.3 and Table 11.
Subjects will continue their study treatment assignment until disease progression, 
unacceptable toxicity or the subject meets other protocol criteria for discontinuation 
(whichever occurs first).  All subjects will have a TCV performed when treatment is 
discontinued.
Baseline IMWG assessments should be completed at Cycle 1 Day 1 prior to first dose of 
study treatment, unless the Screening IMWG assessments were completed within 7 days 
of Cycle 1 Day 1.  Post-baseline IMWG assessments will be performed on Day 1, 
± 7 days of every cycle starting on Cycle 2 Day 1 (Section 5.3.7.1, Appendix E, 
Appendix F, and per the guidelines of Appendix J).
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
43
Disease assessment for each post-baseline IMWG assessment will be performed by the 
Investigator and independently reviewed by a team of multiple myeloma experts (IRC).  
Details regarding the Investigator and IRC assessment progression are provided in 
Section 5.3.7.3.  Interpretations from the IRC will not be sent to sites.
With the completion of the PFS analysis, post-baseline IMWG assessments are no longer 
required to be sent to the IRC and will be reviewed only by the Investigator and/or 
qualified medical site staff.  
An IDMC will periodically review safety and efficacy data.  Once the final Overall 
Survival (OS) analysis is complete (refer to Section 8.1.5.5.2), a final IDMC meeting will 
be held to review safety and efficacy data.  Details regarding the IDMC's review are 
provided in Section 5.5.5.2.
Follow-Up
All subjects should have one Safety Follow-Up Visit approximately 30 days following the 
last dose of study treatment.
Subjects who discontinue study treatment for reasons other than PD (e.g., toxicity, 
non-compliance, etc.) or subjects who receive an off protocol new anti-multiple myeloma 
therapy, will remain on study and continue to be followed for progressive disease per 
IMWG criteria every 4 weeks (± 1 week) following last dose of treatment for the 
first year, and then every 12 weeks (± 1 week) thereafter until PD or until the number of 
OS events required for the final OS analysis is reached, whichever occurs first.
Subjects who experience an event of progressive disease per the IMWG criteria13,14 or 
withdraw from the study will continue to be followed for survival and post-treatment 
information.  Survival information and post-treatment information will be collected 
approximately every 12 weeks (or as needed to allow for more frequent data collection) 
until the endpoint of death, the subject is lost to follow-up, the number of OS events 
required for the final OS analysis is reached, or the study is terminated by AbbVie, 
whichever occurs first.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
44
Subjects who experience an event of progressive disease per the IMWG criteria13,14 or 
withdraw from the study treatment once the number of OS events required for the final 
OS analysis is reached, will be discontinued from the study.
Study visits and assessments are detailed in Section 5.3.1.1.1 and Appendix G.
Figure 1.
Study Schema
5.2
Selection of Study Population
Adult male and female subjects with relapsed or refractory multiple myeloma who are 
sensitive or naïve to proteasome inhibitors, have received 1 to 3 prior lines of therapy for 
multiple myeloma, and who meet all inclusion criteria and none of the exclusion criteria 
will be eligible for enrollment into the study.
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
45
5.2.1
Inclusion Criteria
A subject will be eligible for study participation if he/she meets the following criteria:
1.
Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
2.
Subject has documented relapsed or progressive multiple myeloma on or after any 
regimen or is refractory to the most recent line of therapy.
●
Relapsed myeloma is defined as previously treated myeloma that progresses 
and requires initiation of salvage therapy, but does not meet the criteria for 
refractory myeloma.
●
Refractory myeloma is defined as disease that is nonresponsive (failure to 
achieve minimal response or development of PD) while on primary or salvage 
therapy, or progresses within 60 days of last therapy.
3.
Subject must have received prior treatment with at least one, but no more than 
three, prior lines of therapy for multiple myeloma (refer to Section 5.2.3).
●
A line of therapy consists of ≥ 1 complete cycle of a single agent, a regimen 
consisting of combination of several drugs, or a planned sequential therapy of 
various regimens.
4.
Prior treatment with bortezomib or other proteasome inhibitor is allowed, provided 
ALL of the following criteria are met:
●
Disease is NOT refractory to any proteasome inhibitor, defined as no disease 
progression (i.e., PD, per IMWG or European Society for Blood and Marrow 
Transplantation [EBMT] criteria) while receiving proteasome inhibitor therapy 
or within 60 days after the last dose, AND
●
Best response achieved with any proteasome inhibitor therapy (alone or in 
combination) was at least a PR, AND
●
Subject did not discontinue any proteasome inhibitor due to intolerance or 
≥Grade 3 related toxicity.
5.
Subject has measurable disease at Screening, defined as at least one of the 
following:
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
46
●
Serum M-protein ≥ 0.5 g/dL, OR
●
Urine M-protein ≥ 200 mg in 24-hours, OR
●
Serum immunoglobulin free light chain (FLC) ≥ 10 mg/dL provided serum 
FLC ratio is abnormal.
6.
Subject must meet the following laboratory parameters, per laboratory reference 
range:
●
Absolute neutrophil count (ANC) ≥ 1000/microliter (µL) within 2 weeks prior 
to randomization.  Subjects may use growth factor support to achieve ANC 
eligibility criteria.
●
Platelet count ≥ 50,000/millimeter (mm)3, within 2 weeks prior to 
randomization.  For subjects with > 50% myeloma involvement in the bone 
marrow, a platelet count of ≥ 30,000/mm3, within 2 weeks prior to 
randomization is allowed.  Subjects cannot receive a platelet transfusion within 
72 hours prior to the platelet count used for eligibility.  
●
Hemoglobin ≥ 8.0 gram (g)/deciliter (dL), within 2 weeks prior to 
randomization.  Subjects may receive RBC transfusions in accordance with 
institutional guidelines to meet this criterion.
●
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × 
upper limit of normal range (ULN).
●
Total bilirubin ≤ 1.5 × ULN.  Subjects with documented Gilbert's syndrome 
may have bilirubin > 1.5 × ULN with the approval of the AbbVie TA MD or 
designee (refer to Section 6.1.5).
●
CrCl ≥ 30 mL/minute (min), measured by 24-hour urine collection or calculated 
using Cockcroft-Gault formula.
CrCl = ((140 – age in years) × weight in kg × 0.85 if female) / (72 × serum creatinine in mg/dL)
7.
France and Japan Subjects Only:  PaO2 ≥ 60 millimeter mercury (mmHg) by 
arterial blood gas analysis or SpO2 ≥93% by percutaneous oxygen saturation.
8.
Subject must be ≥ 18 years of age.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
47
9.
Subject must voluntarily sign and date an informed consent, approved by an 
Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to 
the initiation of any screening or study-specific procedures.
10.
If female, subject is either not of childbearing potential, defined as postmenopausal 
for at least 1 year or surgically sterile (bilateral tubal ligation at least 3 months 
before study participation, bilateral oophorectomy and/or hysterectomy) or is of 
childbearing potential and is practicing at least one of the following highly 
effective methods of birth control on Study Day 1 (or earlier) through at least 
90 days after last dose of study treatment.
Examples of approved methods of birth control in this study include the following:
●
Intrauterine device (IUD);
●
Intrauterine hormone-releasing system (IUS);
●
Combined (estrogen and progestogen containing) hormonal contraception (oral, 
intravaginal, transdermal) associated with the inhibition of ovulation, initiated 
at least 3 months prior to Study Day 1.  Also, barrier method must be used 
during this study from initial study drug administration to 90 days after the last 
dose of study drug as drug-drug interaction with venetoclax upon the hormonal 
contraception is unknown;
●
Progestogen-only hormonal contraception (oral, injectable, implantable) 
associated with inhibition of ovulation, initiated at least 3 months prior to Study 
Day 1.  Also, barrier method must be used during this study from initial study 
drug administration to 90 days after the last dose of study drug as drug-drug 
interaction with venetoclax upon the hormonal contraception is unknown;
●
Bilateral tubal occlusion/ligation at least 3 months before study participation;
●
Bilateral tubal occlusion via hysteroscopy (i.e., Essure), provided a 
hysterosalpingogram confirms success of the procedure at least 3 months 
before study participation
●
A vasectomized partner(s) provided the vasectomized partner verbally confirms 
receipt of medical assessment of the surgical success, and is the sole sexual 
partner of the WOCBP trial participant;
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
48
●
Total abstinence:  Refraining from heterosexual intercourse when this is in line 
with the preferred and usual lifestyle of the subject [periodic abstinence 
(e.g., calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable].
Note:  If male, subject agrees to inform their partner(s) that the effects of 
venetoclax on an unborn fetus or embryo in humans are unknown.
11.
Females of childbearing potential must have negative results for pregnancy test 
performed:
●
At Screening on a serum sample obtained within 21 days prior to 
randomization.
●
Prior to dosing on a urine sample obtained on the first day of study drug 
administration, if it has been > 24 hours since obtaining the serum pregnancy 
test results.
●
Females with documented non-childbearing potential (either postmenopausal or 
permanently surgically sterile as defined above) at Screening do not require 
pregnancy testing.
Rationale for Inclusion Criteria
1 – 5, 8
To select the subject population
6 – 7
For the safety of the subjects
9
In accordance with Harmonized Good Clinical Practice (GCP)
10 – 11
The impact of venetoclax on pregnancy is unknown
5.2.2
Exclusion Criteria
A subject will not be eligible for study participation if he/she meets any of the following 
criteria:
1.
Subject is refractory to any proteasome inhibitor, defined as progression on or 
within 60 days of the last dose of a proteasome inhibitor-containing regimen.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
49
2.
Subject has had prior treatment with proteasome inhibitor within 60 days prior to 
first dose of study drug.
3.
Subject has any of the following conditions:
●
Non-secretory multiple myeloma
●
Active plasma cell leukemia i.e., either 20% of peripheral white blood cells 
comprised of plasma cells or > 2.0 × 109/liter (L) circulating plasma cells by 
standard differential
●
Waldenström's macroglobulinemia
●
Amyloidosis
●
POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, 
monoclonal protein, and skin changes)
●
Known Human Immunodeficiency Viral (HIV) infection
●
Active hepatitis B or C infection based on screening blood testing
●
Significant cardiovascular disease, including uncontrolled angina, severe or 
uncontrolled arrhythmia, recent myocardial infarction within 6 months of 
randomization, or congestive heart failure New York Heart Association 
(NYHA) Class ≥ 3
●
France only: Significant cardiovascular or pericardial disease, including 
uncontrolled angina, severe or uncontrolled arrhythmia, recent myocardial 
infarction within 6 months of randomization, congestive heart failure New 
York Heart Association (NYHA) Class ≥ 3
●
Major surgery within 4 weeks prior to randomization
●
Acute infections requiring parenteral therapy (antibiotic, antifungal, or 
antiviral) within 14 days prior to randomization
●
Peripheral neuropathy ≥ Grade 3 or ≥ Grade 2 with pain within 2 weeks prior to 
randomization
●
Uncontrolled diabetes or uncontrolled hypertension within 14 days prior to 
randomization
●
Any other medical condition that, in the opinion of the Investigator, would 
adversely affect the subject's participation in the study
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
50
4.
Subject has a history of other active malignancies, including myelodysplastic 
syndrome (MDS), within the past 3 years prior to study entry, with the following 
exceptions:
●
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 (PSA) levels off treatment
●
Previous malignancy with no evidence of disease, confined and surgically 
resected (or treated with other modalities) with curative intent and unlikely to 
impact survival during the duration of the study
5.
If subject had prior stem cell transplant (SCT), subject has evidence of ongoing 
graft-versus-host disease (GvHD).
6.
Subject has a hypersensitivity or allergy to any of the components of study 
treatment including bortezomib, boron, mannitol, or dexamethasone.
7.
Subject has received prior treatment with a BCL-2 family inhibitor.
8.
Subject has been treated or received any of the following:
●
Allogeneic or syngeneic SCT within 16 weeks prior to randomization.
●
Autologous SCT within 12 weeks prior to randomization.
●
Immunization with live vaccine within 8 weeks prior to randomization.
●
Anti-myeloma monoclonal antibodies within 6 weeks prior to randomization.
●
Any anti-myeloma therapy (other than monoclonal antibodies), including 
chemotherapy, biological, immunotherapy or an investigational therapy, 
including targeted small molecule agents within 2 weeks prior to 
randomization.
●
Anti-myeloma radiotherapy within 14 days prior to randomization.
●
Corticosteroid therapy at a dose equivalent to > 4 mg/day of dexamethasone or 
a single dose of corticosteroid greater than or equal to the equivalence of 
40 mg/day dexamethasone within 2 weeks prior to randomization.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
51
●
A strong or moderate CYP3A inhibitor or inducer within 1 week prior to 
randomization (refer to Section 5.3.1.2).
9.
Japan Subjects Only:  Clinically indicated interstitial pneumonitis, pulmonary 
fibrosis, or abnormal (e.g., ground glass opacity or linear) interstitial shadow 
bilaterally by a chest-computerized tomography (CT) scan (high resolution) 
regardless of symptom, or high value of KL-6, SPA or SP-D, to be consulted with 
chest physician or other expert as necessary.
10.
Female subject who is pregnant, breastfeeding or is considering becoming pregnant 
during the study or for approximately 90 days after the last dose of study 
treatment.
11.
Male subject who is considering fathering a child or donating sperm during the 
study or for approximately 90 days after the last dose of study drug.
Rationale for Exclusion Criteria
1 – 2
To select the appropriate subject population
3 – 9
For the safety of the subjects
10
The impact of venetoclax on pregnancy is unknown
5.2.3
Determination of the Number of Prior Lines of Therapy
A line of therapy consists of at least 1 complete cycle of a single agent, a regimen 
consisting of combination of several drugs, or a planned sequential therapy of various 
regimens.19
A treatment is considered a new line of therapy if any of these 3 following conditions are 
met:
●
Start of a new line of treatment after discontinuation of a previous line:  If a 
treatment regimen is discontinued for any reason and a different regimen is 
started, it should be considered a new line of therapy.  A regimen is considered 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
52
to have been discontinued if all the drugs in that given regimen have been 
stopped.  A regimen is not considered to have been discontinued if only some 
of the drugs of the regimen, but not all, have been discontinued.
●
The unplanned addition or substitution of 1 or more drugs in an existing 
regimen:  Unplanned addition of a new drug or switching to a different drug (or 
combination of drugs) due to any reason is considered a new line of therapy.
●
SCT:  In patients undergoing > 1 SCT, except in the case of a planned tandem 
SCT with a predefined interval (such as 3 months), each SCT (autologous, 
allogeneic, or syngeneic) should be considered a new line of therapy regardless 
of whether the conditioning regimen used is the same or different.  Data on type 
of SCT should also be captured.
5.2.4
Prior and Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medications, 
vitamins and/or herbal supplements) that the subject is receiving at the time of enrollment, 
or receives during the study, must be documented in source documents and electronic case 
report forms (eCRFs) along with the reason for use, date(s) of administration including 
start and end dates, and dosage information including dose, route, and frequency.
The AbbVie TA MD or designee (refer to Section 6.1.5) should be contacted if there are 
any questions regarding prior and concomitant therapies.
5.2.4.1
Pretreatment Requirements
All subjects must start the following treatment at least 24 hours prior to dosing with 
bortezomib:
●
Acyclovir (400 mg orally [PO] twice a day or local standard dosing) or 
valacyclovir (500 mg PO once a day or local standard dosing) or other 
equivalent antiviral during treatment with bortezomib (additional prophylaxis is 
at the Investigator's discretion).
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
53
Prophylaxis for Grade 3 or Serious Infections
All subjects receiving treatment with venetoclax/placebo in combination with a 
proteasome inhibitor must receive antibiotic prophylaxis as outlined in Section 6.1.7.1, 
Management of Cytopenias and Infection. 
Pneumococcal and Influenza Vaccination
All subjects must be vaccinated against pneumococcus and receive a yearly influenza 
vaccination (live attenuated vaccines are not allowed), while on study treatment.  It is 
mandated that pneumococcal and yearly influenza vaccinations be administered after 
signing the updated informed consent for all subjects who have not previously received 
the influenza and/or pneumococcal vaccine within the recommended time frame per local 
and/or institutional vaccination guidelines, unless contraindicated, not available, or not 
applicable per local standard of care.
It is recommended that subjects in Progression Follow-up and/or Survival Follow-up 
remain vaccinated against pneumococcus and receive a yearly influenza vaccination at the 
discretion of the investigator.  
Please refer to local label and/or institutional guidelines for additional information (e.g., 
vaccination/booster schedules) and contraindications regarding pneumococcal and 
influenza vaccinations.  Local and/or institutional vaccination references must be recorded 
in the site source documents.
Pneumococcal and Influenza vaccination information must be recorded on the 
Vaccination eCRF.
COVID-19 Pandemic-Related Acceptable Protocol Modification:
A delay in pneumococcal and/or influenza vaccination may take place per PI discretion if 
the subject tests positive for COVID-19 until such time that the subject has clinically 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
54
recovered or per institutional guidelines. In all other cases, pneumococcal and/or 
Influenza vaccinations should continue as scheduled per protocol.
5.2.4.2
Allowed Treatments
The following concomitant medications are allowed during study treatment.  Please refer 
to Table 1 for a list of restricted medications due to potential drug-drug interaction (DDI) 
when considering the use of the following:
●
Hormonal contraceptives (examples include birth control pills, vaginal rings, or 
patches), associated with inhibition of ovulation for at least 3 months prior to 
taking study treatment.
●
Colony stimulating factors (granulocyte colony-stimulating factor [G-CSF], 
granulocyte-macrophage colony-stimulating factor [GM-CSF]) will be allowed 
per American Society of Clinical Oncology (ASCO) guidelines.20
●
Bisphosphonates intravenous (IV) or PO as indicated per Institutional 
guidelines.
●
Oral proton-pump inhibitor (lansoprazole, omeprazole, esomeprazole, etc.) as 
prophylactic therapy for peptic ulcer disease during treatment with 
dexamethasone.
●
Antimicrobial (including anti-fungal) prophylaxis.
●
Anticoagulants to prevent or treat thromboembolic events.
●
Best supportive care and treatment (e.g., antiemetics, antibiotics, transfusions, 
nutritional support, pain control, etc.).
●
Only low dose corticosteroids (e.g., prednisone ≤ 10 mg PO QD or its 
equivalent), inhaled steroids and topical preparations for reasons other than 
multiple myeloma (e.g., asthma) are allowed during study treatment.  Systemic 
corticosteroids > 10 mg PO QD of prednisone (or its equivalent) should not be 
given on the same day as dexamethasone is administered.  Systemic 
corticosteroids > 10 mg PO QD of prednisone (or its equivalent) are allowed 
when dexamethasone has not been interrupted provided that the dose of 
prednisone (or its equivalent) was given for less than 7 days and the cumulative 
dose was < 120 mg.  For additional guidance and to determine the equivalent 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
55
dose of systemic corticosteroid, please refer to the Corticosteroid Conversion 
Table, Appendix M.
●
Surgery and radiation:
○
Localized radiation therapy to a site of pre-existing disease may be 
permitted while on study.  Following approval by the AbbVie TA MD or 
designee (refer to Section 6.1.5), the subject may initiate or continue with 
protocol therapy without interruption during the course of palliative 
radiation therapy if the Investigator believes that the risk of excessive bone 
marrow suppression or other toxicity is acceptable, and it is in the best 
interest of the subject to do so.
○
If the subject develops a definite increase in the size of existing bone 
lesions or soft tissue plasmacytomas that meets the criteria for progressive 
disease, treatment must be discontinued for progressive disease 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 Case 
Report Form.
5.2.4.3
Excluded and Cautionary Medications
General guidelines regarding excluded and cautionary medications are summarized in 
Table 1.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
56
Table 1.
Excluded and Cautionary Medications
Excluded

Any systemic anti-myeloma therapies other than bortezomib, dexamethasone and venetoclax while 
on study treatment.

Biologic agents (e.g., monoclonal antibodies) for anti-neoplastic intent.
Cautionary, Additional Guidance Noted 

Strong and Moderate CYP3A inhibitors 
Consider alternative medications.  If subject requires use of these medications, use with caution and 
reduce the venetoclax dose by 2-fold for moderate inhibitors and 4-fold for strong inhibitors during 
co-administration.  Patients should be monitored more closely for signs of toxicities and the dose 
may need to be further adjusted.
After discontinuation of CYP3A inhibitor, wait for 3 days before venetoclax dose is increased back 
to the previous dose level.

Strong and Moderate CYP3A inducers
Consider alternative medications.  If subject requires use of these medications, use with caution and 
contact AbbVie TA MD or designee (refer to Section 6.1.5) for guidance.
Cautionary

Warfarin and coumadin derivatives

P-gp substrates

BCRP substrates

OATP1B1/1B3 substrates

P-gp inhibitors

BCRP inhibitors

High Dose Corticosteroidsa
a.
Refer to Appendix M for additional guidance.
A sample list of excluded medications and cautionary medications that fall into the 
categories within Section 5.2.4.3 is contained in Appendix I.  It is not possible to produce 
a 100% exhaustive list of medications that fall into these categories, so if in question, 
please refer to the appropriate product label.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
57
5.3
Efficacy, Pharmacokinetic, Biomarker, Exploratory 
Research and Safety Assessments/Variables
5.3.1
Efficacy and Safety Measurements Assessed
The study visit and procedure schedules for each phase of the study are outlined in 
Appendix D (Schedule of Assessments – Screening), Appendix E (Schedule of 
Assessments – Treatment:  Cycles 1 – 8), Appendix F (Schedule of Assessments –
Treatment:  Cycles 9 and Beyond Through TCV), and Appendix G (Schedule of 
Assessments – Follow-Up).  Additional information regarding pharmacokinetic, 
pharmacogenomics, and biomarker collections can be found in Appendix H.
Japan Subjects Only:  The safety of the first 12 subjects enrolled in the run-in phase will 
be assessed.  Based on the safety results of the first 12 subjects and it is determined that 
enrollment can continue, the study will proceed to the randomized phase. All of the 
subjects in the run-in phase will be hospitalized during Cycle 1.  Operational details are
described in the Japan run-in phase manual.
COVID-19 Pandemic-Related Acceptable Protocol Modification:
Pharmacokinetic, biomarker, and exploratory research samples (Appendix H) may only be 
collected at the study site and are not to be collected if travel restrictions or other changes 
in local regulations in light of the COVID-19 pandemic prevent the subject from visiting 
the study site at a sample collection time point.
5.3.1.1
Study Procedures
The study procedures are discussed in detail in this section, with the exception of 
treatments administered and timing of dose (Section 5.5.1), monitoring of treatment 
compliance (Section 5.5.6) and adverse event information (Section 6.1.1.1).  All study 
data will be recorded on eCRFs.
Study visits may be impacted due to the COVID-19 pandemic.  This may include changes 
such as phone or virtual visits, visits at alternative locations, or changes in the visit 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
58
frequency and timing of study procedures, among others.  Every effort should be made to 
ensure the safety of subjects and site staff, while maintaining the integrity of the study.  
Additional details are provided in the following sections of the protocol, in case visits 
cannot be conducted onsite due to travel restrictions or other pandemic-related reasons:
●
Section 3.5, Benefits and Risks
●
Section 5.1, Overall Study Design and Plan: Description
●
Section 5.2.4.1, Pretreatment Requirements 
●
Section 5.3.1, Efficacy and Safety Measurements Assessed
●
Section 5.3.1.1, Study Procedures
●
Section 5.3.1.1.1, Screening and Treatment Assessments:
○
Informed Consent
○
Concomitant Medications and AE Assessments
○
Physical Examination
○
Vital Signs
○
ECOG Performance Status
○
Patient Reported Outcome (PRO) Assessments
○
Cardiac Assessments
○
Clinical Laboratory Tests
●
Section 5.3.1.1.2, Follow-Up
●
Section 5.3.1.3, Collection and Handling of Biomarker and Exploratory 
Research Samples
●
Section 5.3.7.1, Disease Assessments:
○
Laboratory Tests for Multiple Myeloma
○
Skeletal Survey
○
Plasmacytoma Evaluation
○
Bone Marrow Aspirate and Biopsy
●
Section 5.3.7.3, Evaluation of Disease
●
Section 5.4.1, Discontinuation of Individual Subjects from Treatment
●
Section 5.4.2, Withdrawal from Study Visits
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
59
●
Section 5.5.1, Treatments Administered
●
Section 6.1.5, Adverse Event Reporting
●
Section 6.2, Guidelines for Dose Modifications and Treatment
●
Section 7.0, Protocol Deviations
●
Section 9.2, Ethical Conduct of the Study
●
Section 10.1, Source Documents
●
Section 11.0, Data Quality Assurance
5.3.1.1.1
Screening and Treatment Assessments
Subjects will undergo screening procedures within 21 days prior to randomization.  For 
procedures performed at screening and repeated prior to dosing on Cycle 1 Day 1, the 
later procedure(s) will serve as baseline for clinical assessment.  Procedures that are 
completed as standard of care within 7 days of consent may be considered for screening.  
Informed Consent
Signed informed consent will be obtained from the subject or the subject's legally 
acceptable representative before any study-specific procedures are undertaken or before 
any prohibited medications are withheld from the subject in order to participate in this 
study.  Informed consent is also required for optional exploratory research sampling.  
Details about how informed consent will be obtained and documented are provided in 
Section 9.3.
COVID-19 Pandemic-Related Acceptable Protocol Modification:
Due to the COVID-19 pandemic, it is possible that additional protocol modifications not 
outlined in this protocol may become necessary.  If this situation arises, in addition to the 
study informed consent, additional verbal consent may be obtained prior to these 
adaptations or substantial changes in study conduct in accordance with local regulations.  
All informed consent procedures must be documented within the subject's source 
documents.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
60
Medical and Oncology History
The medical history includes complete medical history, including documentation of any 
clinically significant medical condition(s); history of tobacco and alcohol use. 
Detailed Oncology History
The following will be documented:
●
Date of multiple myeloma diagnosis
●
Histopathology and Cytogenetic information
●
Staging/Grading
●
Any surgical procedures
●
Prior treatments administered (including dates, type of modality, response to 
treatment and reason for treatment discontinuation)
●
Proteasome inhibitor naiveté/sensitivity must be assessed and documented per 
the definitions in Inclusion Criterion 2
●
The number of prior lines of therapy must be assessed and documented per the 
definition provided in Inclusion Criterion 3 and Section 5.2.3.
On Cycle 1 Day 1, any changes observed (i.e., abnormal laboratory or vital sign 
assessment) from the screening assessments, prior to dosing, and not considered related to 
study-specific required procedures will be recorded in the subject's medical or oncology 
history, as applicable and will serve as the subject's baseline.  At each subsequent visit, 
the subject's condition will be reviewed and any clinically significant changes from 
baseline will be recorded in the source documents and on the adverse event eCRF.  
Additional guidance for IMWG diagnostic criteria can be found in Appendix C.
Concomitant Medication and AE Assessments
Concomitant medication and AE assessments will be performed prior to the initial dose at 
each subject visit, per Appendix D, Appendix E, Appendix F, and Appendix G. 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
61
COVID-19 Pandemic-Related Acceptable Protocol Modification:
Due to the COVID-19 pandemic, concomitant medication and adverse event assessment 
visits may be conducted via phone or video conference. Additional guidance for the 
reporting of COVID-19 adverse events (including the capture of specific signs/symptoms 
of infection and testing results) can be found in Section 6.1.5.
Physical Examination
Physical examinations (full and targeted exams), including body weight, will be 
performed per Appendix D, Appendix E, Appendix F, and Appendix G.  The targeted 
physical exam includes an assessment of heart, lung, and abdomen, and any body system, 
guided by the examiner's observations or subject complaints on new or changed 
conditions, symptoms, or concerns.  Target exams can be performed by the Principal 
Investigator (PI) or delegated to qualified medical staff (e.g., a sub-Investigator, nurse, 
etc.).
If the screening physical examination is performed within 7 days of Cycle 1 Day 1, it is 
not required to repeat the exam on Cycle 1 Day 1 unless clinically indicated.  Physical 
examinations after screening may be performed within 72 hours before or after the 
scheduled visit.  Clinically significant changes from baseline will be documented in the 
source documentation and eCRFs as adverse events.
Height will be measured at the Screening Visit only.  For height and weight, subject 
should not wear shoes.
COVID-19 Pandemic-Related Acceptable Protocol Modification:
Due to the COVID-19 pandemic, subject visits may be conducted via phone or video 
conference.  In these situations, body weight may be collected by the subject or caregiver 
as needed, and physical exam may be performed by another licensed practitioner.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
62
Vital Signs
Vital signs will be performed at each visit, per Appendix D, Appendix E, Appendix F, and 
Appendix G.  Vital sign determinations include sitting blood pressure, heart rate, 
respiratory rate, and body temperature.  Vital signs should be measured prior to blood 
collections and prior to dosing with venetoclax/placebo and Bd.  It is recommended that 
vitals should be assessed after the subject has been seated quietly for at least 5 minutes.   
COVID-19 Pandemic-Related Acceptable Protocol Modification:
Due to the COVID-19 pandemic, subject visits may be conducted via phone or video 
conference.  In these situations, vital signs may be obtained by another licensed 
practitioner, or collected by the subject or caregiver as needed.
ECOG Performance Status
The ECOG performance status will be assessed per Appendix D, Appendix E, 
Appendix F, and Appendix G using the following criteria:
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.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
63
COVID-19 Pandemic-Related Acceptable Protocol Modification:
Due to the COVID-19 pandemic, subject visits may be conducted via phone or video 
conference.  If subjects are unable to be assessed by the study site, ECOG performance 
status may be performed by another licensed practitioner.
Patient-Reported Outcome (PRO) Assessments
PRO assessments include BPI-SF, EORTC QLQ-C30, EORTC QLC-MY20, PROMIS 
Cancer Fatigue SF, and EQ-5D-5L.  These assessments will be collected per Appendix D, 
Appendix E, and Appendix F throughout the trial until the final OS analysis.  Once the 
number of OS events required for the final OS analysis is reached, PRO assessments will 
no longer be collected.
Subjects may complete all baseline PRO assessments within 72 hours prior to the 
first dose of venetoclax/placebo.  It is required that PRO assessments be completed prior 
to any other clinical assessments and prior to dosing for subsequent cycle visits.  If a PRO 
assessment is collected on a non-protocol required visit date, as requested per 
Appendix D, Appendix E and Appendix F, this PRO assessment may be reclassified.
BPI-SF
The BPI-SF is a pain-specific measure developed to assess patient-reported severity (or 
intensity) of pain (4 items) and the impact of pain on daily functioning (7 items) in 
patients with cancer pain.21  The four pain severity items assess pain at its "worst," "least,"
"average," and "now" (current pain).  For these items, patients are asked to rate their pain 
on an 11-point numeric rating scale with anchors of 0 (no pain) and 10 (pain as bad as you 
can imagine).  The BPI "worst" pain severity item has been shown to be reliable and valid 
for use as a single item.22  The BPI-SF also includes questions to measure the interference 
of pain in the patient's daily life, including general activity, mood, ability to walk, normal 
work both outside the home and housework, relations to other people, sleep, as well as 
enjoyment of life.  For these items, patients are asked to describe the extent to which pain 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
64
has interfered on an 11-point numeric rating scale with anchors of 0 (does not interfere) to 
10 (completely interferes).
EORTC QLQ-C30
HRQoL and symptoms will be assessed with the EORTC-QLQ-C30 version 3.23  The 
QLQ-C30 is a 30-item subject self-report questionnaire composed of both multi-item and 
single scales, including five functional scales (physical, role, emotional, social, and 
cognitive), three symptom scales (fatigue, nausea and vomiting, and pain), a global health 
status/quality of life scale, and six single items (dyspnea, insomnia, appetite loss, 
constipation, diarrhea, and financial difficulties).  Subjects rate items on a four-point 
scale, with 1 as "not at all" and 4 as "very much."  The QLQ-C30 was developed and 
validated for use in a cancer patient population, and its reliability and validity is highly 
consistent across different language-cultural groups.
EORTC QLQ-MY20
The EORTC QLQ-MY20 was developed as an additional module for the QLQ-C30 and is 
composed of 20 multiple myeloma specific items.24  The QLQ-MY20 includes scales for 
disease symptoms, side effects of treatment, future perspective, and body image.  Values 
for each scale range from 0 to 100.  Subjects rate items on a four-point scale, with 1 as 
"not at all" and 4 as "very much."  The QLQ-MY20 is a reliable and valid instrument for 
measuring quality of life in myeloma patients.
PROMIS Cancer Fatigue SF
The PROMIS® is a system of highly reliable, precise measures of patient-reported health 
status for physical, mental, and social well-being.25  PROMIS instruments measure 
concepts such as pain, fatigue, physical function, depression, anxiety and social function.  
Fatigue will be assessed using the PROMIS Cancer Fatigue SF that has been developed 
for use in oncology populations.26,27  PROMIS Cancer Fatigue SF is a seven item 
questionnaire that assesses the impact and experience of fatigue over the past 7 days.  All 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
65
questions employ the following five response options:  1 = Not at all, 2 = A little bit, 3 = 
Somewhat, 4 = Quite a bit, and 5 = Very much.
EQ-5D-5L
The EQ-5D-5L is a generic preference instrument that has been validated in numerous 
populations.28  The EQ-5D-5L has five dimensions:  mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression.  These dimensions are measured on a five level 
scale:  no problems, slight problems, moderate problems, severe problems, and extreme 
problems.  The EQ-5D-5L also contains a visual analog scale (VAS) to assess the 
subject's overall health.
Table 2.
Patient-Reported Outcome Assessments
Administration Order
Test
Administration Time
1
BPI-SF
Approximately 5 minutes
2
PROMIS Cancer Fatigue SF
Approximately 5 minutes
3
EORTC QLQ-C30
Approximately 12 minutes
4
EORTC QLQ-MY20
Approximately 5 minutes
5
EQ-5D-5L
Approximately 5 minutes
Total Admin Time:  Approximately 32 minutes
COVID-19 Pandemic-Related Acceptable Protocol Modification:
Due to the COVID-19 pandemic, subject visits may be conducted via phone or video 
conference.  All PROs are eligible for completion by interview at such visits; however, if 
it is not possible to complete all PROs during the telephone interview, the PRO 
completion prioritization is as follows (highest to lowest priority): EORTC QLQ-C30, 
EORTC QLQ-MY20, EQ-5D-5L, PROMIS and BPI-SF.  In this situation, the interviewer 
properly delegated for this assessment will read the PRO questions and response options 
to the subject and record the subject responses either on paper or directly into the 
electronic web-based system.  If subject responses are recorded on paper, the Subject ID 
number, visit identification, date and time that each PRO was started and completed 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
66
should be recorded along with the interviewer's name on each page of the paper screen 
report and recorded in the source.  In both cases, the site must also record in the source 
that the PRO data collection was performed remotely along with who collected the 
information.  The subject's ability to view the PRO to understand the questions and 
response options should be preserved.  Sites may share the questionnaire by 
videoconference or send the questionnaires (email or hard copy) to the subjects to allow 
them to read/understand the questions and responses when the subject is providing 
responses over the phone.
Cardiac Assessments
Cardiac assessments will be performed using a 12-lead electrocardiogram.  Data from the 
cardiac assessment will be entered into the electronic data capture (EDC) eCRF within 
5 days of report availability.
12-Lead Electrocardiogram (ECG)
A resting 12-lead ECG will be performed per Appendix D and Appendix F.  An 
appropriately qualified physician at the study site (local reader) will determine if any 
findings outside normal physiological variation are clinically significant.  The local 
reading of the ECG will be used by the Investigator for subject safety assessments, 
including adverse event determination and management, and termination of subjects from 
the study.  The local reader will sign and date the ECG tracing and provide a global 
interpretation using the following categories:
●
normal ECG
●
abnormal ECG – not clinically significant (NCS)
●
abnormal ECG – clinically significant (CS)
●
unable to evaluate
All ECGs will be entered into the eCRF.  If the global interpretation is abnormal (CS), the 
Investigator will provide specifics pertaining to the abnormality (e.g., sinus bradycardia, 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
67
arrhythmias).  The corrected QT interval measurement will be documented only if the 
Investigator selects the "prolonged QT" box for an abnormal ECG.  Correction by the 
Bazett formula (QTcB) is suggested for consistency across sites; however, correction by 
other methods may be acceptable based on discussion with the AbbVie TA MD or 
designee.  A copy of any other ECGs will sent to AbbVie, if requested.  The original ECG 
tracing will be retained in the subject's records at the study site.
COVID-19 Pandemic-Related Acceptable Protocol Modification:
In the event the ECG cannot be performed at the study site due to study modifications 
related to the COVID-19 pandemic, the ECG may be completed at other centers providing 
the modality/technique is equivalent.
Lung Disease Risk Assessment – JAPAN and FRANCE ONLY
All subjects enrolled in Japan and France are required to complete the following 
assessments below:
●
a PaO2 by arterial blood gas analysis or SpO2 by percutaneous oxygen 
saturation at screening will be performed
●
a chest CT (high resolution) scan at screening
Tests may be followed during the study visits at the discretion of the investigator.
Pregnancy Test
For female subjects of childbearing potential, pregnancy testing will be performed per 
Appendix D and Appendix E (if necessary).  Pregnancy tests must have a minimal 
sensitivity of ≥ 25 IU/L.
Subjects considered not of childbearing potential must be surgically sterile or 
postmenopausal for at least 1 year.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
68
Clinical Laboratory Tests
All subjects will undergo the laboratory assessments listed in Table 3 per the schedule in 
Appendix D, Appendix E, and Appendix F.
Certified local laboratories will be utilized to process and provide results for the 
hematology and chemistry labs listed in Table 3.  These data will be used for all data 
analysis.  The appropriate certifications will be collected from the local laboratories.  
A certified central laboratory will be utilized to process and provide results for 
coagulation, viral serologies, urinalysis, and special chemistry labs listed in Table 3.  
These data will be used for all data analysis.  The central laboratory will provide 
instructions regarding the collection, processing, handling, and shipping of samples.  
Qualified medical staff at the study site will review, initial, and date all central and local 
laboratory results.  Any laboratory value outside the reference range that is considered 
clinically significant by the Investigator will be followed as appropriate.
COVID-19 Pandemic-Related Acceptable Protocol Modification:
If travel restrictions or other changes in local regulations in light of the COVID-19 
pandemic prevent the subject from having blood drawn for laboratory testing at the study 
site, if possible, arrange for subjects to have laboratory work done at a local laboratory, 
hospital, or other facility.  Local lab results should be obtained along with reference 
ranges and kept within the subjects' source documentation.  Local lab results should be 
reviewed by the investigator as soon as possible and prior to study drug dispensation.
At minimum, safety lab samples [hematology, chemistry, urine pregnancy testing (women 
of childbearing potential), and coagulation panel (when applicable)] should be collected 
and reviewed by the investigator at least once per cycle to have venetoclax/placebo and 
dexamethasone dispensed.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
69
In case of bortezomib, safety lab samples [hematology, chemistry, urine pregnancy testing 
(women of childbearing potential), and coagulation panel (when applicable)] must be 
collected and reviewed by the investigator prior to each bortezomib administration.  If this 
is not possible, bortezomib cannot be dispensed to the subject.
If safety lab samples cannot be collected and related results reviewed by the investigator 
as described above, venetoclax/placebo, dexamethasone or bortezomib cannot be 
dispensed to the subject.
Coagulation
Prothrombin time (PT)/Activated Partial Thromboplastin Time (aPTT) and International 
Normalized Ratio (INR) will be performed per Appendix D.
Coagulation tests will be done for all subjects at screening and only in subjects being 
treated with medication for thromboembolic prophylaxis thereafter on Day 1 of each 
cycle.  Subjects who are not on vitamin K antagonists do not require coagulation tests 
after screening.
Hepatitis Serologies
Samples will be collected to identify Hepatitis B surface antigen (HBsAg), and 
Hepatitis C Virus antibody (HCV ab) antibody and ribonucleic acid (RNA) if HCV ab is 
positive per Appendix D.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
70
Table 3.
Clinical Laboratory Tests
Hematology – Local Lab
Serum Chemistry – Local Lab
Urinalysis – Central Lab
Hematocrit
Hemoglobin
RBC count
White blood cell (WBC) count
Neutrophils
Lymphocytes
Monocytes
Basophils
Eosinophils
Platelet count (estimate not 
acceptable)
Reticulocyte Count (Screening, 
Day 1 of each cycle, and 
TCV only)
Blood urea nitrogen (BUN) or urea
Creatinine
Total bilirubin
Serum glutamic-pyruvic
transaminase (SGPT/ALT)
Serum glutamic-oxaloacetic
transaminase (SGOT/AST)
Alkaline phosphatase
Sodium
Potassium
Calcium
Inorganic phosphorus
Uric acida
Total protein
Glucose
Albumin
Lactate dehydrogenase (LDH)
Magnesium
Chloride
Specific gravity
Ketones
pH
Protein
Blood
Glucose
Microscopic examination (as 
indicated)
Special Chemistry Labs –
Central Lab
Amylase
Lipase
Serum β2 Microglobulin 
(Sβ2M)
C-Reactive protein (CRP)
Coagulation – Central Lab
PT
aPTT
INR
Viral Serologies – Central Lab
Viral Serology – Local Lab
HBsAg
HCV ab or RNA
SARS-CoV-2b testing
a.
For samples analyzed locally, at room temperature, rasburicase causes enzymatic degradation of the uric acid in 
blood/plasma/serum samples potentially resulting in spuriously low plasma uric acid readings.  The following 
special sample handling procedure must be followed to avoid ex vivo uric acid degradation. 
1.
Uric acid must be analyzed in plasma.  Blood must be collected into pre-chilled 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 pre-cooled centrifuge (4°C).  Finally, the plasma must 
be maintained in an ice water bath and analyzed for uric acid within 4 hours of collection.
b.
SARS-CoV-2 testing performed at local lab for all subjects on study treatment, as clinically indicated per 
Investigator's discretion.
SARS-CoV-2 serology testing (preferred molecular testing e.g., PCR) to be done at any 
timepoint if clinically indicated, per Investigator's decision.  Testing will be performed 
locally.  All COVID-19 test results (both positive and negative), regardless of reason 
administered, must be inserted into EDC on the COVID-19 Status eCRF.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
71
Randomization and Subject (Screening) Number Assignment
Interactive Response Technology (IRT) will be utilized to register (screen, re-screen and 
randomize) subjects on study.  The site will contact the IRT to obtain a screening (subject) 
number once the subject has signed the informed consent and a study-specific procedure 
has been performed (e.g., labs are drawn).  Once the screening number is assigned, if the 
subject is not randomized into the study, the reason for screen failure will be documented 
in the source document and will be captured in the IRT and eCRF.  If the subject is 
randomized into the study, the site will contact the IRT to complete the randomization 
process and obtain the study treatment assignment.  Subject treatment must start within 
5 days after randomization.  All subsequent drug assignments and changes in subject 
status (e.g., treatment completion) will be registered in the IRT.
See Section 5.5.3 for further information.
Dispensing Venetoclax/Placebo
Randomized subjects will receive sufficient quantities of venetoclax/placebo for 21 days 
in each 21-day cycle during the Cycles 1 – 8, and sufficient quantities for 35 days in each 
35-day cycle for Cycles 9 and beyond.  The IRT will assign every bottle of 
venetoclax/placebo to be dispensed to a subject.  Prior to each drug dispensation, site 
personnel must contact IRT for bottle number assignment.  Venetoclax/placebo cannot 
be dispensed without contacting the IRT.  AbbVie or designee will provide specific 
instructions on the use of IRT.
Subjects will be provided with venetoclax/placebo self-administration instructions.  
Subjects will be instructed to store venetoclax/placebo according to specific directions 
included in Section 5.5.2.2.  Subjects are required to return bottles of venetoclax or 
placebo (empty, partially filled, or full) to the study site prior to each cycle and at the 
TCV.
Subjects in Arm 2 (Placebo + Bd) who remain in the study once unblinded, will no longer 
be required to take placebo tablets.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
72
5.3.1.1.2
Follow-Up
After treatment has ended, subjects will be followed for post-therapy information, overall 
survival, non-treatment emergent death information, and progressive disease (if 
applicable).  
At the time the number of OS events required for the final OS analysis is reached, subjects 
will not be followed for post-therapy information, overall survival, non-treatment 
emergent death information, and progressive disease (if applicable) after treatment has 
ended and will be discontinued from the study.
Overall Survival
Survival (i.e., alive or deceased, and if deceased, the date and cause of death) and post 
treatment information will be collected on the appropriate eCRF approximately every 
12 weeks (or as requested by sponsor to support data analysis) beginning on the date of 
progression or discontinuation and continuing either until the endpoint of death, until the 
subject is lost to follow-up, subject withdraws consent, the number of OS events required 
for the final OS analysis is reached, or until study termination by AbbVie, whichever 
occurs first.  The following will be collected for post treatment information:
●
Name(s) of post-therapy regimens
●
Post-therapy dates of initiation and completion
Non-Treatment Emergent Death Collection
After the end of the AE reporting period (in this instance 30 days after the final dose of 
study drug), all deaths reported until the number of OS events required for the final OS 
analysis is reached, including any relevant clinical information leading to the death, 
regardless of cause, should be reported through use of the Non-Treatment Emergent Death 
eCRFs.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
73
Additionally, retrospective relevant clinical information on non-treatment emergent deaths 
which already occurred will be collected from sites that have obtained IRB/EC approval 
to use a waiver of consent to collect such information.  Non-Treatment Emergent Death 
information collected retrospectively should also be recorded on Non-Treatment 
Emergent Death eCRFs.
Non-Treatment Emergent Death information related to deaths reported immediately after 
the number of OS events required for the final OS analysis is reached will no longer be 
collected.
Progressive Disease Assessment
Subjects who discontinue the study treatment for reasons other than PD, even after receipt 
of new anti-multiple myeloma treatment, will be assessed for disease progression (IMWG 
assessment) every 4 weeks (± 1 week) for 1 year following the last dose of study 
treatment, and then every 12 weeks (± 1 week) thereafter until PD.  After PD, the subject 
will continue to be followed for Overall Survival until the number of OS events required 
for the final OS analysis is reached.
COVID-19 Pandemic-Related Acceptable Protocol Modification:
In the event the subject cannot visit the study site for central laboratory and/or research 
sample collection for reasons related to the COVID-19 pandemic, a local accredited 
laboratory may be used to manage subject disease assessment.  Local lab results should be 
obtained along with reference ranges and kept within the subjects' source documentation.  
Local lab results should be reviewed by the investigator as soon as possible.  Additionally, 
the study site should contact the subject by phone or video conference to assess for post-
study myeloma therapy as per Appendix G.  This discussion shall be documented in the 
source documents.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
74
5.3.1.2
Meals and Dietary Requirements
Each dose of venetoclax/placebo will be taken orally once daily with approximately 
240 mL of water within 30 minutes after the completion of breakfast or subject's 
first meal of the day.  Tablets must be swallowed whole and must not be broken, chewed, 
or crushed.
On days that pre-dose PK sampling is required, venetoclax/placebo dosing will occur in 
the morning at the clinic to facilitate PK sampling. 
Subjects may not consume the following:  grapefruit or grapefruit products, Seville 
oranges (including marmalade containing Seville oranges) or starfruit within the 3-day 
period prior to the first study treatment administration and until the last day of treatment is 
completed due to possible CYP3A mediated metabolic interaction.  It is expected that 
sites record if grapefruit products are consumed by the subject during the study.
5.3.1.3
Collection and Handling of Biomarker and Exploratory 
Research Samples
Serum, plasma, bone marrow aspirate and bone marrow core biopsy tissue will be 
collected per Appendix H.  Subjects will also have the option to provide samples for 
exploratory research.  Subjects may still participate in the main study even if they decide 
not to participate in the optional exploratory research.  Samples may be utilized to 
evaluate known and/or novel markers (nucleic acids, peptides/proteins and/or metabolites) 
of disease status, related conditions or to evaluate the association with pharmacokinetics, 
safety or efficacy.  All samples should be prepared, labeled, and shipped as outlined in the
study-specific laboratory manual.  The biomarker rationale is discussed in the Biomarker 
Research Variables Section (Section 5.3.6).
AbbVie (or people or companies working with AbbVie) will store the biomarker and 
exploratory research samples in a secure storage space with adequate measures to protect 
confidentiality.  The samples will be retained while research on venetoclax (or drugs of 
this class) or this disease and related conditions continues, but for no longer than 20 years 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
75
after study completion, or per local requirements.  The procedure for obtaining and 
documenting informed consent is discussed in Section 9.3.
COVID-19 Pandemic-Related Acceptable Protocol Modification: 
Biomarker and exploratory research samples may only be collected at the study site and 
are not to be collected if travel restrictions or other changes in local regulations in light of 
the COVID-19 pandemic prevent the subject from visiting the study site at a sample 
collection time point.
5.3.1.3.1
Samples for Mandatory Biomarker Analysis
A summary table of biomarker samples is found in Appendix H. 
Blood Collection for Plasma Markers
Approximately 12 mL of blood will be collected at the following time points:
●
Cycle 1 Day 1 (Pre-dose)
●
Cycle 5 Day 1 (Pre-dose)
●
Disease Progression or TCV
Blood Collection for Serum Markers
Approximately 3.5 mL of blood will be collected at the following time points:
●
Cycle 1 Day 1 (Pre-dose)
●
Cycle 5 Day 1 (Pre-dose)
●
Disease Progression or TCV
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
76
Pre-Treatment Bone Marrow Core (BMC) Biopsy Tissue Collection for 
Immunohistochemistry (IHC)
One of the following forms of pre-therapy tumor tissue (newly collected tissue or archived 
tissue) should be collected at Screening:
●
Fresh tumor tissue:  It is strongly encouraged that BMC biopsies be collected 
for all subjects to enable biomarker assessments as outlined in the study 
objectives.  BMC biopsies should be performed during screening, unless not 
recommended per Institution guidelines.  Tissue should be fixed in formalin, 
decalcified, and embedded in paraffin according to institutional procedures.  
While sending Formalin-Fixed, Paraffin-Embedded (FFPE) blocks is preferred, 
slides prepared and stored by the local pathology laboratory are acceptable and 
should be prepared as described in the study-specific laboratory manual.  In 
addition, a pathology report, with all the subject identifying information 
redacted, should be submitted along with the tissue sample.
●
Archived BMC 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.  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 all the subject identifying 
information redacted, should be submitted along with the tissue sample.
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:
1.
Assessment of Disease Response by IMWG Criteria (Appendix J)13,14
2.
Quantitative polymerase chain reaction (qPCR) and MRD, 6 mL
3.
Fluorescent In Situ Hybridization (FISH), 4 mL
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
77
qPCR and MRD Sample Collection
A 6 mL aspirate sample will be collected at the following time point for qPCR and 
baseline assessment of disease using MRD assay: 
●
Screening (preferred) or prior to first dose of study treatment (Cycle 1 Day 1)
MRD Assessment
A 3 mL aspirate sample will be collected at the following time points for MRD 
assessment:
●
At the time of suspected CR/stringent complete response (sCR) for 
confirmation of clinical response
●
At approximately 6 months and 12 months after confirmation of CR/sCR for 
subjects who maintain this response
Fluorescent In Situ Hybridization (FISH)
A 4 mL aspirate sample will be collected at the following time point for baseline 
assessment of chromosomal abnormalities, including t(11;14), t(4;14), t(14;16), del 17p, 
5+, 9+, 15+:
●
Screening (preferred) or prior to first dose of study treatment (Cycle 1 Day 1).  
If the bone marrow aspirate collected is not sufficient for FISH analysis, data 
from a historical FISH result may be entered into the EDC eCRF as long as 
results are within 12 weeks from date of first dose.
5.3.1.3.2
Samples for Exploratory Research
For all subjects in the study that consent to optional exploratory research, blood, bone 
marrow core and bone marrow aspirate samples will be collected per Appendix H.  Please 
contact the AbbVie TA MD or designee if necessary for additional information. 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
78
Bone Marrow Core (BMC) Biopsy Tissue Collection for IHC
Sample may be collected at the time of Disease Progression or TCV (prior to the initiation 
of a new anti-myeloma treatment), if deemed feasible by the Investigator.  Tissue should 
be fixed in formalin, 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 and stored as described in the 
study-specific laboratory manual.  In addition, a pathology report, with all the subject 
identifying information redacted, should be submitted along with the tissue samples.
Bone Marrow Aspirate Collection for FISH and qPCR/MRD
Sample may be collected at Disease Progression or TCV, if deemed feasible by the 
Investigator.  Priority of the bone marrow aspirate sample split is as follows:
1.
qPCR/MRD, 6 mL
2.
FISH, 4 mL
Pharmacogenetic Sample (Optional JPMA Category B)
An optional 4 mL whole blood sample for deoxyribonucleic acid (DNA) isolation will be 
collected on Cycle 1 Day 1 (prior to the first dose of study treatment), Cycle 5 Day 1 and 
TCV from each subject who consents to provide samples for exploratory research.
5.3.2
Drug Concentration Measurements
5.3.2.1
Collection of Samples for Analysis
Blood samples for venetoclax, bortezomib (and dexamethasone, only in Japanese 
subjects), and possible metabolite(s) will be collected by venipuncture per Appendix H.
The timing of blood collections will take priority over all other scheduled study activities 
except for dosing.  
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
79
The date and time (to the nearest minute) of each dose of venetoclax/placebo and whether 
or not the venetoclax/placebo dose was taken within approximately 30 minutes after the 
completion of breakfast (or subject's first meal of the day) will be recorded on the 
appropriate eCRF within Medidata RAVE for each scheduled venetoclax or placebo PK 
day and for the 2 days prior to every scheduled venetoclax/placebo PK day.  The date and 
time (start time and end time) of each bortezomib injection/infusion will be recorded to 
the nearest minute.  Sites will ensure that all information is captured through source 
documents.  FOR JAPAN SUBJECTS ONLY:  the date and time (to the nearest minute) 
of each dexamethasone dose will be recorded for the scheduled dexamethasone PK day 
and for the doses immediately prior to and after the scheduled dexamethasone PK day.  
Refer to the study specific laboratory manual for detailed instructions on sample 
collection, processing, and shipment.
Blood Samples for Venetoclax Assay
Blood samples (3 mL) for venetoclax assay will be collected at the following times:
●
Cycle 1 Day 1:  6 hour post dose (optional)
●
Cycles 2, 4, 6 and 8 (Day 1):  0 hour (pre-dose)
A total of 4 – 5 blood samples are planned to be collected per subject for venetoclax PK 
analysis.
Blood Samples for Bortezomib Assay
Blood samples (4 mL) for bortezomib assay will be collected at the following times:
●
Cycle 1 Day 1:  0.5 hour post dose
●
Cycles 2, 4, 6 and 8 (Day 11):  0 hour (pre-dose)
A total of 5 blood samples are planned to be collected per subject for bortezomib PK 
analysis.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
80
Blood Samples for Dexamethasone Assay (Japan Subjects Only)
Japanese subjects enrolled in the run-in phase, blood samples (3 mL) for dexamethasone
assay will be collected at the following times:
●
Cycle 1 Day 1:  0.5 and 6 hour post dose
●
Cycle 1 Day 11:  0 (pre-dose), 0.5, 1, 2, 4, 8 and 24 (Day 12 pre-dose) hours
post dose
A total of 9 blood samples are planned to be collected per subject enrolled in the run-in 
phase for dexamethasone PK analysis.
For the remaining Japanese subjects enrolled after the run-in phase, blood samples (3 mL) 
for dexamethasone assay will be collected at the following times:
●
Cycle 1 Day 1:  0.5 and 6 hour post dose
A total of 2 blood samples are planned to be collected per subject enrolled after the run-in 
phase for dexamethasone PK analysis.
5.3.2.2
Measurement Methods
Plasma concentrations of venetoclax will be determined by the Drug Analysis Department 
at AbbVie using validated method.  Plasma concentrations of other possible metabolites 
from venetoclax may be determined with validated or non-validated methods.
Plasma concentrations of bortezomib and dexamethasone will be determined under the 
supervision of the Drug Analysis Department at AbbVie.
5.3.3
Efficacy Variables
The primary endpoint is PFS based on IMWG criteria for multiple myeloma 
(Appendix J).13,14
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
81
Secondary efficacy endpoints are as follows:  VGPR or better response rate; PROs:  
Worst Pain (BPI-SF), Physical Functioning (EORTC QLQ-C30); OS; PFS in subjects 
with high BCL-2 expression; DOR; TTP; ORR; MRD negativity rate; PROs GHS/QoL 
(EORTC QLQ-C30), and Fatigue (PROMIS Cancer Fatigue SF).
Tertiary efficacy endpoints are CBR, DCR, TTR, TNT, and PROs based on the remaining 
subscales of BPI-SF, EORTC QLQ-C30, EORTC QLQ-M20, and EQ-5D-5L.
Efficacy endpoints and analyses of efficacy are described in Section 8.1.3 and 
Section 8.1.5.
5.3.4
Safety Variables
The following safety evaluations will be performed during the study:  adverse event 
monitoring, vital signs, physical examination, 12-lead ECG and laboratory assessments.
5.3.5
Pharmacokinetic Variables
Values for the PK parameters of venetoclax, including the apparent clearance (CL/F), may 
be determined using a population PK approach.  Additional parameters may be calculated 
if useful in the interpretation of the data.
5.3.6
Biomarker and Exploratory Research Variables
Biospecimens (blood, serum, plasma, bone marrow aspirate and bone marrow core biopsy 
tissue) will be collected to conduct biomarker and exploratory analyses.  The types of 
biomarkers to be analyzed may include, but are not limited to, nucleic acids, proteins, 
lipids or metabolites.  The samples may be analyzed as part of a multi-study assessment of 
factors influencing the subjects' response to the study treatment (or drugs of the same or 
similar class) or the development and progression of the subjects' disease or related 
conditions.  The information learned from analyzing these samples may be used to 
investigate factors influencing response to the study treatment, scientific questions related 
to multiple myeloma, and/or in the development of new therapies and diagnostic tests, or 
technologies.  The results from these analyses may not be included with the study report.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
82
Biospecimens (serum, plasma, bone marrow aspirate and bone marrow core biopsy tissue) 
will be collected to support biomarker objectives of the study.  These include assessment 
of BCL-2 expression at baseline as a predictive biomarker of response to the combination 
of venetoclax with bortezomib and dexamethasone.  BCL-2 protein expression will be 
determined by IHC analysis in bone marrow core biopsy samples.  A pre-defined 
threshold for BCL-2 expression status (high/low) will be utilized to compare median PFS 
between treatment arms in subjects with High BCL-2 expression as a secondary endpoint 
in the study.  Furthermore, BCL-XL and MCL-1 protein expression will be assessed as 
exploratory markers.  Additionally, BCL-2, BCL-XL and MCL-1 gene expression may be 
evaluated in CD138-enriched bone marrow aspirate samples by sequencing-based 
methodologies, including qPCR.  The ratio of target expression (BCL-2) to resistance 
factors (MCL-1/BCL-XL) was found to associate with tumor responses to single agent 
venetoclax treatment in pre-clinical studies of multiple myeloma.9  Clinically, higher 
BCL-2 mRNA expression levels were associated with improved overall response rate in 
the Study M12-901.
Additional biomarker objectives include the assessment of FISH markers that are known 
to be prognostic in MM.  These include, but not limited to, t(11;14), t(4;14), t(14;16), 
del17p, and 5+, 9+, or 15+.  Patient multiple myeloma tumor cells that possess the 
t(11;14) translocation were found to associate with increased sensitivity to venetoclax in 
preclinical studies of MM.9  t(11;14) positive samples also demonstrated a high median 
BCL-2/MCL-1 mRNA ratio.9  FISH analysis will be performed on CD138-enriched 
samples from bone marrow aspirates.
MRD negativity is an emerging component of response assessment in multiple myeloma 
patients who have achieved complete responses.  Recent reports have demonstrated the 
potential prognostic value of MRD detection in multiple myeloma with sensitive assays 
that define immunophenotypic disease specific (via flow cytometry) and/or molecular 
(Allelle Specific Oligonucleotide – Polymerase Chain Reaction [ASO-PCR] or Next 
Generation Sequencing [NGS]) abnormalities.29-32  MRD negativity in bone marrow 
aspirates will be defined at 10–5 threshold as assessed by NGS in subjects at the time of 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
83
suspected CR/sCR, and at 6 and 12 months post-confirmation of CR/sCR for subjects who 
maintained this response.  Exploratory analysis of MRD negativity at 10–4 and 10–6
thresholds may additionally be performed.
Additional exploratory evaluations may include biomarkers related to pathway(s) targeted 
by the study treatment, those believed to be related to the disease or to drug response 
evaluation or association with genetic factors.  Plasma and serum samples may be 
analyzed for mutational status of circulating tumor 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 qPCR-based assays for BCL-2 family members and other nucleic acids or 
proteins known to regulate the expression of these molecules.  Gene sequencing- and 
hybridization-based techniques may also be used on any of the above specimens for 
exploratory biomarker research.
Pharmacogenetic samples may also be analyzed for genetic factors contributing to the 
disease or to the subject's response to venetoclax, or other study treatment in terms of 
pharmacokinetics, efficacy, tolerability, and safety.  Pharmacogenetic research on samples 
from Japan will be restricted to the subject's response to treatment.  Such genetic factors 
may include sequencing and epigenetic testing on genes associated with 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 in the clinical 
study report.
5.3.7
Disease Assessments and IMWG Criteria for Response and 
Progression
5.3.7.1
Disease Assessments
Analysis of serum protein electrophoresis (SPEP), serum protein immunofixation, serum 
quantitative immunoglobulins (sQI), serum free light chains (sFLC), urine protein 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
84
electrophoresis (UPEP), urine protein immunofixation, corrected serum calcium, 
plasmacytoma evaluation (if applicable), skeletal survey, and bone marrow aspirate and 
biopsy, will be utilized for disease assessment.  Subjects will be evaluated using the 
IMWG13,14 criteria for disease response and progression.45
Laboratory Tests for Multiple Myeloma:
All serum and urine laboratory tests for multiple myeloma must be sent to a certified 
central laboratory.  Corrected serum calcium will be based off the serum calcium and 
albumin levels obtained from the local laboratory.
Serum protein immunofixation, SPEP, sQI, sFLC, urine protein immunofixation, and 
UPEP may be performed up to 1 week prior to the scheduled visit day.
Serum Protein Electrophoresis (SPEP), Serum Protein Immunofixation, Serum 
Quantitative Immunoglobulins (sQI)
Blood samples for SPEP, serum protein immunofixation, and sQI testing will be collected 
per Table 4 and Appendix D, Appendix E, Appendix F, and Appendix G.
SPEP and serum immunofixation will be collected for all subjects at baseline and 
throughout the study until PD or withdrawal of consent, regardless of SPEP being 
measurable or M-protein presence at baseline.
Once the number of OS events required for the final OS analysis is reached, SPEP and 
serum immunofixation will continue to be collected only from the subjects on treatment.
At the time that subjects are unblinded, subjects in Arm 1 (Venetoclax + Bd) or Arm 2 
(Placebo + Bd) may continue on study treatment per PI decision, unless PD is presented, 
provided that subjects are benefiting from treatment.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
85
Serum Free Light Chains (sFLC)
Blood samples for sFLC testing will be collected for all subjects per Table 4 and 
Appendix D, Appendix E, Appendix F, and Appendix G. 
Subjects with measurable disease in either SPEP and/or UPEP will be assessed for clinical 
response only based on these two tests and not by the sFLC assay.  sFLC response criteria 
are only applicable to subjects without measurable disease in the serum or urine and to 
fulfill the requirements of sCR per IMWG criteria.
Corrected Serum Calcium
Blood samples for corrected serum calcium testing will be collected for all subjects per 
Table 4 and Appendix D, Appendix E, Appendix F, and Appendix G. 
The determination of corrected serum calcium levels is required to perform disease 
assessment.  If corrected serum calcium is used as a criterion for disease progression, it 
must be confirmed by a second value.  The correction will be done according to the 
following formula:
Corrected Serum Calcium [mg/dL] = Measured serum calcium [mg/dL] + 0.8 × (4 –
serum albumin [g/dL]).
Urine Protein Immunofixation and Urine Protein Electrophoresis (UPEP), 24-Hour 
Urine
Twenty-four-hour urine samples for urine protein immunofixation and UPEP for 
M-protein testing will be collected for all subjects at each Cycle Day 1 visit per Table 4
and Appendix D, Appendix E, Appendix F, and Appendix G.
Importantly, assessment of UPEP M-protein and urine immunofixation at the time of 
possible VGPR or CR/sCR is mandatory, even in subjects without measurable values at 
baseline.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
86
Subjects with measurable disease at baseline by SPEP and UPEP must be followed by 
both SPEP and UPEP assessment of M-protein for response assessment.
COVID-19 Pandemic-Related Acceptable Protocol Modification:
If travel restrictions or other changes in local regulations in light of the COVID-19 
pandemic prevent the subject from visiting the study site for the collection and shipping of 
IMWG laboratory assessments to the central laboratory, a local laboratory, hospital, or 
other facility may be used to manage subject disease assessment of IMWG (Serum 
M-Protein, Urine M-Protein, Serum Free Light Chains).  Local lab results should be 
obtained along with reference ranges and kept within the subject's source documentation.  
Local lab results should be reviewed by the investigator as soon as possible and prior to 
study drug dispensation.
Skeletal Survey
Skeletal survey using conventional radiography (X-Ray) will be done at screening.  Use 
of conventional or low dose CT scan or magnetic resonance imaging (MRI) bone survey 
is acceptable.  If imaging is done on treatment for assessment of progression, the site must 
use the same modality of imaging as used in screening.  Historical skeletal survey results 
obtained within 30 days prior to randomization may be used for Screening provided that 
the images meet the requirements in the Image Acquisition Guidelines.  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 per Table 4 and Appendix D, Appendix E, 
Appendix F and Appendix G.  After the screening procedure, skeletal survey should be 
done while on study only if clinically indicated.  The number and location of skeletal and 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
87
lytic lesions should be recorded on the eCRF.  While the subject is on treatment, survey 
(if done) should record any changes to the number of or size of lytic lesions, as well as the 
number and location of any new skeletal or lytic lesions.
COVID-19 Pandemic-Related Acceptable Protocol Modification:
In the event the skeletal survey cannot be performed at the study site due to study 
modifications related to the COVID-19 pandemic, the skeletal survey may be completed 
at other centers providing the modality/technique is equivalent.
Plasmacytoma Evaluation
Plasmacytoma evaluation should be assessed for all subjects with a history of 
plasmacytomas or if clinically indicated at Screening, via physical examination or 
imaging, and should be completed per Table 4, and Appendix D, Appendix E, 
Appendix F, and Appendix G.  Positron emission tomography (PET) scan or ultrasound 
tests are not acceptable to document the size of extramedullary plasmacytomas.
CT, PETCT (CT component) or MRI (same 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, and to confirm MR or better 
responses if plasmacytoma is present at baseline.
In addition to be reviewed by the Investigator and/or qualified medical site staff, imaging 
scans should be sent within 5 business days of imaging acquisition to an independent 
central imaging vendor.  The central imaging vendor will provide instructions regarding 
the preparation and shipment/upload of the images.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
88
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 tumor measurements must be made in millimeters.  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, PET/CT or MRI scanning are the preferable methods 
of assessment.  Conventional CT, PET/CT or 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, PET/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.  Skin lesions 
must be documented by a photograph with a ruler.
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.  Non-measurable 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.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
89
With the completion of the PFS analysis, imaging scans are no longer required to be sent 
to an independent central imaging vendor and will be reviewed only by the Investigator 
and/or qualified medical site staff.  
COVID-19 Pandemic-Related Acceptable Protocol Modification:
In the event the imaging for plasmacytoma assessment cannot be performed at the study 
site due to study modifications related to the COVID-19 pandemic, the imaging may be 
completed at other centers providing the modality/technique is equivalent.
Bone Marrow Aspirate and Biopsy
Bone marrow aspirate and biopsy should be completed per Table 4 and Appendix D, 
Appendix E, Appendix F, and Appendix G.  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 local laboratory as well as for shipment of a portion to AbbVie 
(or designee) for the biomarker analyses (including BCL-2 expression, qPCR/MRD 
assessment, and FISH subtyping) as described in Section 5.3.1.3 per Appendix H.
Assessment of bone marrow for percentage plasma cells performed locally is required 
within 21 days prior to randomization for baseline assessment and while on study to 
confirm sCR/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 locally at the time of CR (< 5% 
plasma cells) to assess for sCR, if applicable.  Flow cytometry is preferred over IHC for 
assessment of plasma cell clonality.  Flow cytometry will be performed to assess for sCR 
locally per institution standard practice.  If local flow cytometry to assess plasma cell 
clonality is not available at the time of CR, a core biopsy and/or clot section should be 
evaluated by IHC staining for kappa (κ) or lambda (λ) or light chain restriction.  To 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
90
confirm a suspected CR, a second confirmation bone marrow analysis for CR is not 
needed.
A bone marrow aspirate collection is mandatory.  Bone marrow biopsy 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).
COVID-19 Pandemic-Related Acceptable Protocol Modification:
Bone marrow samples may only be collected at the study site and are not to be collected if 
travel restrictions or other changes in local regulations in light of the COVID-19 
pandemic prevent the subject from visiting the study site at a sample collection time point.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
91
Table 4.
Assessments for IMWG Response Criteria
Screening
Cycle 1 
Day 1a
Day 1 of 
Each 
Subsequent 
Cycle
To Confirm 
sCR, CR or 
VGPR
TCV
Post-
Treatmentb
Serum protein 
electrophoresis
X
X
X
X
X
X
Serum protein 
immunofixation
X
X
X
X
X
X
Serum quantitative 
immunoglobulins
X
X
X
X
X
Serum free light 
chains
X
O
O
X (CR/sCR 
only)
O
O
Corrected Serum 
Calcium
X
X
X
X
X
Urine protein 
immunofixation
X
X
Xc
X
Xc
Xc
Urine protein 
electrophoresis
X
X
Xc
X
Xc
Xc
Skeletal survey
X
If clinically indicated
Plasmacytoma 
evaluation
all subjects 
with history of 
plasmacytomas 
or if clinically 
indicated
Performed during treatment only to confirm response of a Minimal 
Response (MR) or better in subjects with plasmacytoma at baseline, or to 
confirm PD, or as clinically indicated.
Bone marrow 
aspirate and biopsy
X
X (sCR or 
CR only)
Xd
CR = Complete Response; sCR = Stringent Complete Response; VGPR = Very Good Partial Response
X
Collect for all subjects.
O
Collect only for subjects without measurable M-protein in Screening serum or urine.
a.
For Cycle 1 Day 1, screening results or assessments may be used if done within 7 days of Cycle 1 Day 1.
b.
Only for subjects who went off study for reasons other than progressive disease and is to be collected every 
approximately 4 weeks following last dose of treatment for 1 year and then approximately every 12 weeks 
thereafter until progression.  Additional IMWG assessments may be performed during treatment based on the 
clinical judgment of the Investigator.  Once the number of OS events required for the final OS analysis is reached, 
IMWG assessments will no longer be collected for subjects in the Progression Follow up period.
c.
UPEP and urine immunofixation should be collected at each Cycle Day 1 visit.  UPEP 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 PD or TCV is optional.
Cross reference:  Rajkumar 2011,13 Durie 200714
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
92
5.3.7.2
IMWG Criteria for Response and Progression
Subjects will be assessed for response using the IMWG response criteria 
(Appendix J).13,14  Disease status categories include sCR, CR, VGPR, PR, MR, defined 
per EBMT criteria, stable disease (SD) and PD.
All response categories (i.e., sCR, CR, VGPR, PR, MR and PD) require two consecutive 
assessments completed by the central lab to be considered confirmed.  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.
Subjects with measurable disease in both serum (SPEP) and urine (UPEP) at study entry 
are required to meet response criteria in both UPEP and SPEP to qualify for a MR or 
better.  On the other hand, criteria for PD only need to be met and confirmed in 
one parameter.
At the time that subjects are unblinded, subjects in Arm 1 (Venetoclax + Bd) or Arm 2 
(Placebo + Bd) may continue on study treatment per PI decision, unless PD is presented, 
provided that subjects are benefiting from treatment.
Stringent Complete Response (sCR)
sCR requires that all of the following criteria be met:
●
Negative immunofixation on 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 marrow (confirmation with repeat bone marrow 
aspirate or biopsy not needed), AND
●
Normal FLC ratio of 0.26 to 1.65 or per laboratory reference range, AND
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
93
●
Absence of clonal plasma cells in bone marrow by immunohistochemistry or 
immunofluorescence or 2 to 4 color flow cytometry (confirmation with repeat 
bone marrow biopsy not needed).
Presence or absence of clonal plasma cells is based upon the k/λ ratio.  An abnormal k/λ 
ratio by immunohistochemistry, and/or flow cytometry and/or immunofluorescence 
requires a minimum of 100 plasma cells for analysis.  An abnormal ratio reflecting 
presence of an abnormal clone is k/λ of ≥ 4:1 or ≤ 1:2.
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 (CR)
CR requires that all of the following criteria be met:
●
Negative immunofixation on 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 marrow (confirmation with repeat bone marrow 
aspirate or biopsy not needed), AND
●
For subjects in whom the only measurable disease is by serum FLC levels, a 
normal FLC ratio of 0.26 to 1.65 (or per laboratory reference range) is required, 
in addition to all the CR criteria listed above.
It is not essential to perform a trephine biopsy, but if a biopsy is performed this must also 
contain < 5% plasma cells.
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.
Very Good Partial Response (VGPR)
VGPR is defined as follows:
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
94
●
Serum and urine M-protein detectable by immunofixation but not on 
electrophoresis OR
●
90% or greater reduction in serum M-protein plus urine M-protein level 
< 100 mg/24-hour
For subjects in whom the only measurable disease is by serum FLC levels, VGPR is 
defined as follows:
●
90% or greater decrease in the difference between involved and uninvolved 
FLC levels
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.
Partial Response (PR)
PR is defined as follows:
●
≥ 50% reduction of serum M-protein AND
●
Reduction in 24-hour urinary M-protein by ≥ 90% or to < 200 mg/24-hour, 
AND
●
≥ 50% reduction in size of soft tissue plasmacytomas, if present at baseline
If serum and urine M-protein levels are unmeasurable, a ≥ 50% decrease in the difference 
between involved and uninvolved FLC levels is required in place of the M-protein 
criteria.
Minimal Response (MR)
Subjects who have reduction in M-protein or plasmacytoma but do not meet the criteria 
for PR are classified as MR if they meet all the following definition:
●
25% – 49% reduction of serum M-protein AND
●
50% – 89% reduction in 24-hour urinary M-protein AND
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
95
●
25% – 49% reduction in size of soft tissue plasmacytomas, if present at 
baseline AND
●
If a skeletal survey is done, no increase in size or number of lytic bone lesions 
(development of compression fracture does not exclude response)
Stable Disease (SD)
SD is defined as not meeting the criteria for sCR, CR, VGPR, PR, MR, or PD.
Subjects with confirmed sCR, CR, VGPR, and PR will be considered to have achieved an 
objective response.  Subjects with objective response and those with MR will be 
considered to have achieved clinical benefit.  Additionally, subjects with clinical benefit 
and those with stable disease lasting at least 8 weeks will be considered to have achieved 
disease control.
Progressive Disease (PD)
PD is determined using the IMWG criteria (Appendix J),13,14 and is defined as any one or 
more of the following:
●
Increase of ≥ 25%* from lowest response level in any of the following:
○
Serum M-protein with an absolute increase of ≥ 0.5 g/dL
○
Serum M-protein increases of ≥ 1 g/dL are sufficient to define relapse if 
starting M-protein is ≥5 g/dL
○
Urine M-protein with an absolute increase of ≥ 200 mg/24-hour
○
For subjects without measurable serum and urine M-protein levels, the 
difference between involved and uninvolved FLC levels with an absolute 
increase of > 10 mg/dL
●
Definite development of new bone lesions or soft tissue plasmacytomas
●
Definite increase in the size of bone lesions or soft tissue plasmacytomas
○
A definite increase in size of bone lesions and/or plasmacytomas is defined 
as ≥ 50% increase from nadir in the sum of the product of the cross-
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
96
diameters (SPD) of > 1 lesion, or ≥ 50% increase in the longest diameter of 
a previous lesion > 1 cm in short axis.45
●
Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL) that 
can be attributed solely to the plasma cell proliferative disorder
*
Note:  The "25% increase" refers to M-protein and, FLC results and does 
not refer to bone lesions, soft tissue plasmacytomas, or hypercalcemia.  
The "lowest response value" does not need to be a confirmed value.
Two consecutive assessments, made at any time before the start of new therapy, are 
required for confirmation of PD per IMWG criteria.  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), two 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.  SPEP and UPEP are also required.
If PD is suspected based on hypercalcemia attributed solely to the plasma cell 
proliferative disorder, the laboratory values for corrected serum calcium should be greater 
than 11.5 mg/dL (2.875 millimole [mmol]/L) and a confirmatory reading should be 
obtained.
The following assessments are not sufficient to determine progressive disease:
●
Rising sFLC or quantitative immunoglobulins.  In this situation, SPEP and 
UPEP should be performed and progressive disease determination should be 
made based on central lab readings.
○
Serum FLC can be used to determine PD according to the IMWG criteria 
only for subjects without measurable serum and urine M protein.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
97
●
Clinical relapse based on indicators that are not part of the IMWG criteria for 
PD (e.g., decrease in hemoglobin, increase in serum creatinine, hyperviscosity), 
and relapse from CR categories should not be considered progressive disease.
●
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 progressive disease by at least one of 
the following assessments prior to the initiation of new therapy:  SPEP, UPEP, 
bone marrow biopsy, plasmacytoma evaluation, skeletal survey, or 
hypercalcemia (attributed solely to myeloma).
Due to delays in receiving response information from the central laboratory and also the 
possible lag time in the manifestation of clinical efficacy, 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 J)13,14 as requiring one or more 
of the following direct indicators of increasing disease and/or end organ dysfunction 
(CRAB features [increased calcium level, kidney (renal) failure, anemia, and destructive 
bone lesions]) that are considered related to the underlying plasma cell proliferative 
disorder:
●
Development of new soft tissue plasmacytomas or bone lesions on skeletal 
survey, MRI or other imaging
●
Definite increase in size of existing plasmacytomas or bone lesions.  A definite 
increase is defined as a 50% (and at least 1 cm) increase as measured serially 
by the sum of the products of the cross-diameters of the measurable lesion
●
Hypercalcemia > 11.5 mg/dL (> 2.875 mM/L)
●
Decrease in hemoglobin of > 2 g/dL (> 1.25 mM) or to < 10 g/dL
●
Rise in serum creatinine by ≥ 2 mg/dL (≥ 177 mM/L)
●
Hyperviscosity
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
98
5.3.7.3
Evaluation of Disease
IMWG assessments will be reviewed by the Investigator per the IMWG criteria 
(Appendix J)13,14 outlined in Section 5.3.7.2.  If the Investigator confirms the subject 
meets the criteria for progressive disease, 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.
IMWG assessments will be performed by the central laboratory.  Investigators may 
choose to submit additional samples to their local laboratory for testing.  All local lab 
results must be entered into the eCRF.
Disease assessment for each post-baseline IMWG assessment will be performed by a team 
of independent multiple myeloma experts (IRC).  The IRC will review subject data in a 
blinded fashion to provide the overall response assessment and associated response 
assessment date.  The IRC will only review clinical data and imaging relevant for the 
disease assessment.  Interpretations from the IRC will not be sent to the site.
A charter will outline the review process for IRC determination of overall response.
With the completion of the PFS analysis, post-baseline IMWG assessments are no longer 
required to be sent to the IRC and will be reviewed only by the Investigator and/or 
qualified medical site staff.
COVID-19 Pandemic-Related Acceptable Protocol Modification:
If travel restrictions or other changes in local regulations in light of the COVID-19 
pandemic prevent the subject from visiting the study site for the collection and shipping of 
IMWG laboratory assessments to the central laboratory, a local laboratory, hospital, or 
other facility may be used to manage subject disease assessment of IMWG (Serum 
M-Protein, Urine M-Protein, Serum Free Light Chains).  Local lab results should be 
obtained along with reference ranges and kept within the subject's source documentation.  
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
99
Local lab results should be reviewed by the investigator as soon as possible and prior to 
study drug dispensation.
5.4
Removal of Subjects from Therapy or Assessment
5.4.1
Discontinuation of Individual Subjects from Treatment
Each subject has the right to withdraw from the study at any time.  In addition, the 
Investigator may discontinue a subject from treatment at any time for any reason if the 
Investigator considers it necessary, including the occurrence of an adverse event or 
noncompliance with the protocol.  Each subject will be withdrawn from the treatment if 
any of the following occur:
●
Disease progression confirmed through IMWG assessments;
●
Subjects who are just on dexamethasone monotherapy;
●
The subject experiences toxicities related to study treatment that requires more 
than a 3-week dose interruption of the study treatment;
●
The subject receives an anti-myeloma treatment not specified in the protocol 
and prior to documented disease progression; 
●
The subject becomes pregnant or begins breastfeeding;
●
Unacceptable toxicity;
●
Noncompliance with the protocol.
If a subject is discontinued from treatment or the study with an ongoing adverse event, the 
Investigator will attempt to provide follow-up until a satisfactory clinical resolution of the 
adverse event is achieved.
At the end of the subject's treatment, a TCV will be completed.
A Safety Follow-Up Visit should be performed for all subjects approximately 30 days 
following last dose of treatment.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
100
A separate Safety Follow-Up Visit does not need to be performed for subjects who had a 
Treatment Completion Visit conducted ≥ 30 days after discontinuation of the study 
treatment and did not require additional follow-up visits for disease or safety assessment.  
If the subject refuses or is unable to attend the Safety Follow-Up Visit, this should be 
noted in the subject's source documentation.
In the event that a positive result is obtained on a pregnancy test for a subject or a subject 
reports becoming pregnant during the study, the administration of the study treatment 
must be discontinued immediately.  The Investigator must report a pregnancy within 
1 working day of the site being aware to one of the AbbVie representatives listed in 
Section 6.1.5.
COVID-19 Pandemic-Related Acceptable Protocol Modification:
The investigator should contact the AbbVie TA MD or designee before discontinuing a 
subject from the study for reasons other than those identified above to ensure all 
acceptable mitigation steps have been explored.
All efforts should be made to obtain safety and disease response information at the 
Treatment Completion visit prior to the subject initiating another therapy.  If travel 
restrictions or other changes in local regulations in light of the COVID-19 pandemic 
prevent the subject from having blood drawn for laboratory testing at the study site at the 
TCV and/or Safety Follow-Up Visit, if possible, arrange for subjects to have laboratory 
work done at a local laboratory, hospital, or other facility.  Local lab results should be 
obtained along with reference ranges and kept within the subject's source documentation.  
Local lab results should be reviewed by the investigator as soon as possible.
Non-Treatment Emergent Death Collection  
Refer to Section 5.3.1.1.2 for more information on Non-Treatment Emergent Death 
Collection.  
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
101
Importantly, if a subject discontinues treatment for a reason other than PD, the 
subject will still be considered "on study" until the number of OS events required 
for the final OS analysis is reached, and followed for diseases assessments until the 
events of PD, death or withdrawal of consent.  Once the number of OS events 
required for the final OS analysis is reached, if a subject discontinues treatment for 
any reason, the subject will be discontinued from the study.
5.4.2
Withdrawal from Study Visits
A subject may decide to discontinue participation in study visits and procedures.  If 
subject withdraws from study visits, the subject must discontinue treatment, and the 
reason for withdrawal must be documented in the subject's medical record and signed by 
the Investigator.  Subject will be followed for OS.
If withdrawal from study visits occurs at the time the number of OS events required for 
the final OS analysis is reached, subject will be discontinued from treatment and from the 
study.
COVID-19 Pandemic-Related Acceptable Protocol Modification:
During the COVID 19 pandemic, it has been necessary to employ mitigation strategies to 
enable the investigator to ensure subject safety and continuity of care.  Additional 
guidance regarding the location of COVID-19 pandemic-related acceptable protocol 
modifications can be found in Section 5.3.1.1.
The investigator should contact the AbbVie TA MD or designee before discontinuing a 
subject from the study for reasons other than those identified in Section 5.4.1 to ensure all 
acceptable mitigation steps have been explored.
5.4.3
Withdrawal from Follow-Up
Subject must request to be withdrawn specifically from survival follow-up; this request 
must be documented in the subject's medical record and signed by the Investigator.  If the 
subject withdraws from survival follow-up, the site staff may use a public information 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
102
source (such as county records) to obtain information about survival status only, as 
appropriate per local regulations.
Once the number of OS events required for the final OS analysis is reached, subjects will 
no longer be followed for progression or survival, and survival follow up withdrawal will 
no longer apply.
5.4.4
Discontinuation of Entire Study
AbbVie may terminate this study prematurely, either in its entirety or at any study site, for 
reasonable cause provided that written notice is submitted in advance of the intended 
termination.  An Investigator may also terminate the study at his/her site for reasonable 
cause, after providing written notice to AbbVie in advance of the intended termination.  
Advance notice is not required by either party if the study is stopped due to safety 
concerns.  If AbbVie terminates the study for safety reasons, AbbVie will immediately 
notify the Investigators by telephone and subsequently provide written instructions for 
study termination.
If, in the judgment of the Investigators and AbbVie, the continued exposure to the study 
treatment represents a significant risk to subjects, the study will be stopped.  The 
following procedures for discontinuation will be followed:
●
If the sponsor has decided to prematurely discontinue the study, the sponsor 
will promptly notify the Investigators in writing as well as regulatory 
authorities of the decision and give detailed reasons for the discontinuation.
●
The Investigators must promptly notify the IEC/IRBs and give detailed reasons 
for the discontinuation.
●
The Investigators must promptly notify the enrolled subjects of the premature 
discontinuation and administer appropriate treatments such as replacement of 
the study treatment, if applicable, by other appropriate regimens.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
103
5.5
Treatments
5.5.1
Treatments Administered
Subjects will take daily venetoclax/placebo 800 mg orally in combination with Bd.  
Venetoclax/placebo should always be given before other agents administered on the same 
day, if applicable.  Subjects will self-administer venetoclax/placebo by mouth QD.  Each 
dose of venetoclax/placebo should be taken all at one time with approximately 240 mL of 
water within 30 minutes after completion of breakfast or the subject's first meal of the 
day.  Tablets must be swallowed whole and must not be broken, chewed, or crushed.  On 
days that pre-dose PK sampling is required, dosing will occur at the clinic to facilitate PK 
sampling.
In cases of vomiting, the subject should not take any additional dose that day and next 
dose should be taken at usual time the next day.  In cases where a dose is missed or 
forgotten, the subject should take the dose as soon as possible, ensuring the dose is taken 
within 8 hours of the missed dose with food.  Otherwise, the dose should not be taken.
Placebo tablet administration will no longer be required for subjects in Arm 2 (Placebo + 
Bd) who remain in the study at the time subjects are unblinded.
Bortezomib (1.3 mg/m2 subcutaneous injection [preferred] or IV) will be given following 
administration of venetoclax/placebo in Cycles 1 – 8 on Days 1, 4, 8 and 11, and for 
Cycles 9 and beyond, on Days 1, 8, 15 and 22 and should be administered per the 
prescribing information.33  Dose capping and dose rounding of bortezomib is permitted 
per institutional guidelines.  The route of administration should not change during the 
study.
Bortezomib dosing frequency may be reduced or discontinued per investigator's decision 
and institutional guidelines once subjects are unblinded.
Dexamethasone (20 mg) will be given orally in Cycles 1 – 8 on Days 1, 2, 4, 5, 8, 9, 11 
and 12, and in Cycles 9 and beyond, Days 1, 2, 8, 9, 15, 16, 22, and 23.  Dexamethasone 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
104
should be administered per the prescribing information.  Dexamethasone should be 
administered the day of bortezomib dosing and the following day, given the protocol 
defined dosing window (bortezomib dosing window is ± 1 day) is maintained.  If 
bortezomib is interrupted or a dose is skipped, dexamethasone should still be administered 
as scheduled per protocol (unless dexamethasone is interrupted due to toxicity).  When 
bortezomib is discontinued and venetoclax/placebo and/or dexamethasone dosing 
continues, adverse events and concomitant medications need only be evaluated on Day 1 
of each cycle visit.
Dexamethasone dosing (frequency and/or dose) may be reduced or discontinued per 
investigator's decision and institutional guidelines once subjects are unblinded.
When unblinding occurs, if subjects from Arm 1 (Venetoclax + Bd) and Arm 2 (Placebo + 
Bd) are on dexamethasone monotherapy, they must be discontinued from the study 
treatment and from the study once the Safety Follow-Up Visit is completed.
TLS prophylaxis should be considered as discussed in Section 6.1.7.2.
COVID-19 Pandemic-Related Acceptable Protocol Modification:
If a subject is unable to come to the study site to pick up their study drug due to 
COVID-19, a direct-to-patient (DTP) study drug shipment can be made, for 
venetoclax/placebo and dexamethasone only, from the study site to the subject, if allowed 
by local regulations.  DTP shipments of venetoclax/placebo or dexamethasone may also 
include additional non-drug study supplies (e.g., patient diaries, 24-hour urine collection 
containers, etc.).  AbbVie will submit any required notifications to the regulatory 
authority as applicable.  Prior to DTP shipping, the study site must confirm it is still safe 
for the subject to continue treatment via onsite (preferred), phone or video conference 
visit, or local assessments as permitted through COVID-19 Pandemic-Related Acceptable 
Protocol Modifications.  These assessments should be documented in the subject's source 
documents accordingly.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
105
Study drug may be shipped from the study site directly to the study subject's home if all 
the following criteria are met:
●
Direct-to-patient (DTP) shipment of study drug is allowed by local regulations 
and the relevant ethics committee
●
Study drug can be administered by the subject at home
●
Subject agrees to have the study drug shipped directly to his/her home
●
Assessment of the following procedures prior to dispensing venetoclax/placebo 
to subjects:  hematology, chemistry, urine pregnancy testing (women of 
childbearing potential), coagulation panel (when applicable), IMWG disease 
assessment (central lab collection preferred, local laboratory acceptable if not 
possible to collect centrally), AE and Concomitant Medication reviews, and 
continuation of TLS prophylaxis and infections (as applicable).
●
Instructions will be provided by AbbVie as to how a study site can initiate a 
DTP shipment using Marken, a global vendor selected by AbbVie to provide 
this service when necessary.
○
Marken is the preferred courier for DTP shipping; however, in extenuating 
circumstances, alternate local couriers may be allowed with prior approval 
from the AbbVie Clinical Contact (or designee) identified in Section 7.0.  
If Marken is not utilized, the study site is responsible for ensuring the 
courier will transport the study drug under appropriate temperature 
controlled conditions and require a signature for delivery.
●
Shipments may also include other non-drug study supplies (e.g., drug dosing 
diaries, 24-hour urine collection containers, etc.).  Subjects should provide 
dosing updates to study site staff during remote phone or video conference 
visits, and return diaries to the study site at the time of the next onsite visit.
●
Prior to arranging shipment, the study site should contact the subject to confirm 
the subject will be available to accept delivery of the shipment.
●
Shipments of study drugs from the study site to a subject's home will be 
appropriately temperature controlled (qualified shipper or temperature 
monitoring) within the labeled storage conditions.  Signature is required upon 
delivery; due to COVID-19 related social distancing, this may be provided by 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
106
the courier after delivery.  Documentation of the shipment is to be retained by 
the clinical site.
●
The site should contact the subject to confirm delivery of the shipment and the 
date and time of the next dose, and document this in the source documents.
●
AbbVie will not receive subject identifying information related to these 
shipments, as the study site will work directly with the courier.
                                                                                                                                                                              
The study site is responsible for meeting IRB/IEC reporting requirements for DTP 
shipments of study drug, and for obtaining consent to provide delivery information (which 
includes subject identifying information) to the courier and documenting this consent in 
source documents.
The study site must keep records of all shipments within the subject source 
documentation.
When DTP shipping is utilized, subjects are not to discard any study drug bottles and/or 
unused study drug.  The subject should return the study drug bottles and any unused study 
drug to the site at the time of the next onsite study visit unless the study site is directed 
otherwise by AbbVie.
Bortezomib should be administered at the study site; however, trained staff (site staff or 
home health) may administer subcutaneous bortezomib in the home setting when 
permitted by the country's regulations and after discussion and approval of the TA MD.
5.5.2
Identity of Investigational Products
Information about the venetoclax/placebo formulations and standard therapy drugs, 
bortezomib and dexamethasone, to be used in this study are presented in Table 5 and 
Table 6.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
107
Table 5.
Identity of Investigational Product
Study Drug
Trademark
Formulation
Route of 
Administration
Venetoclax
N/A
100 mg Tablet, film coated
Oral
Matching Placebo for Venetoclax 
N/A
Tablet, film coated
Oral
Note:
AbbVie will supply venetoclax tablets and a matching placebo for venetoclax.
Table 6.
Identity of Non-Investigational Products
Non-
Investigational 
Products
Trademark
Formulation
Route of Administration
Bortezomib
Velcade® 
Or NAa
3.5 mg/vial
Subcutaneous (preferred) or IV
Dexamethasone
NA
Tabletb
Oral
a.
Generic or branded bortezomib may be used.
b.
Dexamethasone dosage strength may vary based on the source.
Sites are responsible for obtaining bortezomib and dexamethasone.  For operational or 
regulatory purposes, AbbVie may provide non-investigational products depending on 
local requirements.  Bortezomib and dexamethasone should be obtained from a licensed 
pharmacy or wholesaler.  Each site will be responsible for maintaining drug accountability 
records including product description, manufacturer, and lot numbers for all 
non-investigational products dispensed by the site.
5.5.2.1
Packaging and Labeling
Venetoclax/Placebo
The venetoclax/placebo tablets will be packaged in high density polyethylene (HDPE) 
plastic bottles to accommodate the study dosing requirements.  Each bottle will be labeled 
per local regulatory requirements.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
108
Bortezomib
Bortezomib is supplied as a vial containing 3.5 mg powder for solution for injection.  
Each vial must be reconstituted and administered per the applicable Summary of Product 
Characteristics (SmPC)34 or the bortezomib prescribing information.33  Bortezomib will 
be labeled as per country requirements.  Labels must remain affixed to the supplies.
Dexamethasone
Dexamethasone tablets will be labeled as per country requirements.  Labels must remain 
affixed to the supplies.
5.5.2.2
Storage and Disposition of Study Drug and
Non-Investigational Products
Venetoclax/Placebo
Venetoclax/placebo study drug must be stored at 15° to 25°C (59° to 77°F).  The 
investigational products (venetoclax/placebo) are for investigational use only and are to be 
used only within the context of this study.  The study drug supplied for this study must be 
maintained under adequate security and stored under the conditions specified on the label.
Bortezomib
Bortezomib must be stored per locally approved label or SmPC.
Dexamethasone
Dexamethasone must be stored per locally approved label or SmPC.
5.5.3
Method of Assigning Subjects to Treatment Groups
The IRT will randomize subjects into the 2 treatment arms in a 2:1 ratio 
(Venetoclax:Placebo).  Subject randomization will be stratified by prior exposure to 
bortezomib or other proteasome inhibitors (proteasome inhibitor-naïve versus proteasome 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
109
inhibitor-sensitive) and number of prior lines of therapy (1 versus 2 or 3).  The 
stratification factors used for the randomization should be the most recent values on the 
date of randomization.
A bottle number randomization schedule and a subject randomization schedule will be 
generated by the Clinical Statistics Department at AbbVie prior to the start of the study.  
A copy of all randomization schedules will be kept by the Clinical Statistics Department 
at AbbVie and a copy will be forwarded to the IRT vendor.
Japan Subjects Only: The first 12 subjects in Japan will be enrolled in the run-in phase.  
Separate randomization will be used for the first 12 subjects in the run-in phase in Japan, 
the remaining subjects in Japan and subjects in all countries expect Japan.  An identical 
procedure will be used in the three groups of subjects.  Subjects will be stratified based on 
prior exposure to bortezomib or other proteasome inhibitors (proteasome inhibitor naïve
versus sensitive) and the number of prior lines of therapy (1 versus 2 or 3).  There will be 
separate randomization lists for 4 strata within each of the three groups (Japan run-in, the 
rest of the Japan and the rest of the world).  Subjects within a stratum will be randomized 
to venetoclax and placebo arms in 2:1 ratio.  This procedure of randomization will ensure 
at least 6 subjects in Japan to be allocated in venetoclax arm in run-in phase.
5.5.4
Selection and Timing of Dose for Each Subject
Selection of the dose of venetoclax is discussed in Section 5.6.4.  Timing of doses is 
discussed in Section 5.5.1.
5.5.5
Blinding
5.5.5.1
Blinding of Investigational Product
The Investigator, the study site personnel and the subject will remain blinded to each 
subject's treatment with venetoclax/placebo throughout the course of the study.
All subjects will be treated with open-label bortezomib and dexamethasone.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
110
The IRT system can provide access to blinded subject treatment information during the 
study if identification of the study drug is required for medical emergency, i.e., situation 
in which the knowledge of the specific blinded treatment will affect the immediate 
management of the subject/subject's conditions (e.g., antidote is available).  AbbVie must 
then be notified within 24 hours of the blind being broken.  The date and reason that the 
blind was broken must be recorded in the source documentation and eCRF, as applicable.  
Un-blinding of subject treatment information in other exceptional circumstances will 
require approval from the AbbVie TA MD or designee.
5.5.5.2
Blinding of Data for Independent Data Monitoring 
Committee (IDMC)
An IDMC will periodically review the safety and efficacy data for this study in an un-
blinded fashion.  Aggregate blinded clinical safety and efficacy data will be reviewed on a 
real-time basis throughout the course of the study.  Once the final Overall Survival (OS) 
analysis is complete (refer to Section 8.1.5.5.2), a final review of safety and efficacy data 
will be conducted by the IDMC.  AbbVie will continue to monitor subjects' safety data 
after the final IDMC meeting.
Details of the IDMC review will be outlined in the IDMC Charter.
5.5.5.3
Unblinding Process
Once the final OS analysis is complete, an unblinding letter will be sent from the AbbVie 
TA MD to the Principal Investigator of each site taking part in the study.  The PI should 
notify study subjects of treatment allocation by preferred method (e.g., phone, letter) and 
document in the subject’s chart that the subject has been informed of treatment allocation 
and applicable safety information.
5.5.6
Treatment Compliance
The Investigator or his/her designated and qualified representatives will 
administer/dispense the study treatment only to subjects enrolled in the study in 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
111
accordance with the protocol.  The study treatment must not be used for reasons other 
than that described in the protocol.
5.5.7
Drug Accountability
The Investigator or his/her designated representatives will administer study treatment only 
to subjects enrolled in the study.  Documentation of the receipt of supplies will be 
supported by a signed and dated Proof of Receipt or similar document.  A current 
(running) and accurate inventory of study treatment will be kept by the site and will 
include lot number, Proof of Receipt number(s), bottle numbers, and the date on which the 
study treatment is dispensed or administered to the subject.
An overall accountability of the study treatment will be performed and verified by 
AbbVie or the designated monitor(s) throughout the study and at the study site Closeout 
Visit.  Upon completion or termination of the study, all original containers (containing 
partially used or unused study treatment) will be returned to AbbVie according to 
instructions from AbbVie or the designated monitor(s).  If prearranged between AbbVie 
and the site, destruction of used and unused study treatment will be performed at the site.  
Empty containers will be destroyed at the site.  Labels must remain attached to the 
containers.
5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
This is a Phase 3, multicenter, randomized, double blind study to evaluate the efficacy and 
safety of venetoclax plus Bd compared to an active control of placebo plus Bd.  The 
choice of the control group allows for a double blinded assessment of the contribution of 
venetoclax to the safety and efficacy of the backbone regimen of Bd.
The proteasome inhibitor bortezomib combined with dexamethasone has proven 
therapeutic value and is considered to be a standard of care listed in the National 
Comprehensive Cancer Network and the European Society for Medical Oncology 
(ESMO) guidelines as a recognized treatment for patients with previously treated 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
112
MM.13,16,35  Given that bortezomib combined with dexamethasone is one of the standard 
of care therapies in the treatment of relapsed or refractory MM, it makes an ideal 
therapeutic regimen to be used as an active comparator in a randomized, controlled study 
designed to evaluate the therapeutic value of an investigational drug added to the 
bortezomib plus dexamethasone regimen.
5.6.2
Appropriateness of Measurements
Standard PK, statistical, clinical and laboratory procedures will be utilized in this study.
5.6.3
Suitability of Subject Population
Adult male and female subjects with relapsed or refractory MM who are considered 
sensitive or naïve to proteasome inhibitor and received 1 to 3 prior lines of therapy for 
multiple myeloma will be selected to participate in this study.  Due to the expected 
mechanism-based lymphopenia, subjects will be monitored to assess risk for infection.  
As a preventative measure, prophylaxis for viral, fungal, bacterial or Pneumocystis 
infections will be implemented when appropriate.
5.6.4
Selection of Doses in the Study
The dosage regimen of bortezomib and dexamethasone are the doses specified in relapsed 
or refractory multiple myeloma subjects on the bortezomib US package insert and the EU 
SmPC.  For the initial 8 cycles, the currently approved regimen of bortezomib with dosing 
on Days 1, 4, 8 and 11 every 21 days is used.  For extended therapy beyond 8 cycles, 
bortezomib is used per the US package insert on a maintenance schedule of weekly dosing 
on Days 1, 8, 15, 22 every 35 days.  This regimen allows patients who are responding to 
continue their treatment beyond 8 cycles with the less intense and better tolerated weekly 
regimen, which decreases the incidence of peripheral neuropathy, a key limiting toxicity 
with bortezomib.  Similar regimens have been used in other Phase 3 clinical studies with 
bortezomib-based therapies.36-38
The selected 800 mg dosage of venetoclax is based on the results from Study M12-901, a 
Phase 1b study of venetoclax plus Bd in relapsed or refractory multiple myeloma subjects.  
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
113
In this study venetoclax was administered until progression or unacceptable toxicity 
occurred and the maximum tolerated dose (MTD) of venetoclax plus Bd was not reached 
at the highest tested venetoclax dose of 1200 mg QD.  Exposure-response analyses of the 
efficacy and safety from Study M12-901 were conducted based on the available PK, best 
response (per the International Myeloma Working Group [IMWG] criteria), and safety 
(grade ≥ 3 anemia, thrombocytopenia, and neutropenia).  Anemia, thrombocytopenia, and 
neutropenia were selected as they are the toxicities relevant to the venetoclax experience 
to date.  At the time of the analysis, the venetoclax doses ranged from 50 to 1200 mg QD 
in these subjects and the duration of treatment ranged from 9 to 664 days.
Using a population PK exposure-response model, the dose-response relationships of 
efficacy and neutropenia were determined for subjects with typical PK in the population 
that will be enrolled in Study M14-031 (non-refractory to bortezomib and received 1 to 
3 prior treatments).  There was a high predicted probability of achieving MR (or better) 
across all venetoclax dosages in this population, while the probability of VGPR or better 
was predicted to increase with increasing doses through 1200 mg QD.  Similarly, 
neutropenia (grade ≥ 3) rates were generally low through doses of 800 mg QD, increasing 
thereafter.  No relationship between venetoclax exposure and anemia or thrombocytopenia 
was observed.  Based on these preliminary efficacy and safety results, and considering 
treatment compliance considerations, a venetoclax dose of 800 mg QD was selected in 
combination with BD.  
6.0
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/device after it is released for 
distribution.
Complaints associated with any component of this investigational product must be 
reported to the Sponsor (Section 6.3.2).  For adverse events, please refer to Section 6.1
through Section 6.1.5.  For product complaints, please refer to Section 6.3.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
114
6.1
Medical Complaints
The Investigator will monitor each subject for clinical and laboratory evidence of adverse 
events on a routine basis throughout the study.  The Investigator will assess and record 
any adverse event in detail including the date of onset, event diagnosis (if known) or 
sign/symptom, severity, time course (end date, ongoing, intermittent), relationship of the 
adverse event to study treatment, and any action(s) taken.  For serious adverse events 
considered as having "no reasonable possibility" of being associated with study treatment, 
the Investigator will provide an alternative cause of the event.  For adverse events to be 
considered intermittent, the events must be of similar nature and severity.  Adverse 
events, whether in response to a query, observed by site personnel, or reported 
spontaneously by the subject will be recorded.
All adverse events will be followed to a satisfactory conclusion.
6.1.1
Definitions
6.1.1.1
Adverse Event
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment.  An adverse event 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.
Such an event 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 adverse event.  
Worsening in severity of a reported adverse event should be reported as a new adverse 
event.  Laboratory abnormalities and changes in vital signs are considered to be adverse 
events only if they result in discontinuation from the study, necessitate therapeutic 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
115
medical intervention, meet protocol specific criteria (see Section 6.1.7 regarding toxicity 
management) or if the Investigator considers them to be adverse events.
An elective surgery/procedure scheduled to occur during a study will not be considered an 
adverse event if the surgery/procedure is being performed for a pre-existing condition and 
the surgery/procedure has been pre-planned prior to 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 is being done will be considered an adverse event.
A treatment-emergent adverse event is defined as any adverse event with onset or 
worsening reported by a subject from the time that the first dose of venetoclax/placebo, 
bortezomib, or dexamethasone is administered until 30 days have elapsed following 
discontinuation of venetoclax/placebo, bortezomib, and dexamethasone administration.
6.1.1.2
Serious Adverse Events
If an adverse event meets any of the following criteria, it is to be reported to AbbVie as a 
serious adverse event (SAE) within 24 hours of the site being made aware of the serious 
adverse event:
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.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
116
Persistent or 
Significant 
Disability/Incapacity
An event that results in a condition that substantially 
interferes with the activities of daily living of a study 
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.
For serious adverse events with the outcome of death, the date and cause of death will be 
recorded on the appropriate case report form.  Deaths related to disease progression will 
not be recorded as adverse events (see Section 6.1.1.3).
6.1.1.3
Adverse Events Expected Due to Study Related Endpoints
6.1.1.3.1
Deaths
For this protocol, overall survival is an efficacy endpoint.  Deaths that occur during the 
protocol specified adverse event collection period (Section 6.1.4 and Figure 2) that are 
attributed by the investigator solely to progression of multiple myeloma should be 
recorded only on the Death eCRF and the Study Completion Form eCRF.  All other 
on-study deaths, regardless of relationship to study treatment, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (Section 6.1.5).
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
117
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 Adverse Event eCRF.  Generally, only one such event should be reported.  
The term "sudden death" should only be used for the occurrence of an abrupt and 
unexpected death due to presumed cardiac causes in a patient with or without pre-existing 
heart disease, within 1 hour of the onset of acute symptoms or, in the case of an 
unwitnessed death, within 24 hours after the patient 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 Adverse Event eCRF.  If the cause of 
death later becomes available (e.g., after autopsy), "unexplained death" should be replaced 
by the established cause of death.
6.1.1.3.2
Lack of Efficacy or Worsening of Disease
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease are also considered an expected outcome for this study and will not be 
subject to expedited reporting.
6.1.2
Adverse Event Severity
The Investigator will rate the severity of each adverse event according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE 
Version 4.03).39  If a reported adverse event increases in severity, the initial adverse event 
should be given an outcome date and a new adverse event reported to reflect the change in 
severity.  For all reported serious adverse events that increase in severity, the 
supplemental eCRFs also need to be updated to reflect the change in severity.
For adverse events not captured by the Common Terminology Criteria, the following 
should be used:
Grade 1
The adverse event is transient and easily tolerated by the subject (mild).
Grade 2
The adverse event causes the subject discomfort and interrupts the 
subject's usual activities (moderate).
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
118
Grade 3
The adverse event causes considerable interference with the subject's 
usual activities and may be incapacitating (moderate to severe).
Grade 4
The adverse event is life threatening requiring urgent intervention 
(severe).
Grade 5
The adverse event resulted in death of the subject (severe).
6.1.3
Relationship to Study Treatment
The Investigator will use the following definitions to assess the relationship of the adverse 
event to the use of the study treatment:
Reasonable 
Possibility
An adverse event where there is evidence to suggest a causal 
relationship between the study treatment and the adverse event.
No Reasonable 
Possibility
An adverse event where there is no evidence to suggest a causal 
relationship between the study treatment and the adverse event.
The Investigator will assess the relationship of each adverse event to venetoclax, to 
bortezomib, and to dexamethasone.  Some events may be reasonably related to more than 
one drug or to none.  For causality assessments, events assessed as having a reasonable 
possibility of being related to the study treatment will be considered "associated."  Events 
assessed as having no reasonable possibility of being related to study treatment 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 to study treatment.
If an Investigator's opinion of no reasonable possibility of being related to the study 
treatment is given, an "Other" cause of event must be provided by the Investigator for the 
serious adverse event.
6.1.4
Adverse Event Collection Period
All protocol-related serious adverse events and nonserious adverse events must be 
collected from the signing of the study specific informed consent until study treatment 
administration.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
119
Serious and nonserious adverse events occurring after the study-specific informed consent 
is signed but prior to the initial dose of study treatment will be collected only if they are 
considered by the Investigator to be causally related to the study-required procedures.
All serious and nonserious adverse events reported from the time of study treatment 
administration until 30 days following discontinuation of study treatment administration 
have elapsed will be collected, whether elicited or spontaneously reported by the subject.
Adverse event information will be collected as shown in Figure 2.
Figure 2.
Adverse Event Collection
*
Only if considered by the Investigator to be causally related to study-required procedures.
6.1.5
Adverse Event Reporting
In the event of a serious adverse event, whether associated with the study treatment or not, 
the Investigator will notify Clinical Pharmacovigilance within 24 hours of the site being 
made aware of the serious adverse event by entering the serious adverse event data into 
EDC RAVE® system.  Serious adverse events that occur prior to the site having access to 
the RAVE® system, or if RAVE® is not operable, should be documented on the SAE Non-
CRF forms and emailed (preferred route) or faxed to Clinical Pharmacovigilance within 
24 hours of the site or Investigator being made aware of the serious adverse event.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
121
AbbVie will be responsible for Suspected Unexpected Serious Adverse Reactions 
(SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with 
Global and Local Regulation, and Appendix A of the Investigator Brochure will serve as 
the Reference Safety Information (RSI) for the AbbVie IMP.  The RSI in effect at the start 
of a Drug Safety Update Report (DSUR) reporting period serves as the RSI during the 
reporting period.  For follow-up reports, the RSI in place at the time of occurrence of the 
"suspected" Serious Adverse Reaction will be used to assess expectedness.  For 
comparator products being used as non-AbbVie IMPs, the SmPC will serve as the 
Reference Safety Information (RSI) for those non-AbbVie products.
The following definitions will be used for Serious Adverse Reactions (SAR) and 
Suspected Unexpected Serious Adverse Reaction (SUSAR):
SAR
Defined as all noxious and unintended responses to an IMP related 
to any dose administered that result in death, are life-threatening, 
require inpatient hospitalization or prolongation of existing 
hospitalization, result in persistent or significant disability or 
incapacity, or are a congenital anomaly or birth defect.
SUSAR
A suspected SAR:  refers to individual SAE case reports from 
clinical trials where a causal relationship between the SAE and the 
IMP was suspected by either the sponsor or the investigator, is not 
listed is the applicable Reference Safety Information, and meets one 
of the following serious criteria:  results in death, is life-threatening, 
requires hospitalization or prolongation of an existing 
hospitalization, results in persistent or significant disability or 
incapacity, or is a congenital anomaly or birth defect.  All 
individually reported SARs are considered suspected.
In Japan, the principal investigator will provide documentation of all serious adverse 
events to the Director of the investigative site and the Sponsor.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
122
COVID-19 Pandemic-Related Acceptable Protocol Modification:
Supplemental study case report forms should be completed in the event of COVID-19 
related missed/virtual visits, study drug interruptions or discontinuations, or adverse 
events (including capture of specific signs/symptoms of infection and testing results).
COVID-19 infections should be captured as adverse events.  If the event meets the criteria 
for a serious adverse event (SAE), then follow the SAE reporting directions per the 
protocol.  The following COVID-19 related supplemental eCRFs should be completed 
(for both serious and non-serious events):
●
COVID-19 Supplemental Signs/Symptoms
●
COVID-19 Status Form
Subjects with a confirmed (viral test positive) or suspected COVID-19 infection must 
interrupt all study drugs until the COVID-19 viral clearance criteria in Section 6.2 are 
met.  There are no time limits for study drug interruption as long as no permanent study 
discontinuation criteria have been met.  The investigator should notify the AbbVie TA 
MD or designee listed above before reintroducing any study drugs in subjects with 
confirmed or suspected COVID-19 infection.
6.1.6
Pregnancy
Pregnancy in a study subject must be reported to an AbbVie representative (Section 6.1.5) 
within 1 working day of the site becoming aware of the pregnancy.  Subjects who become 
pregnant during the study must be discontinued (Section 5.4.1).
All subjects should be informed that contraceptive measures (refer to Inclusion Criteria 
for the details on contraception) should be taken throughout the study and for at least 
90 days post last dose of study treatment.  Male subjects should inform their partner(s) 
that the effects of Venetoclax on an unborn fetus or embryo in humans are unknown.  
Information regarding a pregnancy occurrence in a study subject and the outcome of the 
pregnancy will be collected.  In the event of a pregnancy occurring in the partner of an 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
123
enrolled subject, written informed consent for release of medical information from the 
partner must be obtained prior to the collection of any pregnancy-specific information, 
and the pregnancy will be followed to outcome.
Pregnancy in a study subject is not considered an adverse event.  The medical outcome for 
either mother or infant, meeting any serious criteria including an elective or spontaneous 
abortion, is considered a serious adverse event and must be reported to AbbVie within 24 
hours of the site becoming aware of the event.
6.1.7
Toxicity Management
6.1.7.1
Management of Cytopenias and Infection
Venetoclax could lead to suppression of lymphocytes (B and T sub-types).  In addition, 
clinically significant neutropenia may also be observed in this study.  Both lymphopenia 
and neutropenia could increase the risk for infections, including opportunistic infections.  
All subjects receiving treatment with venetoclax/placebo in combination with a 
proteasome inhibitor must receive antibiotic prophylaxis with Bactrim forte® (1 tablet 
3 times a week) or equivalent therapy while on treatment.  Additionally, Levofloxacin 
(500 mg daily, adjusted for renal function as necessary) or equivalent antibiotic therapy 
per institutional guidelines must be administered for the first 90 days on study and when 
Grade 4 neutropenia develops (ANC < 500 cells/µL) and continued until the neutropenia
improves to Grade 3 or better (ANC > 500 cells/µL).  Subjects may receive antibiotic 
prophylaxis for at least 30 days upon disease progression or after the discontinuation of 
the proteasome inhibitor and/or venetoclax/placebo at the discretion of the investigator.  
Furthermore, it is recommended that subjects deemed at high risk of infection may receive 
immunoglobulin replacement therapy (i.e., IV immunoglobulin) per institutional 
guidelines or at the Investigator's discretion.
If the patient has hypersensitivity to these agents or develops unacceptable toxicity or 
intolerance, and a suitable alternative agent is not available, the subject may be removed 
from this treatment in consultation with the AbbVie Medical Monitor.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
124
The use of antibiotics that are moderate or strong CYP3A4 inhibitors should be avoided 
or used with caution and with appropriate dose modification as per protocol.
For all other subjects on venetoclax/placebo (not in combination with a proteasome 
inhibitor), prophylaxis should be considered at the Investigator's discretion.  Anti-
infective prophylaxis and G-CSF for the management of neutropenia may be considered 
per institutional guidelines.  Note:  Potential for drug-drug interactions should be 
considered.  Please refer to Appendix I for a description of excluded and cautionary 
medications.  
All antibiotic and supportive therapies are not required but may be continued at the 
discretion of the investigator for subjects in Arm 2 (Placebo + Bd) once unblinded.
All subjects with MM receiving venetoclax/placebo should be closely monitored for 
infections and in the event of a Grade ≥ 3 or serious infection, treatment with 
venetoclax/placebo should be interrupted, and upon resolution, treatment can be resumed 
at a reduced dose or discontinued, depending on Investigator's clinical judgment. 
Note:  Please refer to Table 8 for guidance on dose interruptions and/or reductions related 
to hematological and non-hematological toxicities.
All anti-infective prophylaxis measures and growth factor use should be appropriately 
recorded in the eCRF.
6.1.7.2
Management of Tumor Lysis Syndrome
TLS has been reported in patients with multiple myeloma with significant disease burden 
when treated with bortezomib or dexamethasone because of the potential for rapid onset 
of cell lysis with this agent.40  TLS has also been reported in patients with chronic 
lymphocytic leukemia with significant tumor burden when initiating venetoclax (initial 
5 weeks period of tumor debulking)12,13  No TLS event has been reported in the Phase 1 
studies with venetoclax plus Bd in multiple myeloma.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
125
Subjects with high tumor burden (e.g., Durie-Salmon or International Staging System 
[ISS] Stage II/III), rapidly increasing M-protein or light chains or high proliferative 
activity, plasmablastic morphology, unfavorable karyotype or compromised renal function 
(CrCl < 50 mL/minute) may be at higher risk of developing TLS.41
Consider TLS prophylaxis with oral hydration (at least 1 – 2 liters, as tolerable, each day) 
in all subjects at least 72 hours prior to the first day of dosing with venetoclax/placebo.  
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, and 
manage abnormalities in serum creatinine, uric acid and electrolytes promptly.  For 
subjects at higher risk, more intensive measures (e.g., intravenous hydration, frequent 
monitoring of labs, hospitalization, etc.) should be considered at the Investigator 
discretion.  All TLS prophylaxis measures should be appropriately recorded in the eCRF.
6.2
Guidelines for Dose Modifications and Treatment
If the dose of one drug in the study treatment (i.e., bortezomib, dexamethasone, or 
venetoclax/placebo) is delayed outside of the protocol allowed window or interrupted for 
any reason (i.e., – subject missed dose, dose held due to toxicity, etc.), the dose will be 
considered missed and the subject will continue on in the cycle (i.e., – if Cycle 2 Day 1 
dose of bortezomib is held and not completed with ±1 day window, Cycle 2 Day 1 would 
be considered missed and subject would continue to be evaluated for dosing at Cycle 2 
Day 4).  If a dose is held, all assessments listed for that day would still be completed, with 
the exception of PK samples.  Every effort should be made to follow the planned dosing 
schedule; however, delays of up to 7 days in the initiation of a cycle, beginning at Cycle 2 
Day 1, due to toxicity or scheduling issues will be allowed.
The subject will be considered still on protocol treatment as long as at least one of 
the specified drugs in the study treatment is being administered.  
Subjects experiencing a 21-day delay in all drugs that are part of the study treatment 
(bortezomib, dexamethasone, and venetoclax/placebo) due to an AE(s) related to study 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
126
treatment should be discontinued from study treatment.  Subjects experiencing delays 
unrelated to study treatment, for example due to radiation therapy may delay study 
treatment up to 42 days.  Delays greater than 21 days must be discussed with the TA MD 
or designee (refer to Section 6.1.5).
Interruption/Discontinuation of Study Drug Due to Confirmed or Suspected 
COVID-19 Infection:
Subjects with a confirmed (viral test positive) or suspected COVID-19 infection must 
interrupt all study drugs until the following COVID-19 viral clearance criteria are met and 
COVID-19 related complications do not change the subject's risk/benefit ratio per 
Investigator assessment.
Confirmed COVID-19 infection:
●
Symptomatic subjects:  At least 2 negative viral tests in a row, ≥ 24 hours apart 
after at least 14 days have passed since recovery, defined as resolution of fever 
without use of antipyretics and improvement in respiratory symptoms (e.g., 
cough, shortness of breath)
●
Asymptomatic subjects:  At least 2 negative viral tests in a row, ≥ 24 hours 
apart after at least 14 days have passed since prior positive result (note:  
subjects who develop symptoms will follow guidance above for symptomatic 
subjects)
Suspected COVID-19 infection:
●
Subjects with suspected COVID-19 infection should interrupt treatment with 
study drugs while viral testing is pending.  Treatment may be reinitiated upon 
confirmation of negative viral test result and notification to the AbbVie TA MD 
or designee.
The TA MD should be notified by the PI of any modification in planned study drug 
administration due to COVID-19.  In addition, the investigator should contact the 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
127
AbbVie TA MD before reintroducing any study drugs in subjects with confirmed or 
suspected COVID-19 infection.
Interruptions in study drug dosing due to the above COVID-19 testing guidance for 
subjects must be discussed with the AbbVie TA MD, along with the possibility of 
premature discontinuation from the study drug dosing period.  There are no time limits for 
study drug interruption if no permanent study discontinuation criteria have been met.  For 
subjects that experienced study drug interruptions greater than 42 days, two IMWG 
samples must be taken in order to rule out progressive disease prior to restarting study 
drug.  Follow protocol Section 5.3.7.1, Section 5.4.1, and Appendix G for subjects who 
discontinue study drug.
Frequency or timing of COVID-19 testing and intervals between testing for the above 
viral clearance criteria may be adjusted to account for epidemiologic trends, updated 
information regarding infectivity, and local/institutional guidelines.
COVID-19 Pandemic-Related Acceptable Protocol Modification:
Subjects who cannot attend an onsite visit to receive scheduled administration of
bortezomib should interrupt treatment with bortezomib until the subject is able to attend 
the study visit for treatment upon further discussion with AbbVie TA MD or designee.
At this time, dose holds are not recommended, unless for infections or other AEs 
according to the protocol. The Investigator should evaluate the benefit risk for each study 
patient and treat accordingly, even if this results in temporarily withholding treatment.
●
Subject restart after interruption may be allowed following the instructions 
under "Interruption/Discontinuation of Study Drug Due to Confirmed or 
Suspected COVID-19 Infection" in Section 6.2 above.
●
Permanent discontinuation is not recommended, even if a longer treatment free 
interval will occur.  These cases should be assessed on a case-by-case basis 
with the AbbVie TA MD or designee.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
128
●
Any dose hold or interruption that is due to COVID-19 pandemic, should be 
thoroughly documented within the subject source documentation.
6.2.1
Dose Modifications or Delays for Venetoclax/Placebo 
Toxicities
Dose modifications and treatment guidelines for venetoclax/placebo-related toxicities are 
provided in Table 7 and Table 8.
Table 7.
Venetoclax/Placebo* Dose Levels
Dose Level
Venetoclax/Placebo
Dose Level 1
800 mg QD
Dose Level –1
600 mg QD
Dose Level –2
400 mg QD
Dose Level –3
200 mg QD
*
Once subjects are unblinded, venetoclax toxicity management will no longer apply for subjects in Arm 2 (Placebo 
+ Bd).
If the dose of venetoclax/placebo at dose level –3 is not tolerable, then no further 
reductions will be allowed and venetoclax/placebo should be discontinued.  Upon 
resolution of the AE leading to dose reduction, the dose of venetoclax/placebo can be 
increased once following Table 7 guidelines, based on the Investigator's clinical 
judgment.  If the AE recurs upon increasing the dose of venetoclax/placebo, then the 
subject should remain at the reduced and tolerated dose level.  Guidelines in Table 9
should also be followed for venetoclax/placebo-toxicity related dose reductions when 
moderate or strong CYP3A inhibitors are concomitantly administered.  
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
129
Table 8.
Hematological and Non-Hematological Toxicities Related to 
Venetoclax/Placebo*
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 may be administered with 
venetoclax/placebo if clinically indicated.

For Grade 4 neutropenia without infection, anti-infective prophylaxis 
with Levofloxacin (500 mg once daily, adjusted for renal function) or 
equivalent antibiotic therapy, per institutional guidelines must be 
administered until the neutropenia improves to Grade 3 or better 
(ANC > 500 cells/µL) (See Section 6.1.7.1).

First episode:  Interrupt venetoclax/placebo and once the toxicity has 
resolved to Grade 1 or baseline level, venetoclax/placebo may be 
resumed at the same dose.

For subsequent episodes:  Interrupt venetoclax/placebo.  Consider 
using G-CSF as clinically indicated. Follow dose reduction 
guidelines in Table 7 when resuming treatment with 
venetoclax/placebo after resolution.  A larger dose reduction may 
occur at the discretion of the physician and according to the dose 
reduction guidelines in Table 7.
Grade ≥ 3 or Serious 
Infections

Interrupt venetoclax/placebo and upon resolution, treatment can be 
resumed at a reduced dose or discontinued, depending on 
Investigator's clinical judgment. 
Grade 3 or 4 
non-hematologic events

First episode:  Interrupt venetoclax/placebo.  Once toxicity has 
resolved to Grade ≤ 1 or baseline, venetoclax/placebo may be 
resumed at the same dose.  No dose modification is required.

For subsequent episodes:  Interrupt venetoclax/placebo.  Follow dose 
reduction guidelines in Table 7 when resuming treatment with 
venetoclax/placebo after resolution.  A larger dose reduction may 
occur at the discretion of the physician and according to the dose 
reduction guidelines in Table 7.
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 (see Table 7).

For any events of clinical TLS, resume at a reduced dose following 
resolution.
*
Once subjects are unblinded, venetoclax toxicity management will no longer apply for subjects in Arm 2 (Placebo 
+ Bd).
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
130
6.2.2
Dose Modifications for Moderate or Strong CYP3A Inhibitors 
Used with Venetoclax/Placebo
Use of venetoclax/placebo with moderate or strong CYP3A4 inhibitors should be avoided 
and the investigator should consider alternative medications.  If the administration of a 
moderate or strong CYP3A4 is absolutely necessary based on the investigator's clinical 
judgment, then the venetoclax/placebo dose should be reduced during the period it is co-
administered with a moderate or strong CYP3A4.  Dose reductions for venetoclax/placebo 
dose levels used with moderate and strong CYP3A inhibitors are provided on Table 9.  
Subjects should be monitored more closely for signs of toxicities and the dose may need 
to be further adjusted.  After discontinuation of CYP3A inhibitor, wait for 3 days before 
venetoclax/placebo dose is increased back to previous dose level.
Table 9.
Dose Modifications for Venetoclax/Placebo:*  Moderate or Strong 
CYP3A Inhibitor Use
Dose Level
(From Table 7)
Venetoclax/Placebo Dose
No Moderate or Strong 
CYP3A Inhibitor
With Moderate 
CYP3A Inhibitor
With Strong 
CYP3A Inhibitor
Dose Level 1
800 mg QD
400 mg QD
200 mg QD
Dose Level –1
600 mg QD
300 mg QD
100 mg QD
Dose Level –2
400 mg QD
200 mg QD
100 mg QD
Dose Level –3
200 mg QD
100 mg QD
Interrupt 
venetoclax/placebo 
temporarily
*
Once subjects are unblinded, moderate or strong CYP3A inhibitors dose modification will no longer apply for 
subjects in Arm 2 (Placebo + Bd).
6.2.3
Toxicities Related to Bortezomib/Dexamethasone
The following serious adverse events have been reported in subjects treated with 
bortezomib as a single agent in a study of bortezomib versus dexamethasone in subjects 
with relapsed multiple myeloma:  pyrexia, diarrhea, dyspnea, pneumonia, and vomiting.  
In another study comparing subcutaneous and intravenous formulations of bortezomib in 
subjects with relapsed multiple myeloma, additional serious adverse events were reported 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
131
in the intravenous bortezomib treatment arm:  peripheral sensory neuropathy, and renal 
failure.  A full description of all adverse events associated with bortezomib can be found 
in the bortezomib prescribing information.33
Dose reductions and treatment guidelines for bortezomib and dexamethasone-related 
toxicities are provided in Table 10 and Table 12 and represent general recommendations.  
Please refer to the bortezomib33 and dexamethasone42 prescribing information for 
additional information.  
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
132
Table 10.
Dose Reductions and Treatment Guidelines for Toxicity Related to 
Bortezomib
Toxicity
Recommended Action
Grade 3 non-hematological or Grade 4 
hematological (other than neuropathy)
Withhold bortezomib therapy until the symptoms 
of the toxicity resolve.  When toxicity resolves, 
bortezomib therapy may be reinitiated at a 25% 
reduced dose.  (1.3 mg/m2 reduces to 
1 mg/m2/dose; 1 mg/m2/dose reduces to 
0.7 mg/m2/dose).
Peripheral Neuropathy:a

Grade 1 (asymptomatic; loss of deep tendon 
reflexes or parasthesia) without pain or loss 
of function
No action

Grade 1 with pain or Grade 2 (moderate 
symptoms; limiting instrumental Activities of 
Daily Living [ADL]b)
For subjects receiving twice-weekly bortezomib, 
only, change treatment schedule to 1.3 mg/m2 once 
per week (Day 1, 8 and 15 in a 21-day cycle)
OR
Reduce bortezomib current dose by one level 
(1.3 mg/m2 to 1 mg/m2 to 0.7 mg/m2)

Grade 2 with pain or Grade 3 (severe 
symptoms; limiting self care ADLc)
Withhold bortezomib therapy until toxicity 
resolves to baseline or ≥ Grade 1.  When toxicity 
resolves, reinitiate with a reduced dose of 
bortezomib at 0.7 mg/m2 once per week.

Grade 4 (life-threatening consequences; 
urgent intervention indicated)
Discontinue bortezomib
a.
Grading based on NCI Common Terminology Criteria CTCAE v4.0.
b.
Instrumental ADL:  refers to preparing meals, shopping for groceries or clothes, using telephone, managing money, 
etc.
c.
Self-care ADL:  refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications and not 
bedridden.
Dose reduction levels and treatment guidelines for dexamethasone-related toxicities are 
provided in Table 11 and Table 12.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
133
Table 11.
Dose Reductions for Dexamethasone
Dexamethasone
Reduced Dexamethasone Doses
Dose –1
Dose –2
Dose –3
20 mg
12 mg
8 mg
4 mg
Table 12.
Treatment Guidelines for Toxicity Related to Dexamethasone
Body System
Symptom
Recommended Action
Gastrointestinal
Dyspepsia, gastric or duodenal 
ulcer, gastritis Grades 1 – 2 
(requiring medical 
management)
Treat with H2 blockers, sucralfate, or proton pump 
inhibitor.  If symptoms persist despite above 
measures, decrease dexamethasone dose by 
1 dose level.
Gastrointestinal
≥ Grade 3 (requiring 
hospitalization or surgery)
Hold dexamethasone until symptoms adequately 
controlled.  Restart at 1 dose decrement along 
with concurrent therapy with H2 blockers, 
sucralfate, or proton pump inhibitor.  If symptoms 
persist despite above measures, reduce to dose 
level –3 or discontinue dexamethasone 
permanently.
Gastrointestinal
Acute pancreatitis
Discontinue dexamethasone permanently.
Cardiovascular
Edema ≥Grade 3 (limiting 
function and unresponsive to 
therapy or anasarca)
Diuretics as needed, and restart dexamethasone at 
1 dose decrement; if edema persists despite above 
measures, decrease dose by another level.  
Discontinue dexamethasone permanently if 
symptoms persist despite second reduction.
Neurology
Confusion or mood alteration 
> Grade 2 (interfering with 
function ± interfering with 
activities of daily living)
Hold dexamethasone until symptoms resolve.  
Restart at 1 dose decrement.  If symptoms persist 
despite above measures, decrease by another level 
or discontinue dexamethasone permanently.
Musculoskeletal
Muscle weakness > Grade 2 
(symptomatic and interfering 
with function ± interfering with 
activities of daily living)
Decrease dexamethasone by 1 dose level.  If 
weakness persists, decrease dose by 1 more dose 
level.  Discontinue dexamethasone permanently if 
symptoms persist.
Metabolic
Hyperglycemia ≥ Grade 3
Treatment with insulin or oral hypoglycemic 
agents as needed.  If uncontrolled despite above 
measures, decrease dose by 1 dose level until 
levels are satisfactory.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
134
6.3
Product Complaint
6.3.1
Definition
A Product Complaint is any Complaint (see Section 6.0 for the definition) related to the 
biologic or drug component of the product.
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 (example:  printing illegible), 
missing components/product, or packaging issues.
Any information available to help in the determination of causality to the events outlined 
directly above should be captured.
6.3.2
Reporting
Product Complaints concerning the investigational product must be reported to the 
Sponsor within 1 business day of the study site's knowledge of the event via the Product 
Complaint form.  Product Complaints that occur during the study will be followed-up to a 
satisfactory conclusion.  All follow-up information is to be reported to the Sponsor (or an 
authorized representative) and documented in source as required by the Sponsor.  Product 
Complaints associated with adverse events will be reported in the study summary.  All 
other complaints will be monitored on an ongoing basis.
Product Complaints may require return of the product with the alleged complaint 
condition.  In instances where a return is requested, every effort should be made by the 
Investigator to return the product within 30 days.  If returns cannot be accommodated 
within 30 days, the site will need to provide justification and an estimated date of return.
The description of the complaint is important for AbbVie in order to enable AbbVie to 
investigate and determine if any corrective actions are required.
 






Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
137
8.1
Statistical and Analytical Plans
8.1.1
Definition for Analysis Populations
Intent-To-Treat (ITT) analysis set consists of all randomized subjects.  The data from the 
ITT population will be analyzed by the treatment group assignment given at the time of 
randomization, even if the subject does not receive the correct treatment or is not 
compliant to the protocol procedures.
Unless otherwise noted, the ITT analysis set will be used for baseline characteristics and 
efficacy analyses.
Safety analysis set consists of all randomized subjects who take at least one dose of study 
drug.  Patients who received venetoclax at the first actual dosing day will be considered as 
venetoclax plus Bd group and otherwise they will be considered as placebo plus Bd 
group.
The safety analysis set will be used for safety analyses.
8.1.2
Baseline Characteristics
All baseline summary statistics and analyses will be based on characteristics prior to the 
initiation of any component of study treatment (or randomization for non-treated 
subjects).  Unless otherwise stated, baseline for a given variable will be defined as the last 
value for that variable obtained prior to the first dose of any component of study treatment 
(or randomization for non-treated subjects).
Continuous demographic data (e.g., age, height, and weight) will be summarized with 
means, standard deviation, minimum, maximum, and range.  Frequencies and percentages 
will be computed for categorical data (e.g., sex, race, number of prior therapies [1 versus 
2 versus 3], prior exposure to bortezomib or other proteasome inhibitors [proteasome 
inhibitor-sensitive versus proteasome inhibitor-naïve], MM stage [I versus II versus III], 
biomarkers, geography [North America versus EU versus Rest of World]), and baseline 
ECOG performance status.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
138
Frequencies and percentages will be computed for each medical history parameter.
8.1.3
Efficacy Endpoints
8.1.3.1
Primary Efficacy Endpoint
The primary endpoint is PFS based on IMWG criteria for multiple myeloma 
(Appendix J) 13,14 per IRC assessment.
For a given subject, PFS is defined as the number of days from the date the subject was 
randomized to 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.  
Events of death will be included for subjects who had not experienced an event of PD.  If 
the subject does not have an event of PD and the subject has not died, the subject's data 
will be censored.  Detailed event and censoring information for PFS are provided in 
Table 13.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
139
Table 13.
Event and Censoring Date Used in PFS
Situation
Option for End-Date
Outcome
No baseline assessment
Date of randomization
Censor
PD or death at scheduled 
assessment date or before the 
next scheduled assessment
If there is documented PD then date of PD.  
Otherwise date of death
Event
PD or death after exactly 
one missing assessment
If there is documented PD then date of PD.  
Otherwise date of death
Event
PD or death after two or more 
consecutive missing assessments
If no adequate assessment is available prior to 
PD/death then date of randomization. 
Otherwise, date of the last adequate assessment prior 
to PD/death
Censor
No PD and no death
If no adequate assessment is available then date of 
randomization.
Otherwise, date of the last adequate assessment
Censor
Start of new anti-cancer therapy 
prior to PD/death
If no adequate assessment is available prior to start of 
new anti-cancer therapy then date of randomization.  
Otherwise, date of the last adequate assessment prior 
to start of new anti-cancer therapy
Censor
8.1.3.2
Secondary Efficacy Endpoints
Secondary efficacy endpoints are as follows:  VGPR or better response rate; PROs:  
Worst Pain (BPI-SF), Physical Functioning (EORTC QLQ-C30); OS; PFS in subjects 
with high BCL-2 expression; DOR; TTP; ORR; MRD negativity rate; PROs GHS/QoL 
(EORTC QLQ-C30), and Fatigue (PROMIS Cancer Fatigue SF).  The patient-reported 
outcome instruments area described in detail in Section 5.3.1.1.1.
VGPR or better response rate is defined as the proportion of subjects with documented 
CR, sCR, or VGPR.
For a given subject, DOR is defined as the number of days from the subject's date of 
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 does not have an event of PD 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
140
and the subject has not died due to multiple myeloma, the subject's data will be censored.  
Detailed event and censoring information for DOR are provided in Table 14.
Table 14.
Event and Censoring Date Used in DOR
Situation
Option for End-Date
Outcome
No baseline assessment
Date of randomization
Censor
PD or death due to multiple myeloma at 
scheduled assessment date or before the 
next scheduled assessment
If there is documented PD then date of PD.  
Otherwise date of death
Event
PD or death due to multiple myeloma after 
exactly one missing assessment
If there is documented PD then date of PD.  
Otherwise date of death
Event
PD or death due to multiple myeloma after 
two or more consecutive 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
Start of new anti-cancer therapy prior to 
PD/Death
Date of the last adequate assessment prior to 
start of new anti-cancer therapy
Censor
For subjects who never achieve a documented response (PR or better), the subject's data 
will not be included in the analysis of DOR.
For a given subject, time to death (OS) is defined as the number of days from the date the 
subject was randomized to the date of the subject's death due to any cause.  All events of 
death will be included, regardless of whether the event occurred while the subject was still 
taking study drug or after the subject discontinued study drug.  If a subject has not died, 
the data will be censored at the date last known to be alive.
For a given subject, TTP is defined as the number of days from the date the subject was 
randomized to the date of first documented PD or death due to multiple myeloma, 
whichever occurs first.  If the subject does not have an event of PD and the subject has not 
died due to multiple myeloma, the subject's data will be censored.  Detailed event and 
censoring information for TTP are provided in Table 15.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
141
Table 15.
Event and Censoring Date Used in TTP
Situation
Option for End-Date
Outcome
No baseline assessment
Date of randomization
Censor
PD or death due to multiple 
myeloma at scheduled 
assessment date or before the 
next scheduled assessment
If there is documented PD then date of PD.  
Otherwise date of death
Event
PD or death due to multiple 
myeloma after exactly 
one missing assessment
If there is documented PD then date of PD.  
Otherwise date of death
Event
PD or death due to multiple 
myeloma after two or more 
consecutive missing assessments
If no adequate assessment is available prior 
to PD/death then date of randomization.  
Otherwise, date of the last adequate 
assessment prior to PD/death
Censor
No PD and no death due to 
multiple myeloma
If no adequate assessment is available then 
date of randomization.  Otherwise, date of 
the last adequate assessment
Censor
Start of new anti-cancer therapy 
prior to PD/death
If no adequate assessment is available prior 
to start of new anti-cancer therapy then date 
of randomization. 
Otherwise, date of the last adequate 
assessment prior to start of new anti-cancer 
therapy
Censor
ORR is defined as the proportion of subjects with documented PR or better.
MRD negativity will be defined at 10–5 threshold as described in Section 5.3.6.
8.1.3.3
Tertiary Efficacy Endpoints
Tertiary efficacy endpoints are CBR, DCR, TTR, TNT, and PROs based on the remaining 
subscales of BPI-SF, EORTC QLQ-C30, EORTC QLQ-MY20, and EQ-5D-5L.
CBR is defined as the proportion of subjects with documented MR or better.  DCR is 
defined as the proportion of subjects with documented MR or better or SD lasting at least 
8 weeks.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
142
For a given subject, TTR is defined as the number of days from the date the subject was 
randomized to the date of first documented response (PR or better).
Detailed event and censoring information for TTR are provided in Table 16.
Table 16.
Event and Censoring Date Used in TTR
Situation
Option for End-Date
Outcome
No baseline assessment
Date of randomization
Censor
Documented response at scheduled 
assessment date or before the next 
scheduled assessment
Date of response
Event
Documented response after exactly 
one missing assessment
Date of response
Event
Documented response after two or 
more consecutive missing 
assessments
If no adequate assessment is available prior to 
response then date of randomization.  Otherwise, 
date of the last adequate assessment prior to 
response
Censor
No documented response
If no adequate assessment is available then date of 
randomization.  Otherwise, date of the last adequate 
assessment
Censor
Start of new anti-cancer therapy 
prior to response
If no adequate assessment is available prior to start 
of new anti-cancer therapy then date of 
randomization. 
Otherwise, date of the last adequate assessment 
prior to start of new anti-cancer therapy
Censor
For a given subject, TNT is defined as the number of days from the date the subject was 
randomized to the date of receiving new anti-cancer therapy.  If the subject does not 
receive new anti-cancer therapy, the subject's data will be censored at the subject's last 
known date of follow-up for new anti-cancer therapy.
PROs based on subscales of the BPI-SF, EORTC QLQ-C30, EORTC QLC-MY20, and 
EQ-5D-5L will be statistically analyzed.  Details will be provided in the statistical 
analysis plan (SAP).
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
143
8.1.4
Timing of Efficacy Analyses and Safety Evaluations
Efficacy and safety analyses will be performed when approximately 136 PFS events per 
IRC assessment are observed.  If the observed treatment benefit with respect to PFS is 
both statistically and clinically significant, patients will still continue to be followed for 
overall survival with no treatment cross-over.
8.1.5
Statistical Analyses of Efficacy
8.1.5.1
Primary Analysis of Efficacy
The study is designed to test the following primary statistical hypothesis:
: (	)Venetoclax + Bd = (	)Placebo + Bd   vs.  : (	)Venetoclax +Bd ≠(	)Placebo + Bd ,
where S(t) is the survivorship function of PFS at time t.
For PFS, a stratified two-sided log-rank test with two-sided type-I error rate of α = 0.05 
(one-sided type I error rate of α = 0.025) will be used to test the primary null hypothesis.  
The hazards ratio (HR) for treatment effect will be estimated and its two-sided 95% 
confidence interval will be provided.  The estimation will be based on a Cox's 
proportional hazards model with treatment and stratification factors included.
In addition, survivorship functions will be estimated by using Kaplan-Meier product-limit 
method.  Estimated survival curves will be presented.  The estimations will be performed 
by treatment group.  If reached, median PFS time and its two-sided 95% confidence 
intervals will be presented by treatment group.
8.1.5.2
Secondary Analyses of Efficacy
VGPR or better response rate and ORR will be analyzed by using 
Cochran-Mantel-Haenszel test.  Estimated rates along with corresponding 95% 
confidence intervals will be presented.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
144
To assess PFS in subjects with high BCL-2 expression, a subgroup analysis will be 
performed for the primary endpoint PFS by BCL-2 expression levels (high/low).
The cutoff used for categorization of BCL-2 expression levels and alternative and 
additional supportive biomarker research on BCL-2 expression levels, if deemed 
necessary and helpful in understanding the drug effect, will be specified in the SAP.
DOR and TTP will be analyzed by using stratified log-rank test.
The hazards ratios for treatment effect will be estimated and two-sided 95% confidence 
intervals will be provided.  The estimation will be based on a Cox's proportional hazards 
model with treatment and stratification factors in it.
In addition, survivorship functions will be estimated by using Kaplan-Meier product-limit 
method.  Estimated survival curves will be presented.  The estimations will be performed 
by treatment group.  If reached, median time to event and its two-sided 95% confidence 
intervals will be presented by treatment group.
The OS will be analyzed by using a stratified two-sided 3-look group sequential log-rank 
test with a cumulative two-sided type-I error rate of α = 0.05 (one-sided type I error rate 
of α = 0.025).  The hazards ratio for treatment effect will be estimated and its two-sided 
95% confidence interval will be provided.  The estimation will be based on a Cox's 
proportional hazards model with treatment and stratification factors in it.
In addition, survivorship functions will be estimated by using Kaplan-Meier product-limit 
method.  Estimated survival curves will be presented.  The estimations will be performed 
by treatment group.  If reached, median OS time and its two-sided 95% confidence 
intervals will be presented by treatment group.
DOR will be analyzed only based on data from responders (PR or better) out of the ITT 
analysis set.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
145
For PROs, change in score from baseline will be compared between treatment arms for 
the following domains:  Worst Pain (BPI-SF), Physical Functioning (EORTC QLQ-C30), 
Fatigue (PROMIS-Fatigue), and Global Health Status/QoL (EORTC QLQ-C30).
MRD negativity rate will be analyzed by using Cochran-Mantel-Haenszel test.  Estimated 
rates along with corresponding 95% confidence intervals will be presented.
Statistical analysis of secondary endpoints will be described in detail in the SAP.
8.1.5.3
Tertiary Analyses of Efficacy
CBR and DCR will be analyzed by using Cochran-Mantel-Haenszel test.  Estimated rates 
along with corresponding 95% confidence intervals will be presented.
TTR and TNT will be analyzed by using stratified log-rank test.
The hazards ratios for treatment effect will be estimated and two-sided 95% confidence 
intervals will be provided.  The estimation will be based on a Cox's proportional hazards 
model with treatment and stratification factors in it.
In addition, survivorship functions will be estimated by using Kaplan-Meier product-limit 
method.  Estimated survival curves will be presented.  The estimations will be performed 
by treatment group.  If reached, median time to event and its two-sided 95% confidence 
intervals will be presented by treatment group.
Descriptive statistics will be used to summarize patient-reported outcomes based on the 
remaining subscales of BPI-SF, EORTC QLQ-C30, EORTC QLC-MY20, and 
EQ-5D-5L.
Alternative tertiary efficacy statistical analyses may be performed if deemed necessary 
and helpful in understanding the drug effect, which will be specified in the SAP.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
146
8.1.5.4
Additional Sensitivity and Supportive Efficacy Analyses
As sensitivity analysis, the primary endpoint PFS will be analyzed with the following 
changes: 
1.
PFS based on assessment by Investigator.
2.
Using the actual event date of PD or death as event date, regardless of the number 
of preceding missing assessments.
3.
Not considering taking new anticancer therapy as a reason for censoring.  
4.
A robustness analysis will be performed using a stratified, adjusted Cox model, 
i.e., the MODEL statement will include the treatment group variable; and, e.g., age 
group (< 65 years/≥ 65 years), renal function, cytogenetic (high risk/standard risk), 
prior stem cell transplant (yes/no), BCL-2 expression (high/low) and MM stage as 
covariates.  The stratification factors will be reflected in the STRATA statement.  
HR and 2-sided 95% CIs will be provided.  Covariates with large number of 
missing data or small number of subjects within a category may be excluded or 
combined as appropriate.
Supportive subgroup analysis will be performed for the primary endpoint PFS and 
alternative additional sensitivity and supportive efficacy statistical analyses may be 
performed if deemed necessary and helpful in understanding the drug effect, which will 
be specified in the SAP.
8.1.5.5
Interim Analysis
8.1.5.5.1
Progression Free Survival
There is no Interim Analysis for Progression Free Survival.
8.1.5.5.2
Overall Survival
The OS will be analyzed by using a stratified two-sided 3-look group sequential log-rank 
test with a cumulative two-sided type-I error rate of α = 0.05 (one-sided type I error rate 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
147
of α = 0.025).  A separate α-spending approach will be used for OS.  The final OS 
analysis will be performed when approximately 116 OS events are observed.  The interim 
analyses for OS will be considered at the time of the PFS analysis and when 
approximately 75% of the total 116 OS events are observed (87 OS events).  
8.1.5.6
Multiplicity Adjustments
Statistical tests for the secondary endpoints will be implemented in the testing strategy to 
maintain family-wise two-sided type I error rate at 0.05.  Each of these tests will be 
performed at an overall two-sided significance level of 0.05.  Statistical testing of the 
secondary endpoints will be performed only if the primary efficacy analysis of PFS is 
significant.
The testing order and details of testing procedures will be provided in the SAP.
8.1.6
Safety Assessments
The safety of venetoclax plus Bd and placebo plus Bd will be assessed by evaluating 
study treatment exposure, adverse events, serious adverse events, deaths, and changes in 
laboratory determinations and vital sign parameters.
8.1.7
Statistical Analyses of Safety
8.1.7.1
Duration of Study Treatment
A summary of the number of days and/or cycles subjects were exposed to study treatment 
will be provided.
8.1.7.2
Adverse Events
Analyses of adverse events will include only "treatment-emergent" events, i.e., those that 
have an onset on or after the day of the study treatment.  Analyses will not include those 
that have an onset greater than 30 days after the last dose of the study drug.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
148
Treatment-emergent adverse events will be coded and summarized by system organ class 
and preferred term according to the Medical Dictionary for Regulatory Activities 
(MedDRA) adverse event coding dictionary.  The percentage of subjects experiencing an 
adverse event at a given severity, NCI CTCAE version 4.03 toxicity grade and 
relationship to study treatment will be provided.
8.1.7.3
Serious Adverse Events
Serious adverse events will be summarized using the same methods as adverse events 
described above in Section 8.1.7.2.
8.1.7.4
Deaths
The number of subject deaths will be summarized 1) for deaths occurring while the 
subject was still receiving study drug in this study, 2) for deaths occurring off treatment 
within 30 days after the last dose of study drug, and 3) for all deaths in this study 
regardless of the number of days after the last dose of study drug.
8.1.7.5
Longitudinal Analyses of Laboratory and Vital Signs Data
Changes from baseline may be summarized for each scheduled post-baseline visit and for 
the Treatment Completion Visit for hemoglobin, platelet, neutrophil, absolute leukocyte 
count, creatinine, and calcium, and vital sign parameters.  If more than one measurement 
exists for a subject on a particular day, an arithmetic average will be calculated.  This 
average will be considered to be that subject's measurement for that day.  Post-baseline 
measurements more than 30 days after the last dose of randomized study drug will not be 
included.  Subjects that do not have a baseline measurement or do not have any 
post-baseline measurements will not be included.
8.1.7.6
Analyses of Laboratory Data Using NCI CTCAE
Where applicable, laboratory values will be categorized according to the NCI CTCAE 
version 4.03 grades, and shifts from baseline grade to maximum and final post-baseline 
grades will be assessed.  The baseline and final grades will be defined respectively as the 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
149
grade of the last measurement collected prior to the first dose of any component of study 
treatment, and as the grade of the last post-baseline measurement collected no more than 
30 days after the last dose of study drug.  If multiple values are available for a post 
baseline measurement, then the value with the highest NCI CTCAE grade will be used in 
the assessment of shift.
Detailed listings of data for subjects experiencing NCI CTCAE Grade 3 to 4 blood 
chemistry and hematology values will be provided.  All measurements collected, 
regardless of the number of days after the last dose of study drug, will be included in these 
listings.
8.1.7.7
Analyses of Vital Signs Using Criteria for Potentially 
Clinically Significant Vital Sign Values
Detailed listings of data for subjects experiencing potentially clinically significant vital 
sign values according to the AbbVie-defined criteria for vital sign values will be provided.  
All measurements collected, regardless of the number of days after the last dose of study 
drug, will be included in these listings.
8.1.7.8
Pharmacokinetics
Plasma concentrations of venetoclax and bortezomib (and dexamethasone, JAPAN
subjects only) will be tabulated for each subject by visit.
An analysis of venetoclax plasma concentrations may be performed using a nonlinear 
mixed effect population PK modeling approach.  The results from the population PK 
analysis may not be reported in the clinical study report.  Additional analyses may be 
performed if useful in the interpretation of the data.
8.2
Determination of Sample Size
In order to calculate the required number of PFS events, median PFS of placebo plus Bd 
and venetoclax plus Bd are assumed to be 9 months and 16.25 months, respectively 
(HR = 0.554, under the assumption of proportionality).  Log-rank test with two-sided 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
150
type I error rate of α = 0.05 (one-sided type I error rate of α = 0.025) and power of 
1 – β = 90% is used for sample size calculations.  
Under the assumptions above and using a 2:1 randomization ratio to the two arms 
(venetoclax plus Bd versus placebo plus Bd) a total of 136 PFS events per IRC 
assessment are required.  To observe 136 PFS events per IRC assessment, approximately 
280 subjects will be randomized.
With accrual assumed as in Table 17, and the assumed overall dropout rate of 16%, the 
accrual of 280 subjects will take approximately 15 months and 136 PFS events per IRC 
assessment are expected to be reached after approximately 26 months.
The accrual and the blinded PFS rate will be assessed during the conduct of the trial to 
determine if the sample size should be adjusted to ensure timely achievement of the 
required 136 PFS events per IRC assessment.
Table 17.
Accrual Information
Accrual Information
Period No.
Starting at Time (Months)
Accrual Rate 
(Number of Subjects/Month)
1
0
0.5
2
2
5
3
4
19
4
7
39
5
12
10
In order to calculate the required number of OS events, median OS of placebo plus Bd and 
venetoclax plus Bd are assumed to be 24 months and 40 months, respectively (HR = 0.6, 
under the assumption of proportionality).  The study design includes 2 pre-specified 
interim analyses for the secondary endpoint OS.  The final OS analysis will be performed 
when approximately 116 OS events are observed.  The first OS interim analysis will be at 
the time of PFS analysis.  The second OS interim analysis will be based on approximately 
75% of the total 116 OS events (87 OS events).  Two-sided log-rank test with a 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
151
cumulative two-sided type I error rate of α = 0.05 (one-sided type I error rate of 
α = 0.025) is used for the 3-look group sequential plan.  Group sequential plan using Lan 
and DeMets43 α-spending approach with O'Brien-Fleming type boundaries will be applied 
for the OS efficacy analyses.
Approximately 58 OS events are expected at the time of PFS analysis.
Power calculations for a range of different effect sizes are presented in Table 18.
Table 18.
Power Calculation
PFS Analysis (Primary Endpoint)
OS Analysis (Secondary Endpoint)
HR
Power (%)
HR
Power (%)
0.5
95.6
0.5
93.7
0.55
90.0
0.55
85.2
0.6
79.3
0.6
72.8
0.65
64.8
0.65
58.1
The sample size calculation was performed using the software EAST version 6.4.
9.0
Ethics
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB)
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol 
amendments, the Investigator's Brochure, the informed consent and all other forms of 
subject information related to the study (e.g., advertisements used to recruit subjects) and 
any other necessary documents be reviewed by an IEC/IRB.  The IEC/IRB will review the 
ethical, scientific and medical appropriateness of the study before it is conducted.  
IEC/IRB approval of the protocol, informed consent and subject information and/or 
advertising, as relevant, will be obtained prior to the authorization of drug shipment to a 
study site.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
152
Any amendments to the protocol will require IEC/IRB approval prior to implementation 
of any changes made to the study design.  The Investigator will be required to submit, 
maintain and archive study essential documents according to International Conference in 
Harmonization (ICH) GCP.
Any serious adverse events that meet the reporting criteria, as dictated by local 
regulations, will be reported to both responsible Ethics Committees and Regulatory 
Agencies, as required by local regulations.  During the conduct of the study, the 
Investigator should promptly provide written reports (e.g., ICH Expedited Reports, and 
any additional reports required by local regulations) to the IEC/IRB of any changes that 
affect the conduct of the study and/or increase the risk to subjects.  Written documentation 
of the submission to the IEC/IRB should also be provided to AbbVie.
9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, ICH GCP guidelines, 
applicable regulations and guidelines governing clinical study conduct and ethical 
principles that have their origin in the Declaration of Helsinki.  Responsibilities of the 
clinical Investigator are specified in Appendix A.
In the event a significant disaster/crisis (e.g., epidemic/pandemic, natural disaster, 
conflict/combat) occurs leading to difficulties in performing protocol-specified 
procedures, AbbVie will engage with study site personnel in efforts to ensure the safety of 
subjects, maintain protocol compliance, and minimize risks to the integrity of the study 
while trying to best manage subject continuity of care.  This may include alternative 
methods for assessments (e.g., phone contacts or virtual site visits), alternative locations 
for data collection (e.g., use of a local laboratory instead of a central lab), and shipping 
investigational product and/or supplies direct to subjects to ensure continuity of treatment 
where allowed.  COVID-19 pandemic-related acceptable protocol modifications are 
detailed throughout the protocol.  In all cases, these alternative measures must be allowed 
by local regulations and permitted by IRB/IEC.  Investigators should notify AbbVie if any 
urgent safety measures are taken to protect the subjects against any immediate hazard.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
153
9.3
Subject Information and Consent
The Investigator or his/her representative will explain the nature of the study to the 
subject, and answer all questions regarding this study.  Prior to any study-related 
screening procedures being performed on the subject, the informed consent statement will 
be reviewed and signed and dated by the subject, the person who administered the 
informed consent, and any other signatories according to local requirements.  A copy of 
the informed consent form 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 to confirm that informed consent was obtained prior to any study-related 
procedures and that the subject received a signed copy.
Information regarding incentives 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.
In the event a subject withdraws consent to participate from the study, stored biomarker 
samples will continue to be used for research and analysis.  In the event that a subject 
would like to withdraw consent for research using these samples, the subject may request 
that their samples be withdrawn.  Once AbbVie receives the request, remaining biomarker 
samples will be destroyed.  If the subject changes his/her consent, and the samples have 
already been tested, those results will still remain as part of the overall research data.
An informed consent, approved by an IRB/IEC, must be voluntarily signed and dated 
before samples are collected for optional exploratory research.  The nature of the testing 
should be explained and the subject given an opportunity to ask questions.  The informed 
consent must be signed before the samples are collected and any testing is performed.  If 
the subject does not consent to provide samples for the optional exploratory research, it 
will not impact their participation in the study.
In the event a subject withdraws from the main study, optional exploratory research
samples will continue to be stored and analyzed unless the subject specifically withdraws 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
154
consent for the optional samples.  If consent is withdrawn for the optional sampling, the 
subject must inform their study doctor, and once AbbVie is informed, the optional 
samples will be destroyed.  However, if the subject withdraws his/her consent and the 
samples have already been tested, those results will still remain as part of the overall 
research data.
9.3.1
Informed Consent Form and Explanatory Material
In Japan, the principal investigator will prepare the consent form and explanatory material 
required to obtain subject's consent to participate in the study with the cooperation of the 
sponsor and will revise these documents as required.  The prepared or revised consent 
forms and explanatory material will be submitted to the sponsor.  Approval of the IRB 
will be obtained prior to use in the study.
9.3.2
Revision of the Consent Form and Explanatory Material
In Japan, when important new information related to the subject's consent becomes 
available, the principal investigator will revise the consent form and explanatory material 
based on the information without delay and will obtain the approval of the IRB prior to 
use in the study.  The investigator will provide the information, without delay, to each 
subject already participating in the study, and will confirm the intention of each subject to 
continue the study or not.  The investigator shall also provide a further explanation using 
the revised form and explanatory material and shall obtain written consent from each 
subject of their own free will to continue participating in the study.
10.0
Source Documents and Case Report Form 
Completion
10.1
Source Documents
Source documents are defined as original documents, data, and records.  These may 
include hospital records, clinical and office charts, laboratory data/information, pharmacy 
dispensing and other records, recorded data from automated instruments, microfiches, 
photographic negatives, microfilm or magnetic media, and/or x-rays.  Data collected 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
155
during this study must be recorded on the appropriate source document.  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).
The Investigator/institution will permit study-related monitoring, audits, IEC/IRB review, 
and regulatory inspection(s), providing direct access to source data documents.
During the COVID-19 pandemic, remote data review/verification of data may be 
employed if allowed by the local regulatory authority, IRB/IEC, and the study site.
10.2
Case Report Forms
Case report forms (CRFs) must be completed for each subject screened/enrolled in this 
study.  These forms will be used to transmit information collected during the study to 
AbbVie and regulatory authorities, as applicable.  The CRF data for this study are being 
collected with an EDC system called Rave® provided by the technology vendor Medidata 
Solutions Incorporated, NY, USA.  The EDC system and the study-specific eCRFs will 
comply with Title 21 Code of Federal Regulations (CFR) Part 11.  The documentation 
related to the validation of the EDC system is available through the vendor, Medidata, 
while the validation of the study-specific eCRFs will be conducted by AbbVie and will be 
maintained in the Trial Master File at AbbVie.
The Investigator will document subject data in his/her own subject files.  These subject 
files will serve as source data for the study.  All eCRF data required by this protocol will 
be recorded by investigative site personnel in the EDC system.  All data entered into the 
eCRF will be supported by source documentation.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
156
The Investigator or an authorized member of the Investigator's staff will make any 
necessary corrections to the eCRF.  All change information, including the date and person 
performing the corrections, will be available via the audit trail, which is part of the EDC 
system.  For any correction, a reason for the alteration will be provided.  The eCRFs will 
be reviewed periodically for completeness, legibility, and acceptability by AbbVie 
personnel (or their representatives).  AbbVie (or their representatives) will also be allowed 
access to all source documents pertinent to the study in order to verify eCRF entries.  The 
Principal Investigator will review the eCRFs for completeness and accuracy and provide 
his or her electronic signature and date to eCRFs as evidence thereof.
Medidata will provide access to the EDC system for the duration of the trial through a 
password-protected method of internet access.  Such access will be removed from 
Investigator sites at the end of the site's participation in the study.  Data from the EDC 
system will be archived on appropriate data media (CD-ROM, etc.) and provided to the 
Investigator at that time as a durable record of the site's eCRF data.  It will be possible for 
the Investigator to make paper printouts from that media.
Patient-reported data must be completed for each subject enrolled in this study.  These 
data are being collected with an Electronic Patient Reported Outcome (ePRO) system 
called Trialmax, provided by the technology vendor Signant Health of Plymouth Meeting, 
PA, USA. The ePRO system is in compliance with Title 21 CFR Part 11.  The 
documentation related to the system validation of the ePRO system is available through 
the vendor, Signant Health, while the user acceptance testing of the study specific PRO 
design will be conducted and maintained at AbbVie.
The subject will be entering the data on an electronic device; the data will be uploaded to 
a server.  The data on the server will be considered source, and maintained and managed 
by Signant Health.
Internet access to the ePRO data will be provided by Signant Health for the duration of 
the study.  This access will be available for the duration of the study to the site 
investigator, as well as delegated personnel.  Such access will be removed from 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
157
investigator sites following the receipt of the study archive.  Data from the ePRO system 
will be archived on appropriate data media (CD-ROM, etc.) and provided to the 
investigator at that time as a durable record of the site's ePRO data.  It will be possible for 
the investigator to make paper print-outs from that media.
The ePRO data will be collected electronically via a tablet device into which the patient 
will directly enter the required pieces of information.  The electronic device will be 
programmed to allow data entry for only the visits specified in the protocol and will not 
allow for patients to complete more than one of the same assessments at any one visit.  All 
data entered on the device will be immediately stored to the device itself and 
automatically uploaded to a central server administrated by Signant Health.  The 
Investigator and delegated staff will be able to access all uploaded patient entered data via 
a password protected website, up until the generation, receipt and confirmation of the 
study archive.
11.0
Data Quality Assurance
AbbVie will ensure that the clinical trial is conducted with a quality management system 
that will define quality tolerance limits in order to ensure human subject protection and 
reliability of study results.  Data will be generated, documented, and reported in 
compliance with the protocol, ICH GCP, and applicable regulatory requirements.
Prior to enrolling any subject in the study, a study training visit will be held with AbbVie 
personnel, the Investigator(s), and the study coordinators/project manager(s).  This 
meeting will include a detailed discussion and review of the protocol and essential 
documents, performance of study procedures, case report form completion and specimen 
collection methods.
The AbbVie monitor will monitor the study site throughout the study.  Source document 
review will be made against entries on the case report forms and a quality assurance check 
will be performed to ensure that the Investigator is complying with the protocol and 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
158
regulations.  In addition, after the case report forms are retrieved, a review of the data will 
be conducted by a physician or representative at AbbVie.
All data hand-entered in the database will be verified at AbbVie.  Any discrepancies will 
be reviewed against the hard-copy case report form and corrected on-line.  After 
completion of the entry process, computer logic and manual checks will be created to 
identify such items as inconsistent study dates.  Any necessary corrections will be made to 
the database via the appropriate change form/electronic CRF.
Routine hematology, serum chemistry and serology, and urinalysis tests will be conducted 
using a certified clinical laboratory.  Laboratory reference ranges will be obtained prior to 
the initiation of the study and must be entered into Medidata RAVE EDC and updated as 
necessary throughout the course of the study.  A review of all laboratory results will be 
conducted by the AbbVie monitor, the Investigator and other appropriate personnel from 
AbbVie.
During the COVID-19 pandemic, remote data review/verification of data may be 
employed if allowed by the local regulatory authority, IRB/IEC, and the study site.
12.0
Use of Information
All information concerning venetoclax processes, basic scientific data, or formulation 
information, supplied by AbbVie and not previously published is considered confidential 
information.
The information developed during the conduct of this clinical study is also considered 
confidential and will be used by AbbVie in connection with the development of 
venetoclax.  This information may be disclosed as deemed necessary by AbbVie to other 
clinical Investigators, other pharmaceutical companies, and to governmental agencies.  To 
allow for the use of the information derived from this clinical study and to ensure 
complete and thorough analysis, the Investigator is obligated to provide AbbVie with 
complete test results and all data developed in this study and to provide direct access to 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
159
source data/documents for study-related monitoring, audits, IEC/IRB review, and 
regulatory inspection.
This confidential information shall remain the sole property of AbbVie, shall not be 
disclosed to others without the written consent of AbbVie, and shall not be used except in 
the performance of this study.
The Investigator will maintain a confidential subject identification code list of all subjects 
enrolled in the study, including each subject's name, subject number, address, phone 
number and emergency contact information.  This list will be maintained at the study site 
with other study records under adequate security and restricted access, and will not be 
retrieved by AbbVie.
Any research that may be done using research samples from this study will be 
experimental in nature and the results will not be suitable for clinical decision making or 
subject management.  Hence, the subject will not be informed of individual results, should 
analyses be performed, nor will anyone not directly involved in this research.  
Correspondingly, researchers will have no access to subject identifiers.  Individual results
will not be reported to anyone not directly involved in this research other than for 
regulatory purposes.  Data from research may be provided to investigators, used in 
scientific publications, or presented at medical conventions.  Research information will be 
published or presented only in a way that does not identify any individual subject.
13.0
Completion of the Study
The Investigator will conduct the study in compliance with the protocol and complete the 
study within the timeframe specified in the contract between the Investigator (Director of 
the Site in Japan) and AbbVie.  Continuation of this study beyond this date must be 
mutually agreed upon in writing by both the Investigator and AbbVie.  The Investigator 
(Director of the Site in Japan) will provide a final report to the IEC/IRB following 
conclusion of the study, and will forward a copy of this report to AbbVie or their 
representative.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
160
The Investigator (Director of the Site in Japan) must retain any records related to the study 
according to local requirements.  If the Investigator (Director of the Site in Japan) is not 
able to retain the records, he/she must notify AbbVie to arrange alternative archiving 
options.
AbbVie will select the signatory coordinating Investigator from the Investigators who 
participate in each multi-center study.  Selection criteria for this signatory Investigator 
will be based on level of participation, and significant knowledge of the clinical research, 
investigational drug, and study protocol.  The signatory Investigator for the study will 
review and sign the final study report in accordance with the European Agency for the 
Evaluation of Medicinal Products (EMEA) Guidance on Investigator's Signature for Study 
Reports.
At the time the number of OS events required for the final OS analysis is reached, the end 
of study is defined as the date of the last subject's last Safety Follow-Up Visit.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
161
14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for venetoclax and the 
product labeling for bortezomib and dexamethasone.
2.
I have read this protocol and agree that the study is ethical.
3.
I agree to conduct the study as outlined and in accordance with all applicable 
regulations and guidelines.
4.
I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol.
5.
I agree that all electronic signatures will be considered the equivalent of a 
handwritten signature and will be legally binding.
Protocol Title: 
A Phase 3, Multicenter, Randomized, Double Blind, Study of 
Bortezomib and Dexamethasone in Combination with Either 
Venetoclax or Placebo in Subjects with Relapsed or Refractory 
Multiple Myeloma Who are Sensitive or Naïve to Proteasome 
Inhibitors
Protocol Date:
16 December 2020
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
162
15.0
Reference List
1.
Becker N.  Epidemiology of multiple myeloma.  Recent Results Cancer Res.  
2011;183:25-35.
2.
Harousseau JL, Dreyling M; ESMO Guidelines Working Group.  Multiple 
myeloma:  ESMO clinical recommendations for diagnosis, treatment and 
follow-up.  Ann Oncol.  2009;20 (Suppl 4):97-9.
3.
Röllig C, Knop S, Bornhäuser M.  Multiple myeloma.  Lancet.  
2015;385(9983):2197-208.
4.
Siegel R, Ma J, Zou Z, et al.  Cancer statistics, 2014.  CA Cancer J Clin.  
2014;64(1):9-29.
5.
Kvam AK, Waage A.  Health-related quality of life in patients with multiple 
myeloma - does it matter?  Haematologica.  2015;100(6):704-5.
6.
Kent EE, Ambs A, Mitchell SA, et al.  Health-related quality of life in older adult 
survivors of selected cancers:  data from the SEER-MHOS linkage.  Cancer.  
20151;121(5):758-65.
7.
Kumar SK, Dispenzieri A, Lacy MQ1, 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.
Moreau P, Pylypenko H, Grosicki S, et al.  Subcutaneous versus intravenous 
administration of bortezomib in patients with relapsed multiple myeloma:  a 
randomised, phase 3, non-inferiority study.  Lancet Oncol.  2011;12(5):431-40.
9.
Touzeau C, Dousset C, Le Gouill S, et al.  The BCL-2 specific BH3 mimetic 
ABT-199:  a promising targeted therapy for t(11;14) multiple myeloma.  Leukemia.  
2014;28(1):210-2.
10.
Marsden VS, Strasser A.  Control of apoptosis in the immune system:  Bcl-2, BH3 
only proteins and more.  Annu Rev Immunol.  2003;21:71-104.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
163
11.
Wilson H, O'Connor A, Czuczman S, et al.  Phase 1/2a study of navitoclax 
(ABT-263) in relapsed or refractory lymphoid malignancies [abstract 0292].  
Haematologica.  2010;95(S2):116-7.
12.
AbbVie.  ABT-199 Investigator's Brochure Edition 12.0.  14 January 2020.
13.
Rajkumar SV, Harousseau JL, Durie BG, et al.  Consensus recommendations for 
the uniform reporting of clinical trials:  report of the International Myeloma 
Workshop Consensus Panel 1.  Blood.  2011;117(18):4691-5.
14.
Durie BG, Harousseau JL, Miguel JS, et al.  International uniform response criteria 
for multiple myeloma.  Leukemia.  2006;20(9):1467-73.  Erratum in:  Leukemia.  
2007;21(5):1134.
15.
Richardson PG, Sonneveld P, Schuster MW, et al.  Bortezomib or high-dose 
dexamethasone for relapsed multiple myeloma.  N Engl J Med.  2005;352:2487-98.
16.
Moreau P, Pylypenko H, Grosicki S, et al.  Subcutaneous versus intravenous 
administration of bortezomib in patients with relapsed multiple myeloma:  a 
randomised, phase 3, non-inferiority study.  Lancet Oncol.  2011;12(5):431-40.
17.
Engelhardt M, Kleber M, Udi J, et al.  Consensus statement from European experts 
on the diagnosis, management, and treatment of multiple myeloma:  from standard 
therapy to novel approaches.  Leuk Lymphoma.  2010;51(8):1424-43.
18.
Kouroukis TC, Baldassarre FG, Haynes AE, et al.  Bortezomib in multiple 
myeloma:  systematic review and clinical considerations.  Curr Oncol.  
2014;21(4):e573-603.
19.
Rajkumar SV, Richardson P, San Miguel JF.  Guidelines for determination of the 
number of prior lines of therapy in multiple myeloma.  Blood.  2015;126(7):921-2.
20.
Smith, TJ, Bohlke, GH, Lyman, KR, et al.  Recommendations for the wse of WBC 
growth factors:  american society of clinical oncology clinical practice guideline 
update.  Journal of Clinical Oncology.  2015;33(28):3199-3212.
21.
Cleeland CS:  Pain assessment in cancer.  In Effect of Cancer on Quality of Life.  
Edited by Osaba D.  Boca Raton:  CRC Press; 1991:21.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
164
22.
Atkinson TM, Mendoza TR, Sit L, et al.  The Brief Pain Inventory and its "pain at 
its worst in the past 24 hours" item:  clinical trial endpoint considerations.  Pain 
Med.  2010;11:337-346.
23.
Aaronson NK, Ahmedzai S, Bergman B, et al.  The European Organization for 
Research and Treatment of Cancer QLQ-C30:  a quality-of-life instrument for use 
in international clinical trials in oncology.  J Natl Cancer Inst.  1993;85(5):365-76.
24.
Cocks K, Cohen D, Wisloff F, et al.  An international field study of the reliability 
and validity of a disease-specific questionnaire module (the QLQ-MY20) in 
assessing the quality of life of patients with multiple myeloma.  Eur J Cancer.  
2007;43:1670-8.
25.
Cella D, Yount S, Rothrock N, et al.  The patient-reported outcomes measurement 
information system (PROMIS):  progress of an NIH roadmap cooperative group 
during its first 2 years.  Med Care.  2007;45(5 Suppl 1):S3-S11.
26.
Garcia SF, Cella D, Clauser SB, et al.  Standardizing patient-reported outcomes 
assessment in cancer clinical trials:  a patient-reported outcomes measurement 
information system initiative.  J Clin Oncol.  2007;25(32):5106-12.
27.
Cella D, Riley W, Stone A, et al.  The patient-reported outcomes measurement 
information system (PROMIS) developed and tested its first wave of adult sel 
reported health outcome item banks:  2005-2008.  J Clin Epidemiol.  
2010;63(11):1179-94.
28.
EQ-5D-5L and EQ-5D-VA.  Available from:  http://www.euroqol.org.
29.
Mailankody S, Korde N, Lesokhin AM, et al.  Minimal residual disease in multiple 
myeloma:  bringing the bench to the bedside.  Nat Rev Clin Oncol.  
2015;12(5):286-95.
30.
Rawstron AC, Child JA, de Tute RM, et al.  Minimal residual disease assessed by 
multiparameter flow cytometry in multiple myeloma:  impact on outcome in the 
Medical Research Council Myeloma IX Study.  J Clin Oncol.  2013;31(20):2540-7.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
165
31.
Paiva B, Gutiérrez NC, Rosiñol L, et al.  High-risk cytogenetics and persistent 
minimal residual disease by multiparameter flow cytometry predict unsustained 
complete response after autologous stem cell transplantation in multiple myeloma.  
Blood.  2012;119(3):687-91.
32.
Martinez-Lopez J, Lahuerta JJ, Pepin F, et al.  Prognostic value of deep sequencing 
method for minimal residual disease detection in multiple myeloma.  Blood.  
2014;123(20):3073-9.
33.
Velcade® (bortezomib) for Injection [US prescribing information].  Cambridge, 
Ma; Millennium Pharmaceuticals, Inc., 2017.
34.
Velcade® (bortezomib) [Summary of Product Characteristics].  Beerse, Belgium; 
Janssen-Cilag Ltd., 2018.
35.
Moreau P, San-Miguel J, Ludwig H, et al.  Multiple myeloma:  ESMO clinical 
practice guidelines for diagnosis, treatment and follow-up.  Ann Oncol.  
2013;24 (Suppl 6):vi133-7.
36.
San-Miguel SF, Hungria VT, Yoon SS, et al.  Panobinostat plus bortezomib and 
dexamethasone versus placebo plus bortezomib and dexamethasone in patients 
with relapsed or relapsed and refractory multiple myeloma:  a multicenter, 
randomized, double-blind phase 3 trial.  Lancet Oncol.  2014;15(11):1195-206.
37.
Garderet L, Iacobelli S, Moreau P, et al.  Superiority of the triple combination of 
bortezomib-thalidomide-dexamethasone over the dual combination of thalidomide 
dexamethasone in patients with multiple myeloma progressing or relapsing after 
autologous transplantation:  the MMVAR/IFM 2005-04 randomized phase III trial 
from the chronic leukemia working party of the European Group for Blood and 
Marrow Transplantation.  J Clin Oncol.  2012;30(20):2475-82.
38.
Dimopoulos MA, Moreau P, Palumbo A, et al.  Carfilzomib and dexamethasone 
(Kd) vs bortezomib and dexamethasone (Vd) in patients (pts) with relapsed 
multiple myeloma (RMM):  results from the phase III study ENDEAVOR.  J Clin 
Oncol.  2015;33 (Suppl):abstr 8509.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
166
39.
National Cancer Institute.  Common Terminology Criteria for Adverse Events 
(CTCAE), v4.03.  Accessed on:  14 June 2010.  Available from:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
40.
Sezer O, Vesole, DH, Singhal, S, et al.  Bortezomib-induced tumor lysis syndrome 
in multiple myeloma.  Clin Lymphoma Myeloma.  2006:7(3):233-5.
41.
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):938-941.
42.
Dexamethasone [US prescribing information].  Columbus, OH; West-Ward 
Pharmaceuticals, 2015.
43.
Lan KKG, DeMets DL.  Discrete sequential boundaries for clinical trials.  
Biometrika.  1983;70(3):659-63.
44.
Howard SC, Jones DP, Pui CH.  The tumor lysis syndrome.  N Engl J Med.  
2011;364(19):1844-54.
45.
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:e328-46.
46.
Dixon JS.  Second-line Agents in the Treatment of Rheumatic Diseases.  Informa 
Health Care.  1991;456.
47.
Meikle AW, Tyler FH.  Potency and duration of action of glucocorticoids.  Am J of 
Med.  1977;63;200.
48.
Webb R, Singer M.  Oxford Handbook of Critical Care.  Oxford; New York:  
Oxford University Press, 2005.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
167
Appendix A.
Responsibilities of the Clinical Investigator
Clinical research studies sponsored by AbbVie are subject to the Good Clinical Practices 
(GCP) and local regulations and guidelines governing the study at the site location.  In 
signing the Investigator Agreement in Section 14.0 of this protocol, the Investigator is 
agreeing to the following:
1.
Conducting the study in accordance with the relevant, current protocol, making 
changes in a protocol only after notifying AbbVie, except when necessary to 
protect the safety, rights or welfare of subjects.
2.
Personally conducting or supervising the described investigation(s).
3.
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., independent ethics committee [IEC] or 
institutional review board [IRB]) review and approval of the protocol and 
amendments.
4.
Reporting adverse experiences that occur in the course of the investigation(s) to 
AbbVie and the site director.
5.
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).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the 
study about their obligations in meeting the above commitments.
7.
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.
8.
Maintaining records demonstrating that an ethics committee reviewed and 
approved the initial clinical investigation and all amendments.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
168
9.
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.
10.
Following the protocol and not make any changes in the research without ethics 
committee approval, except where necessary to eliminate apparent immediate 
hazards to human subjects.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
169
Appendix B.
List of Protocol Signatories
Name
Title
Functional Area
Director
Statistics
Study Project Manager I
Clinical
Study Management Associate III
Clinical
Executive Medical Director, Hematology
Clinical
Medical Director
Clinical
Director
Clinical Pharmacology
Principal Bioanalytical Investigator
Bioanalysis
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
170
Appendix C.
Revised International Myeloma Working Group Diagnostic 
Criteria for Multiple Myeloma
Definition of Multiple Myeloma
Clonal bone marrow plasma cells ≥ 10% or biopsy-proven bony or extramedullary 
plasmacytoma* and any one or more of the following myeloma defining events:
Myeloma defining events:
1.
Evidence of end organ damage that can be attributed to the underlying plasma cell 
proliferative disorder, specifically:
●
Hypocalcaemia:  serum calcium > 0.25 mmol/L (> 1 mg/dL) higher than the 
upper limit of normal or > 2.75 mmol/L (>11 mg/dL)
●
Renal insufficiency:  creatinine clearance† < 40 mL per minute or serum 
creatinine > 177 μmol/L (> 2 mg/dL)
●
Anemia:  haemoglobin value of > 20 g/L below the lower limit of normal, or a 
haemoglobin value < 100 g/L
●
Bone lesions:  one or more osteolytic lesions on skeletal radiography, CT, or 
PET-CT‡
2.
Any one or more of the following biomarkers of malignancy:
●
Clonal bone marrow plasma cell percentage* ≥ 60%
●
Involved:uninvolved serum free light chain ratio§ ≥ 100
●
> 1 focal lesions¶ on MRI studies
PET-CT = 18F-fluorodeoxyglucose PET with CT
*
Clonality should be established by showing κ/λ-light-chain restriction on flow cytometry, immunohistochemistry, 
or immunofluorescence.  Bone marrow plasma cell percentage should preferably be estimated from a core biopsy 
specimen; in case of a disparity between the aspirate and core biopsy, the highest value should be used. 
†
Measured or estimated by validated equations.
‡
If bone marrow has less than 10% clonal plasma cells, more than one bone lesion is required to distinguish from 
solitary plasmacytoma with minimal marrow involvement.
§
These values are based on the serum Freelite assay (The Binding Site Group, Birmingham, UK).  The involved free 
light chain must be ≥ 100 mg/L. 
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
171
¶
Each focal lesion must be 5 mm or more in size.
 






Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
174
Screening
Event ↓
Screening
Comments
Corrected Serum Calcium
X
Will be completed based on values obtained from certified local laboratory.
Urine Protein Immunofixation
X
24-hour urine collection.  Will be completed per certified central laboratory.
Urine Protein Electrophoresis
X
24-hour urine collection.  Will be completed per certified central laboratory.
Skeletal Survey
X
Skeletal survey consists of lateral radiograph of skull, anteroposterior and lateral views of 
spine, and antero-posterior views of pelvis, ribs, femora, tibiae, fibulae, humeri, ulnae and 
radii.  Historical results obtained within 30 days prior to randomization may be used at 
Screening provided that the images meet the requirements in the Image Acquisition 
Guidelines.  Use of conventional or low dose CT scan, or MRI bone survey is acceptable.
Chest CT
X
JAPAN ONLY
Plasmacytoma Evaluation
X
CT, PET/CT or MRI (same method should be used throughout study) should be performed in 
all subjects with a history of plasmacytomas or if clinically indicated at baseline to assess for 
the presence of extramedullary plasmacytoma.
Bone Marrow Aspirate
X
Samples should be collected for IMWG assessments at the local laboratory and additional 
samples should be sent for biomarker analysis at the central laboratory.  Refer to Appendix H
for additional samples.
IHC Bone Marrow Core Biopsy
X
Bone marrow core biopsy (fixed formalin paraffin embedded [FFPE] core) should be 
collected and used for IMWG assessments per institutional guidelines and analyzed at the 
local laboratory and additional samples should be sent for biomarker analysis at the central 
laboratory.  Refer to Appendix H for additional samples.
RANDOMIZATION
Once all screening procedures have been performed and eligibility has been confirmed, 
subject can be randomized.  The first dose of study treatment must be administered within 
5 days of date of randomization.
 






Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
177
Cycles 1 – 8 Event ↓Day →
1
2
4
5
8
9
11
12
Rest Days 
13 – 21
Comments
Serum Free Light Chains
X
Collect only for subjects with no measurable M-protein in Screening 
serum or urine, and/or to confirm sCR or CR only.  Will be completed per 
certified central laboratory.
Corrected Serum Calcium
X
Serum calcium and albumin from peripheral blood at Day 1 of each cycle 
until disease progression, even if subject is on subsequent therapy; if used 
as a criterion for disease progression, it must be confirmed by a 
second value.
Urine Protein Immunofixation
X
24-hour collection.  Collect at Day 1 of each cycle.  
Must be collected to confirm sCR, CR, or VGPR regardless of whether 
M-protein was measurable at baseline.  Will be completed per certified 
central laboratory.
Urine Protein Electrophoresis
X
Skeletal Survey
If clinically indicated
Same method should be used throughout the study.
Plasmacytoma Evaluation
Preformed during treatment only to confirm response of 
Minimal Response (MR) or better, or to confirm 
Progressive Disease, or as clinically indicated
CT, PET/CT or MRI – same method should be used throughout study.
Bone Marrow Aspirate and Biopsy
Mandatory for confirmation of sCR and CR, or if 
clinically indicated
Bone marrow aspirate is mandatory.  Bone marrow biopsy is mandatory if 
indicated per institutional guidelines, otherwise the marrow core is 
optional.  However, if a patient has a suspected CR and flow cytometry is 
unavailable, then a bone marrow biopsy is required for 
immunohistochemistry (IHC).  Plasma cell percentage and light chain 
restriction assessments are required.  Samples should be collected for 
assessment at the local laboratory for IMWG assessments.  If available, 
additional samples should be obtained for biomarker analysis at the 
central laboratory.  Refer to Appendix H for additional samples.
Response per IMWG Criteria
X
 








Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
181
Cycles 9 and Beyond Event ↓Day →
1
2
8
9
15
16
22
23
Rest 
Days 
24 – 35
Treatment 
Completion 
Visit
Comments
Serum Quantitative Immunoglobulins
X
X
Will be completed per certified central laboratory.
Serum Free Light Chains
X
X
Collect only for subjects with no measurable M-protein in 
Screening serum or urine, and/or to confirm sCR or CR only.  
Will be completed per certified central laboratory.
Corrected Serum Calcium
X
X
Serum calcium and albumin from peripheral blood at Day 1 
of each cycle until disease progression, even if subject is on 
subsequent therapy; if used as a criterion for disease 
progression, it must be confirmed by a second value.
Urine Protein Immunofixation
X
X
24-hour collection.  Collect at Day 1 of each cycle.  
Must be collected to confirm sCR, CR, or VGPR regardless 
of whether M-protein was measurable at baseline.  Will be 
completed per certified central laboratory.
Urine Protein Electrophoresis
X
X
Skeletal Survey
If clinically indicated.
Same method should be used throughout the study.
Plasmacytoma Evaluation
Performed during treatment only to confirm response of Minimal 
Response (MR) or better, or to confirm Progressive Disease, or as 
clinically indicated
CT, PET/CT or MRI – same method should be used 
throughout study.
Bone Marrow Aspirate and Biopsy
Mandatory for confirmation of sCR and CR, if applicable.  Optional 
at time of disease progression, if clinically indicated or as an optional 
procedure.
Bone marrow aspirate is mandatory and bone marrow biopsy 
is done if part of the SOC, otherwise is optional.  However, if 
a patient has a CR and flow cytometry is unavailable, then a 
bone marrow biopsy is required for immunohistochemistry 
(IHC).  Plasma cell percentage and light chain restriction 
assessments are required.  Samples should be collected for 
assessment at the local laboratory for IMWG assessments and 
additional samples should be sent for biomarker analysis at 
the central laboratory.  Refer to Appendix H for additional 
samples.
Response per IMWG Criteria
X
X
 




Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
183
Cycles 9 and Beyond Event ↓Day →
1
2
8
9
15
16
22
23
Rest 
Days 
24 – 35
Treatment 
Completion 
Visit
Comments
Dosing with Bortezomib
X
X
X
X
Dosing window is ± 1 day, but there must be at least 72 hours 
between doses.  If Bortezomib is held, clinic visits on Day 8, 
15 and 22 visits can be skipped and AEs/ConMeds should be 
evaluated on Day 1 Only.
Bortezomib dosing frequency may be reduced or 
discontinued per investigator's decision and institutional 
guidelines once subjects are unblinded.
Dosing with Dexamethasone
X
X
X
X
X
X
X
X
Dexamethasone should be administered the day of 
bortezomib dosing and the following day.  If bortezomib 
dosing is held, dexamethasone should be administered as 
scheduled (unless interrupted due to toxicity).
Dexamethasone dosing (frequency and/or dose) may be 
reduced or discontinued per investigator's decision and 
institutional guidelines once subjects are unblinded.
When unblinding occurs, if subjects from Arm 1 (Venetoclax 
+ Bd) and Arm 2 (Placebo + Bd) are on dexamethasone 
monotherapy, they must be discontinued from the study 
treatment and from the study once the Safety Follow-Up 
Visit is completed.
 




Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
185
Post-Treatment Event ↓Visit →
Safety Follow-Up
Progression Follow-Up
Survival Follow-Up
Comments
Around 30 Days After 
Discontinuation of Study 
Treatment or Before Start 
of Subsequent Treatment 
(Whichever Occurs First)
Q4 Weeks (± 1 Week) 
Following Last Dose of 
Treatment for Subjects 
Discontinued for 
Reasons Other than PD 
for 1 Year; Q 12 Weeks 
(± 1 Week) Thereafter
Approximately 
Q12 Weeks for All 
Subjects 
Non-Treatment Emergent Death 
Collection
X
X
X
After the end of the AE reporting period (in this 
instance 30 days after the final dose of study 
drug), all deaths, including any relevant clinical 
information leading to the death, regardless of 
cause, should be reported through use of the Non-
Treatment Emergent Death eCRFs.  
Once the number of final OS events is reached, 
Non-Treatment Emergent Death collection will no 
longer be required.
Refer to Section 5.3.1.1.2 for details.
Survival Status
X
X
X
Approximately every 12 weeks (or as requested 
by sponsor to support data analysis) beginning on 
the date of progression or discontinuation and 
continuing either until the endpoint of death, until 
the subject is lost to follow-up, subject withdraws 
consent, or until study termination by AbbVie, 
whichever occurs first.  
Once the number of final OS events is reached, 
progression and survival follow up survival status 
collection will no longer be required.
Refer to Section 5.3.1.1.2 for details.
 




Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
187
Post-Treatment Event ↓Visit →
Safety Follow-Up
Progression Follow-Up
Survival Follow-Up
Comments
Around 30 Days After 
Discontinuation of Study 
Treatment or Before Start 
of Subsequent Treatment 
(Whichever Occurs First)
Q4 Weeks (± 1 Week) 
Following Last Dose of 
Treatment for Subjects 
Discontinued for 
Reasons Other than PD 
for 1 Year; Q 12 Weeks 
(± 1 Week) Thereafter
Approximately 
Q12 Weeks for All 
Subjects 
Corrected Serum Calcium
X
Serum calcium and albumin from peripheral blood 
at Day 1 of each cycle until disease progression, 
even if subject is on subsequent therapy; if used as 
a criterion for disease progression, it must be 
confirmed by a second value.
Once the number of final OS events is reached, 
progression follow up assessments will no longer 
be required.
Urine Protein Immunofixation
X
24-hour collection.  Collect at Day 1 of each 
cycle.  Must be collected to confirm sCR, CR, or 
VGPR regardless of whether M-protein was 
measurable at baseline.  Will be completed per 
certified central laboratory.
Once the number of final OS events is reached, 
progression follow up assessments will no longer 
be required.
Urine Protein Electrophoresis
X
Skeletal Survey
X
If clinically indicated.  Same method should be 
used throughout the study.
Once the number of final OS events is reached, 
progression follow up assessments will no longer 
be required.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
188
Post-Treatment Event ↓Visit →
Safety Follow-Up
Progression Follow-Up
Survival Follow-Up
Comments
Around 30 Days After 
Discontinuation of Study 
Treatment or Before Start 
of Subsequent Treatment 
(Whichever Occurs First)
Q4 Weeks (± 1 Week) 
Following Last Dose of 
Treatment for Subjects 
Discontinued for 
Reasons Other than PD 
for 1 Year; Q 12 Weeks 
(± 1 Week) Thereafter
Approximately 
Q12 Weeks for All 
Subjects 
Plasmacytoma Evaluation
X
Performed only to confirm response of Minimal 
Response (MR) or better, or to confirm 
Progressive Disease, or as clinically indicated.  
CT, PET/CT or MRI – same method should be 
used throughout study if possible.
Once the number of final OS events is reached, 
progression follow up assessments will no longer 
be required.
Bone Marrow Aspirate and 
biopsy
X
Optional at time of disease progression, if 
clinically indicated or as an optional procedure.
Once the number of final OS events is reached, 
progression follow up assessments will no longer 
be required.
Response per IMWG Criteria
X
Once the number of final OS events is reached, 
progression follow up assessments will no longer 
be required.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
189
Appendix H.
Pharmacokinetic, Pharmacogenetic, and Biomarker Collection
Schedule of Pharmacokinetic Blood Collection for Venetoclax/Placebo and Bortezomib (and Dexamethasone, JAPAN Subjects 
Only)
Collection Times
Cycle 1 Day 1
Cycle 1 Day 11
(Japanese Subjects Enrolled 
in the run-in Phase Only)
Cycles 2, 4, 6, 8 Day 1
Cycles 2, 4, 6, 8 Day 11
Venetoclax/Placebo
6 hrs post-dose (optional)
--
0 (pre-dose)
--
Bortezomib
30 mins (0.5 hr) post-dose
--
--
0 (pre-dose)
Dexamethasone 
(Subjects enrolled in Japan 
only)
0.5 and 6 hour post dose
0 (pre-dose), 0.5, 1, 2, 4, 8 and 
24 (Day12, pre-dose) hours 
post dose
--
--
Notes:
All "pre-dose" samples in venetoclax/placebo PK sampling are relative to venetoclax or placebo administration.  All "pre-dose" samples in bortezomib PK sampling are 
relative to bortezomib administration.  JAPAN-ONLY:  All "pre-dose" samples in dexamethasone PK sampling are relative to dexamethasone administration.
The date and time (to the nearest minute) of each venetoclax or placebo dose taken, and whether or not the venetoclax or placebo dose was taken within 30 minutes after 
completing breakfast (or first meal of the day), will be recorded on the eCRF for every scheduled venetoclax/placebo PK day and for the 2 days prior to every scheduled 
venetoclax or placebo PK day.
The date and time (to the nearest minute) of each bortezomib dose taken will be recorded on the eCRF for every scheduled bortezomib PK day and for the 2 doses 
(i.e., Days 4 and 8) prior to every scheduled bortezomib PK day.
The date and time (to the nearest minute) of each dexamethasone dose taken will be recorded (Japanese subjects only) on the eCRF for the scheduled dexamethasone PK 
day and for the doses immediately prior to and after the scheduled dexamethasone PK day.
Samples should be drawn on actual day of dosing.  
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
190
Schedule of Pharmacogenetic and Biomarker Collection
Sample Collections (Sample 
Type)
Screening
C1D1
C5D1
Confirmation 
of sCR/CR
Approximately 
6 Months
Post 
Confirmation 
of sCR/CR
Approximately 
12 Months
Post 
Confirmation 
of sCR/CR
Treatment 
Completion 
Visit
Comments
OPTIONAL 
EXPLORATORY 
RESEARCH SAMPLE –
PHARMACOGENETIC
X
X
X
One 4 mL whole blood sample for 
DNA isolation will be collected at 
C1D1 (prior to first dose of study 
treatment), C5D1, and the 
Treatment Completion Visit from 
each subject who consents to 
provide samples for 
pharmacogenetic analysis.  
BIOMARKER SAMPLES
Serum Markers
X
X
X
3.5 mL
Plasma Markers
X
X
X
12 mL
Bone Marrow Biopsy:
    IHC
X
(Mandatory, 
unless biopsy is 
not performed 
per Institutional 
guidelines)
X 
(Optional)
Samples should be assessed for 
IMWG first, and samples should 
be sent for biomarker analysis at 
the central lab. 
Fresh samples are preferred, 
however, samples collected within 
12 weeks prior to first dose of 
study treatment that are 
representative of the subject's 
current disease, without 
intervening treatment, will be 
accepted.  Core block or tissue 
slides are acceptable.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
191
Sample Collections (Sample 
Type)
Screening
C1D1
C5D1
Confirmation 
of sCR/CR
Approximately 
6 Months
Post 
Confirmation 
of sCR/CR
Approximately 
12 Months
Post 
Confirmation 
of sCR/CR
Treatment 
Completion 
Visit
Comments
Bone Marrow Aspirate 
Samples should be assessed for 
IMWG first, and samples should 
be sent for biomarker analysis at 
the central lab.
At Screening, fresh samples 
should be obtained within 21 days 
prior to first dose of study 
treatment and when possible, 
should be obtained after all other 
eligibility criteria have been met.
For subjects who achieve an sCR 
or CR and continue to have this 
response, a bone marrow aspirate 
will be collected for MRD 
assessment at approximately
6 months and 12 months post-
confirmed CR/sCR.
     qPCR and MRD 
X 
(6 mL)
X 
(3 mL – for 
MRD only)
X
(3 mL – for 
MRD only)
X
(3 mL – for 
MRD only)
X
(6 mL –
Optional)
     FISH 
X 
(4 mL)
X
(4 mL –
Optional)
 




Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
193
1
Moderate CYP3A inhibitor per venetoclax FDA USPI.
2
Closely monitor the international normalized ratio (INR).
Note that this is not an exhaustive list.  For an updated list, see the following link:  
●
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResour
ces/DrugInteractionsLabeling/ucm093664.htm
In addition to the medications listed in this table, subjects receiving venetoclax/placebo
should not consume grapefruit, grapefruit products, Seville oranges (including marmalade 
containing Seville oranges) or starfruits.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
194
Appendix J.
IMWG Response Criteria for Multiple Myeloma
Response Subcategory 
Response Criteriaa
Stringent complete 
response (sCR)*

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

Normal FLC (free light chain) ratio and

Absence of clonal cells in bone marrowb by immunohistochemistry or 
immunofluorescencec or 2 to 4 color flow cytometry
Complete response 
(CR)*

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 (VGPR)*

Serum and urine M-component detectable by immunofixation but not on 
electrophoresis or

≥ 90% reduction in serum M-component plus urine M component 
< 100 mg per 24-hr 
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 (PR)

≥ 50% reduction of serum M-protein and

Reduction in 24-hr urinary M-protein by ≥ 90% or to < 200 mg per 
24-hr
o
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.

≥ 50% reduction in the size of soft tissue plasmacytomas is also 
required, if present at baseline.
Minimal response (MR)

25% – 49% reduction of serum M-protein and

50% – 89% reduction in 24-hour urinary M-protein and

25% – 49% reduction in size of soft tissue plasmacytomas, if present at 
baseline, and

No increase in size or number of lytic bone lesions (development of 
compression fracture does not exclude response).
Stable disease (SD)e
Not meeting criteria for sCR, CR, VGPR, PR, MR or progressive disease 
(PD).
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
195
a.
All response categories require two consecutive assessments made at anytime before the institution of any new 
therapy; all categories also require no known evidence of progressive or new bone lesions if radiographic studies 
were performed.  Radiographic studies are not required to satisfy these response requirements.
b.
Confirmation with repeat bone marrow biopsy not needed.
c.
Presence/absence of clonal cells is based upon the k/λ ratio.  An abnormal k/λ ratio by immunohistochemistry, 
and/or flow cytometry and/or immunofluorescence requires a minimum of 100 plasma cells for analysis.  An 
abnormal ratio reflecting presence of an abnormal clone is k/λ of ≥ 4:1 or ≤ 1:2.
d.
Measurable disease for this study is defined as meeting at least one of the following three measurements:  Serum 
M-protein ≥ 0.5 g/dL (≥ 5 g/L) or Urine M-protein ≥ 200 mg/24 hr or serum FLC assay with an involved FLC level 
≥ 10 mg/dL (≥ 100 mg/L) provided serum FLC ratio 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.
Note:
* Clarification to IMWG criteria for coding CR and VGPR in subjects in whom the only measurable 
disease is by serum FLC levels:  CR in such subjects is defined as a normal FLC ratio of 0.26 – 1.65 in 
addition to CR criteria listed above.  VGPR in such subjects is defined as a > 90% decrease in the difference 
between involved and uninvolved free light chain 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 on serum, urine, both, or neither.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
196
Relapse Subcategory 
Relapse Criteria
Progressive disease 
(PD)*
Requires any one or more of the following:

Increase of ≥ 25% from lowest response level in any of the following:
o
Serum M-proteina absolute increase ≥ 0.5 g/dL, and/or
o
Urine M-protein absolute increase ≥ 200 mg/24-hr, and/or
o
In subjects without measurable serum and urine M-protein levels, 
the difference between involved and uninvolved FLC levels (the 
absolute increase must be > 10 mg/dL), and/or

Definite development of new bone lesions or soft tissue plasmacytomas, 
and/or 

Definite increase in the size of existing bone lesions or soft tissue 
plasmacytomas
o
A definite increase in size of bone lesions and/or plasmacytomas is 
defined as ≥ 50% increase from nadir in the sum of the product of 
the cross-diameters (SPD) of > 1 lesion, or ≥ 50% increase in the 
longest diameter of a previous lesion > 1 cm in short axis.45

Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL) 
that can be attributed solely to the plasma cell proliferative disorder.
Clinical Relapse
Requires any one or more of the following direct indicators of increasing 
disease and/or end organ dysfunction (CRAB features).b

Development of new soft tissue plasmacytomas or bone lesions on 
skeletal survey, MRI or other imaging, and/or

Definite increase in size of existing plasmacytomas or bone lesions.  A 
definite increase is defined as a 50% (and at least 1 cm) increase as 
measured serially by the sum of the products of the cross diameters of 
the measurable lesion, and/or

Hypercalcemia > 11.5 mg/dL (> 2.875 mmol/L), and/or

Decrease in hemoglobin of ≥ 2 g/dL dL (≥ 1.25 mmol/L) or < 10 g/dL, 
and/or

Rise in serum creatinine by > 2 mg/dL (≥ 177 mmol/L), and/or

Hyperviscosity
a.
For progressive disease, serum M-component increases of ≥ 1 g/dL are sufficient to define relapse if starting 
M-component is ≥ 5 g/dL.
b.
For purposes of calculating time to progression and progression-free survival, CR subjects should also be evaluated 
using criteria listed above for progressive disease.
*
The "25% increase" refers to M-protein, FLC, and bone marrow results and does not refer to bone lesions, soft 
tissue plasmacytomas, or hypercalcemia.  The "lowest response value" does not need to be a confirmed value.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
197
Appendix K.
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 mg/dL 
(475.8 μmol/liter)
N/A
Hyperphosphatemia
Phosphorus > 4.5 mg/dL 
(1.5 mmol/liter)
N/A
Hyperkalemia
Potassium > 6 mmol/liter
Cardiac dysrhythmia or sudden 
death probably or definitely 
caused by hyperkalemia
Hypocalcemia
Corrected calcium < 7.0 mg/dL 
(1.75 mmol/liter) or ionized 
calcium < 1.12 mg/dL 
(0.3 mmol/liter)#
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!
N/A
Increase in the serum creatinine 
level of 0.3 mg/dL 
(26.5 μmol/liter) or the presence 
of oliguria (average urine output 
of < 0.5 mL/kg/hr over a 6-hour 
period)
*
Laboratory TLS requires two 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 column.
#
Corrected Serum Calcium = [mg/dL] = Measured serum calcium [mg/dL] + 0.8 × (4 – serum albumin [g/dL]).
!
Acute kidney injury, unless attributable to another cause, represents clinical TLS even if criteria for laboratory TLS 
are not satisfied.
Note:
Laboratory tumor lysis syndrome and at least one clinical complication.
Cross reference:  Howard SC 201144
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
198
Appendix L.
Japan Specific Information
1.0
Clinical Expense and Compensation
1.1
Expenditure of the Clinical Expense
The sponsor will pay the expenses related to this study to the investigative site in 
accordance with "Special Healthcare Expenditure."  The expenses of screening test, etc. 
will be paid based on the contract concluded with each investigative site.  To lighten the 
burden imposed on the subject with participation to the study, transportation expenses, 
etc. will be paid to the subjects via participating investigative site in accordance with the 
rules of the investigative site.
1.2
Compensation for Health Impairment and Insurance
1.
If a subject suffers some sort of health impairment due to this study, the 
investigative site will provide treatment and take other necessary measures.  
Among the expenses required for the treatment, the amount not covered by health 
insurance that the patient must pay directly will be borne by the sponsor only when 
the event is associated with the use of the study drug.
2.
When a subject suffers health impairment during this study and a dispute occurs or 
might occur between the investigative site and the subject, the investigative site 
will report it to the sponsor immediately, and resolve it.  The sponsor will 
cooperate with the investigative site in resolving the problem.
3.
When the investigative site must compensate to the subject's health impairment 
caused by this study, the compensation paid by the investigative site and the 
expenses related to any dispute will be borne in full by the sponsor, except in cases 
where the responsibility for the problem is attributed to the investigative site.  This 
shall not apply to cases where the health impairment occurred because the 
investigative site performed the study with marked deviation from the GCP or the 
protocol or because of a deliberate action or a major error by investigative site.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
199
4.
When a subject suffers health impairment during this study and liability for 
compensation arises, the sponsor will compensate in accordance with the SOP 
regarding the compensation prepared in advance.
5.
The sponsor will obtain clinical study insurance and will take other necessary 
measures to cover the claims and compensation required in such cases.
1.3
Pharmacogenetic Testing
Pharmacogenetic testing on samples collected in Japan will be restricted to the subject's 
response to study treatment in terms of pharmacokinetics, efficacy, tolerability, and 
safety.
 


Venetoclax
M14-031 Protocol Amendment 8
EudraCT 2015-004411-20
200
Appendix M.
Corticosteroid Conversion Table
Corticosteroid Conversion Table46-48
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
 

SAP_001.pdf: 
Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
1
1.0
Title Page
Statistical Analysis Plan
Study M14-031
A Phase 3, Multicenter, Randomized, Double Blind 
Study of Bortezomib and Dexamethasone in 
Combination with Either Venetoclax or Placebo in 
Subjects with Relapsed or Refractory Multiple 
Myeloma Who are Sensitive or Naïve to Proteasome 
Inhibitors
Date:  16 Jan 2019
Version 3.0
NCT02755597


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
2
2.0
Table of Contents
1.0
Title Page..................................................................................1
2.0
Table of Contents.....................................................................2
3.0
Introduction .............................................................................5
4.0
Study Background...................................................................5
4.1
Objective....................................................................................................5
4.2
Study Design..............................................................................................6
4.3
Endpoint.....................................................................................................8
4.3.1
Primary Efficacy Endpoint ........................................................................8
4.3.2
Secondary Efficacy Endpoint ....................................................................9
4.3.3
Tertiary Efficacy Endpoints.....................................................................14
4.3.4
Safety Endpoint........................................................................................18
4.4
Multiplicity Testing Procedures for Type-I Error Control ......................18
4.5
Missing Data Imputation..........................................................................19
5.0
Analysis Populations .............................................................19
6.0
Analysis Conventions ............................................................20
7.0
Subject Disposition................................................................24
8.0
Demographics, Baseline Characteristics, Medical 
History, and Previous/Concomitant Medications ..............25
8.1
Demographic and Baseline Characteristics .............................................25
8.2
Medical History .......................................................................................27
8.3
Prior/Concomitant Medications and Prior Multiple Myeloma 
Therapies..................................................................................................28
8.4
Other ........................................................................................................28
9.0
Study Treatment Exposure and Compliance......................29
9.1
Exposure to Study Treatment...................................................................29
9.2
Compliance ..............................................................................................32
10.0
Efficacy Analyses...................................................................32
10.1
General Considerations............................................................................32
10.2
Primary Efficacy Analysis .......................................................................33
10.3
Secondary Efficacy Analyses...................................................................34
10.4
Tertiary Efficacy Analyses.......................................................................35


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
3
10.5
Efficacy Subgroup Analyses....................................................................35
11.0
Safety Analyses ......................................................................37
11.1
General Considerations............................................................................37
11.2
Analysis of Adverse Events.....................................................................38
11.2.1
Treatment-Emergent Adverse Events ......................................................39
11.2.2
Serious Adverse Events ...........................................................................42
11.2.3
Adverse Events Leading to Discontinuation, Dose Reduction, or 
Dose Interruption of Study Treatment and Leading to Death..................42
11.2.4
Deaths ......................................................................................................42
11.2.5
Listing of Adverse Events........................................................................43
11.2.6
Adverse Event Rates by Subgroup ..........................................................43
11.3
Analysis of Laboratory and Vital Signs...................................................44
11.3.1
Analyses of Laboratory Data Using NCI CTCAE...................................44
11.3.2
Assessment of Drug-Induced Liver Injury ..............................................45
11.3.3
Laboratory Assessments for Tumor Lysis Syndrome..............................45
11.3.4
Analyses of Vital Signs Using Criteria for Potentially Clinically 
Significant Values....................................................................................46
11.4
Analysis of ECG Parameters....................................................................47
12.0
Pharmacokinetics ..................................................................47
13.0
Appendix – PRO assessments...............................................47
14.0
References...............................................................................52
List of Tables
Table 1.
Event and Censoring Date Used in PFS ....................................................9
Table 2.
Scoring Algorithm ...................................................................................11
Table 3.
Event and Censoring Date Used in DOR.................................................12
Table 4.
Event and Censoring Date Used in TTP..................................................13
Table 5.
Event and Censoring Date Used in TTR..................................................15
Table 6.
Time Windows for Longitudinal Analysis of PROs................................24
Table 7.
Demographic and Baseline Characteristics (Continuous Variables).......25
Table 8.
Demographic and Baseline Characteristics (Categorical Variables).......26
Table 9.
Selected Adverse Events..........................................................................41


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
4
Table 10.
Laboratory Criteria for TLS.....................................................................46
Table 11.
Criteria for Potential Clinical Significance in Vital Signs 
Variables ..................................................................................................46
Table 12.
BPI-SF Scales ..........................................................................................48
Table 13.
EORTC QLQ-C30 Scales........................................................................49
Table 14.
QLQ-MY20 scales...................................................................................51
List of Figures
Figure 1.
Study Schema.............................................................................................7


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
5
3.0
Introduction
This statistical analysis plan (SAP) describes the statistical analysis for Venetoclax 
(ABT-199/GDC-0199) study Protocol M14-031.  It provides details on planned statistical 
analyses for efficacy and safety endpoints, interim analysis, and multiplicity control 
strategies.
Unless noted otherwise, all analyses will be performed using SAS version 9.3 or later 
(SAS Institute Inc., Cary, NC 27513) under the Unix operating system.  EAST version 6.4 
or later (Cytel Inc.®) will be used to determine stopping boundaries in the group 
sequential plan.
4.0
Study Background
4.1
Objective
Primary Objective:
The primary objective of the study is to compare progression free survival (PFS) based on 
the International Myeloma Working Group (IMWG) Criteria,1,2 as determined by an 
Independent Review Committee (IRC), between treatment arms in subjects with relapsed 
or refractory multiple myeloma who are considered sensitive or naïve to proteasome 
inhibitors and received 1 to 3 prior lines of therapy for multiple myeloma.
Secondary Objectives:
The secondary objectives are to compare, between treatment arms, the following:
1.
Overall Response Rate (ORR)
2.
Very Good Partial Response (VGPR) or better response rate
3.
Overall Survival (OS)
4.
Physical Functioning
5.
Worst Pain


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
6
6.
PFS in subjects with high BCL-2 expression
7.
Duration of response (DOR)
8.
Time to progression (TTP)
9.
Minimal residual disease (MRD) negativity rate
10.
Global Health Status (GHS)/Quality of Life (QoL) (European Organization for 
Research and Treatment of Cancer Quality of Life Questionnaire Core [EORTC 
QLQ-C30])
11.
Fatigue (Patient Reported Outcomes Measurement Information System [PROMIS] 
Cancer Fatigue Short Form [SF])
12.
Safety
Tertiary Objectives:
The tertiary objectives of the study are to assess
1.
Clinical benefit rate (CBR)
2.
Disease control rate (DCR)
3.
Time to response (TTR)
4.
Time to next treatment (TNT)
5.
Other PRO endpoints (remaining subscales/items from BPI-SF, EORTC QLQ-C30, 
EORTC Quality of Life Questionnaire Multiple Myeloma Module 
[EORTC QLQ-MY20], and EuroQol EQ-5D-5L), and a preliminary assessment of 
potential biomarkers for association with PK, safety and efficacy.
4.2
Study Design
Study M14-031 is a Phase 3, multicenter, randomized, double blind study of bortezomib 
and dexamethasone in combination with either venetoclax or placebo in subjects with 


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
7
relapsed or refractory multiple myeloma who are sensitive or naïve to proteasome 
inhibitors (PI).
Figure 1.
Study Schema
There are two treatment arms:
●
Arm 1: Venetoclax plus Bortezomib (B) and Dexamethasone (d)
●
Arm 2: Placebo plus Bd
Once screening procedures are completed and eligibility is confirmed, subjects are 
randomized in 2:1 ratio to Arm 1 and Arm 2 using the following stratification factors:
1.
Prior exposure to proteasome inhibitors (naïve versus sensitive), and
2.
Number of prior lines of therapy (1 versus 2 or 3)
Separate randomization lists are used for the following groups of subjects:


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
8
1.
Subjects from countries other than Japan
2.
Subjects from Japan 
a.
Run-in phase
b. Rest of the subjects
In total 12 subjects are randomized in run-in phase in Japan to assess safety of the 
experimental treatment.  The rest of the subjects in Japan are randomized once the 
experimental treatment is observed to be safe.  Details on this are in the protocol.
Disease assessment will be based on IMWG response criteria for multiple myeloma.  
Each post-baseline IMWG assessment will be performed by the investigator and IRC 
(Independent Review Committee).  Details regarding the IRC review are provided in the 
IRC Charter for Study M14-031.  An independent data monitoring committee (IDMC) 
will periodically review safety data.  Details regarding the IDMC's review are provided in 
the IDMC Charter for Study M14-031.
4.3
Endpoint
Unless noted otherwise, endpoints related to IMWG are per IRC assessments.  Also, 
unless noted otherwise, for efficacy endpoints related to response, responses occurred on 
or before start date of new cancer therapy will be considered.  
4.3.1
Primary Efficacy Endpoint
The primary endpoint is progression-free survival (PFS) based on IMWG criteria for 
multiple myeloma.  The PFS is defined as the number of days from the date of 
randomization to the date of the first documented PD or death due to any cause, 
whichever occurs first.  
PFS (days) = Date of first documented PD or death due to any cause –
Date of Randomization + 1


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
9
Details on event and censoring rules for PFS are provided in Table 1.
Table 1.
Event and Censoring Date Used in PFS
Situation
Date of Censor or Event
Outcome
No/inadequate baseline assessment
Date of randomization
Censor
PD or death at scheduled assessment 
date or before the next scheduled 
assessment
If there is documented PD then date of PD.  
Otherwise date of death
Event
PD or death after exactly 
one missing assessment
If there is documented PD then date of PD.  
Otherwise date of death
Event
PD or death after two or more 
consecutive missing assessments
If no adequate assessment is available prior to 
PD/death then date of randomization.  
Otherwise, date of the last adequate assessment 
prior to PD/death
Censor
No PD and no death
If no adequate assessment is available then date 
of randomization.
Otherwise, date of the last adequate assessment
Censor
Start of new anti-cancer therapy 
prior to PD or death
Date of last adequate assessment prior to start 
of new anti-cancer therapy.  If no adequate 
assessment is available prior to start of new 
anti-cancer therapy then date of randomization.
Censor
All PFS events will be included, regardless of whether the event occurred while the 
subject was still taking study drug or had previously discontinued study drug.  The 
primary efficacy analysis will be performed when approximately 136 PFS events per IRC 
assessments are observed.
4.3.2
Secondary Efficacy Endpoint
The following are secondary efficacy endpoints.
Overall Response Rate (ORR):
ORR is defined as the proportion of subjects with documented sCR, CR, VGPR or PR.


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
10
VGPR or better response rate:
VGPR or better response rate is defined as the proportion of subjects with documented 
sCR, CR, or VGPR.
Overall Survival (OS):
OS is defined as the number of days from the date of randomization to the date of death 
due to any cause.  All events of death will be included, regardless of whether the event 
occurred while the subject was still taking study drug or after the subject discontinued 
study drug.
OS (days) = Date of death due to any cause – Date of Randomization + 1
If a subject is not known to have died, OS will be censored at the date of last contact, 
which is defined in Section 6.0.
Physical Functioning (EORTC QLQ-C30):
For Physical Functioning scale, scores will be computed according to procedures outlined 
in the EORTC QLQ-C30 scoring manual, available at http://groups.eortc.be/qol/manuals.  
The patient-reported outcome instruments are described in detail in Section 13.0.  The 
endpoint is change from baseline.
Worst Pain (Brief Pain Inventory – Short Form [BPI-SF])):
For Worst Pain, scores will be computed according to procedures outlined in BPI-SF 
scoring manual, available at https://www.mdanderson.org/documents/Departments-and-
Divisions/Symptom-Research/BPI_UserGuide.pdf.  The patient-reported outcome 
instruments are described in detail in Section 13.0.  The endpoint is change from baseline.
PFS in subjects with high BCL-2 expression:
PFS is defined in Section 4.3.1.  Subjects with high or low BCL-2 expression are defined 
through central laboratory testing by immunohistochemistry (IHC) and based on the pre-


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
11
specified scoring algorithm in Table 2.  Subjects who are randomized but have missing or 
indeterminate central laboratory IHC results for BCL-2 protein expression will be 
considered as missing BLC-2 expression status.
Table 2.
Scoring Algorithm
Clinical 
Status
Clinical 
Score
Description
Low
0
No staining in tumor cells or < 50% tumor cells with cytoplasmic staining of 
any intensity
1 +
≥ 50% of tumor cells with weak or higher cytoplasmic staining but < 50% of 
tumor cells with moderate or strong staining intensity
High
2 +
≥ 50% of tumor cells with moderate or higher cytoplasmic staining but < 50% 
of tumor cells with strong staining intensity
3 +
≥ 50% of tumor cells with strong cytoplasmic staining
Duration of Response (DOR):
DOR is defined as the number of days from the date of first documented response (PR or 
better) to the date of first documented PD or death due to multiple myeloma, whichever 
occurs first.
DOR (days) = Date of first documented PD or death due to multiple myeloma – Date of 
First Documented Response (PR or better) + 1
Subjects who never achieve a documented response (PR or better) will be excluded from 
the analysis of DOR.  Details on event and censoring rules for DOR are provided in 
Table 3.


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
12
Table 3.
Event and Censoring Date Used in DOR
Situation
Date of Censor or Event
Outcome
PD or death due to multiple myeloma at
scheduled assessment date or before the 
next scheduled assessment
If there is documented PD then date of PD.  
Otherwise date of death
Event
PD or death due to multiple myeloma 
after exactly one missing assessment
If there is documented PD then date of PD.  
Otherwise date of death
Event
PD or death due to multiple myeloma 
after two or more consecutive 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
Start of new anti-cancer therapy prior to 
PD/Death
Date of the last adequate assessment prior 
to start of new anti-cancer therapy
Censor
Time to Progression (TTP):
TTP is defined as the number of days from the date of randomization to the date of first 
documented PD or death due to multiple myeloma, whichever occurs first.
TTP (days) = Date of first documented PD or death due to multiple myeloma –
Date of Randomization + 1
Details on event and censoring rules for TTP are provided in Table 4.


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
13
Table 4.
Event and Censoring Date Used in TTP
Situation
Date of Censor or Event
Outcome
No/inadequate baseline 
assessment
Date of randomization
Censor
PD or death due to multiple 
myeloma at scheduled 
assessment date or before the 
next scheduled assessment
If there is documented PD then date of PD.  
Otherwise date of death
Event
PD or death due to multiple 
myeloma after exactly 
one missing assessment
If there is documented PD then date of PD.  
Otherwise date of death
Event
PD or death due to multiple 
myeloma after two or more 
consecutive missing assessments
If no adequate assessment is available prior to 
PD/death then date of randomization.  Otherwise, 
date of the last adequate assessment prior to 
PD/death
Censor
No PD and no death due to 
multiple myeloma
If no adequate assessment is available then date 
of randomization.  Otherwise, date of the last 
adequate assessment
Censor
Start of new anti-cancer therapy 
prior to PD/death
If no adequate assessment is available prior to 
start of new anti-cancer therapy then date of 
randomization. 
Otherwise, date of the last adequate assessment 
prior to start of new anti-cancer therapy
Censor
Minimal Residual Disease (MRD) negativity rate:
MRD negativity rate is defined as the proportion of subjects who have negative MRD by 
bone marrow aspirate at any time point after randomization and before progression or 
starting subsequent therapy.  For the purpose of secondary efficacy endpoint, MRD 
negativity will be defined at 10–5 threshold (less than one residual myeloma cell per 
105 total nucleated cells) as measured by centralized testing of bone marrow aspirate by 
NGS.  MRD positive subjects include subjects of which all tested samples were found to 
be MRD positive or indeterminate.  Subjects with missing or unevaluable MRD status 
will be considered as MRD positive.  The MRD negativity rate will be calculated for each 
treatment group based on the ITT population (Check Section 5.0 for the definition of ITT 
population).


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
14
GHS/QoL (EORTC QLQ-C30):
The GHS/QoL scale specific scores will be calculated from the 22 items in EORTC QLQ-
C30 for each subject based on the QLQ-C30 instruction.  Higher scores are indicative of 
better HRQOL.  The QLQ-C30 is described in detail in Section 13.0.  The endpoint is 
score change from baseline.
Fatigue (PROMIS Cancer Fatigue SF):
For PROMIS Cancer Fatigue SF 7a, scores will be computed according to the procedures 
outlined in the PROMIS Fatigue scoring manual, available at 
https://www.assessmentcenter.net/Manuals.aspx.  Higher scores are indicative of worse 
levels of fatigue.  The Cancer Fatigue SF is described in detail in Section 13.0.  The 
endpoint is score change from baseline.
4.3.3
Tertiary Efficacy Endpoints
The following are tertiary efficacy endpoints.  
Clinical Benefit Rate (CBR):
CBR is defined as the proportion of subjects with documented MR or better. 
Disease Control Rate (DCR):
DCR is defined as the proportion of subjects with documented MR or better or SD lasting 
at least 8 weeks.
Time to Response (TTR):
The TTR is defined as the number of days from the date of randomization to the date of 
first documented response (PR or better).
TTR (days) = Date of First Documented response (PR or better) – Date of Randomization 
+ 1


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
15
Details on event and censoring rules for TTR are provided in Table 5.
Table 5.
Event and Censoring Date Used in TTR
Situation
Date of Censor or Event
Outcome
Documented response at 
scheduled assessment date or 
before the next scheduled 
assessment
Date of response
Event
Start of new anti-cancer therapy 
prior to response
If no adequate assessment is available prior to start 
of new anti-cancer therapy then date of 
randomization. 
Otherwise, date of the last adequate assessment prior 
to start of new anti-cancer therapy
Censor
No documented response
If no adequate post baseline assessment is available 
then date of randomization. 
Otherwise, date of the last adequate assessment
Censor
Time to Next Treatment (TNT):
The TNT is defined as the number of days from the date of randomization to the starting 
date of new anti-cancer therapy (Other than study treatment). 
TNT (days) = Starting date of any anti-cancer therapy – Date of Randomization + 1
Subjects not taking new anti-cancer therapy will be censored at the date of last contact.
Minimal Residual Disease (MRD) 10–4 and 10–6 negativity rates.
MRD negativity rate is defined as the proportion of subjects who have negative MRD by 
bone marrow aspirate at any time point after randomization and before progression or 
starting subsequent therapy. For the purpose of tertiary efficacy endpoints, MRD 
negativity will be defined at 10–4 and 10–6 thresholds (less than one residual myeloma cell 
per 104 and 106 total nucleated cells, respectively) as measured by centralized testing of 
bone marrow aspirate by NGS.  MRD positive subjects include subjects of which all 
tested samples were found to be MRD positive or indeterminate.  Subjects with missing or 


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
16
unevaluable MRD status will be considered as MRD positive.  The following tertiary 
efficacy analyses will be perform for MRD negativity.
1.
MRD negativity based on 10–4 and 10–6 threshold:  Rate of subjects with MRD 
negativity in the ITT analysis set
2.
MRD negativity based on 10–4, 10–5 and 10–6 threshold:  Rate of subjects with 
MRD negativity along with CR/sCR in the ITT analysis set
3.
MRD negativity based on 10–4, 10–5 and 10–6 threshold:  Rate of subjects with 
MRD negativity among the subjects with CR/sCR in the ITT analysis set
EORTC QLQ-MY20:
For EORTC QLQ-MY20, the endpoints are scores change from baseline.  Scores will be 
summarized for four scales:  
●
Future perspective
●
Body image
●
Disease symptoms
●
Side effects of treatment
Scores for each scale will be computed according to procedures outlined in 
EORTC QLQ-MY20 scoring manual, available at 
http://www.eortc.be/qol/files/ScoringInstructions/MY20_summary.pdf and Section 13.0.
EQ 5D-5L:
For EQ 5D-5L, the endpoints are scores change from baseline.  Scores will be 
summarized for six scales:
●
Mobility
●
Self-care
●
Usual activities


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
17
●
Pain/Discomfort
●
Anxiety/Depression
●
EQ VAS score
Scores for each scale will be computed according to procedures outlined in EQ 5D-5L 
scoring manual, available at https://euroqol.org/wp-content/uploads/2016/09/EQ-5D-
5L_UserGuide_2015.pdf. 
Remaining Subscales of BPI-SF and EORTC QLQ-C30
Remaining subscales of BPI-SF are Pain Severity and Pain Interference.  Scores for each 
subscale will be computed according to BPI-SF scoring manual, respectively.  The 
endpoints are score change from baseline.
Remaining subscales of EORTC QLQ-C30 are
●
Role Function
●
Emotional Functioning
●
Cognitive Functioning
●
Social Functioning
●
Fatigue
●
Nausea and Vomiting
●
Pain
●
Dyspnea
●
Insomnia
●
Appetite Loss
●
Constipation
●
Diarrhea
●
Financial Difficulties
Scores for each subscale will be computed according to EORTC QLQ-C30 scoring 
manual, respectively.  The endpoints are score change from baseline.


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
18
4.3.4
Safety Endpoint
The following are safety endpoints.
●
Adverse Events (AE)
●
Serious Adverse Events (SAE)
●
Deaths
●
Electrocardiography (ECG)
●
Vital sign parameters
●
Laboratory results
4.4
Multiplicity Testing Procedures for Type-I Error Control
Statistical tests for selected secondary endpoints will be implemented in the testing 
strategy to maintain family-wise two-sided type I error rate at 0.05.15,16  Each of these 
tests will be performed at an overall two-sided significance level of 0.05 (or equivalently 
one-sided significant level of 0.025).  Statistical testing of the selected secondary 
endpoints will be performed only if the primary efficacy analysis of PFS is significant. 
The following are selected secondary endpoints and testing order:
1.
ORR
2.
VGPR or better response rate
3.
OS
4.
Physical Functioning (EORTC QLQ-C30)
5.
Worst Pain (BPI-SF)
The following testing procedure will be used for the selected secondary endpoints:
1.
If the primary endpoint, PFS, is statistically significant then ORR will be tested; 
2.
If ORR is statistically significant then VGPR or better response rate will be tested;


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
19
3.
If VGPR or better response rate is significant then OS will be tested using group 
sequential method.  There will be two interim analyses of OS at the time of PFS 
analysis and at the time of observing approximately 75% of the total targeted OS 
events.  The final OS analysis will be performed when approximately 116 OS 
events are available.  The overall two-sided significance level for OS analysis will 
be kept at 0.05 (Equivalently one-sided significance level 0.025).  Lan and DeMets 
α-spending method with O'Brien-Fleming type boundaries will be used to derive 
the significance level for OS at interim and final analyses.
4.
If OS is significant then Physical Functioning (EORTC QLQ-C30) will be tested. 
This analysis will be based on data cut for the PFS analysis.
5.
If Physical Functioning (EORTC QLQ-C30) is significant then Worst Pain (BPI-
SF) will be tested.  This analysis will be based on data cut for the PFS analysis.
4.5
Missing Data Imputation
No missing data imputation is planned for the study.  Instead, missing data is addressed 
by adequate censoring as described in Section 4.3.  In addition, missing data handling 
methods for PRO endpoints are provided in Section 13.0.
5.0
Analysis Populations
Intent-To-Treat (ITT) analysis set:
The ITT analysis set consists of all randomized subjects.  The data from the ITT 
population will be analyzed by the treatment group assignment given at the time of 
randomization, even if the subject does not receive treatment, does not receive the correct 
treatment or is not compliant to the protocol procedures.
Safety analysis set:
The safety analysis set consists of all randomized subjects who take at least one dose of 
study drug (Venetoclax or Placebo).  Subjects who received venetoclax at the first actual 


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
20
dosing day will be considered as Venetoclax plus Bd group and otherwise they will be 
considered as Placebo plus Bd group.  For IDMC review (refer to Section 4.2), the data 
from the safety population will be analyzed by the treatment group assignment given at 
the time of randomization.
6.0
Analysis Conventions
Data Cutoff Date and Data set
The cutoff date for the primary PFS analysis is Nov. 26, 2018.  This cutoff date will be 
applied to all efficacy and safety analyses. 
Only data with an assessment or event start date (e.g., vital sign assessment date or start 
date of an AE) prior to or on the cut-off date will be included in the analysis.  
All events with a start date before or on the cut-off date and an end date after the cut-off 
date will be reported as 'continuing at the cut-off date.'  The same rule will be applied to 
events starting before or on the cut-off date and not having a documented end date.  This 
approach applies in particular to AE and concomitant medication reports.  For these 
events, the end date will not be imputed and therefore will not appear in the listings.
If it is required to impute an end date to perform a specific analysis (e.g., for a dose 
administration record with a missing end date or an end date after the cut-off date, the cut-
off date will be imputed as end date to allow the calculation of treatment exposure 
duration and dose intensity), the imputed date will be displayed and flagged in the listings.
Date of Randomization
The date of randomization is defined as the date that the Interactive Response Technology 
(IRT) issued a randomization number.
Definition of PFS event
The PFS event is derived from the following:


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
21
1.
Death due to any cause is a PFS event.
2.
A documented progressive disease is a PFS event if it is due to imaging per 
IMWG.  The reason for any documented progressive disease will be provided by 
both IRC and Investigator, respectively.
3.
A documented progressive disease is a PFS event if it is due to non-imaging per 
IMWG AND a consecutive assessment confirms the results.  The reason for any 
documented progressive disease will be provided by both IRC and Investigator, 
respectively.
Date of Last Contact
The date of last contact will be derived from the following list of data panels:
●
Vital signs
●
Physical exam
●
Lab variables, including SAE lab reports
●
ECOG performance status
●
PRO measures
●
Study drug administration
●
IMWG assessments
●
Transfusions
●
Electrocardiogram
●
Adverse event
●
Concomitant Medication
●
Laboratory sample collection (e.g., biomarker)
●
Survival follow-up
Definition of Study Drug and Study Treatment
1.
Study drug refers to Venetoclax or Placebo.


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
22
2.
Study treatment refers to
●
Venetoclax + Bortezomib + Dexamethasone
●
Placebo + Bortezomib + Dexamethasone
3.
Study treatment components refer to
●
Venetoclax/Placebo or
●
Bortezomib or
●
Dexamethasone
Stratum information used for analyses
For all stratified analyses based on the ITT, stratification information will be used as 
provided by the IRT.  The stratification factors are:
1.
Prior exposure to proteasome inhibitors (naïve versus sensitive), and
2.
Number of prior lines of therapy (1 versus 2 or 3)
Dealing with Multiple Values within the Same Visit
If there are multiple measurements/samples within the same post-baseline visit, the last 
measurement/sample within the visit (sorted by date and as available by time or repeat 
measurements) will be used in the analysis by visit or overall.  For any analyses regarding 
outlier or abnormal assessments, all post-baseline values will be included (i.e., scheduled, 
unscheduled, repeat).  For any other analyses, only scheduled visits will be included.  This 
applies to quantitative and qualitative variables.
In addition, for PRO analysis, if more than one assessment is completed on the day of, or 
prior to a scheduled visit, the assessment performed closest to the scheduled visit will be 
used.  In case the assessments are equidistant to the scheduled visit, the last assessment 
will be used for analyses. In case multiple assessments are performed on the same day 
and assessment time is not collected, the average of the assessment results will be used for 
analyses.


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
23
Definition of Baseline
For all analyses where baseline values are used, "baseline" refers to the last non-missing 
observation collected on or prior to the date of the first dose of any component of study 
treatment (for treated subjects) or the date of randomization (for non-treated subjects).  
Safety assessments that are related to a serious adverse event that occurred on the date of 
the first dose of any component of study treatment are excluded when applying this 
algorithm.
Definition of Final Observation
For PROs, laboratory, and vital signs variables, the final observation is defined as the last 
non-missing observation collected after baseline within 30 days following the last dose of 
study drug.
Definition of Study Rx Days (Days Relative to the First Dose of Study Treatment)
Study Rx Days are calculated for each time point of interest and provide a quantitative 
measure of days between the event and the first dose of any component of study 
treatment.  If event date is earlier than the date of treatment start then Rx day = event 
date – treatment start date.  Otherwise, Rx day = event date – treatment start date + 1.
Definition of Cycle Rx Days (Days Relative to the First Dose of Study Treatment in 
Each Cycle)
Cycle Rx Days for each cycle (cycle length for one cycle is defined as 21 days for 
Cycles 1 – 8, and as 35 days for Cycles 9 and beyond) are calculated for each time point 
relative to first dose of any component of study treatment in each cycle.
Definition of Analysis Windows
During the treatment period, all time points and corresponding time windows are based on 
Cycle Rx Days.  For visit-wise longitudinal analyses of PROs the time windows are 
specified in Table 6.


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
24
Table 6.
Time Windows for Longitudinal Analysis of PROs
Scheduled Visit
Nominal Cycle Rx Day
Time Window (Cycle Rx Day Range)
Cycle 1 Day 1 
BASELINE
As baseline definition
Cycle 3 Day 1
1
(Day 2 of Cycle 1, Day 11 of Cycle 4)
Cycle 3 Day 1*
1
(Day 2 of Cycle 1, Day 21 of Cycle 3)
Cycle Y Day 1 
1
(Day –10 of Cycle Y, Day 11 of Cycle Y + 1)
Cycle Y Day 1*
1
(Day –10 of Cycle Y, Day 21 of Cycle Y)
Cycle 9 Day 1
1
(Day -10 of Cycle 9, Day 17 of Cycle 10)
Cycle 9 Day 1*
1
(Day -10 of Cycle 9, Day 35 of Cycle 9)
Cycle Z Day 1 
1
(Day –18 of Cycle Z, Day 17 of Cycle Z + 1)
Cycle Z Day 1*
1
(Day –18 of Cycle Z, Day 35 of Cycle Z)
Note:
Y represents Cycles 5, and 7.  Z represents odd cycles starting from Cycle 11.*: For subject who had last 
PRO assessment at the corresponding cycle or missing next cycle visit.
Definition of Creatinine Clearance (CrCl) and Body Surface Area (BSA)
CrCl = ((140 – age in years) × weight in kg × 0.85 if female) / (72 × serum creatinine 
in mg/dL)
BSA = ݓ݄݁݅݃ݐሺ݇݃ሻ଴.ସଶହൈ݄݄݁݅݃ݐሺܿ݉ሻ଴.଻ଶହൈ0.007184
7.0
Subject Disposition
The ITT population will be used for the subject disposition summaries.  The summary 
will be provided by treatment groups and overall population for all sites (pooled).  Unless 
noted otherwise, there will be no statistical comparison between treatment groups.  
Number and percentage (%) of subjects for each of the following categories will be 
provided:
●
Randomized subjects
●
Treated subjects
●
Discontinued study treatment
●
Discontinued Venetoclax or Placebo


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
25
●
Discontinued Bortezomib
●
Discontinued Dexamethasone
●
Discontinued from study
●
Ongoing (Treatment, Progression Follow Up, Survival Follow Up)
In addition, the number and percentage of subjects who discontinued study treatment will 
be summarized by reason (primary and all reasons separately for Venetoclax or Placebo, 
Bortezomib and Dexamethasone, respectively).
8.0
Demographics, Baseline Characteristics, Medical 
History, and Previous/Concomitant Medications
The ITT population will be used for these summaries.  Unless noted otherwise, there will 
be no statistical comparison between treatment groups for demographics, baseline 
characteristics, medical history or previous/concomitant medications.
8.1
Demographic and Baseline Characteristics
Demographic and baseline characteristics will be summarized by treatment groups and 
overall population.  Continuous demographic data (e.g., age, height, and weight), shows 
in Table 7, will be summarized by the mean, standard deviation, median, minimum, and 
maximum values, which will be calculated using only the non-missing observations.  
Frequencies and percentages will be computed for categorical data, shows in Table 8.
Table 7.
Demographic and Baseline Characteristics (Continuous Variables)
Continuous Variable
Age
Body weight
Body height
Time since diagnosis
Number of prior lines of therapies


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
26
Table 8.
Demographic and Baseline Characteristics (Categorical Variables)
Categorical variable (possible values)
Age group (< 65 years/ ≥ 65 years)
Sex (Male/Female)
Race
Ethnicity
ECOG performance Status (0/1/2/ > 2/missing)
Prior lines of MM therapy (1/2/3/ > 3)
Prior exposure to proteasome inhibitors (PI) (sensitive/naïve)
Prior exposure to an immunomodulatory drug (IMiD) (naive/sensitive/refractory)
Prior exposure to bortezomib (sensitive/naïve)
Prior exposure to lenalidomide (naïve/sensitive/refractory)
Prior exposure to a PI and an IMiD (yes/no)
Prior exposure to an alkylating agent (yes/no)
Prior exposure to an anti-CD38 monoclonal antibody (yes/no)
Disease refractory to last line of therapy (yes/no)
Multiple Myeloma ISS stage (I/II/III)
Soft tissue plasmacytomas present at screening (yes/no)
Bone and lytic lesions present at baseline (yes/no)
Prior stem cell transplant (autologous/allogeneic/syngeneic)
t (11;14) status (negative/positive/unknown)
t (4;14) status (negative/positive/unknown)
t (14;16) status (negative/positive/unknown)
t (14;20) status (negative/positive/unknown)
17p status (deleted/not deleted/unknown)
1q gain (present/not present/unknown)
Ch9 gain OR Ch11 gain OR Ch15 gain (present/not present/unknown)
Geography (North America/EU/South America/Asia-Pacific)
Creatinine clearance (< 30/30 - < 60/60 - < 90/ ≥ 90 mL/min)
Type of measurable disease per CRF (IgG/IgA/Other)
IMWG consensus risk (High/Standard)
Chromosomal Abnormality (CA) risk by FISH (High/Standard)


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
27
Risk stratification per IMWG consensus will be defined according to the IMWG 
consensus on risk stratification in multiple myeloma:4
IMWG consensus High-risk:
●
ISS staging at screening of Stage II or III AND
●
t (4;14) positive OR 17p deletion
IMWG consensus Standard-risk:
●
ISS staging at screening of Stage I OR
●
ISS staging at screening of Stage II or III AND t (4;14) negative AND 17p not 
deleted
Risk stratification per chromosomal abnormality (CA) by FISH will be defined:17
CA High-risk:
●
t (4;14) positive OR t (14;16) positive OR 17p deletion
CA Standard-risk:
●
t (4;14) negative AND t (14;16) negative AND 17p not deleted
For risk stratification, subjects with missing ISS staging or missing or indeterminate 
t (4;14), t (14;16) or 17p status that do not allow for a categorization per above will be 
excluded from summary statistics.
8.2
Medical History
Medical history and ongoing conditions, including MM-related conditions and symptoms 
will be summarized and listed.


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
28
8.3
Prior/Concomitant Medications and Prior Multiple Myeloma 
Therapies
Concomitant Medications:
Concomitant medications are defined as medications (other than study treatment) taken 
after the first dose of any component of study treatment and within 30 days of the last 
dose of any component of study treatment.  Concomitant medications will be reported by 
generic name assigned by the World Health Organization (WHO) dictionary.
The number and percentage of subjects who take at least one concomitant medication will 
be summarized.  For summaries of concomitant medications, if an incomplete start date 
was collected for a medication, the medication will be assumed to be a concomitant 
medication unless there is evidence that confirms that the medication was not a 
concomitant medication (e.g., the medication end date was prior to the first dose of study 
drug).
Prior medication:
A prior medication is defined as any medication taken prior to the first dose of any 
component of study drug and collected in the CRF.  The number and percentage of 
subjects who take at least one prior medication will be summarized.
8.4
Other
The number of patients randomized will be provided by country, investigational site and 
treatment group.  The number and percentage of patients in each analysis set (ITT and 
safety) will be summarized by stratum and treatment group.
Moreover, frequencies will be provided for by treatment group and stratification factors.  
A summary for the primary reason(s) for screening failure will be presented.
All data collected at baseline, including the source of subject referral, childbearing 
potential, and pregnancy test results, will be listed.  Demographic information on 
screening failures will be listed.  Patients who have received treatment different from 


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
29
intended treatment as determined by the IRT as well as patients who have been 
randomized according to incorrect stratum will be listed.
9.0
Study Treatment Exposure and Compliance
Analyses of study treatment exposure and compliance listed below will be performed on 
the safety analysis set by treatment groups.  Unless noted otherwise, there will be no 
statistical comparison for these analyses.
9.1
Exposure to Study Treatment
Duration of study treatment exposure
Duration of study treatment exposure will be calculated as the number of days between 
the start and end of the study treatment.
Duration of study treatment exposure (days) = date of last administration of study 
treatment – date of first administration of study treatment + 1
For Risk Management Plan: Patient-years of exposure
Patient-years of exposure is computed as:
Patient-years of exposure (pt-yrs) = Sum of duration of study treatment for all subjects 
(day)/365.25
Duration of study treatment component exposure
Duration of study treatment component exposure will be calculated as the number of days 
between the start and end dates for the study treatment component
Duration of study treatment component exposure (days) = 
Date of last administration study treatment component – Date of first administration study 
treatment component + 1


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
30
Cumulative dose
The cumulative dose is defined as the total dose given during the study treatment
exposure and will be summarized by study treatment component and treatment group. 
For patients who did not take any drug the cumulative dose is by definition equal to 0.
Dose intensity (DI) and relative dose intensity (RDI)
The following DI or planned DI (PDI) (per protocol) calculations apply for both IV and 
oral dosing.  In the case of IV dosing, the dose was given based on BSA calculation of DI 
or PDI involves BSA in the division.  The RDI will be summarized separately for each of 
the study treatment components.  
Venetoclax/placebo and Dexamethasone
DIሺmg/dayሻൌ
Cumulative dose ሾmgሿ
∑
Actual duation of cycle c ሾdayሿ
୩
ୡୀଵ
where k = total number of cycles.
PDI is defined as follows:
1.
The last cycle length is not shorter than planned cycle length
PDIሺmg/dayሻൌ
Cumulative planned dose ሾmgሿ
∑
Planned duration of cycle c ሾdayሿ
୩
ୡୀଵ
2.
The last cycles length is shorter than planned cycle length
PDIሺmg/dayሻ
ൌ
Total planned dose for first k െ1 cycles ሾmgሿ
൅total planned dose for actual duration of the last cycle k
∑
Planned duration of cycle c ൅Actual duration of the last cycle ሾdayሿ
୩ିଵ
ୡୀଵ
k is the actual total number of cycles.


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
31
RDI is defined as 
RDIሾ%ሿൌDI ሾmg/dayሿ
PDI ሾmg/dayሿൈ100
Bortezomib
Dose intensity (DI) over study period for bortezomib is defined as 
DIሺmg/mଶ/dayሻൌ
∑
Total actual dose in cycle c ሺmgሻ
BSAୡሺmଶሻ
୩
ୡୀଵ
∑
Actual duration of cycle c ሺdaysሻ
୩
ୡୀଵ
where k = total number of cycles.
1.
The last cycle length is not shorter than planned cycle length
PDIሺmg/mଶ/dayሻൌ
∑
Total planned dose for cycle c ሾmg/mଶሿ
୩
ୡୀଵ
∑
Planned duration of cycle c ሺdaysሻ
୩
ୡୀଵ
2.
The last cycle length is shorter than planned cycle length
PDIሺmg/mଶ/dayሻ
ൌ
∑
Total planned dose for cycle c ሾmg/݉ଶሿ
൅Total planned dose for actual duration of the last cycle k ሾmg/mଶሿ
୩ିଵ
ୡୀଵ
∑
Planned duration of cycle c ൅Actual duration of the last cycle k ሺdaysሻ
୩ିଵ
ୡୀଵ
where k = total number of cycles.
RDI is defined as 
RDI ሾ%ሿൌDI ሾmg/݉ଶ/dayሿ
PDI ሾmg/݉ଶ/dayሿൈ100
The RDI will be summarized based on eCRF data on the drug administration pages.  All 
analyses will be provided by treatment groups for each study treatment component. 


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
32
Descriptive statistics, including the mean, standard deviation, median, minimum, and 
maximum will be presented for duration of exposure and RDI.  Number and percentage of 
subjects who have dose reductions or interruptions, as well as their reasons, will be 
provided. Number of cycles of study treatment received will be provided.  In addition 
summary statistics of cumulative dose and frequencies for RDI (%) will be provided by 
treatment group for the following categories:
●
0 to < 50%
●
50% to < 70%
●
70% to < 90%
●
90% to < 110%
●
≥ 110%
9.2
Compliance
To assess compliance, a listing of protocol deviations will be given.
10.0
Efficacy Analyses
10.1
General Considerations
Unless noted otherwise, all efficacy analyses will be performed by treatment group.  The 
following stratification factors will be considered when applicable:
1.
Prior exposure to proteasome inhibitors (naïve versus sensitive), and
2.
Number of prior lines of therapy (1 versus 2 or 3)
If a subject has the blind prematurely broken before the cutoff date used for data analysis, 
the date of the break will be set as the cutoff date for this subject.
For time-to-event endpoints, survivorship functions will be estimated by using Kaplan-
Meier product-limit methodology.  Estimated survival curves will be presented.  If 


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
33
reached, median time to event and its two-sided 95% confidence interval will be 
presented.
10.2
Primary Efficacy Analysis
PFS per IRC assessment is the primary efficacy endpoint.  The study is designed to test 
the following primary statistical hypothesis:
ܪ଴: ܵሺݐሻVenetoclax + Bd ൌܵሺݐሻPlacebo + Bd   vs.  ܪଵ: ܵሺݐሻVenetoclax +Bd ്ܵሺݐሻPlacebo + Bd
where S(t) is the survivorship function of PFS at time t.  A stratified log-rank test with a 
two-sided type-I error rate of α = 0.05 (one-sided type I error rate of α = 0.025) will be 
used to test the primary null hypothesis.  The hazard ratio (HR) for treatment effect will 
be estimated and its two-sided 95% confidence interval will be provided.  The estimation 
will be based on a Cox proportional hazards model with treatment and stratification 
factors included.
As sensitivity analyses, the primary endpoint PFS will be analyzed with the following 
changes:
1.
PFS based on assessment by investigator.
2.
Not considering two or more consecutive missing assessment as a reason for 
censoring PFS events (per IRC).
3.
Not considering new anticancer therapy as a reason for censoring PFS events (per 
IRC).
A robustness analysis will be performed including the following prognostic factors into 
the Cox proportional hazards model:  treatment group, and other covariates including, but 
not limited to, age group (< 65 years/ ≥ 65 years), renal function per Creatinine Clearance, 
prior stem cell transplant (yes/no), and MM ISS stage (I/II/III) as covariates.  The 
stratification factors will be reflected in the STRATA statement.  HR and 2-sided 95% CIs 


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
34
will be provided.  Covariates with a large amount of missing data or small number of 
subjects within a category may be excluded or combined as appropriate.
10.3
Secondary Efficacy Analyses
VGPR or better response rate, MRD negativity rate and ORR will be analyzed by using 
stratified Cochran Mantel Haenszel test based on strata at randomization.  Estimated rates 
along with corresponding exact 95% confidence intervals as derived by the Clopper-
Pearson method will be presented.
DOR and TTP will be analyzed by using stratified log-rank tests.  The HR for treatment 
effect will be estimated and two-sided 95% confidence intervals will be provided.  The 
estimation will be based on a Cox proportional hazards model that includes treatment and 
stratification factors.  DOR will be analyzed only based on data from responders (PR or 
better) out of the ITT analysis set.
OS will be analyzed by using a stratified, two-sided, 3-look group sequential log-rank test 
with a cumulative two-sided type-I error rate of α = 0.05 (one-sided type I error rate of 
α = 0.025).  The HR for treatment effect will be estimated and two-sided 95% confidence 
intervals will be provided.  The estimation will be based on a Cox proportional hazards 
model that includes treatment and stratification factors.
For PROs, change in score from baseline will be statistically compared between treatment 
arms for the following:  Global Health Status/QoL (EORTC QLQ C30), Worst Pain (BPI-
SF), Physical Functioning (EORTC QLQ-C30), and Fatigue (PROMIS-Fatigue).  In order 
to analyze PRO variables, assessments will be time plotted using time-windows (Table 6).  
Change from baseline will be analyzed by a repeated measurement model.  Stratification 
factors, age group and treatment group will be included as fixed factors and the baseline 
value as a covariate.  Furthermore, time and treatment by time interaction will be included 
in the model.  The repeated correlation structure in the timepoints will be assessed by 
using the Bayesian Information Criterion (BIC).  The following covariance structures will 
be explored:  Unstructured (TYPE = UN), compound symmetry (TYPE = CS) and 


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
35
first-order autoregressive (TYPE = AR(1)).  The type resulting in the lowest BIC will be 
used for analysis.  Treatment and treatment by time interaction will tested simultaneously 
at two sided significance level 0.05 to test treatment effect.  Also, unless noted otherwise, 
for EORTC and PROMIS endpoints, data collected on or before start date of new cancer
therapy will be considered.
10.4
Tertiary Efficacy Analyses
CBR, DCR and MRD negativity rate will be analyzed using Cochran-Mantel-Haenszel 
test based on strata at randomization.  Estimated rates along with corresponding exact 
95% confidence intervals as derived by the Clopper-Pearson method will be presented.
TTR and TNT will be analyzed using stratified log-rank tests.  The HR for treatment 
effect will be estimated and two-sided 95% confidence intervals will be provided.  The 
estimation will be based on a Cox proportional hazards model that includes treatment and 
stratification factors.
For PROs, descriptive statistics will be used to summarize change from baseline in 
patient-reported outcomes based on the remaining subscales of BPI-SF, 
EORTC QLQ-C30, European Organization for Research and Treatment of Cancer Quality 
of Life Questionnaire Multiple Myeloma Module [EORTC QLQ-MY20], and Euroqol 
EQ-5D-5L.
10.5
Efficacy Subgroup Analyses
To evaluate the impact of demographic and baseline characteristics on the primary 
efficacy endpoint, the following subgroup analyses will be performed:
●
Disease refractory to last line of therapy (yes/no)
●
Prior exposure to proteasome inhibitors (naïve/sensitive)
●
Prior exposure to an immunomodulatory drug (IMID) 
(naive/sensitive/refractory)
●
Prior exposure to bortezomib (naïve/sensitive)


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
36
●
Prior exposure to lenalidomide (naive/sensitive/refractory)
●
Prior exposure to a proteasome inhibitor and an IMiD (yes/no)
●
Prior exposure to an alkylating agent (yes/no)
●
Number of prior lines of therapy (1/2 or 3)
●
Age group (< 65 years/ ≥ 65 years)
●
Sex (male/female)
●
Race (White/Black/Asian/Other)
●
Multiple Myeloma ISS stage (I/II/III)
●
Renal function at baseline  (Severe impairment (CrCl < 30 mL/min); moderate 
impairment (CrCl 30 - < 60 mL/min); mild impairment (CrCl 60 -
< 90 mL/min); normal function (CrCl ≥ 90 mL/min))
●
IMWG consensus risk (High/Standard)
●
CA risk (High/Standard)
●
t (11;14) status (negative/positive/unknown)
●
Prior stem cell transplant (yes/no) 
●
Geographic region (North America/EU/South America/Asia-Pacific)
●
BCL-2 expression (high/low) as defined through central laboratory testing by 
immunohistochemistry (IHC) and based on the pre-specified scoring algorithm 
in Table 2.  Subjects who are randomized but have missing or indeterminate 
central laboratory IHC results for BCL2 expression will be excluded for the 
subgroup analysis.
●
BCL2 gene expression (≥ cutoff/ < cutoff) as defined through central 
laboratory testing of bone marrow aspirates by quantitative polymerase chain 
reaction (qPCR) using the ΔCt method.  High BCL2 expression will be defined 
as BCL2 expression normalized to TMEM55B (2–ΔCt) greater than or equal to 
the 1st, 2nd, and 3rd quartile expression values calculated from randomized 
subjects with central laboratory qPCR results for BCL2 gene expression.  ΔCt 
= Ct BCL2 (target gene) – Ct TMEM55B (reference gene).  Subjects who are 
randomized but have missing or indeterminate central laboratory qPCR results 
for BCL2 gene expression will be excluded for the subgroup analysis.


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
37
●
BCL2:BCL2L1 gene expression (≥ cutoff/ < cutoff) as defined through central 
laboratory testing of bone marrow aspirates by quantitative polymerase chain 
reaction (qPCR) using the ΔCt method.  High BCL2:BCL2L1 expression will 
be defined as BCL2 expression relative to BCL2L1 (2–ΔΔCt) greater than or 
equal to the 1st, 2nd, and 3rd quartile expression values calculated from 
randomized subjects with central laboratory qPCR results for BCL2 and 
BCL2L1 gene expression.  ΔCt for BCL2 = Ct BCL2 (target gene) – Ct 
TMEM55B (reference gene).  ΔCt for BCL2L1 = Ct BCL2L1 (target gene) –
Ct TMEM55B (reference gene).  ΔΔCt for BCL2:BCL2L1 = ΔCt BCL2 - ΔCt 
BCL2L1.  Subjects who are randomized but have missing or indeterminate 
central laboratory qPCR results for BCL2 and BCL2L1 gene expression will 
be excluded for the subgroup analysis.
●
BCL-2 and BCL-XL expression levels (positive profile/negative profile) as 
defined through central laboratory testing of bone marrow core biopsy tissue 
by immunohistochemistry (IHC) and the pre-specified scoring algorithm in 
Table 2. Two subgroups will be defined as follows:
○
Positive Profile:  High BCL-2 and Low BCL-XL
○
Negative Profile:  High BCL-2 and High BCL-XL OR Low BCL-2 and 
High BCL-XL OR Low BCL-2 and Low BCL-XL.
Subjects who are randomized but have missing or indeterminate central laboratory IHC 
results for BCL-2 and BCL-XL expression will be excluded for the subgroup analysis.  
HRs and 2-sided 95% CIs will be provided based on the Cox proportional hazards model.  
This model will include the factors treatment and the stratification factors using the BY 
statement to derive estimates by subgroup.  Point estimates of HR and 2-sided 95% CI 
will be provided by subgroup in a forest plot.
11.0
Safety Analyses
11.1
General Considerations
Safety analyses will be performed on the Safety Analysis Set by treatment group.  There 
will be no statistical comparison for these analyses.


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
38
For basophils, eosinophils, lymphocytes, monocytes, neutrophils and reticulocytes, 
reporting in tables will be done only for absolute values.  If sites have provided only a % 
and no absolute value, conversion from % to absolute will be performed according to the 
following formulas:
●
Basophils [absolute value] = basophils [%] • leukocytes [absolute value], same 
for eosinophils, lymphocytes, monocytes, and neutrophils
●
Reticulocytes [absolute value] = reticulocytes [%] • erythrocytes [absolute 
value]
Reference intervals for absolute values will be used (i.e., reference intervals will not be 
converted).
For urea, reporting in tables will be done only as blood urea nitrogen (BUN).  In case sites 
have provided only a urea value and no BUN value, conversion from Urea to BUN will be 
performed according to the following formula:
●
BUN [mmol/L] = urea [mmol/l]/2.14
11.2
Analysis of Adverse Events
Analyses of adverse events will include only "treatment-emergent" events.  Treatment-
emergent adverse events (TEAE) are those which either begin or increase in severity after 
the first dose of study treatment.  Operationally, TEAE is defined as any adverse event 
that has an onset on or after the day of the first dose of the study treatment.  Analyses will 
not include those TEAE that have an onset greater than 30 days after the last dose of the 
study drug.  Events for which the onset date is the same as the study treatment start date 
are assumed to be treatment-emergent.  If an incomplete onset date was collected for an 
adverse event, the event will be assumed to be treatment-emergent unless there is other 
evidence that confirms that the event was not treatment-emergent (e.g., the event end date 
was prior to the study treatment start date).


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
39
11.2.1
Treatment-Emergent Adverse Events
The number and percentage of subjects experiencing treatment-emergent adverse events 
will be summarized for the following categories:
●
Adverse events by primary system organ class and preferred term
●
Adverse events by primary system organ class and preferred term, by
subgroups (Section 11.2.6)
●
Adverse events with NCI-CTCAE toxicity grade 3 or 4 by primary system 
organ class and preferred term
●
Adverse events with NCI-CTCAE toxicity grade 3, 4 or 5 by primary system 
organ class and preferred term
●
Serious adverse events by primary system organ class and preferred term
●
Adverse events with suspected relationship to Venetoclax/Placebo by primary 
system organ class and preferred term
●
Adverse events with suspected relationship to Bortezomib by primary system 
organ class and preferred term
●
Adverse events with suspected relationship to Dexamethasone by primary 
system organ class and preferred term
●
Adverse events leading to death by primary system organ class and preferred 
term
●
Adverse events leading to Venetoclax/Placebo discontinuation by primary 
system organ class and preferred term
●
Adverse events leading to Bortezomib discontinuation by primary system 
organ class and preferred term
●
Adverse events leading to Dexamethasone discontinuation by primary system 
organ class and preferred term
●
Adverse events leading to Venetoclax/Placebo dose reduction by primary 
system organ class and preferred term 
●
Adverse events leading to Bortezomib dose reduction by primary system organ 
class and preferred term


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
40
●
Adverse events leading to Dexamethasone dose reduction by primary system 
organ class and preferred term
●
Adverse events leading to Venetoclax/Placebo temporary interruption by 
primary system organ class and preferred term
●
Adverse events leading to Bortezomib temporary interruption by primary 
system organ class and preferred term
●
Adverse events leading to Dexamethasone temporary interruption by primary 
system organ class and preferred term
●
Any adverse event of neutropenia with NCI-CTCAE toxicity grade 3 or 4 and 
concurrent serious adverse event of infection
●
Any adverse event of thrombocytopenia with NCI-CTCAE toxicity grade 3 or 
4 and concurrent serious adverse event of hemorrhage
●
Any adverse event of lymphopenia and concurrent serious infection
●
Any adverse event of neutropenia with NCI-CTCAE toxicity grade 3 or 4 
leading to Venetoclax or Placebo discontinuation
●
Selected adverse events by preferred terms (Table 9)


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
41
Table 9.
Selected Adverse Events
Risk
Search Criteria
Tumor Lysis Syndrome
SMQ – "Tumour lysis syndrome" (Narrow-scope)
Neutropenia Expanded Search
PT terms – "Neutropenia," "Neutrophil count decreased," "Febrile 
neutropenia," "Agranulocytosis," "Neutropenic infection," and 
"Neutropenic sepsis"
Neutropenia and Neutrophil Count 
Decreased
PT terms – "Neutropenia," "Neutrophil count decreased"
Serious Infection
SAEs in the SOC of "Infections and Infestations"
Second Primary Malignancy 
SMQ – "Malignant tumours" (Narrow) and "Myelodysplastic 
syndromes" (Narrow)
Lymphopenia
PT terms – "Lymphopenia" and "Lymphocyte count decreased"
Anemia
PT terms – "Anaemia" and "Haemoglobin decreased"
Thrombocytopenia
PT terms – "Thrombocytopenia" and "Platelet count decreased"
Drug Induced Liver Injury (DILI)
SMQ – "Drug related hepatic disorders – comprehensive search"
Peripheral Neuropathy 
Peripheral Neuropathy SMQ – "narrow"
Sepsis 
PTs including the word 'sepsis' + PT 'septic shock'
Serious Opportunistic infections
Opportunistic infection _ CMQ (BCL2 inhibitor product specific)
An AE will be considered "concurrent" with a cytopenia event (eg, serious infection 
concurrent with neutropenia expanded search) if the onset of the AE was no more than 
7 days prior to the onset of the cytopenia event and no more than 7 days after the end of 
the cytopenia event.
Adverse Events by Primary System Organ Class and Preferred Term
The number and percentage of subjects experiencing adverse events will be tabulated 
according to the primary MedDRA system organ class (SOC) and MedDRA preferred 
term (PT).  Subjects reporting more than one adverse event for a given MedDRA PT will 
be counted only once for that term.  Subjects reporting more than one type of adverse 
event within a MedDRA SOC will be counted only once for that SOC.  Subjects reporting 
more than one type of adverse event will be counted only once in the overall total.


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
42
Adverse Events by SOC/PT and by NCI-CTCAE Toxicity Grade
Adverse events will also be summarized by SOC/PT and by maximum NCI-CTCAE 
toxicity grade.  If a subject has an adverse event with an unknown NCI-CTCAE toxicity 
grade, then the subject will be counted in the category of "unknown," even if the subject 
has another occurrence of the same adverse event with a grade present.  The only 
exception is if the subject has another occurrence of the same adverse event with the most 
extreme grade.  In this case, the subject will be counted under this grade.
11.2.2
Serious Adverse Events
Serious adverse events will be summarized by System Organ Class and Preferred Term 
using the same methods as adverse events described above in Section 11.2.1.
11.2.3
Adverse Events Leading to Discontinuation, Dose 
Reduction, or Dose Interruption of Study Treatment and 
Leading to Death
The number and percentage of subjects experiencing adverse events leading to 
discontinuation, dose reduction, or dose interruption of Venetoclax or 
Placebo/Bortezomib/Dexamethasone will be summarized by SOC/PT separately for all 
combinations.
The number and percent of subjects experiencing adverse events leading to death will be 
tabulated according to the primary SOC and PT.
11.2.4
Deaths
The number of subject deaths will be summarized for:
●
Deaths occurring while the subject was still receiving study drug
●
Deaths occurring off treatment within 30 days after the last dose of study drug
●
Deaths in this study regardless of the number of days after the last dose of 
study drug


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
43
11.2.5
Listing of Adverse Events
The following additional summaries of adverse events will be prepared:
●
Listing of all adverse events
●
Listing of all serious adverse events
●
Listing of Grade 3 - 4 adverse events leading to death
●
Listing of all adverse events leading to death
●
Subject deaths occurring ≤ 30 days after last dose of study drug
●
Subject deaths occurring > 30 days after last dose of study drug
11.2.6
Adverse Event Rates by Subgroup
Treatment-emergent adverse events may be assessed for the subgroups defined below:
●
Age (< 65 years/ ≥ 65 years))
●
Gender 
●
Race (white, black, Asian, other)
●
Region (US, EU, and ROW)
●
Renal Function at Baseline:
○
Normal renal function:  Creatinine Clearance (CrCl) ≥ 90 mL/min;
○
Mild renal impairment:  CrCl ≥ 60 to < 90 mL/min
○
Moderate renal impairment:  CrCl ≥ 30 to < 60 mL/min
○
Severe renal impairment:  CrCl < 30 mL/min
●
Hepatic Function at Baseline:
○
Normal hepatic function:  total bilirubin ≤ 1 mg/dL and Aspartate Amino 
Transferase (AST) ≤ 40 U/L
○
Mild hepatic impairment:  total bilirubin ≤ 1 mg/dL and AST > 40 U/L, or 
total bilirubin > 1.0 to ≤ 1.5 mg/dL and any AST
○
Moderate hepatic impairment:  total bilirubin > 1.5 to ≤ 3 mg/dL and any 
AST
○
Severe hepatic impairment: total bilirubin > 3 mg/dL and any AST


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
44
11.3
Analysis of Laboratory and Vital Signs
Changes from baseline may be summarized for each scheduled post-baseline visit and for
the Treatment Completion Visit for hemoglobin, platelet count, neutrophil count, absolute 
leukocyte count, creatinine, and calcium.  Post-baseline measurements more than 30 days 
after the last dose of randomized study drug will not be included.  Subjects that do not 
have a baseline measurement or do not have any post-baseline measurements will not be 
included.
Descriptive statistics will include the mean, standard deviation, and median for baseline, 
and mean, standard deviation, median, minimum, and maximum for change from baseline 
for each scheduled post-baseline visit, and the Treatment Completion Visit by treatment 
group.
11.3.1
Analyses of Laboratory Data Using NCI CTCAE
For hematology and chemistry variables for which NCI CTCAE 4.03 criteria exist, 
baseline and post-baseline hematology and chemistry variable observations will be 
categorized as grade 0 to grade 4.
Criteria are specified for the assignment of grades with values between 1 and 4.  The 
criteria are unidirectional:  any one set of criteria constitute a screening either for low or 
high values of potential clinical significance.
For laboratory tests for which a normal range limit is one end of the grade 1 range then 
values that are either within the normal range or outside it in direction opposite the test 
will be classified as grade 0 values.  For other tests, values outside the grade 1 range in the 
direction opposite that of the test will be classified as grade 0.
There can be instances in which the criteria for more than one grade apply to a lab test
value.  In those instances the highest applicable grade will be assigned.


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
45
For each graded variable, shifts from baseline grade to treatment-emergent maximum 
post-baseline grades (but no more than 30 days after the last dose of study drug) will be 
assessed.
Detailed listings of data for subjects experiencing NCI CTCAE Grade 3 to 4 blood 
chemistry and hematology values will be provided.  All measurements collected, 
regardless of the number of days after the last dose of study drug, will be included in these 
listings.
11.3.2
Assessment of Drug-Induced Liver Injury
The number and percentage of subjects in each treatment group who have at least 
one observed post-baseline value meeting the following criteria will be tabulated
●
Alanine Amino Transferase (ALT) > 3 × Upper Limit Normal (ULN)
●
AST > 3 × ULN
●
AST or ALT > 3 × ULN
●
Total bilirubin value > 2 × ULN
●
ALT or AST > 3 × ULN AND Total bilirubin > 2 × ULN within 72 hours.
A listing of all observed ALT, AST, and total bilirubin values will be generated for 
subjects with an observed value meeting any of these criteria.
11.3.3
Laboratory Assessments for Tumor Lysis Syndrome
To determine if a subject's laboratory values qualify for Tumor Lysis Syndrome (TLS), 
the Howard criteria2 will be assessed.  The Howard definition for laboratory TLS requires 
≥ 2 of the metabolic abnormalities specified in Table 10 post-baseline and within 24 hours 
of each other.


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
46
Table 10.
Laboratory Criteria for TLS
Element
Value
Uric Acid
> 476 μmol/L
Potassium
> 6.0 mmol/L
Inorganic Phosphorus
> 1.5 mmol/L
Calcium
< 1.75 mmol/L
The following summaries of laboratory criteria will be provided:
●
Number and percentage of subjects meeting the definition of laboratory TLS 
(at least two values meeting the criteria in Table 10, occurring within 24 hours 
of each other).
●
Listing of all values for these four analyses for each subject meeting the 
definition of laboratory TLS at least once during treatment.
11.3.4
Analyses of Vital Signs Using Criteria for Potentially 
Clinically Significant Values
Vital sign variables are:  sitting systolic blood pressure, sitting diastolic blood pressure, 
pulse and temperature.
Vital signs values will be assessed for potential clinical significance (PCS) through the 
application of criteria developed at AbbVie as detailed in the following table:
Table 11.
Criteria for Potential Clinical Significance in Vital Signs Variables
Vital Signs Variables
Criterion
Definition of Potentially Clinically Significant
Systolic Blood Pressure
High
Value ≥ 160 mmHg
Diastolic Blood Pressure
High
Value ≥ 100 mmHg
Pulse
Low
Value < 50 bpm
High
Value ≥ 120 bpm
Temperature 
Low
Value < 36°C
High
Value ≥ 38.5°C


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
47
Detailed listings of data for subjects experiencing PCS vital sign values according to the 
AbbVie-defined criteria will be provided.  All measurements collected will be included in 
these listings, regardless of the number of days after the last dose of study drug.
11.4
Analysis of ECG Parameters
A summary of the number and percentage of subjects who have at least one observation in 
the following categories will be provided:
●
abnormal ECG – clinically significant (Yes/No)
A listing will also be prepared that will include details about all abnormal ECG findings.
12.0
Pharmacokinetics
Plasma concentrations of Venetoclax and Bortezomib (and Dexamethasone, Japan 
subjects only) will be tabulated for each subject by visit, and summary statistics will be 
computed for each sampling time.  Samples with significant sampling time deviations will 
be excluded from summary statistics calculations.
For the Japan subjects during the run-in phase, pharmacokinetic parameter values for 
Dexamethasone will be tabulated for each subject by visit, and summary statistics will be 
computed for each parameter.
13.0
Appendix – PRO assessments
PRO assessments include:  BPI-SF, EORTC QLQ-C30, EORTC QLC MY20, PROMIS 
Cancer Fatigue SF, and EQ-5D-5L.
BPI-SF
The BPI-SF is a pain-specific measure developed to assess patient-reported severity (or 
intensity) of pain (4 items) and the impact of pain on daily functioning (7 items) in 
patients with cancer pain.7  The four pain severity items assess pain at its "worst," "least," 
"average," and "now" (current pain).  For these items, patients are asked to rate their pain 


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
48
on an 11-point numeric rating scale with anchors of 0 (no pain) and 10 (pain as bad as you 
can imagine).  The BPI "worst" pain severity item has been shown to be reliable and valid 
for use as a single item.8  The BPI-SF also includes questions to measure the interference 
of pain in the patient's daily life, including general activity, mood, ability to walk, normal 
work (both outside the home and housework), relationships with other people, sleep, and 
enjoyment of life.  For these items, patients are asked to describe the extent to which pain 
has interfered on an 11-point numeric rating scale with anchors of 0 (does not interfere) to 
10 (completely interferes).
Table 12.
BPI-SF Scales
Scales
Items
Pain Severity*
BPI2-Pain Right Now
BPI2-Pain at its Least in Last 24 Hours
BPI2-Pain on the Average
BPI2-Pain at its Worst in Last 24 Hours
Pain Interference**
BPI2-Pain Interfered Enjoyment of Life
BPI2-Pain Interfered General Activity
BPI2-Pain Interfered Walking Ability
BPI2-Pain Interfered with Mood
BPI2-Pain Interfered with Normal Work
BPI2-Pain Interfered with Relations
BPI2-Pain Interfered with Sleep
*Calculated as sum of scores of all 4 items and then dividing by 4.  This gives the Pain Severity score out of 10.
**Calculated as sum of scores of all 7 items and then dividing by 7.  This gives the Pain Severity score out of 10.
EORTC QLQ-C30
HRQoL, functioning, and symptoms will be assessed with the EORTC-QLQ-C30 
version 3.9  The QLQ-C30 is a 30-item subject self-report questionnaire composed of both 
multi-item and single scales, including five functional scales (physical, role, emotional, 
social, and cognitive), three symptom scales (fatigue, nausea and vomiting, and pain), a 
global health status/quality of life scale, and six single items (dyspnea, insomnia, appetite 
loss, constipation, diarrhea, and financial difficulties).  The subjects rate items on a 


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
49
four point scale, with 1 as "not at all" and 4 as "very much."  The QLQ-C30 was 
developed and validated for use in a cancer patient population, and its reliability and 
validity is highly consistent across different language cultural groups.  The items and 
scales of the QLQ-C30 are as in Table 13:
Table 13.
EORTC QLQ-C30 Scales
Scale
Number of 
Items
Item 
Range
Item 
Numbers
Global Health Status/Quality of Life
Global Health Status/Quality of Life
QL2
2
6
29, 30
Functional Scales
Physical Functioning*
PF2
5
3
1 – 5
Role Function*
RF2
2
3
6 – 7
Emotional Functioning*
EF
4
3
21 – 24
Cognitive Functioning*
CF
2
3
20, 25
Social Functioning*
SF
2
3
26 – 27
Symptom Scales
Fatigue
FA
3
3
10, 12, 18
Nausea and Vomiting
NV
2
3
14, 15
Pain
PA
2
3
9, 19
Dyspnoea
DY
1
3
8
Insomnia
SL
1
3
11
Appetite Loss
AP
1
3
13
Constipation
CO
1
3
10
Diarrhoea
DI
1
3
17
Financial Difficulties
FI
1
3
28
*
Function Scales.
Note:
Item range is the difference between the possible maximum and the minimum response to individual items.
Scoring algorithms for scales are as follows:
For all Scales, the Raw Score (RS) is the mean of the component items (I):
If items I1, I2…, In are included in a scale, the procedures are as follows:


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
50
Raw Score (RS) = (I1 + I2 + … + In) / (number of non-missing items),
Then the Functional Scales:
Score = (1 - (RS - 1) / range) × 100
where range is provided in Table 13.
For example, to calculate Emotional Functioning (EF),
RSEF = (I21 + I22 + I23 + I24) / 4
ScoreEF = (1 - (RSEF - 1) / 3) × 100
If a subject completed more than 50% of the items in a scale, then the raw score of that 
subject will contribute to the summary statistics of that scale.  If a subject completed less 
than 50% of the items in a scale, then the raw score of that subject will be dropped from 
the calculation of the summary statistics of that scale.
EORTC QLQ-MY20
The EORTC QLQ-MY20 was developed as an additional module for the QLQ-C30 and is 
composed of 20 items specific to multiple myeloma.10  The QLQ-MY20 includes scales 
for disease symptoms, side effects of treatment, future perspective, and body image.  
Values for each scale range from 0 to 100.  The subjects rate items on a four-point scale, 
with 1 as "not at all" and 4 as "very much."  The QLQ-MY20 is a reliable and valid 
instrument for measuring quality of life in myeloma patients.


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
51
Table 14.
QLQ-MY20 scales
Scale
Number 
of Items
Item 
Range
QLQ-MY20 Item 
Numbers
Functional Scales/items
Future perspective
MYFP
3
3
18 - 20
Body image
MYBI
1
3
17
Symptom Scales
Disease symptoms
MYDS
6
3
1 - 6
Side effects of treatment
MYSE
10
3
7 - 16
PROMIS Cancer Fatigue SF
The PROMIS® is a system of highly reliable, precise measures of patient-reported health 
status for physical, mental, and social well-being.11  PROMIS instruments measure 
concepts such as pain, fatigue, physical function, depression, anxiety and social function.  
Fatigue will be assessed using the PROMIS Cancer Fatigue SF that has been developed 
for use in oncology populations.12,13  PROMIS Cancer Fatigue SF is a seven item 
questionnaire that assesses the impact and experience of fatigue over the past 7 days.  All 
questions employ the following five response options:  1 = Not at all, 2 = A little bit, 
3 = Somewhat, 4 = Quite a bit, and 5 = Very much.  The score is calculated as below:
Score = Sum of score from all questions × 7/Total number of answered questions
If 4 or more questions were not being answered, then the score is considered as missing.  
The details of scoring method can be found in the scoring manual 
https://www.assessmentcenter.net/documents/PROMIS%20Fatigue%20Scoring%20Manu
al.pdf.
EQ-5D-5L
The EQ-5D-5L is a generic preference instrument that has been validated in numerous 
populations.14  The EQ-5D-5L has five dimensions:  mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression.  These dimensions are measured on a five level 


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
52
scale:  no problems, slight problems, moderate problems, severe problems, and extreme 
problems.  The EQ-5D-5L also contains a visual analog scale (VAS) to assess the 
subject's overall health.  Detailed EQ-5D-5L scoring method can be found at 
https://euroqol.org/wp-content/uploads/2016/09/EQ-5D-5L_UserGuide_2015.pdf.
14.0
References
1.
Rajkumar SV, Harousseau JL, Durie B, et al.  Consensus recommendations for the 
uniform reporting of clinical trials:  report of the International Myeloma Workshop 
Consensus Panel 1.  Blood.  2011;117(18):4691-5.
2.
Durie BG, Harousseau JL, Miguel JS, et al.  International uniform response criteria 
for multiple myeloma.  Leukemia.  2006;20(9):1467-73.
3.
Lan KKG, DeMets DL.  Discrete sequential boundaries for clinical trials.  
Biometrika.  1983;70(3):659-63.
4.
Chng WJ, Dispenzieri A, Chim CS, et al.  IMWG consensus on risk stratification in 
multiple myeloma.  Leukemia.  2014;28(2):269-77.
5.
Osoba D, Rodrigues G, Myles J, et al.  Interpreting the significance of changes in 
health-related quality-of-life scores.  J Clin Oncol.  1998;16(1):139-44.
6.
Yost KJ, Eton DT, Garcia SF, et al.  Minimally important differences were 
estimated for six patient-reported outcomes measurement information system-
cancer scales in advanced-stage cancer patients.  J Clin Epidemiol.  
2011;64(5):507-16.
7.
Cleeland CS.  Pain assessment in cancer.  In Effect of Cancer on Quality of Life.  
Osaba D, editor.  Boca Raton:  CRC Press; 1991:21.
8.
Atkinson TM, Mendoza TR, Sit L, et al.  The brief pain inventory and its "pain at 
its worst in the past 24 hours" item:  clinical trial endpoint considerations.  Pain 
Med.  2010;11(3):337-46.
9.
Aaronson NK, Ahmedzai S, Bergman B, et al.  The European Organization for 
Research and Treatment of Cancer QLQ-C30:  a quality-of-life instrument for use 
in international clinical trials in oncology.  J Natl Cancer Inst.  1993;85(5):365-76.


Venetoclax
M14-031 – Statistical Analysis Plan
Version 3.0 – 16 Jan 2019
53
10.
Cocks K, Cohen D, Wisloff F, et al.  An international field study of the reliability 
and validity of a disease-specific questionnaire module (the QLQ-MY20) in 
assessing the quality of life of patients with multiple myeloma.  Eur J Cancer.  
2007;43(11):1670-8.
11.
Cella D, Yount S, Rothrock N, et al.  The patient-reported outcomes measurement 
information system (PROMIS):  progress of an NIH roadmap cooperative group 
during its first two years.  Med Care.  2007;45 (5 Suppl 1):S3-S11.
12.
Garcia SF, Cella D, Clauser SB, et al.  Standardizing patient-reported outcomes 
assessment in cancer clinical trials:  a patient-reported outcomes measurement 
information system initiative.  J Clin Oncol.  2007;25(32):5106-12.
13.
Cella D, Riley W, Stone A, et al.  The patient-reported outcomes measurement 
information system (PROMIS) developed and tested its first wave of adult self-
reported health outcome item banks:  2005-2008.  J Clin Epidemiol.  
2010;63(11):1179-94.
14.
EQ-5D-5L and EQ-5D-VA.  Available from:  http://www.euroqol.org.
15.
Hung HM, Wang SJ, O'Neill R.  Statistical considerations for testing multiple 
endpoints in group sequential or adaptive clinical trials.  J Biopharm Stat.  
2007;17(6):1201-10.
16.
Glimm E, Maurer W, Bretz F.  Hierarchical testing of multiple endpoints in group-
sequential trials.  Stat Med.  2010;29(2):219-28.
17.
Palumbo A, Avet-Loiseau H, Oliva S, et al.  Revised International Staging System 
for Multiple Myeloma:  A Report From International Myeloma Working Group.  
J Clin Oncol.  2015;33(26):2863-9.