Clinical trial NCT01592370
Conditions: Non-Hodgkin's Lymphoma Hodgkin Lymphoma Multiple Myeloma
Sponsor: Bristol-Myers Squibb
Start date: 2012-08-02; Completion date: 2024-07-09
Enrollment: 316 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine the side effects of treatment of the combination of nivolumab and daratumumab in participants with relapsed/refractory multiple myeloma.

Detailed description:
NOTE: Currently, this study is only open to nivolumab+daratumumab vs daratumumab monotherapy in multiple myeloma patients.

Arms: arm 1: Nivolumab solution intravenously as specified

Non-randomized

Enrollment is closed for this cohort arm 2: Nivolumab and Ipilimumab solution intravenously as specified

Non-randomized

Enrollment is closed for this cohort arm 3: Non-randomized

Nivolumab: 3 mg/kg given every 2 weeks Lirilumab: 3 mg/kg given every 4 weeks

Enrollment is closed for this cohort arm 4: Randomized

Nivolumab:

Cycle 1: 240 mg Day 15 Cycle 2-6: 240 mg Days 1, 15 Cycle 7 \& beyond: 480 mg Day 1

Daratumumab:

Cycle 1-2: 16 mg/kg Days 1, 8, 15, 22 Cycle 3-6: 16 mg/kg Days 1, 15 Cycle 7 \& beyond: 16 mg/kg Day 1

Pomalidomide:

4 mg po (by mouth) daily on Days 1 - 21 of each 28-day cycle

Dexamethasone:

Weeks without daratumumab dosing:

* 40 mg po daily (Days 1, 8, 15, 22) of each 28-day cycle for participants ≤ 75 years old
* 20 mg po daily (Days 1, 8, 15, 22) of each 28-day cycle for participants \> 75 years old

Weeks with daratumumab dosing:

* 20 mg iv before the daratumumab infusion and 20 mg po after the daratumumab infusion in participants ≤ 75 years old
* 16 mg iv before the daratumumab infusion and 4 mg po after the daratumumab infusion in participants \> 75 years old

Enrollment is closed for this cohort arm 5: Randomized

Nivolumab:

Cycle 1: 240 mg Day 15 Cycle 2 \& beyond: 480 mg Day 1

Daratumumab:

Cycle 1-2: 16 mg/kg Days 1, 8, 15, 22 Cycle 3-6: 16 mg/kg Days 1, 15 Cycle 7 \& beyond: 16 mg/kg Day 1
Interventions: intervention 1: Nivolumab intervention 2: Ipilimumab intervention 3: Lirilumab intervention 4: Daratumumab intervention 5: Pomalidomide intervention 6: Dexamethasone
Intervention descriptions: intervention 1: Administered by intravenous (IV) infusion intervention 2: Administered by IV infusion intervention 3: Administered by IV infusion intervention 4: Administered by IV infusion intervention 5: Administered PO intervention 6: Administered PO and by IV infusion

Protocol documents:
Prot_000.pdf: 


Clinical Protocol
CA209039
BMS-936558
Nivolumab
Revised Protocol No.: 15
Date: 23-Apr-2019
2
who receives this document without due authorization from BMS is requested to return it 
to BMS or promptly destroy it. All other rights reserved.
Replace all previous version(s) of the protocol with this revised protocol and please provide a 
copy of this revised protocol to all study personnel under your supervision, and archive the 
previous versions.
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Clinical Protocol
CA209039
BMS-936558
Nivolumab
Revised Protocol No.: 15
Date: 23-Apr-2019
3
DOCUMENT HISTORY
Document
Date of Issue
Summary of Changes
Revised Protocol 15 
23-Apr-2019 
Major changes include:
• Incorporated Administrative Letter 10
• Updated the medical monitor
• Removed all references to the lirilumab/nivolumab and 
nivolumab monotherapy cohorts.
• Removed all references to the dose selection phase.
• Removed references to non-Hodgkin and Hodgkin lymphoma.
• Added option for split-dosing of daratumumab at C1D1
• Added requirements for HBV DNA testing and updated 
requirements for hepatitis B and C criteria and testing to 
address daratumumab safety concerns
• Clarified timing of interim and final analyses.
• Deleted appendices that are no longer applicable
Administrative Letter 
10
30-Apr-2018 
Updated EUDRACT number and UTN.
Deleted Exclusion Criteria 2., j), ii) and iii)
In Table 5.1-7, in Cohort B, corrected every 4 cycles to start at cycle 
9 instead of 11.
Revised Protocol 14 
15-Feb-2018 
Major changes:
• In compliance with requests from the FDA, enrollment into the 
nivolumab +daratumumab with and without pomalidomide 
(ND±Pd: Cohort A) has been stopped.  Cohort B (nivolumab 
+daratumumab vs daratumumab monotherapy [ND, D]) has 
been opened, with at 2:1 randomization. 
o Eligibility changes to the patient population for 
patients to be enrolled in Cohort B and toxicity 
stopping rules for the ND arm have been 
incorporated.  
o Cohort B patients(only) treated in the ND arm: 
Dose regimen change: nivolumab 480 mg every 4 
weeks (Day 1) will begin at Cycle 2 rather than at 
Cycle 7 and continue until the end of treatment.
Cycle 1 dose: 240 mg on Day 15. 
• The biomarker assessments have been aligned to the multiple
myeloma program wide biomarkers evaluations.
•
All content related to the nivolumab +ipilimumab combination 
has been removed because all study procedures for this cohort, 
including follow-up evaluations, have been completed. 
Of note, Revised Protocol 13 was not activated at the study sites.
All changes are further detailed in the Summary of Key Changes.
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Clinical Protocol
CA209039
BMS-936558
Nivolumab
Revised Protocol No.: 15
Date: 23-Apr-2019
4
Document
Date of Issue
Summary of Changes
Revised Protocol 13 
04-Aug-2017
Major changes are corrections and updates pertinent only to the 
nivolumab/daratumumab cohorts as follows:
• Changes in eligibility for subjects with multiple myeloma (MM) 
for enrollment in the nivolumab/daratumumab cohorts include: 
− Eligible subjects must have failed prior treatment with an 
immune modulatory drug (IMiD) and/or a proteasome 
inhibitor (PI) rather than the requirement of failure to 
treatment with both prior treatment types. Refractory and 
relapsed refractory definitions removed as criterion 
definitions.
− Subjects who received prior treatment with pomalidomide 
are no longer excluded from eligibility. 
• The randomization ratio has been changed to a 2:1 ratio, which 
increases the nivolumab + daratumumab + pomalidomide (ND-
Pd) regimen cohort to 40 and reduces the nivolumab + 
daratumumab (ND) regimen cohort to 20. The sample size 
calculation has been updated to support change in randomization 
ratio.
• Changes to the biomarkers plan were made to align with the 
program level approach and small corrections were made to the 
biomarkers collections schedule to ensure consistency 
throughout the protocol.  In addition, Biomarker collections 
from peripheral blood specimens have been clarified to remove 
duplicate collections.
• Daratumumab specific requirements for dose delays and 
discontinuation, drug preparation and administration, prevention 
and management of infusion related reactions, and permitted and 
restricted treatments have been aligned with the daratumumab 
IB and daratumumab standard protocol elements.
Administrative Letter 
07
21-Jul-2017
Corrected inclusion criteria for subjects with MM in the 
nivolumab/daratumumab cohorts to accurately specify prior use of 
antimyeloma therapy. 
Administrative Letter 
06 
09-Mar-2017 
Corrected error on Biomarker Sampling Schedule Table 5.1-6
Revised Protocol 12 
19-Jan-2017 
Incorporates Amendment 13
Amendment 13 
19-Jan-2017
This amendment includes corrections and updates pertinent only to 
the nivolumab/daratumumab cohorts. Additional biomarkers 
evaluations from peripheral blood specimens have been included.
Daratumumab specific requirements for eligibility, dose delays and 
discontinuation, drug preparation and administration. Prevention and 
management of infusion related reactions, and permitted and 
restricted treatments have been aligned with the daratumumab IB and 
daratumumab standard protocol elements.
Administrative Letter 
05
22-Nov-2016
Corrected Schedule of Assessment to align with Section 5.2.1.2 for 
IMWG response and provided clarification for location of bone 
marrow samples.
Administrative Letter 
18-Oct-2016
Corrected errors in exclusion criterion for QTC prolongation and 
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Clinical Protocol
CA209039
BMS-936558
Nivolumab
Revised Protocol No.: 15
Date: 23-Apr-2019
5
Document
Date of Issue
Summary of Changes
04
platelet count in criteria to resume treatment with daratumumab. 
Administrative Letter 
03
23-Aug-2016
Clarification for inconsistencies between the age groups for 
dexamethasone dosing defined in the dosing schema and in protocol 
body, and to provide details for specific bone marrow assessments 
included in the IMWG response criteria.
Revised Protocol 11 
09-Aug-2016 
Incorporates Amendment 12
Amendment 12 
09-Aug-2016
Adds an additional set of cohorts (approximately 60 additional 
subjects) for dose expansion in multiple myeloma patients treated 
with Nivolumab and Daratumumab with or without Pomalidomide 
and Dexamethasone
Administrative Letter 
02
03-Feb-2016 
Change in Study Director/Central Medical Monitor
Revised Protocol 10 
01-Oct-2015 
Incorporates Amendment 11
Amendment 11 
01-Oct-2015 
Update follow up requirements
Revised Protocol 09 
15-Apr-2015 
Incorporates Amendment 10
Amendment 10 
15-Apr-2015
Retrospectively collect radiographic images for blinded independent 
central review
Revised Protocol 08 
05-Feb-2015 
Incorporates Amendment 09
Amendment 09 
05-Feb-2015
Removes exploratory cohorts from the nivolumab/ipilimumab 
cohorts
Revised Protocol 07 
02-Dec-2014 
Incorporates Amendment 08
Amendment 08 
02-Dec-2014 
Revises protocol to meet FDA guidance.
Revised Protocol 06 
20-Aug-2014 
Incorporates Amendment 07
Amendment 07 
20-Aug-2014
Adds an additional set of cohorts (approximately 80 additional 
subjects) for dose expansion with combination of lirilumab and 
nivolumab
Revised Protocol 05 
19-Dec-2013 
Incorporates Amendment 06
Amendment 06 
19-Dec-2013
Adds an additional set of cohorts (approximately 75 additional 
subjects) for dose escalation and dose expansion with combination of 
ipilimumab and nivolumab.
Revised Protocol 04 
10-Oct-2013 
Incorporates Amendment 05
Amendment 05 
10-Oct-2013 
Includes corrections for protocol clarity.
Revised Protocol 03 
25-Jun-2013 
Incorporates Amendment 04
Amendment 04 
25-Jun-2013
Eliminate the CML cohort in the expansion phase as recruitment 
would be difficult due to lack of concomitant therapy with a tyrosine 
kinase inhibitor and increase the size of the remaining four cohorts 
from 16 to 23 subjects to redistribute the allotted patients from the 
eliminated CML cohort.
Revised Protocol 02 
06-Mar-2013 
Incorporates Amendment 03
Amendment 03 
06-Mar-2013
Inclusion of non-clinical safety findings related to reproductive 
toxicology data
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Clinical Protocol
CA209039
BMS-936558
Nivolumab
Revised Protocol No.: 15
Date: 23-Apr-2019
6
Document
Date of Issue
Summary of Changes
Revised Protocol 01  
21-Dec-2012 
Incorporates  Administrative Letter 01 and Amendment 02
Amendment 02 
21-Dec-2012
Eliminate the highest (10 mg/kg) of three dose levels scheduled to be 
examined, require that 8 of 16 subjects with multiple myeloma be 
required to undergo bone marrow biopsy while on therapy, and 
modify the discontinuation criteria to be more stringent
Administrative Letter 
01 
23-May-2012 
Update Medical Monitor
Original Protocol 
13-Mar-2012 
Not applicable
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Clinical Protocol
CA209039
BMS-936558
Nivolumab
Per Revised Protocol 14, Cohort B (ND, D) has been added to the study and is open to enrollment. 
Cohort B is open for enrollment per Revised Protocol 14.
* Split dosing is available for Cycle 1 Day 1.
Study  Population: MM  subjects  with  detectable  disease  (serum  M-protein ≥0.5  g/dl,  OR  urine  M-protein 
≥200 mg/24-hour collection sample, OR involved serum free-light chain (sFLC) ≥100 mg/L provided FLC ratio is 
abnormal), with ECOG 0-1, who either received at least 3 prior lines of therapy
 (including an IMiD and a PI) or are 
double  refractory  to  IMiD  and  PI  are  eligible.  Excluded  are  MM subjects  with  solitary  bone  or  extramedullary 
plasmocytoma  as  only  evidence of  plasma  cell  dyscrasia,  MGUS,  SMM,  amyloidosis,  Waldenstrom’s 
macroglobulinemia, POEMS syndrome, active plasma cell leukemia, or subjects who received any antibody or drug 
specifically targeting T cell co-stimulation or checkpoint pathways or anti-CD38 monoclonal antibodies. 
Study Assessments 
Safety  Evaluation:  Adverse  events  will  be  assessed  continuously  during  the  study  and for  100  days  post  last 
treatment.  Adverse  events  will  be  coded  using  
the  most  current version  of  MedDRA  and  
reviewed  for  potential 
significance and importance. Adverse events will be evaluated according to the NCI CTCAE Version 4.0. 
Stopping Rules for toxicity have been incorporated in Section 3.1.1.1.
Efficacy  Evaluation:  Bone  marrow  aspirate  samples  for  cyotmetry  and  molecular  MRD  assessments  will  be 
collected  at  specified  
time  points  and  will  be  analyzed  at  Sponsor  designated  
laboratories.  For  
response, subjects 
will be evaluated using the modified International Myeloma Working Group (IMWG) criteria (Appendix 3). Serum 
and  urine  samples  
for  efficacy  
laboratory  assessments  will  be  collected  every  4 weeks  from  Cycle  1  Day  1  until 
disease  progression.  All  response (≥ PR)and  progression  categories  require  2 consecutive  assessments  for 
confirmation. 
For  Cohort  B,  all  efficacy  laboratory  assessments  (SPEP/SIFE),  UPEP/UIFE,  sFLC)  will  be  done  at a  central 
laboratory, except for corrected calcium and disease status in bone marrow (ie, plasma cell percentage and clonality) 
which will be done locally. For Cohort A, local laboratories will be used for all efficacy assessments.
To assess potential daratumumab and nivolumab interference with serum M protein quantification, samples may be 
analyzed to distinguish daratumumab and nivolumab from endogenous myeloma protein (M protein).
Pharmacokinetic  Evaluation:  Sparse  blood  samples  
for  nivolumab pharmacokinetic  assessments  will  be  collected 
from all subjects at specified time points.
Study Population: Multiple Myeloma
ND - D Mono Cohort B
Randomization 2:1 N= ~60
ND regimen: Multiple myeloma (N= 40)
Each cycle is 28 days
Nivolumab:
Cycle 1: 240 mg iv Day 15
Cycle 2 & beyond: 480 mg iv Day 1
Daratumumab:
Cycle 1*-2: 16 mg/kg iv Days 1, 8, 15, 22
Cycle 3-6: 16 mg/kg iv Days 1, 15
Cycle 7 & beyond: 16 mg/kg iv Day 1
D Mono regimen: Multiple myeloma (N= 20)
Each cycle is 28 days
Daratumumab:
Cycle 1*-2: 16 mg/kg iv Days 1, 8, 15, 22
Cycle 3-6: 16 mg/kg iv Days 1, 15
Cycle 7 & beyond: 16 mg/kg iv Day 1
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Clinical Protocol
CA209039
BMS-936558
Nivolumab
Immunogenicity  Evaluations:  Blood  samples  to  evaluate  development  of  positive  nivolumab  anti-drug  antibody 
(ADA) response will be collected at specified time points for all subjects.
Biomarker  Evaluation:  Biomarkers  will  be  analyzed  in  peripheral  blood and  bone  marrow  aspirate  to  better 
understand  how  the  immune  microenvironment  may  contribute  to  immune  evasion,  
the  progression  of  multiple 
myeloma,  and  potential  synergies  between nivolumab  and daratumumab.  Residual  sample  material available  after 
completion of the designated analyses may be used in the future for identification of additional predictive markers or 
to enhance understanding of disease biology.
Statistical Considerations
Sample Size:
Per  Revised Protocol  14,  Cohort  A  (ND ±Pd) is  closed  to enrollment,  and  Cohort  B  (ND  and  D)  
is  open  for 
enrollment.
The planned sample size for Cohort B (ND, D) will be approximately 60 treated subjects, randomized in a 2:1 ratio
in favor of the ND arm.
This  
is  a  Phase  1/2 study  and  
the  sample  size  
in  Cohort  B is  not powered  
for  statistical hypothesis  
testing  but  
is 
designed to evaluate both safety profile and clinical benefit of nivolumab with daratumumab.
If  
the  
true  
toxicities  
incidence  
rate  
in  a  cohort  
is  20%  
then  with  20  patients  
in  D  cohort,  
there  
is  7%  chance  of 
observing 0 - 1 toxicities (false negative rate). If the true toxicities incidence rate in a cohort is 5% rather than 20%, 
then there is 26% chance that there will be at least 2 toxicities in 20 subjects (false positive rate). If the true toxicities 
incidence  rate  
in  a  cohort  
is  20%  
then  with  40  patients  
there  
is  3%  chance  of  observing  0  - 3  
toxicities  (false 
negative rate). If the true toxicities incidence rate in a cohort is 5% rather than 20%, then there is 14% chance that 
there will be at least 4 toxicities in 40 subjects (false positive rate).
In 2 daratumumab monotherapy  studies in relapsed/refractory MM patients, including a Phase 1/2 dose  escalation 
study (GEN501)iin patients with at least 2 lines of prior therapy and a Phase 2 study (SIRIUS)
iiin patients with at 
least 3 lines of prior therapy, the ORR were 36% and 29.2% respectively.
In  
two  combination  studies  
in  
relapsed/refractory  MM  patients  with  at  
least  2  
lines  of  prior  
therapy,  
including  a 
Phase  1b  study  of  daratumumab  
in  combination  with  pomalidomide and  dexamethasone iiiand  a  Phase  1  dose-
escalation study of pembrolizumab in combination with lenalidomide and dexamethasone,ivthe ORR were 60%.
Table 8.1-1 summarizes the 95% exact CI for the target ORRs ranging from 30% to 80% with sample size of 20 or 
40 in a cohort. At observed ORR ≥ 55% with 20 subjects,  
the lower bound of the 95% CI is 31.5%. At observed 
ORR≥ 77.5% with 40 subjects, the lower bound of the 95% CI is 61.5%.
Table 8.1-2 summarizes the 95% exact CI for the target MRD-target negativity rates ranging from 10% to 30% with
sample size of 20 or 40 in a cohort. At observed MRD-target negativity rates ≥ 30% with 20 subjects and observed 
MRD-target  negativity  rates ≥ 20%  with  40  subjects,  the  lower  bound  of  the  95%  CI  are  11.9%  and  9.1% 
respectively  compares favorably to historical MRD-target negativity rate of 8% in recurrent pretreated relapsed or 
refractory MM.
Endpoints:
Safety:
The  primary  objective  
is  
to  characterize  
the  safety  and  
tolerability  of  nivolumab  and  daratumumab.  The  primary 
objective will be measured by:
• Number and percent of subjects that experience drug-related grade 3-4 AEs occurring up to 100 days after the 
last dose of study drug. [Time Frame - On a continuous basis up to 100 days after the last dose of study drug];
• Number and percent of subjects that experience drug-related grade 3-4 SAEs occurring up to 100 days after the 
last dose of study drug. [Time Frame - On a continuous basis up to 100 days after the last dose of study drug];
• Number  and  percent  of  subjects  with  clinical  laboratory  abnormalities  by  worst  toxicity  grade  by 
NCI CTCAE version 4.0 (as assessed at the planned times listed in Section 5.1). [Time Frame - On a continuous 
basis up to 100 days after the last dose of study drug].
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3.4.1.4 Guidelines for Management of Daratumumab-Related Infusion 
Reactions
 ...............................................................................................
 
3.4.1.5 Surgery and Radiation 
.................................................................... 
3.4.2 Other Restrictions and Precautions 
......................................................... 
3.4.2.1 Treatment of Infusion Reactions 
..................................................... 
3.4.2.2 Guidelines for Nivolumab-related Infusion Reactions ................... 
3.5 Discontinuation of Subjects from Treatment 
.................................................... 
3.5.1 Additional Discontinuation Criteria - Nivolumab/Daratumumab Cohorts
.....................................................................................................................
3.6 Post Study Drug Follow-up in Nivolumab/Daratumumab Cohorts (Cohorts A 
and B) 
................................................................................................................ 
3.6.1 Withdrawal of Consent ............................................................................ 
3.6.2 Lost to Follow-Up 
.................................................................................... 
4 TREATMENTS 
......................................................................................................... 
4.1 Study Treatments - Nivolumab/Daratumumab Cohorts 
................................... 
4.1.1 Investigational Product 
............................................................................ 
4.1.1.1 Nivolumab in the Nivolumab/Daratumumab Cohorts 
.................... 
4.1.1.2 Daratumumab 
................................................................................. 
4.1.2 Noninvestigational Product 
..................................................................... 
4.1.2.1 Pomalidomide 
................................................................................. 
4.1.2.2 Dexamethasone 
............................................................................... 
4.1.3 Study Drug Storage, Preparation and Administration 
............................ 
4.1.4 Selection and Timing of Dose for Each Subject....................................... 
4.1.4.1 Nivolumab 
....................................................................................... 
4.1.4.2 Daratumumab 
................................................................................. 
4.1.4.3 Pomalidomide in the ND-Pd Cohort (Cohort A) 
............................ 
4.1.4.4 Dexamethasone in the ND-Pd Cohort (Cohort A) 
.......................... 
4.1.5 Dose Delay, Interruption, or Discontinuation 
......................................... 
4.1.5.1 Nivolumab 
....................................................................................... 
4.1.5.2 Daratumumab 
................................................................................. 
4.1.5.3 Pomalidomide 
................................................................................. 
4.1.5.4 Dexamethasone 
............................................................................... 
4.1.6 Recommended Dose Reductions for Nivolumab/Daratumumab Cohorts 
4.1.7 Treatment During Follow-up 
................................................................... 
4.2 Method of Assigning Subject Identification 
..................................................... 
4.3 Blinding/Unblinding 
......................................................................................... 
4.4 Treatment Compliance 
...................................................................................... 
4.5 Destruction and Return of Study Drug 
............................................................. 
4.5.1 Destruction of Study Drug 
....................................................................... 
4.5.2 Return of Study Drug 
............................................................................... 
5 STUDY ASSESSMENTS AND PROCEDURES 
..................................................... 
5.1 Flow Chart/Time and Events Schedule Daratumumab/Nivolumab Cohorts 
.... 
5.2 Study Materials 
................................................................................................. 
5.3 Safety Assessments 
........................................................................................... 
5.3.1 Laboratory Assessments........................................................................... 
5.4 Efficacy Assessments 
........................................................................................ 
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Clinical Protocol
BMS-936558
CA209039
Nivolumab
Revised Protocol No.: 15
Date: 23-Apr-2019
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Clinical Protocol
CA209039
BMS-936558
Nivolumab
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 
ETHICAL CONSIDERATIONS
2.1 
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonization (ICH) and in accordance with the ethical principles 
underlying  European  Union  Directive  2001/20/EC  and  the  United  States  Code  of  Federal 
Regulations, Title 21, Part 50 (21CFR50).
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and  the  subject  informed  consent  will  receive  Institutional  Review  Board/Independent  Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All  potential  serious  breaches  must  be  reported  to  BMS  immediately.  A serious  breach  is  a 
breach  of  
the  conditions  and  principles  of  GCP  in  connection  with  
the  study  or  
the  protocol, 
which is likely to affect, to a significant degree, the safety or physical or mental integrity of the 
subjects of the study or the scientific value of the study.
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Clinical Protocol
CA209039
BMS-936558
Nivolumab
Personnel  involved  in  conducting  this  study  will  be  qualified  by  education,  training,  and 
experience to perform their respective tasks.
This  study  will  not  use  
the  services  of  study  personnel  where  sanctions  have  been  
invoked  or 
where there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
2.2 
Institutional Review Board/Independent Ethics Committee 
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from  the  IRB/IEC  for  the  protocol,  consent  form,  subject  recruitment  materials 
(eg, advertisements),  and  any  other  written  information  to  be  provided  to  subjects.  The 
investigator or BMS should also provide the IRB/IEC with a copy of the Investigator Brochure 
or product labeling information to be provided to subjects and any updates. 
The  investigator  or  BMS  should  provide  the  IRB/IEC  with  reports,  updates  and  other 
information (eg, expedited safety reports, amendments, and administrative  
letters) according to 
regulatory requirements or institution procedures.
2.3 
Informed Consent
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given to subjects, their legally acceptable representatives 
are  clearly  and  fully  informed  about  the  purpose,  potential  risks,  and  other  critical  issues 
regarding clinical studies in which the subject volunteers to participate. 
BMS  will provide  
the  investigator  with  an  appropriate  (ie, Global  or  Local)  sample  informed 
consent  
form  which  will  
include  all  elements  
required  by  
ICH,  GCP  and  applicable  
regulatory 
requirements. The sample informed consent form will  adhere to the ethical principles that have 
their origin in the Declaration of Helsinki.
Investigators must:
1) Provide a copy of the consent form and written information about the study in the language 
in  which  the  subject  is  most  proficient  prior  to  clinical  study  participation.  The  language 
must be non-technical and easily understood. 
2) Allow  time  necessary  for  subject  or  subject
's  legally  acceptable  representative  to  inquire 
about the details of the study.
3) Obtain  an  informed  consent  signed  and  personally  dated  by  the  subject  or  the  subject
's 
legally  acceptable  representative  and  by  the  person  who  conducted  the  informed  consent 
discussion. 
4) Obtain  the  IRB/IEC’s  written  approval/favorable  opinion  of  the  written  informed  consent 
form and any other information to be provided to the subjects, prior to the beginning of the 
study, and after any revisions are completed for new information.
5) If informed consent is initially given by a subject’s legally acceptable representative or legal 
guardian, and the subject subsequently  becomes  capable of  making and communicating  his 
Revised Protocol No.: 15
Date: 23-Apr-2019
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or  her  informed  consent  during  
the  study,  consent  must  additionally  be  obtained from  
the 
subject.
6) Revise the informed consent whenever important new information becomes available that is 
relevant to the subject
's consent. The investigator, or a person designated by the investigator, 
should  fully  inform  the  subject  or  the  subject
's  legally  acceptable  representative  or  legal 
guardian, of all pertinent aspects of the study and of any new information  relevant  
to  
the 
subject
's  willingness  
to  continue  participation  
in  
the  study.  This  communication  should  be 
documented. 
The  confidentiality  of  records  that  could  identify  subjects  must  be  protected,  respecting  the 
privacy and confidentiality rules applicable to regulatory requirements, the subjects
' signed ICF 
and, in the US, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to subject records. 
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
3 
INVESTIGATIONAL PLAN
3.1 
Study Design and Duration
This is a Phase 1/2, open-label, multicenter, study of nivolumab, a fully human monoclonal IgG4 
antibody targeting the PD-1 membrane receptor on T cells. 
NIVOLUMAB/DARATUMUMAB COHORTS
Combination  cohorts  will  evaluate  the  combination  of  nivolumab and  daratumumab  in 
relapsed/refractory MM patients. 
Per Revised Protocol 14, Cohort A is closed to enrollment. Patients who are already on treatment 
in this cohort will continue to receive study treatment as long as they derive clinical benefit and 
do not meet the protocol defined criteria for discontinuation (Section 4.1.5). See Figure 3.1-1.
Cohort B (ND, D) has been added to the study and is open to enrollment. See Figure 3.1-2.
The study will consist of Screening (up to 28 days), Treatment (until disease progression), and 
Follow-up. 
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Figure 3.1-1: 
Study Design for Cohort A (ND ±Pd)Cohort A is closed for enrollment 
per Revised Protocol 14
Study Population:
Multiple Myeloma
Randomization 1:1
ND-Pd regimen: Multiple myeloma 
Each cycle is 28 days
Nivolumab:
Cycle 1: 240 mg iv Day 15
Cycle 2-6: 240 mg iv Days 1, 15 
Cycle 7 & beyond: 480 mg iv Day 1
Daratumumab:
Cycle 1-2: 16 mg/kg iv Days 1, 8, 15, 22
Cycle 3-6: 16 mg/kg iv Days 1, 15
Cycle 7 & beyond: 16 mg/kg iv Day 1
Pomalidomide:
4 mg po daily (Days 1-21) of each 28-day cycle
Dexamethasone:
Weeks without daratumumab dosing
40  mg  po  per  day  
(Days  1,  8,  15,  22)  of  each 
28-day cycle for subjects ≤75 years old 
20  mg  po  per  day  
(Days  1,  8,  15,  22)  of  each 
28-day cycle for subjects > 75 years old 
ND regimen: Multiple myeloma 
Each cycle is 28 days
Nivolumab:
Cycle 1: 240 mg iv Day 15
Cycle 2-6: 240 mg iv Days 1, 15 
Cycle 7 & beyond: 480 mg iv Day 1
Daratumumab:
Cycle 1-2: 16 mg/kg iv Days 1, 8, 15, 22
Cycle 3-6: 16 mg/kg iv Days 1, 15
Cycle 7 & beyond: 16 mg/kg iv Day 1
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Figure 3.1-2: 
Study Design for Cohort B (ND and D) Cohort B is open for enrollment 
per Revised Protocol 14.
* Split dosing is available for Cycle 1 Day 1. See Section 4.1.1.2.
Dosing schematics for the nivolumab/daratumumab cohorts are provided in Appendix 6.
Approximately  60  eligible  MM subjects  will  beenrolled  
in Cohort  B  
(ND  and  D)  and  will  be 
randomized in a 2:1 ratio in favor of the ND regimen. Subjects will continue treatment as long as 
the  subject  has  clinical  benefit  from  the  treatment  and  does  not  meet  criteria  for  treatment 
discontinuation. 
All  AE data will  be  monitored on an ongoing basis for safety. Stopping rules for toxicity in the 
nivolumab-daratumumab arm are specified in Section 3.1.1.1.
For  assessment  of  MRD  by  molecular  and  cytometry  approaches  
to detect  disease  
in  
the  bone 
marrow,  all MM  subjects  will  require  bone  marrow  aspirates at  the  time points  described  in
Table 5.1-6.
Bone  marrow  and  peripheral  blood  samples  are  also  needed  to  better  understand  how  the 
immune  microenvironment  may  contribute  to  immune  evasion,  the  progression  of  multiple 
myeloma,  and  potential  synergies  between  nivolumab  and  daratumumab.  Bone  marrow  from 
every  harvest  should  also  be  submitted  
for  biomarker  analysis, as  described in Table  5.1-6.  At 
the  time  of  the  scheduled  bone  marrow  aspirate,  the  PI  will  determine  if  there  have  been 
significant  changes  in  the  clinical  course  to  suggest  that  subjects  can  no  longer  undergo  the 
procedure safely. Similarly, the PI will determine if there have been significant changes in
the clinical course to suggest that subjects can no longer safely undergo the additional 
peripheral blood collection for biomarkers assessments. These subjects may continue therapy.
Clinical  
response  will  be  assessed  based  on  
the  modified  
IMWG  criteria  based  on  serum  and 
urine  laboratory  assessments  every  4  weeks  from  Cycle  1  Day  1  until  disease  progression, 
Study Population: Multiple myeloma
ND - D Mono Cohort B
Randomization 2:1 N= ~60
ND regimen: Multiple myeloma (N= 40)
Each cycle is 28 days
Nivolumab:
Cycle 1: 240 mg iv Day 15
Cycle 2 & beyond: 480 mg iv Day 1
Daratumumab:
Cycle 1*-2: 16 mg/kg iv Days 1, 8, 15, 22
Cycle 3-6: 16 mg/kg iv Days 1, 15
Cycle 7 & beyond: 16 mg/kg iv Day 1
D Mono regimen: Multiple myeloma (N= 
20)
Each cycle is 28 days
Daratumumab:
Cycle 1*-2: 16 mg/kg iv Days 1, 8, 15, 22
Cycle 3-6: 16 mg/kg iv Days 1, 15
Cycle 7 & beyond: 16 mg/kg iv Day 1
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irrespective  of  dose  delays  or  treatment  interruptions.  All  response  (≥PR)  and  progression 
categories  require  2  consecutive  laboratory  assessments  to  confirm  response  or  progression 
before  initiation  of  any  new  therapy.  If  progression  is  confirmed  at  the  second  laboratory 
assessment, all study treatment will be discontinued. 
To  assess potential  daratumumab  and  nivolumab  interference  with serum  M  protein 
quantification,  samples  may  be  analyzed to  distinguish  daratumumab  and  nivolumab  from 
endogenous myeloma protein (M protein).
Subjects  who  experience  AEs  
that  
require  discontinuation  of  daratumumab  may  be  allowed  
to 
continue therapy with nivolumab (if randomized to the ND arm), with or without pomalidomide 
and dexamethasone, (if randomized to the NDPd arm) if deemed in their best interest by both the 
PI and the BMS medical monitor. Subjects must be deriving clinical benefit.
Subjects  who  experience  AEs  that  require  discontinuation  of  nivolumab  may  be  allowed  to 
continue therapy with daratumumab (if randomized to ND arm), with or without pomalidomide 
and dexamethasone, (if randomized to NDPd arm), if deemed in their best interest by both the PI 
and the BMS medical monitor. Subjects must be deriving clinical benefit.
Subjects who experience AEs that require discontinuation of nivolumab and daratumumab in the 
ND-Pd  cohort  may  be  allowed  
to  continue  
therapy  with  pomalidomide  and  dexamethasone,  
if 
deemed  
in  
their  best  
interest  by  both  
the  PI  and  
the  BMS  medical  monitor.  Subjects  must  be 
deriving clinical benefit.
Subjects  who  experience  AEs  that  require  discontinuation  or  delay  of  pomalidomide  in  the 
ND-Pd  cohort  may  be  allowed  to  continue  therapy  with  nivolumab,  daratumumab,  and 
dexamethasone,  
if  deemed  
in  
their  best  
interest  by  both  
the  PI and  
the  BMS  medical  monitor. 
Subjects must be deriving clinical benefit.
Subjects  who  experience  AEs  that  require  discontinuation  or  delay  of  dexamethasone  in  the 
ND-Pd  cohort  may  be  allowed  to  continue  therapy  with  nivolumab,  daratumumab,  and 
pomalidomide,  
if  deemed  
in  
their  best  
interest  by  both  
the  PI  and  
the  BMS  medical  monitor. 
Subjects must be deriving clinical benefit.
3.1.1 
Stopping Rules
3.1.1.1 
Stopping Rules for Toxicity in the ND Arm
The ND arm will be stopped if any of the following safety events are observed:
• Grade ≥ 3 nivolumab  
immune-related adverse events: ≥10% occurrence  
in the first 50% of 
treated patients 
• Grade 5 adverse events, excluding those due to disease progression, cumulative rate: ≥20% 
occurrence in the first 50% of treated patients. 
3.2 
Post Study Access to Therapy
At  
the  conclusion  of  
the  study,  subjects  who  continue  
to  demonstrate  clinical  benefit  will  be 
eligible  to  receive  study  drug.  Study  drug  will  be provided  via  an  extension  of  the  study,  a 
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rollover  study  requiring  approval  by  responsible  health  authority  and  ethics  committee  or 
through another mechanism at the discretion of BMS. BMS reserves the right to terminate access 
to  study  drug  if  any  of  the  following  occur:  a) the  marketing  application  is  rejected  by 
responsible health authority; b) the study is terminated due to safety concerns; c) the subject can 
obtain  medication  from  a  government  sponsored  or  private  health program;  or  d) therapeutic 
alternatives become available in the local market.
3.3 
Study Population
For entry into the study, the following criteria MUST be met.
3.3.1 
Inclusion Criteria
1. Signed Written Informed Consent
a) Voluntary  signed  and  dated  IRB/IEC  approved  written  informed consent  form  in 
accordance with regulatory and institutional guidelines. This must be obtained before the 
performance of any protocol related procedures that are not a part of standard of care
2. Target Population
a) ECOG Performance of 0 or 1. (See Appendix 1)
b) Not applicable per Revised Protocol 14.
c) Not applicable per Revised Protocol 14.
d) Not applicable per Revised Protocol 14.
e) Subjects must meet the following:
i) Must  have  measurable disease  as  measured  by  presence  of  monoclonal 
immunoglobulin  protein  in  a  serum  electrophoresis:  IgG,  IgA,  IgM,  (M-protein 
≥0.5 g/dl),  OR  urine  M-protein ≥200  mg/24-hour  collection  sample,  OR  involved 
serum free-light chain (sFLC)≥100 mg/L provided FLC ratio is abnormal
ii) Must have corrected serum calcium < 11.5 mg/dL within 2 weeks of randomization 
iii) Must consent to bone marrow aspirate or biopsy. 
iv) Must be at least 14 days from use of prior anti-myeloma therapy (approved therapies), 
and at least 28 days or 5 half-lives, whichever is longer, from use of any experimental 
drug therapy or plasmapheresis. Bisphosphonates use is permitted if initiated prior to 
the first dose of study medication.
v) Must be more than 12 weeks post autologous transplant
vi) Not applicable per Revised Protocol 14
vii) Not applicable per Revised Protocol 14
viii) Not applicable per Revised Protocol 14
(1) Not applicable per Revised Protocol 13
(2) Not applicable per Revised Protocol 13
ix) No applicable per Revised Protocol 14
x) Must meet one of the criteria below:
(1) Subject  has  received  at  least  3  prior  lines  of  therapy  including  a  proteasome 
inhibitor [PI] and an immunomodulatory agent [IMiD] 
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       OR
(2) Subject has disease that is double refractory to a PI and an IMiD*
* NOTE:  Refractory  is  defined  as  disease  progression  on  or  within  60  days  of 
treatment with a PI and an IMiD, given in the same or different lines of therapy. 
f) Not applicable per Revised Protocol 14.
g) Not applicable per Revised Protocol 14.
h) Not applicable per Revised Protocol 14.
i) Not applicable per Revised Protocol 14.
j) Prior palliative radiation must have been completed at least 2 weeks prior to study Day 1
k) Toxicities  related  to  prior  therapy  must  have  returned  to  Grade 1  or  less,  except  for 
alopecia. Peripheral neuropathy must be Grade 1 or less.
l) Adequate bone marrow function defined as:
i) Absolute  neutrophil  count ≥1000/μl (no growth factor within 1 week of study drug 
administration;  no  pegylated  growth  factors  within  3  weeks  of  first  drug 
administration)
ii) Hemoglobin ≥8 g/dL. No transfusions are allowed within 72 hours prior to qualifying 
laboratory value. Recombinant human erythropoietin not permitted within 3 weeks of 
study drug administration.
iii) Platelet  count ≥75 X 103/μl  or  >  30  x  10
3/μL  
if ≥50%  of  bone  marrow  nucleated 
cells  were  plasma  cells.  Qualifying laboratory  value  must  occur  at  
the  most  recent 
measurement  prior  
to  study  entry.  No  
transfusion  
to  achieve  
this  
level  
is  permitted
within 72 hours prior to qualifying laboratory value.
m) Adequate renal parameters defined as:
i) Creatinine  clearance  (CrCl)≥30  ml/min  measured  by  24-hour  urine  collection  or 
estimated by the Cockcroft-Gault formula
ii) Adequate hepatic parameters defined as:
(1) AST <3 x ULN
(2) ALT <3 x ULN
(3) Bilirubin ≤1.5 x ULN (except subjects with Gilbert’s Syndrome, who must have 
a total bilirubin < 3.0 mg/dL and direct bilirubin < 0.5 mg/dL
n) Ability  to  comply  with  treatment,  PK,  and immune-monitoring  sample  collection 
(when indicated) and required study follow up
o) Not applicable per Protocol Amendment 12.
p) Not applicable per Revised Protocol 14
q) Not applicable per Revised Protocol 14
r) Not applicable per Revised Protocol 14
s) Not applicable per Revised Protocol 14
t) Not applicable per Revised Protocol 14
u) Not applicable per Revised Protocol 14
v) Not applicable per Revised Protocol 13
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3. Age and Reproductive Status
a) (See Section 3.3.3for the definition of WOCBP) Men and women ≥18 years of age
b) Women  of  childbearing  potential  (WOCBP)  must  agree  to  follow instructions  for 
method(s) of contraception from the time of enrollment through the duration of treatment 
with  study  drug  plus  5  months  after  the  last  dose  of  investigational  product. (See 
Appendix 4for birth control instructions)
c) Women  of  childbearing  potential  (WOCBP)  must  have  2 negative  serum  or  urine 
pregnancy  tests (minimum  sensitivity  25 IU/L  or  equivalent  units of  HCG):  one 
10-14 days prior to start of the study drug, and another within 24 hours prior to the start 
of study drug.
d) Women must not be breastfeeding
e) Sexually active  
fertile  men who are sexually active with  WOCBP  must agree to follow 
instructions for method(s) of contraception for the duration of treatment with study drug
plus 7 months after the last dose of investigational product.
f) Azoospermic  males  and  WOCBP  who  are  not  heterosexually  active are exempt from 
contraceptive  requirements.  However  they  must  still undergo  pregnancy  testing  as 
described in this section.
g) Not applicable per Revised Protocol 14.
4. Not applicable per Revised Protocol 14.
Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on 
the  importance  of  pregnancy  prevention  and  the  implications  of an  unexpected  pregnancy 
Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on 
the use of highly effective methods of contraception. Highly effective methods of contraception 
have a failure rate of < 1% when used consistently and correctly. At a minimum, subjects must 
agree to the use of two methods of contraception, with one method being highly effective and the 
other  method  being  either  highly  effective  or  less  effective  as  listed  in  the  informed  consent 
document.
3.3.2 
Exclusion Criteria
1. Target Disease Exceptions
a) Not applicable per Revised Protocol 14
b) Subjects  with  a  history  of  central  nervous  system  involvement  by  hematologic 
malignancy or symptoms suggestive of central nervous system involvement
c) Not applicable per Revised Protocol 14
d) Not applicable per Revised Protocol 14
e) Subjects are excluded if they have:
i) Solitary  bone  or  extramedullary plasmacytoma  as  
the  only  evidence  of  plasma  cell 
dyscrasia
ii) Monoclonal  gammopathy  of  undetermined  significance  (MGUS),  smoldering 
multiple myeloma (SMM), primary amyloidosis, Waldenstrom’s macroglobulinemia, 
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or  POEMS  syndrome  (plasma  cell  dyscrasia  with  poly  neuropathy, organomegaly, 
endocrinopathy, monoclonal protein, and skin changes)
iii) Active plasma cell leukemia (defined as either 20% of peripheral blood white blood 
cell count comprised of plasma/CD138+ cells or an absolute plasma cell count of 2 x 
109/L)
2. Medical History and Concurrent Diseases
a) Subjects  with  concomitant  second  malignancies  (except adequately  treated 
non-melanomatous skin cancers, melanoma in situ surgically resected, carcinoma in situ 
of  
the  breast,  superficial  bladder  cancer,  prostate cancer  or  
in  situ  cervical  cancers)  are 
excluded unless a complete remission was achieved as it is empirically determined based 
on the malignancy and treatment provided prior to study entry and no additional therapy 
is required or anticipated to be required during the study period
b) Subjects with an active, known, or suspected autoimmune disease. Subjects with type I 
diabetes  mellitus,  hypothyroidism only  requiring  hormone  replacement,  skin  disorders
(such  as  vitiligo,  psoriasis,  or  alopecia)  not  
requiring  systemic  
treatment,  or  conditions 
not expected to recur in the absence of an external trigger are permitted to enroll.
c) A  serious  uncontrolled  medical  disorder  or  active  infection  which  would  impair  the 
ability of the subject to receive protocol therapy or whose control may be jeopardized by 
the complications of this therapy
d) Deep vein thrombosis not adequately controlled
e) Uncontrolled or significant cardiovascular disease including, but not limited to any of the 
following:
i) myocardial infarction or stroke/TIA within the past 12 months
ii) unstable or poorly controlled angina within the past 3 months
iii) any  history  of clinically  significant  arrhythmias  (such as ventricular  tachycardia, 
ventricular fibrillation or torsades de pointes)
iv) QTc prolongation > 480 msec
v) history  of  other  clinically  significant  heart  disease  (ie, cardiomyopathy,  congestive 
heart  failure  with  NYHA  functional  classification  III-IV,  pericarditis,  significant 
pericardial effusion)
vi) requirement for daily supplemental oxygen therapy
f) Prior  therapy  with  an  anti-PD-1,  anti-PD-L1,  anti-PD-L2,  anti-CD137  or  anti CTLA-4 
antibody  (or  any  other  antibody  or  drug  specifically  targeting T-cell  costimulation  or 
checkpoint pathways). 
g) Not applicable per Revised Protocol 07
h) Not applicable per Revised Protocol 011
i) Prior organ allograft or allogeneic bone marrow transplantation
j) Any of the following: 
i) Prior treatment with anti CD38 monoclonal antibodies.
ii) Not applicable per Revised Protocol 14
iii) Not applicable per Revised Protocol 14
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iv) Treatment with corticosteroids within 2 weeks of the first dose of study drug, except 
for the equivalent of ≤10  mg prednisone per day or corticosteroids with  minimal to 
no systemic absorption (ie, topical or inhaled steroids) or for short course (≤4 days) 
of 40 mg dexamethasone or equivalent for emergency use (baseline M proteins must 
be  drawn  after  
this  short  course  and  prior  to  randomization).  Adrenal  replacement 
steroid  doses  >  10  mg  daily  prednisone  equivalent,  are  permitted  
in  
the  absence  of 
active autoimmune disease
v) Major cardiac  surgery within 8 weeks prior to the  
first dose of study drug; all other 
major  surgery  within  4  weeks  prior to the  
first  study  drug  dose.  Kyphoplasty  
is  not 
considered  major  surgery;  subjects  should  have  been  fully  recovered  from  any 
surgical related toxicities
vi) Known chronic obstructive pulmonary disease (COPD) with a forced expiratory 
volume in 1 second (FEV1) <50% of predicted normal.
vii)Known moderate or severe persistent asthma within the past 2 years, or uncontrolled 
asthma of any classification. Subjects who currently have controlled intermittent 
asthma or controlled mild persistent asthma are allowed to participate in the study.
k) Vaccination  with  live  attenuated  vaccines  within  4  weeks  of  first  study  agent 
administration
3. Physical and Laboratory Test Findings
a) Positive  
for  human  
immunodeficiency  virus  
(HIV  1/2)  antibody (may  obtain  additional 
testing  or  substitute  
testing  per  
institutional  guidelines  
to  
rule  out  
infection),  or  known 
acquired immunodeficiency syndrome (AIDS)
b) Not applicable per Revised Protocol 15.
c) Not applicable per Revised Protocol 14.
d) Seropositive  for  hepatitis  B  (defined  by  a  positive  test  for hepatitis  B  surface  antigen 
[HBsAg]).  Subjects  with  resolved  infection  (ie,  subjects  who  are  HBsAg  negative  but 
positive for antibodies to hepatitis B core antigen [antiHBc] and/or antibodies to hepatitis 
B surface antigen [antiHBs]) must be screened using real-time polymerase chain reaction 
(PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive 
will  be  excluded.  EXCEPTION:  Subjects  with  serologic  findings  suggestive  of  HBV 
vaccination  
(antiHBs  positivity  as  
the  only  serologic  marker)  AND  a  known  history  of 
prior HBV vaccination, do not need to be tested for HBV DNA by PCR.
e) Seropositive  for  hepatitis  C  (except  in  the  setting  of  a  sustained  virologic  response 
[SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy).
4. Allergies and Adverse Drug Reaction
a) History of Grade 4 anaphylactic reaction to monoclonal antibody therapy
b) Not applicable per Revised Protocol 15.
c) History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins
d) Known  hypersensitivity or  allergy  
to  biopharmaceuticals  produced  in  Chinese  hamster 
ovary cells or any component of the daratumumab formulation.
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5. Not Applicable per Revised Protocol 11. 
6. Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
subjects and that the results of the study can be used. It is imperative that subjects fully meet all 
eligibility criteria. No exception to the entry criteria is permitted.
3.3.3 
Women of Childbearing Potential
Women of childbearing potential (WOCBP) include any female who has experienced menarche 
and  who  has  not  undergone  successful  surgical  sterilization  (hysterectomy,  bilateral  tubal 
ligation,  or  bilateral oophorectomy),  and  who  
is  not  postmenopausal.  Menopause  
is  defined  as 
12 months  of  amenorrhea  
in  a  woman  over  age  45  years  
in  
the  absence of other biological or 
physiological causes. In addition, females under the age of 55 years must have a serum follicle 
stimulating hormone, (FSH) level > 40 mIU/mL to confirm menopause.
*Females  treated  with hormone  replacement  therapy,  (HRT)  are  likely  to  have  artificially 
suppressed  FSH  
levels and  may require a washout period  
in order to obtain a physiologic  FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration of 
the  washout  period  below  are  suggested  guidelines  and  the  investigators  should  use  their 
judgement in checking serum FSH levels.
• 1 week minimum for vaginal hormonal products (rings, creams, gels)
• 4 week minimum for transdermal products
• 8 week minimum for oral products
Other parenteral products may require washout periods as  
long as 6  months. If the serum  FSH 
level  is  >  40  mIU/ml  at  any  time  during  the  washout  period,  the  woman  can  be  considered 
postmenopausal.
3.4 
Concomitant Treatments
Subjects  are  permitted  the  use  of  topical,  ocular,  intranasal, intra-articular,  and  inhalational 
corticosteroids  (with  minimal  systemic  absorption).  Immunosuppressive  doses  (eg,  prednisone 
> 10 mg/day  or  equivalent)  and/or  physiologic  replacement  doses  of  systemic  corticosteroids 
(eg, prednisone  10  mg/day)  are  permitted  in  the  context  of  treating  AEs.  A  brief  (less  than 
3 weeks) course of corticosteroids  
for prophylaxis (eg, contrast dye allergy) or for treatment of 
non-autoimmune  conditions  (eg,  delayed-type  hypersensitivity  reaction  caused  by  a  contact 
allergen) is permitted.
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3.4.1 
Nivolumab/Daratumumab Cohorts: Concomitant Treatments
3.4.1.1 
Prohibited and/or Restricted Treatments  
Any  systemic,  anti-myeloma  therapy  other  than  the  study  drugs  is  prohibited while  on  study 
therapy. Concomitant steroids, other than weekly dexamethasone within the ND-Pd regimen, or 
steroids as pre- and post-infusion medication for daratumumab infusions, or steroids allowed (as 
defined  in  eligibility  criteria  in Section  3.3.2)  are  prohibited  unless  used  to  treat  an  AE. 
Guidelines  
for  selection  and  use  of  other  concomitant medications  should  be  derived  
from  
the 
daratumumab, pomalidomide, and dexamethasone prescribing information.
Avoid  co-administration  of  pomalidomide  with  strong  
inhibitors of  CYP1A2  unless  medically 
necessary. Co-administration of pomalidomide with drugs that are strong inhibitors of CYP1A2 
(eg, ciprofloxacin, enoxacin and fluvoxamine) and CYP3A4/5 (eg, ketoconazole) or P-gp could 
increase  pomalidomide  exposure  and  should  be  avoided,  unless  medically  necessary.100Other 
than study medications, administration of any therapeutic or diagnostic investigational agent (for 
any indication) is prohibited while on study therapy without prior Sponsor approval.
Immunosuppressive agents are prohibited (unless utilized to treat drug-related AEs).
3.4.1.2 
Required Treatment
Subjects  must  
receive  antibiotic  prophylaxis,  per  
institutional  guidelines  or  PI  discretion.  
(See 
note in Section 3.4.1.1regarding certain classes of antibiotics.)
Subjects  must  receive  pre-infusion  and  post-infusion  medications  (Section  4.1.4.2)  with  each 
dose  of  daratumumab,  per  the  currently  approved  (USPI)/pharmacy  reference  manual (See 
Section 3.4.1.4).
98
All  MM  subjects  receiving  daratumumab  are  required  to  initiate oral  antiviral  prophylaxis  to 
prevent herpes zoster reactivation within 1 week of starting treatment and continue for 3 months 
following treatment, per the currently approved (USPI)/pharmacy reference manual.
98
In all MM subjects receiving daratumumab, Pneumocystis carinii pneumonia (PCP) prophylaxis 
should be considered, as per institutional guidelines.
In  all  MM  subjects  receiving  daratumumab,  dexamethasone  and  other  steroids  may  induce 
gastritis. Medications to prevent gastritis are permitted per institutional guidelines,  
for example 
proton  pump  
inhibitors  
(omeprazole  or  equivalent)  or  sucralfate,  or  H2  blockers  
(ranitidine  or 
equivalent).
MM  subjects  receiving  pomalidomide  in  the  ND-Pd  arm must  receive  thromboembolic 
prophylaxis,  per  institutional  guidelines  or  PI  discretion.  Examples  of  commonly  used 
thrombo-embolic  prophylaxis  medications  include  aspirin,  low  molecular  weight  heparin,  and 
vitamin K antagonists.
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3.4.1.3 
Permitted at Investigator Discretion
IV  or  inhaled  corticosteroids,  diphenhydramine,  acetaminophen/ paracetamol,  leukotriene 
inhibitors (montelukast sodium), or long-acting bronchodilators for the management of infusion 
reactions.  Additional  supportive  measures  should  be  provided  as  indicated  including  the 
following:
• oxygen inhalation
• epinephrine
• oral antiviral and antimicrobial prophylaxis
• prophylactic anti-emetics
• Prevention  of  constipation  (eg,  adequate  hydration,  high-fiber diet,  and  stool  softeners  if 
needed)
• Colony stimulating factors, erythropoietin, and transfusion of platelets and red blood cells
• bisphosphonates
• antivirals
• Loperamide  
is  
recommended  for  
the  
treatment  of  diarrhea,  starting  at  
the  
time  of  
the  first 
watery  stool.  The  loperamide  dose  and  regimen  is  according  to  institutional  guidelines. 
Prophylactic loperamide is not recommended.
• Adequate hydration is recommended for prevention of myeloma-related kidney disease
• Vaccines with inactive virus
Per  the  ASCO  2007  Clinical Practice  Guidelines,101 bisphosphonate  therapy  should  be 
administered for a period of 2 years in MM subjects. At 2 years, the investigator should seriously 
consider discontinuing bisphosphonates in subjects with at least stable disease, although further 
use is at the discretion of the investigator.
Routine  clinical  practice  for  monitoring  and  prevention  of  osteonecrosis  of  the  jaw 
(ie, comprehensive dental exam, treating active oral infections, eliminating sites of high risks for 
oral  infection,  excellent  oral  hygiene  and  avoiding  invasive  dental  procedures  while  on 
treatment) must be followed.
• Erythropoietin (EPO) or erythropoiesis stimulating agents (prior and ongoing use according 
to the package insert and institutional guidelines)
• Red blood cell or platelet transfusion
• Prophylactic administration of G-CSF for neutropenic subjects or therapeutic use in subjects 
with serious  neutropenic complications (such as tissue  
infection, sepsis syndrome or fungal 
infection) may be considered at the investigator
's discretion, consistent with 2006 American 
Society of Clinical Oncology guidelines.
For  subjects  who  are  diagnosed  with  HBV  reactivation  while  on  treatment, study  treatment 
should  be  interrupted  until  the  infection  is  adequately  controlled.  Upon  resumption  of  study 
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treatment, concomitant antiviral prophylaxis as per local standard of care should be considered.
Primary antiviral prophylaxis for HBV is permitted as per local standard of care.
3.4.1.4 
Guidelines for Management of Daratumumab-Related Infusion 
Reactions
MM  subjects  
treated  with  daratumumab  will  
receive  pre-infusion  and  post-infusion  medication 
with  each  daratumumab  infusion,  according  to  the  currently  approved  (USPI)/pharmacy 
reference manual
98(see Section 4.1.4.2). 
Management  of  daratumumab  infusion  related  reactions  should  be done  according  to  the 
currently approved (USPI)/pharmacy reference manual.98
Pre-infusion medication
On daratumumab infusion days, all subjects will receive the following medications up to 3 hours 
prior to daratumumab infusion:
• Paracetamol (acetaminophen) 650-1000 mg IV or PO
• An antihistamine (diphenhydramine 25-50  mg IV or PO, or equivalent but avoid IV use of 
promethazine) (see Appendix 8for list of antihistamines that may be used)
• A  corticosteroid:  methylprednisolone  100  mg  IV  or  PO  or  equivalent  for  Cycle  1  Day  1, 
Cycle  1  Day  2  
(split  dosing  of  daratumumab  only),  and  Cycle  1  Day  8  and  60  mg  for  all 
subsequent doses (in the absence of IRR  adverse  events  
in the  
first 2 weeks). Substitutions 
for methylprednisolone are allowed (see Appendix 8).
• Leukotriene Inhibitor (optional) on Cycle 1 Day 1: montelukast 10 mg PO, or equivalent.
If  necessary,  all  PO  pre-infusion  medications  may  be  administered  outside  of  
the  clinic  on  
the 
day of the infusion, provided they are taken within 3 hours before the infusion.
Subjects  randomized  to ND-Pd  regimen will  not  receive  any  additional  corticosteroid  as 
pre-infusion medication besides the dexamethasone dose included in the treatment regimen
(SeeSection 4.1.4.4). The dexamethasone dose should  be administered 1 hour prior to the start 
of daratumumab infusion and it can be administered prior to nivolumab infusion.
Subjects  randomized  to  ND  or  D  regimens  will receive  methylprednisolone100  mg,  or 
equivalent, administered intravenously within 1 hour of the start of daratumumab infusion. It can 
be  administered  prior  to  nivolumab  infusion.  Following  the  second  infusion,  the  dose  of 
corticosteroid may be reduced (oral or intravenous methylprednisolone 60 mg). Substitutions for 
methylprednisolone are allowed, please refer toAppendix 9.
Post-infusion Medication
For the  prevention  of  delayed  
infusion-related  
reactions, all  subjects  will receive  corticosteroid 
medication as described below. 
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Subjects randomized to the ND-Pd regimen will not receive any additional corticosteroid as 
post-infusion medication besides the dexamethasone dose included in the treatment regimen 
as specified in Section 4.1.4.4).
Subjects randomized to the ND o r   D  r e g i m e n s   will receive long- or intermediate-
acting corticosteroid (20  mg methylprednisolone orally or IV or equivalent in accordance 
with  
local  standards)on  
the  2  days  following  all  daratumumab  
infusions  
(beginning  
the  day 
after the infusion). Except for split 1stdose, please start post infusion steroid on Cycle 1 Day 
3.
In  
the  absence  of  infusion  related  AEs  after  
the  first  3  infusions,  postinfusion corticosteroids 
should be administered per investigator discretion
For  subjects  with  a  higher  
risk  of  
respiratory  complications  
(eg,  subjects  with  mild  asthma  or 
subjects with COPD who have an FEV1 <80% at screening or developed FEV1 <80% during the 
study without any medical history) the following postinfusion medications should be considered:
Antihistamine (diphenhydramine or equivalent) 
• Leukotriene inhibitor (montelukast or equivalent)
• Short-acting β2 adrenergic receptor agonist such as salbutamol aerosol 
• Control medications for lung disease (eg, inhaled corticosteroids ± long-acting β2 adrenergic 
receptor agonists for subjects with asthma; long-acting bronchodilators such as tiotropium or 
salmeterol ±inhaled corticosteroids for subjects with COPD)
In addition, these at-risk subjects may be hospitalized for monitoring for up to 2 nights after an 
infusion.  If  subjects  are  hospitalized,  then  their  spirometry  test  (FEV1)  should  be  performed 
before discharge. If these subjects are not hospitalized, then a follow up telephone call should be 
made to monitor their condition within 48 hours after all infusions. If no infusion-related reaction 
has  occurred,  the  follow-up  telephone call  48 hours  after  the  infusion  is  not  required.  If  the 
subject  has  not  experienced  a significant  medical  event  but  is  hospitalized  overnight  only  for 
observation,  then  the  hospitalization  should  not  be  reported  as  a  serious  adverse  event. 
Investigators  may  prescribe  bronchodilators,  H1-antihistamines,  and  corticosteroids  that  are 
deemed necessary to provide adequate supportive care in the event a bronchospasm occurs after 
subjects are released from the hospital/clinic. If an at-risk subject experiences no major infusion-
related  reactions,  then  these  post-infusion  medications  may  be  waived  after  4  doses  at  the 
investigator’s discretion.
Any post-infusion medication will be administered after the infusion has completed.
Management of Infusion-Related Reactions
• Subjects should be carefully observed during daratumumab infusions. Trained study staff at 
the  clinic  should  be  prepared  
to  
intervene  
in  case  of  any  
infusion  
reactions,  and  
resources 
necessary  for  resuscitation  must  be  available.  Attention  to  staffing should  be  considered 
when multiple subjects will be dosed at the same time. 
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• For infusion reactions of any grade/severity, immediately interrupt the daratumumab infusion 
and  manage  symptoms. Management of  
infusion  
reactions  may  
further require reduction  
in 
the rate of infusion, or treatment discontinuation of daratumumab.
• Grade  1-2  
(mild  
to  moderate):  Once  
reaction  symptoms  
resolve,  
resume  
the  
infusion  at  no 
more than half the rate at which the reaction occurred. If the patient does not experience any 
further reaction symptoms,  
infusion rate escalation  may resume  at  
increments and  
intervals 
as appropriate as outlined in Table 4.1.4.2-1.
• Grade  3  (severe):  Once  reaction  symptoms  resolve,  consider  restarting  the  infusion  at  no 
more  
than  half  
the  rate  at  which  
the  reaction  occurred.  If  
the subject  does  not  experience 
additional symptoms, resume infusion rate escalation at increments and intervals as outlined 
in  Table 4.1.4.2-1.  Repeat  the  procedure  above  in  the  event  of  recurrence  of  Grade  3 
symptoms.  Permanently  discontinue  daratumumab  upon  
the  
third  occurrence  of  a  Grade  3 
infusion-related reaction.
• Grade 4 (life threatening): Permanently discontinue daratumumab treatment.
3.4.1.5 
Surgery and Radiation 
Use  of  
radiotherapy  or  surgical  
intervention  must  be  
recorded  on  
the  appropriate  Case  Report 
Form. Localized radiation therapy to a site of pre-existing disease is permitted while on study.
Following  approval  by  the  medical  monitor,  the  subject  may  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 disease progression (see Appendix  3) treatment  must 
be  discontinued  for  progressive  disease  regardless  of  whether  radiation  therapy  is  initiated 
(Section 3.5).
3.4.2 
Other Restrictions and Precautions
3.4.2.1 
Treatment of Infusion Reactions
Infusion  reactions  should  be  graded  according  to  CTCAE Version 4.0  allergic 
reaction/hypersensitivity.  These  reactions  may  manifest  with  signs  and  symptoms  that  may 
include,  but  are  not  limited  to fever,  chills,  headache,  rash, pruritus,  arthralgias, hypo-or 
hypertension, bronchospasm or other symptoms. Severe infusion reactions require the immediate 
interruption  of  study  drug  therapy  and  permanent  discontinuation  from  further  treatment. 
Appropriate  medical therapy  
including epinephrine, corticosteroids,  
intravenous antihistamines, 
bronchodilators,  and  oxygen should  be  available  for  use  in  the treatment  of  such  reactions. 
Subjects should  be carefully observed until the complete resolution of all signs  and symptoms. 
Following  an  infusion  reaction,  subjects  should  be  premedicated  with  acetaminophen  and 
diphenhydramine for future treatments.
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Nivolumab contains only human immunoglobulin protein sequences, and is therefore unlikely to 
be  
immunogenic and  
induce  
infusion or hypersensitivity reactions. However,  
if such  a reaction 
were  
to occur,  
it  might  manifest  with  
fever,  chills,  
rigors, headache,  
rash,  pruritus,  arthralgias, 
hypo- or hypertension, bronchospasm, or other allergic-like reactions. All Grade 3 or 4 infusion 
reactions should be reported within 24 hours to the BMS Medical Monitor and reported as a SAE 
if  criteria are  met. Infusion reactions  should  be graded according to NCI CTCAE (version 4.0) 
guidelines.
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines, as appropriate.
3.4.2.2 
Guidelines for Nivolumab-related Infusion Reactions
For  Grade  1  symptoms:(Mild  reaction;  infusion  interruption  not  
indicated;  intervention  not 
indicated)
Remain  at  bedside  and  monitor  subject  until  recovery  from  symptoms.  The  following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg (or 
equivalent)  and/or  acetaminophen/paracetamol  325  to  1000 mg  at  least  30 minutes  before 
additional nivolumab administrations.
For  Grade  2  symptoms: (Moderate  reaction  requires  therapy  or  infusion  interruption  but 
responds promptly  to  symptomatic  treatment  [eg,  antihistamines,  non-steroidal 
anti-inflammatory  drugs,  narcotics,  corticosteroids,  bronchodilators,  IV fluids];  prophylactic 
medications indicated for ≤24 hours):
• Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat the subject with 
diphenhydramine  50  mg  IV (or  equivalent)  and/or  acetaminophen/paracetamol  325  to 
1000 mg; remain at bedside and monitor subject until resolution of symptoms. Corticosteroid 
and/or  bronchodilator  
therapy  may  also  be  administered  as  appropriate.  If  the  infusion  is 
interrupted,  
then  restart  
the  infusion  at 50%  of  the  original  infusion  rate  when  symptoms 
resolve;  if  no  further  complications  ensure  after  30  minutes,  
the  rate  may  be  increased to 
100% of the original infusion rate. Monitor subject closely. Ifsymptoms recur then no further 
nivolumab will be administered at that visit.
• For  future  infusions,  the  following prophylactic  premedications  are  recommended: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg 
should  be  administered  at  least  30 minutes  before nivolumab  infusions.  If  necessary, 
corticosteroids (up to 25 mg of hydrocortisone or equivalent) may be used.
For Grade  3  or  Grade  4  symptoms:(Severe  reaction,  Grade 3:  prolonged  [ie,  not  rapidly 
responsive  to  symptomatic  medication  and/or  brief  interruption of  infusion];  recurrence  of 
symptoms  following  initial  improvement;  hospitalization  indicated  for  other  clinical  sequelae 
[eg,  renal  impairment,  pulmonary  infiltrates].  Grade 4:  life-threatening;  pressor  or ventilatory 
support indicated):
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• Immediately discontinue  
infusion of  nivolumab. Begin  an IV  
infusion of  normal saline and 
treat  the  subject  as  follows:  Recommend  bronchodilators,  epinephrine  0.2 to 1 mg  of  a 
1:1000  solution  for  subcutaneous  administration  or  0.1  to  0.25 mg  of  a  1:10,000 solution 
injected  slowly  for  IV administration,  and/or  diphenhydramine  50mg  IV  with 
methylprednisolone 100 mg IV (or equivalent), as needed. Subject should be monitored until 
the  investigator  is  comfortable  that  the  symptoms  will  not  recur. Nivolumab  will  be 
permanently discontinued.Investigators should follow their institutional guidelines for the 
treatment  of  anaphylaxis.  Remain at  bedside  and  monitor  subject  until  recovery  from 
symptoms.
In  the  case  of  late-occurring hypersensitivity  symptoms  (e.g., appearance  of  a  localized  or 
generalized pruritus  within  1 week  after  treatment),  symptomatic  treatment  may  be  given 
(eg, oral antihistamine or corticosteroids).
3.5 
Discontinuation of Subjects from Treatment
Subjects  MUST  discontinue  investigational  product  (and  noninvestigational  product  at  the 
discretion of the investigator) for any of the following reasons:
• Withdrawal of informed consent (subject’s decision to withdraw for any reason)
• Any clinical AE, abnormal laboratory test results or intercurrent illness which, in the opinion 
of the investigator, indicates that continued participation in the study is not in the best interest 
of the subject
• Grade 3 or 4 uveitis related to nivolumab
• Pregnancy
• Termination of the study by BMS
• Loss of ability to freely provide consent through imprisonment or involuntary  
incarceration 
for treatment of either a psychiatric or physical (e.g., infectious disease) illness
• Documented  and  confirmed disease  progression  or  clinical  deterioration  while  receiving 
active study therapy
• Stopping rules as defined in Section 3.1.1.1.
• Severe nivolumab immune-mediated adverse events, as described in Appendix 5.
3.5.1 
Additional Discontinuation Criteria - Nivolumab/Daratumumab Cohorts
In addition to the criteria defined above, subjects in the nivolumab/daratumumab cohorts (Cohort 
A and B) must discontinue study treatments for any of the following reasons:
• Confirmed progressive disease according to IMWG criteria (Appendix 3).
• Subjects  who  receive  any  non-protocol  specified  systemic  anti-myeloma  therapy  before 
documented  progression  will  be  discontinued from  all  study  treatment;  however,  tumor 
assessments will continue at 4-week intervals until documented progression.
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• Subjects experiencing a Grade 4 infusion reaction related to daratumumab must discontinue 
daratumumab.  Subjects  may  continue  nivolumab with  or  without pomalidomide  and 
dexamethasone  treatment. Refer  to Section  4.1.5.2for  additional  reasons  to  discontinue 
daratumumab dosing permanently. 
• Subjects  experiencing  treatment  related  angioedema,  Grade  4  rash,  exfoliative  or  bullous 
rash, Stevens  Johnson  syndrome,  or  toxic  epidermal  necrolysis  must  discontinue 
pomalidomide and nivolumab. Subjects may continue on daratumumab and dexamethasone.
• Subjects  experiencing ≥8-week delay  in  all  study  drugs  (nivolumab,  daratumumab, 
pomalidomide, and dexamethasone)  due  to  an  AE(s)  related  to  study  treatment  must  be 
discontinued from  all study  treatment.  Subjects  experiencing  delays  unrelated  to  study 
therapy,  for  example  due  to  radiation  therapy,  may  delay  study treatment  up  to  84  days. 
Further delays may be allowed after discussion with the BMS Medical Monitor.
• Subjects experiencing a Grade 4 or the third occurrence of a Grade 3 daratumumab infusion 
reaction must permanently discontinue daratumumab
• Subjects experiencing a Grade 3 or 4 infusion reaction related to nivolumab must discontinue 
nivolumab.  Subjects  may  continue  daratumumab  with  or  without  pomalidomide  and 
dexamethasone  treatment. Refer  to Section  4.1.5.1for  additional  reasons  to  discontinue 
nivolumab dosing permanently.
Continuation  of  study  treatments  in  the  circumstance  of  one  or more  study  treatments  being 
discontinued or delayed should follow these criteria: 
• Subjects who experience  AEs that require discontinuation of daratumumab may  be allowed 
to  continue  
therapy  with  nivolumab,  with  or  without  pomalidomide  and  dexamethasone,  
if
deemed in their best interest by both the PI and the BMS medical monitor. Subjects must be 
deriving clinical benefit.
• Subjects who experience  AEs that require discontinuation of  nivolumab  may  be  allowed to 
continue  
therapy  with  daratumumab,  with  or  without  pomalidomide  and  dexamethasone,  
if 
deemed in their best interest by both the PI and the BMS medical monitor. Subjects must be 
deriving clinical benefit.
• Subjects who experience AEs that require discontinuation of nivolumab and daratumumab in 
the ND-Pd arm may be allowed to continue therapy with pomalidomide and dexamethasone, 
if deemed in their best interest by both the PI and the BMS medical monitor. Subjects must 
be deriving clinical benefit.
• Subjects  who  experience  AEs  
that  
require  discontinuation  or  delay  of  pomalidomide  
in  
the 
ND-Pd arm may be allowed to continue therapy with nivolumab, daratumumab,  and 
dexamethasone, if deemed in their best interest by both the PI and the BMS medical monitor. 
Subjects must be deriving clinical benefit.
• Subjects who experience AEs that require discontinuation or delay of dexamethasone in the 
ND-Pd arm may be allowed to continue therapy with nivolumab, daratumumab,  and 
pomalidomide, if deemed in their best interest by both the PI and the BMS medical monitor. 
Subjects must be deriving clinical benefit.
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All  subjects  who  discontinue  should  comply  with  protocol  specified  follow-up  procedures  as 
outlined  in Section  5.  The  only  exception  to  this  requirement  is  when  a  subject  withdraws 
consent  for  all  study  procedures  or  loses  the  ability  to  consent  freely  (ie,  is  imprisoned  or 
involuntarily incarcerated for the treatment of either a psychiatric or physical illness).
If  a  subject  was  withdrawn  before  completing  the  study,  the  reason  for  withdrawal  must  be 
entered on the appropriate case report form (CRF) page.
3.6 
Post Study Drug Follow-up in Nivolumab/Daratumumab Cohorts
(Cohorts A and B)
PFS  and  OS  are  efficacy  endpoints  of  
the  study.  Post treatment study  
follow-up  
is  essential  
to 
preserving subject safety and the integrity of the study. Subjects who discontinue study treatment 
prior to progression must continue to be followed for collection of protocol-defined PFS.
Subjects who discontinue study therapy may also continue to be followed for OS data.
BMS  may  
request  
that  survival  data  be  collected  on  all  
treated/randomized  subjects  outside  of 
the  protocol-defined  window. At  the  time  of  this  request, each  subject  will  be  contacted  to 
determine their survival status unless the subject has withdrawn consent for all contacts or is lost 
to follow-up.
3.6.1 
Withdrawal of Consent
Subjects who request to discontinue study drug will remain in the study and must continue to be 
followed  for  protocol  specified  follow-up  procedures.  The  only exception  to  this  is  when  a 
subject specifically withdraws consent for any further contact with him/her or persons previously 
authorized by subject to provide this information. Subjects should notify the investigator of the 
decision  to  withdraw  consent  from  future  follow-up  in  writing, whenever  possible.  The 
withdrawal of consent should be explained in detail in the medical records by the investigator, as 
to  whether  
the  withdrawal  is  from  further  
treatment  with  study drug  only  or  also  from  study 
procedures and/or post treatment study follow-up, and entered on the appropriate CRF page. In 
the  event  that  vital  status  (whether  the  subject  is alive  or  dead)  is  being  measured,  publicly 
available  
information should  be used to determine vital  status only as appropriately directed  
in 
accordance with local law.
3.6.2 
Lost to Follow-Up
All  reasonable  efforts  must  be  made  
to  
locate  subjects  
to  determine  and  report  
their  ongoing 
status.  This  
includes  
follow-up  with  persons  authorized  by  
the subject  as  noted  above.  Lost to 
follow-up is defined by the inability to reach the subject after a minimum of three documented 
phone calls, faxes, or emails as well as lack of response by subject to one registered mail letter. 
All attempts should be documented in the subject’s medical records. If it is determined that the 
subject has died, the site will use permissible local methods to obtain the date and cause of death.
If  
investigator’s use of third-party representative  
to assist  
in the  
follow-up portion of the study 
has  been  included  in  the  subject’s  informed  consent,  then  the  investigator  may  use  a 
Sponsor-retained  third-party  representative  to  assist  site  staff  with  obtaining  subject’s  contact 
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information or other public  vital status data necessary to complete the  
follow-up portion of the 
study.  The  site  staff  and  
representative  will  consult  publicly available  sources,  such  as  public 
health  registries  and  databases,  in  order  to  obtain  updated contact  information.  If  after  all 
attempts, the subject remains lost to follow-up, then the last known alive date as determined by 
the investigator should be reported and documented in the subject’s medical records.
4 
TREATMENTS
Study  drugs  include  both  Noninvestigational  (NIMP)  and  Investigational  Medicinal  Products 
(IMP) and can consist of the following:
• All products, active or placebo, being tested or used as a comparator in a clinical trial
• Study required premedication, and
• Other  drugs  administered  as  part  of  the  study  that  are  critical  to  claims  of efficacy 
(eg, backbone therapy, rescue medications)
Investigational Product
An investigational product, also known as investigational medicinal product in some regions, is 
defined  as  a  pharmaceutical  form  of an  active  substance  or  placebo  being  
tested  or  used  as  a 
reference in a clinical study, including products already with a marketing authorization but used 
or  assembled  (formulated  or  packaged)  differently  than  the  authorized  form,  or  used  for  an 
unauthorized indication, or when used to gain further information about the authorized form.
The investigational product should be stored in a secure area according to local regulations. It is 
the  
responsibility  of  
the  
investigator to  ensure  
that  
investigational  product  
is  only  dispensed  
to 
study subjects. The  
investigational product must be dispensed only  
from official study  sites  by 
authorized personnel according to local regulations. 
In this protocol, investigational product(s) is/are: nivolumab and daratumumab.
Noninvestigational Product
Other  medications  used  as  support  or  escape medication  for  preventative,  diagnostic,  or 
therapeutic  reasons,  as  components  of  the  standard  of  care  for a  given  diagnosis,  may  be 
considered as noninvestigational products.
Handling and Dispensing
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental  conditions  (temperature,  light,  and  humidity)  as determined  by  the  sponsor.  If 
concerns regarding the quality or appearance of the study drug arise, do not dispense the study 
drug and contact the sponsor immediately.
Investigational product documentation must be maintained that includes all processes required to 
ensure  drug  is  accurately  administered.  This  includes  documentation  of  drug  storage, 
administration  and,  as  applicable,  storage  temperatures,  reconstitution,  and  use  of  required 
processes (eg, required diluents, administration sets).
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For  nivolumab and daratumumab, please  
refer  
to  
the  current  
IB/pharmacy  
reference  sheets  
for 
storage, handling and preparation instructions.
4.1 
Study Treatments - Nivolumab/Daratumumab Cohorts
For product descriptions seeTable 4.1-1. Non-investigational medicinal product will  be used to 
treat infusion reactions as described in Section 3.4.2.1.
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Table 4.1-1: 
Product Description - Nivolumab/Daratumumab Cohorts, Treatment Period
Product Description and 
Dosage Form
Potency
IP/
Non IP
Primary Packaging
(Volume)/ Label 
Type
Secondary 
Packaging
(Qty) /Label Type
Appearance
Storage 
Conditions
(per label)
BMS-936558-01 
(nivolumab) Solution for 
injection
100 mg (10 mg/mL) 
IP
10 mL vial/ 
Open-Label 
5 or 10 vials per 
carton/ Open-Label
Clear to opalescent, 
colorless to pale yellow 
liquid. May contain 
particles.
2 - 8°C Protect 
from light and 
freezing.
Pomalidomide Capsules*
1 mg, 2 mg, 3 mg, 
and 4 mg
Non IP
Market Product 
Configuration
Market Product 
Configuration
As per US commercial 
product.
As per Package 
Insert
Daratumumab Injection 
for Intravenous Infusion
100 mg (20 mg/mL) 
and/or 400 mg 
(20 mg/mL)
IP
Vial
Carton
Colorless to pale yellow 
solution in a vial.
As per Package 
Insert/ clinical 
supply label
Dexamethasone 
Solution**
4 mg/mL, 8 mg/mg, 
or other strengths
Non IP
Various Packaging 
Configurations
Various Packaging 
Configurations
Various
As per Package 
Insert
Dexamethasone tablets**
2 mg, 4 mg, or other 
strengths
Non IP
Various Packaging 
Configurations
Various Packaging 
Configurations
Various
As per Package 
Insert
IP= investigational product
*Pomalidomide should be obtained by the investigator sites standard prescribing procedures where allowed.
**Dexamethasone solution and tablets will be procured by the investigative sites.
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4.1.1 
Investigational Product
4.1.1.1 
Nivolumab in the Nivolumab/Daratumumab Cohorts
Cohort  A  subjects:  nivolumab  will  be  administered  at  a  dose  of 240  mg  as  an  intravenous 
infusion over 30 minutes every 2 weeks (Day 15 of Cycle 1, and Days 1 and 15 of each 28 day 
cycle during Cycles 2 through 6). Starting Cycle 7 and beyond, nivolumab will be administered 
at a dose of 480 mg as an intravenous infusion over 30 minutes every 4 weeks (Day1 of each 28 
day cycle). 
Cohort B subjects: randomized to ND treatment (only): nivolumab will be administered at a dose 
of 240  mg as  an  
intravenous  
infusion over 30  minutes on Day 15 of Cycle 1. Starting  Cycle 2
and beyond, nivolumab will be administered at a dose of 480 mg as an intravenous infusion over 
30 minutes every 4 weeks (Day 1 of each 28 day cycle).
Please refer to the nivolumab investigator brochure and/or pharmacy reference sheet/manual for 
guidelines  on  drug  preparation  and  administration.  Flush  the  intravenous  line  at  the  end  of 
infusion.
4.1.1.2 
Daratumumab
Daratumumab injection for IV infusion is considered IMP for this study. Daratumumab vials
must be stored in accordance with the package insert (USPI) /clinical supply labeling.
70
Daratumumab is an immunoglobulin G1 kappa (IgG1κ) human monoclonal antibody against
CD38 antigen,  produced in a mammalian cell line (Chinese Hamster  Ovary [CHO]) using
recombinant DNA technology. The molecular weight of daratumumab  
is approximately 148
kDa.
Daratumumab is supplied as a colorless to pale yellow preservative-freesolution for intravenous
infusion in single-dose vials. Daratumumab must be diluted with 0.9% Sodium Chloride
Injection, USP and to be administered as IV infusion according to the infusion rates specified in
the (USPI)/pharmacy reference manual.
70
Daratumumab can cause severe infusion reactions, whereabout half of all patients in the studies
to date experienced a reaction, mostduring the first infusion. Infusion reactions can also occur
with subsequent infusions. Nearly all reactions occurredduring infusion or within 4hours of
completing the daratumumab infusion.
Because of this high risk of infusion related reactions daratumumab infusions will be
administered per the approved (USPI)/pharmacy reference manual70 by a healthcare
professional, with immediate access to emergency equipment and appropriate medicalsupport to
manage infusion reactions if they occur, and all subjects will receive pre-infusion and post-
infusion medication per the approved (USPI)/pharmacy reference manual.70
Before administration the drug product should be stored and prepared as per the instructions in 
current (USPI)/pharmacy reference manual.70The dose of daratumumab to be administered to a 
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subject will  be calculated  by  multiplying the  subject’s weight (kg) by 16  mg/kg. The  subject’s 
predose weight on Day 1 of each cycle will be used to calculate the dose for each cycle. The dose 
does  not  need  
to  be  
recalculated  
for  weight  changes  
that  are  < 10%  
from  baseline.  Each  dose 
should  be  infused  as  per  instructions  in  the  current  daratumumab  (USPI)/pharmacy  reference 
manual.70
For  
the  administration  of  
the  first  16 mg/kg  dose  of  daratumumab,  in  additional  
to  previously 
approved single first infusion on Cycle 1 Day 1, a split-dosing regimen (ie, splitting the first dose 
over two consecutive days at 8 mg/kg on Cycle 1 Days 1 and 2) was recently approved in EU, 
US, and Canada. Investigators are allowed to opt for the split-dosing regimen. 
The  
infusion  start  and  stop time will  be  
recorded  
in  
the  CRF.  
If  
the  
infusion  
is  stopped  mid-
session for any reason, the stop/start time must be recorded together with an explanation.
Indirect Antiglobulin Test (IAT)
Blood Type, Rh, and IAT should be done before the first dose of daratumumab.Subject RBC
phenotyping (standard or extended) is an alternative option to the IAT test, if locally required.
Either method must be completed prior to first daratumumab infusion.
Daratumumab interferes with the Indirect Antiglobulin Test (IAT), which is a routine pre-
transfusion test performed to identify a  patient’s  antibodies to  minor  antigens  so that suitable
donor blood can be given for transfusion. Daratumumab does not interfere with /RhD
typing. CD38 is expressed at very low levels on erythrocytes. Daratumumabbinds to the CD38
on erythrocytes, which results in a positive IAT (also known as the Indirect Coombs Test).
This positive result masks the detection of antibodies to minor antigens and may prevent or
delay blood banks from issuingdonor blood for transfusion. This effect occursduring
daratumumab treatment and for up to 6 months after treatment ends. Subjects will receive a
patient identification wallet card for the study that includes the blood profile (ABO, Rh, and
IAT or phenotyping) determined before the first infusion of daratumumab along with
information on the IAT interference for healthcare providers/blood banks. Subjects are to
carry this card throughout the treatment period and for atleast 6 months after treatment ends.
Blood banks can eliminate the daratumumab IAT interference with IAT  by treating  
reagent 
RBCs with dithiothreitol (DTT).102
Possible methods for blood banks to provide safe RBCs for transfusion to subjects
receiving daratumumab include:
1) Providing ABO/RhD compatible, phenotypically  (standard  or extended  phenotyping) or
genotypically matched units
2) Providing ABO/RhD compatible,  K-negative  units after ruling out or identifying
alloantibodies using DTT-treated reagent RBCs.
Uncrossmatched, ABO/RhD compatible RBC units should be administered if transfusion is
needed emergently as per local blood bank practice.
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Despite daratumumab binding to CD38 on erythrocytes, no indication of clinically significant
hemolysis has been observed in daratumumab studies. For additional details, refer to the
Daratumumab IB/package insert.
4.1.2 
Noninvestigational Product
In this protocol, non-investigational products consist of: 
• Pomalidomide (Pomalyst®) capsules 1 mg, 2 mg, 3 mg, and 4 mg
• Dexamethasone tablets and concentrate for solution for IV infusion
• Products  used  
for  daratumumab  pre- and  post-infusion  medication (refer to Section  3.4.1.4
and (USPI)/pharmacy reference manual).98
4.1.2.1 
Pomalidomide
Pomalidomide  is  an  analogue  of  thalidomide.  Thalidomide  is  a  known  human  teratogen  that 
causes severe life-threatening human birth defects. If pomalidomide is taken during pregnancy, it 
may  cause  birth  defects  or  death to  an  unborn  baby.  Females  must  not  get  pregnant:  
(1) for  at 
least  4 weeks  before  starting  pomalidomide,  (2) while  taking  pomalidomide,  (3) during  any 
interruptions  in  pomalidomide  treatment  and  (4) for  at  least  4  weeks  after  their  last  dose  of 
pomalidomide.  Furthermore,  subjects  
taking  pomalidomide  should  
refrain  
from donating  blood 
(until at least 90 days) or sperm (until at least 4 weeks) after last dose of pomalidomide. 
Because of this potential toxicity and to avoid fetal exposure to pomalidomide, pomalidomide is 
only available under a special restricted distribution program. Each risk management program is
country  or  
region  specific.  Under  
these  programs,  only  prescribers  and  pharmacists  
registered 
with the program can prescribe and dispense the product. In addition, pomalidomide must only 
be  dispensed  to  subjects  who  are  registered  and  meet all  the  conditions  of  the  local 
pomalidomide  risk  management  program  or  meet all  the  conditions  of  the  Pomalidomide 
Pregnancy  Risk  Prevention  Plan.  Subjects  who  have  the  potential  of  pregnancy  must  be 
instructed about contraception and undergo the scheduled pregnancy tests. Pomalidomide should 
be taken in accordance with local label.
WOCBP  must  have  negative  pregnancy  testing  and  must  use  contraception  methods  before 
initiating pomalidomide.
4.1.2.2 
Dexamethasone
Dexamethasone  tablets  and  solution  for  IV  infusion  is  considered  non-IMP  for  this  study. 
Marketed  product will  be  utilized  for  
this  study  and  should  be  stored  in accordance  with  
the 
package insert.103
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4.1.3 
Study Drug Storage, Preparation and Administration
Please  refer  to  the  current  version  of  the  IB  and/or  pharmacy  reference  sheets  for  complete 
storage,  handling,  dispensing,  and  infusion  information  for  nivolumab,  and  to  the  current 
(USPI)/pharmacy reference manual
98for daratumumab, and dexamethasone IV. 
Nivolumab vials must be stored at a temperature of 2° to 8°C and should be protected from light 
and  freezing.  If  stored  in  a  glass  front  refrigerator,  vials  should  be  stored  in  the  carton. 
Recommended  safety  measures  for  preparation  and  handling  of  nivolumab  include laboratory 
coats  and  gloves.  For  details  on  prepared  drug  storage  and  use time  of  nivolumab  under  
room 
temperature/light and refrigeration, please refer to the nivolumab IB section for “Recommended 
Storage and Use Conditions” and/or pharmacy reference sheets.
Nivolumab injection is to be administered as an IV infusion through a 0.2-micron to 1.2-micron 
pore size, low-protein binding polyethersulfone membrane in-line filter at the protocol-specified 
doses. It is not to be administered as an IV push or bolus injection. Nivolumab injection can be 
infused  undiluted  (10  mg/mL)  or  diluted  with 0.9%  Sodium  Chloride  Injection,  USP  or  5% 
Dextrose  
Injection,  USP  
to  protein  concentrations  as  
low  as  1  mg/mL.  Care  must  be  
taken  
to 
assure  sterility  of  the  prepared  solution  as  the  product  does  not  contain  any  antimicrobial 
preservative or bacteriostatic agent.
Daratumumab  infusion  solution  will  be  prepared  as  a  1,000-mL  (first  dose,  unless  using  split 
dose) or 500-mL (second and subsequent doses) dilution of daratumumab in sterile, pyrogen-free 
0.9% Sodium Chloride Injection, USP. Preparation of infusion bags should be done on the day of 
the  planned  infusion.  Daratumumab  must  be  administered  as  an  IV  infusion  given  through  a 
well-functioning IV catheter by using an infusion pump or syringe pump. Daratumumab must be 
filtered by using an inline filter (0.2 μM) during the infusion. Manuals with detailed descriptions 
for preparation and administration of daratumumab will be supplied to each pharmacy and site.
In  addition  to  administering  a  full  dose  of  16 mg/kg  on  Cycle  1 Day  1,  “split-dosing”  of 
daratumumab (ie, 8 mg/kg on Cycle 1 Day 1 and 8 mg/kg on Cycle 1 Day 2) can be utilized for 
Cohort  B at  the  investigator’s  discretion.  The  first  split-dose infusion  will  be  prepared  as  a
500-mL  dilution  of  8  mg/kg  of  daratumumab  given  on  Days  1  and  2  of  Cycle  1.  If  these 
2 infusions are well-tolerated (absence of > Grade 1 IRR), the second week of daratumumab will 
be  given  as  a  16  mg/kg  dose  diluted  in  500  cc  of  normal  saline.  If  the  first  2  doses  of 
daratumumab  are  not  well-tolerated  (defined  as  > Grade  1  IRR),  then  the  second  week  of 
daratumumab will  be given as 16  mg/kg  
in 1000  mL on Cycle 1 Day 8. From Cycle 1 Day 15 
and beyond, the dose of daratumumab will not be split and will be the standard 16-mg/kg dose. 
The dilution will be in 1000 cc of normal saline until the subject completes an infusion without 
> Grade  1  
IRR.  For  all  
infusions,  daratumumab  will  be  prepared  
in  sterile,  pyrogen  
free 0.9% 
NaCl.  Preparation  of  the  infusion  bags  should  be  done  on  the  day  of  the  planned  infusion. 
Daratumumab  must  be  administered  as  an  IV  infusion  given  through  a  well-functioning  IV 
catheter  by  using  an  infusion  pump.  The  study  drug  must  be  filtered  by  using  an  inline  filter 
(0.2 μM)  during  the  infusion.  Manuals  with  detailed  descriptions  for  preparation  and 
administration of daratumumab will be supplied to each pharmacy and site.
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Infusion-related  supplies  (eg,  IV  bags,  in-line  filters,  0.9%  NaCl  solution,  pump)  will  not  be 
supplied by the sponsor and should be purchased locally if permitted by local regulations.
When more than one study drugs are to be administered as IV infusion on the same day, separate 
infusion bags and filters must be used for each infusion. Nivolumab is to be administered first. 
The  nivolumab  infusion  must  be promptly  followed  by  a  saline  flush  to  clear  the  line  of 
nivolumab  before  starting  the  daratumumab  infusion.  The  second infusion  will  always  be 
daratumumab  and  will  start  no  sooner  than  30  minutes  after  completion  of  the  nivolumab 
infusion.
4.1.4 
Selection and Timing of Dose for Each Subject
4.1.4.1 
Nivolumab
Cohort A
• Nivolumab  will  be  administered  at  a  dose  of  240  mg  as  an  intravenous  infusion  over  30 
minutes  on  Day  15  during  Cycle  1,  and  on  Days  1  and  15  during  Cycles  2  
through  6  
(ie, 
every  2  weeks  of  each  28-day  cycle).  Starting  Cycle  7  and  beyond,  nivolumab  will  be 
administered at a dose of 480 mg as an IV infusion over 30 minutes every 4 weeks (Day 1 of 
each 28-day cycle).
• Nivolumab  can  be  delayed  within  a  3-day  window  of  Day  1  and  Day  15,  during  Cycles  1 
through  6,  as  
long  as  
the  12-day  
interval  between  2  nivolumab  doses  
is  
respected.  During 
Cycles 7 and beyond, nivolumab can be delayed within a week, as long as the 21-day interval 
between 2 nivolumab doses is respected. Doses that fall outside the allowed window should 
be skipped.
Cohort B
• Patients randomized to ND treatment (only): nivolumab will be administered at a dose of 240 
mg as an intravenous infusion over 30 minutes on Day 15 of Cycle 1. Starting Cycle 2 and 
beyond, nivolumab will be administered at a dose of 480 mg as an intravenous infusion over 
30 minutes every 4 weeks (Day 1 of each 28 day cycle).
• Cycle 1 dose (C1D15) can be delayed within a 3 day window from Day 15. Doses that fall 
outside the allowed window should be skipped. 
• From  Cycle 2 (C2D1) and  beyond, nivolumab can  be delayed within  
in a 7 day window of 
Day 1, as long as the 21-day interval between two 480 mg nivolumab doses is respected, and 
a 12-day interval between C1D15 and C2D1 is respected. Doses that fall outside the allowed 
window should be skipped.
Nivolumab  should  be  administered  before  daratumumab.  There  are no  pre-medications 
recommended for nivolumab.
Subjects should be carefully  monitored for infusion reactions during nivolumab administration. 
If an acute infusion reaction is noted, subjects should be managed according to Section 3.4.2.1.
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There will be no dose escalations or reductions of nivolumab allowed. Doses of nivolumab may 
be  interrupted,  delayed,  or  discontinued  depending  on  how  well the  subject  tolerates  the 
treatment.
4.1.4.2 
Daratumumab
Daratumumab will be administered at a dose of 16 mg/kg as an IV infusion every week (Days 1, 
8, 15, and 22 of each 28-day cycle) during Cycles 1 and 2. As an option, in Cycle 1, the first full 
dose of daratumumab at 16 mg/kg may be split into 2 doses at 8 mg/kg and administered via IV 
on  Cycle  1  Days  1  and  2.  From  Cycles  3  
through 6, daratumumab  will  be  administered  every 
2 weeks (Days 1 and 15 of each 28-day cycle), then starting Cycle 7 and beyond, daratumumab 
will  be  administered  every  4  weeks  (Day  1  of  each  28-day  cycle).  The  infusion  rates should 
closely follow the specifications of the currently approved (USPI)/pharmacy reference manual.98
All  
infusions will  be planned as outpatient visits. Subjects will receive preinfusion  medications 
and postinfusion medications as detailed in the protocol.
Daratumumab should be administered after nivolumab.
MM  subjects randomized  to  the  ND or  D regimens will  receive  pre- and  post-infusion 
medication  for  daratumumab  infusion  per  the  daratumumab  label, as  described  (in Section
3.4.1.4. 
MM subjects randomized to ND-Pd regimen will receive the treatment regimen dexamethasone 
dose split as IV pre-infusion and oral post-infusion on weeks with daratumumab infusions, and 
only  oral  in  the  weeks  without  daratumumab  infusion  (see Section 4.1.4.4).  No  additional 
corticosteroids  besides  the  dexamethasone  dose  included  in  the treatment  regimen  will  be 
administered to the ND-Pd subjects.
The dilution volumes and infusion rates for C1D1 (16 mg/kg), and optional split-dosing of C1D1 
(8 mg/kg)  and  C1D2  (8  mg/kg),  C1D8  (16  mg/kg),  and  subsequent  infusions are  provided  in 
Table  4.1.4.2-1.  The  sponsor  may  modify  the  infusion  rates  or  the  preinfusion medications 
prospectively  based  upon  the  information  collected  to  date  from  this  and  other  studies. 
Additional details for administration times and rates, as well as preinfusion medications, will be 
provided  in  the  administration  guidelines  (study  site  investigational  product  and  procedures 
manual/package insert).
Table 4.1.4.2-1: 
Daratumumab Infusion Rates
Dilution Volume
Initial Infusion 
Rate (first hour)
Increments of 
Infusion Rate
Maximum Infusion 
Rate
C1D1
(16 mg/kg single 
dose)
1000 mL 
50 mL/hour
50 mL/hour 
every hour
200 mL/hour
Optional split-
dosing: C1D1 and 
C1D2
(8 mg/kg split dose)
500 mL 
50 mL/hour
50 mL/hour 
every hour
200 mL/hour
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Table 4.1.4.2-1: 
Daratumumab Infusion Rates
Dilution Volume
Initial Infusion 
Rate (first hour)
Increments of 
Infusion Rate
Maximum Infusion 
Rate
C1D8a,b
(16 mg/kg)
500 mL 
50 mL/hour
50 mL/hour 
every hour
200 mL/hour
Subsequent 
infusions
c
500 mL 
100 mL/hour
50 mL/hour 
every hour
200 mL/hour
a If  the  subject’s  first  infusion  of  daratumumab  at  16  mg/kg  is  well-tolerated,  subsequent  infusions  will  be 
administered at an initial rate of 100 mL/hour and increased by 50-mL/hour increments at 60-minute intervals, as 
tolerated, to a maximum rate of 200 mL/hour.
b If the subject’s first 2 infusions of 8 mg/kg daratumumab are well-tolerated (defined as an absence of IRR >Grade 
1), the first infusion of 16 mg/kg daratumumab will be administered at an initial rate of 50 mL/hour and increased 
by 50-mL/hour increments at 60-minute intervals, as tolerated, to a maximum rate of 200 mL/hour. If the 8 mg/kg 
infusions are not well-tolerated (defined as IRR >Grade 1), the dose on C1D8 should be given in 1000 mL.
c Modified  rates  should  only  be  used  if  the  first  2 16  mg/kg  infusions  of  daratumumab  were  well-tolerated  as 
defined by an absence of > Grade 1 infusion-related reactions during a final infusion rate of ≥100 mL/hr
Vital  signs  should  be  monitored  extensively throughout  daratumumab  infusion(s)  on  Cycle  1 
Day 1 (16 mg/kg) or Cycle 1 Days 1  & 2 (split-dosing at 8 mg/kg). For subsequent infusions, 
vital signs should be measured before the start of the infusion and at the end of the infusion. If a 
subject  experiences any  significant  medical  event,  
then  
the  
investigator  should  assess  whether 
the subject should stay overnight for observation. If the subject has not experienced a significant 
medical event but is hospitalized overnight only for observation, then the hospitalization should 
not be reported as a serious adverse event.
There will be no dose escalations or reductions of daratumumab allowed. Doses of daratumumab 
may  be  interrupted,  delayed,  or  discontinued  depending  on  how  well  
the  subject  
tolerates  
the 
treatment.
4.1.4.3 
Pomalidomide in the ND-Pd Cohort (Cohort A)
Pomalidomide will be administered orally at the dose of 4 mg daily on Days 1 - 21 of each 28-
day cycle. Pomalidomide should be taken without food (at least 2 hours before or 2 hours after a 
meal).
Subjects should be instructed that if a dose of pomalidomide has been missed and it has been less 
than  12  hours  since  the  subject’s  regular  dosing  time,  to  take pomalidomide  as  soon  as  the 
subject remembers. If it has been more than 12 hours, the dose must be skipped. Subjects should 
not take 2 doses at the same time.
4.1.4.4 
Dexamethasone in the ND-Pd Cohort (Cohort A)
At the investigator’s discretion, the oral dexamethasone dose may be given as a split dose over 
2 consecutive days each week. 
The administration of dexamethasone is summarized inTable 4.1.4.4-1.
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Table 4.1.4.4-1: 
Dexamethasone Dosing 
Age
Day 1
Day 8
Day 15
Day 22
Cycles 1-2
≤75 years old
20 mg IV before daratumumab infusion
20 mg PO after daratumumab infusion
> 75 years old 
16 mg IV before daratumumab infusion
4 mg PO after daratumumab infusion
Cycles 3-6
≤75 years old
20 mg IV before 
daratumumab infusion
20 mg PO after 
daratumumab infusion
40 mg PO
20 mg IV before 
daratumumab 
infusion
20 mg PO after 
daratumumab 
infusion
40 mg PO
> 75 years old 
16 mg IV before 
daratumumab infusion
4 mg PO after 
daratumumab infusion
20 mg PO
16 mg IV before 
daratumumab 
infusion
4 mg PO after 
daratumumab 
infusion
20 mg PO
Cycle 7 and Beyond
≤75 years old
20 mg IV before 
daratumumab infusion
20 mg PO after 
daratumumab infusion
40 mg PO 
40 mg PO 
40 mg PO
> 75 years old 
16 mg IV before 
daratumumab infusion
4 mg PO after 
daratumumab infusion
20 mg PO 
20 mg PO 
20 mg PO
On  weeks  with  daratumumab  
infusion,  dexamethasone  will  be  administered  as  a  split  dose  as 
described  in Table  4.1.4.4-1.  The  IV  dose  can  be  administered  approximately  1  hour  prior  
to 
every daratumumab infusion (can be administered before nivolumab infusion).
On  weeks  without  daratumumab  infusion,  dexamethasone  will  be  administered  orally  only  as 
described in Table 4.1.4.4-1.
If daratumumab dosing is skipped or discontinued, dexamethasone will be administered orally as 
in weeks without daratumumab.
4.1.5 
Dose Delay, Interruption, or Discontinuation
If the dose of  nivolumab, daratumumab, pomalidomide and/or dexamethasone  
is  
interrupted or 
discontinued,  
the  
treatment  with  
the  other  drugs  may  continue  as  scheduled  
if  deemed  
in  
their 
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best  
interest  by  both  
the  PI  and  
the  BMS  medical  monitor.  Subjects  must  be  deriving  clinical 
benefit. 
Each  cycle  is  28  days.  While  dose  delays  (within  
the  allowed  window  determined  below  for 
nivolumab  and  daratumumab)  or  
interruptions  are  permitted,  
the start  of  each  cycle  cannot  be 
delayed and is fixed (ie, anchored) relative to Cycle 1 Day 1. Adjustments to the Cycle 1 Day 1 
anchored schedule should not be performed. Should the start of a cycle be delayed, it is expected 
the following cycle begin as anchored to Cycle 1 Day 1. Delayed doses which fall outside of the 
allowed window for delay for the respective cycle should be skipped. Subjects may continue on 
study therapy even if components of the study therapy must be discontinued.
Please consult the BMS Medical Monitor or any questions regarding dose interruption or study 
therapy discontinuation.
4.1.5.1 
Nivolumab
Cohort A
During Cycles 1 through 6, subjects may be dosed no less than 12 days from the previous dose. 
Nivolumab can  be delayed within a 3-day window of Day 1 and Day 15 as  
long as the 12-day 
interval  between  2  nivolumab  240  mg  doses  is  respected.  Doses  
that  fall  outside  
the  allowed 
window should be skipped. 
The first dose in Cycle 7 (Day 1) may be dosed no less than 12 days from the previous dose and 
for  subsequent  doses  it  should  be  dosed  no  less  than  21  days  from  the  previous  dose.  From 
Cycle 7 and beyond, nivolumab can be delayed within a 7-day window of Day 1 as long as the 
12-day  and  21-day  intervals  for  the  first  480  mg dose  and  subsequent  480  mg  doses, 
respectively,  between  2  nivolumab  doses  is  respected.  Doses  that  fall  outside  the  allowed 
window should be skipped.
Cohort B
Cycle  1  dose  (C1D15)  can  be  delayed  within a  3  day windowfrom  Day 15.  Doses  that  fall 
outside the allowed window should be skipped. 
From Cycle 2 (C2D1) and beyond, nivolumab can be delayed within a7 day window from Day 
1, as long as the 21-day interval between two 480 mg nivolumab doses is respected, and a 12-day 
interval  between  C1D15  and  C2D1  
is respected.  
.  Doses  
that  
fall outside  
the  allowed  window 
should be skipped.
Nivolumab Dose Delays Due to AEs
Nivolumab administration should be delayed for the following:
• Grade 2 non-skin, drug-related AE, with the exception of fatigue
• Grade 2 drug-related creatinine, AST, ALT and/or Total Bilirubin abnormalities
• Grade 3 skin, drug-related AE
• Grade 3 drug-related laboratory abnormality, with the following exceptions: 
−Grade 3 lymphopenia or asymptomatic amylase or lipase does not require dose delay
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−Grade ≥3 AST, ALT, Total Bilirubin will require dose discontinuation 
• Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the investigator, warrants delaying the dose of study medication.
Participants who require delay of nivolumab should be re-evaluated weekly or more frequently if 
clinically indicated and resume nivolumab dosing when re-treatment criteria are met.
Criteria to Resume Treatment with Nivolumab
In order to initiate a new infusion of nivolumabthe following criteria must be met: 
• Platelet count ≥25 x 109/L (platelet transfusion support is allowed)
• ANC ≥0.50 x 109/L (growth factor support is strongly recommended if ANC < 1.0 x 109/L)
Subjects  may  resume  treatment  with  nivolumab  when  the  drug-related  AE(s)  resolve(s)  to 
Grade≤1 or baseline, with the following exceptions:
• Subjects may resume treatment in the presence of Grade 2 fatigue
• Subjects who have not experienced a Grade 3 drug-related skin AE may resume treatment in 
the presence of Grade 2 skin toxicity 
• Subjects  with  baseline  Grade  1  AST/ALT  or  total  bilirubin  who  require  dose 
delays/interruptions for reasons other than a 2-grade shift in AST/ALT or total bilirubin may 
resume treatment in the presence of Grade 2 AST/ALT OR total bilirubin
• Subjects  with combined  Grade  2  AST/ALT  AND  total bilirubin  values  meeting 
discontinuation parameters should have treatment permanently discontinued
• Drug-related  pulmonary  
toxicity,  diarrhea,  colitis,  uveitis  or  neurologic  
toxicity  must  have 
resolved  to  baseline  before  treatment  is  resumed.  Subjects  with  persistent  Grade  1 
pneumonitis  after  completion  of  a  steroid  
taper  over  at  
least  1  month  may  be  eligible  for 
retreatment if discussed with and approved by the BMS Medical Monitor.
• Drug-related  endocrinopathies  adequately controlled  with  only  physiologic  hormone 
replacement may resume treatment after consultation with the BMS Medical Monitor.
Dose  delay/interruption  of  nivolumab  which  results  in  treatment interruption of > 8 weeks 
require treatment discontinuation, with exceptions as noted below.
Nivolumab Dose Discontinuation Due to Adverse Events
Nivolumab treatment should be permanently discontinued for the following reasons:
• Any Grade 2 drug-related uveitis, eye pain or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within the re-treatment period OR requires 
systemic treatment
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• Any Grade 3  non-skin, drug-related AE  
lasting > 7 days, with the  
following exceptions  
for 
laboratory  abnormalities,  drug-related  uveitis,  pneumonitis,  bronchospasm,  hypersensitivity 
reactions, infusion reactions, and endocrinopathies:
−Grade  3  drug-related  uveitis,  pneumonitis,  bronchospasm, neurologic  toxicity, 
myocarditis,  hypersensitivity  reaction,  or  infusion  reaction  of  any  duration  requires 
discontinuation
• Grade 3 drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement  do  not  require  discontinuation.  Adrenal  insufficiency  requires  discontinuation 
regardless of control with hormone replacement
−Grade  3  drug-related  laboratory  abnormalities  do  not  require  
treatment  discontinuation 
except:
♦Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires 
discontinuation
♦Grade ≥3 drug-related AST, ALT or Total Bilirubin requires discontinuation*
♦Concurrent AST or ALT > 3 x ULN and total bilirubin > 2x ULN
*  In  most  cases  of  Grade  3  AST  or  ALT  elevation, study  treatment  will  be  permanently 
discontinued.  If  the  investigator  determines  a  possible  favorable  benefit/risk  ratio  that 
warrants continuation of study treatment, a discussion between the investigator and the BMS 
Medical Monitor/designee must occur.
• Any Grade 4 drug-related adverse event or laboratory abnormality (including but not limited 
to creatinine,  AST,  ALT, or Total Bilirubin), except for the  
following events which do not 
require discontinuation:
−Grade 4 neutropenia ≤7 days
−Grade 4 lymphopenia or leukopenia or asymptomatic amylase or lipase
−Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae  and  are  corrected  with  supplementation/appropriate  management  within  72 
hours of their onset
−Grade 4 drug-related endocrinopathy adverse events, such as, hyper- or hypothyroidism, 
or  glucose  intolerance,  which  resolve  or  are  adequately  controlled  with  physiologic 
hormone  
replacement  
(corticosteroids,  
thyroid  hormones)  or  glucose-controlling  agents, 
respectively, may not require discontinuation after discussion with and approval from the 
BMS Medical Monitor.
• Any  event that  
leads  
to  delay  
in  dosing  
lasting  >  8  weeks  
from the  previous  dose  
requires 
discontinuation, with the following exceptions:
−Dosing  delays  to  allow  for prolonged  steroid tapers  to  manage  drug-related  AEs  are 
allowed. Prior to re-initiating treatment in a subject with a dosing delay lasting > 8 weeks 
from the previous dose, the BMS medical monitor must be consulted. Tumor assessments 
should  continue  as  per  protocol  even  if  dosing  is  delayed/interrupted.  Periodic  study 
visits to assess safety and  
laboratory studies should also continue as clinically  
indicated 
during such dosing delays/interruption.
−Dosing delays lasting > 8 weeks from the previous dose that occur for non-drug-related 
reasons  may  be allowed  
if approved  by the BMS  medical  monitor. Prior to  
re-initiating 
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treatment in a subject with a dosing delay  
lasting > 8 weeks, the BMS medical  monitor 
must be consulted. Tumor assessments should continue as per protocol even if dosing is 
delayed/interrupted.  Periodic  study  visits  
to  assess  safety  and  
laboratory  studies  should 
also continue as clinically indicated during such dosing delays/interruption.
• Any  AE,  laboratory  abnormality,  or  intercurrent illness  which,  in  the  judgment  of  the 
Investigator,  presents  a  substantial  clinical  risk  to  the  subject  with  continued  nivolumab 
dosing.
• Immune-mediated adverse events as described in Appendix 5.
4.1.5.2 
Daratumumab
In  Cycles  1  
to  2,  daratumumab  doses  
that  
fall  outside  of  
the  pre-specified  window  of  +3 days 
must be skipped.
In  Cycle  3  through  6,  daratumumab  dosing  may  be  delayed  for  up to  1  week.  If  unable  to 
administer within 1 week, then the dose should be skipped and resumption of the daratumumab 
continues per the protocol defined schedule.
From Cycle 7 and beyond, daratumumab can be delayed within a 21-day window. Doses that fall 
outside the allowed window should be skipped.
Subjects experiencing a Grade 4 (life threatening) infusion reaction related to daratumumab must 
permanently discontinue daratumumab. 
Daratumumab Dose Delays Due to AEs
On the first day of each new treatment cycle and before each daratumumab dose, the subject will 
be  evaluated  for  possible  toxicities  that  may  have  occurred  after  the  previous  dose(s).  Dose 
modifications or delays will be made based on the toxicity experienced during the previous cycle 
of therapy or newly encountered on Day 1 of a cycle.
Daratumumab administration should be delayed if any of the following criteria below are met, to 
allow for recovery from toxicity related to the study drug:
• Grade 4 hematologic toxicity except for grade 4 lymphopenia 
• Grade ≥3 thrombocytopenia
• Febrile neutropenia
• Neutropenia with infection, of any grade
• Grade ≥3 non-hematologic toxicities with the following exceptions:
−Grade 3 nausea or Grade 3 vomiting that responds to antiemetic treatment within 7 days
−Grade 3 diarrhea that responds to antidiarrheal treatment within 7 days
−Grade 3 fatigue or asthenia that was present at baseline or thatlasts for < 7 days after the 
last administration of daratumumab
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If  daratumumab  administration  does  not  commence  within  the  prespecified  windows  of  the 
scheduled  administration  date (Table  4.1.5.2-1), that  respective  dose  should  be  skipped. 
Administration may resume at the next planned dosing date. A missed dose will not be made up.
Table 4.1.5.2-1: 
Daratumumab Windows of Dosing Resumption
Cycles
Dosing Frequency 
Skip dose window 
Dosing Resumption
1 and 2
Weekly (QW)
> 3 days 
Next planned weekly dosing date
3 to 6
Biweekly (Q2W)
> 7 days 
Next planned biweekly dosing date
7 and beyond 
Every 4 weeks (Q4W) 
> 21 days
Next planned every 4 weeks dosing 
date
Criteria to Resume Treatment with Daratumumab 
Administration  of  daratumumab  may  be  restarted  upon  recovery  from toxicity to Grade 2 or 
baseline,  with  
the  exception  
that  Grade  2  
laryngeal  edema  or  Grade  2  bronchospasm  must  be 
fully recovered.
Any adverse event deemed to be related to daratumumab that requires  a dose hold of  more than 
4 weeks  (Cycle  1  to  Cycle  6)  or  more  than  6  weeks  (Cycle  7  and  beyond)  will  result  in 
permanent discontinuation of daratumumab.
In order to initiate a new infusion of daratumumabthe following criteria must be met:
• Platelet count ≥50 x 109/L (platelet transfusion support is allowed)
• ANC ≥0.50 x 109/L (growth factor support is strongly recommended if ANC< 1.0 x 10
9/L).
For  subjects  who  have  experienced  HBV  
reactivation  while  on  study  
treatment,  
if  
the  benefits 
outweigh  
the  
risks,  study  
treatment  may  be  
resumed  with  concomitant  antiviral  prophylaxis  as 
per local standard of care.
Daratumumab Dose Discontinuation Due to Adverse Events
Daratumumab treatment should be permanently discontinued for the following reasons:
• Grade 4 infusion reaction related to daratumumab. 
• The 3rd occurrence of a Grade 3 daratumumab infusion related reaction 
• Subjects  experiencing ≥8-week  delay  in  all  study  drugs  (nivolumab,  daratumumab, 
pomalidomide,  and  dexamethasone)  due  to  an  AE(s)  related  to  study  treatment  must  be 
discontinued from  all study  treatment.  Subjects  experiencing  delays  unrelated  to  study 
therapy,  for  example  due  to  radiation  therapy,  may  delay  study treatment  up  to  84  days. 
Further delays may be allowed after discussion with the BMS Medical Monitor.
• Any daratumumab related AE that requires a dose hold of > 4 weeks (Cycle 1 to Cycle 6) or 
> 6  weeks  
(Cycle  7  and  beyond)  will  
result  
in  permanent  discontinuation  of  daratumumab, 
unless,  upon  consultation  with  the  sponsor  and  the  review  of  safety  and  efficacy, 
continuation is agreed upon. 
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4.1.5.3 
Pomalidomide
Pomalidomide  
interruption  should  be  performed  as  clinically  
indicated  at  
the  discretion  of  
the 
investigator. Subjects should be instructed that if a dose of pomalidomide has been missed and it 
has been less than 12 hours since the subject’s regular dosing time, to take pomalidomide as soon 
as the subject remembers. If it has been more than 12 hours, the dose must be skipped. Subjects 
should not take 2 doses at the same time.
In order to initiate a new cycle of pomalidomide, the following criteria must be met:
• Platelet count ≥50 x 109/L
• ANC ≥0.50 x 109/L (growth factor support is strongly recommended if ANC < 1.0 x 109/L)
• Nonhematologic AEs must be resolved or improved as outlined in Section 4.1.6.
4.1.5.4 
Dexamethasone
Dexamethasone interruption should be performed as clinically indicated at the discretion of the 
investigator. For subjects receiving daratumumab, the weekly dexamethasone that coincides with 
or  
is  
temporally  closest  
to  
the  next  daratumumab  dosing  must  be  administered  as  part  of  
the 
pre-infusion medication for daratumumab per the guidance in Section 4.1.4.2.
4.1.6 
Recommended Dose Reductions for Nivolumab/Daratumumab Cohorts
The  criteria  presented  in  this  section  for  dose  modification  of dexamethasone and 
pomalidomideare  meant  as  general  guidelines.  They  are  based  on  current  US  standards  of 
clinical practice. Local standards may differ and may be followed. Dose modification may occur 
in  the  setting  of  lower  grade  toxicity  if  the  investigator,  in consultation  with  the  Medical 
Monitor/Sponsor, believes that it is in the interest of subject safety.
Dexamethasone
Dexamethasone  dose  reductions  for  toxicity  must  be  performed  as  clinically  indicated.  Dose 
reductions  and  recommended  management  should  follow  the  guidance  inTable  4.1.6-1. 
Deviations  
to the  
recommended  dose  
reductions  are  allowed  based  on  
the  clinical  
judgment of 
the investigator.
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Table 4.1.6-1: 
Dexamethasone Dose Reductions
CTCAE 
Category
Adverse Event
Treatment Adjustment
Gastrointestinal
Dyspepsia, gastric or duodenal 
ulcer, gastritis
Grade 1 - 2 
(requiring medical management)
Treat with a proton pump inhibitor.
If symptoms persist despite above measures, decrease by 
1 dose level.
≥Grade 3 
(requiring hospitalization or 
surgery)
Hold dexamethasone until symptoms are adequately 
controlled. Reduce by 1 dose level and resume along with 
concurrent therapy with a proton pump inhibitor.
If symptoms persist despite above measures, reduce to dose 
level -3 (dose withheld).
Acute pancreatitis
Reduce to dose level -3 (dose withheld).
Cardiovascular
Edema
≥Grade 3 (limiting function and 
unresponsive to therapy or 
anasarca)
Use diuretics as needed, and decrease dexamethasone by 
1 dose level. If edema persists despite above measures, 
decrease by another dose level.
Neurology
Confusion or Mood alteration 
≥Grade 2 (interfering with 
function ±interfering with 
activities of daily living)
Hold dexamethasone until symptoms resolve.
Decrease by 1 dose level and resume.
If symptoms persist despite above measures, decrease by 
another dose level.
Musculoskeletal
Muscle weakness 
≥Grade 2 (symptomatic and 
interfering with function ±
interfering with activities of 
daily living)
Hold dose until muscle weakness is ≤Grade 1.
Decrease dexamethasone by 1 dose level and resume.
If weakness persists despite above measures, decrease by 
another dose level.
Metabolic
Hyperglycemia
≥Grade 3 or higher
Treat with insulin or oral hypoglycemics as needed. If 
uncontrolled despite above measures, decrease by 1 dose 
level until glucose levels are satisfactory.
Constitutional
Insomnia ≥Grade 2
Decrease by 1 dose level and resume.
Dose reduction for persistent Grade 2 or Grade ≥3 AEs believed to be related to dexamethasone 
and not listed above are permitted. 
On  weeks  with  daratumumab  infusion,  regardless  of  dexamethasone  dose  reduction,  at  least 
20 mg  
for  subjects ≤75  years  old  or  at  
least  16  mg  
for  subjects  >  75  years  old  of  
the  weekly 
dexamethasone dose must be administered IV as part of the premedication for daratumumab with 
the  remainder  of  the  weekly  dexamethasone  dose  administered  orally  (PO)  post-infusion. 
Contact the Medical Monitor to discuss dexamethasone IV premedication for subjects who reach 
dose level -3 and must discontinue dexamethasone due to dose limiting toxicity.
On days without daratumumab, no IV dexamethasone should be administered (Table 4.1.6-2).
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Table 4.1.6-2: 
Dexamethasone Dose Levels
Dose Level 
Reducing Dexamethasone on 
Weeks with Daratumumab
Reducing Dexamethasone on 
Weeks Without Daratumumab
PO
IV
PO
IV
0
≤75 years old - 20 mg
20 mg
≤75 years old - 40 mg
N/A
> 75 years old - 4 mg 
16 mg 
> 75 years old - 20 mg
-1
≤75 years old - 12 mg
20 mg
≤75 years old - 20 mg
N/A
> 75 years old - 2 mg 
16 mg 
> 75 years old - 12 mg
-2
≤75 years old - 0 mg
20 mg
≤75 years old - 12 mg
N/A
> 75 years old - 0 mg 
16 mg 
> 75 years old - 8 mg
-3
≤75 years old - 0 mg
Contact 
Medical 
Monitor
≤75 years old - 0 mg
N/A
> 75 years old - 0 mg
> 75 years old - 0 mg
Pomalidomide
Below  are  the  recommended  dose  adjustments  for  
the  management  of  thrombocytopenia  and 
neutropenia  judged  by  the  investigator  to  be related  to  pomalidomide.  Information  in Table 
4.1.6-3 and Table  4.1.6-4 is  based  on  pomalidomide  prescribing  information,  which  contains 
additional  guidance  on  pomalidomide  dosing.  
Investigators  should  
follow  
the  guidelines  
in  
the 
prescribing  information  for  pomalidomide.104 Some  clinically  relevant  events  and  their 
management are presented below.
Table 4.1.6-3: 
Treating Thrombocytopenia Related to Pomalidomide
When Platelet Count:
Recommended Course:
• Fall to < 25,000 per mm3
• Interrupt  pomalidomide  treatment,  follow  Complete 
Blood Count weekly.
• Return to ≥ 50,000 per mm3
• Resume pomalidomide at 3 mg daily
• For each subsequent drop < 25,000 mm3
• Interrupt pomalidomide treatment
• Return to ≥50,000 mm
3
• Resume pomalidomide at 1 mg less than previous dose
Table 4.1.6-4: 
Treating Neutropenia Related to Pomalidomide
When Neutrophil Count:
Recommended Course:
• Fall to < 500 per mm3or febrile neutropenia
(fever ≥38.5oC and ANC < 1,000 mm3)
• Interrupt  pomalidomide  treatment,  follow  Complete 
Blood Count weekly.
• ANC returns to ≥1000 per mm
3
• Resume pomalidomide at 3 mg daily
• For each subsequent drop < 500 mm3
• Interrupt pomalidomide treatment
• Return to ≥1000 mm3
• Resume pomalidomide at 1 mg less than previous dose
ANC, absolute neutrophil count. In case of neutropenia, consider the use of growth factors in subject management.
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If necessary to co-administer strong inhibitors of CYP1A2 in the presence of strong inhibitors of 
CYP3A4 and P-glycoprotein, consider reducing pomalidomide dose by 50%.104
4.1.7 
Treatment During Follow-up
MM  subjects  in  the  nivolumab/daratumumab  cohorts  will  receive  treatment  until  disease 
progression  and  will  not  be  eligible  for  additional  study  
therapy  after  confirmation  of  disease 
progression.
4.2 
Method of Assigning Subject Identification
After informed consent has been obtained, the subject must be enrolled into the study by calling 
an  
interactive  voice response system (IVRS) to obtain the subject number. The exact procedure 
for using the IVRS will be detailed in a separate document.
4.3 
Blinding/Unblinding
Not applicable.
4.4 
Treatment Compliance
Study drug will be administered in the clinical facility. The investigator or their designated study 
personnel  will  maintain  a  
log  
(Drug Accountability  Log)  of  all  study  drugs  
received  dispensed 
and destroyed. The investigator and the study personnel will ensure that each subject receives the 
calculated dose of the study drug based on body weight. 
Drug  supplies  will  be  inventoried  and  accounted  for  throughout the  study.  The  Drug 
Accountability  Log  will  be  reviewed  by  the  study  monitor during site  visits  and  at  the 
completion of the study. Any discrepancy should be brought to the attention of the Sponsor.
4.5 
Destruction and Return of Study Drug
4.5.1 
Destruction of Study Drug
For  this  study,  study  drugs  (those  supplied  by  BMS  or  sourced  by  the  investigator)  such  as 
partially used study drug containers, vials and syringes may be destroyed on site. 
Any  unused  study  drugs  can  only  be  destroyed  after  being  inspected  and  reconciled  by  the 
responsible BMS Study Monitor unless study drug containers must be immediately destroyed as 
required for safety, or to meet local regulations (eg, cytotoxics or biologics).
On-site destruction is allowed provided the following minimal standards are met:
• On-site disposal practices must not expose humans to risks from the drug.
• On-site  disposal  practices  and  procedures  are  in  agreement  with  applicable  laws  and 
regulations, including any special requirements for controlled or hazardous substances.
• Written procedures for on-site disposal are available and  
followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request.
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• Records  are  maintained  that  allow  for  traceability  of  each  container,  including  the  date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method  of  disposal,  ie,  incinerator,  licensed  sanitary  landfill,  or  licensed  waste  disposal 
vendor must be documented.
• Accountability and disposal records are complete, up-to-date, and available  
for the Monitor 
to review throughout the clinical trial period.
If  conditions  for  destruction  cannot  be  met  the  responsible  BMS  Study  Monitor  will  make 
arrangements for return of study drug.
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
4.5.2 
Return of Study Drug
If  study  drug  will  not  be  destroyed  upon  completion  or  termination  of  the  study,  all  unused 
and/or partially used study drug that was supplied by BMS must be returned to BMS. The return 
of study drug will be arranged by the responsible BMS Study Monitor. 
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
 
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5.2 
Study Materials
• Instructions and kits for collections, processing and shipment of blood and tissue samples
• Investigator Brochure
• Local laboratory data entry instructions
• IVRS registration instructions
• Study drug supplies
• CRF Instructions
• SAE forms
• Pregnancy Surveillance Forms
• CTCAE version 4.0.
5.3 
Safety Assessments
Adverse  events  will  be  assessed  continuously during  the  study  and  for  100  days  post  last 
treatment.  Adverse  events  will  be  coded  using  the  most  current version  of  MedDRA  and 
reviewed  for  potential  significance  and  clinical  importance.  Adverse  events  will  be  evaluated 
according to the NCI CTCAE Version 4.0 dated June 14, 2010. Subjects should be followed until 
all  treatment-related  AEs have  recovered  to  baseline  or  are  deemed  irreversible  by  the 
investigator.
Only data  
for the procedures and assessments specified  
in this protocol should  be submitted to 
BMS.  Additional  procedures  and  assessments  may  be  performed  as part  of  standard  of  care; 
however, the data for these assessments should remain in the subject’s medical record and should 
not  be  provided  to  BMS,  unless  specifically  requested  from  the Sponsor.  Safety  assessments 
must be done prior to dosing. The local safety labs (complete blood count, chemistry panel) and 
procedures may be collected or performed up to 3 days prior to the visit. For subjects who skip a 
dose, local safety labs results must be collected at least once per cycle.
All subjects will be assessed for safety. Safety evaluations include assessments of AEs, clinical 
laboratory  tests  (hematology,  chemistry),  vital  sign  measurements,  and  physical  examination 
with assessment of ECOG PS. Investigators are responsible for monitoring the safety of subjects 
who have entered this study and for alerting the Sponsor to any event that seems unusual, even if 
this  event  may  be  considered  an  unanticipated  benefit  to  the subject.  The  investigator  is 
responsible for appropriate medical care of subjects during the study.
5.3.1 
Laboratory Assessments
Laboratory  assessments  for  safety  will  be  performed  at  local  laboratories.  Safety  laboratory 
assessments are listed in the Flow Chart/Time and Events Schedule presented in Section 5.1.
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5.4 
Efficacy Assessments
Efficacy assessment will be conducted and reported on the eCRF using the appropriate efficacy 
assessment  based  on  tumor  
type.  Subjects  with  multiple  myeloma will  be  evaluated  with  the 
International  Myeloma  Working  Group  Uniform  Response  Criteria  to  define  response  and 
progressive disease (Appendix 3).
5.4.1 
Efficacy Assessments in the Nivolumab/Daratumumab Cohorts
Efficacy  endpoints  in  MM  subjects  in  the  nivolumab/daratumumab cohorts  will  be  based  on 
analysis of  molecular and cytometry  minimal residual disease (MRD) and  based on serum and 
urine electrophoresis (SPEP and UPEP) with  
immunofixation, sFLC (for those with sFLC only 
disease),  corrected calcium  (serum  calcium  and  serum  albumin),  imaging  and  bone  marrow 
assessments, all at predefined intervals as specified in Section 5.1. 
Assessments  done  at  
local  
laboratories versus  central  
laboratories are  
indicated  
in Section 5.1. 
Assessments for molecular and cytometry MRD, and of SPEP, UPEP and sFLC will be based on 
central  
lab  
results,  whereas  assessments  of  bone  
lesions,  extramedullary  plasmacytomas,  bone 
marrow  disease  assessment  and  corrected  calcium  will  be  based  on  local  analysis  at  
the  site.
Efficacy assessments in subjects in the nivolumab-daratumumab Cohort A will be performed at 
the respective local laboratory.
5.4.1.1 
Primary Efficacy Assessment: MRD
Molecular  minimum  
residual  disease  
(MRD)  assessment  will  be  performed  via  
the  Adaptive®
ClonoSIGHT assay and bone marrow aspirate samples are required at the following time points:
• Bone marrow aspirate samples at Screening, Day 1 Cycle 4 or at the time of VGPR or better, 
whichever  occurs  first,  and  every  6  cycles thereafter  until  disease  progression.  
In  subjects 
with  confirmed  PD  prior  
to  Day  1  Cycle  4,  bone  marrow  aspirate will  be  performed  upon 
confirmation of PD. If bone marrow aspirate was inadvertently not collectedor unable to be 
collected at  
these  required  
time points,  
the  study  medical  Monitor  should  be  contacted  
to 
discuss the timing of the collection
Cytometry  MRD  from  bone  marrow aspirates  will  be  done  at  the  same  time points  as  for 
molecular MRD, except for the Screening timepoint.
5.4.1.2 
Secondary Efficacy Assessment: IMWG Response
Modified  IMWG  Response  criteria  in  Appendix  3 will  be  used  for  
the  efficacy  analysis.  All 
response and progression categories require 2 consecutive assessments to confirm response and 
progression  before  initiation  of  any  new  
therapy.  For  
the  purposes  of  
this  study,  all  subjects’ 
tumor  assessments  by  myeloma  laboratory  tests  (SPEP  M  protein  and  UPEP  M  protein 
quantification, corrected calcium (calcium and  albumin), and  serum  
free  
light chain) should  be 
re-evaluated per the protocol-stated frequency relative to the date of first dose of study drug until 
disease progression  based  on  Appendix  3,  irrespective  of  dose  delays  or  treatment  cycle. If 
subject does not have documented disease progression as defined in Appendix 3 at the time 
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of  study  drug  discontinuation,  then  tumor  assessments  must  continue  to  be  performed 
according  to  the  same  schedule  described  above  until  disease  progression  even  if  a 
subsequent  anti-myeloma  
treatment  
is  
initiated  prior  
to  disease  progression. Subjects  will 
be  followed  every  12  weeks,  or  more  frequently,  after  disease  progression  for  survival, 
subsequent  myeloma  therapy,  and, for  subjects  treated  with  pomalidomide,  development  of 
second primary malignancy.
All  efficacy  laboratory  assessments  (SPEP,  UPEP,  serum/urine  immunofixation,  and  sFLC) 
should  be  done  through  the  central  laboratoryfor  subjects  in Cohort  B,  except  for  corrected 
calcium  (serum  calcium  and  serum  albumin) which  will  be  done  locally.  Bone  marrow 
assessments  for  plasma  cell  percentage  and  light  chain  restriction  (clonality  by  IHC  or  flow 
cytometry) will be done locally per institution standard practice. For any SPEP, UPEP, or sFLC 
assessment performed locally, in lieu of a central laboratory assessment, (ie, if the subject cannot 
complete a visit at the study  site), M protein absolute quantification (eg, g/dL or mg/24  hrs)  
in 
serum  and  urine  or  sFLC  (eg,  mg/L  or  mg/dL) must  be  performed.  Any  laboratory  samples 
analyzed  locally,  including  for  efficacy,  must  be  entered  on  the  appropriate  CRF/eCRF  as 
requested by the Sponsor to properly assess efficacy per protocol criteria.
Subjects in Cohort A will have all efficacy assessments performed at the local laboratory.
Laboratory Assessments for Multiple Myeloma
All  
laboratory efficacy assessments  must be performed until disease progression or withdrawal 
of consent, even if the subject is discontinued from study therapy and has started new myeloma 
therapy. Confirmation of ≥PR or PD is required on 2 consecutive assessments for serum, urine 
and sFLC.
Daratumumab  is  a  human  IgG  kappa  monoclonal  antibody  that  can  be  detected  on  both,  
the 
serum  protein  electrophoresis  (SPEP)  and  immunofixation  (IFE)  assays  used  for  the  clinical 
monitoring  of  endogenous  M-protein.  This  interference  can  impact  the  determination  of 
complete  response  and  of  disease  progression  by  International  Myeloma  Working  Group 
(IMWG) criteria in some patients with IgG kappa myeloma protein.
It  
is  
likely  
that  nivolumab  may  also  be  detected  by  SPEP  and  
immunofixation  but  
this  
is  still 
under  investigation. Serum  or  peripheral  blood  samples  collected  during  the  study  may  be 
analyzed  for  the  presence  of  monoclonal  antibody  interference with  endogenous  patient  M 
protein quantification.
1) Serum: SPEP for M protein quantification, total serum protein, serumimmunofixation, and 
quantitative immunoglobulin assay.
a. Serum  Immunofixation  (IFE)  is  required  at  baseline  and  to  confirm  CR  regardless  of 
whether measurable M-protein was present at baseline.
b. Subjects with measurable disease in SPEP will be assessed for response based on SPEP 
and not by the serum FLC assay.
c. Subjects with measurable disease in both SPEP and UPEP will be assessed for response 
based on these two tests and not by the serum FLC assay.
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d. Subjects with FLC only disease should be monitored by sFLC only
2) Serum free light chain (sFLC): 
a. Subjects without measurable serum M-protein (ie, < 0.5 g/dL [5 g/L]) or urine M-protein 
(ie, < 200 mg [0.2 g]per 24 hours) and considered oligosecretory must have sFLC 
assessed at each cycle until progression.
b. SPEP and UPEP must be monitored at all time points in oligosecretory patients for 
potential disease progression determination. 
c. Serum for sFLC must be collected at time of serum and urine IFE negativity to confirm 
sCR in all subjects.
3) Urine:  24-hour  urine  collection  for  M protein  quantification  and  
immunofixation.  24-hour 
urine must be collected with each cycle for all subjects.
a. Urine  Immunofixation  (IFE)  is  required  at  baseline  and  to  confirm  CR,  regardless  of 
whether measurable M-protein was present at baseline.
b. Subjects with measurable disease in UPEP will be assessed for response based on UPEP 
and not by the serum FLC assay.
4) Bone marrow aspiration/biopsy(Section 5.6.1.1):
a. Bone  marrow  aspirate  for evaluation  of  percentage  plasma  cells  and  light  chain 
restriction: samples  are  required  at  Cycle  4  Day  1  or  at the  
time  of  VGPR  or better, 
whichever occurs first, and then every 6 cycles thereafter until PD (second bone marrow 
sample not required for confirmation). See Section 5.4.1.1.
b. Bone  marrow  biopsy is  not  required  by  protocol  unless  an  aspirate  sample  (at  any 
timepoint above) is not available due to a dry tap.
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Table 5.4.1.2-1: 
Bone Marrow Samples
Sample 
Local Laboratory 
Central Laboratory 
Aspirate  
Samples are required at the following times: 
• Screening (plasma cell percentage 
only)
• C4D1 or ≥VGPR, whichever occurs 
first, then every 6 cycles until 
progression
• In subjects with progression before
C4D1, bone marrow aspirate should 
be done upon progression 
confirmation.
Evaluationof plasma cell percentage and light 
chain restriction assessments (clonality by 
IHC or flow cytometry) performed locally per 
institution standard practice
Genetic assessments (FISH): samples are 
required at screening
Biomarker assessments: samples are required at 
• Screening 
• C4D1 or ≥VGPR, whichever occurs 
first, then every 6 cycles until 
progression
• In subjects with progression before 
C4D1, bone marrow aspirate should be
done upon progression confirmation
Biopsy
Not required by protocol unless an aspirate 
sample (at any timepoint above) is not 
available due to a dry tap 
NA
Genetic  assessments  (FISH)  should  be  performed  by  the  central  laboratory  on  a  fresh  bone 
marrow sample.  However,  
if  a  new  bone  marrow  sample  collection  
is  not  
feasible  and  
if  
this 
assessment was performed locally during the screening period, the local results must be entered 
into the eCRF. Contact BMS medical monitor in these cases.
5) Serum  Corrected  Calcium:  Serum  corrected calcium  should  be  collected  with  each  cycle 
for all subjects until disease progression.
Corrected Calcium, mg/dL = (0.8 x [Normal Albumin, g/dL - Subject’s Albumin, g/dL] + Serum 
Ca, mg/dL
Imaging Assessments for Myeloma
Skeletal Survey
Skeletal  survey,  by  conventional  
radiography,  for  metastatic  disease  will  be  performed  within 
28 days of randomization in all subjects. Skeletal survey will be performed on study if clinically 
indicated (development of compression fracture does not exclude response). Use of conventional 
or  low  dose  CT  scan  (ie,  of  the  spine)  or  PET/CT bone  survey  is acceptable.  If  imaging  is 
performed  on  
treatment  
for  assessment  of  progression,  
the  site must  use  
the  same  modality  of 
imaging as used in screening. The number and location of skeletal lesions and whether they are 
lytic  should  be  
recorded  on  
the  eCRF.  On-treatment  survey  should  
record  whether  
there  
is  an 
increase in the number or size of lytic lesions.
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Assessment of Extramedullary Plasmacytoma
Computed  
tomography  or  MRI  should  be  performed at  screening,  if  clinically  indicated  or  
if 
patient had a previous extramedullary or bone 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 (i.e., pain, concern for disease
progression), whether or not present at baseline, and at the time of CR/sCR assessment.
A  sum  of  the  products  of  the  longest  diameters  and  longest  perpendicular  diameter  for  all 
measurable lesions will be calculated at screening. 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  and 
non-measurable  
lesions  are  
to be  
followed  
throughout the  
trial.  All  assessments  
to  be  used  
for 
tumor response evaluation, including the baseline assessment, must be performed using the same 
method for repeat assessment. CT and MRI scanning are the preferable methods of assessment. 
Conventional CT and MRI should be performed with contiguous cuts of 10 mm or less or with 
cuts  of  5  (or  10)  mm  if  spiral  CT  scanning  is  used.  Imaging-based  evaluation  is  preferred  
to 
evaluation by clinical examination. Evaluation by chest x-ray is less preferable than CT or MRI, 
and  should  only  be  used  for  well-defined  lesions  surrounded  by aerated  lung.  Clinical 
examination  
is  only  acceptable  when  
lesions  are  superficial,  such  as  a  skin  nodule  or  palpable 
lymph  node. Skin  
lesions  must be documented by a photograph with a ruler. Ultrasound  
is  not 
acceptable for documentation of measurable disease.
For patients with MM, duplicate copies of all imaging studies used for tumor response evaluation 
will be made available for review by the Sponsor 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 or MRI. The minimum diameter size should be at least twice the 
slice thickness.
Non-measurable  disease  are  all  other  
lesions (or  sites  of  disease),  
including  
those  
that  are too 
small (ie, 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.
5.4.2 
Bone Marrow Biopsy and Aspiration
Bone marrow aspirates will be mandated for all subjects for biomarker assessments at screening, 
C4D1 or ≥VGPR, whichever occurs first, then every 6 cycles until progression. In subjects with 
progression before C4D1, bone marrow aspirate should be done upon progression confirmation.
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Bone marrow aspirates will be required in all subjects in these cohorts. Bone marrow biopsy is 
optional. Bone marrow biopsy is required if an aspirate sample (at any required time point) is not 
available due to a dry tap.
At  
the  
time  of  
the  scheduled bone  marrow  aspirate,  
the  PI  will  determine  if  
there  have  been 
significant  changes  in  the  clinical  course  to  suggest  that  subjects  can  no  longer  undergo  the 
procedure  safely.  These  subjects  for  whom  
the  PI  
finds  
the  degree  of  
risk  associated  with  
the 
procedure not acceptable may continue therapy.
The first aspirate will be obtained prior to therapy (within 28 days). The next aspirates must be 
obtained  at  Day  1  Cycle  4 or at  
the  
time  of  VGPR  or better,  whichever  occurs  
first,  and  
then 
every 6 cycles until disease progression. 
At  
the  time  of  disease  progression  or  end  of  treatment, bone  marrow  aspirate  collections  are
optional but strongly encouraged to investigate the mechanisms of resistance to the therapy (See 
Section 5.6.1.1). SeeTable 5.1-6for collection time points.
In subjects with confirmed PD prior to Day 1 Cycle 4, bone  marrow aspirate  must be obtained 
upon confirmation of PD.
Bone marrow biopsies are not required by protocol unless an aspirate sample (at any time point 
inTable 5.1-6) is not available due to a dry tap and can be used only for disease assessment. 
5.5 
Pharmacokinetic Assessments
5.5.1 
Pharmacokinetic Collection & Processing
Table  5.1-7lists  the PK sampling  schedule  to  be  followed  in  the  daratumumab combination
cohorts. Cmin  will  be  reported  for all  subjects  with  available  data  for  
the  assessment  of  PK. 
Cmin and concentrations at end-of-infusion will  be reported for all subjects with available data 
for the assessment of PK. Serial samples will  be  collected after the  
first dose and at additional 
time points. All on-treatment predose and end-of-infusion PK time points are  
intended to align 
with  days  on  which  study  drug  is  administered.  If  dosing  occurs  on  a  different  day,  the  PK 
sampling  should  be  adjusted  accordingly.  Further  details  of  sample  collection, processing, and 
shipment are provided in the laboratory manual.
5.5.2 
Pharmacokinetic Sample Analyses
The serum samples will  be analyzed  
for nivolumab  by  validated  methods. In addition, selected 
serum samples  may  be analyzed  by  an exploratory  analytical  method that  measures  nivolumab 
and/or  daratumumab  for  technology  exploration  purposes;  exploratory  results  will  not  be 
reported.
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5.10 
Results of Central Assessments
All  myeloma  efficacy  
laboratory  assessments  
in  Cohort  B  should  be  performed  by  
the  central 
laboratory.  Investigative  site  staff  will  receive reports  of  the  results  on  an  ongoing  basis  for 
treatment  decisions  and  patient  management  throughout  the  study.  Any  laboratory  samples 
analyzed locally, including those for efficacy, must be entered on the appropriate CRF/eCRF as 
requested by the Sponsor to properly assess efficacy per protocol criteria.
6 
ADVERSE EVENTS
An Adverse Event (AE)is defined as any new untoward medical occurrence or worsening of a 
preexisting  medical condition  
in a clinical  
investigation  subject administered an  
investigational 
(medicinal) product and that does not necessarily have a causal relationship with this treatment. 
An  AE can therefore  be any  unfavorable and unintended sign (such  as an abnormal  
laboratory 
finding),  symptom,  or  disease temporally  associated  with  the  use  of  investigational  product, 
whether or not considered related to the investigational product.
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The causal relationship to study drug is determined by a physician and should be used to assess 
all AEs. The casual relationship can be one of the following:
• Related: There is a reasonable causal relationship between study drug administration and the 
AE.
• Not related: There is not a reasonable causal relationship between study drug administration 
and the AE.
The  term  "reasonable  causal  relationship"  means  there  is  evidence  to  suggest  a  causal 
relationship. 
Adverse  events  can  be  spontaneously  reported  or  elicited  during  open-ended  questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.)
6.1 
Serious Adverse Events
A Serious Adverse Event (SAE)is any untoward medical occurrence that at any dose: 
• results in death
• is life-threatening (defined as an event in which the subject was at risk of death at the time of 
the  event;  
it  does  not  
refer  
to  an  event  which  hypothetically  might  have  caused  death  
if  
it 
were more severe)
• requires  inpatient hospitalization  or  causes  prolongation  of  existing  hospitalization 
(seeNOTEbelow)
• results in persistent or significant disability/incapacity
• is a congenital anomaly/birth defect 
• is  an  
important  medical  event  
(defined  as  a  medical  event(s)  
that  may  not  be  
immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific  judgment,  may  jeopardize  the  subject  or  may  require intervention  [eg,  medical, 
surgical]  to  prevent  one  of  the  other  serious  outcomes  listed  in  the  definition  above.) 
Examples of such events include, but are not limited to, intensive treatment in an emergency 
room  or  at  home  for allergic  bronchospasm;  blood  dyscrasias  or  convulsions  that  do not 
result  in  hospitalization.)  Potential  drug  induced  liver  injury  (DILI)  is  also  considered  an 
important medical event. (See Section 6.6for the definition of potential DILI.)
Suspected  
transmission  of  an  
infectious  agent  
(eg,  pathogenic  or nonpathogenic)  via  
the  study 
drug is an SAE.
Although  pregnancy,  overdose,  cancer,  and  potential  drug  induced  liver  injury  (DILI)  are  not 
always  serious  by  regulatory  definition,  these  events  must  be  handled  as  SAEs. 
(SeeSection 6.1.1for reporting pregnancies.)
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NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 
−a  visit  to  the  emergency  room  or  other  hospital  department  < 24 hours,  that  does  not 
result in admission (unless considered an important medical or life-threatening event)
−elective surgery, planned prior to signing consent
−admissions as per protocol for a planned medical/surgical procedure
−routine  health  assessment  requiring  admission  for  baseline/trending  of  health  status 
(eg, routine colonoscopy)
−medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases
−admission  encountered  for  another  life  circumstance  that carries  no  bearing  on  health 
status  and  requires  no  medical/surgical  intervention  (eg,  lack of  housing,  economic 
inadequacy, caregiver respite, family circumstances, administrative reason).
6.1.1 
Serious Adverse Event Collection and Reporting
Sections  5.6.1  and  5.6.2  in  the  nivolumab  IB  represent  the  Reference  Safety  Information  to 
determine expectedness of SAEs for expedited reporting. Following the subject’s written consent 
to  participate  in  the  study,  all  SAEs,  whether  related  or  not  related  to  study drug,  must  be 
collected, including those thought to be associated with protocol-specified procedures. All SAEs 
must be collected that occur during the screening period and within 100 days of discontinuation 
of dosing or within 30 days of the last visit for screen failures. For subjects randomized but never 
treated  with  any  study  drug,  SAEs  should  be  collected  for  30  days  from  the  date  of 
randomization.
The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure.
An SAE report should be completed for any event where doubt exists regarding its seriousness. 
If the investigator believes that an SAE is not related to study drug, but is potentially related to 
the conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship should be specified in the narrative section of the SAE Report Form.
SAEs,  whether  
related  or  not  
related  
to  study  drug,  and  pregnancies  must  be  
reported to  BMS 
(or designee) within 24 hours. SAEs must be recorded on the SAE Report Form; pregnancies on 
a Pregnancy Surveillance Form (electronic or paper forms). When using paper forms, the reports 
are to be transmitted via email or confirmed facsimile (fax) transmission to:
SAE Email Address: See Contact Information list.
SAE Facsimile Number: See Contact Information list.
For  studies  capturing  SAEs/pregnancies  through  electronic  data capture  (EDC),  electronic 
submission is the required method for reporting. The paper forms should be used and submitted 
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immediately, only in the event the electronic system is unavailable for transmission. When paper 
forms are used, the original paper forms are to remain on site.
SAE Telephone Contact(required for SAE and pregnancy reporting): See Contact Information 
list.
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term[s] initially reported.) 
If  an  ongoing  SAE  changes  
in  
its  
intensity  or  
relationship  
to  study  drug  or  
if  new  
information 
becomes available, a follow-up SAE report should be sent within 24 hours to BMS (or designee) 
using the same procedure used for transmitting the initial SAE report.
All SAEs should be followed to resolution or stabilization.
A SUSAR (Suspected, Unexpected Serious  Adverse Reaction)  
is a  subset of SAEs and will  be 
reported  
to  
the  appropriate  regulatory  authorities  and  investigators  following  local  and  global 
guidelines and requirements. 
6.2 
Nonserious Adverse Events
Anonserious adverse eventis an AE not classified as serious.
6.2.1 
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information should begin at initiation of study drug. Nonserious 
AE  information  should  also  be  collected  from  the  start  of  a  placebo lead-in  period  or  other 
observational period intended to establish a baseline status for the subjects. All non-serious AEs
(not  only  those  deemed  to  be  treatment-related)  should  be  collected  continuously during  the 
treatment period and for a minimum of 100 days following the last dose of study drug treatment.
Nonserious  AEs  should  be  followed  
to  
resolution  or  stabilization,  or  
reported  as  SAEs  
if  
they 
become  serious  (seeSection  6.1.1).  Follow-up  is  also  required  for  nonserious  AEs  
that  cause 
interruption or discontinuation of study drug and for those present at the end of study treatment 
as appropriate. All identified nonserious AEs must be recorded and described on the nonserious 
AE page of the CRF (paper or electronic). 
Completion  of  supplemental  CRFs  may  be  requested  for  AEs  and/or  
laboratory  abnormalities 
that are reported/identified during the course of the study.
6.3 
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form (paper or electronic) as appropriate:
• Any laboratory test result that is clinically significant or meets the definition of an SAE 
• Any laboratory  test  result  abnormality  that  required  the  subject  to  have  study  drug 
discontinued or interrupted
• Any laboratory test result abnormality that required the subject to receive specific corrective 
therapy.
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It is expected that wherever possible, the clinical  
rather than  
laboratory term would  be used  by 
the reporting investigator (eg, anemia versus low hemoglobin value).
6.4 
Pregnancy
If,  following  initiation  of  the  investigational  product,  it  is discovered  that  a  study  subject  is 
pregnant or may  have  been pregnant at the time  of  
investigational product exposure, including 
during at least time to washout plus one ovulatory cycle (30 days) for a total of 23 weeks, or plus 
one  spermatogenesis  cycle  (90  days)  for  a  
total  of  31  weeks  after  product  administration,  
the 
investigator  must  immediately  notify  the  BMS  Medical  Monitor/designee  of  this  event  and 
complete  and  forward  a  Pregnancy  Surveillance  Form  to  BMS  Designee  within  24  hours  of 
awareness of the event and in accordance with SAE reporting procedures.
In  most  cases,  the  study  drug  will  be  permanently  discontinued in  an  appropriate  manner 
(eg, dose tapering if necessary for subject safety). Please call the BMS Medical Monitor within 
24 hours of awareness of the pregnancy.
Follow-up  
information  
regarding  
the  course of  
the  pregnancy,  
including  perinatal  and  neonatal 
outcome  and,  where  applicable,  offspring  information,  must  be  reported  on  the  Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
6.5 
Overdose
An overdose is defined as accidental or intentional administration of any dose of product that is 
considered  both  excessive  and  medically  important.  All  occurrences  of  overdose  must  be 
reported as SAEs (seeSection 6.1.1for reporting details).
6.6 
Potential Drug Induced Liver Injury (DILI)
Wherever  possible,  
timely  confirmation  of  initial  liver-related  
laboratory  abnormalities  should 
occur  prior  to  the  reporting  of  a  potential  DILI  event.  All  occurrences  of  potential  DILIs, 
meeting the defined criteria, must be reported as SAEs (see Section 6.1.1for reporting details).
Potential drug induced liver injury is defined as
1) AT (ALT or AST) elevation > 3 times upper limit of normal (ULN)
AND
2) Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase),
AND
3) No  other  immediately  apparent  possible  causes  of  AT  elevation  and  hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic.
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6.7 
Other Safety Considerations
Any  significant  worsening  noted  during  interim  or  final  physical  examinations, 
electrocardiogram, x-ray filming, any other potential safety assessment required or not required 
by protocol should also be recorded as a nonserious or serious AE, as appropriate, and reported 
accordingly.
Second primary malignancies (SPMs) will be collected throughout the study for subjects treated 
with  pomalidomide  and includes  assessments  during  survival  follow-up.  All  SPMs  
that  occur 
during the screening period and within 100 days of discontinuation of dosing will be reported as 
an  SAE  
regardless  of  
relationship  
to  study  drug.  Additionally, any  SPM  
that  occurs  after  
this 
timeframe and considered related to study drug will be reported as an SAE. All other SPMs will 
be collected and reported on a separate CRF page.
7 
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
Not applicable.
8 
STATISTICAL CONSIDERATIONS
 
 
 
  
 
 
 
 
 
 
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8.2 
Populations for Analyses
• All Enrolled Subjects:  All subjects who sign  
informed consent form and were registered  
in 
IVRS.
• All  Treated  Subjects:  All  subjects  who  receive  at  least  one dose  of  nivolumab  and/or 
daratumumab.
• Response  Evaluable  Subjects:  All  
treated  subjects  with  measurable  disease  at  baseline  and 
one of the following: 1) at least one on-treatment efficacy assessment, 2) clinical progression, 
or 3) death.
• Pharmacokinetic  (PK)  Subjects:  All  subjects  who  receive  at  least  one  dose  of  study 
medication and have available serum concentration data.
• Biomarker Subjects: All subjects who receive at least one dose of study medication and have 
available biomarker data
• Immunogenicity Subjects: All subjects who receive at least one dose of study medication and 
have available ADA data.
8.3 
Endpoints
8.3.1 
Primary Endpoint(s)
8.3.1.1 
Safety
The  primary  objective  relates  to  evaluate  the  safety  and  tolerability  of  the  nivolumab and 
daratumumab combination therapy in subjects with relapsed/refractory MM. This objective will 
be measured by the following endpoints:
• Number and percent of subjects that experience drug-related grade 3-4 AEs occurring up to 
100 days  after  the  last  dose  of  study  drug.  [Time  Frame  - On  a  continuous  basis  up  to 
100 days after the last dose of study drug];
• Number and percent of subjects that experience drug-related grade 3-4 SAEs occurring up to 
100 days  after  the  last  dose  of  study  drug.  [Time  Frame  - On  a  continuous  basis  up  to 
100 days after the last dose of study drug];
• Number and percent of subjects with clinical laboratory abnormalities by worst toxicity grade 
by  NCI CTCAE version  4.0 (as  assessed at  the  planned  times  listed  in Section  5.1). 
(Time Frame - On a continuous basis up to 100 days after the last dose of study drug).
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8.3.2 
Secondary Endpoint(s)
8.3.2.1 
Efficacy
The secondary objective relating to efficacy is to assess the preliminary antitumor activity in the 
combination  of  nivolumab and  daratumumab  in  subjects  with  relapsed/refractory  MM.  This 
objective  will  be  measured  by minimal  
residual  disease  status  
(MRD),  objective response  
rate 
(ORR),  duration  of  response  (DOR),  and  progression-free  survival  (PFS)  for  MM  subjects  in 
each treatment regimen group.
Minimal Residual Disease (MRD) in the Nivolumab/Daratumumab Cohorts
Both cytometry and molecular MRD from bone marrow aspirate will be evaluated. 
The time point for MRD negative status for MM subjects in the nivolumab/daratumumab cohorts 
is a dichotomized variable for quantifiable MRD detection.
The first MRD negativity status is defined as the first negative status designation over the study 
as  a  whole,  recorded  between  the  date  of  first  dose  and  the  last  efficacy  assessment  prior  
to 
subsequent therapy.
The best MRD negativity status is defined as the best status designation with the minimum MRD 
levels  over  
the  study  as  a  whole,  
recorded  between  
the  date  of first  dose  and  
the  
last  efficacy 
assessment prior to subsequent therapy.
Objective Response Rate (ORR)
Best  overall  response  (BOR) is  defined  as  the  best  response  designation  over  the  study  as  a 
whole,  recorded  between  the  date  of  first  dose  and  the  last  efficacy  assessment  prior  to 
subsequent therapy.
Objective response rate is defined as the proportion of subjects who had a BOR of either partial 
response  (PR)  or  complete  response  (CR)  divided  by  the  number  of  treated  subjects  (or 
response-evaluable subjects).
Duration of Objective Response (DOR)
The duration of response is defined as the time when the measurement criteria are first met for 
objective response until the date of documented disease progression or death, whichever occurs 
first. For subjects who neither progress nor die, the duration of response will be censored at the 
date of their last disease assessment.
Progression Free Survival (PFS)
Progression free survival (PFS) is defined as the time between date of randomization and date of 
progression  or  death,  whichever  occurs  first.  Subjects  who  die without  a  reported  prior 
progression  will  be considered to have progressed on the date of their death. Subjects who did 
not progress or die will be censored on the date of their last efficacy assessment. Subjects who 
did not have any on study efficacy assessments will be censored on the date of randomization.
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8.3.2.2 
Pharmacokinetic
The  following  pharmacokinetic  parameters  of  nivolumab  will  be  derived  from  serum 
concentration  
time  profiles  
for all  subjects  and  subjects  
following  
the  
full  PK  profile  sampling 
schedule  in  the  combination  cohorts.  Cmin  and  Ceoinf  will  be  reported  for all  subjects  with 
available  data.  These  parameters are  used  to  measure  the  secondary  objective  related  to 
pharmacokinetics.
Cmax - Maximum observed serum concentration
Tmax - Time of maximum observed serum concentration
In addition, the following parameters will be determined for all subjects:
Cmin- Serum  concentration  achieved  at  
the  end  of  dosing  interval  (trough  concentration,  all 
subjects)
AUC(0-T)-Area under the plasma  concentration-time curve  
from time zero to the  
last time of 
the last quantifiable concentration.
AUC(TAU)- Area under the concentration-time curve in one dosing interval
Ceoinf - Serum concentration achieved at the end of study drug infusion
8.3.2.3 Immunogenicity
The secondary objective relating to immunogenicity will be measured by the ADA status both at 
the  sample  level  and  at  the  subject  level.  At  the  sample  level a  sample  is  characterized  as 
baseline ADA-positive, ADA-positive or ADA-negative to each study drug. At the subject level, 
relevant  ADA  endpoints  
include proportion  of  subjects  with  a  Baseline  ADA-positive  sample, 
and  proportion  of  ADA-positive  subjects  for each  study  drug.  Time points  for  collection  are 
specified inTable 5.1-7. Additional details will be presented in the SAP.
 
 
 
 
 
 
8.4 
Analyses
8.4.1 
Demographics and Baseline Characteristics
Subject  demographics  and  baseline  characteristics  including  age,  sex,  race,  ethnicity,  weight, 
baseline disease diagnosis, and  medical conditions will  be summarized  by treatment group and 
overall using descriptive statistics.
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8.4.2 
Efficacy Analyses
MRD  negativity  status  for  MM  subjects  in  the  nivolumab/daratumumab  cohorts  will  be 
evaluated  by  time points.  The  frequency  of  the  MRD  negativity  status  and  the  best  MRD 
negativity  status  will  be  summarized  by  treatment  group.  The  cross  tabulation  of  the  MRD 
negativity  status  and  BOR  will  be  presented.  Summary  statistics  of  
the  MRD  
levels  and  
their 
corresponding  percent  changes  from  baseline  will  be  tabulated  by  planned  study  day  by 
treatment group. Potential association between the first/best MRD negativity status with PFS and 
OS  may be  evaluated as  appropriate.  Additional  details  will  be  presented  in  the  Statistical 
Analysis Plan.
Individual  best overall  
response (BOR),  duration  of  
response  and  PFS  will  be  
listed,  using  
the 
IMWG Uniform Response Criteria for Multiple Myeloma.
106
BOR  outcomes  will  be  
tabulated  by treatment  group.  The  objective  response  rate  (ORR)  and 
corresponding  95%  exact  CI will  be  provided  by  treatment  group.  The  median  duration  of 
response  and  PFS  and  corresponding  two-sided  95%  CIs will  be  estimated  by  Kaplan-Meier 
methodology. The analysis of overall survival would be exploratory. Kaplan-Meier plots of PFS, 
DOR, and OS will be provided. 
Final analysis will be performed after all treated subjects have been followed for a minimum of 3
months to evaluate the efficacy endpoints. 
8.4.3 
Safety Analyses
All recorded AEs will be listed and tabulated by system organ class, preferred term, and dose and 
coded according to the most current version of MedDRA
All recorded AEs will  be  
listed and tabulated by  system organ class, preferred term, treatment, 
dose and coded according to the most current version of MedDRA across disease types. A subset 
of adverse event tables may be summarized by disease type. DLTs will be described by treatment 
and  dose.  The  incidence  of  AEs will  be  reviewed  for  potential  significance  and  clinical 
importance.  AEs  will  be  coded according to the  most current  version of MedDRA. Vital  signs 
and  clinical  laboratory  
test  
results  will  be  listed  and  summarized  by  
treatment  and  dose.  Any 
significant  physical  examination  findings  and  
results  of  clinical  
laboratory  
tests  will  be  
listed. 
ECG results will be evaluated by the investigator and abnormalities, if present, will be listed.
8.4.4 
Pharmacokinetic Analyses
Summary  statistics  will  be  tabulated  for  
the  pharmacokinetic  parameters  of  nivolumab  in  the 
presence of daratumumab by treatment, disease type, dose and study week as appropriate for all 
subjects receiving  nivolumab  monotherapy and subjects  
following the  
full PK profile  sampling 
schedule in the combination cohorts. Cmin will be summarized for all subjects. To describe the 
dependency on dose, scatter plots of Cmax and AUC(0-T) versus dose will be provided for each 
day  measured by treatment and study drug. To assess attainment of steady state, plots of Cmin 
versus  
time  will  be provided  by  
treatment  and  by  study  drug  
for all  subjects.  Pharmacokinetic 
concentrations  of  nivolumab  from  all  subjects  will  be  
listed,  and  may  be  used  
in  combination 
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with  other  studies  for  exposure-response  or  population  PK modeling,  which  will  be  part  of  a 
separate report.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.4.7 
Other Analyses
8.4.7.1 Immunogenicity
A  listing  will  be  provided  of  all  available  immunogenicity  data.  Additionally,  a  listing  of 
immunogenicity  data  from  those ADA  positive  subjects  will be  provided.  The  frequency  of 
baseline positive subjects, and frequency of ADA positive subjects will be provided by treatment
group. The frequency of neutralizing antibodies will be provided based on data availability. To 
examine the potential relationship  between immunogenicity  and safety, the  
frequency  and type 
of  AEs  of  special  interest  may  be  examined  by  overall  immunogenicity  status.  Associations 
between  pre-dose  concentrations  of  nivolumab,  biomarkers,  efficacy, and  corresponding  ADA 
assessments may be explored. Additional details will be provided in the SAP.
8.5 
Interim Analyses
Administrative interim analyses may be performed as needed prior to completion of the study in 
order to facilitate program decisions and to support presentations or publications. 
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In  addition  to  
the  administrative  interim  analyses  over  the  course  of  the  study, safety  and/or 
efficacy updates may also be performed according to health authority requests.
8.5.1 
Nivolumab Daratumumab Cohort B
An interim analysis to evaluate preliminary safety and efficacy is scheduled for Cohort B when 
50% of treated patients from each treatment arm (ND and D) have had a minimum of 3 months 
of follow-up.
9 
STUDY MANAGEMENT
9.1 
Compliance
9.1.1 
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and  be prepared  by, BMS. The  
investigator should  not implement any 
deviation  or  change  to  
the  protocol  without  prior  review  and  documented  approval/favorable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior 
to  obtaining  
IRB/IEC  approval/favorable  opinion,  as  soon  as  possible  
the  deviation  or  change 
will be submitted to:
• IRB/IEC for review and approval/favorable opinion
• BMS
• Regulatory Authority(ies), if required by local regulations
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to BMS.
If  an  amendment  substantially  alters  the  study  design  or  increases  the  potential  risk  to  the 
subject: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable  opinion;  
(2) the  
revised  
form  must  be  used  
to  obtain  consent  
from  subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is an administrative letter, investigators must inform their IRB(s)/IEC(s).
9.1.2 
Monitoring
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data  quality  and  study  integrity.  On  site  
they  will  review  study  records  and  directly  compare 
them with source documents, discuss the conduct of the study with the  
investigator, and verify 
that the facilities remain acceptable. 
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In  addition,  
the  study  may  be  evaluated  by  BMS  
internal  auditors  and  government  
inspectors 
who  must be allowed access to CRFs, source documents, other study  
files, and  study  
facilities. 
BMS audit reports will be kept confidential.
The  investigator  must  notify  BMS  promptly  of  any  inspections  scheduled  by  regulatory 
authorities, and promptly forward copies of inspection reports to BMS. 
9.1.3 
Investigational Site Training
Bristol-Myers Squibb will provide quality  
investigational staff training prior to study  
initiation. 
Training  topics  will  include  but  are  not  limited  to:  GCP,  AE  reporting,  study  details  and 
procedure, electronic CRFs, study documentation, informed consent, and enrollment of WOCBP.
9.2 
Records
9.2.1 
Records Retention
The  
investigator  must  
retain  all  study  
records  and  source  documents  for  
the  maximum  period 
required  by  applicable  regulations  and  guidelines,  or  institution  procedures,  or  for  
the  period 
specified by BMS, whichever is longer. The investigator must contact BMS prior to destroying 
any records associated with the study.
BMS will notify the investigator when the study records are no longer needed.
If  the  investigator  withdraws  from  the  study  (eg,  relocation,  retirement),  
the  records  shall  be 
transferred  
to  a  mutually  agreed  upon  designee  
(eg,  another  
investigator, IRB).  Notice  of  such 
transfer will be given in writing to BMS.
9.2.2 
Study Drug Records 
It  is  the  responsibility  of  the  investigator  to  ensure  that  a  current  disposition  record  of 
investigational product  
(those  supplied  by  BMS)  
is  maintained  at  each  study  site  where  study 
drug and are inventoried and dispensed. Records or logs must comply with applicable regulations 
and guidelines and should include:
• amount received and placed in storage area
• amount currently in storage area
• label identification number or batch number 
• amount dispensed to and returned by each subject, including unique subject identifiers
• amount transferred to another area/site for dispensing or storage
• nonstudy disposition (eg, lost, wasted) 
• amount destroyed at study site, if applicable
• amount returned to BMS
• retain samples for bioavailability/bioequivalence, if applicable 
• dates and initials of person responsible for Investigational Product dispensing/accountability, 
as per the Delegation of Authority Form.
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BMS will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
9.2.3 
Case Report Forms
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or  entered  as  a  control  
in  
the  
investigation.  Data  
that  are  derived  from  source  documents  and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. 
For  sites  using  
the  BMS  electronic  data  capture  
tool,  electronic  CRFs  will  be  prepared  for  all 
data collection fields except for fields specific to SAEs and pregnancy, which will be reported on 
the paper or electronic SAE form and Pregnancy Surveillance form, respectively. Spaces may be 
left  blank  only  
in  
those  circumstances  permitted  by  study-specific  CRF  completion  guidelines 
provided by BMS. 
The  confidentiality  of  records  that  could  identify  subjects  must  be  protected,  respecting  the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, including any paper or electronic SAE/pregnancy CRFs, must be promptly 
reviewed, signed, and dated  by the  
investigator or qualified physician who  
is a subinvestigator 
and who is delegated this task on the Delegation of Authority Form. For electronic CRFs, review 
and approval/signature is completed electronically through the BMS electronic data capture tool. 
The  investigator  must  retain  a  copy  of  the  CRFs  including  records  of  the  changes  and 
corrections.
Each  individual electronically  signing  electronic  CRFs  must  meet  BMS  
training  requirements 
and  must  only  access  the  BMS  electronic  data  capture  tool  using  the  unique  user  account 
provided by BMS. User accounts are not to be shared or reassigned to other individuals.
9.3 
Clinical Study Report and Publications
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will  be  selected considering the  
following criteria: 
Subject recruitment (eg, among the top quartile of enrollers)
The data collected during this study are confidential and proprietary to BMS. Any publications 
or abstracts arising from this study require approval by BMS prior to publication or presentation 
and  must  adhere  
to  BMS’s  publication  
requirements  as  set  forth in  
the  approved  clinical  
trial 
agreement  (CTA).  All  draft  publications,  including  abstracts  or  detailed  summaries  of  any 
proposed presentations, must be submitted to BMS at the earliest practicable time for review, but 
at any event not less than 30 days before submission or presentation unless otherwise set forth in 
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the  CTA.  BMS  shall  have  the  right  to  delete  any  confidential  or  proprietary  information 
contained in any proposed presentation or abstract and may delay publication for up to 60 days 
for purposes of filing a patent application.
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10 
GLOSSARY OF TERMS
Term
Definition
Adverse Reaction 
An adverse event that is considered by either the investigator or 
BMS as related to the investigational product
Unexpected Adverse 
Reaction
An adverse reaction, the nature or severity of which is not 
consistent with the applicable product information 
(eg, Investigator Brochure for an unapproved investigational 
product)
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11 
LIST OF ABBREVIATIONS
ABO
Antibodies blood group
ADA
Anti-drug antibody
AE
Adverse event
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
AST
Aspartate aminotransferace
BM
Bone marrow
BMSC
Bone marrow stromal cells
BOR
Best overall response
BORR
Best overall response rate
BP
Blood pressure
CDC
Complement-dependent cytotoxicity
CI
Confidence interval
CR
Complete response
CRF
Case report form
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
Cytotoxic T lymphocyte-associated antigen 4
DLT
Dose-limiting toxicity
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
FDA
Food and Drug Administration
FISH
Fluorescence in situ hybridization
FSH
Follicle stimulating hormone
GCP
Good clinical practices
GCSF
Granulocyte colony stimulating factor
HBV SAg 
Hepatitis B-virus surface antigen
HCV RNA 
Hepatitis C virus ribonucleic acid
HIPAA
Health Information Portability and Accountability Act
HL
Hodgkin lymphoma
HLA
Human leukocyte antigen
HSCT
Hematopoietic stem cell transplant
ICF
Informed Consent Form
IEC
Independent Ethics Committee
iMiD
Immune modulatory drug
IP
Investigational product
IRB
Institutional Review Board
ITIM
Immunoreceptor tyrosine inhibitory motif
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ITSM
Immunoreceptor tyrosine-based switch motif
IV
Intravenous
KIR
Killer immunoglobulin-like receptor
LFTs
Liver function tests
mAb
Monoclonal antibody
MDSC
Myeloid-derived suppressor cells
MedDRA 
Medical Dictionary for Regulatory Activities
MHC
Major histocompatibility complex
MM
Multiple myeloma
MRD
Minimal residual disease
MRI
Magnetic resonance imaging
MTD
Maximum-tolerated dose
NK
Natural killer
NSCLC
Non small cell lung cancer
ORR
Objective response rate
OS
Overall survival
PD
Progressive disease
PD-1
Programmed death-1
PD-L1
Programmed death ligand 1
PD-L2
Programmed death ligand 2
PET
Positron emission tomography
PFS
Progression free survival
PMBL
Primary mediastinal B cell Lymphoma
PO
By mouth
PPK
Population pharmacokinetics
PR
Partial response
RCC
Renal cell carcinoma
SAE
Serious adverse event
SD
Stable disease
TCR
T-cell receptor
TTP
Time to progression
ULN
Upper limit of normal
US
United States
(USPI)
United States prescribing information
VGPR
Very good partial response
WOCBP
Women of child bearing potential
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Revised Protocol No.: 10
Date: 01-Oct-2015
2
Replace all previous version(s) of the protocol with this revised protocol and please provide a 
copy of this revised protocol to all study personnel under your supervision, and archive the 
previous versions
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Revised Protocol No.: 10
Date: 01-Oct-2015
3
DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised Protocol 10 01-Oct-2015 
Incorporates Amendment 11
Amendment 11 
01-Oct-2015 
Update follow up requirements
Revised Protocol 09 15-Apr-2015 
Incorporates Amendment 10
Amendment 10 
15-Apr-2015 
Retrospectively collect radiographic images for blinded independent 
central review
Revised Protocol 08 05-Feb-2015 
Incorporates Amendment 09
Amendment 09 
05-Feb-2015 
Removes exploratory cohorts from the nivolumab/ipilimumab cohorts
Revised Protocol 07 02-Dec-2014 
Incorporates Amendment 08
Amendment 08 
02-Dec-2014 
Revises protocol to meet FDA guidance.
Revised Protocol 06 20-Aug-2014 
Incorporates Amendment 07
Amendment 07 
20-Aug-2014 
Adds an additional set of cohorts (approximately 80 additional 
subjects) for dose expansion with combination of lirilumab and 
nivolumab
Revised Protocol 05 19-Dec-2013 
Incorporates Amendment 06
Amendment 06 
19-Dec-2013 
Adds an additional set of cohorts (approximately 75 additional 
subjects) for dose escalation and dose expansion with combination of 
ipilimumab and nivolumab.
Revised Protocol 04 10-Oct-2013 
Incorporates Amendment 05
Amendment 05 
10-Oct-2013 
Includes corrections for protocol clarity.
Revised Protocol 03 25-Jun-2013 
Incorporates Amendment 04
Amendment 04 
25-Jun-2013 
Eliminate the CML cohort in the expansion phase as recruitment would 
be difficult due to lack of concomitant therapy with a tyrosine kinase 
inhibitor and increase the size of the remaining four cohorts from 16 to 
23 subjects to redistribute the allotted patients from the eliminated 
CML cohort.
Revised Protocol 02 06-Mar-2013 
Incorporates Amendment 03
Amendment 03 
06-Mar-2013 
Inclusion of non-clinical safety findings related to reproductive 
toxicology data
Revised Protocol 01  21-Dec-2012 
Incorporates  Administrative Letter 01 and Amendment 02
Amendment 02 
21-Dec-2012 
Eliminate the highest (10 mg/kg) of three dose levels scheduled to be 
examined, require that 8 of 16 subjects with multiple myeloma be 
required to undergo bone marrow biopsy while on therapy, and modify 
the discontinuation criteria to be more stringent
Administrative 
Letter 01 
23-May-2012 
Update Medical Monitor
Original Protocol 
13-Mar-2012 
Not applicable
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Figure 1:
Study Design 
Study Population: Subjects with the following relapsed or refractory tumors: B cell lymphoma particularly, 
primary mediastinal B cell Lymphoma (PMBL), T cell lymphoma, Multiple Myeloma (MM), Hodgkin Lymphoma 
(HL), or Chronic Leukemias are eligible. Granulocyte count must be > 1000/μL and platelet count > 50,000/μL. 
Subjects with myelodysplasia, polycythemia vera, idiopathic thrombocythemia, myelofibrosis, acute leukemias, 
blast phase CML, T cell lymphoblastic or Burkitt lymphoma are excluded. Subjects with autoimmune disorders are 
excluded.
Study Assessments:
Safety Evaluation: Adverse events will be assessed continuously during the study and for 100 days post last 
treatment. Adverse events will be coded using the most current version of MedDRA and reviewed for potential 
significance and importance. Adverse events will be evaluated according to the NCI CTCAE Version 4.0. 
Subjects should be followed until all treatment-related adverse events have recovered to baseline or are deemed 
irreversible by the investigator. 
Pharmacokinetic Evaluation: Serial blood samples for pharmacokinetic assessments will be collected from all 
subjects at specified time points.
Efficacy Evaluation: Subjects with non-Hodgkin’s lymphoma or Hodgkin lymphoma will be evaluated using the 
International Workshop to Standardize Response Criteria for non-Hodgkin’s Lymphomas (Appendix 1), subjects 
with multiple myeloma with the International Myeloma Working Group Uniform Response Criteria to define 
response and progressive disease (Appendix 3), subjects with CML with the CML criteria for evaluation 
(Appendix 2), and subjects with cutaneous T cell Lymphoma with the Clinical End Points and Response Criteria in 
Mycosis Fungoides and Sezary Syndrome. Radiographic images may be collected for blinded independent central 
review.
Dose Escalation Phase (12 - 18 pts) 
Relapsed/refractory hematologic 
malignancy
Treatment
Study 
Population
Approx.110
1 mg/kg
3 mg/kg
Dose Expansion Phase
Multiple Myeloma (approximately 23 pts)
Hodgkin/PMBL/ (approximately 23 pts)
B cell lymphoma (approximately 23 pts)
T cell lymphoma (approximately 23 pts)
Expansion Dose selected on
the  basis  of  safety  
determination  in  dose  
escalation phase.
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Immunogenicity Analyses: A listing will be provided of all available immunogenicity data. Additionally, a listing 
of immunogenicity data from those subjects with at least one positive ADA at any time point will be provided by 
dose regimen. The frequency of subjects with at least one positive ADA assessment, and frequency of subjects who 
develop ADA after a negative baseline assessment will be provided by dose. The frequency of neutralizing 
antibodies will be provided based on data availability. To examine the potential relationship between 
immunogenicity and safety, the frequency and type of AEs of special interest may be examined by overall 
immunogenicity status. Associations between pre-dose concentrations of nivolumab and corresponding 
ADA assessments may be explored.
Safety Analyses: All recorded adverse events will be listed and tabulated by system organ class, preferred term, and 
dose and coded according to the most current version of MedDRA across disease types. A subset of adverse event 
tables may be summarized by disease type. The incidence of adverse events will be reviewed for potential 
significance and clinical importance. Vital signs and clinical laboratory test results will be listed and summarized by 
dose. Any significant physical examination findings and results of clinical laboratory tests will be listed. 
ECG results will be evaluated by the investigator and abnormalities, if present, will be listed.
Efficacy Analyses: Individual best overall response (BOR), duration of response and PFS will be listed, using 
appropriate response criteria for each disease type: the IMWG Uniform Response Criteria for Multiple Myeloma, 
standard criteria for Lymphoma, the Clinical End Points and Response Criteria in Mycosis Fungoides and Sezary 
Syndrome for cutaneous T cell Lymphoma, and cytogenic, hematologic and molecular response criteria for CML. 
BOR outcomes will be tabulated by disease type and dose. The objective response rate (ORR) and corresponding 
95% exact confidence interval will be provided by tumor type. The median duration of response and PFSR at select 
time points and corresponding two-sided 95% confidence intervals will be estimated by Kaplan-Meier methodology, 
by disease type, depending on data availability. The analysis of overall survival would be exploratory. Kaplan-Meier 
plots of PFS and overall survival will be provided by tumor type. ORR, duration of response and PFS analyses will 
include subjects in the dose expansion phase and subjects in the dose escalation phase matching those in the dose 
expansion phase by disease type and dose. Individual changes in the tumor burden over time may be presented 
graphically based on data availability within a disease type.
Radiographic images may be collected for blinded independent central review. Details of this analysis will be 
documented in a separate document.
Biomarker Analyses: The potential association between PD-L1 expression levels as measured by 
immunohistochemistry and clinical efficacy measures will be assessed using methods such as Fisher’s exact test if 
sample size is large enough to allow meaningful analysis or other methodology as appropriate.
The pharmacodynamic effect of nivolumab on exploratory biomarkers will be assessed by summary statistics and 
investigated graphically. Patterns of change in these exploratory biomarkers over time and how the patterns differ 
among dose levels may be investigated using appropriate modeling, for example, by linear mixed effects models.
IPILIMUMAB/NIVOLUMAB COHORTS
For the combination of nivolumab and ipilimumab administered concurrently, data will be compared to that 
obtained from subjects who were enrolled previously in the nivolumab monotherapy portion of this study.
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s): Intravenous (IV) infusion of nivolumab at doses of 1 mg/kg or 3 mg/kg and ipilimumab at doses of 
1 mg/kg or 3 mg/kg. Therapy will be administered every three weeks for four doses followed by nivolumab alone at 
3 mg/kg every 2 weeks for a total of two years of therapy.
Study Phase: 1
Research Hypothesis:The purpose of these combination cohorts is to evaluate the safety profile and tolerability, 
and to identify dose limiting toxicities (DLT) and a tolerated dose of the combination of nivolumab and ipilimumab 
in subjects with select relapsed or refractory hematologic malignancies.
Objective(s):
Primary Objective: To establish the dose limiting toxicities and a tolerated dose of the combination of nivolumab 
and ipilimumab in subjects with select relapsed or refractory hematologic malignancies.
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Study Population: Subjects with the following relapsed or refractory tumors: Multiple Myeloma, Hodgkin 
Lymphoma, Primary Mediastinal B Cell Lymphoma, Diffuse Large B Cell Lymphoma, Follicular Lymphoma, and 
T cell Lymphoma are eligible. Subjects with the following are excluded: myelodysplasia, polycythemia vera, 
idiopathic thrombocythemia, myelofibrosis, acute and chronic leukemias, T cell lymphoblastic lymphoma or Burkitt 
lymphoma. Subjects with autoimmune disorders are excluded.
Study Assessments:
Safety Evaluation:Adverse events will be assessed continuously during the study and for 100 days post last 
treatment. Adverse events will be coded using the most current version of MedDRA and reviewed for potential 
significance and importance. Adverse events will be evaluated according to the NCI CTCAE Version 4.0. 
Subjects should be followed until all treatment related adverse events have recovered to baseline or are deemed 
irreversible by the investigator. 
Pharmacokinetic Evaluation:Blood samples for pharmacokinetic assessments of nivolumab and ipilimumab will
be collected from all subjects at specified time points.
Efficacy Evaluation:Subjects with non-Hodgkin’s lymphoma or Hodgkin lymphoma will be evaluated using the 
International Workshop to Standardize Response Criteria for non-Hodgkin’s Lymphomas (Appendix 1), subjects 
with cutaneous T cell lymphoma with the Clinical End Points and Response Criteria in Mycosis Fungoides and 
Sezary Syndrome (Appendix 2) and subjects with multiple myeloma with the International Myeloma Working 
Group Uniform Response Criteria to define response and progressive disease (Appendix 3). Radiographic images 
may be collected for blinded independent central review.
Immunogenicity Evaluation:Blood samples to evaluate development of positive anti-drug antibody (ADA) 
response will be collected to each of nivolumab and ipilimumab at specified time points for all subjects.
Biomarker Evaluation:The pharmacodynamic characteristics of nivolumab in combination with ipilimumab will 
be assessed by quantifying biomarkers in peripheral blood and tumor tissue (when collected). Biomarkers will also 
be analyzed in peripheral blood and tumor tissue in order to identify markers that may predict response to treatment. 
Residual sample material available after completion of the designated analyses may be used in the future for
identification of additional pharmacodynamic or predictive markers or to enhance understanding of disease biology.
Statistical Considerations:
Sample Size:In a tumor cohort, if 3 (21%) or 4 (29%) responses are observed with 14 subjects in each cohort, then 
the lower limit of the 90% one-sided confidence intervals for the objective response rate would be 8% and 
13% respectively. These calculations are based on the Clopper-Pearson method for exact confidence intervals.
In addition, if the true ORR in a tumor cohort is 20% then with 14 patients in each cohort there is 80% chance of 
observing at least 2 responses and 96% chance of observing at least 1 response, or 20% chance of observing 
0 or 1 response (false negative rate) and 4% chance of observing 0 response (false negative rate). If the true ORR in 
a tumor cohort is 5% rather than 20%, then there is 15% chance that there will be at least 2 responses in 14 subjects 
(false positive rate).
Endpoints:
Safety:
The primary objective is to characterize the safety and tolerability of nivolumab and ipilimumab. The primary 
objective will be measured by:
•
Number and percent of subjects that experience drug-related grade 3-4 AEs occurring up to 100 days after the 
last dose of study drug. [Time Frame - On a continuous basis up to 100 days after the last dose of study drug];
•
Number and percent of subjects that experience drug-related grade 3-4 SAEs occurring up to 100 days after the 
last dose of study drug. [Time Frame - On a continuous basis up to 100 days after the last dose of study drug];
•
Number and percent of subjects with clinical laboratory abnormalities by worst toxicity grade by 
NCI CTCAE version 4.0 (as assessed at the planned times listed in section 5.1). [Time Frame - On a continuous 
basis up to 100 days after the last dose of study drug].
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Pharmacokinetics: PK parameters including Cmax, Cmin, Ceoinf, Tmax, AUC(0-T), and AUC(TAU) of 
nivolumab and ipilimumab derived from serum concentration versus time data. 
Efficacy:Individual best overall response (BOR), duration of response, objective response rate (ORR), progression 
free survival rate (PFSR) and overall survival for all treated subjects, and mSWAT score for subjects with cutaneous 
T cell lymphoma.
Immunogenicity:The frequency of baseline ADA positive subjects and ADA positive subjects.
Biomarker:PD-L1 expression levels as measured by immunohistochemistry.
Analyses:
Pharmacokinetic Analyses: Summary statistics will be tabulated for the pharmacokinetic parameters of nivolumab 
and/or ipilimumab by treatment, disease type, dose and study week and a subset of subjects in the tumor cohorts 
following the full PK profile sampling schedule. Cmin will be summarized for all subjects. To describe the 
dependency on dose, scatter plots of nivolumab Cmax and AUC(0-T) versus dose will be provided for each day 
measured treatment and study drug. To assess attainment of steady state, plots of Cmin versus time will be provided
by treatment and by study drug for all subjects. Pharmacokinetic concentrations of nivolumab and ipilimumab from 
all subjects will be listed, and may be used in combination with other studies for exposure response or population 
pharmacokinetic modeling, which will be part of a separate report.
Immunogenicity Analyses: A listing will be provided of all available immunogenicity data. Additionally, a listing 
of immunogenicity data from those ADA positive subjects will be provided. The frequency of baseline positive 
subjects, and frequency of ADA positive subjects will be provided by treatment and dose. The frequency of 
neutralizing antibodies will be provided based on data availability. To examine the potential relationship between 
immunogenicity and safety, the frequency and type of AEs of special interest may be examined by overall 
immunogenicity status. Associations between pre-dose concentrations of nivolumab and ipilimumab, biomarkers, 
efficacy and corresponding ADA assessments may be explored.
Safety Analyses: All recorded adverse events will be listed and tabulated by system organ class, preferred term, 
treatment, and dose and coded according to the most current version of MedDRA across disease types. A subset of 
adverse event tables may be summarized by disease type. The incidence of adverse events will be reviewed for 
potential significance and clinical importance. Vital signs and clinical laboratory test results will be listed and 
summarized by treatment and dose. Any significant physical examination findings and results of clinical laboratory 
tests will be listed. ECG results will be evaluated by the investigator and abnormalities, if present, will be listed.
Efficacy Analyses: Individual BOR, duration of response and PFS will be listed, using appropriate response criteria 
for each disease type: the IMWG Uniform Response Criteria for Multiple Myeloma, standard criteria for 
Lymphoma, the Clinical End Points and Response Criteria in Mycosis Fungoides and Sezary Syndrome for 
cutaneous T cell Lymphoma. BOR outcomes will be tabulated by disease type, treatment and dose. The ORR and 
corresponding 95% exact confidence interval will be provided by tumor type. The median duration of response and 
PFSR at select time points and corresponding two-sided 95% confidence intervals will be estimated by Kaplan-
Meier methodology, by disease type, depending on data availability. The analysis of overall survival would be 
exploratory. Kaplan-Meier plots of PFS and overall survival will be provided by tumor type. ORR, duration of 
response and PFS analyses will include subjects in tumor cohorts and subjects in exploratory schedule evaluation 
matching those in tumor cohorts by disease type, treatment and dose. Individual changes in the tumor burden over 
time may be presented graphically based on the availability of data within a disease type. To evaluate the response 
in skin for subjects with cutaneous T cell lymphoma, the percentage change from baseline on the mSWAT score will 
be derived and listed.
Radiographic images may be collected for blinded independent central review. Details of this analysis will be 
documented in a separate document.
Biomarker Analyses: The potential association between PD-L1 expression levels as measured by 
immunohistochemistry and clinical efficacy measures will be assessed using methods such as Fisher’s exact test if 
sample size is large enough to allow meaningful analysis or other methodology as appropriate. The 
pharmacodynamic effect of monotherapy nivolumab and combination therapy with nivolumab and ipilimumab on 
exploratory biomarkers will be assessed by summary statistics and investigated graphically. Patterns of change in 
these exploratory biomarkers over time and how the patterns differ among dose levels may be investigated using 
appropriate modeling, for example, by linear mixed effects models.
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Date: 01-Oct-2015
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Residual sample material available after completion of the designated analyses may be used in the future for 
identification of additional pharmacodynamic or predictive markers or to enhance understanding of disease biology.
Statistical Considerations:
Sample Size:In a tumor cohort, if 4 (20%) or 5 (25%) responses are observed with 20 subjects in each cohort, then 
the lower limit of the 90% one-sided confidence intervals for the objective response rate would be 
9% and 13% respectively. In a tumor cohort, if 3 (10%) or 6(20%) responses are observed with 30 subjects in each 
cohort, then the lower limit of the 90% one-sided confidence intervals for the objective response rate would be 
4% and 11% respectively. These calculations are based on the Clopper-Pearson method for exact confidence 
intervals.
In addition, if the true ORR in a tumor cohorts is 20% then with 20 patients in each cohort there is 93% chance of 
observing at least 2 responses, or 7% chance of observing 0 or 1 response (false negative rate). If the true ORR in a 
tumor type is 5% rather than 20%, then there is 26% chance that there will be at least 2 responses in 20 subjects 
(false positive rate). If the true ORR in a tumor cohort is 20% then with 30 patients in each cohort there is 
88% chance of observing at least 4 responses, or 12% chance of observing 3 or fewer responses (false negative rate). 
If the true ORR in a tumor type is 5% rather than 20%, then there is 6% chance that there will be at least 4 responses 
in 30 subjects (false positive rate).
Approximately 130 subjects are expected to be enrolled in tumor cohorts.
Endpoints:
Safety:
The primary objective is to characterize the safety and tolerability of nivolumab and lirilumab. The primary 
objective will be measured by:
•
Number and percent of subjects that experience drug-related grade 3-4 AEs occurring up to 100 days after the 
last dose of study drug. [Time Frame - On a continuous basis up to 100 days after the last dose of study drug];
•
Number and percent of subjects that experience drug-related grade 3-4 SAEs occurring up to 100 days after the 
last dose of study drug. [Time Frame - On a continuous basis up to 100 days after the last dose of study drug];
•
Number and percent of subjects with clinical laboratory abnormalities by worst toxicity grade by 
NCI CTCAE version 4.0 (as assessed at the planned times listed in section 5.1). [Time Frame - On a continuous 
basis up to 100 days after the last dose of study drug].
Pharmacokinetics: PK parameters including Cmax, Cmin, Ceoinf, Tmax, AUC(0-T), and AUC(TAU) of 
nivolumab and lirilumab derived from serum concentration versus time data. 
Efficacy:Individual best overall response (BOR), duration of response, objective response rate (ORR), progression 
free survival rate (PFSR) and overall survival for all treated subjects, and mSWAT score for subjects with cutaneous 
T cell lymphoma.
Immunogenicity:The frequency of baseline ADA positive subjects and ADA positive subjects.
Biomarker:PD-L1 expression levels as measured by immunohistochemistry.
Analyses:
Pharmacokinetic Analyses: Summary statistics will be tabulated for the pharmacokinetic parameters of nivolumab 
in the presence of lirilumab by treatment, disease type, dose and study week. Cmin will be summarized for all 
subjects. To describe the dependency on dose, scatter plots of nivolumab Cmax and AUC(0-T) versus dose will be 
provided for each day measured treatment and study drug. To assess attainment of steady state, plots of Cmin versus 
time will be provided by treatment and by study drug for all subjects. Pharmacokinetic concentrations of nivolumab 
and lirilumab from all subjects will be listed, and may be used in combination with other studies for exposure 
response or population pharmacokinetic modeling, which will be part of a separate report.
Immunogenicity Analyses: A listing will be provided of all available immunogenicity data. Additionally, a listing 
of immunogenicity data from those ADA positive subjects will be provided. The frequency of baseline positive 
subjects, and frequency of ADA positive subjects will be provided by treatment and dose. The frequency of 
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neutralizing antibodies will be provided based on data availability. To examine the potential relationship between 
immunogenicity and safety, the frequency and type of AEs of special interest may be examined by overall 
immunogenicity status. Associations between pre-dose concentrations of nivolumab and lirilumab, biomarkers, 
efficacy and corresponding ADA assessments may be explored.
Safety Analyses: All recorded adverse events will be listed and tabulated by system organ class, preferred term, 
treatment, and dose and coded according to the most current version of MedDRA across disease types. A subset of 
adverse event tables may be summarized by disease type. The incidence of adverse events will be reviewed for 
potential significance and clinical importance. Vital signs and clinical laboratory test results will be listed and 
summarized by treatment and dose. Any significant physical examination findings and results of clinical laboratory 
tests will be listed. ECG results will be evaluated by the investigator and abnormalities, if present, will be listed.
Efficacy Analyses: Individual BOR, duration of response and PFS will be listed, using appropriate response criteria 
for each disease type: the IMWG Uniform Response Criteria for Multiple Myeloma, standard criteria for 
Lymphoma, the Clinical End Points and Response Criteria in Mycosis Fungoides and Sezary Syndrome for 
cutaneous T cell Lymphoma. BOR outcomes will be tabulated by disease type, treatment and dose. The ORR and 
corresponding 95% exact confidence interval will be provided by tumor type. The median duration of response and 
PFSR at select time points and corresponding two-sided 95% confidence intervals will be estimated by Kaplan-
Meier methodology, by disease type, depending on data availability. The analysis of overall survival would be 
exploratory. Kaplan-Meier plots of PFS and overall survival will be provided by tumor type. ORR, duration of 
response and PFS analyses will include subjects in tumor cohorts by disease type, treatment and dose. Individual 
changes in the tumor burden over time may be presented graphically based on the availability of data within a 
disease type. To evaluate the response in skin for subjects with cutaneous T cell lymphoma, the percentage change 
from baseline on the mSWAT score will be derived and listed.
Radiographic images may be collected for blinded independent central review. Details of this analysis will be 
documented in a separate document.
Biomarker Analyses: The potential association between PD-L1 expression levels as measured by 
immunohistochemistry and clinical efficacy measures will be assessed using methods such as Fisher’s exact test if 
sample size is large enough to allow meaningful analysis or other methodology as appropriate. The 
pharmacodynamic effect of combination therapy with lirilumab on exploratory biomarkers will be assessed by 
summary statistics and investigated graphically. Patterns of change in these exploratory biomarkers over time and 
how the patterns differ among dose levels may be investigated using appropriate modeling, for example, by linear 
mixed effects models.
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2 
ETHICAL CONSIDERATIONS
2.1 
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonization (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50).
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to BMS immediately. A serious breach is a 
breach of the conditions and principles of GCP in connection with the study or the protocol, 
which is likely to affect, to a significant degree, the safety or physical or mental integrity of the 
subjects of the study or the scientific value of the study.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or 
where there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
2.2 
Institutional Review Board/Independent Ethics Committee 
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, subject recruitment materials 
(eg, advertisements), and any other written information to be provided to subjects. The 
investigator or BMS should also provide the IRB/IEC with a copy of the Investigator Brochure 
or product labeling information to be provided to subjects and any updates. 
The investigator or BMS should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
2.3 
Informed Consent
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given to subjects, their legally acceptable representatives 
are clearly and fully informed about the purpose, potential risks, and other critical issues 
regarding clinical studies in which the subject volunteers to participate. 
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BMS will provide the investigator with an appropriate (ie, Global or Local) sample informed 
consent form which will include all elements required by ICH, GCP and applicable regulatory 
requirements. The sample informed consent form will adhere to the ethical principles that have 
their origin in the Declaration of Helsinki.
Investigators must:
1) Provide a copy of the consent form and written information about the study in the language 
in which the subject is most proficient prior to clinical study participation. The language 
must be non-technical and easily understood. 
2) Allow time necessary for subject or subject
's legally acceptable representative to inquire 
about the details of the study.
3) Obtain an informed consent signed and personally dated by the subject or the subject
's 
legally acceptable representative and by the person who conducted the informed consent 
discussion. 
4) Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent 
form and any other information to be provided to the subjects, prior to the beginning of the 
study, and after any revisions are completed for new information.
5) If informed consent is initially given by a subject’s legally acceptable representative or legal 
guardian, and the subject subsequently becomes capable of making and communicating his 
or her informed consent during the study, consent must additionally be obtained from the 
subject.
6) Revise the informed consent whenever important new information becomes available that is 
relevant to the subject
's consent. The investigator, or a person designated by the investigator, 
should fully inform the subject or the subject
's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
subject
's willingness to continue participation in the study. This communication should be 
documented. 
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules applicable to regulatory requirements, the subjects
' signed ICF 
and, in the US, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to subject records. 
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
3 
INVESTIGATIONAL PLAN
3.1 
Study Design and Duration
This is a Phase 1, open-label, multicenter, dose-escalation, and multidose study of nivolumab a 
fully human monoclonal IgG4 antibody targeting the PD-1 membrane receptor on T cells. 
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The study will consist of Screening (up to 28 days), Treatment (up to 2 years), and Follow-up 
(up to 12 months) with the possibility of Retreatment and Follow up (up to 12 months and 
100 days) (SeeFigure 3.1-1). The first dose administered will be followed by a three week 
period for pharmacokinetic and pharmacodynamic assessment of nivolumab. A response 
assessment following administration of the first dose will be obtained. Therapy will be given on 
an every two week schedule thereafter with response assessment performed at Weeks 8, 16, 24,
and then every 16 weeks thereafter. The scheduled response assessments must be completed 
before the next dose of therapy.
IPILIMUMAB/NIVOLUMAB COHORTS
Combination cohorts will evaluate the combination of nivolumab and ipilimumab. 
The study will consist of Screening (up to 28 days), Treatment (up to 2 years), and Follow-up.
See Figure 3.1-2.
LIRILUMAB/NIVOLUMAB COHORTS
Combination cohorts will evaluate the combination of nivolumab and lirilumab. 
The study will consist of Screening (up to 28 days), Treatment (up to 2 years), and Follow-up. 
See Figure 3.1-3. 
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Figure 3.1-1: 
Study Design for Nivolumab Monotherapy
Subjects will receive study drug as detailed in Figure 3.1-1. The operating characteristics of 6+3 
design in the dose escalation phase is examined in Appendix 5.
Dose Escalation Phase (12 - 18 pts) 
Relapsed/refractory hematologic 
malignancy
Treatment
Study 
Population
Approx. 110
1 mg/kg
3 mg/kg
Dose Expansion Phase
Multiple Myeloma (approximately 23 pts)
Hodgkin/PMBL (approximately 23 pts)
B cell lymphoma (approximately 23 pts)
T cell lymphoma (approximately 23 pts)
Expansion Dose selected on 
the  basis  of  safety  
determination  in  dose  
escalation phase.
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Figure 3.1-2: 
Study Design for Nivolumab and Ipilimumab Combination Therapy
Subjects will receive study drug as detailed in Figure 3.1-2.
Study 
Population
Approx. 75
Tumor Cohort
Multiple Myeloma (approximately 14 pts)
Hodgkin/PMBL (approximately 32 pts)
B cell lymphoma (approximately 14 pts)
- diffuse large B cell lymphoma or follicular 
lymphoma
T cell lymphoma (approximately 14 pts)
3 mg/kg of nivolumab and 
1 mg/kg of ipilimumab
     four doses
     followed by nivolumab alone at 3 mg/kg
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monitoring of hematologic parameters with dose interruption or discontinuation parameters is 
included in the study. If a dose of 1 mg/kg is above the MTD, a lower dose may be considered by 
protocol amendment.
IPILIMUMAB/NIVOLUMAB COHORTS
Subjects in tumor cohorts will be treated at a dose of 3 mg/kg nivolumab in combination with 
1 mg/kg ipilimumab. The combination will be administered every 3 weeks for 4 doses, followed 
by monotherapy with nivolumab at 3 mg/kg every 2 weeks for up to 2 years of study therapy 
total. All adverse event data will be monitored on an ongoing basis for safety. If the above dose 
is not acceptable, then alternative doses may be considered, including 1 mg/kg nivolumab in 
combination with 3 mg/kg ipilimumab or 1 mg/kg nivolumab in combination with 1 mg/kg 
ipilimumab.
LIRILUMAB/NIVOLUMAB COHORTS
See Section 3.1.2Expansion Cohorts
3.1.1.1 
Dose Limiting Toxicity
Dose limiting toxicity (DLT) will be determined based on the incidence and intensity of drug 
related adverse events (AEs) occurring up to two weeks after the administration of the third dose 
of nivolumab or 7 weeks after initiation of therapy whichever is longer.
IPILIMUMAB/NIVOLUMAB COHORTS
Dose limiting toxicity (DLT) will be determined based on the incidence and intensity of drug 
related adverse events (AEs) occurring within 3 cycles (9 weeks) of combination therapy. 
Subjects who experience delays will remain evaluable for safety, if they receive 3 cycles within 
12 weeks. Toxicity will be graded by CTCAE v 4.0.
Dose Limiting Hepatic Toxicity
DLT will be hepatotoxicity as evidenced by any of the following:
• AST or ALT > 5 - 10X ULN for > 2 weeks
• AST or ALT > 10X ULN irrespective of duration
• AST or ALT > 8X ULN irrespective of duration (only for IPILIMUMAB/NIVOLUMAB 
COHORTS
• Total bilirubin > 5X ULN irrespective of duration
• Concurrent AST or ALT > 3X ULN and total bilirubin > 2X ULN (potential Hy’s Law case)
Dose Limiting Hematologic Toxicity
• Grade 4 neutropenia lasting more than 5 days
• Febrile neutropenia of any duration (ANC < 1.0 x 109/L, fever > 38.5 degrees Celsius)
• Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding or any requirement 
for platelet transfusion
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• Grade 4 anemia, unexplained by underlying disease
Dose Limiting Non-hematologic Toxicity
Grade 2 or greater eye pain or reduction of visual acuity that does not respond to topical therapy 
and does not improve to Grade 1 severity within 2 weeks of starting therapy or requires systemic 
treatment.
Clinically relevant Grade 3 or greater non-hepatic and non-hematologic toxicity excluding 
lymphopenia, asymptomatic lipase or amylase or laboratory abnormalities that correct to 
grade 1 within 72 hours after treatment. Toxicity will be graded by CTCAE v 4.0.
DLTs that occur after the decision to dose escalate will be used to determine the recommended 
phase 2 dose for this population.
No dose escalations or de-escalations are permitted within each subject’s treatment. A subject 
who is withdrawn from the study before the completion of the first seven weeks of treatment 
(before 3 cycles and 9 weeks for subjects enrolled in the IPILIMUMAB/NIVOLUMAB 
COHORTS) or a reason other than a DLT may be replaced. Subjects who experience dose 
limiting toxicity may resume treatment as per Section 4.1.7upon resolution, providing that 
criteria for permanent discontinuation are not met (Section 4.1.9).
The occurrence of clinically meaningful drug related AEs requires early recognition and prompt 
intervention. Management algorithms are available for suspected pulmonary, gastrointestinal, 
hepatic, renal, endocrine, neurological and skin toxicities. The recommendation is to follow the 
nivolumab IB adverse event algorithm.
3.1.2 
Expansion Cohorts
To further characterize safety and efficacy 4 expansion cohorts will be enrolled. These 
hematologic malignancies were selected based on the expression of PD-L1 by the tumor or 
expression of PD-1 on infiltrating T cells in the tumor. The diseases that will be explored are 
HL/PMBL, T cell lymphoma, B cell lymphoma and multiple myeloma. A total of 6 or 9 subjects 
must be enrolled at the MTD (or the highest dose studied where ≤1 of 6 or ≤2 of 9 subjects 
experiences a DLT if the MTD is not identified) before any subject is dosed in the expansion 
cohorts. If none of the first 5 subjects have a DLT by the end of seven weeks of treatment in the 
dose escalation phase of the study, enrollment to the primary expansion cohorts can begin 
immediately following the enrollment of the sixth subject. Archived tumor tissue from every 
surgical resection should be obtained and submitted for biomarker analysis
IPILIMUMAB/NIVOLUMAB COHORTS
To further characterize safety and efficacy, 4 tumor cohorts will be enrolled. All subjects in the 
4 tumor cohorts will be required to have archived tumor tissue available at the time of screening, 
and will be required to undergo tumor biopsy while on-study (seeTable 5.1-6). Archived tumor 
tissue from every surgical resection should be obtained and submitted for biomarker analysis.
If archived tumor is not available at the time of screening, the subject must agree to undergo 
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biopsy before the administration of study therapy and also while on-study (seeTable 5.1-6). 
At the time of the biopsy while on-study, the PI will determine if there have been significant 
changes in the clinical course to suggest that subjects can no longer undergo biopsy safely. 
These subjects will continue therapy, but may be replaced. The diseases that will be explored are 
HL/PMBL, T cell lymphoma, B cell lymphoma (diffuse large B cell lymphoma and follicular 
lymphoma only), and multiple myeloma.
LIRILUMAB/NIVOLUMAB COHORTS
Subjects in tumor cohorts will be treated at a dose of 3 mg/kg nivolumab in combination with 
3 mg/kg lirilumab. Nivolumab will be administered every 2 weeks and lirilumab will be 
administered every 4 weeks (in combination with nivolumab) for up to two years of study 
therapy total. All adverse event data will be monitored on an ongoing basis for safety. If the 
above dose is not acceptable, then alternative doses may be utilized, including 3 mg/kg 
nivolumab in combination with 1 mg/kg lirilumab.
To characterize safety and efficacy, four tumor cohorts will be enrolled. The diseases that will be 
explored are HL/PMBL, T cell lymphoma, B cell lymphoma (diffuse large B cell lymphoma and 
follicular lymphoma only), and multiple myeloma. All subjects in the four tumor cohorts will be 
required to have archived tumor tissue available at the time of screening. Archived tumor tissue 
from every surgical resection should be obtained and submitted for biomarker analysis. 
If archived tumor is not available at the time of screening, the subject must agree to undergo 
biopsy before the administration of study therapy. Subjects will also be required to undergo 
tumor biopsy while on-study Table 5.1-9. At the time of the biopsy while on-study, the PI will 
determine if there have been significant changes in the clinical course to suggest that subjects 
can no longer undergo biopsy safely. These subjects may continue therapy.
Guidelines for Continuation of Therapy
Response assessment will be evaluated using the appropriate response criteria in Appendices 1, 
2, and 3. Response assessments for all subjects will occur at the specified intervals 
(results of assessments must be reviewed and documented before the next dose of treatment, with 
the exception of subjects with multiple myeloma, if the result will not change the decision to 
administer the dose).
The expected duration of treatment on this study is 2 years. If a subject is eligible to continue 
receiving treatment, the next dose should be given no earlier than 14 (±) 2 days, or 21 (±)2days 
when nivolumab and ipilimumab are given together, and no later than 6 weeks after the last dose 
of the prior treatment to maximize dose intensity. No subject will be permitted dose escalations 
or de-escalations.
Subjects who meet the following conditions will continue to be treated:
• Subjects with a best overall response (BOR) of complete response (CR), partial response 
(PR) or stable disease (SD) will continue to receive study drug until the first occurrence of 
either: 1) achievement of a confirmed CR; 2) clinical deterioration suggesting that no further 
benefit from treatment is likely; 3) meets criteria for discontinuation of study therapy as 
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outlined in Sections 3.1.1.1Dose Limiting Toxicity and 3.5Discontinuation of Subjects from 
Treatment; 4) other intolerability to therapy; or 5) administration of 2 years of therapy
• Unconfirmed CR: Subject will receive an additional cycle of treatment until confirmation of 
the CR at the next scheduled imaging time point
• Confirmed CR: Subjects will stop treatment and enter the first Follow-Up Period
• PR or stable disease (SD): Subjects will continue to receive study drug until confirmed CR, 
PD (under the conditions defined below), toxicity (as defined below), or for 2 years. Subjects 
will then enter the first Follow-up Period
• PD: Accumulating evidence indicates that the emergence of objective responses to agents 
that activate anti-tumor immune responses follows delayed kinetics of weeks or months, and 
can be preceded by initial apparent radiological progression or the appearance of new lesions 
or some enlarging lesions while certain target lesions are regressing (“mixed response”). It is 
thus reasonable, in the absence of clinical deterioration, to continue to treat these subjects 
until progression is both confirmed and found to have worsened at a subsequent imaging 
evaluation. Evidence of PD will be based on a comparison with baseline (or nadir) scans or 
other evaluations.
Subjects with PD should be managed in the study as follows:
Subjects will be permitted to continue study therapy beyond PD as measured by the appropriate 
evaluation criteria as long as they meet the following criteria:
• Clinical benefit as assessed by the investigator
• Disease progression is not rapid
• Tolerance of study drug
• Stable performance status
• Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (eg, CNS metastases)
• Subjects have provided written informed consent prior to receiving additional treatment with 
nivolumab and ipilimumab.
The assessment of clinical benefit should be balanced by clinical judgment as to whether the 
subject is clinically deteriorating and unlikely to receive any benefit from continued treatment. 
The decision to continue treatment should be discussed with the BMS Medical Monitor and 
documented in the study records. Palliative radiotherapy or surgical resection of isolated lesions 
is permitted in these subjects and will not preclude the continued treatment with study therapy.
Subjects should discontinue study therapy upon evidence of further progression, defined as an 
additional 10% or greater increase in tumor burden volume from the time of initial progression 
(including all target lesions and new measurable lesions) or similar criteria in tumor types 
without measurable lesions.
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Subjects who experience AEs that require discontinuation while receiving both nivolumab and 
ipilimumab may be allowed to continue therapy with nivolumab only, if deemed in their best 
interest by both the PI and the BMS medical monitor. Subjects must be deriving clinical benefit.
Subjects who experience AEs that require discontinuation while receiving both nivolumab and 
lirilumab may be allowed to continue therapy with nivolumab only, if deemed in their best 
interest by both the PI and the BMS medical monitor. Subjects must be deriving clinical benefit.
Re-initiation of Study Therapy for Subjects in Follow-up Period
Subjects entering the follow-up period with ongoing disease control (ongoing CR, PR, or SD) 
may reinitiate study therapy upon confirmed disease progression after discussion and agreement 
with the BMS Medical Monitor. Subjects reinitiating study therapy should continue to meet 
eligibility criteria at the time study drug resumes and should not have experienced a DLT 
requiring permanent discontinuation of study therapy. Subjects will receive study therapy at the 
same dose level that they received prior to entering the follow-up period. Subjects that resume 
study therapy in this setting may receive study therapy for up to one additional year. Subjects 
who have completed 1 year of follow-up without evidence of disease progression will not be 
considered eligible for re-initiation of study therapy. Additional safety and efficacy summaries 
will be presented for those subjects who reinitiated study therapy.
IPILIMUMAB/NIVOLUMAB COHORTS
Subjects enrolled in the nivolumab and ipilimumab combination cohorts will not be eligible for 
re-initiation of study therapy for progression in the follow-up period.
LIRILUMAB/NIVOLUMAB COHORTS
Subjects enrolled in the nivolumab and lirilumab combination cohorts will not be eligible for 
re-initiation of study therapy for progression in the follow-up period.
3.1.3 
Stopping Rules
3.1.3.1 
Stopping Rules for Clinical Deterioration
Accumulating evidence indicates that the emergence of objective responses to agents that 
activate anti-tumor immune responses follows delayed kinetics of weeks or months, and can be 
preceded by initial apparent radiological progression or appearance of new lesions or some 
enlarging lesions while certain target lesions are regressing (“mixed response”). It is thus 
reasonable to allow for these possibilities and continue to treat the subject until progression is 
confirmed and found to be advancing and continuing at the next imaging assessment. These 
considerations should be balanced by clinical judgment as to whether the subject is clinically 
deteriorating and unlikely to receive any benefit from continued treatment.
Such deterioration will be assessed to have occurred after a clinical event that, in the 
Investigator’s opinion, is attributable to disease progression, is unlikely to reverse with continued 
study treatment and therefore indicates that the subject is not benefiting from study treatment and 
cannot be managed by the addition of supportive care (such as bisphosphonates and/or bone 
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directed radiotherapy, thoracentesis or paracentesis of accumulating effusions). The decision to 
continue or stop treatment should be discussed with the BMS Medical Monitor and will be 
documented in the study files.
Examples of events that may, in the Investigator’s opinion, indicate a lack of clinical benefit 
include, but are not limited to, the following:
• Performance status decrease of at least 2 points from baseline
• skeletal related events defined by the following: 
−pathologic bone fracture in the region of cancer involvement 
−cancer related surgery to bone 
−spinal cord or nerve root compression
• Bladder outlet or uretheral obstruction
• Development of new central nervous system metastases
• Any setting where the initiation of new anti-neoplastic therapy has been deemed beneficial to 
the subject even in the absence of any such documented clinical events.
3.2 
Post Study Access to Therapy
At the conclusion of the study, subjects who continue to demonstrate clinical benefit will be 
eligible to receive study drug. Study drug will be provided via an extension of the study, a 
rollover study requiring approval by responsible health authority and ethics committee or 
through another mechanism at the discretion of BMS. BMS reserves the right to terminate access 
to study drug if any of the following occur: a) the marketing application is rejected by 
responsible health authority; b) the study is terminated due to safety concerns; c) the subject can 
obtain medication from a government sponsored or private health program; or d) therapeutic 
alternatives become available in the local market.
3.3 
Study Population
For entry into the study, the following criteria MUST be met.
3.3.1 
Inclusion Criteria
1. Signed Written Informed Consent
a) Voluntary signed and dated IRB/IEC approved written informed consent form in 
accordance with regulatory and institutional guidelines. This must be obtained before the 
performance of any protocol related procedures that are not a part of standard of care
2. Target Population
a) ECOG Performance of 0 or 1. (See Appendix 4)
b) Subjects must have histological confirmation of relapsed or refractory hematologic 
malignancy
c) Subjects with non-Hodgkin lymphoma or Hodgkin lymphoma must have at least one 
measureable lesion > 1.5 cm as defined by lymphoma response criteria. Subjects must 
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also have an additional lesion that is amenable for biopsy. Subjects with cutaneous T cell 
lymphoma do not require a measureable lesion. Subjects with lesions in a previously 
radiated field as the sole site of measurable disease will be permitted to enroll provided 
the lesion has demonstrated clear progression and can be measured accurately. 
(SeeAppendix 1)
d) Subjects with cutaneous T cell lymphoma must have measurable disease by mSWAT 
(See Appendix 2)
e) Subjects with MM must have detectable disease as measured by presence of monoclonal 
immunoglobulin protein in a serum electrophoresis: IgG, IgA, IgM, (M-protein ≥0.5 g/dl 
or serum IgD M-protein ≥0.05 g/dl) or serum free-light chain or 24 hour urine with free 
light chain. Excluded are subjects with only plasmacytomas, plasma cell leukemia, or 
non-secretory myeloma
f) Subjects must be more than 100 days post autologous transplant
g) Life expectancy of at least 3 months
h) For subjects with lymphoma, must have a fresh biopsy or either an archived formalin 
fixed tissue block, or 7 to 15 slides of tumor sample for performance of correlative 
studies. All subjects in the nivolumab/ipilimumab and nivolumab/lirilumab cohorts must 
have a fresh biopsy or either an archived formalin fixed tissue block, or 7 to 15 slides of 
tumor sample for performance of correlative studies. Archived tumor tissue from every 
surgical resection should be obtained and submitted for biomarker analysis.
i) Subjects must have received at least one prior chemotherapy regimen. Subjects must be 
off therapy for at least 3 weeks (3 weeks for subcutaneous, 2 weeks for oral agents, 
1 week for topical agents) prior to Day 1
j) Prior palliative radiation must have been completed at least 2 weeks prior to study Day 1
k) Toxicities related to prior therapy must have returned to Grade 1 or less, except for 
alopecia. Peripheral neuropathy must be Grade 2 or less
l) Adequate bone marrow function defined as:
i) Absolute neutrophil count ≥1000/μl (stable off any growth factor within 1 week of 
study drug administration) (2)Hemoglobin ≥9g/dL (transfusion to achieve this level 
is permitted) (3)Platelet count ≥50 X 103/μl (transfusion to achieve this level is not 
permitted)
m) Adequate renal parameters defined as:
i) CrCl > 40 ml/min (Cockcroft-Gault formula)
ii)Adequate hepatic parameters defined as:
(1)AST ≤3 x ULN
(2)ALT ≤3 x ULN
(3)Bilirubin ≤1.5 x ULN (except subjects with Gilbert’s Syndrome, who must have 
a total bilirubin < 3.0 mg/dL and direct bilirubin < 0.5 mg/dL
n) Ability to comply with treatment, PK, and immune-monitoring sample collection 
(when indicated) and required study follow up
o) Oxygen saturation ≥94% at rest, without oxygen supplementation
p) Approval to undergo on-treatment biopsy
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q) Subjects with Hodgkin lymphoma or non Hodgkin’s lymphoma can have a history of 
brentuximab vedotin treatment or be brentuximab vedotin naive to be eligible. Subjects 
are not required to have failed brentuximab vedotin treatment to be eligible for the study
r) Subjects with CD 30 positive anaplastic large cell lymphoma must have a history of prior 
treatment with brentuximab vedotin
s) Subjects with follicular lymphoma must have received ≥ 2 prior treatment lines; each of 
the two prior treatment lines must include rituximab and/or an alkylating agent
t) Subjects with Diffuse Large B Cell Lymphoma (DLBCL) must have relapsed after high 
dose conditioning chemotherapy and ASCT or after failure of at least one prior multi-
agent chemotherapy regimen in subjects who are ineligible for ASCT.
u) Subjects with Multiple Myeloma must have failed at least 2 prior regimens to include 
receiving an immunomodulatory agent and a proteasome inhibitor
v) Subjects with a prior history of chemotherapy-induced or radiation-induced pulmonary 
toxicity require confirmation of diffusing capacity of the lung for carbon monoxide 
(DLCO) over 60% (adjusted for hemoglobin) by a pulmonary function test prior to study 
enrollment
w) Normal thyroid hormone levels/function at baseline including subjects who are controlled 
with hormone replacement therapy
3. Age and Reproductive Status
a) (See Section 3.3.3for the definition of WOCBP) Men and women ≥18 years of age
b) Women of childbearing potential (WOCBP) must use highly effective methods of birth 
control for up to 23 weeks after the last dose of investigational product to minimize the 
risk of pregnancy. WOCBP must follow instructions for birth control for the entire 
duration of the study including a minimum of 23 weeks after dosing has been 
completed.(See Appendix 6 for birth control instructions)
c) Women must have a negative serum or urine pregnancy test (minimum sensitivity 
25 IU/L or equivalent units of HCG) within 24 hours prior to the start of investigational 
product
d) Women must not be breastfeeding
e) Sexually active fertile men must use highly effective birth control if their partners are 
WOCBP. Men that are sexually active with WOCBP must follow instructions for birth 
control for the entire duration of the study and a minimum of 31 weeks after dosing has 
been completed.
3.3.2 
Exclusion Criteria
1. Target Disease Exceptions
a) Subjects with myelodysplasia, polycythemia vera, idiopathic thrombocythemia, 
myelofibrosis, acute leukemias, CML, T cell lymphoblastic or Burkitt lymphoma
b) Subjects with a history of central nervous system involvement by hematologic 
malignancy or symptoms suggestive of central nervous system involvement
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c) Subjects with a history of chest radiation ≤ 24 weeks prior to first dose of study 
medication
d) Subjects who were exposed to ≥ 1000 mg of BCNU as part of a conditioning regimen
2. Medical History and Concurrent Diseases
a) Subjects  with  concomitant  second  malignancies  (except adequately  treated 
non-melanomatous skin cancers, melanoma in situ surgically resected, carcinoma in situ 
of the breast, superficial bladder cancer, prostate cancer or in situ cervical cancers) are 
excluded unless a complete remission was achieved as it is empirically determined based 
on the malignancy and treatment provided prior to study entry and no additional therapy 
is required or anticipated to be required during the study period
b) Subjects with any active autoimmune disease or a history of known or suspected 
autoimmune disease, or history of syndrome that requires systemic corticosteroids or 
immunosuppressive medications, except for subjects with vitiligo, resolved childhood 
asthma/atopy, controlled thyroid disorders
c) A serious uncontrolled medical disorder or active infection which would impair the 
ability of the subject to receive protocol therapy or whose control may be jeopardized by 
the complications of this therapy
d) Deep vein thrombosis not adequately controlled
e) Uncontrolled or significant cardiovascular disease including, but not limited to any of the 
following:
i) myocardial infarction or stroke/TIA within the past 6 months
ii) uncontrolled angina within the past 3 months
iii) any history of clinically significant arrhythmias (such as ventricular tachycardia, 
ventricular fibrillation or torsades de pointes)
iv) QTc prolongation > 480 msec
v) history of other clinically significant heart disease (ie, cardiomyopathy, congestive 
heart failure with NYHA functional classification III-IV, pericarditis, significant 
pericardial effusion)
vi) requirement for daily supplemental oxygen therapy
f) Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137 or anti CTLA-4 
antibody (or any other antibody or drug specifically targeting T-cell costimulation or 
checkpoint pathways). Prior therapy with an anti-KIR antibody
g) Not applicable per Protocol Amendment 07
h) Non-oncology vaccine therapies for prevention of infectious diseases (eg HPV vaccine) 
within 4 weeks of study drug administration. The inactivated seasonal influenza vaccine 
can be given to subjects before treatment and while on therapy without restriction. 
Influenza vaccines containing live virus or other clinically indicated vaccinations for 
infectious diseases (ie, pneumovax, varicella, etc.) may be permitted; but must be 
discussed with the Sponsor’s Medical Monitor and may require a study drug washout 
period prior to and after administration of vaccine (not applicable after amendment 011)
i) Prior organ allograft or allogeneic bone marrow transplantation
j) Subjects with symptomatic interstitial pneumonitis
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3. Physical and Laboratory Test Findings
a) Positive for human immunodeficiency virus (HIV 1/2) antibody (may obtain additional 
testing or substitute testing per institutional guidelines to rule out infection), or known 
acquired immunodeficiency syndrome (AIDS)
b) Positive tests for hepatitis B virus surface antigen (HBsAg) or hepatitis C antibody 
(may obtain additional testing or substitute testing per institutional guidelines to rule out 
infections).
c) Ejection fraction less than 50%
4. Allergies and Adverse Drug Reaction
a) History of Grade 4 anaphylactic reaction to monoclonal antibody therapy
5. Sex and Reproductive Status
a) WOCBP who are unwilling or unable to use an acceptable method to minimize the risk of 
pregnancy for the entire study period and for at least 23 weeks after the last dose of 
investigational product.
b) Women who are pregnant or breastfeeding
c) Women with a positive pregnancy test on enrollment or prior to investigational product 
administration
d) Sexually active fertile men not using effective birth control if their partners are WOCBP 
for at least 31 weeks after the last dose of investigational product.
6. Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
subjects and that the results of the study can be used. It is imperative that subjects fully meet all 
eligibility criteria. No exception to the entry criteria is permitted.
3.3.3 
Women of Childbearing Potential
Women of childbearing potential (WOCBP) include any female who has experienced menarche 
and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal 
ligation, or bilateral oophorectomy), and who is not postmenopausal. Post menopause is defined 
as: 
• Amenorrhea ≥12 consecutive months without another cause, and a documented serum 
follicle stimulating hormone (FSH) level > 35 mIU/mL or 
• Women with irregular menstrual periods and a documented serum follicle stimulating 
hormone (FSH) level > 35 mIU/mL or
• NOTE: FSH level testing is not required for women ≥62 years old with amenorrhea of ≥1 
year
• Women on hormone replacement therapy (HRT)
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Women who are using oral or other hormonal contraceptives, such as vaginal products, skin 
patches, or implanted or injectable products, or mechanical products, such as an intrauterine 
device or barrier methods (diaphragm, condoms, spermicides), to prevent pregnancy or who are 
practicing abstinence or who have a sterile (eg, vasectomy) partner should be considered to be of 
childbearing potential.
3.4 
Concomitant Treatments
Subjects are permitted the use of topical, ocular, intranasal, intra-articular, and inhalational 
corticosteroids (with minimal systemic absorption). Immunosuppressive doses (eg, prednisone 
> 10 mg/day or equivalent) and/or physiologic replacement doses of systemic corticosteroids 
(eg, prednisone 10 mg/day) are permitted in the context of treating adverse events. A brief course 
of corticosteroids for prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune
conditions (eg, delayed-type hypersensitivity reaction caused by a contact allergen) is permitted.
3.4.1 
Prohibited and/or Restricted Treatments
• Concurrent chemotherapy, hormonal therapy or immunotherapy regimens
• Systemic corticosteroids (doses greater than prednisone 10 mg/day or equivalent) within 
7 days of study entry are prohibited.
• Concurrent immunosuppressive agents
• Concurrent use of Rank Ligand inhibitors
• Vaccines except as noted in Section 3.4.
• Bisphosphonates are allowed for the treatment of bone pain or hypercalcemia.
3.4.2 
Other Restrictions and Precautions
3.4.2.1 
Treatment of Infusion Reactions
Infusion  reactions  should  be  graded  according  to  CTCAE Version 4.0  allergic 
reaction/hypersensitivity. These reactions may manifest with signs and symptoms that may 
include, but are not limited to fever, chills, headache, rash, pruritus, arthralgias, hypo-or 
hypertension, bronchospasm or other symptoms. Severe infusion reactions require the immediate 
interruption of study drug therapy and permanent discontinuation from further treatment. 
Appropriate medical therapy including epinephrine, corticosteroids, intravenous antihistamines, 
bronchodilators, and oxygen should be available for use in the treatment of such reactions. 
Subjects should be carefully observed until the complete resolution of all signs and symptoms. 
Following an infusion reaction, subjects should be premedicated with acetaminophen and 
diphenhydramine for future treatments.
Nivolumab, ipilimumab and lirilumab contain only human immunoglobulin protein sequences.
However, infusion reactions have been observed. If such a reaction were to occur, it might 
manifest with fever, chills, rigors, headache, rash, pruritis, arthralgias, hypo- or hypertension, 
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bronchospasm, or other symptoms. All Grade 3 or 4 infusion reactions should be reported within 
24 hours to the BMS Medical Monitor and reported as a SAE if criteria are met. Infusion 
reactions should be graded according to NCI CTCAE (version 4.0) guidelines.
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines, as appropriate:
For Grade 1 symptoms:(Mild reaction; infusion interruption not indicated; intervention not 
indicated)
The following prophylactic premedications are recommended for future infusions: 
diphenhydramine 50 mg (or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) at 
least 30 minutes before additional study drug administrations.
For Grade 2 symptoms:(Moderate reaction requires therapy or infusion interruption but 
responds  promptly  to  symptomatic  treatment  [eg,  antihistamines,  non-steroidal 
anti-inflammatory drugs, narcotics, corticosteroids, iv fluids]; prophylactic medications indicated 
for ≤24 hours)
Stop the study drug infusion, begin an IV infusion of normal saline, and treat the subject with 
diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen); 
remain at bedside and monitor subject until resolution of symptoms. Corticosteroid therapy may 
also be administered as appropriate. If the infusion is interrupted, then restart the infusion at 50% 
of the original infusion rate when symptoms resolve. Monitor subject closely. If symptoms recur 
then no further study drug will be administered at that visit. Subsequent infusions should be 
administered over 2 hours. The amount of study drug infused must be recorded on the case report 
form (CRF). The following prophylactic premedications are recommended for future infusions: 
diphenhydramine 50 mg (or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) 
should be administered at least 30 minutes before additional study drug administrations. If 
necessary, corticosteroids (recommended dose: up to 25 mg of SoluCortef or equivalent) may be 
used.
For Grade 3 or Grade 4 symptoms:(Severe reaction, Grade 3: prolonged [ie, not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of 
symptoms following initial improvement; hospitalization indicated for other clinical sequelae 
[eg, renal impairment, pulmonary infiltrates]. Grade 4: life-threatening; pressor or ventilatory 
support indicated). Immediately discontinue infusion of study drug. Begin an IV infusion of 
normal saline, and treat the subject as follows: Recommend bronchodilators, epinephrine 
0.2 to 1 mg of a 1:1,000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 
1:10,000 solution injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Subject should be monitored until the 
investigator is comfortable that the symptoms will not recur. Study drug will be permanently 
discontinued. Investigators should follow their institutional guidelines for the treatment of 
anaphylaxis. Remain at bedside and monitor subject until recovery from symptoms. In the case 
of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized 
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pruritus  within  1 week  after  treatment),  symptomatic treatment  may be  given 
(eg, oral antihistamine, or corticosteroids).
3.5 
Discontinuation of Subjects from Treatment
Subjects MUST discontinue investigational product (and noninvestigational product at the 
discretion of the investigator) for any of the following reasons:
• Withdrawal of informed consent (subject’s decision to withdraw for any reason)
• Any clinical adverse event (AE), abnormal laboratory test results or intercurrent illness 
which, in the opinion of the investigator, indicates that continued participation in the study is 
not in the best interest of the subject
• Grade 3or 4 uveitis
• Unable to reduce corticosteroids to 10 mg or less of prednisone or equivalent per day within 
12 weeks
• Pregnancy
• Termination of the study by BMS
• Loss of ability to freely provide consent through imprisonment or involuntary incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness
• Documented and confirmed disease progression or clinical deterioration while receiving 
active study therapy
• Stopping rules as defined in Section 3.1.3.
All subjects who discontinue should comply with protocol specified follow-up procedures as 
outlined in Section 5. The only exception to this requirement is when a subject withdraws 
consent for all study procedures or loses the ability to consent freely (ie, is imprisoned or 
involuntarily incarcerated for the treatment of either a psychiatric or physical illness).
If a subject was withdrawn before completing the study, the reason for withdrawal must be 
entered on the appropriate case report form (CRF) page.
4
TREATMENTS
Study drugs include both Noninvestigational (NIMP) and Investigational Medicinal Products 
(IMP) and can consist of the following:
• All products, active or placebo, being tested or used as a comparator in a clinical trial
• Study required premedication, and
• Other drugs administered as part of the study that are critical to claims of efficacy 
(eg, backbone therapy, rescue medications)
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4.1 
Study Treatments
For product descriptions seeTable 4.1-1. Non-investigational medicinal product will be used to 
treat infusion reactions as described in Section 3.4.2.1.
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Table 4.1-1: 
Product Description - Treatment Period
Product Description 
and Dosage Form
Potency 
Primary Packaging
(Volume)/ Label Type
Secondary Packaging
(Qty) /Label Type
Appearance 
Storage Conditions
(per label)
BMS-936558-01 
(nivolumab) Solution for 
injection
100 mg (10 mg/mL) 
10 mL vial/ 
Open-Label 
5 or 10 vials per carton/ 
Open-Label
Clear to opalescent, 
colorless to pale yellow 
liquid. May contain 
particles.
2 - 8°C Protect from 
light and freezing.
Ipilimumab Solution for 
Injection
200 mg (5 mg/mL) 
40 mL per vial/Open-
label
4 vials per 
carton/Open-label
Clear, colorless to pale 
yellow liquid. May 
contain particles
2 to 8°C. Protect from 
light and freezing.
BMS-986015-01 
(lirilumab) Solution for 
injection
100 mg (10 mg/mL) 
10 ml vial/open-label 
6 vials per carton/ 
Open-label
Clear to opalescent, 
colorless liquid. 
Essentially free of 
particles
2 to 8°C
Protect from light and 
freezing.
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4.1.1 
Investigational Product
An investigational product, also known as investigational medicinal product in some regions, is 
defined as a pharmaceutical form of an active substance or placebo being tested or used as a 
reference in a clinical study, including products already with a marketing authorization but used 
or assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study subjects. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations. 
In this protocol, investigational product(s) is/are: nivolumab, ipilimumab and lirilumab.
4.1.2 
Noninvestigational Product
Other medications used as support or escape medication for preventative, diagnostic, or 
therapeutic reasons, as components of the standard of care for a given diagnosis, may be 
considered as noninvestigational products.
In this protocol, noninvestigational products is/are: medications listed in Section 3.4.2.1used to 
treat infusion reactions. These are sourced by the investigator as are all drug administration 
supplies.
4.1.3 
Handling and Dispensing
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by the sponsor. If 
concerns regarding the quality or appearance of the study drug arise, do not dispense the study 
drug and contact the sponsor immediately.
Investigational product documentation must be maintained that includes all processes required to 
ensure drug is accurately administered. This includes documentation of drug storage, 
administration and, as applicable, storage temperatures, reconstitution, and use of required 
processes (eg, required diluents, administration sets).
For nivolumab, ipilimumab, and lirilumab, please refer to the current IB/pharmacy reference 
sheets for storage, handling and preparation instructions.
4.1.3.1 
Study Drug Preparation and Administration
BMS-936558 (nivolumab) is to be administered as a 60 minute IV infusion. Ipilimumab is to be 
administered as a 90 minute infusion. Lirilumab is to be administered as a 60 minute IV infusion.
When both study drugs are to be administered on the same day, separate infusion bags and filters 
must be used for each infusion. Nivolumab is to be administered first. The nivolumab infusion 
must be promptly followed by a saline flush to clear the line of nivolumab before starting the 
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ipilimumab or lirilumab infusion. The second infusion will always be ipilimumab or lirilumab, 
and will start no sooner than 30 minutes after completion of the nivolumab infusion.
4.1.4 
Dose Modifications
There will be no dose adjustments allowed for study drugs with the exception of changes due to 
fluctuations in weight.
4.1.5 
Intrasubject Dose Escalation
No intrasubject dose escalation will be allowed.
4.1.6 
Dose Reductions
Study drug dose reductions are not permitted in this study.
4.1.7 
Criteria to Resume Treatment
IPILIMUMAB/NIVOLUMAB COHORTS and LIRILUMAB/NIVOLUMAB COHORTS
DOSE DELAY CRITERIA
Dose delay criteria apply for all drug-related adverse events attributed to nivolumab, ipilimumab, 
or both.
• Any DLT criteria
• Any persistent Grade 2 AE (with the exception of fatigue, weakness, skin AEs, laboratory 
abnormalities). Treatment may resume when the AE resolves to Grade 1.
• AST or ALT > 3X ULN. Treatment may resume when the AE resolves to Grade 1.
• Any adverse event, laboratory abnormality, or condition that, in the judgment of the 
investigator, warrants delaying the dose of study medication.
If dose delay is necessary, both nivolumab and ipilimumab must be delayed until treatment can 
resume. If a delay prevents subsequent infusion of ipilimumab, the dose of ipilimumab should be 
replaced as soon as possible. At least 19 days must elapse between the replacement dose of 
ipilimumab and the administration of the next dose of the combination.
If dose delay is necessary, both nivolumab and lirilumab must be delayed until treatment can 
resume. If a delay prevents subsequent infusion of lirilumab, the dose of lirilumab should be 
replaced as soon as possible.
Subjects may resume treatment when the drug-related AE(s) resolve(s) to Grade 1 or baseline 
value (except for grade 2 fatigue, grade 2 weakness, asymptomatic lipase or amylase) for which 
subjects are not required to delay treatment) unless the AE meets the criteria for permanent 
discontinuation (Section 4.1.9) Comprehensive algorithms for supportive care for subjects 
treated with nivolumab are included in this protocol (see Appendix 7). Subjects must resume 
treatment within 6 weeks from the previous dose. Treatment may be resumed after 6 weeks if the 
PI and BMS medical monitor agree that the benefit/risk justify continuing study therapy.
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In the case of endocrine-related AEs, hormone replacement therapy may be utilized to restore
physiologic function and to permit retreatment with study drug. If this is not possible the subject 
must be discontinued from study therapy.
4.1.8 
Infusion Delays and Missed Doses
In the case that an infusion cannot be administered at a scheduled visit, it has to be administered 
as soon as possible. If the delay is between 1 and 7 days, the procedures at the original scheduled 
visit should be performed. If the delay is more than 7 days, the procedures at the next visit should 
be performed. Response assessment should never be skipped. Subjects with infusion delays of 
greater than 6 weeks should normally discontinue treatment and enter the Follow-up Period with 
the exception of delays related to prophylactic vaccinations as outlined in Section 3.4.1or after 
specific consultation and agreement between the investigator and BMS Medical Monitor in 
settings where benefit/risk may justify continued study therapy (eg, subject deriving clinical 
benefit who requires prolonged steroid taper for management of non-DLT AEs).
4.1.9 
Permanent Discontinuation Due to Adverse Event(s)
Subjects will be required to permanently discontinue study therapy for the following drug related 
adverse events:
1) Any DLT as defined in Section 3.1.1.1, with the following exceptions:
a) grade 3 fever that returns to grade 1 or less within 3 days, and is not associated with 
hemodynamic compromise (including hypotension, or clinical or laboratory evidence of 
end organ perfusion impairment)
b) grade 3 diarrhea, nausea, vomiting, or abdominal pain that returns to grade 1 or baseline 
within 3 days with medical intervention
c) grade 3 pruritus or rash that returns to grade 1 or baseline within 7 days or baseline with 
medical intervention
d) grade 3 endocrinopathy that is well controlled by hormone replacement
e) grade 3 tumor flare (defined as pain, irritation or rash that localizes to sites of known or 
suspected tumor)
2) Subjects who develop recurrent grade 3 treatment related adverse reactions should be 
permanently discontinued from study drug.
The consideration to re-initiate study therapy under these exceptions will be made on a case by 
case basis after considering the overall benefit/risk profile and in consultation between the 
investigator and the study sponsor. In cases where the adverse event meets the criteria for 
permanent discontinuation from study therapy, but the investigator and the sponsor believe that 
re-initiation of study therapy may be potentially beneficial and justified, details will be submitted 
in advance to the FDA for review, prior to re-initiation of study therapy.
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4.1.10 
Discontinuation Due to Confirmed Complete Response
Subjects with a CR may continue to receive study therapy until response confirmation or for an 
additional 16 weeks (whichever is longer) and then enter the follow-up period. Subjects that 
achieve a confirmed complete response and enter follow-up may be eligible for additional study 
therapy upon confirmed disease progression as described in protocol in Section 3.1.2. Subjects 
enrolled in the nivolumab and ipilimumab or nivolumab and lirilumab combination cohorts will 
not be eligible for additional study therapy if they progress during the follow-up period.
4.2 
Method of Assigning Subject Identification
After informed consent has been obtained, the subject must be enrolled into the study by calling 
an interactive voice response system (IVRS) to obtain the subject number. The exact procedure 
for using the IVRS will be detailed in a separate document.
4.3 
Selection and Timing of Dose for Each Subject
Subjects will be entered sequentially into the dose level currently accruing up to a maximum 
of 6. If a DLT occurs in two subjects, that level will be expanded to include 9 subjects. Once the 
determination that the dose level is safe has been made, the next level can begin accrual.
4.4 
Blinding/Unblinding
Not applicable.
4.5 
Treatment Compliance
Study drug will be administered in the clinical facility. The investigator or their designated study 
personnel will maintain a log (Drug Accountability Log) of all study drugs received dispensed 
and destroyed. The investigator and the study personnel will ensure that each subject receives the 
calculated dose of the study drug based on body weight. 
Drug supplies will be inventoried and accounted for throughout the study. The Drug 
Accountability Log will be reviewed by the study monitor during site visits and at the 
completion of the study. Any discrepancy should be brought to the attention of the Sponsor.
4.6 
Destruction and Return of Study Drug
4.6.1 
Destruction of Study Drug
For this study, study drugs (those supplied by BMS or sourced by the investigator) such as 
partially used study drug containers, vials and syringes may be destroyed on site. 
Any unused study drugs can only be destroyed after being inspected and reconciled by the 
responsible BMS Study Monitor unless study drug containers must be immediately destroyed as 
required for safety, or to meet local regulations (eg, cytotoxics or biologics).
On-site destruction is allowed provided the following minimal standards are met:
• On-site disposal practices must not expose humans to risks from the drug.
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• On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.
• Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request.
• Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal 
vendor must be documented.
• Accountability and disposal records are complete, up-to-date, and available for the Monitor 
to review throughout the clinical trial period.
If conditions for destruction cannot be met the responsible BMS Study Monitor will make 
arrangements for return of study drug.
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
4.6.2 
Return of Study Drug
If study drug will not be destroyed upon completion or termination of the study, all unused 
and/or partially used study drug that was supplied by BMS must be returned to BMS. The return 
of study drug will be arranged by the responsible BMS Study Monitor. 
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 
 
 
 
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5.2 
Study Materials
• Instructions and kits for collections, processing and shipment of blood and tissue samples
• Investigator Brochure
• Local laboratory data entry instructions
• IVRS registration instructions
• Study drug supplies
• CRF Instructions
• SAE forms
• Pregnancy Surveillance Forms
• CTCAE version 4.0.
5.3 
Safety Assessments
Adverse events will be assessed continuously during the study and for 100 days post last 
treatment. Adverse events will be coded using the most current version of MedDRA and 
reviewed for potential significance and clinical importance. Adverse events will be evaluated 
according to the NCI CTCAE Version 4.0 dated June 14, 2010. Subjects should be followed until 
all treatment-related adverse events have recovered to baseline or are deemed irreversible by the 
investigator.
5.4 
Efficacy Assessments
Efficacy assessment will be conducted and reported on the eCRF using the appropriate efficacy 
assessment based on tumor type. Subjects with non-Hodgkin’s lymphoma or Hodgkin lymphoma 
will be evaluated using the International Workshop to Standardize Response Criteria for 
non-Hodgkin’s Lymphomas (Appendix 1), subjects with multiple myeloma with the 
International Myeloma Working Group Uniform Response Criteria to define response and 
progressive disease (Appendix 3), and subjects with cutaneous T cell Lymphoma with the 
Clinical End Points and Response Criteria in Mycosis Fungoides and Sezary Syndrome76
(Appendix 2). Radiographic images may be collected for blinded independent central review.
5.4.1 
Tumor biopsy and Bone Marrow Biopsy and Aspiration
Tumor biopsies will be collected to evaluate the immune infiltrate and tumor for expression of 
immune modulating proteins, such as PD-L1 and LAG-3, prior to and during study therapy. Prior 
to therapy, archived tumor tissue from every surgical resection should be obtained and submitted 
for biomarker analysis. During the tumor cohorts phase of the study, core tumor biopsies will be 
mandated for all subjects in all four tumor cohorts. All other subjects may volunteer to undergo 
biopsies at any time during therapy if deemed clinically safe. Core tumor biopsies may be 
obtained from clinically palpable tumors or visualized by imaging studies. The investigator, in 
consultation with the radiology staff, must determine the degree of risk associated with the 
procedure and find it acceptable. Excisional biopsies may also be performed to obtain tumor 
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biopsy samples. Invasive procedures that require general anesthesia should not be performed to 
obtain a biopsy specimen. If a surgical procedure is performed for a clinical indication, then that 
sample may be used for research purposes if the subject consents to its use. Bone marrow 
biopsies and aspirates will be obtained using institutional standards for these procedures. Fine 
needle aspirates are not allowed because the architecture of the tumor in its microenvironment 
cannot be assessed.
When subjects are considered for re-initiation of therapy in the follow-up period, investigators 
are strongly encouraged to collect an additional core biopsy prior to re-initiation of therapy, if 
determined to be of acceptable clinical risk. Biopsy of tumor in this setting will aid in identifying 
potential mechanisms of escape from anti-tumor effects of nivolumab. This biopsy will also be 
prepared for FFPE and fresh frozen sections.
Lymphoma Cohorts:
During the tumor cohorts phase of the study, four core tumor biopsies will be required for all 
subjects in the Hodgkin lymphoma, B cell lymphoma and T cell lymphoma cohorts. These 
biopsies should be obtained prior to therapy and prior to week 7 (prior to week 9 for subjects in 
the nivolumab/lirilumab cohorts). The pre-treatment biopsy is not required if archived sample 
that is from a recent biopsy (within four months of initiation of study drug) is available 
(either a formalin fixed block or 7-15 slides that contain tumor). This will be utilized for IHC 
analyses. If a fresh tumor biopsy is collected, two cores will be placed in formalin for IHC 
analysis and the remaining will be placed in RNAlater solution to be utilized for RNA analysis as 
described in Section 5.6. On-treatment biopsies for all patients with lymphoma will otherwise be 
optional. Collection of 4 cores is ideal. Nevertheless, if this is not possible due to safety concerns 
or other medical reasons, collection of fewer core biopsies is acceptable. Priority should be 
placed on placing cores in formalin for IHC analysis. If 3 cores are taken, place 2 cores in 
formalin and 1 in RNAlater. If 2 cores are taken, place 1 in formalin and 1 in RNAlater. If 1 core 
is taken, place 1 core in formalin. See Table 5.1-6and Table 5.1-9for collection time points.
Multiple Myeloma Cohorts:
During the tumor cohorts phase of the study, two bone marrow biopsies and aspirates will be 
required for all subjects in the myeloma cohort. The first biopsy should be obtained prior to 
therapy. All patients on this study are required to undergo bone marrow biopsy and aspiration at 
the time of screening to rule out myelodysplasia. Therefore, at this time, one additional core 
sample and 16 ml of aspirate should be obtained. The second biopsy should be obtained prior to 
week 7 (prior to week 9 for subjects in the nivolumab/lirilumab cohorts). These samples will be 
utilized for exploratory analysis of immune function and receptor occupancy that is described in 
Section 5.6. On-treatment bone marrow biopsy and aspiration for all patients with bone marrow 
involvement will otherwise be optional. Bone marrow biopsy and aspiration may also be
required as part of standard clinical care, such as to document progression and to document 
complete response. Extra biopsy and aspirate samples should be obtained if possible to allow for 
research assessment as listed above. See Table 5.1-6 and Table 5.1-9 for collection time points.
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5.5 
Pharmacokinetic Assessments
5.5.1 
Pharmacokinetic Collection & Processing
Table 5.1-4 lists the sampling schedule to be followed for all subjects in the nivolumab 
monotherapy cohorts. Table 5.1-7lists the sampling schedule to be followed in the combination 
cohorts; 5 subjects in each of the tumor cohorts will follow the full PK profile schedule, the 
remaining subjects in the tumor cohorts will follow the sparse sampling schedule. Table 5.1-9
lists the sampling schedule to be followed in the lirilumab combination cohorts. Cmin will be 
reported for all subjects with available data for the assessment of pharmacokinetics. Serial 
samples will be collected after the first dose and at additional time points. All on-treatment 
predose and end-of-infusion PK time-points are intended to align with days on which study drug 
is administered. If dosing occurs on a different day, the PK sampling should be adjusted 
accordingly. Further details of sample collection, processing and shipment are provided in the 
laboratory manual.
5.5.2 
Pharmacokinetic Sample Analyses
The serum samples will be analyzed for nivolumab and/or ipilimumab and/or lirilumab by 
validated methods. In addition, selected serum samples may be analyzed by an exploratory 
analytical method that measures nivolumab and/or ipilimumab and/or lirilumab for technology 
exploration purposes; exploratory results will not be reported.
 
 
 
 
 
 
 
 
 
 
 
 
 
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5.9 
Results of Central Assessments
Not applicable.
6
ADVERSE EVENTS
An Adverse Event (AE)is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation subject administered an investigational 
(medicinal) product and that does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of investigational product, 
whether or not considered related to the investigational product.
The causal relationship to study drug is determined by a physician and should be used to assess 
all adverse events (AE). The casual relationship can be one of the following:
• Related: There is a reasonable causal relationship between study drug administration and the 
AE.
• Not related: There is not a reasonable causal relationship between study drug administration 
and the AE.
The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship. 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.)
6.1 
Serious Adverse Events
A Serious Adverse Event (SAE)is any untoward medical occurrence that at any dose: 
• results in death
• is life-threatening (defined as an event in which the subject was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe)
• requires inpatient hospitalization or causes prolongation of existing hospitalization 
(seeNOTEbelow)
• results in persistent or significant disability/incapacity
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• is a congenital anomaly/birth defect 
• is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) 
Examples of such events include, but are not limited to, intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not 
result in hospitalization.) Potential drug induced liver injury (DILI) is also considered an 
important medical event. (See Section 6.6for the definition of potential DILI).
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study 
drug is an SAE.
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs. 
(See Section 6.1.1 for reporting pregnancies).
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 
−a visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered an important medical or life-threatening event)
−elective surgery, planned prior to signing consent
−admissions as per protocol for a planned medical/surgical procedure
−routine health assessment requiring admission for baseline/trending of health status 
(eg, routine colonoscopy)
−medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases
−admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (eg, lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason).
6.1.1 
Serious Adverse Event Collection and Reporting
Following the subject’s written consent to participate in the study, all SAEs, whether related or 
not related to study drug, must be collected, including those thought to be associated with 
protocol-specified procedures. All SAEs must be collected that occur during the screening period
and within 100 days of discontinuation of dosing.
The investigator should report any SAE that occurs after these time periods and that is believed 
to be related to study drug or protocol-specified procedure.
An SAE report should be completed for any event where doubt exists regarding its seriousness. 
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If the investigator believes that an SAE is not related to study drug, but is potentially related to 
the conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship should be specified in the narrative section of the SAE Report Form.
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS 
(or designee) within 24 hours. SAEs must be recorded on the SAE Report Form; pregnancies on 
a Pregnancy Surveillance Form (electronic or paper forms). When using paper forms, the reports 
are to be transmitted via email or confirmed facsimile (fax) transmission to:
SAE Email Address: See Contact Information list.
SAE Facsimile Number: See Contact Information list.
For studies capturing SAEs/pregnancies through electronic data capture (EDC), electronic 
submission is the required method for reporting. The paper forms should be used and submitted 
immediately, only in the event the electronic system is unavailable for transmission. When paper 
forms are used, the original paper forms are to remain on site.
SAE Telephone Contact(required for SAE and pregnancy reporting): See Contact Information 
list.
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to BMS (or designee) 
using the same procedure used for transmitting the initial SAE report.
All SAEs should be followed to resolution or stabilization.
6.2 
Nonserious Adverse Events
Anonserious adverse eventis an AE not classified as serious.
6.2.1 
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information should begin at initiation of study drug. Nonserious 
AE information should also be collected from the start of a placebo lead-in period or other 
observational period intended to establish a baseline status for the subjects. All non-serious 
adverse events (not only those deemed to be treatment-related) should be collected continuously 
during the treatment period and for a minimum of 100 days following the last dose of study drug
treatment.
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (seeSection 6.1.1). Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of study drug and for those present at the end of study treatment 
as appropriate. All identified nonserious AEs must be recorded and described on the nonserious 
AE page of the CRF (paper or electronic). 
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Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported/identified during the course of the study.
6.3 
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form (paper or electronic) as appropriate:
• Any laboratory test result that is clinically significant or meets the definition of an SAE 
• Any laboratory test result abnormality that required the subject to have study drug 
discontinued or interrupted
• Any laboratory test result abnormality that required the subject to receive specific corrective 
therapy.
It is expected that wherever possible, the clinical rather than laboratory term would be used by 
the reporting investigator (eg, anemia versus low hemoglobin value).
6.4 
Pregnancy
If, following initiation of the investigational product, it is discovered that a study subject is 
pregnant or may have been pregnant at the time of investigational product exposure, including 
during at least 6 half lives after product administration, the investigational product will be 
permanently discontinued in an appropriate manner (eg, dose tapering if necessary for subject 
safety).
The investigator must immediately notify the BMS (or designee) Medical Monitor of this event 
and complete and forward a Pregnancy Surveillance Form to BMS (or designee) within 24 hours 
and in accordance with SAE reporting procedures described in Section 6.1.1. 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information, must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
6.5 
Overdose
An overdose is defined as accidental or intentional administration of any dose of product that is 
considered both excessive and medically important. All occurrences of overdose must be 
reported as SAEs (see Section 6.1.1 for reporting details).
6.6 
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, 
meeting the defined criteria, must be reported as SAEs (see Section 6.1.1 for reporting details).
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8.2 
Populations for Analyses
• All Enrolled Subjects: All subjects who sign informed consent form and were registered in 
IVRS.
• All Treated Subjects: All subjects who receive at least one dose of nivolumab and/or 
ipilimumab and/or lirilumab.
• Response Evaluable Subjects: All treated subjects with measurable disease at baseline and 
one of the following: 1) at least one on-treatment efficacy assessment, 2) clinical progression, 
or 3) death.
• Pharmacokinetic (PK) Subjects: All subjects who receive at least one dose of study 
medication and have available serum concentration data.
• Biomarker Subjects: All subjects who receive at least one dose of study medication and have 
available biomarker data
• Immunogenicity Subjects: All subjects who receive at least one dose of study medication and 
have available ADA data.
8.3 
Endpoints
8.3.1 
Primary Endpoint(s)
8.3.1.1 
Safety
The primary objective relates to establishing the dose limiting toxicities and maximum tolerated 
dose for monotherapy with nivolumab, combination therapy with nivolumab and ipilimumab,
and combination therapy with nivolumab and lirilumab in subjects with select relapsed/refractory 
hematologic malignancies. This objective will be measured by the following endpoints:
• Number and percent of subjects that experience drug-related grade 3-4 AEs occurring up to 
100 days after the last dose of study drug. [Time Frame - On a continuous basis up to 
100 days after the last dose of study drug];
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• Number and percent of subjects that experience drug-related grade 3-4 SAEs occurring up to 
100 days after the last dose of study drug. [Time Frame - On a continuous basis up to 
100 days after the last dose of study drug];
• Number and percent of subjects with clinical laboratory abnormalities by worst toxicity grade 
by NCI CTCAE version 4.0 (as assessed at the planned times listed in Section 5.1). 
[Time Frame - On a continuous basis up to 100 days after the last dose of study drug].
8.3.2 
Secondary Endpoint(s)
8.3.2.1 
Efficacy
The secondary objective relating to efficacy is to assess the preliminary antitumor activity of 
various doses of monotherapy nivolumab, the combination of nivolumab and ipilimumab, and 
the combination of nivolumab and lirilumab in subjects with relapsed/refractory hematologic 
malignancy. This objective will be measured by tabulations of individual BOR and analyses of 
the ORR, duration of response, and PFS. The BOR outcomes will be based on the disease 
specific criteria (specified in Appendices 1, 2, and 3).
Best Overall Response (BOR)
BOR is defined as the best response designation over the study as a whole, recorded between the 
date of first dose and the last efficacy assessment prior to subsequent therapy.
Progression Free Survival Rate (PFSR)
The PFSR is defined as the proportion of subjects remaining progression free or surviving to 
time t, where t = 8, 16 and 24 weeks for patients receiving monotherapy nivolumab, 
t = 7, 13, 21, and 29 weeks for patients receiving the combination of nivolumab and ipilimumab, 
and t = 9, 17, 25, and 41 weeks for patients receiving the combination of nivolumab and 
lirilumab. This probability will be calculated by the product limit method (Kaplan-Meier 
estimate) which takes into account censored data.
Progression free survival (PFS), computed for all treated subjects, is defined as the time between
date of first dose of study therapy and date of progression or death, whichever occurs first. 
Subjects who die without a reported prior progression will be considered to have progressed on 
the date of their death. Subjects who did not progress or die will be censored on the date of their 
last efficacy assessment. Subjects who did not have any on study efficacy assessments will be 
censored on the date of the first dose of study drug.
Objective Response Rate (ORR)
Objective response rate is defined as the proportion of subjects whose BOR one of the following 
responses divided by the number of treated subjects (or response-evaluable subjects).
• For lymphoma and myeloma subjects whose BOR is either partial response (PR) or complete 
response (CR)
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Duration of Objective Response
The duration of response is defined as the time when the measurement criteria are first met for 
objective response until the date of documented disease progression or death. For subjects who 
neither progress nor die, the duration of response will be censored at the date of their last disease 
assessment.
Modified Severity Weighted Assessment Tool (mSWAT)
Response in Skin for subjects with cutaneous T cell lymphoma is evaluated by the mSWAT 
score which is reported by investigators.
76
8.3.2.2 
Pharmacokinetic
The following pharmacokinetic parameters of nivolumab, ipilimumab, and lirilumab will be 
derived from serum concentration time profiles for all subjects receiving nivolumab
monotherapy and subjects following the full PK profile sampling schedule in the combination 
cohorts (approximately five subjects in each of the tumor cohorts). Cmin will be reported for all 
subjects with available data. These parameters are used to measure the secondary objective 
related to pharmacokinetics.
Cmax - Maximum observed serum concentration
Tmax - Time of maximum observed serum concentration
In addition, the following parameters will be determined for all subjects:
Cmin- Serum concentration achieved at the end of dosing interval (trough concentration, all 
subjects)
AUC(0-T)-Area under the plasma concentration-time curve from time zero to the last time of 
the last quantifiable concentration.
AUC(TAU)- Area under the concentration-time curve in one dosing interval
Ceoinf - Serum concentration achieved at the end of study drug infusion
8.3.2.3 
Immunogenicity
The secondary objective relating to immunogenicity will be measured by the ADA status both at 
the sample level and at the subject level. At the sample level a sample is characterized as 
baseline ADA-positive, ADA-positive or ADA-negative to each study drug. At the subject level, 
relevant ADA endpoints include proportion of subjects with a Baseline ADA-positive sample, 
and proportion of ADA-positive subjects for each study drug. Time points for collection are 
specified in Table 5.1-4,Table 5.1-7and Table 5.1-9. Additional details will be presented in the 
SAP.
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8.3.2.4 
Biomarker
The secondary objective of associating PD-L1 expression levels with clinical efficacy measures 
will be assessed using PD-L1 expression levels by immunohistochemistry as specified in Table 
5.1-4, Table 5.1-6, and Table 5.1-9and secondary efficacy endpoints.
 
 
 
 
 
8.4 
Analyses
8.4.1 
Demographics and Baseline Characteristics
Subject demographics and baseline characteristics including age, sex, race, ethnicity, weight, 
baseline disease diagnosis, and medical conditions will be summarized by treatment and dose 
level using descriptive statistics.
8.4.2 
Efficacy Analyses
Individual best overall response (BOR), duration of response and PFS will be listed, using 
appropriate response criteria for each disease type: the IMWG Uniform Response Criteria for 
Multiple Myeloma, standard criteria for Lymphoma, and the Clinical End Points and Response 
Criteria in Mycosis Fungoides and Sezary Syndrome for cutaneous T cell Lymphoma.76,82,83
BOR outcomes will be tabulated by disease type, treatment and dose. The objective response rate 
(ORR) and corresponding 95% exact confidence interval will be provided by disease type. The 
median duration of response and PFSR at select time points (8, 16, and 24 weeks for patients 
receiving monotherapy nivolumab, 7, 13, 21, and 29 weeks for patients receiving the 
combination of nivolumab and ipilimumab and 9, 17, 25, and 41 weeks for patients receiving the 
combination of nivolumab and lirilumab) and corresponding two-sided 95% confidence intervals 
will be estimated by Kaplan-Meier methodology, by disease type, depending on data availability. 
The analysis of overall survival would be exploratory. Kaplan-Meier plots of PFS and OS will be 
provided. ORR, duration of response and PFS analyses will include subjects in the dose 
expansion phase and subjects in the dose escalation phase matching those in the dose expansion 
phase by disease type, treatment, and dose. Individual changes in the tumor burden over time 
may be presented graphically based on data availability within a tumor type.
To evaluate the response in skin for subjects with cutaneous T cell lymphoma, the percentage
change from baseline on the mSWAT score will be derived and listed.
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8.4.3 
Safety Analyses
All recorded adverse events will be listed and tabulated by system organ class, preferred term, 
and dose and coded according to the most current version of MedDRA
All recorded adverse events will be listed and tabulated by system organ class, preferred term, 
treatment, dose and coded according to the most current version of MedDRA across disease 
types. A subset of adverse event tables may be summarized by disease type. DLTs will be 
described by treatment and dose. The incidence of adverse events will be reviewed for potential 
significance and clinical importance. AEs will be coded according to the most current version of 
MedDRA. Vital signs and clinical laboratory test results will be listed and summarized by 
treatment and dose. Any significant physical examination findings and results of clinical 
laboratory tests will be listed. ECG results will be evaluated by the investigator and 
abnormalities, if present, will be listed.
8.4.4 
Pharmacokinetic Analyses
Summary statistics will be tabulated for the pharmacokinetic parameters of nivolumab, 
nivolumab in the presence of ipilimumab, and nivolumab in the presence of lirilumab by 
treatment, disease type, dose and study week as appropriate for all subjects receiving nivolumab 
monotherapy and subjects following the full PK profile sampling schedule in the combination 
cohorts (approximately five subjects in each of the tumor cohorts and subjects in the exploratory 
dose evaluation cohorts). Cmin will be summarized for all subjects. To describe the dependency 
on dose, scatter plots of Cmax and AUC(0-T) versus dose will be provided for each day 
measured by treatment and study drug. To assess attainment of steady state, plots of Cmin versus 
time will be provided by treatment and by study drug for all subjects. Pharmacokinetic 
concentrations of nivolumab, ipilimumab and lirilumab from all subjects will be listed, and may 
be used in combination with other studies for exposure-response or population pharmacokinetic 
modeling, which will be part of a separate report.
 
 
 
 
 
 
 
 
 
 
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8.5 
Interim Analyses
Administrative interim analyses may be performed at several times prior to completion of the 
study in order to facilitate program decisions and to support presentations or publications. 
9 
STUDY MANAGEMENT
9.1 
Compliance
9.1.1 
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and be prepared by, BMS. The investigator should not implement any 
deviation or change to the protocol without prior review and documented approval/favorable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
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If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior 
to obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change 
will be submitted to:
• IRB/IEC for review and approval/favorable opinion
• BMS
• Regulatory Authority(ies), if required by local regulations
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
subject: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is an administrative letter, investigators must inform their IRB(s)/IEC(s).
9.1.2 
Monitoring
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare 
them with source documents, discuss the conduct of the study with the investigator, and verify 
that the facilities remain acceptable. 
In addition, the study may be evaluated by BMS internal auditors and government inspectors 
who must be allowed access to CRFs, source documents, other study files, and study facilities. 
BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory 
authorities, and promptly forward copies of inspection reports to BMS. 
9.1.3 
Investigational Site Training
Bristol-Myers Squibb will provide quality investigational staff training prior to study initiation. 
Training topics will include but are not limited to: GCP, AE reporting, study details and 
procedure, electronic CRFs, study documentation, informed consent, and enrollment of WOCBP.
9.2 
Records
9.2.1 
Records Retention
The investigator must retain all study records and source documents for the maximum period 
required by applicable regulations and guidelines, or institution procedures, or for the period 
specified by BMS, whichever is longer. The investigator must contact BMS prior to destroying 
any records associated with the study.
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BMS will notify the investigator when the study records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, IRB). Notice of such 
transfer will be given in writing to BMS.
9.2.2 
Study Drug Records 
It is the responsibility of the investigator to ensure that a current disposition record of 
investigational product (those supplied by BMS) is maintained at each study site where study 
drug and are inventoried and dispensed. Records or logs must comply with applicable regulations 
and guidelines and should include:
• amount received and placed in storage area
• amount currently in storage area
• label identification number or batch number 
• amount dispensed to and returned by each subject, including unique subject identifiers
• amount transferred to another area/site for dispensing or storage
• nonstudy disposition (eg, lost, wasted) 
• amount destroyed at study site, if applicable
• amount returned to BMS
• retain samples for bioavailability/bioequivalence, if applicable 
• dates and initials of person responsible for Investigational Product dispensing/accountability, 
as per the Delegation of Authority Form.
BMS will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
9.2.3 
Case Report Forms
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. 
For sites using the BMS electronic data capture tool, electronic CRFs will be prepared for all 
data collection fields except for fields specific to SAEs and pregnancy, which will be reported on 
the paper or electronic SAE form and Pregnancy Surveillance form, respectively. Spaces may be 
left blank only in those circumstances permitted by study-specific CRF completion guidelines 
provided by BMS. 
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).
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The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, including any paper or electronic SAE/pregnancy CRFs, must be promptly 
reviewed, signed, and dated by the investigator or qualified physician who is a subinvestigator 
and who is delegated this task on the Delegation of Authority Form. For electronic CRFs, review 
and approval/signature is completed electronically through the BMS electronic data capture tool. 
The investigator must retain a copy of the CRFs including records of the changes and 
corrections.
Each individual electronically signing electronic CRFs must meet BMS training requirements 
and must only access the BMS electronic data capture tool using the unique user account 
provided by BMS. User accounts are not to be shared or reassigned to other individuals.
Clinical Study Report and Publications A Signatory Investigator must be selected to sign the 
clinical study report. 
For this protocol, the Signatory Investigator will be selected considering the following criteria:
• External Principal Investigator designated at protocol development
• Subject recruitment (eg, among the top quartile of enrollers)
• Involvement in trial design
• Other criteria (as determined by the study team)
The data collected during this study are confidential and proprietary to BMS. Any publications 
or abstracts arising from this study require approval by BMS prior to publication or presentation 
and must adhere to BMS’s publication requirements as set forth in the approved clinical trial 
agreement (CTA). All draft publications, including abstracts or detailed summaries of any 
proposed presentations, must be submitted to BMS at the earliest practicable time for review, but 
at any event not less than 30 days before submission or presentation unless otherwise set forth in 
the CTA. BMS shall have the right to delete any confidential or proprietary information 
contained in any proposed presentation or abstract and may delay publication for up to 60 days 
for purposes of filing a patent application.
9.3 
Clinical Study Report and Publications
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected considering the following criteria:
Subject recruitment (eg, among the top quartile of enrollers)
The data collected during this study are confidential and proprietary to BMS. Any publications 
or abstracts arising from this study require approval by BMS prior to publication or presentation 
and must adhere to BMS’s publication requirements as set forth in the approved clinical trial 
agreement (CTA). All draft publications, including abstracts or detailed summaries of any 
proposed presentations, must be submitted to BMS at the earliest practicable time for review, but 
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at any event not less than 30 days before submission or presentation unless otherwise set forth in 
the CTA. BMS shall have the right to delete any confidential or proprietary information 
contained in any proposed presentation or abstract and may delay publication for up to 60 days 
for purposes of filing a patent application.
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10 
GLOSSARY OF TERMS
Term
Definition
Adverse Reaction 
An adverse event that is considered by either the investigator or 
BMS as related to the investigational product
Unexpected Adverse 
Reaction
An adverse reaction, the nature or severity of which is not 
consistent with the applicable product information 
(eg, Investigator Brochure for an unapproved investigational 
product)
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LIST OF ABBREVIATIONS
ADA
Anti-drug antibody
ALT
Alanine aminotransferase
APC
Antigen presenting cells
AST
Aspartate aminotransferace
BOR
Best overall response
BORR
Best overall response rate
BP
Blood pressure
CI
Confidence interval
CR
Complete response
CRF
Case report form
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
Cytotoxic T lymphocyte-associated antigen 4
DLT
Dose-limiting toxicity
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDC
Electronic Data Capture
FDA
Food and Drug Administration
FSH
Follicle stimulating hormone
GCP
Good clinical practices
GCSF
Granulocyte colony stimulating factor
HBV SAg 
Hepatitis B-virus surface antigen
HCV RNA 
Hepatitis C virus ribonucleic acid
HIPAA
Health Information Portability and Accountability Act
HL
Hodgkin lymphoma
HLA
Human leukocyte antigen
HSCT
Hematopoietic stem cell transplant
ICF
Informed Consent Form
IEC
Independent Ethics Committee
IP
Investigational product
IRB
Institutional Review Board
ITIM
Immunoreceptor tyrosine inhibitory motif
ITSM
Immunoreceptor tyrosine-based switch motif
IV
Intravenous
KIR
Killer immunoglobulin-like receptor
LFTs
Liver function tests
mAb
Monoclonal antibody
MedDRA 
Medical Dictionary for Regulatory Activities
MHC
Major histocompatibility complex
MRI
Magnetic resonance imaging
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MTD
Maximum-tolerated dose
NK
Natural killer
ORR
Objective response rate
PD
Progressive disease
PD-1
Programmed death-1
PD-L1
Programmed death ligand 1
PD-L2
Programmed death ligand 2
PET
Positron emission tomography
PMBL
Primary mediastinal B cell Lymphoma
PR
Partial response
SAE
Serious adverse event
SD
Stable disease
SNP
Single nucleotide polymorphism
TCR
T-cell receptor
ULN
Upper limit of normal
WBC
White blood cell
WOCBP
Women of child bearing potential
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SAP_001.pdf: 
Statistical Analysis Plan for 
 
Official Title of Study 
MULTIPLE PHASE 1/2 SAFETY COHORTS OF NIVOLUMAB MONOTHERAPY OR 
NIVOLUMAB COMBINATION REGIMENS ACROSS RELAPSED/REFRACTORY 
HEMATOLOGIC MALIGNANCIES 
NCT01592370 
 
September 8, 2021 


 
 
STATISTICAL ANALYSIS PLAN 
FOR HEMATOLOGIC MALIGNANCY 
 
MULTIPLE PHASE 1/2 SAFETY COHORTS OF NIVOLUMAB MONOTHERAPY OR 
NIVOLUMAB COMBINATION REGIMENS ACROSS RELAPSED/REFRACTORY 
HEMATOLOGIC MALIGNANCIES 
 
 
PROTOCOL CA209039 
 
VERSION # 3.2 
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These monotherapy cohorts will consist of Screening (up to 28 days), Treatment (up to 2 years), 
and Clinical Follow-up (up to 12 months) and Survival Follow-up (up to 2 years).  There is also 
the  possibility  of  Retreatment  (up  
to  1  year)  and  Follow  up  (up  
to  120  days).  The  first  dose 
administered  will  be  followed  by  a  three-week  period  for  pharmacokinetic  and 
pharmacodynamic assessment of nivolumab. A response assessment following administration of 
the first dose will be obtained. Therapy will be given on an every two week schedule thereafter 
with response assessments performed at Weeks 8, 16, 24 and then every 16 weeks thereafter. The 
scheduled response assessments must be completed before the next dose of therapy. 
IPILIMUMAB/NIVOLUMAB COHORTS 
These combination cohorts will evaluate the combination of nivolumab and ipilimumab. 
These combination cohorts will consist of Screening (up to 28 days), Treatment (up to 2 years), 
and Follow-up. 
LIRILUMAB/NIVOLUMAB COHORTS 
These combination cohorts will evaluate the combination of nivolumab and lirilumab. 
These combination cohorts will consist of Screening (up to 28 days), Treatment (up to 2 years), 
and Follow-up. 
NIVOLUMAB/DARATUMUMAB COHORTS 
Cohort  A  will  evaluate  the  combination  of  nivolumab  and  daratumumab  with  or  without 
pomalidomide and dexamethasone in subjects with relapsed/refractory MM that received at least 
2 prior regimens including at least 2 consecutive cycles of IMID and PI alone or in combination, 
and  were  refractory  to  their  last  treatment,  and  pomalidomide, nivolumab,  and  daratumumab 
naïve. 
Cohort  B  will  evaluate  
the  combination  of  nivolumab  and  daratumumab  
in  
relapsed/refractory 
MM subjects that either received at least 3 prior lines of therapy (including an IMID or PI) or are 
double refractory to IMID and PI, and were nivolumab and daratumumab naive. 
The design of the combination cohorts will consist of Screening (up to 28 days), Treatment (until 
disease progression), and Follow-up (i.e., safety follow-up Visit 1 and 2, and long-term survival 
follow-up). 
2.1.1
 Study
 
Design
 
2.1.1.1  Nivolumab  
Monotherapy  
Dose  
Escalation  
Dose Limiting Toxicity 
NIVOLUMAB MONOTHERAPY COHORTS 
Dose  
limiting  
toxicity  
(DLT)  will  be  determined  based  on  
the  
incidence  and  
intensity  of  drug 
related adverse events (AEs) occurring up to two weeks after the administration of the third dose 
of nivolumab or 7 weeks  after initiation of therapy whichever is longer. 
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Dose Limiting Hematologic Toxicity 
DLT  will  be  Grade  4  neutropenia  that  does  not  resolve  to  Grade 3  or  less  within  5  days  of 
initiation of filgrastim (G-CSF), the need for platelet transfusion or a platelet count < 10,000/μL. 
The development of a transfusion requirement or an increase in transfusion requirement of more 
than  
two  units  of  blood  every  
two  weeks  over  a  six  week  period will  also  be  considered  dose 
limiting unless an alternative cause is identified. 
Dose Limiting Non-hematologic Toxicity 
Grade 2 or greater eye pain or reduction of visual acuity that does not respond to topical therapy 
and does not improve to Grade 1 severity within 2 weeks of starting therapy or requires systemic 
treatment. 
Clinically  relevant  Grade  3  or  greater  non-hematologic  toxicity  excluding  lymphopenia, 
asymptomatic  
lipase  or  amylase  or  
laboratory  abnormalities  
that  correct  
to  grade  1  within  72 
hours after treatment. Toxicity will be graded by CTCAE v 4.0. 
DLTs that occur after the decision to dose escalate will be used to determine the recommended 
phase II dose for this population. 
No  dose  escalations  or  de-escalations  are  permitted  within  each  subject’s  
treatment.  A  subject 
who is withdrawn from the study before the completion of the first seven weeks of treatment for 
a reason other than a DLT may be replaced. Subjects who experience dose limiting toxicity may 
resume treatment as per Section 4.1.7 of the protocol upon resolution, providing that criteria for 
permanent discontinuation are not met (Section 4.1.9 of the protocol). 
2.1.2
 Expansion
 
Cohorts
 
NIVOLUMAB MONOTHERAPY COHORTS 
To  
further  characterize  safety  and  efficacy  4  expansion  cohorts  will  be  enrolled.  The  diseases 
that  will  be  explored  are  Hodgkin  Lymphoma  (HL)/  primary  mediastinal  B  cell  Lymphoma 
(PMBL), T cell lymphoma, B cell lymphoma, and multiple myeloma. A total of 6 or 9 subjects 
must be enrolled  at  
the  MTD (or the highest  dose studied where ≤ 1 of  6 or ≤ 2 of 9 subjects 
experiences  a  DLT  
if  
the  MTD  
is  not  
identified)  before  any  subject  
is  dosed  
in  
the  expansion 
cohorts. If none of the first 5 subjects have a DLT by the end of seven weeks of treatment in the 
dose  escalation  phase  of  the  study,  enrollment  to  the  primary  expansion  cohorts  can  begin 
immediately following the enrollment of the sixth subject. 
IPILIMUMAB/NIVOLUMAB COHORTS 
To further characterize safety and efficacy, 4 tumor cohorts will be enrolled. The diseases  
that 
will  be  explored  are  HL/PMBL,  T  cell  lymphoma,  B  cell  lymphoma (diffuse  large  B  cell 
lymphoma and follicular lymphoma only), and multiple myeloma. 
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To characterize safety and efficacy, four tumor cohorts will be enrolled. The diseases that will be 
explored are HL/PMBL, T cell lymphoma, B cell lymphoma (diffuse large B cell lymphoma and 
follicular lymphoma only), and multiple myeloma.  
NIVOLUMAB/DARATUMUMAB COHORTS 
Cohort A (ND, ND-Pd): 60 subjects will be randomized at a 1:1 ratio to the ND arm or the ND-
Pd arm, respectively.  
 
Cohort  B  (ND,  D):  60  subjects  will  be  randomized  in  a  2:1  ratio  to  the  ND  and  D  arms, 
respectively. 
2.2  
Treatment Assignment 
For patients receiving monotherapy nivolumab, nivolumab ill be administered as an IV infusion 
on treatment day 1 followed by a 3 week interval to evaluate pharmacokinetics and duration of 
pharmacodynamics effects and then every two weeks for up to 2 years.  Two dose levels will be 
explored, 1 mg/kg or 3 mg/kg, which will be administered at Week 1 and Week 3, then every 2 
weeks. Therapy will be continued for up to 2 years with the potential for one additional year of 
therapy for retreatment eligible subjects in follow up. 
For patients receiving nivolumab in combination with ipilimumab therapy, nivolumab at 3 mg/kg 
and ipilimumab at 1 mg/kg will be administered every three weeks  
for four doses  
followed by 
nivolumab alone at 3 mg/kg every 2 weeks for a total of two years of therapy. 
For patients receiving nivolumab in combination with lirilumab therapy, nivolumab 3 mg/kg will 
be administered every 2 weeks, and lirilumab 3 mg/kg will be administered every 4 weeks for a 
total of two years of therapy. 
For subjects in Cohort A, nivolumab will be administered at a dose of 240 mg as an intravenous 
infusion  over  30  minutes  on  Day  15  during  Cycle  1,  and  on  Days 1  and  15  during  Cycles  2 
through 6 (ie, every 2 weeks of each 28-day cycle). Starting Cycle 7 and beyond, nivolumab will 
be administered at a dose of 480 mg as an IV infusion over 30 minutes every 4 weeks (Day 1 of 
each 28-day cycle). Daratumumab will be administered at a dose of 16 mg/kg as an IV infusion 
every week (Days 1, 8, 15, and 22 of each 28-day cycle) during Cycles 1 and 2. During Cycles 3 
through  6  daratumumab  will  be  administered  every  2  weeks  (Days 1  and  15  of  each  28-day 
cycle), then starting Cycle 7 and beyond, daratumumab will be administered every 4 weeks (Day 
1 of each 28-day cycle). Pomalidomide in the ND-Pd treatment arm will be administered orally 
at  
the dose of 4 mg daily  on Days  1  
-  21 of each 28-day  cycle. Dexamathesone in  
the  ND-Pd 
treatment arm will be administered as described in section 4.1.4.4. of the protocol. 
For subjects in Cohort B, those randomized to ND treatment will receive nivolumab at a dose of  
240 mg as an intravenous infusion over 30 minutes on Day 15 of Cycle 1. Starting Cycle 2 and  
beyond, nivolumab will be administered at a dose of 480 mg as an intravenous infusion over 30  
minutes every 4 weeks (Day 1 of each 28 day cycle). Daratumumab will be administered at a  
dose of 16 mg/kg as an IV infusion every week (Days 1, 8, 15, and 22 of each 28-day cycle)  
during Cycles 1 and 2. During Cycles 3 through 6 daratumumab will be administered every 2  
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weeks (Days 1 and 15 of each 28-day cycle), then starting Cycle 7 and beyond, daratumumab  
will be administered every 4 weeks (Day 1 of each 28-day cycle). 
 
Nivolumab should be administered before daratumumab on the days when both nivolumab and 
daratumumab are administered.  
 
After informed consent has been obtained, the subject must be enrolled into the study by calling 
an interactive voice response system (IVRS) to obtain the subject number.  
2.3  
Blinding and Unblinding 
This is an open label study. 
2.4  
Protocol Amendments 
Revised  protocol  01  
(21-Dec-2012)  
incorporated  Administrative  Letter  01  and  Amendment  01 
and 02. 
Amendment  number  02  
(21-Dec-2012)  eliminated  
the  highest  
(10  mg/kg)  of  
three  dose  
levels 
scheduled to be examined; it required that 8 of 16 subjects with multiple myeloma be required to 
undergo bone marrow biopsy while on therapy, and modified the discontinuation criteria to  be 
more stringent. 
Amendment number 03 (6-Mar-2013) updated the Summary of Safety section in the protocol to 
include new preliminary reproductive toxicology data. 
Amendment  number  04  
(25-Jun-2013)  eliminated  
the  CML  cohort  
in the  expansion  phase  and 
increased the size of remaining four cohorts from 16 to 23. 
Amendment  number  05  (10-Oct-2013)  corrected  some  minor  errors  and  
inconsistencies  
in  
the 
protocol. 
Amendment number 06  
(19-Dec-2013)  added  cohorts using  a combination of ipilimumab and 
nivolumab in  order to  determine if the combination  
results  
in  
increased  efficacy  with  
tolerable 
safety, compared to monotherapy with nivolumab alone. 
Amendment  number  07  (20-Aug-2014)  Adds  an  additional  set  of  cohorts  (approximately  80 
additional subjects) for dose expansion with combination of lirilumab and nivolumab 
Amendment number 08 (02-Dec-2014) Revises protocol to meet FDA guidance. 
Amendment  number  09  (05-Feb-2015)  Removes  exploratory  cohorts  from  the 
nivolumab/ipilimumab cohorts. 
Amendment number 10 (15-Apr-2015) Retrospectively  collect  
radiographic images  
for blinded 
independent central review. 
Amendment number 11 (01-Oct-2015) Update follow up requirements. 
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Amendment  number  12  (09-Aug-2016)  Adds  an  additional  set  of  cohorts  (approximately  60 
additional subjects) for dose expansion in multiple myeloma patients treated with nivolumab and 
daratumumab with or without pomalidomide and dexamethasone.  
Amendment number 13 (04-Aug-2017) Corrected and updated nivolumab/daratumumab cohorts. 
Amendment  number14  (15-Feb-2018)  Remove  nivolumab  +  ipilimumab cohorts  and  update 
corresponding  sections.  Add  Cohort  B  (nivolumab+daratumumab)  vs  daratumumab 
monotherapy [ND, D]) 
Amendment  number  15  (23-Apr-2019):  Removed  nivolumab+lirilumab and  nivolumab 
monotherapy cohort.  
2.5  
Data Monitoring and Other External Committees 
A  post-hoc  IRRC  will  be  utilized  
in  
this  study  
for  determination  of  IRRC-assessed  endpoints, 
ORR duration of response (DOR), CR and PR rates, time to CR and PR, and duration of CR and 
PR for cHL subjects in the nivolumab monotherapy cohort only. The IRRC reviews all available 
tumor  assessment  scans  for  all  treated  cHL  subjects  receiving  nivolumab  monotherapy  only. 
Details of IRRC responsibilities and procedures were specified in the IRRC charter. 
3  
OBJECTIVES 
3.1  
Primary 
Nivolumab  monotherapy  cohorts:  To  establish  
the  dose  
limiting  
toxicities,  maximum  
tolerated 
dose and recommended phase 2 dose for nivolumab up to a maximum of 3 mg/kg administered 
every 2 weeks to subjects with relapsed/refractory hematologic malignancy.  
Ipilimumab/nivolumab cohorts: To establish the dose limiting toxicities and a tolerated dose of 
the  combination  of  nivolumab  and  ipilimumab  in  subjects  with  select  relapsed  or  refractory 
hematologic malignancies. 
Lirilumab/nivolumab cohorts: To establish the tolerated  dose of the  combination of nivolumab 
and lirilumab in subjects with select relapsed/refractory hematologic malignancies. 
Nivolumab/daratumumab cohorts: To establish the tolerability of the combination of nivolumab 
and  daratumumab,  with  or  without  pomalidomide  and  dexamethasone,  in  subjects  with 
relapsed/refractory MM. 
 
3.2  
Secondary  
3.3 
NON-NIVOLUMAB/DARATUMUMAB COHORTS 
 To  characterize  the  pharmacokinetics  of  nivolumab  when  administered  as  a  single  agent, 
nivolumab and ipilimumab when administered in combination,  and nivolumab and lirilumab 
when administered in combination. 
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 Number and percent of subjects that experience drug-related grade 3-4 AEs occurring up 
to 100 days after the last dose of study drug. [Time Frame - On a continuous basis up to 
100 days after the last dose of study drug]; 
 Number  and percent  of  subjects  
that  experience  drug-related  grade  3-4  SAEs  occurring 
up to 100 days after the last dose of study drug. [Time Frame - On a continuous basis up 
to 100 days after the last dose of study drug]; 
 Number and percent of subjects with clinical laboratory abnormalities by worst toxicity 
grade by NCI CTCAE version 4.0. [Time Frame - On a continuous basis up to 100 days 
after the last dose of study drug]. 
4.2  
Secondary 
4.2.1
 Pharmacokinetics
 
The  following  pharmacokinetic  parameters  of  nivolumab,  ipilimumab,  and  lirilumab,  will  be 
derived  
from  serum  concentration  
time  profiles  of  subjects  and used  
to  measure  
the  secondary 
objective related to pharmacokinetics at time points specified in section 5.1 of the protocol: 
Cmax - Maximum observed serum concentration 
Tmax - Time of maximum observed serum concentration 
Cmin - Serum concentration achieved at the end of dosing interval (trough concentration) 
AUC(0-T)  
-Area under the plasma concentration-time curve from  
time zero to  
the last time of 
the last quantifiable concentration 
AUC(TAU) - Area under the concentration-time curve in one dosing interval 
Ceoinf - Serum concentration achieved at the end of study drug infusion 
4.2.2
 Efficacy
 
The  secondary  objective  relating  
to  efficacy  
is  
to  assess  
the  preliminary  antitumor  activity  of 
monotherapy  nivolumab,  the  combination  of  nivolumab  and  ipilimumab,  the  combination  of 
nivolumab  and  lirilumab  across  select  relapsed  or  refractory  hematologic  malignancies.  This 
objective will be measured by tabulations of individual BOR and analyses of the ORR, duration 
of  
response,  Progression  Free  Survival  Rate  
(PFS  Rate),  and  Progression  Free  Survival  
(PFS). 
The BOR outcomes will be based on the disease specific criteria (specified in Appendices 1, 2, 
and 5 of the protocol) for lymphoma, Cutaneous T-Cell and MM, respectively. Response will be 
based on efficacy assessments per section 5 of the protocol.  
Following  protocol  amendment  10  which  allowed  for  radiological images  to  be  collected  for 
independent  central  review,  subjects  with  cHL  receiving  monotherapy  nivolumab  were 
retrospectively  evaluated  by  an  IRRC  (2007  IWG  criteria).    Unless  otherwise  specified,  the 
efficacy  endpoints  will  be  derived  based  on  both  
investigator  assessment  per  
the  International 
Workshop to Standardized Response Criteria for Lymphoma per protocol appendix 1 and IRRC 
assessment according to the 2007 IWG criteria. The investigator-based efficacy endpoints would 
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be  the  primary  efficacy  endpoints,  and  the  IRRC-based  efficacy endpoints  would  be  the 
secondary efficacy endpoints. 
In addition, the preliminary antitumor activity of nivolumab in combination with daratumumab 
will  be  evaluated  
in  subjects  with  
relapsed/refractory  MM  
in  Cohorts  A  and  B.  This  endpoint 
will be measured by MRD, ORR, DOR and PFS in each treatment regimen group. 
Best Overall Response (BOR) 
The  Investigator-reported  BOR  is  defined  as  the  investigator  determined  best  response 
designation  over  the  study  as  a  whole  (or  at  specific  landmark interim  analyses),  recorded 
between  
the  date  of  
first  dose  and  
the  date  of  objectively  documented  progression,  whichever 
occurs first. The Investigator-reported BOR is captured in CRF form.  
The  IRRC-assessed  BOR  for  cHL  nivolumab  monotherapy  patients  is  defined  as  the  best 
response designation recorded between the date of first dose and the date of initial documented 
progression per the 2007 IWG criteria or the date of subsequent anticancer therapy, whichever 
occurs first. Allogeneic SCT and ASCT will be considered as subsequent anticancer therapy. For 
subjects  without  documented  progression  or  subsequent  anticancer  therapy,  all  available 
response  designations  will  contribute  to  the  BOR  determination.  For  subjects  who  continue 
treatment  beyond  progression,  
the  BOR  should  be  determined  based  on  
response  designations 
recorded up to the time of the initial 2007 IWG defined progression. The IRRC-assessed BOR is 
applicable only to cHL subjects receiving nivolumab monotherapy. 
Progression Free Survival Rate (PFS Rate) 
The PFSR is  defined as  
the probability of a subject  
remaining progression free or surviving to 
time t, where t = 6, 12, 18 and 24 months This probability will be calculated by the product limit 
method (Kaplan-Meier estimate) which takes into account censored data. 
Progression Free Survival (PFS) 
The  primary  definition  of  PFS  is  defined  as  the  time  from  the  date  of  first  dose  of  study 
medication to the date of first confirmed disease progression or death, or the time between date 
of  randomization  and  the  date  of  first  documented  progression  or  death  for 
nivolumab/daratumumab  cohorts.  Subjects  who  remain  alive  and  have  not  progressed  will  be 
censored  on  the  last  adequate  tumor  assessment  date  on  or  prior  to  the  date  of  subsequent 
therapy.
 Allogeneic SCT and ASCT will be considered as subsequent therapy. Subjects who did 
not have any post-baseline efficacy assessment and did not die will be censored on the date of 
first dose of study medication or date of randomization for nivolumab/daratumumab cohorts. 
 
The secondary definition of PFS (ITT definition) is defined as the time from the date of first dose 
of study medication to the date of first disease progression or death, or the time between date of 
randomization  and  date  of  progression  or  death.
 Subjects  who  remain  alive  and  have  not 
progressed  will  be  censored  on  
the  
last  adequate  
tumor  assessment  date. Subjects  who  did  not 
have any post-baseline efficacy assessment and did not die will be censored on the date of first 
dose of study medication or date of randomization for nivolumab/daratumumab cohorts. 
 
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For MM subjects, an adequate tumor assessment visit for ruling out progression will require the 
following  information:  Serum  monoclonal  paraprotein  results,  if  measurable  at  baseline  and 
Urine monoclonal paraprotein results, if measurable at baseline, or for subjects who do not have 
measurable  serum  and  urine  monoclonal  paraprotein  results,  serum  free  light  chain  results,  if 
measurable at baseline.  
 
Sensitivity  analyses  will  be  performed  based  on  an  alternate  censoring  scheme  
to  account  for 
non-uniform  and  infrequent  tumor assessment  schedules.  For  this  analysis,  subjects  will  be 
censored  on  their  last  visit  date,  defined  as  the  last  date  of dosing,  tumor  assessment  or  lab 
assessment, whichever occurs last.  
 
Table 1: 
Censoring Scheme for Primary and Sensitivity Analysis PFS 
Situation 
Primary 
Sensitivity 
No progression per response criteria, 
no death and no subsequent 
anticancer therapy 
Censored on the date of last tumor 
assessment 
Censored on the date of last visit 
date 
No progression per response criteria, 
no death and with subsequent 
anticancer therapy 
Censored on the date of last tumor 
assessment prior or on the date of 
initiation of the subsequent 
anticancer therapy 
Censored on the date of last visit 
prior or on the date of initiation of 
the subsequent anticancer therapy 
Progression per response criteria 
without a subsequent anticancer 
therapy started 
Event on the date of the first 
documented tumor progression per 
response criteria 
Event on the date of the first 
documented tumor  progression per 
response criteria 
Progression or death after a 
subsequent anticancer therapy 
started 
Censored on the date of last tumor 
assessment prior or on the date of 
initiation of the subsequent 
anticancer therapy 
Censored on the date of last visit 
prior or on the date of initiation of 
the subsequent anticancer therapy 
Death without progression per 
response criteria and without 
subsequent anticancer therapy 
started 
Event on the date of death 
Event on the date of death 
 
Objective Response Rate (ORR) 
Objective  response  rate  is  defined  as  the  proportion  of  subjects  whose  BOR  is  one  of  the 
following responses divided by the number of treated subjects or number of randomized subjects 
in nivolumab/daratumumab cohort. 
 for lymphoma subjects whose BOR is either complete remission or partial remission 
 for  myeloma  subjects  whose  BOR  
is  stringent  complete  
response, complete  
response,  very 
good partial response, or partial response 
 
Duration of Response 
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Duration of response will be only calculated for subjects with best overall response of objective 
response defined as above. The duration of response is defined as the time  between the date of 
first  documented  objective  response  and  the  date  of  first  documented  disease  progression,  or 
death, whichever is earlier. Subjects who remain alive and have not progressed will be censored 
on  
the  
last  adequate  efficacy  assessment  date  prior  
to  subsequent  cancer  
therapy.  
  Allogeneic 
SCT and ASCT will be considered as subsequent therapy. 
Sensitivity  analyses  will  be  performed  based  on  an  alternate  censoring  scheme  (same  as  PFS 
censoring scheme) to  account for non-uniform and infrequent tumor assessment schedules. For 
this analysis, subjects will be censored on their last visit date, defined as the last date of dosing, 
tumor assessment or lab assessment, whichever occurs last.  
Duration of response will be evaluated for responders (PR or CR for lymphoma subjects; SCR, 
CR, VGPR, or PR for myeloma subjects) only. 
Time to Response (TTR) 
Time  
to  
response  
is  defined  as  
the  
time  
from  date  of  
first  dose  of  study  medication  or  date  of 
randomization  for  nivolumab/daratumumab  to  the  date  of  the  first  documented  objective 
response. Time to response will only be evaluated in subjects with minimal objective response of 
PR. 
Time to best response is defined as the time from date of first dose of study medication or date of 
randomization for nivolumab/daratumumab to the date of the best overall response.  
Tumor Measurements (Lymphoma) 
For  Hodgkin/PMBL,  T  cell  
lymphoma,  B  cell  
lymphoma  subjects,  
target  
lesion  
tumor  burden 
will be derived from tumor measurements. 
Serum and Urine M-Protein and Free Light Chain (Myeloma) 
Serum  and  urine  
tests  will  be  performed  for  Myeloma  subjects.  
 For  
the  complete  
list  of  
the 
serum and urine tests, please refer to section 5.1 of the protocol. 
FDG-PET Assessment (HL or PMBL) 
FDG-PET/CT imaging scans  were performed  at  
screening,  and the  end of treatment  
for HL  or 
PMBL subjects. The FDG-PET endpoints are the overall assessment of the scan. 
mSWAT (cutaneous T cell lymphoma) 
Response in skin for subjects with cutaneous T cell lymphoma will be evaluated by the mSWAT 
score which is reported by investigators. 
Minimal Residual Disease (MRD) 
In  the  nivolumab/daratumumab  cohorts,  MRD  from  bone  marrow  aspirate  will  be  evaluated. 
MRD  will  be  assessed  by  Next  Generational  Flow  Cytometry  (NGF)  and  Next  Generational 
Sequencing (NGS).  
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5  
SAMPLE SIZE AND POWER 
NIVOLUMAB MONOTHERAPY COHORTS 
The  sample  size  in  the  escalation  phase  is  not  based  on  statistical  consideration,  but  rather 
depends  on  the  number  of  observed toxicities;  between  6  and  9  subjects  are  expected  to  be 
treated at each dose. At the dose expansion cohorts, approximately 23 subjects are expected to be 
enrolled in each of four tumor types and treated at the previously determined MTD or if no MTD 
is identified a maximum dose of 3 mg/kg. 
In  an  expansion  cohort,  
if  4  
(17.4%)  or  5  
(21.7%)  
responses  are  observed  with  23  subjects  
in 
each  cohort,  
then  
the  
lower  
limit  of  
the  90%  one-sided  confidence  
intervals  for  
the  objective 
response  rate  would  be  7.8%  and  11.0%  respectively.  These  calculations  are  based  on  the 
Clopper-Pearson method for exact confidence intervals. 
In  addition,  
if  
the  
true  ORR  
in  a  
tumor  
type/expansion  cohort  
is  20%  
then  with  23  patients  
in 
each  cohort  there  is  86.7%  chance  of  observing  at  least  3  responses  or  13.3%  chance  of 
observing 0, 1 or 2 responses (false negative rate). If the true ORR in a tumor type is 5% rather 
than 20%, then there is 10.5% chance that there will be at least 3 responses in 23 subjects (false 
positive rate). 
IPILIMUMAB/NIVOLUMAB COHORTS 
In a tumor cohort, if 3 (21%) or 4 (29%) responses are observed with 14 subjects in each cohort, 
then  
the  
lower  
limit  of  
the  90%  one-sided  confidence  
intervals for  
the  objective  
response  
rate 
would be 8% and 13% respectively. These calculations are based on the Clopper-Pearson method 
for exact confidence intervals. 
In addition, if the true ORR in a tumor cohort is 20% then with 14 patients in each cohort there is 
80% chance of observing at least 2 responses and 96% chance of observing at least 1 response, 
or 20% chance of observing 0 or 1 response (false negative rate) and 4% chance of observing 0 
response  
(false  negative  
rate).  
If  
the  
true  ORR  
in  a  
tumor  cohort  
is  5%  
rather  
than  20%,  
then 
there is 15% chance that there will be at least 2 responses in 14 subjects (false positive rate). 
The sample size in the exploratory schedule evaluation is not based on statistical considerations, 
but rather depends on the number of observed toxicities; between 3 and 9 subjects are expected 
to be treated in cohorts 3 and 4. 
Subsequent cohorts may be tested if required. 
Administration of the study drug to 9 subjects at a dose level in exploratory schedule evaluation 
provides 90% probability of observing at least one occurrence of any adverse event that would 
occur with a 22% incidence in the population from which the sample is drawn. 
Approximately 6-18 subjects are expected to be enrolled in exploratory schedule evaluation and 
approximately 56 in tumor expansion. 
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LIRILUMAB/NIVOLUMAB COHORTS 
In a tumor cohort, if 4 (20%) or 5 (25%) responses are observed with 20 subjects in each cohort, 
then  
the  
lower  
limit  of  
the  90%  one-sided  confidence  
intervals for  
the  objective  
response  
rate 
would  be  9%  and  13%  respectively.  In  a  
tumor  cohort,  
if  3  (10%)  or  6  (20%)  responses  are 
observed with 30 subjects in each cohort, then the lower limit of the 90% one-sided confidence 
intervals for the objective response rate would be 4% and 11% respectively. These calculations 
are based on the Clopper-Pearson method for exact confidence intervals. 
In addition, if the true ORR in a tumor cohorts is 20% then with 20 patients in each cohort there 
is  93%  chance  of  observing  at  
least  2  responses,  or  7%  chance  of  observing  0  or  1  response 
(false negative rate). If the true ORR in a tumor type is 5% rather than 20%, then there is 26% 
chance that there will be at least 2 responses in 20 subjects (false positive rate). If the true ORR 
in a tumor cohort is 20% then with 30 patients in each cohort there is 88% chance of observing at 
least 4 responses, or 12% chance of observing 3 or fewer responses (false negative rate). 
If the true ORR in a tumor type is 5% rather than 20%, then there is 6% chance that there will be 
at least 4 responses in 30 subjects (false positive rate). 
Approximately 130 subjects are expected to be enrolled in tumor cohorts. 
The  probability  (%)  of  observing  at  least  a  certain  response  rate  given  a  true  ORR  (%)  is 
presented in Table 8.1-1 of the protocol. 
NIVOLUMAB/DARATUMUMAB COHORTS 
Cohort A (ND ± Pd) is closed to enrollment. 
 
The  planned  sample  size  for  Cohort  B  (ND,  D)  will  be  approximately  60  treated  subjects, 
randomized in a 2:1 ratio to the ND and D arms, respectively. The sample size is not powered for 
statistical hypothesis testing, but designed to evaluate both the safety profile and clinical benefit 
of nivolumab in combination with daratumumab.  
 
If the true toxicities incidence rate in a cohort is 20% then with 20 patients in the D cohort there 
is a 7% chance of observing 0 - 1 toxicities (false negative rate). If the true toxicities incidence 
rate  
in  a  cohort  
is  5%  
rather  
than  20%,  
then  
there  
is  26%  chance  
that  
there  will  be  at  
least  2 
toxicities  
in  20  subjects  
(false  positive  
rate).  
If  
the  
true  
toxicities  
incidence  
rate  
in  a  cohort  
is 
20% then with 40 patients in ND cohort there is 3% chance of observing 0  
- 3 toxicities (false 
negative rate). If the true toxicities incidence rate in a cohort is 5% rather than 20%, then there is 
14% chance that there will be at least 4 toxicities in 40 subjects (false positive rate). 
 
In two daratumumab monotherapy studies in relapsed/refractory MM patients, including a Phase 
1/2 dose escalation study (GEN501) in patients with at least 2 lines of prior therapy and a 
Phase 2 study (SIRIUS) in patients with at least 3 lines of prior therapy, the ORR were 36% 
and 29.2% respectively.  
In two combination studies in relapsed/refractory MM patients with at 
least 2 lines of prior therapy, including a Phase 1b study of daratumumab in combination with 
pomalidomide  and  dexamethasone  and  a  Phase  1  dose-escalation  study  of  pembrolizumab  in 
combination with pomalidomide and dexamethasone, the ORR were 60%. At observed ORR ≥ 
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55% with 20 subjects, the lower bound of the 95% CI exceeds 31.5%. At observed ORR ≥ 77.5% 
with 40 subjects, the lower bound of the 95% CI exceeds 61.5%. 
 
At  observed  MRD  negative  
rate ≥ 30%  with  20  subjects  and  observed  MRD-target  negativity 
rates ≥ 20% with 40 subjects, the lower bound of the 95% CI are 11.9% and 9.1% respectively, 
compares favorably to historical MRD-target negativity rate of 8% in the target population. 
6  
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS FOR 
ANALYSES 
6.1  
Study Periods 
NIVOLUMAB MONOTHERAPY COHORTS 
This study consists of Screening (up to 28 days), Treatment (up to 2 years), Clinical Follow-up 
(up  to  12  months)  and  Survival  Follow-up  (up  to  2  years).    There  is  also  the  possibility  of 
Retreatment (up to 1 year) and Follow up (up to 120 days). 
IPILIMUMAB/NIVOLUMAB COHORTS 
The study will consist of Screening (up to 28 days), Treatment (up to 2 years), and Follow-up. 
LIRILUMAB/NIVOLUMAB COHORTS 
The study will consist of Screening (up to 28 days), Treatment (up to 2 years), and Follow-up. 
NIVOLUMAB/DARATUMUMAB COHORTS 
The study will consist of Screening (up to 28 days), Treatment (until disease progression), and 
Follow-up. 
6.2  
Treatment Regimens 
Table 2: 
Treatment Information 
Regimen 
Specification 
Nivolumab 
Nivo 1 
Nivolumab 
Nivo 3 
Nivolumab + Ipilimumab 
Nivo 3 + Ipi 1 
Nivolumab + Lirilumab 
Nivo 3 + Liri 3 
Cohort A 
Nivolumab + Daratumumab + Pomalidomide + Dexamethasone 
Nivolumab + Daratumumab  
 
Nivo + Dara + Pom + Dex 
Nivo + Dara  
Cohort B 
Nivolumab + Daratumumab  
Daratumumab 
 
Nivo+Dara  
Dara 
 
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6.3  
Populations for Analyses 
 All Enrolled Subjects: All subjects who sign informed consent  
form  and were registered in 
IVRS. 
 All  Randomized  MM  subjects:  All  enrolled  MM  subjects  who  were  
randomized  
to  one  of 
nivolumab and daratumumab cohorts. 
 All  Treated  Subjects:  All  subjects  who  signed  
informed  consent and  received  at  
least  one 
dose of study medication are considered treated and are included in the treated population 
 Pharmacokinetic  (PK)  Population:  All  subjects  who  receive  at  least  one  dose  of  study 
medication and have available serum concentration data. 
 Response  Evaluable  Subjects:  All  
treated  subjects  with  measurable  disease  at  baseline  and 
one of the following: 1) at least one on-treatment efficacy assessment, 2) clinical progression, 
or 3) death. 
 Immunogenicity evaluable subjects:  
 Nivolumab  ADA  Evaluable  Subjects:  all  treated  subjects  with  baseline  and  at  least  1 
postbaseline nivolumab immunogenicity assessment. 
 Ipilimumab  ADA  Evaluable  Subjects:  all  treated  subjects  with  baseline  and  at  least  1 
postbaseline Ipilimumab immunogenicity assessment. 
 Lirilumab  ADA  Evaluable  Subjects:  all  treated  subjects  with  baseline  and  at  least  1 
postbaseline Lirilumab immunogenicity assessment. 
 All  Treated  PD-L1  Evaluable  Subjects:  All  treated  subjects  with  quantifiable  PD-L1 
expression (ie excludes indeterminate and unknown). 
 All  MRD  Evaluable  Subjects:  All  subjects  
in  Cohorts  A  and  B  with  available  MRD  status 
data. 
7  
STATISTICAL ANALYSES 
7.1  
General Methods 
All  analysis  will  be  performed  in  SAS  using  version  8.2  or  higher.  Some  figures  will  be 
generated using S-Plus. 
Continuous  variables  will  be  summarized  using  descriptive  statistics,  
i.e.  medians,  minimums, 
maximums  and  means  with  standard  deviations.  Categorical  variables  will  be  summarized  by 
frequencies and percents. Percentages will be rounded and, therefore, may not always add up to 
100. 
Unless  specified  otherwise,  analyses  will  be  performed  by  disease  
type  within  each  
treatment 
group. 
7.2  
Study Conduct 
7.2.1
 Accrual
 
Number (%) of subjects accrued by country and investigational site will be presented on the all 
enrolled subjects. The corresponding listing will be provided. 
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7.2.2
 Protocol
 
Deviation
 
Deviation from protocol inclusion and exclusion criteria will be listed for all treated subjects for 
nivolumab  monotherapy  cohorts,  nivolumab/lirilumab  cohorts,  nivolumab/Ipilimumab  cohorts 
and all randomized MM subjects for nivolumab/daratumumab cohorts. 
7.3  
Study Population 
7.3.1
 Subject
 
Disposition
 
The  number  of  subjects  enrolled  
into  
the  study,  
the  number  of  subjects  entering  
the  
treatment 
period  or  the  number  of  subjects  randomized  and  the  number  of  subjects  enrolled  but  not 
randomized/treated together with the reasons for not being dosed will be summarized.  
The  number  of  
treated  subjects,  
the  number  of  subjects  discontinuing  during  
treatment  period 
along with the reasons for discontinuation, and the number of subjects continued to be followed 
after  discontinuing  will  be  summarized  by  dose  level  or  by  treatment  arm  for 
nivolumab/daratumumab cohorts.   
All related data will be listed. 
7.3.2  
Demographics and Other Baseline Characteristics 
Subject demographics and baseline characteristics will be summarized for all treated subjects for 
nivolumab  monotherapy  cohorts,  nivolumab/lirilumab  cohorts,  nivolumab/Ipilimumab  cohorts 
and all randomized MM subjects for nivolumab/daratumumab cohorts. 
Demographic  characteristics  
include  age  
in  years,  age  category (<65  vs.  ≥  65; ≥ 75),  gender, 
race, ethnicity, ECOG, and weight. 
Baseline characteristics include: baseline disease characteristics (disease diagnosis, stage), prior 
therapy  surgery,  radiotherapy  and  systemic  cancer  therapy),  general  medical  history,  and 
baseline cytogenetic status.   
For multiple myeloma subjects, baseline disease characteristics include time to study entry from 
disease  diagnosis,  ISS  stage,  IMWG  risk  stage,  prior  systemic  cancer  therapy,  prior  ASCT, 
refractoriness  to  prior  therapies  (i.e.,  IMiD,  PI,  last  treatment),  type  of  measurable  disease, 
percentage bone marrow plasma cells, general medical history, and cytogenetic profile at study 
entry.  
The  risk  factors  for  potential  events  such  as  pulmonary  related  events  will  be  listed  by  dose 
levels for nivolumab monotherapy cohort. 
All related data will be listed.   
7.3.3
 Prior
 
Anti-Cancer
 
Therapy
 
For non-nivolumab/daratumumab cohorts, the following will be summarized: 1. by disease type 
and treatment arms, 2. by prior ASCT (subjects who were treated with prior ASCT) and ASCT 
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naive (subjects  who weren’t treated with  prior ASCT) within disease type and treatment  arms, 
and 3. by Responders vs. Non-Responders. 
 Number of prior regimens 
 Best response to prior systemic therapy 
 Best response to the most recent prior systemic therapy 
 Time from completion of the most recent prior regimen to the 1st dose of study medication 
 
For nivolumab-daratumumab cohorts, refractoriness to prior anti-myeloma therapy is defined as 
progression that occurred on treatment or within 60 days of the last dose of the respective prior 
treatment.  A  subject  will  not  be  considered  as  refractory  to  a prior  therapy  if  the  date  of 
progression  
to  
the  respective  prior  
treatment  
is  missing.  Missing/partial  dates  will  be  
imputed 
according to the rule in Section 8. 
 
For nivolumab/daratumumab cohorts, the following will be derived and summarized: 
 Number of prior regimens 
 Refractory to a IMiD  
 Refractory to Proteasome Inhibitor (PI) 
 Refractory to both IMiD and PI 
 Refractory to most recent prior therapy  
IMiD  includes  lenalidomide,  thalidomide,  and  pomalidomide.  PI  includes  bortezomib, 
carfilzomib,  and  ixazomib.  Refractory  status  to  PI  or  IMiD  will  be  derived  for  subjects  who 
received at least two consecutive cycles (2 months) of PI or IMiD,  
 
7.4  
 Extent of Exposure 
Summaries of exposure will be based on all treated subjects. 
7.4.1
 Study
 
Therapy
 
For  nivolumab,  ipilimumab,  lirilumab,  daratumumab,  pomalidomide  and  dexamethasone,  the 
following parameters will be listed and summarized. 
 Number of doses 
 Duration of therapy 
 Cumulative dose per subject 
 Dose intensity per subject (/week) 
 Relative dose intensity per subject 
 
Cumulative dose (mg/kg) is defined as:  
the sum  over the duration of the study of all delivered 
doses (mg/kg) per subject. 
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BOR outcomes will be tabulated. A frequency distribution of the BOR outcomes together with 
ORR with corresponding 2-sided 95% exact confidence interval will be tabulated. 
Objective Response Rate 
The objective response rate (ORR) and corresponding two-sided 95% exact confidence interval 
will be provided by within each treatment cohort by disease type, and by treatment arm within 
each nivolumab/daratumumab cohorts based on the Clopper-Pearson method. 
Duration of Response 
The median duration of response will be estimated by Kaplan-Meier methodology depending on 
data  availability.  The  corresponding  95%  confidence  interval  will  be  derived  based  on 
Greenwood formula and log-log transformation.  The number of subjects still in response at the 
time of database lock will be indicated. If number of responders is small, the above analysis may 
not be performed.  Duration of response will be listed. 
Progression Free Survival 
Kaplan-Meier plots of PFS will be provided. PFS Rate at select time points will be estimated by 
Kaplan-Meier  methodology,  and  
the  corresponding  
two-sided  95%  confidence  
interval  will  be 
derived based on Greenwood formula depending on data availability.  
Time to Response 
TTR  will  be  derived  and  listed. TTR  will  be  summarized  in  a  swimmer  plot.  Time  to  best 
response will be derived and listed for nivolumab/daratumumab cohorts. 
Tumor Measurements (Lymphoma) 
For  lymphoma  subjects,  tumor  measurements,  target  lesions  tumor  burden  (the  sum  of  the 
products of the greatest diameters) at each visit, along with corresponding percent change from 
baseline, will be listed. 
Individual  percent  changes  in  the  target  lesion  tumor  burden  over  time  may  be  presented 
graphically  
(a.k.a  spider  plot)  
(Hodgkin/PMBL,  T-cell  
lymphoma,  B-cell  
lymphoma)  based  on 
data availability within a disease type. 
The  individual  maximum  tumor  reduction  from  baseline  may  be  presented  graphically  (a.k.a 
waterfall plot) based on data availability within a disease type. 
Spider plot and waterfall plot will exclude multiple myeloma and cutaneous T-cell Lymphoma 
patients. 
Tumor measurements for subjects received treatment beyond progression will be listed. 
Overall Survival 
Median overall survival and corresponding two-sided 95% confidence interval will be estimated 
by K-M method. Kaplan-Meier plots of OS will be provided.  
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The descriptive median, minimum and maximum will be calculated for the duration of follow-
up. 
Serum and Urine M-Protein and serum Free Light Chain (Myeloma) 
Summary  statistics  for  serum  and  urine  test  results,  and  corresponding  changes  (or  percent 
changes) from baseline will be tabulated.  
For patients with measurable disease in serum M-protein (=>0.5 g/dL) and/or measurable disease 
in  urine M-protein  
(=>200 mg/24  hours), the individual percent changes  
in  
the M-protein  over 
time will be presented graphically (a.k.a spider plot). If the disease is not measurable  by  either 
serum  M-Protein  (<0.5  g/dL)  or  urine  M-protein  (<200  mg/24  hours),  the  individual  percent 
changes in the serum free light chain over time will be presented graphically (a.k.a spider plot).  
FDG-PET Assessment (HL or PMBL) 
The number and percentage of subjects with PDG-PET scan performed will be summarized by 
visit  
for HL  and PMBL  subjects. Among subjects  with  PDG-PET scan performed, the number 
and percentage of subjects with abnormal findings will be summarized by visit. 
All related data will be listed.  
mSWAT Score 
To  evaluate  
the  
response  
in  skin  
for  subjects  with  cutaneous  T cell  
lymphoma,  
the  percentage 
change from baseline on the mSWAT score will be derived and listed at subject level. 
MRD (nivolumab-daratumumab) 
Analyses  of  MRD  status  will  be  based  on  all  evaluable  MRD  subjects  and  performed  at  each 
sensitivity level. Both molecular and cytometry MRD status from bone marrow aspirate will be 
evaluated. MRD negativity status will be evaluated by timepoints. Summary statistics of time to 
the  first  MRD  negativity  will  be  provided  by  treatment  group  for  subjects  achieving  MRD 
negative  status.  Cumulative  MRD  negativity  rates  will  be  tabulated  at  the  first  on-study 
assessment  (i.e,  C4D1  or  >VGPR,  whichever  occurs  first)  and  every  6  months  thereafter 
depending  on  
the  data  availability.  Median  duration  of  
the  MRD negativity  and  corresponding 
two-sided  95%  CI  will  be  analyzed  by  KM  product  limit  method  for  subjects  who  achieved 
MRD  negative  status  depending  on the  data  availability.  A  plot of  individual  time  course  of 
abnormal bone marrow plasma cells will be produced.  
 
7.6  
Safety 
Safety  summary  tables  will  be  generated  for  all  treated  subjects.  Listings  will  include  all 
available data. 
7.6.1
 Death
 
See CORE Safety SAP.1 
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7.6.2  
Serious Adverse Events 
See CORE Safety SAP.1 
7.6.3  
Adverse Events Leading to Discontinuation of Study Therapy 
See CORE Safety SAP.1 
7.6.4  
Adverse Events Leading to Dose Modification 
See CORE Safety SAP.1 
7.6.5
 Adverse
 
Events
 
See CORE Safety SAP.1 
7.6.6  
Select Adverse Events 
See CORE Safety SAP.1 
7.6.7
 Immune
 
Modulating
 
Medication
 
See CORE Safety SAP.1 
7.6.8
 Multiple
 
Events
 
See CORE Safety SAP.1 
7.6.9
 Laboratory
 
Parameters
 
See CORE Safety SAP.1 
7.6.10
 Vital
 
Signs
  
See CORE Safety SAP.1 
7.6.11
 Immunogenicity
 
Analysis
 
Immunogenicity analyses will be performed separately for Nivolumab ADA Evaluable Subjects. 
See CORE Safety SAP.1 
7.6.12
 Pregnancy
 
See CORE Safety SAP.1 
7.6.13  
Clinical Safety Program (CSP) 
See CORE Safety SAP.1 
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Statistical Analysis Plan 
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BMS-936558 
Nivolumab 
29 
 
 
 
8  
CONVENTIONS 
In  general,  EmBARC  standard  time  windowing,  imputation  rules,  and  counting  rules  will  be 
applied. 
 For death dates, the following conventions will be used for imputing partial dates: 
 If only the day of the month is missing, the 1
st of the month will be used to replace the 
missing  day.  The  
imputed  date  will  be  compared  
to  
the  
last  known  alive  date  and  
the 
maximum will be considered as the death date.  
 If the month or the year is missing, the death date will be imputed as the last known alive 
date.  
 If the date is completely missing but the reason for death is present, the death date will be 
imputed as the last known date alive.  
 For date of progression  after start  of study therapy, the following conventions  will be used 
for imputing partial dates:  
 If only the day of the month is missing, the 1
st of the month will be used to replace the 
missing day. In case of the date of death is present and complete, the imputed progression 
date will be compared to the date of death. The minimum of the imputed progression date 
and date of death will be considered as the date of progression.  
 If the day and month are missing or a date is completely missing, it will be considered as 
missing.  
 For  date  of  progression  to  prior  therapies,  the  following  conventions  will  be  used  for 
imputing partial dates:  
 If only the day of the month is missing, the 1
st of the month will be used to replace the 
missing day.  
 If the day and month are missing or a date is completely missing, it will be considered as 
missing.  
 For  date  of  progression  to  prior  therapies,  the  following  conventions  will  be  used  for 
imputing partial dates:  
 If only the day of the month is missing, the 1
st of the month will be used to replace the 
missing day.  
 If the day and month are missing or a date is completely missing, it will be considered as 
missing.  
 For other partial/missing dates, the following conventions were used:  
 If only the day of the month is missing, the 15
th of the month will be used to replace the 
missing day.  
 If both the day and the month are missing, “July 1” will be used to replace the missing 
information.  
 If a date is completely missing, it will be considered as missing.  
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Statistical Analysis Plan 
CA209039 
BMS-936558 
Nivolumab 
30 
 
 
8.1  
Safety Data Conventions 
Safety  data  will  be  handled  according  to  the  BMS  safety  data  conventions  (described  in 
“Analysis of Safety Data”). This document includes descriptions on how to analyze AE data as 
well as how to handle partial dates, missing dates, and unknown end dates when analyzing safety 
data. 
8.2  
Baseline Measurements 
For  laboratory  measures  the  following  will  be  used,  in  a  hierarchical  sequence,  to  select  the 
baseline (if a criterion does not apply it would be skipped in the sequence): 
 The baseline value corresponds to the last lab drawn prior to first dose of study drug; 
 If  both  local  and  central  laboratory  values  qualify  as  baseline  according  to  the  above 
criterion, the central laboratory value will be used as the baseline value. 
 
For all other measures (tumor, vital etc.) the baseline value is the last value prior to the first dose 
of study drug. 
8.3  
Multiple Measurements 
Laboratory Measures 
For tabulations of changes from baseline the following will be used, in a hierarchical sequence, 
to select the post-treatment measurement included in the analysis (if a criterion does not apply it 
would be skipped in the sequence): 
 If multiple laboratory measurements are obtained within the same scheduled time frame, then 
the measurement obtained on the time closest to the target time/day will be used; 
 If  more  than  one  value  meets  the  above  criterion,  then  the  measurement  obtained  on  the 
earlier time will be used; 
 If  both  local  and  central  laboratory  values  qualify  as  baseline  according  to  the  above 
criterion, the central laboratory value will be used as the baseline value; 
 If more than one value meets the above criterion, then the average value will be used. 
 
For  
tabulations  by  CTC  grade  and  summarized  by  worst  
toxicity  grade,  
if  multiple  
laboratory 
measurements are obtained within a analysis period (post-baseline), then the worst measurement 
within the analysis period, respectively, will be used. 
Vital Signs 
The  following  criteria  will  be  used,  in  a  hierarchical  sequence,  to  select  the  post-treatment 
measurement included in the analysis: 
 If multiple vital sign measurements are obtained within the same scheduled time frame, then 
the measurement obtained on the time closest to the target time/day will be used; 
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