Phase 1b/2a Multicenter, Open-label, Dose-escalation Study to Determine the Maximum Tolerated Dose, Assess the Safety, Tolerability, Pharmacokinetics and Efficacy of CC-220 As Monotherapy and in Combination With Other Treatments in Subjects With Multiple Myeloma
Phase: PHASE1
Conditions: Multiple Myeloma
Sponsor: Celgene

Official Title of Study: 
A Phase 1b/2a Multicenter, Open-label, Dose-escalation Study to Determine the Maximum Tolerated 
Dose, Assess the Safety, Tolerability, Pharmacokinetics and Efficacy of CC-220 as Monotherapy and in 
Combination with Other Treatments in Subjects with Multiple Myeloma 
 
NCT Number: NCT02773030 
Document Date (Date in which document was last revised): 05 Jan 2022 
 
 
 

EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
1
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
TITLE PAGE
A PHASE 1B/2A MULTICENTER, OPEN-LABEL, DOSE-
ESCALATION STUDY TO DETERMINE THE 
MAXIMUM TOLERATED DOSE, ASSESS THE SAFETY,
TOLERABILITY, PHARMACOKINETICS AND
EFFICACY OF CC-220 AS MONOTHERAPY AND IN 
COMBINATION WITH OTHER TREATMENTS IN 
SUBJECTS WITH MULTIPLE MYELOMA
PROTOCOL NUMBER:
CC-220-MM-001
DATE FINAL:
08 Mar 2016
AMENDMENT No. 1
05 May 2016
AMENDMENT No. 2
25 Aug 2016
AMENDMENT No. 3
17 Mar 2017
AMENDMENT No. 4
03 Oct 2017
AMENDMENT No. 5
04 Apr 2018
AMENDMENT No. 6
27 Aug 2018
AMENDMENT No. 7
23 Apr 2019
AMENDMENT No. 8
04 Oct 2019
AMENDMENT No. 9
08 Jul 2020
AMENDMENT No. 10
05 Jan 2022
EudraCT NUMBER:
2016-000860-40
IND NUMBER:
129254
SPONSOR NAME/ ADDRESS:
Celgene Corporation
86 Morris Avenue
Summit, NJ 07901
CONFIDENTIAL
This protocol is provided to you as an Investigator, potential Investigator, or 
consultant for review by you, your staff, and ethics committee/institutional review 
board.  The information contained in this document is regarded as confidential 
and, except to the extent necessary to obtain informed consent, may not be 
disclosed to another party unless such disclosure is required by law or regulations.  
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CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
2
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
Persons to whom the information is disclosed must be informed that the 
information is confidential and may not be further disclosed by them.
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CC-220
Protocol CC-220-MM-001
Celgene Corporation
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CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION 
Contact Information:
Name:  
Title:  
Address:  86 Morris Ave, Summit, NJ 07901- United States
Phone:  
E-mail: 
Contact Information:
Name:  
Title:  
Address:  86 Morris Ave, Summit, NJ 07901- United States
Phone:  
E-mail: 
Note: The back-up 24-hour global emergency contact call center should only be used if you 
are not able to reach the Clinical Research Physician(s) or Medical Monitor or designee for 
emergency calls.
Back-up 24-hour Global Emergency Contact Call Center: 
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CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
4
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
See appended electronic signature page
Signature of Celgene Therapeutic Area Head
dd mmm yyyy
Printed Name of Celgene Therapeutic Area Head and Title
By my signature, I indicate I have reviewed this protocol and find its content to be 
acceptable.  
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EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
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CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Site Principal Investigator
dd mmm yyyy
Printed Name of Site Principal Investigator
Institution Name:_______________________________________
By my signature, I agree to personally supervise the conduct of this study at my study 
site and to ensure its conduct is in compliance with the protocol, informed consent, 
Institutional Review Board (IRB)/Ethics Committee (EC) procedures, instructions from
Celgene representatives, the Declaration of Helsinki, International Council for
Harmonisation (ICH) Good Clinical Practices Guidelines, and local regulations 
governing the conduct of clinical studies.
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EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
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CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
COORDINATING PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Coordinating Principal Investigator
dd mmm yyyy
Printed Name of Coordinating Principal Investigator
Institution Name:_______________________________________
By my signature, I agree the protocol has been written to comply with ICH Good 
Clinical Practices guidelines and agree to offer guidance throughout the study as 
needed.
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EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
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CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
PROTOCOL SUMMARY
Study Title
A Phase 1b/2a Multicenter, Open-label, Dose-escalation Study to Determine the Maximum 
Tolerated Dose, Assess the Safety, Tolerability, Pharmacokinetics and Efficacy of CC-220 As 
Monotherapy and in Combination with Other Treatments in Subjects with Multiple Myeloma
Indication
Subjects with relapsed and refractory multiple myeloma (RRMM) and newly diagnosed multiple 
myeloma (NDMM) are eligible for the study, as further detailed in Table 1.
Table 1:
Study Population
Part
Cohort
Eligibility
1 (dose 
escalation)
A: monotherapy (MonoT)
B: CC-220 + DEX (DoubleT)
E: CC-220 + daratumumab + 
DEX (CC-220Dd)
G1: CC-220 + carfilzomib + DEX 
(CC-220Kd)
G2: CC-220 + carfilzomib + DEX 
(CC-220Kd)
Received at least two prior therapies including 
lenalidomide or pomalidomide and a proteasome 
inhibitor.
Documented PD during or within 60 days from the 
last dose of their last anti-myeloma therapy.
F: CC-220 + bortezomib + DEX 
(CC-220Vd)
Received at least one prior therapy including 
lenalidomide or pomalidomide and a proteasome 
inhibitor.
Documented PD during or within 60 days from the 
last dose of their last anti-myeloma therapy.
2 (dose 
expansion)
C: monotherapy (MonoT)
Received at least two prior therapies including 
lenalidomide or pomalidomide, a proteasome 
inhibitor, and a CD38 antibody.
Documented PD during or within 60 days from the 
last dose of their last anti-myeloma therapy.
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CC-220
Protocol CC-220-MM-001
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Confidential and Proprietary
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CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
Table 1: Study Population (Continued)
Part
Cohort
Eligibility
2 (dose 
expansion)
D: CC-220 + DEX (DoubleT)
Received at least three prior therapies including 
lenalidomide, pomalidomide, a proteasome 
inhibitor, a glucocorticoid and a CD38 antibody.
Refractory to an immunomodulatory agent, a 
proteasome inhibitor, a glucocorticoid, and a 
CD38 antibody. Refractory is defined as disease 
that is nonresponsive on therapy (failure to 
achieve minimal response or development of 
progressive disease while on therapy) or 
progresses within 60 days of last dose.
Documented PD during or within 60 days from 
the last dose of their last anti-myeloma therapy.
I: CC-220 + DEX (DoubleT) in 
post-BCMA RRMM
Received at least 3 prior therapies including 
lenalidomide or pomalidomide, a proteasome 
inhibitor, a CD38 antibody, and a prior BCMA-
targeted therapy.
Documented PD during or within 60 days from 
the last dose of their last anti-myeloma therapy. 
Subjects who had CAR T therapy as their last 
myeloma therapy must have documented disease 
progression.
J1: CC-220 + bortezomib + 
DEX (CC-220Vd) for 8 cycles 
followed by CC-220 + DEX 
Newly diagnosed multiple myeloma and not 
eligible for ASCT
J2: CC-220 + bortezomib + 
DEX (CC-220Vd) for 4 to 6 
cycles as induction followed by 
ASCT with or without 
maintenance as part of SOC
Newly diagnosed multiple myeloma and eligible 
for ASCT
K: CC-220 + daratumumab + 
DEX (CC-220Dd)
Newly diagnosed multiple myeloma and not 
eligible for ASCT
Abbreviations: ASCT = autologous stem cell transplant; BCMA = B-cell maturation antigen; CAR T = Chimeric 
Antigen Receptor T-cell Therapy; DEX = dexamethasone; PD = progressive disease; NDMM = newly diagnosed 
multiple myeloma; RRMM = relapsed refractory multiple myeloma; SOC = standard of care.
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CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
9
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
Objectives
Primary
Part 1

To determine the maximum tolerated doses (MTDs) and/or recommended Phase 2 
doses (RP2Ds) of CC-220 as monotherapy (MonoT), in combination with 
dexamethasone (DEX) (DoubleT), in combination with DEX and daratumumab 
(DARA) (CC-220Dd), in combination with DEX and bortezomib (BTZ) (CC-220Vd) 
and in combination with DEX and carfilzomib (CFZ) (CC-220Kd) in subjects with 
RRMM.
Part 2

To determine the efficacy of CC-220 in combination with DEX (DoubleT) in subjects 
with RRMM in Cohort D, as measured by overall response rate (ORR).
Secondary 

To evaluate the safety of CC-220 as MonoT, in combination with DEX (DoubleT), in 
combination with DEX and DARA (CC-220Dd), in combination with DEX and BTZ 
(CC-220Vd) and in combination with DEX and CFZ (CC-220Kd) in subjects with 
RRMM.

To evaluate the preliminary efficacy and safety of CC-220 in combination with DEX 
and BTZ (CC-220Vd), and in combination with DEX and DARA (CC-220Dd) in 
subjects with NDMM, including subjects who are eligible for ASCT and subjects 
who are not eligible for ASCT.

To evaluate additional efficacy parameters of CC-220 in combination with DEX 
including time-to-response (TTR), duration of response (DOR), progression-free 
survival (PFS), and overall survival (OS) in subjects with RRMM in Cohort D.

To assess the preliminary efficacy of CC-220 as MonoT, in combination with DEX
(DoubleT), in combination with DEX and DARA (CC-220Dd), in combination with 
DEX and BTZ (CC-220Vd), and in combination with DEX and CFZ (CC-220Kd) in 
subjects with RRMM in Part 1.

To assess the preliminary efficacy and safety of CC-220 in combination with DEX in 
subjects with RRMM who have received prior B-cell maturation antigen (BCMA)-
targeted therapy.

To evaluate the pharmacokinetics (PK) of CC-220 in subjects with RRMM and 
NDMM.
Exploratory 

To explore genomic, molecular and immune biomarkers, including immune 
activation/exhaustion markers and cytokines, for mechanism of action of CC-220 and 
their correlation to clinical outcome measures and pharmacodynamics (Pd).

To evaluate dose-related immune effects of CC-220.
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CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
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CC-220-MM-001 Amendment 10 Final: 05 Jan 2022

To evaluate the PK of metabolite M12 in subjects with RRMM.
 

To evaluate the safety for the combination of CC-220Dd when DARA is administered 
as subcutaneous (SC) injection.

In Part 2 of the study,


 

To explore minimal residual disease (MRD) in subjects who achieve a very good 
partial response (VGPR) or better and its correlation to clinical outcome measures
in subjects with RRMM and NDMM.

 
 
 
Study Design
This study is designed as a Phase 1b/2a study consisting of two parts: dose escalation (Part 1) for 
CC-220 MonoT, CC-220 in combination with DEX, CC-220 in combination with DEX and 
DARA, CC-220 in combination with DEX and BTZ and CC-220 in combination with DEX and 
CFZ; and the expansion of the RP2D (Part 2) for CC-220 MonoT and CC-220 in combination 
with DEX (DoubleT) for RRMM, and CC-220 in combination with DEX and BTZ, and CC-220 
in combination with DEX and DARA for NDMM.
Part 1 (Dose-escalation)
Part 1 will consist of a dose-escalation phase with CC-220 given for 21 days of a 28-day cycle 
(14 days of a 21-day cycle for Cohort F) using a 3+3 design. There will be six cohorts in Part 1 
of the study. Cohort A will enroll subjects treated with CC-220 (MonoT) to determine the MTD 
and/or the RP2D of MonoT, Cohort B will enroll subjects treated with CC-220 and DEX 
(DoubleT) to determine the MTD and/or the RP2D of DoubleT, Cohort E will enroll subjects 
treated with CC-220 in combination with intravenous (IV) DARA and DEX (CC-220Dd), 
Cohort F will enroll subjects treated with CC-220 in combination with BTZ and DEX (CC-
220Vd), Cohort G1 will enroll subjects treated with CC-220 in combination with DEX and once 
weekly CFZ, and Cohort G2 may be opened to enroll subjects treated with CC-220 in 
combination with DEX and twice weekly CFZ to determine the MTD and/or RP2D of these 
triplet therapies. All subjects within the same dose-level cohort will be treated and observed for 
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EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
11
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
at least 28 days (Cycle 1) after the first dose of CC-220 before initiation of the next dose-level 
cohort may begin, with the exception of subjects in Cohort F who will be treated and observed 
for 21 days (Cycle 1) after the first dose. 
Once the MTD and/or RP2D is determined in Cohort E (CC-220Dd), 13 subjects will be enrolled 
at this dose level using SC DARA to evaluate the safety and tolerability with the SC formulation. 
The decision to evaluate any additional subjects with the SC formulation will be at the discretion 
of the Dose Escalation Committee (DEC), based on their review of the data.
Escalation to the next higher dose level will be determined by the DEC that includes an 
Independent Expert Reviewer (IER).
Cohorts A, B, E, G1 and G2 will have a 21 out of 28-day dosing regimen of CC-220 and Cohort 
F will have a 14 out of 21-day dosing regimen of CC-220. The treatment with investigational 
product (IP) will be continued until progressive disease (PD), unacceptable toxicity or the subject 
withdraws consent.
Subjects assigned to MonoT, Cohort A, who develop PD will have the option to receive DEX in 
addition to CC-220 after consultation with the Medical Monitor. The subject’s dose of CC-220 
will not be higher than the dose of CC-220 used in combination with DEX in Cohort B that has 
been determined to be safe. The site will be informed of the dose of CC-220 to be administered 
when DEX is added. Progressive disease must be confirmed in accordance with International 
Myeloma Working Group (IMWG) criteria. 
For Cohorts A (if DEX is added after PD), B, E, and G1 the starting dose of DEX will be 40 mg 
on Days 1, 8, 15 and 22 of each 28-day cycle for subjects who are ≤75 years of age. For subjects 
who are > 75 years of age, the starting dose of DEX is 20 mg on Days 1, 8, 15 and 22 of each 28-
day cycle. Subjects who surpass the age of 75 years while on treatment may be switched to the 
20 mg dose based on the Investigator’s best judgement. For Cohort G2, the dose of DEX is 20 
mg given on Days 1, 2, 8, 9, 15, 16, 22, 23 of each 28-day cycle. For Cohort F, the dose of DEX 
is 40 mg (or 20 mg if > 75 years of age) given on Days 1, 8, and 15 of each 21-day cycle. This 
treatment will continue until PD, unacceptable toxicity or the subject withdraws consent. 
For Cohorts A and B, the starting dose level of CC-220, dose level 1, is 0.3 mg for both cohorts.
A dose level -1, of 0.15 mg, may also be evaluated if the starting dose level of 0.3 mg for 21 
days of a 28-day cycle is not tolerated (refer to Table 2).
The starting dose level of CC-220 in Cohorts E and F is detailed in Table 3. 
The dose level assignments of CC-220 in Cohorts G1 and G2 are detailed in Table 4.
Approximately 34 subjects in Cohort A and 72 subjects in Cohort B will be treated and evaluated 
in Part 1 for MTD and/or RP2D. Approximately 85 additional subjects will be allocated to one of 
the four triplet regimen cohorts (Cohorts E, F, G1 and G2). The total number of subjects in Part 1 
depends on the number of dose levels needed to establish the MTD and/or RP2D and may 
exceed these approximations.
The MTD may be the RP2D. The RP2D may also be determined by PK and biomarker data as 
well as the safety and preliminary efficacy data from Part 1, as applicable. The decision to 
determine the RP2D will be made in consultation with the DEC.
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CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
12
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
During the dose-escalation phase (Part 1), the decision to evaluate subsequent dose levels will be 
considered and documented by the DEC based on their review of clinical and laboratory safety 
data for all subjects in the cohorts. Additional dose levels up to 25% greater than the previous 
dose level declared tolerable by the DEC may be explored or dose levels expanded based on the 
DEC’s evaluation and recommendation.
Part 2 (Expansion)
The initiation of Part 2 will begin when the RP2D is established in Part 1 in one of the following 
cohorts: Cohort A, Cohort B, Cohort E or Cohort F. The start of Part 2 does not require that all
cohorts have determined the RP2D. Each cohort is independent. Part 2 cohorts may begin once 
the RP2D is determined for that cohort in Part 1. All expansion decisions will be determined by
the DEC after review of all safety, PK, biomarker and preliminary efficacy data, as applicable.
During Part 2, the DEC (including the IER) will continue to review the safety data and any other 
data deemed relevant so that subject safety is ensured.
Cohort C (MonoT Expansion)

Once the RP2D is established for Cohort A (MonoT) by the DEC, the expansion 
cohort may be initiated (Part 2).

Up to 24 subjects may be enrolled to further evaluate safety and assess preliminary 
efficacy.

Subjects may start CC-220 at the RP2D based on safety, preliminary efficacy, PK and 
biomarker data from Part 1.
Following the 08 Nov 2019 DEC review of Cohort A, the 1 mg dose level was deemed tolerable. 
It was agreed that further investigation of CC-220 monotherapy was more appropriate in a newly 
diagnosed multiple myeloma maintenance setting. Therefore, Cohort C will not be opened.
Cohort D (DoubleT Expansion)
Once the RP2D is established for Cohort B (DoubleT) by the DEC, the expansion cohort may be 
initiated (Part 2). As of 18 Oct 2019, the DEC has recommended the 1.6 mg dose level as the 
RP2D for CC-220 plus DEX. A group sequential design (Jennison, 1999) will be used to 
evaluate the efficacy and safety of CC-220 (at the RP2D of 1.6 mg) plus DEX in Cohort D.
Stage 1 

In Stage 1, following the treatment of 40 subjects, an interim analysis will be 
performed to evaluate the preliminary efficacy of CC-220 plus DEX at the RP2D of 
1.6 mg.  
Stage 2

If the results from Stage 1 do not cross the futility boundary (see Section 9.10), an
additional 61 subjects may be treated to confirm the efficacy and safety of CC-220 
plus DEX at the RP2D of 1.6 mg.
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CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
13
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
Cohort I (DoubleT Expansion in Post-BCMA RRMM)

Once the RP2D is established for Cohort B (CC-220 plus DEX), this expansion 
cohort may be initiated. As of 18 Oct 2019, the DEC has recommended the 1.6 mg 
dose level as the RP2D for CC-220 plus DEX.

Up to 40 subjects who have received prior BCMA-targeted therapy may be enrolled
to evaluate the safety and preliminary efficacy of CC-220 plus DEX at the RP2D for 
this patient population. Minimum of 40% of the cohort will have prior BCMA-
targeted CAR T therapy. The IRT will be used to monitor the inclusion of these 
subjects.
Cohort J1 (CC-220Vd in NDMM and not eligible for ASCT)

Once the RP2D is established for Cohort F (CC-220Vd) by the DEC, this expansion 
cohort may be initiated.
 

Approximately 75 subjects may be enrolled to evaluate the safety and preliminary 
efficacy of up to 3 dose levels of CC-220 (1.0 mg, 1.3 mg, and 1.6 mg) in 
combination with BTZ and DEX in NDMM subjects who are not eligible for ASCT.
Up to approximately 25 subjects per dose level may be enrolled. Additional subjects 
may be enrolled in any of the dose levels upon consultation with the DEC, based on 
review of the data.
Cohort J2 (CC-220Vd in NDMM eligible for ASCT)

Once the RP2D is established for Cohort F (CC-220Vd) by the DEC, this expansion 
cohort may be initiated.

Approximately 50 subjects may be enrolled to explore the safety and preliminary 
efficacy of CC-220 in combination with BTZ and DEX in NDMM subjects who are 
eligible for ASCT.
Cohort K (CC-220Dd in NDMM and not eligible for ASCT)

Once the RP2D is established for Cohort E (CC-220Dd) by the DEC (IV DARA), this 
expansion cohort may be initiated. 
 

Approximately 75 subjects may be enrolled to evaluate the safety and preliminary 
efficacy of up to 3 dose levels of CC-220 (1.0 mg, 1.3 mg, and 1.6 mg) in 
combination with SC DARA and DEX in NDMM subjects who are not eligible for 
ASCT. Up to approximately 25 subjects per dose level may be enrolled. Additional 
subjects may be enrolled in any of the dose levels upon consultation with the DEC, 
based on review of the data.
Any of the cohorts may be removed and/or terminated from the study based on emerging PK, Pd, 
efficacy or safety data, in consultation with the DEC.
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Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
14
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
Investigator response assessments will be used to determine the efficacy outcome throughout the 
study. An Independent Response Committee (IRC) may also be set up to review efficacy data 
from Part 2 RRMM Cohorts C, D, and/or I. The IRC will determine the tumor response to 
therapy based on the IMWG uniform Response Criteria as well as time of response (including 
PD) for each subject. The IRC will adjudicate efficacy data according to the IRC Charter.
The treatment with IP may be continued in all cohorts until disease progression, unacceptable 
toxicity or the subject withdraws consent except for Cohort J2. Subjects in Cohort J2 will receive 
CC-220Vd for up to 6 cycles or until PD, unacceptable toxicity or withdrawal of consent, 
whichever is earlier. Subjects will be allocated by Interactive Response Technology (IRT) in 
parallel to an appropriate cohort based on eligibility status and on cohort slot availability.
Enrollment of NDMM subjects in Cohort J1 at the 1.6 mg dose level will start according to 
Protocol Amendment No. 9. Upon approval of Protocol Amendment No. 10, subjects will be 
allocated evenly into all open J1 and K dose level cohorts. Subjects will be allocated to each dose 
level cohort based on a fixed sequence via the IRT.
Subjects assigned to MonoT, Cohort C, who develop PD will have the option to receive DEX in 
addition to CC-220 after consultation with the Medical Monitor. The subject’s dose of CC-220 
will not be higher than the dose of CC-220 used in combination with DEX in Cohort B that has 
been determined to be safe. If the RP2D has been reached in Cohort B, that dose will be used in 
this situation. The site will be informed of the dose of CC-220 to be administered when DEX is 
added. Progressive disease must be confirmed in accordance with IMWG criteria. For Cohort D, 
Cohort I and for Cohort C (if DEX is added after PD), the starting dose of DEX will be 40 mg on 
Days 1, 8, 15 and 22 of each 28-day cycle for subjects who are ≤75 years of age. For subjects 
who are > 75 years of age, the starting dose of DEX is 20 mg on Days 1, 8, 15 and 22 of each 28-
day cycle. Subjects who surpass the age of 75 years while on treatment may be switched to the 
20 mg dosage based on the Investigator’s best judgement. This treatment will continue until PD, 
unacceptable toxicity or the subject withdraws consent. 
All subjects who discontinue study treatment in Part 1 or Part 2 of the study for a reason other 
than PD or withdrawal of consent from the study will be followed for response assessment every 
28 days (every 21 days for Cohort F) until PD or until a subsequent myeloma regimen has been 
started. Subjects in Cohort J1 and Cohort K will be followed every cycle for the first 2 years and 
thereafter, every 3 months until PD or until a subsequent myeloma regimen has been started. 
Subjects in Cohort J2, following induction and ASCT with or without maintenance, will be 
followed for response assessment during the Post-Treatment Response follow-up every 3 months 
until PD or until a subsequent anti-myeloma regimen has been started.
Table 2:
Cohort and Dose Level Assignments for MonoT (Cohort A and C) and 
DoubleT (Cohort B, D and I)
Part
Dose-Level
Cohort A (MonoT)
Cohort B (DoubleT)
CC-220a (28-d Cycle)
CC-220 a + DEX
b (28-d Cycle)
Part 1
-1
0.15 mg 
0.15 mg +DEX
Starting dose 1
0.3 mg 
0.3 mg +DEX
2
0.45 mg 
0.45 mg +DEX
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Confidential and Proprietary
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Table 2:
Cohort and Dose Level Assignments for MonoT (Cohort A and C) and 
DoubleT (Cohort B, D and I)  (Continued)
Part
Dose-Level
Cohort A (MonoT)
Cohort B (DoubleT)
CC-220a (28-d Cycle)
CC-220 a + DEX
b (28-d Cycle)
3
0.6 mg 
0.6 mg +DEX
4
0.75 mg 
0.75 mg +DEX
5
0.9 mg 
0.9 mg +DEX
6
1 mg 
1 mg +DEX
7 and 
subsequent
Up to 25% increase above the 
prior dose levelc
Up to 25% increase above the prior 
dose levelc + DEX
Part 2
Dose-Level
Cohort C (MonoT) (28-d Cycle)
Cohorts D and I (DoubleT) (28-d 
Cycle)
CC-220a
CC-220a + DEX
b
MTD/RP2D 
MTD/RP2D (1.6 mg) +DEX
Abbreviations: d = day; DEX=dexamethasone; DoubleT = combination treatment with 2 drugs; MonoT = 
monotherapy; MTD = maximum tolerated dose; PO = by mouth; RP2D = recommended Phase 2 dose.
a CC-220 dosing schedule: daily for 21 days of each 28-day cycle.
b DEX dosing: 40 mg (20 mg for subjects who are >75 years of age) PO on Days 1, 8, 15 and 22.
c Subsequent dose increases will be up to 25% higher than the prior dose level, as determined by the DEC. See 
Section 1.3.6.3.
Table 3:
Cohort and Dose Level Assignments for Cohorts E, F, J1, J2 and K
Part 
1
Dose 
Level
Cohort E (CC-220Dd) - 28-day Cycle
Cohort F (CC-220Vd) - 21-day Cycle
CC-
220a,c
Daratumumab 
(IV)f
C1-2: Days 1, 8, 15, 
22
C3-6: Days 1, 15
≥C7: Day 1
DEX
Days 1, 8, 15 
and 22
CC-
220 a,d
Bortezomib 
(SC)
C1-8: Days 1, 4, 
8, 11
≥C9: Days 1, 8
DEX
Days 1, 8, 15
-1
0.9
mg
16 mg/kg
40 mg
(≤ 75 years)
20 mg
(> 75 years)
0.9
mg
1.3 mg/m2
40 mg (≤ 75 
years)
20 mg (> 75 
years)
Starting 
dose 1
1 mg
16 mg/kg
1 mg
1.3 mg/m2
2
1.1
mg
16 mg/kg
1.1
mg
1.3 mg/m2
3 and 
subsequent
Up to 25% increase above the prior dose 
levelb + DARA + DEX
Up to 25% increase above the prior dose 
levelb + BTZ + DEX
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EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
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Confidential and Proprietary
16
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
Table 3:
Cohort and Dose Level Assignments for Cohorts E, F, J1, J2 and K 
(Continued)
Part 
2 
Dose 
Level
Cohort K (CC-220Dd)g
Cohorts J1 and J2 (CC-220Vd)e
-
1.0 mg, 1.3 mg and 1.6 mg of CC-220 + 
DARA + DEX 
1.0 mg, 1.3 mg and 1.6 mg of CC-220 + 
BTZ + DEX 
Abbreviations: BTZ = bortezomib; C = cycle; DARA = daratumumab; DEC = dose escalation committee; DEX = 
dexamethasone; IV = intravenous; RP2D = recommended Phase 2 dose; SC = subcutaneous
a The starting dose of CC-220 in Cohorts E and F will be one dose level below the maximum dose in Cohort B that 
has been determined to be safe by the DEC.
b Subsequent dose increases will be up to 25% higher than the prior dose level, as determined by the DEC. See 
Section 1.3.6.3.
c CC-220 dosing schedule: daily for 21 days of each 28-day cycle.
d CC-220 dosing schedule: daily for 14 days of each 21-day cycle.
e See Section 7.2.1.2 for details of treatment schedule in Cohorts J1 and J2.
f Once the MTD and/or RP2D is determined in Cohort E (CC-220Dd), an additional 13 subjects will be enrolled at 
this dose level using SC DARA. See Section 7.2.1.1 for details of treatment dose and schedule for SC DARA.
g See Section 7.2.1.2 for details of treatment schedule in Cohort K.
Table 4:
Cohort and Dose Level Assignments for Cohorts G1 and G2
Abbreviations: C = cycle; CFZ = carfilzomib; D = day; DEC = dose escalation committee; DEX = dexamethasone;
IV = intravenous.
Dose Level
Cohort G1 (CC-220Kd) - 28-day cycle
Cohort G2 (CC-220Kd) - 28-day cycle
CC-220a,b,c
Carfilzomib 
(IV)d
Days 1, 8, 15
Oral DEX
Days 1, 8, 15, 
22
CC-220a,b,c
Carfilzomib 
(IV)d
Days 1, 2, 8, 9, 
15, 16
Oral DEX
Days 1, 2, 8, 
9, 15, 16, 22, 
23
-1
1 mg
20 mg/m2
C1D1
56 mg/m2
thereafter
40 mg 
(≤ 75 years)
20 mg 
(> 75 years)
1 mg
20 mg/m2 C1D1 
and C1D2
27 mg/m2
thereafter
20 mg
Starting 
Dose 1
1.1 mg 
20 mg/m2
C1D1
56 mg/m2
thereafter
1.1 mg 
20 mg/m2 C1D1 
and C1D2
27 mg/m2
thereafter
2
1.1 mgc
20 mg/m2
C1D1
70 mg/m2
thereafter
1.1 mgc
20 mg/m2 C1D1 
and C1D2
56 mg/m2
thereafter
3 and 
subsequent
Up to 25% 
increase 
above prior 
dosec
20 mg/m2
C1D1
56 OR 70 
mg/m2
thereafterd
Up to 25% 
increase 
above prior 
dosec
20 mg/m2 C1D1 
and C1D2 
27 OR 56 
mg/m2
thereafterd
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EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
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Confidential and Proprietary
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CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
a The starting dose of CC-220 in triplet regimen cohorts will be one dose level below the maximum dose in Cohort 
B that has been determined to be safe by the DEC. 
b CC-220 dosing schedule: daily for 21 days of each 28-day cycle.
c The CC-220 dose will be determined by the DEC. Subsequent dose increases will be up to 25% higher than the 
prior dose level, as determined by the DEC. See Section 1.3.6.3.
d Dosing regimen for CFZ will be determined by the DEC.
Different dosing regimens for CFZ may be evaluated, depending on DEC recommendation.
The study will be conducted in compliance with International Council for Harmonisation (ICH) 
Good Clinical Practices (GCPs).
Study Population
Part 1 (dose escalation):
Eligible subjects must have a documented diagnosis of RRMM and must have documented 
disease progression on or within 60 days from the last dose of their last myeloma therapy.  

Subjects eligible for Cohorts A, B, E, G1, and G2 must have received at least two 
prior myeloma regimens including lenalidomide or pomalidomide and a proteasome 
inhibitor.

Cohort F subjects must have received at least one prior regimen including 
lenalidomide or pomalidomide and a proteasome inhibitor. 
Part 2 (dose expansion):
Dose expansion in RRMM
Eligible subjects must have a documented diagnosis of RRMM and must have documented 
disease progression on or within 60 days from the last dose of their last myeloma therapy.
Subjects who had CAR T therapy as their last myeloma therapy must have documented disease 
progression.

Subjects eligible for Cohort C must have received at least two prior myeloma 
regimens including lenalidomide or pomalidomide, a proteasome inhibitor, and a 
CD38 antibody.

Subjects eligible for Cohort D must have received at least three prior myeloma 
regimens including lenalidomide, pomalidomide, a proteasome inhibitor, a 
glucocorticoid and a CD38 antibody. Subjects in Cohort D will also be required to be 
refractory to an immunomodulatory agent, a proteasome inhibitor, a glucocorticoid, 
and a CD38 antibody. 

Subjects eligible for Cohort I must have received at least three prior myeloma 
regimens including lenalidomide or pomalidomide, a proteasome inhibitor, a CD38 
antibody, and prior BCMA-targeted therapy. 
Dose expansion in NDMM

Subjects eligible for Cohort J1 and Cohort K must have newly diagnosed multiple 
myeloma and are those for who ASCT is not planned for initial therapy or are not 
considered by the investigator as eligible for ASCT.
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CC-220
Protocol CC-220-MM-001
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
Subjects eligible for Cohort J2 must have newly diagnosed multiple myeloma and are 
considered by the investigator as eligible for ASCT.
Length of Study
The study will consist of the Screening and Treatment phases for subjects in all dose-escalation 
cohorts (Part 1) as well as the expansion cohorts (Part 2). A Long-term Follow-up phase will be 
added for subjects in Part 2 RRMM expansion Cohorts C, D, and I. The Screening phase of this 
study may not exceed a 28-day window prior to the start of IP (Cycle 1 Day 1). 
This is followed by the Treatment phase consisting of 28-day cycles for all cohorts except 
Cohorts F, J1 and J2 which consists of 21-day cycles. Treatment at each dose level and in each 
part of the study will continue until PD, unacceptable toxicity or the subject withdraws consent
in all cohorts except for Cohorts J2. Subjects in Cohort J2 will receive CC-220Vd for up to 
6 cycles or until PD, unacceptable toxicity or withdrawal of consent, whichever is earlier. There 
will be an End of Treatment (EOT) Visit to collect safety and efficacy assessments. For subjects 
in Cohort J2, the EOT Visit is considered either 3 months (±7 days) post ASCT (prior to any 
maintenance therapy, if applicable) or at any other moment for treatment discontinuation, 
whichever is earlier.
There will be a 28-day post-treatment visit to obtain safety assessments.
All subjects who discontinue study treatment in Part 1 or Part 2 of the study for a reason other 
than PD will enter the Post Treatment Response Follow Up phase and will be followed for 
response assessment every 28 days (21 days for Cohort F) until PD or until a subsequent
myeloma regimen has been started (please refer to the Table of Events for the respective cohort). 
Additionally, subjects in Cohort J2, following induction, ASCT with or without maintenance, 
will be followed for response assessment during the Post-Treatment Response Follow Up visits 
every 3 months until PD or until a subsequent anti-myeloma regimen has been started whereby a 
Post-Treatment Response Follow Up Discontinuation visit will be performed.
All RRMM subjects (Cohorts C, D, and I) enrolled in Part 2 of the study will have long-term 
follow-up. Subjects will be contacted every 3 months for 5 years from the date of the last subject 
enrolled in the study (or longer if clinically indicated) to learn of the subject’s death from any 
cause, to continue second primary malignancy (SPM) surveillance and to collect data on 
subsequent anti-myeloma therapies including date of progression. 
The End of Trial is defined as either the date of the last long-term follow-up data collection, or 
the date of receipt of the last data point from the last subject that is required for primary, 
secondary and/or exploratory analysis, as prespecified in the protocol, whichever is the later date.
At the conclusion of the study, if the study intervention is not available as an approved treatment 
in the local country, participants who continue to demonstrate clinical benefit will be eligible to 
receive Sponsor-supplied study intervention. If the study treatment is not available as an 
approved and available treatment, study intervention will be provided via an extension of the 
study, or a rollover study requiring approval by the responsible Health Authority and ethics 
committee, or through another mechanism at the discretion of the Sponsor. The Sponsor reserves 
the right to terminate access to the supplied study intervention treatment if any of the following 
occur: a) the study is terminated due to safety concerns; b) the development of CC-220 is 
terminated for other reasons, including, but not limited to, lack of efficacy and/or not meeting the 
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EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
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CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
study objectives; c) the participant can obtain medication from a government-sponsored or other 
health program. In all cases, the Sponsor will follow local regulations.
Study Treatments
CC-220 will be provided as an investigational product by Celgene Corporation in formulated 
capsules. 
Subjects enrolled in countries where DEX, IV DARA, SC DARA, BTZ, and/or CFZ are
commercially available may obtain commercially available product through their local hospital 
pharmacy or licensed distributer (as applicable) and in accordance with local guidelines. Celgene 
will provide DEX, IV DARA, SC DARA, BTZ, and/or CFZ where supplies are not 
commercially available, or not readily available, or not provided by regulation. 
Overview of Key Efficacy Assessments

Myeloma paraprotein

Serum immunoglobulins

Serum free light chains

Immunofixation

Bone marrow aspirate (BMA)/bone marrow biopsy (BMB)

Radiographic imaging assessments of lytic bone lesions

Extramedullary plasmacytomas (EMPs) assessments

MRD assessment for response of VGPR or better (Part 2)

Eastern Cooperative Oncology Group (ECOG) Performance Status 
Overview of Key Safety Assessments

Adverse events (AEs) including AEs of special interest (AESIs) which would include 
second primary malignancies

Complete physical examination including vital signs and venous thromboembolism 
(VTE) monitoring

Clinical laboratory evaluations (hematology, serum chemistry, urinalysis)

Renal function assessments

Pancreatic function assessments (part of chemistry panel)

Ophthalmologic assessment if clinically indicated

12-lead electrocardiograms 

Pregnancy testing/counseling

Concomitant medications and procedures
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EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
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CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
Overview of Pharmacokinetic Assessments
Subjects in Part 1 and Part 2 will be required to participate in sparse PK sampling as a participant 
in the main study. An additional subset of subjects will be assigned to participate in the intensive 
PK sample collection. Both intensive and sparse PK samples will be collected to evaluate CC-
220, and as appropriate, its R-enantiomer CC-17195 in plasma. The pharmacologically active 
metabolite, M12, will also be quantified in an exploratory manner. Please refer to Section 6.5 for 
further details.
Cohorts A and B
Sparse PK Sampling
Pharmacokinetic blood samples will be collected in all subjects at the following time points:

Cycles 1-4, Days 8, 15, 22: one pre-dose sample per visit
Intensive PK Sampling
Participation in the intensive PK assessment will be selective. In addition to the sparse PK 
sampling time points, frequent collection of PK blood samples will be performed in 
approximately 2 subjects per dose level (a total of 8 subjects at minimum) at the following time 
points:

Cycle 1, Day 15: 1, 2, 3, 4, 6, 8 hours and 24 hours after administration of CC-220. 
At each timepoint, approximately 6 mL of blood will be collected.
Cohorts C and D
Sparse PK Sampling
Pharmacokinetic blood samples will be collected in all subjects at the following time points:

Cycles 1-4, Day 15: one pre-dose sample per visit.
Intensive PK Sampling
In addition to the sparse PK sampling, frequent collection of PK blood samples will be 
performed in approximately 10 subjects enrolled. Samples will be collected at the following 3 
time points:

Cycle 1, Day 15: 1 timepoint at 2 h, 1 timepoint between 4-8 h, and 1 timepoint at 24 
hours after administration of CC-220.
At each time point, approximately 3 mL of blood will be collected. The CC-220 concentration in 
plasma will be determined.
Cohorts E, F, G1, G2
Sparse PK Sampling
Pharmacokinetic blood samples will be collected in subjects at the following time points:

Cycles 1-4, Days 8, 15: one pre-dose sample per visit.
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EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
21
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
Intensive PK Sampling
In addition to the sparse PK sampling, frequent collection of PK blood samples will be 
performed in approximately 1 subject per dose level of each cohort. Samples will be collected at 
the following 3 time points:

Cycle 1, Day 8: 1 timepoint at 2 h, 1 timepoint between 4-8 h, and 1 timepoint at 24 
hours after administration of CC-220.
At each timepoint, approximately 3 mL of blood will be collected.
Cohorts I and K
Sparse PK Sampling
Pharmacokinetic blood samples will be collected in all subjects at the following time points:

Cycles 1-2, Day 15: 1 timepoint at pre-dose and 1 timepoint at 2 hours after 
administration of CC-220.
At each timepoint, approximately 3 mL of blood will be collected.
There is no intensive PK sampling in Cohorts I and K.
Cohorts J1 and J2
All subjects will participate in sparse PK as a participant in the main study. Only sparse PK 
samples will be collected to evaluate the concentrations of CC-220 in plasma. At each time
point, approximately 3 mL of blood will be collected.
Sparse PK Sampling
Pharmacokinetic blood samples will be collected in subjects at the following time points:

Cycles 1-2, Day 8: 1 timepoint at pre-dose and 1 timepoint at 2 hours after 
administration of CC-220.
There is no intensive sampling in Cohorts J1 and J2.
Overview of Biomarkers for Pharmacodynamic Assessments
The following assessments will be mandatory in the dose escalation (Part 1) and not collected in 
the expansion (Part 2). 

To evaluate the pharmacodynamic (Pd) effects of CC-220 on Aiolos and other Pd 
biomarkers (by protein expression) in peripheral blood cell components including 
mononuclear cells and secreted cytokines. 
Blood collection time points:

Cycle (C)1 Day(D) 1 – pre-dose, 3, 5 hours post dose

C1D12 – pre-dose, 3, 5 hours post dose. For Cohorts G1 and G2, this assessment 
will be performed on C1D15. Note, in all cohorts, the acceptable window for this 
assessment is C1D11 to C1D15.
Approved
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EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
22
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022

To explore TCR (T-cell receptor) clonality in peripheral blood.
Blood collection time points: 

C1D1– pre-dose

C2D15– pre-dose

C4D15– pre-dose

At IP discontinuation (EOT)

To explore the Pd effects of CC-220 on T-cell counts in peripheral blood. This 
lymphocyte subset panel is obtained from existing hematology sampling; no 
additional sampling is required.
Blood collection time points for all Cohorts except Cohorts F, G1 and G2:

Cycle 1 Days 1, 8, 12, 15, 22, 26– pre-dose

Cycles 2-4 Days 1, 8, 15, 22– pre-dose

Cycles 5+ Days 1, 15– pre-dose
Blood collection timepoints for Cohort F:

Cycle 1 Days 1, 8, 12, 15– pre-dose when applicable

Cycles 2-4 Days 1, 8, 15– pre-dose when applicable

Cycles 5+ Days 1, 15 – pre-dose when applicable
Blood collection timepoints for Cohorts G1 and G2:

Cycles 1-4 Days 1, 8, 15– pre-dose

Cycles 5+ Days 1, 15– pre-dose

For Cohorts B, G1, and G2, up to 3 subjects in each dose level at select United States
(US) sites may be selected for the following assessment: To evaluate the Pd effects of 
CC-220 on Aiolos and Ikaros in mononuclear cells with a novel exploratory assay.
The IRT will be used to monitor inclusion of these participants.
Blood collection time points:

C1D1 – pre-dose, 3, 6 hours post dose

C1D2 – pre-dose

C1D15 – pre-dose, 3 hours post dose

For Cohort F, up to 3 subjects in each dose level at select US sites may be selected 
for the following assessment: To evaluate the Pd effects of CC-220 on Aiolos and 
Ikaros in mononuclear cells with a novel exploratory assay. The IRT will be used to 
monitor inclusion of these participants.
Blood collection time points:

C1D1 – pre-dose, 3, 6 hours post dose

C1D2 – pre-dose
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EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
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CC-220-MM-001 Amendment 10 Final: 05 Jan 2022

C1D11 – pre-dose, 3 hours post dose
The following assessments will be mandatory in dose escalation (Part 1) and mandatory in 
expansion (Part 2) 

To explore the pharmacodynamic (Pd) effects of CC-220 on T-Cell Activation in 
peripheral blood.
Blood collection time points:

C1D1 – pre-dose, 3, 5 hours post dose

C1D12 – pre-dose, 3, 5 hours post dose. For Cohorts C, D, G1, G2, and K this 
assessment will be performed on C1D15. For Cohorts J1 and J2, this assessment 
will be performed on C1D11. Note, in all cohorts, the acceptable window for this 
assessment is C1D11 to C1D15.

To explore Pd effects of CC-220 on immune cells in peripheral blood and association 
of baseline levels of these populations with response or resistance to CC-220
Blood collection time points for Part 1 Cohorts A, B, E, F, G1, and G2: 

C1D1 – pre-dose

C2D1 – pre-dose

C2D15 – pre-dose

C4D1 – pre-dose

C4D15 – pre-dose 

C6D15– pre-dose 

At IP discontinuation (EOT)
Blood collection time points for Cohorts C, D, I and K: 

C1D1 – pre-dose

C2D1 – pre-dose

C2D15 – pre-dose

C6D15– pre-dose 

EOT
Blood collection time points for Cohort J1:

C1D1 – pre-dose

C4D8– pre-dose

C8D8– pre-dose 

EOT
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EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
Celgene Corporation
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CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
Blood collection time points for Cohort J2:

C1D1 – pre-dose

C4D8 – pre-dose

EOT

To explore the pharmacogenomics of CC-220 response.
Blood collection time points:

C1D1 – pre-dose

To explore the association of CC-220 response or resistance to baseline levels and Pd 
changes in protein expression, gene expression, cytogenetics, copy number 
abnormalities and/or mutations in tumor cells and tumor microenvironment in the 
bone marrow
Bone marrow aspirate (BMA)/ BMB collection time points (please refer to Table 18
for further details on BMA/BMB sample collection plan):

Screening BMA (and if possible, BMB)

C2D15 – 3-6 hours post dose BMA (and if possible, BMB). (C2D11 for Cohort F
and Cohort J1)

Confirmatory BMA (and if possible, BMB) for complete response (CR) (by 
International Myeloma Working Group [IMWG] criteria, see Appendix B)

BMA (and if possible, BMB) taken at time of PD/treatment discontinuation or 
any time after PD and before the start of subsequent myeloma therapy

Optional: BMA and/or BMB taken at any time during the study period at request 
of investigator
The following will be mandatory in the expansion (Part 2) only.

To explore the effects of CC-220 on MRD negativity in subjects achieving a response 
of VGPR or better until progression of disease (PD)
BMA collection time points (please refer to Table 18 for details on BMA/BMB 
sample collection plan):

Screening

Confirmatory BMA (and, if possible, BMB) for complete response (CR)

To evaluate the duration of MRD negativity and changes in MRD status in 
responding subjects, a BMA after achieving response of VGPR or better until disease 
progression. Please refer to Table 18 for further details on timepoints.

Only applicable for approximately 20 subjects enrolled in Cohort D at select US 
sites: To evaluate the pharmacodynamic (Pd) effects of CC-220 on Aiolos and Ikaros 
in mononuclear cells with a novel exploratory assay. The IRT will be used to monitor 
inclusion of these participants.
Blood collection time points:
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EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
25
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022

C1D1 – pre-dose, 3, 6 hours post dose

C1D2 – pre-dose

C1D15 – pre-dose, 3 hours post dose

Only applicable for approximately 20 subjects enrolled in Cohort D at select US 
sites:
 
 The IRT will be used to monitor inclusion of these participants.
Blood collection time points:

C1D1 – pre-dose

C2D1 – pre-dose

C2D15 – pre-dose

Only applicable for approximately 5 subjects enrolled in Cohort D at one pre-
identified US site: To evaluate time-matched concentration of CC-220 in peripheral 
blood and tumor microenvironment and assess the correlation between concentration, 
pharmacodynamic changes in tumor microenvironment, and outcome measures. The 
IRT will be used to monitor inclusion of these participants.
BMA and blood collection timepoints:

Screening

C1D8 – 3-6 hours post dose

C2D15 – 3-6 hours post dose

 
Other Assessments

Beta 2 (β2)-microglobulin

Cytogenetic testing by fluorescence in situ hybridization (FISH) at Screening

Statistical Methods
The primary objective of Part 1 of the study is to determine the MTD and/or RP2D of CC-220 as 
monotherapy, in combination with DEX, and in combination with DEX and DARA, BTZ, or 
Approved
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EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
26
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
CFZ in subjects with RRMM. Safety endpoints such as dose-limiting toxicity (DLT), treatment-
emergent AEs, serious AEs (SAEs), and AEs of special interest (AESIs) will be summarized by 
cohort and dose level (described in Section 9.9). Preliminary efficacy of CC-220 as 
monotherapy, in combination with DEX, and in combination with DEX and DARA, BTZ, or 
CFZ will also be assessed with available data.
The expansion part of the study (Part 2) will be used to further evaluate the safety and efficacy of 
CC-220 as monotherapy and in combination with DEX in subjects with RRMM, and in 
combination with BTZ or DARA and DEX in subjects with NDMM.
In Cohort C, up to 24 subjects may be enrolled to further evaluate safety and assess preliminary 
efficacy.
The primary objective of Cohort D is to determine the efficacy of CC-220 plus DEX in subjects 
with RRMM, as measured by ORR, which is defined as the proportion of subjects with a partial 
response (PR) or better. The sample size is calculated based on a group sequential design 
(Jennison, 1999) for a one-sample binomial test with normal approximation. One interim
analysis for futility at 40% information and one final analysis are planned. The null hypothesis is 
ORR ≤ 12% and the alternative hypothesis is ORR > 12%. Assuming a treatment benefit of ORR 
≥ 24%, a sample size of 101 subjects would provide 90% power at a one-sided 0.025 alpha level.
(Sample size calculation used EAST version 6.4.)
One interim analysis is planned at 40% information reached, ie, the interim analysis will be 
performed at approximately the first 40 treated subjects. The results of the interim analysis will 
be used for futility assessment only, for which a stopping boundary will be applied based on a 
beta spending function of gamma distribution with gamma = -2. The one-sided p-value to reject 
the alternative hypothesis (for futility) is p ≥ 0.656, which is corresponding to ≤ 10% observed 
response rate at the time of interim analysis (assuming 40% information at interim analysis, may 
be adjusted according to actual percent of information available).
In Cohort I, up to 40 subjects will be enrolled to explore the safety profile and preliminary 
efficacy of CC-220 plus DEX in the post-BCMA treatment patient population. An ORR of 20% 
is considered as minimum clinically meaningful in this heavily pretreated patient population with 
prior BCMA-targeted therapy exposure. Bayesian continuous monitoring method will be applied 
to monitor the ORR. If the posterior probability of ORR less than or equal to 20% is greater than 
0.8, then the cohort will be stopped for futility. Otherwise, enrollment will continue to up to 
40 subjects to explore the safety profile and assess the preliminary efficacy CC-220 plus DEX in
this patient population.
For Cohorts J1, J2 and K, the very good partial response or better (≥VGPR) rate is considered an 
important and clinically relevant efficacy parameter to explore the treatment effect for NDMM 
patient population (Durie, 2018; Facon, 2018). In the SWOG S0777 study, the ≥VGPR rate in 
NDMM subjects not eligible for ASCT following 8 cycles of RVd (lenalidomide in combination 
with bortezomib and dexamethasone) is 57%. In the IFM2009 study, the ≥VGPR rate in NDMM 
subjects eligible for ASCT following 4 cycles of RVd induction therapy is 57% (IFM 2009 and 
SWOG S0777 Clinical Study Reports; Data on File). In the MAIA study, the ≥ VGPR rate in 
NDMM subjects not eligible for transplant following DRd (daratumumab in combination with 
lenalidomide and dexamethasone) treatment is 81% at a median follow-up of 56.2 months
(Facon, 2021). A sample size of approximately 50 subjects in Cohort J2 and up to approximately 
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75 subjects each for Cohorts J1 and K (with up to approximately 25 subjects in each of the three 
CC-220 dose levels) is considered clinically adequate to explore the preliminary efficacy, safety, 
and PK profile of CC-220Vd and CC-220Dd in this patient population. Summaries of subject 
disposition, demographic and baseline disease characteristics, treatment exposure, efficacy, 
safety, PK, and Pd will be provided. Categorical data will be summarized by frequency 
distributions (number and percent of subjects) and continuous data will be summarized using 
descriptive statistics (means, standard deviations, medians, minimums, and maximums).  
Severity of Treatment-emergent AEs (TEAEs) will be summarized by National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.0. The frequency of 
TEAEs will be tabulated by Medical Dictionary for Regulatory Activities (MedDRA) Version 18 
or higher by system organ class and preferred term.  Selected laboratory analytes, vital signs, and 
12-lead ECGs will be summarized.  All data will also be presented in by-subject listings.
Investigator response assessments will be used to determine the response outcome throughout the 
study. An IRC may also be set up to review efficacy data from Part 2 RRMM Cohorts C, D, 
and/or I. The IRC will determine the tumor response to therapy based on the IMWG uniform 
Response Criteria as well as time of response (including PD) for each subject. The IRC will 
adjudicate efficacy data according to the IRC Charter.
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TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
PROTOCOL SUMMARY ..........................................................................................................7
1.
INTRODUCTION..................................................................................................37
1.1.
Disease Background ...............................................................................................37
1.2.
Compound Background ..........................................................................................38
1.2.1.
CC-220...................................................................................................................38
1.2.1.1.
Mechanism of Action of CC-220 ............................................................................38
1.2.1.2.
Nonclinical Experience...........................................................................................38
1.2.1.3.
Overview of Nonclinical Pharmacokinetics ............................................................40
1.2.1.4.
Overview of Nonclinical Toxicology......................................................................42
1.2.1.5.
Clinical Experience.................................................................................................43
1.2.2.
Dexamethasone ......................................................................................................43
1.3.
Rationale ................................................................................................................43
1.3.1.
Immunomodulating Compounds in Multiple Myeloma ...........................................43
1.3.2.
Daratumumab.........................................................................................................44
1.3.3.
Bortezomib.............................................................................................................46
1.3.4.
Carfilzomib ............................................................................................................46
1.3.5.
CC-220 in Multiple Myeloma.................................................................................47
1.3.6.
Rationale for Dose, Schedule and Regimen Selection .............................................47
1.3.6.1.
Dose of CC-220 in MonoT (Cohort A) and DoubleT (Cohort B).............................47
1.3.6.2.
Dose of CC-220 in Triplet Regimens (Cohorts E, F, G1 and G2) ............................48
1.3.6.3.
Rationale for Dose Increments in Dose Escalation..................................................48
1.3.6.4.
Rationale for Dose Levels in NDMM Cohorts J1 and K..........................................50
1.3.6.5.
Schedule.................................................................................................................50
1.3.6.6.
Regimen .................................................................................................................51
1.3.7.
Rationale for Choice of Combination Compounds ..................................................52
1.3.8.
Rationale for Pharmacodynamics and Potential Predictive Biomarkers ...................53
1.3.9.
Rationale for Cytogenetic Assessments...................................................................55
1.3.10.
Rationale for Minimal Residual Disease Assessments.............................................55
1.3.11.
Rationale for Cohort D Updated Design..................................................................56
1.3.12.
Rationale for Cohort I.............................................................................................56
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1.3.13.
Rationale for NDMM Cohorts (J1, J2, and K).........................................................57
1.3.14.
Rationale for Addition of Subcutaneous Daratumumab...........................................59
2.
STUDY OBJECTIVES AND ENDPOINTS...........................................................61
3.
OVERALL STUDY DESIGN ................................................................................66
3.1.
Study Design ..........................................................................................................66
3.1.1.
Dose Escalation (Part 1)..........................................................................................67
3.1.1.1.
Dose Escalation Committee....................................................................................68
3.1.1.2.
Dose-limiting Toxicity............................................................................................69
3.1.2.
Expansion (Part 2)..................................................................................................69
3.2.
Study Duration for Subjects....................................................................................73
3.3.
End of Trial ............................................................................................................73
4.
STUDY POPULATION.........................................................................................74
4.1.
Number of Subjects ................................................................................................74
4.2.
Inclusion Criteria....................................................................................................74
4.3.
Exclusion Criteria...................................................................................................77
5.
TABLE OF EVENTS.............................................................................................81
6.
PROCEDURES....................................................................................................125
6.1.
Screening Period...................................................................................................125
6.2.
Treatment Period ..................................................................................................127
6.2.1.
End of Treatment Visit .........................................................................................128
6.2.2.
28-Day Post Treatment Visit.................................................................................130
6.2.3.
Post Treatment Response Assessment...................................................................130
6.2.4.
Long-term Follow-up............................................................................................130
6.3.
Efficacy Assessment.............................................................................................130
6.3.1.
Bone Marrow Aspirate and/or Biopsy...................................................................132
6.3.2.
Bone Lesion Assessment ......................................................................................135
6.3.3.
Extramedullary Plasmacytoma Assessments.........................................................136
6.3.4.
Assessment of Response.......................................................................................136
6.3.5.
Independent Response Committee (IRC) Assessment ...........................................136
..137
..137
..137
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137
6.5.
Pharmacokinetics..................................................................................................138
6.6.
Biomarkers, Pharmacodynamics and Pharmacogenomics .....................................140
7.
DESCRIPTION OF STUDY TREATMENTS......................................................145
7.1.
Description of Investigational Product(s)..............................................................145
7.2.
Treatment Administration and Schedule ...............................................................146
7.2.1.
Treatment Schedule ..............................................................................................146
7.2.1.1.
Part 1 (Dose Escalation)........................................................................................146
7.2.1.2.
Part 2 (Expansion) ................................................................................................149
7.2.2.
Dexamethasone ....................................................................................................151
7.2.3.
Daratumumab.......................................................................................................151
7.2.3.1.
Subcutaneous Daratumumab.................................................................................152
7.2.4.
Carfilzomib ..........................................................................................................153
7.3.
Dose Reduction and Interruption ..........................................................................154
7.3.1.
Dose Modification Instructions for CC-220 ..........................................................155
7.3.2.
Dose Modification Instructions for Dexamethasone..............................................157
7.3.3.
Dose Modification Instructions for Daratumumab.................................................158
7.3.3.1.
Daratumumab Interruption or Missed Doses .........................................................159
7.3.4.
Dose Modification Instructions for Bortezomib ....................................................159
7.3.5.
Dose Modification Instructions for Carfilzomib....................................................160
7.4.
Overdose ..............................................................................................................163
7.4.1.
CC-220 Overdose .................................................................................................163
7.5.
Method of Treatment Assignment.........................................................................163
7.6.
Packaging and Labeling........................................................................................164
7.7.
Investigational Product Accountability and Disposal ............................................164
7.8.
Investigational Product Compliance......................................................................164
8.
CONCOMITANT MEDICATIONS AND PROCEDURES..................................165
8.1.
Permitted Concomitant Medications and Procedures.............................................165
8.2.
Prohibited Concomitant Medications and Procedures............................................165
8.3.
Required Concomitant Medications and Procedures..............................................167
9.
STATISTICAL CONSIDERATIONS ..................................................................169
9.1.
Overview..............................................................................................................169
9.2.
Study Population Definitions ................................................................................169
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9.3.
Sample Size and Power Considerations.................................................................169
9.4.
Subject Disposition...............................................................................................170
9.5.
Background and Demographic Characteristics......................................................170
9.6.
Medical History....................................................................................................171
9.7.
Concomitant Medications and Procedures.............................................................171
9.8.
Efficacy Analysis..................................................................................................171
9.8.1.
Overall Response Rate (ORR) ..............................................................................171
9.8.2.
Very Good Partial Response or Better Rate...........................................................171
9.8.3.
Time to Response (TTR) ......................................................................................171
9.8.4.
Response Duration (DoR).....................................................................................172
9.8.5.
Progression-free Survival (PFS)............................................................................172
9.8.6.
Overall Survival (OS)...........................................................................................172
9.9.
Safety Analysis.....................................................................................................172
9.10.
Interim Analysis ...................................................................................................173
9.11.
Other Topics.........................................................................................................173
9.11.1.
Pharmacokinetic Analysis.....................................................................................173
9.11.2.
Exploratory Analysis ............................................................................................174
.174
.174
174
10.
ADVERSE EVENTS............................................................................................175
10.1.
Monitoring, Recording and Reporting of Adverse Events .....................................175
10.2.
Evaluation of Adverse Events...............................................................................175
10.2.1.
Seriousness...........................................................................................................175
10.2.2.
Severity/Intensity..................................................................................................177
10.2.3.
Causality ..............................................................................................................177
10.2.4.
Duration ...............................................................................................................178
10.2.5.
Action Taken........................................................................................................178
10.2.6.
Outcome...............................................................................................................178
10.3.
Abnormal Laboratory Values................................................................................178
10.4.
Pregnancy.............................................................................................................179
10.4.1.
Females of Childbearing Potential ........................................................................179
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10.4.2.
Male Subjects.......................................................................................................180
10.5.
Reporting of Serious Adverse Events....................................................................180
10.5.1.
Safety Queries ......................................................................................................181
10.6.
Expedited Reporting of Adverse Events................................................................181
10.7.
Adverse Events of Special Interest........................................................................181
10.7.1.
Second Primary Malignancies (SPMs)..................................................................182
11.
DISCONTINUATIONS .......................................................................................183
11.1.
Treatment Discontinuation....................................................................................183
11.2.
Study Discontinuation ..........................................................................................183
12.
EMERGENCY PROCEDURES...........................................................................184
12.1.
Emergency Contact...............................................................................................184
12.2.
Emergency Identification of Investigational Products ...........................................184
13.
REGULATORY CONSIDERATIONS.................................................................185
13.1.
Good Clinical Practice..........................................................................................185
13.2.
Investigator Responsibilities .................................................................................185
13.3.
Subject Information and Informed Consent...........................................................186
13.4.
Confidentiality......................................................................................................186
13.5.
Protocol Amendments...........................................................................................186
13.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ..............................................................................................................186
13.7.
Ongoing Information for Institutional Review Board/ Ethics Committee ..............187
13.8.
Termination of the Study ......................................................................................187
14.
DATA HANDLING AND RECORDKEEPING...................................................189
14.1.
Data/Documents ...................................................................................................189
14.2.
Data Management.................................................................................................189
14.3.
Record Retention..................................................................................................189
15.
QUALITY CONTROL AND QUALITY ASSURANCE......................................191
15.1.
Study Monitoring and Source Data Verification....................................................191
15.2.
Audits and Inspections..........................................................................................191
15.3.
Product Quality Complaint ...................................................................................191
16.
PUBLICATIONS .................................................................................................193
17.
REFERENCES.....................................................................................................194
18.
APPENDICES......................................................................................................203
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Appendix A:
Table of Abbreviations ....................................................................................203
Appendix B:
International Myeloma Working Group Uniform Response Criteria 2016 ........209
Appendix C:
ECOG Performance Status...............................................................................213
Appendix D:
CC-220 Pregnancy Prevention Plan for Subjects in Clinical Trials...................214
..225
Appendix F:
Risk/Benefit Assessment ..................................................................................231
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LIST OF TABLES
Table 1:
Study Population ......................................................................................................7
Table 2:
Cohort and Dose Level Assignments for MonoT (Cohort A and C) and 
DoubleT (Cohort B, D and I)..................................................................................14
Table 3:
Cohort and Dose Level Assignments for Cohorts E, F, J1, J2 and K .......................15
Table 4:
Cohort and Dose Level Assignments for Cohorts G1 and G2..................................16
Table 5:
Estimated Median and Mean AUC0-τ (CV%) of CC-220 by Dose in RRMM 
Subjects (CC-220-MM-001)...................................................................................49
Table 6:
Observed CC-220 AUC0-τ (CV%) by Dose in Healthy Volunteers (CC-220-
CP-002)..................................................................................................................50
Table 7:
Study Objectives.....................................................................................................61
Table 8:
Study Endpoints .....................................................................................................62
Table 9:
Table of Events for Part 1 Cohorts A (monotherapy) and B (CC-220+DEX): 
28-day Cycle ..........................................................................................................81
Table 10:
Table of Events for Part 1 Cohort E (CC-220Dd): 28-day Cycle .............................86
Table 11:
Table of Events for Part 1 Cohort F (CC-220Vd): 21-day Cycle .............................91
Table 12:
Table of Events for Part 1 Cohort G1 (CC-220Kd once weekly): 28-day 
Cycle......................................................................................................................96
Table 13:
Table of Events for Part 1 Cohort G2 (CC-220Kd twice weekly): 28-day 
Cycle....................................................................................................................101
Table 14:
Table of Events for Part 2 Cohorts C (monotherapy), D, and I (CC-
220+DEX): 28-day Cycle .....................................................................................106
Table 15:
Table of Events for Part 2 Cohort J1 (CC-220Vd in NDMM and not eligible 
for ASCT) ............................................................................................................111
Table 16:
Table of Events: Part 2 Cohort J2 (CC-220Vd in NDMM and Eligible for 
ASCT): 21-day Cycle ...........................................................................................115
Table 17:
Table of Events for Part 2 Cohort K (CC-220Dd): 28-day Cycle...........................120
Table 18:
Bone Marrow Aspirate and/or Biopsy Sample Collection Plan..............................133
Table 19:
Daratumumab Pre- and Post-administration Medications......................................151
Table 20:
Conversion Table for Glucocorticoid Dose ...........................................................152
Table 21:
Dose Modification Instructions for CC-220 ..........................................................156
Table 22:
Dose Level Reduction (DLR) for CC-220.............................................................157
Table 23:
Dose Modification for Dexamethasone-related Toxicities .....................................158
Table 24:
Dose Level Reduction for Dexamethasone............................................................158
Table 25:
Daratumumab-related Toxicity Management ........................................................159
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Table 26:
Bortezomib Dose Modification.............................................................................160
Table 27:
Dose Level Reductions for Bortezomib.................................................................160
Table 28:
Carfilzomib Dose Modifications...........................................................................161
Table 29:
Dose Level Reductions for Carfilzomib ................................................................162
Table 30:
Medications that are CYP3A4/5 Strong Inhibitors and Inducers............................166
Table 31:
Stopping Rules for Cohort I..................................................................................173
Table 32:
Abbreviations and Specialist Terms......................................................................203
Table 33:
International Myeloma Working Group Uniform Response Criteria......................209
Table 34:
ECOG Performance Status....................................................................................213
Table 35:
Risk Assessment...................................................................................................232
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LIST OF FIGURES
Figure 1:
Comparison of Estimated CC-220 PK Exposure (AUC0-τ) in RRMM 
Subjects (CC-220-MM-001)...................................................................................49
Figure 2:
Overall Study Design..............................................................................................72
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1.
INTRODUCTION
1.1.
Disease Background 
Multiple myeloma (MM) is a B-cell neoplasm characterized by the malignant transformation of 
plasma cells and the accumulation of clonal plasma cells in the bone marrow (Kumar, 2018; 
Palumbo, 2011). The malignant proliferation of the plasma cell clone causes increasing levels of 
monoclonal protein (M-protein) in the serum and urine and may result in bone marrow failure, 
suppression of uninvolved immunoglobulin levels, and skeletal destruction. Clinical 
complications of progressive MM include recurrent infections, cytopenias, renal failure, 
hyperviscosity syndrome, hypercalcemia, bone pain, and pathologic fractures (Munshi, 2012). 
Despite a better understanding of the disease biology and the introduction of therapeutic options 
with new mechanisms of action, MM is not curable with current therapies. The overall 5-year 
relative survival rate was 52.2% in 2016 (Noone, 2018). Most subjects still experience disease 
relapse and require several lines of therapy, with the course of MM characterized by 
subsequently more aggressive disease and shorter periods of remission following sequential lines 
of treatment (Agarwal, 2017; Larocca, 2017; van de Velde, 2017; Moreau, 2017; Yong, 2016). 
For patients with newly diagnosed multiple myeloma (NDMM), the choice of initial therapy is 
determined by the patient’s age, fitness, and the presence of comorbidities (Kumar, 2018;
Ludwig, 2014; Moreau, 2017; Palumbo, 2015).  High-dose chemotherapy followed by 
autologous stem cell transplant (ASCT) has demonstrated superior outcomes compared with 
other treatment options and is the treatment of choice for patients with NDMM provided they are 
eligible, based on their age, comorbidities and functional status. The current optimal treatment 
paradigm for patients determined to be eligible for ASCT is initial induction therapy followed by 
treatment with high-dose chemotherapy and an ASCT, followed by maintenance treatment (with 
or without consolidation therapy). For those patients not considered eligible for ASCT, treatment 
with combination induction regimens including alkylators, proteasome inhibitors (PIs), 
immunomodulatory agents, steroids and novel agents are currently considered standard of care.  
Even with optimal upfront therapy the vast majority of MM subjects progress/relapse and further 
treatment is needed. For these relapsed and refractory (RRMM) subjects, treatment options have 
also improved over time. With the introduction of newer classes of approved anti-myeloma 
agents, including monoclonal antibodies (eg, daratumumab and elotuzumab), advanced 
generation PIs (eg, carfilzomib, ixazomib), immunomodulatory compounds (eg, pomalidomide) 
and histone deacetylase inhibitors (eg, panobinostat), RRMM subjects can expect some degree of 
response (Botta, 2017; Dimopoulos, 2016a; Dimopoulos, 2016b; Lonial, 2015; Moreau, 2016; 
Palumbo, 2016; San Miguel, 2014; Stewart, 2015). Unfortunately, despite these advances in the 
treatment of MM, the vast majority of the subjects will ultimately relapse regardless of treatment 
choice. Additionally, with each relapse, tumors typically recur more aggressively, leading to 
decreased response duration and ultimately leading to refractory MM, which is associated with 
shortened survival times. Additional safe and effective therapies are needed to improve long-
term survival for subjects with MM (Kumar, 2012).
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1.2.
Compound Background
1.2.1.
CC-220
1.2.1.1.
Mechanism of Action of CC-220 
Recent research on the mechanism of action of lenalidomide (LEN), pomalidomide (POM), and
thalidomide suggest that in tumor cells and T cells, these compounds bind cereblon, a component 
of an E3 ubiquitin ligase complex, to induce ubiquitination and degradation of the transcription 
factors Aiolos and Ikaros. Preclinical studies have shown that the loss of cereblon or a binding 
partner, such as deoxyribonucleic acid (DNA) damage-binding protein 1 (DDB1), decreases or 
eliminates the antitumor and immunomodulatory activity of lenalidomide and pomalidomide,
respectively (Gandhi, 2014; Ito, 2010; Lopez-Girona, 2012; Zhu, 2011). CC-220, structurally 
similar to the “-domide” class of drugs (including thalidomide, lenalidomide, and pomalidomide) 
also binds directly to cereblon, but with 20-fold higher potency than lenalidomide or 
pomalidomide (Report 2610; Matyskiela, 2018). Upon engagement with cereblon, the 
thalidomide analogs induce ubiquitination and proteasomal degradation of Ikaros (encoded by 
the gene Ikaros family zinc finger 1 [IKZF1]) and Aiolos (encoded by the gene Ikaros family 
zinc finger 3 [IKZF3]) (Gandhi, 2014; Krönke, 2014; Lu, 2014). Ikaros and Aiolos are key 
transcription factors regulating immune cell development and homeostasis (John, 2011). Aiolos 
and Ikaros have also recently been shown to be involved in the survival and function of tumor 
cells of the B-cell lineage, including multiple myeloma cells (tumor cells derived from antibody-
secreting plasma cells) (Lopez-Girona, 2012; Zhu, 2011), and activated B-cell-like diffuse large 
B-cell lymphoma (DLBCL) (tumor cells derived from the antibody-secreting 
plasmablasts) (Yang, 2012). In addition, Aiolos and Ikaros are also involved in regulating
cytokine release from T cells, including interleukin-2 (IL-2) and tumor necrosis factor-alpha 
(TNF-α) (Lopez-Girona, 2012).
Therefore, through more potent binding of cereblon and modulation of its function within the 
DDB1 and Cullin 4A (DDB1-CUL4A) ubiquitin ligase complex to induce degradation of Aiolos 
and Ikaros, CC-220 may be able to suppress the detrimental effects of malignant plasma cells 
and induce anti-tumor T-cell responses. Treatment of human whole blood with CC-220 has been 
shown to result in reduced expression of Aiolos and Ikaros proteins in lymphocytes, 
granulocytes, and monocytes (Aiolos) in vitro (Report 7637-007), with the effect in total 
lymphocytes, B cells, and T cells being time-and-concentration-dependent. Significant 
reductions in Aiolos and Ikaros proteins were observed as early as 1 hour after treatment 
initiation, with as little as 10 nM CC-220. Over time, Aiolos and Ikaros degradation continued to 
increase in lymphocytes, eventually exceeding 90% reduction at 18 hours in the presence of 1μM 
CC-220.
1.2.1.2.
Nonclinical Experience
1.2.1.2.1. Antiproliferative Activity
1.2.1.2.1.1. Effects on Tritiated Thymidine Incorporation in Cultured Normal Cells
The effect of CC-220 on cell growth in primary normal human aortic smooth muscle cells 
(AoSMC) and normal human lung fibroblasts (NHLF) was assessed (Report 5827-34). The half 
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maximal inhibitory concentration (IC50) for inhibition of 3H-thymidine incorporation was > 10 
μM in both cell types. Results indicated that CC-220 did not inhibit cell growth in normal 
primary human nonimmune cells (Report 5827-34).
CC-220 was also tested for its effects on anti-immunoglobulin M (IgM)-induced 3H-thymidine 
incorporation into normal CD19 + B cells. Incubation of CD19 + B cells with CC-220 was 
associated with an increase in 3H-thymidine incorporation in a 5-day assay. However, B-cell 
proliferation was quite low in these 5-day cultures and 3H-thymidine incorporation in the control 
cells decreased considerably over the 5-day assay period. The increase in thymidine 
incorporation in CD19 + B cells exposed to CC-220 on Day 5 reflected a protection of normal B 
cells from apoptosis. The results suggest that CC-220 promoted immunomodulatory effects and, 
under B cell stimulation conditions (anti-IgM), led to a protection of normal B cells from 
apoptosis.
1.2.1.2.1.2. Multiple Myeloma Cell Lines
The effect of CC-220 on myeloma cell proliferation was investigated using 16 human MM cell 
lines (HMCLs) representative of the genetic and phenotypic heterogeneity of ΜM (Report 
201006C-V1). CC-220 had potent antiproliferative activity in 12 of the MM cell lines, with IC50 
values ranging from < 0.1 nM in the Mm’s multiple myeloma line to 320 nM in the XF 2
multiple myeloma cell line. Sensitivity of HMCLs to concentration-dependent growth inhibition 
by CC-220 was independent of the genetic background of the ΜM line. Four cell lines were not 
sensitive to growth inhibition by CC-220, including the JIM-3 and XF-7 lines.
In additional investigations, the antiproliferative activity of CC-220 in lenalidomide-sensitive 
and lenalidomide-refractory MM cell lines was also investigated (Report 2610). CC-220 
inhibited cell growth in the 4 lenalidomide-refractory subclones (IC50 values ranging from 0.51 
to 1.58 μM) after incubation with the cells for 5 days, although with lower potency than 
exhibited in the parent H929 MM cell line (IC50 = 0.01 μM) or the dimethyl sulfoxide (DMSO)-
treated subclone (IC50 = 0.04 μM).
1.2.1.2.1.3. Natural Killer Cell Activity Against Diffuse Large B Cell Lymphoma Cell 
Lines
Natural killer (NK) cells play an important role in innate immunity. Activated NK cells lyse 
tumor cells and virus-infected cells. Interleukin-2 has been shown to activate NK cells, thereby 
contributing to the innate immune response against tumors and virally infected cells.  
CC-220 enhanced NK cell interferon-gamma (IFN-γ) production in response to stimulation with 
IL-2 in the presence of immobilized immunoglobulin G (IgG) in a concentration-dependent 
manner (Report 5707-134). The concentration of CC-220 providing 50% of maximal production 
(EC50) of IFN-γ was 12 nM.
The potential of CC-220 to enhance a second human NK cell killing activity, antibody dependent 
cellular cytotoxicity (ADCC), was assessed using rituximab-coated cells from several different 
lymphoma cell lines. The level of cytotoxicity in the presence of 100 nM CC-220 was enhanced 
relative to rituximab alone in the DoHH2 follicular lymphoma cell line (double; 58% vs 26%), 
the Farage diffuse large B cell lymphoma (DLBCL) cell line (nearly quadruple; 44% vs 12%), 
the WSU-DLCL2 DLBCL cell line (55% vs 26%), the Riva DLBCL line (56% vs 24%), and the 
Raji Burkitt’s lymphoma cell line (43% vs 31%).
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1.2.1.2.1.4. B Cell Immunomodulation
The expression of transcription factors Aiolos and Ikaros in peripheral blood mononuclear cells 
(PBMC) in vitro was found to be sensitive to nanomolar concentrations of CC-220 (Report 7637-
007). Reduction of Ikaros protein expression in human B cells, T cells, and total lymphocytes 
was time and concentration-dependent. Significant reductions in Aiolos and Ikaros proteins in 
lymphocytes were observed as early as 1 hour after treatment initiation, with as little as 10 nM 
CC-220. Over time, Aiolos and Ikaros degradation in lymphocytes continued to increase, 
eventually exceeding 90% reduction at 18 hours in the presence of 1 μM CC-220. Reduction of 
Ikaros protein also occurred in granulocytes and monocytes as well, and reduction of Aiolos 
production was observed in monocytes.
1.2.1.2.1.5. T Cell Immunomodulation
The T-cell immunomodulatory activity of CC-220 was evaluated in an anti-CD3-stimulated 
human T-cell assay that measured secreted levels of cytokines and chemokines released (Report 
5802-148). In the presence of T-cell stimulatory antibody, concentrations of CC-220 as low as 1 
nM enhanced production of the IL-2, IL-3, IL-5, IL-13, IFN-γ, granulocyte-macrophage colony 
stimulating factor, RANTES (regulated upon activation, normal T cell expressed and secreted), 
and TNF-α. Costimulation of T cells with CC-220 had the greatest impact on production of IL-2, 
which was enhanced 14- to 19-fold at concentrations of 10 nM to 10 μM CC 220.  
For further information, refer to the CC-220 Investigator Brochure (IB). 
1.2.1.3.
Overview of Nonclinical Pharmacokinetics
A battery of in vitro and in vivo studies have been conducted to characterize the absorption, 
pharmacokinetics (PK), distribution, and metabolism of CC-220. Robust and reproducible 
bioanalytical methods for the quantitation of CC-220 levels were developed and used in PK and 
toxicokinetic studies. 
Pharmacokinetics, oral bioavailability and tissue distribution (only rat) of CC-220 were 
evaluated in Sprague-Dawley rats, Cynomolgus monkeys as well as female rabbits. The systemic 
clearance of CC-220 was moderate both in rats and monkeys (approximately 1/2 to 1/5 hepatic 
blood flow). The volume of distribution was high in rats (approximately 5-fold of the body water 
volume) but moderate in monkeys (approximately 2-fold of the body water volume), suggesting 
good tissue distribution of CC-220. The terminal half-life (t1/2) of CC-220 was approximately 2.8 
to 6.8 hours in rats and approximately 1.5 hours in monkeys. Following a single or multiple oral 
dosing of CC-220 in rats, monkeys and female rabbits, the exposure of CC-17195 
(R-enantiomer) was low CC-220 (≤ 11.4% of CC-220) suggesting low in vivo chiral inversion of 
CC-220 to its R-enantiomer. Following oral dosing to animals, CC-220 was rapidly absorbed and 
the median time to maximum plasma concentration of drug (Tmax) generally ranged from 0.5 to 
2.0 hours post-dose. CC-220 exhibited ≥ 60% oral bioavailability in rats and 20% in monkeys.
Generally, following single or multiple oral doses of CC-220 to rats, systemic exposures were 
slightly higher (30% to 110%) in females than in males. However, in monkeys, no consistent sex 
differences in exposures were observed following multiple dosing. In rats and rabbits, the 
systemic exposure of CC-220 increased in an approximately dose proportional manner and no
notable accumulation was observed. In monkeys, the systemic exposure of CC-220 increased in 
a greater than dose-proportional manner, and there was some accumulation observed 
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(accumulation ratio of 1.0 to 2.6). Following oral administration of racemate (CC-16915) to rats 
and monkeys, the systemic exposures of CC-17195 (R-enantiomer) were generally lower than 
CC-220 free base (S-enantiomer) suggesting higher clearance of R-enantiomer. 
Following a single oral administration of [14C]CC-220 to rats, CC-220 derived radioactivity was 
widely distributed into tissues, with most tissue concentrations peaking between 0.5 to 2 hours, 
followed by rapid decrease to below quantifiable levels by 120 hours. CC-220 demonstrated a 
reversible melanin binding affinity to pigmented tissue in rats such as uveal tract. There was 
minimal distribution of radioactivity into brain of rats. Following oral administration of 
[14C]CC-220 to rats or monkeys, excretion of radioactivity was rapid and nearly complete 
(>90%). In rats and monkeys, the predominant route of elimination of radioactivity was in the 
feces. Majority of the absorbed drug was excreted via the bile as metabolites into feces and the 
excretion of intact drug was a minor component in monkeys and represented ≤19% of dose in 
rats.
Following multiple oral doses of CC-220 to female pregnant rabbits, the placental transfer of 
CC-220, determined as a ratio of fetal-to-maternal plasma concentrations, was very low (0.0227 
to 0.0368) suggesting limited fetal exposure to CC-220.
Plasma protein binding of CC-220 was moderate in mouse, rat, monkey and human but high in 
female rabbit. No notable differences were observed in plasma protein binding over the 
concentration ranges tested, suggesting no saturation of plasma protein binding. Blood to plasma 
concentration ratios ranged from approximately 0.7 to 1.3, suggesting minimal preferential 
partitioning into blood cells.
In vitro, CC-220 was subjected to extensive biotransformations in hepatocytes of multiple 
species. In human and animal species, CC-220 was subjected to multiple oxidative metabolism, 
primarily on the morpholino ring, resulting in the formation of N-oxide (M1) and keto derivative 
(M12), as well as other morpholino ring transformation products. CC-220 also underwent non-
enzymatic hydrolysis of the imide bonds in cell-free media, with approximately 20% hydrolysis 
formed in a 4-hour incubation. Qualitatively all metabolites formed in human hepatocytes were 
also formed in hepatocytes of rat or monkey, the two species used for preclinical safety testing. 
Oxidative metabolism in CC-220 was mediated by cytochrome (CYP) 3A4/5 isozymes.
In vivo, metabolism of CC-220 was evaluated following oral dose of [14C]CC-220 in rats and 
monkeys. Intact CC-220 was the predominant circulating component, representing >72% and 
47% of plasma radioactivity in rats and monkeys respectively. The absorbed drug was excreted 
as metabolites of CC-220 and excretion of intact drug was minor. In vivo metabolism of CC-220 
was consistent with in vitro profiles, and the primary metabolic pathway was oxidation of the 
morpholino functional group, hydrolysis of glutarimide ring of parent and oxidized metabolites 
as well as a combination of these pathways.  
CC-220 did not show notable inhibition or induction of CYP enzymes. Therefore, CC-220 is 
unlikely to precipitate clinically relevant pharmacokinetic drug-drug interactions due to 
inhibition or induction of CYP enzymes when co-administered with CYP substrates. CC-220 is a 
substrate for both permeability glycoprotein (P-gp) and breast cancer resistance protein (BCRP).  
CC-220 is a weak inhibitor of P-gp (IC50 >50 µM) and a moderate inhibitor of BCRP (IC50 = 
22.3 µM). CC-220 is projected to be administered at low doses. Hence, the gut or systemic 
concentrations of CC-220 are likely to be lower than the IC50; therefore, CC-220 is not 
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anticipated to cause any clinically relevant drug-drug interactions due to inhibition of these 
transporters.
1.2.1.4.
Overview of Nonclinical Toxicology
To date, CC-220 toxicities have been evaluated in a series of repeat-dose toxicity studies (up to 6 
months in Sprague-Dawley rats and up to 9 months in Cynomolgus monkeys), safety 
pharmacology and genetic toxicity studies in vitro and in vivo and a dose range finding 
embryofetal development (EFD) study in pregnant New Zealand White rabbits. The rat and 
Cynomolgus monkey were chosen as the standard rodent and nonrodent species for in vivo 
safety studies based on the comparative metabolic patterns in humans. In addition, monkeys 
following CC-220 treatment produced pharmacodynamic (Pd) effects comparable to those 
observed in healthy human volunteers.
In rats, no CC-220-related adverse effects were noted at the highest dose of 20 mg base/kg/day 
(no-observed-adverse-effect-level [NOAEL]) after 6 months of dosing. CC-220 mean systemic 
exposures of 16100 and 21900 ng•hr/mL for males and females, respectively.
In monkeys, multiple systemic effects of CC-220 observed were primarily due to its 
pharmacologic effects on the immune system. These changes were observed in blood and 
lymphatic organs (decreased peripheral blood B, T, and natural killer (NK) cells as well as 
monocytes, altered cellularity in the B and T cell areas, and increased/altered heterogeneous cell 
mixtures in lymphoid organs), gastrointestinal tract (unformed/watery stool leading to decreased 
body weight gain and increased magnitude of subacute/chronic inflammation in cecum/colon), 
eye (increased incidence of minimal mononuclear cell infiltrates in the uveal tract), and bone 
marrow (myeloid hyperplasia). The impact of CC-220 treatment on humoral responses (either 
enhancement or attenuation) to keyhole limpet hemocyanin (KLH) in monkeys was dependent 
on the timing of immunization in relation to the timing of CC-220 dosing. Additional CC-220-
related effects in monkeys were observed in pancreas (degranulation/atrophy in acinar cells), 
testes/epididymides (bilateral hypospermatogenesis along with increased spermatogenic 
epithelial cell debris in epididymal lumen), liver (biliary epithelial hypertrophy/hyperplasia with 
mononuclear/mixed inflammatory cell infiltrates), lungs (increased alveolar macrophages and 
decreased goblet cell secretion in trachea), and salivary glands (decreased serous cell secretion 
ie, decreased acinar cell granules). Among all CC-220-related systemic effects in monkeys, only 
peripheral blood B-cell count was differentially affected by different dose schedules with the 
greatest decrease noted upon once daily (QD) dosing.
Overall, adverse effects of frequent unformed/watery stools and body weight loss requiring 
palliative care, marked decrease in peripheral blood B cells, significantly decreased cellularity in 
lymphoid organs and bilateral hypospermatogenesis were observed at 0.40 mg base/kg/day in the 
9-month oral toxicity study in monkeys. Thus, the NOAEL in this study was 0.12 mg 
base/kg/day with a mean area under the curve over 24 hours (AUC24hr) of 77.6 ng•hr/mL.
The death of one monkey at 0.75 mg base/kg/day on Day 22 of the 1-month dose schedule study 
was associated with central nervous system (CNS)-related clinical signs and diffused 
astrogliosis. These CNS findings in a single animal were unlikely to be causally related to CC-
220 based on the lack of CNS-related effects in monkeys receiving doses of up to 1, 0.75, and 
0.4 mg base/kg/day for 1, 3, and 9 months, respectively.
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CC-220 was not mutagenic in the Ames assay. CC-220 was positive in 1 of 3 experimental 
conditions in the in vitro clastogenicity assay; however, CC-220 was negative in the in vivo 
genetic toxicity studies in rats (micronucleus formation in bone marrow and DNA damage in 
liver [Comet assay]). These negative results from an in vivo study generated weight of evidence 
that was considered sufficient to demonstrate a lack of significant genotoxicity risk with CC-220 
in humans.
In the CNS safety pharmacology study of rats, no CC-220-related effects on the CNS functions 
were noted at doses up to 50 mg base/kg, the highest dose evaluated (no-observed-effect-level 
[NOEL]). In an exploratory hERG (human ether à go related gene) study with CC-17220 (free 
base of CC-220) with concentrations up to 100 μM, the IC50 (the concentration of CC-220 
required for 50% inhibition of the hERG ion channel currents) was determined to be 91.4 µM 
(41 μg/mL). In monkeys administered CC-220 up to 1 mg base/kg, the highest dose evaluated, 
no changes in cardiovascular functions and no adverse effects on respiratory functions were 
observed. Therefore, 1 mg base/kg/day is the NOEL for cardiovascular function and the no-
observed-adverse-effect-level (NOAEL) for respiratory function in monkeys.
In a dose-range finding EFD toxicity study in pregnant rabbits, no CC-220-related maternal 
toxicity was noted at a dose range of 1 to 50 mg base/kg/day. CC-220 related developmental 
toxicities (decreased mean fetal body weight, increased incidences of small thymus and fused 
sternebrae) were observed primarily at 50 mg base/kg/day.
In conclusion, toxicology profile of CC-220 adequately supports the conduct of clinical trials in 
RRMM patients receiving CC-220 upon chronic treatment duration. Please refer to the IB for 
detailed descriptions of the findings from nonclinical PK and toxicology studies of CC-220.
1.2.1.5.
Clinical Experience 
Please refer to the IB for detailed information concerning the available pharmacology, 
toxicology, drug metabolism, clinical studies and adverse event (AE) profile of the 
investigational product (IP). Please refer to Appendix F. 
1.2.2.
Dexamethasone
Dexamethasone, a synthetic adrenal corticosteroid, has been used in North America and in the 
European Union (EU) for relapsed MM and has been widely used in combination with novel 
agents in several studies of relapsed/refractory and newly diagnosed MM (Richardson, 2005).
The potential synergistic antiproliferative activities of immunomodulatory compounds (IMiDs) 
and dexamethasone (DEX) have been previously established in both in vitro and in 
vivo (Gandhi, 2010; ImnovidTM SmPC; Pomalyst® PI; Revlimid® PI; Revlimid™SmPC; 
Thalidomide™SmPC; Thalomid® PI). 
1.3.
Rationale
1.3.1.
Immunomodulating Compounds in Multiple Myeloma
Thalidomide analogs, lenalidomide and pomalidomide are key components in the treatment of 
hematological malignancies through their actions on cereblon (Zhu, 2011). All three cereblon-
binding compounds (thalidomide, lenalidomide and pomalidomide) are approved for use in the 
treatment of MM, and lenalidomide is approved for the treatment of mantle cell lymphoma and 
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myelodysplastic syndrome. These compounds are currently under investigation for a number of 
other hematologic malignancies.
The immunomodulatory effect of thalidomide, lenalidomide and pomalidomide, was soon 
recognized as a major determinant of their anti-MM activity (Davies, 2001). IMiDs are now 
incorporated into therapies for RRMM and newly-diagnosed MM (NDMM) due to a series of 
approvals based on their remarkable clinical activity (Benboubker, 2014; Richardson, 2014; 
Richardson, 2006b; San-Miguel, 2013).
Immunomodulating compounds (IMiDs®) may affect the immune system in several ways, such 
as inducing immune response, enhancing activity of immune cells, altering and modulating the 
induction of pro-and anti-inflammatory cytokines, and inhibiting inflammation. IMiDs are also 
antiangiogenic. Although their precise mechanism of action is currently under investigation, 
these agents offer promise for their anticancer and anti-inflammatory activities.
Refer to the approved drug labels for detailed information.
1.3.2.
Daratumumab
Daratumumab (DARA) is a human IgG1k monoclonal antibody that binds with high affinity to a 
unique epitope on CD38. It is a targeted immunotherapy that attacks tumor cells that overexpress 
CD38, a transmembrane glycoprotein, in a variety of hematological malignancies including 
multiple myeloma. 
In the United States (US), Darzalex® injection for intravenous use (IV DARA) is approved for 
the treatment of adult patients with MM:

in combination with lenalidomide and dexamethasone in newly diagnosed patients 
who are ineligible for autologous stem cell transplant and in patients with RRMM 
who have received at least one prior therapy

in combination with bortezomib, melphalan and prednisone in newly diagnosed 
patients who are ineligible for autologous stem cell transplant

in combination with bortezomib, thalidomide, and dexamethasone in newly 
diagnosed patients who are eligible for autologous stem cell transplant

in combination with bortezomib and dexamethasone in patients who have received at 
least one prior therapy

in combination with carfilzomib and dexamethasone in patients who have received 
one to three prior lines of therapy

in combination with pomalidomide and dexamethasone in patients who have received 
at least two prior therapies including lenalidomide and a proteasome inhibitor

as monotherapy, in patients who have received at least three prior lines of therapy 
including a proteasome inhibitor (PI) and an immunomodulatory agent or who are 
double-refractory to a PI and an immunomodulatory agent
Darzalex FasproTM (daratumumab and hyaluronidase-fihj; SC DARA), for SC use is approved in 
the US for the treatment of adult patients with MM: 
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
in combination with bortezomib, melphalan and prednisone in newly diagnosed 
patients who are ineligible for ASCT

in combination with lenalidomide and dexamethasone in newly diagnosed patients
who are ineligible for ASCT and in patients with RRMM who have received at least 
one prior therapy 

in combination with bortezomib, thalidomide, and dexamethasone in newly 
diagnosed patients who are eligible for ASCT

in combination with bortezomib and dexamethasone in patients who have received at 
least one prior therapy

in combination with pomalidomide and dexamethasone in patients who have received 
at least one prior line of therapy including lenalidomide and a PI

as monotherapy, in patients who have received at least three prior lines of therapy 
including a PI and an immunomodulatory agent or who are double-refractory to a PI 
and an immunomodulatory agent
In the European Union (EU), IV DARA is approved:

in combination with lenalidomide and dexamethasone or with bortezomib, melphalan 
and prednisone for the treatment of adult patients with newly diagnosed multiple 
myeloma who are ineligible for autologous stem cell transplant

in combination with bortezomib, thalidomide and dexamethasone for the treatment of 
adult patients with newly diagnosed multiple myeloma who are eligible for 
autologous stem cell transplant

in combination with lenalidomide and dexamethasone, or bortezomib and 
dexamethasone, for the treatment of adult patients with multiple myeloma who have 
received at least one prior therapy

as monotherapy for the treatment of adult patients with relapsed and refractory 
multiple myeloma, whose prior therapy included a PI and an immunomodulatory 
agent and who have demonstrated disease progression on the last therapy
Subcutaneous DARA is approved in the EU for the treatment of subjects with MM:

in combination with lenalidomide and dexamethasone or with bortezomib, melphalan 
and prednisone for the treatment of adult patients with NDMM who are ineligible for 
ASCT

in combination with bortezomib, thalidomide and dexamethasone for the treatment of 
adult patients with NDMM who are eligible for ASCT

in combination with lenalidomide and dexamethasone, or bortezomib and 
dexamethasone, for the treatment of adult patients with MM who have received at 
least one prior therapy

as monotherapy for the treatment of adult patients with RRMM, whose prior therapy 
included a PI and an immunomodulatory agent and who have demonstrated disease 
progression on the last therapy
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Please refer to the current label for more information (Darzalex PI; Darzalex SmPC; Darzalex 
Faspro PI).
1.3.3.
Bortezomib
Bortezomib is a proteasome inhibitor. It is specifically designed to inhibit the chymotrypsin-like 
activity of the 26S proteasome in mammalian cells. The 26S proteasome is a large protein 
complex that degrades ubiquitinated proteins. Bortezomib mediated proteasome inhibition 
affects cancer cells in a number of ways, including, altering regulatory proteins, which control 
cell cycle progression and nuclear factor kappa B (NF-kB) activation. Inhibition of the 
proteasome results in cell cycle arrest and apoptosis. NF-kB is a transcription factor whose 
activation is required for many aspects of tumorigenesis, including cell growth and survival, 
angiogenesis, cell-cell interactions, and metastasis.
In the United States (US), bortezomib is authorized for the treatment of subjects with multiple 
myeloma (Velcade® PI). In the European Union (EU), bortezomib is authorized as monotherapy 
or in combination with pegylated liposomal doxorubicin or dexamethasone in adult subjects who 
have received at least 1 prior therapy and who have already undergone or are unsuitable for stem 
cell transplantation. In the NDMM setting, bortezomib is authorized in combination with 
lenalidomide and dexamethasone (Revlimid SmPC), or melphalan and prednisone in subjects 
with previously untreated multiple myeloma who are not eligible for transplant, and in 
combination with dexamethasone or with thalidomide and dexamethasone as initial treatment for 
adult subjects with previously untreated MM who are eligible for transplant (Velcade SmPC).  
1.3.4.
Carfilzomib
Carfilzomib (CFZ) is a tetrapeptide epoxyketone proteasome inhibitor that irreversibly binds to 
the N-terminal threonine-containing active sites of the 20S proteasome, the proteolytic core 
particle within the 26S proteasome, and displays little to no activity against other protease 
classes. Carfilzomib exhibits antiproliferative and proapoptotic activities in preclinical models in 
hematologic tumors. In animals, carfilzomib inhibits proteasome activity in blood and tissue and 
delayed tumor growth in models of multiple myeloma.
In the United States, carfilzomib is approved for use in combination with dexamethasone or with 
lenalidomide plus dexamethasone for the treatment of subjects with relapsed or refractory 
multiple myeloma who have received one to three lines of therapy. It is also approved as a single 
agent for the treatment of subjects with relapsed or refractory multiple myeloma who have 
received at least one line of therapy, and more recently the Food and Drug Administration (FDA)
approved a once-weekly dosing option of carfilzomib to use in combination with dexamethasone 
for subjects with RRMM (Kyprolis® PI).
In the EU, carfilzomib is approved for use in combination with dexamethasone or with 
lenalidomide plus dexamethasone for the treatment of subjects with RRMM who have received 
at least one prior therapy (Kyprolis SmPC).
Please refer to the current CFZ label for more information (Kyprolis PI; Kyprolis SmPC).
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1.3.5.
CC-220 in Multiple Myeloma
CC-220 is an orally available novel cereblon-modulating agent that has multiple effects on cells 
of the immune system, including immune cell tumors, B cells and T cells, as well as nonimmune 
cell types such as fibroblasts and endothelial cells. CC-220 has immunomodulatory activity on 
both lymphoid and myeloid cells and demonstrate antifibrotic activity.
CC-220 shares a similar mechanism of action with lenalidomide and pomalidomide but has 
increased potency and unique pharmacokinetic properties. Based on these properties, CC-220 is 
expected to show improved efficacy and tolerability in the treatment of MM.
Please refer to the CC-220 IB for detailed information.
1.3.6.
Rationale for Dose, Schedule and Regimen Selection 
The primary objective in Part 1 of this study is to determine the maximum tolerated doses 
(MTDs) and/or recommended phase 2 dose (RP2D) of CC-220 as monotherapy (MonoT), in 
combination with DEX (DoubleT), and in combination with DEX and DARA, bortezomib 
(BTZ), or CFZ (in triplet regimen).
1.3.6.1.
Dose of CC-220 in MonoT (Cohort A) and DoubleT (Cohort B)
The starting dose of 0.3 mg QD is supported by the Phase 1 data that showed 0.3 mg QD x 28-
day dosing was well tolerated in healthy subjects and exhibited sustained effects on multiple Pd 
parameters.
Dose levels and dose schedule of CC-220 for evaluation in the CC-220-MM-001 study are based 
on data from two completed studies in healthy adults (CC-220-CP-001 and CC-220-CP-002) and 
preliminary safety data from the CC-220-SLE-001 study. 
Study CC-220-CP-001 was a Phase 1 study to evaluate the safety, tolerability, PK, and Pd of a 
single oral dose of 0.03; 0.1; 0.3; 1; 2; 4; and 6 mg CC-220. CC-220 was well tolerated by 
healthy subjects when CC-220 was administered as single doses up to 6 mg.
Study CC-220-CP-002 was a Phase 1 study to evaluate the safety, tolerability, PK, and Pd of 
multiple oral doses of CC-220.  Various multiple oral dose regimens of CC-220 were evaluated: 
0.3 mg QD for 14 days; 1 mg QD for 28 days; 0.3 mg QD for 28 days; 1 mg QD for 7 days 
followed by a washout of 7 days and a further 7 days of treatment with 1 mg QD; 0.3 mg once 
every 3 days x 14 days for 5 total doses; and 1 mg once every 7 days x 28 days for 4 total doses. 
During the CC-220-CP-002 study, three subjects experienced a dose-limiting toxicity of Grade 3 
neutropenia after 3 weeks of continuous 1 mg QD dosing with CC-220 (after the Day 21 visit). 
The dosing of all subjects in that cohort was discontinued during study Week 4 and this dose 
(CC-220 1 mg QD, continuous) was established as a non-tolerated dose. Per discontinuation of 
dosing with CC-220, the decreased neutrophil counts in these subjects recovered to normal or to
low but not clinically significant values by the Day 28 visit.  
Please refer to the IB for detailed information concerning the available pharmacology, 
toxicology, drug metabolism, clinical studies and adverse events profile of CC-220.
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1.3.6.2.
Dose of CC-220 in Triplet Regimens (Cohorts E, F, G1 and G2)
As of 11 January 2019, 8 dose levels (0.3, 0.45, 0.6, 0.75, 0.9,1,1.1, and 1.2 mg) of CC-220 in 
combination with DEX (Cohort B) were explored. One out of six evaluable subjects in the 1.2 
mg dose level experienced a DLT of Grade 4 sepsis. Based on the protocol dose escalation 
criteria, the Dose Escalation Committee (DEC) recommended to continue the per protocol dose 
escalation of CC-220 in combination with dexamethasone.
The starting dose of CC-220 in triplet regimen cohorts (Cohorts E, F, G1, and G2) will be one 
dose level below the maximum dose level of CC-220 that has been determined to be safe in 
Cohort B. Since there were no DLTs observed in the 1.1 mg dose level, the DEC has approved 1
mg (one dose level below 1.1 mg) CC-220 as the starting dose in combination with IV DARA
and DEX for Cohort E and in combination with BTZ and DEX for Cohort F. The starting dose of 
CC-220 in combination with CFZ and DEX for Cohorts G1 and G2 will be 1.1 mg (one dose 
level below 1.2 mg).
1.3.6.3.
Rationale for Dose Increments in Dose Escalation
CC-220 has been dosed up to 6 mg in a single ascending dose study (CC-220-CP-001) and 1 mg 
QD in a multiple ascending dose study (CC-220-CP-002) in healthy volunteers. The geometric 
mean Cmax and AUCs increased in a dose proportional manner from 0.3 mg to 6 mg and the 
geometric mean coefficient of variation (CV%) ranged from approximately 20%-40% after a 
single dose and at steady state. Population PK analysis on pooled healthy volunteer and RRMM 
data demonstrates that RRMM subjects treated with CC-220 display similar exposure and PK 
characteristics as healthy volunteers, with slight increases in variability (Refer to Figure 1,
Table 5 and Table 6).
In the present study, at doses above 0.9 mg, dosing ascends in increments of 0.1 mg. Based on 
estimated PK parameters from this study’s data, historical data variability, and the less than 10% 
increases in dose, clinically significant differences in exposure are not being achieved with 0.1 
mg dose escalations.
In addition, preliminary data generated from the dose finding part of the present study thus far 
has reported a favorable safety profile of CC-220 as monotherapy and in combination with DEX 
in heavily pretreated subjects with RRMM who failed multiple prior therapies. As of 11 January 
2019, a total 83 subjects have been treated with CC-220 at doses ranging from 0.3 to 1.2 mg, 
including 25 subjects in Cohort A (monotherapy) and 58 subjects in Cohort B (CC-220 + DEX). 
To date, the MTD/RP2D of CC-220 has not yet been reached at the dose levels studied in any 
cohort. Two DLTs, Grade 3 lower respiratory tract infection and Grade 4 neutropenia, were 
observed in Cohort A at the 0.75 and 0.9 mg dose levels, respectively. One DLT of Grade 4 
sepsis was observed in Cohort B at the 1.2 mg dose level. Consequently, 3 additional subjects 
were enrolled into each cohort dose level per the protocol DLT/MTD definition criteria. No 
further DLTs were observed, thus dose escalation in both cohorts is ongoing.  
In Cohort A (monotherapy), the most frequently occurring Grade 3/4 AEs were neutropenia 
(36%), infections (24%), anemia (20%), and thrombocytopenia (12%). In Cohort B (CC-220 + 
DEX), the most frequently occurring Grade 3/4 AEs included neutropenia (26%), anemia (23%), 
infections (19%), and thrombocytopenia (11%). 
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Protocol CC-220-MM-001
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Therefore, based on the totality of the data, dose increases of up to 25% as determined by the 
DEC are implemented for subsequent dose level explorations.
Figure 1:
Comparison of Estimated CC-220 PK Exposure (AUC0-τ) in RRMM 
Subjects (CC-220-MM-001)
Abbreviations: AUC0-τ = area under the concentration-time curve over the dosing interval; PK = 
pharmacokinetic; RRMM = relapsed/refractory multiple myeloma.
Box plot: The lower and upper edges of the box represent the 25th and the 75th percentiles, respectively. 
Whiskers indicate the maximum and minimum, respectively. The black line represents the median and the 
red circles represent the observed data. The red circles outside the whiskers represent the outliers.
Table 5:
Estimated Median and Mean AUC0-τ (CV%) of CC-220 by Dose in RRMM 
Subjects (CC-220-MM-001)
Treatment
N
Median AUC0-τ
(ng*hr/ml)
Mean AUC0-τ
(ng*hr/ml) (CV%)
0.3 mg
13
20.64
22.4 (20.9)
0.45 mg
7
27.36
37.87 (59.2)
0.6 mg
7
52.80
51.63 (41.4)
0.75 mg
9
54.24
52.56 (17.1)
0.9 mg
15
64.80
76.51 (45.2)
1.0 mg
8
69.0
65.31 (29.3)
1.1 mg
3
73.20
107.4 (76.8)
Abbreviations: AUC0-τ = area under the concentration-time curve over the dosing interval; CV = coefficient of 
variation; N = number of subjects; RRMM = relapsed/refractory multiple myeloma.
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Table 6:
Observed CC-220 AUC0-τ (CV%) by Dose in Healthy Volunteers (CC-220-
CP-002)
Treatment
N
Mean AUC0-τ (ng*hr/ml) 
(CV%)
0.3 mg
6
14.78(29.0)
1 mg
5
71.78 (39.4)
Abbreviations: AUC0-τ = area under the concentration-time curve over the dosing interval; CV = coefficient of 
variation; N = number of subjects.
1.3.6.4.
Rationale for Dose Levels in NDMM Cohorts J1 and K
The 1.0 mg, 1.3 mg and 1.6 mg dose levels of CC-220 are selected for further evaluation in 
combination with bortezomib and dexamethasone (Cohort J1) and in combination with 
daratumumab and dexamethasone (Cohort K) in NDMM subjects not eligible for transplant. 
Some key data from the CC-220-MM-001 study have been taken into consideration for the 
selection of these 3 dose levels to be further investigated in Part 2 of the study:

 
 
 

While CC-220 showed pharmacodynamic activity at all doses tested, activity in the 
immune compartment showed dose dependent trends in Cohort B (CC-
220+dexamethasone) that appeared to be saturating between the 1.0 and 1.6 mg 
doses. However, in Cohort E (CC-220Dd) and Cohort F (CC-220Vd), 
pharmacodynamic activity in the immune compartment at the 1.0 mg dose appeared 
lower than the 1.3 or 1.6 mg dose, suggesting peak immune activity of CC-220 may 
require a higher dose in combination with either daratumumab or bortezomib.

 
 
 

The CC-220 exposure (ie, AUCss) increased in a dose-related manner with a 
moderate variability (approximately 46% [CV%]) over the tested dose range (0.3 mg 
to 1.6 mg) based on the popPK analysis. Given the extent of PK variabilities, the 
interval between the proposed doses (1.0 mg, 1.3 mg and 1.6 mg) will likely mitigate 
exposure overlaps and cover a wide range of exposures for dose optimization.
1.3.6.5.
Schedule
A 21 out of 28-day treatment cycle for CC-220 was supported by data from a Celgene 
translational development study, “In Vitro Evaluation of Effect of CC-220 on Neutrophil 
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Maturation.” This study reported that continuous dosing of CC-220 blocked neutrophil 
differentiation with no significant impact on proliferative capacity or viability of these cells. This 
effect could be only slightly mitigated by reducing CC-220 exposure to 5 out of 7 days per week 
to reflect a 2-day drug holiday in the clinic. Complete CC-220 removal for 5 days was necessary 
to fully restore normal maturation of neutrophils. This data suggests that a 21/28-day schedule is 
a more appropriate starting schedule for this Phase 1 study.
For Cohort E (CC-220 + DARA + DEX), a 21 out of 28-day treatment cycle for CC-220 will be 
kept in accordance with the approved label for Darzalex in RRMM (Darzalex PI; Darzalex
SmPC; Darzalex Faspro PI).
For Cohort F (CC-220 + BTZ + DEX), a 14 out of 21-day treatment cycle for CC-220 will be 
implemented in accordance with the approved label for Velcade® in RRMM (Velcade PI; 
Velcade SmPC).
For Cohorts G1 and G2 (CC-220 + CFZ + DEX), a 21 out of 28-day treatment cycle for CC-220 
will be implemented in accordance with the approved label for Kyprolis® in RRMM (Kyprolis
PI; Kyprolis SmPC).
For Cohort I (CC-220 + DEX), a 21 out of 28-day treatment cycle for CC-220 will be 
implemented.
For Cohort J1 (CC-220 + BTZ + DEX), a 14 out of 21-day treatment cycle for CC-220 will be 
implemented according to the standard of care for Velcade for the first 8 cycles (Velcade PI; 
Velcade SmPC). Thereafter, after the discontinuation of bortezomib, a 21 out of 28-day 
treatment cycle for CC-220 + DEX will be implemented. 
For Cohort J2 (CC-220 + BTZ + DEX), a 14 out of 21-day treatment cycle for CC-220 will be 
implemented according to the standard of care for Velcade (Velcade PI; Velcade SmPC).
For Cohort K (CC-220 + DARA + DEX), a 21 out of 28-day treatment cycle for CC-220 will be 
kept in accordance with the approved label for Darzalex and Darzalex Faspro (Darzalex Faspro 
PI; Darzalex SmPC).
1.3.6.6.
Regimen
CC-220 Monotherapy (MonoT)
CC-220 has not previously been tested in vivo in MM; therefore, in order to gain data on single-
agent safety and potential efficacy, a CC-220 monotherapy arm has been included. 
Subjects assigned to MonoT, Cohort A (Part 1) or Cohort C (Part 2) who develop PD will have 
the option to receive DEX in addition to CC-220 after consultation with the Medical Monitor. 
The subject’s dose of CC-220 will not be higher than the dose of CC-220 in combination with 
DEX tested in Cohort B (Part 1) that is considered safe or the same as the RP2D in Cohort D 
(Part 2). The site will be informed of the dose of CC-220 to be administered when DEX is added. 
Progressive disease must be confirmed in accordance with IMWG criteria. The starting dose of 
DEX will be 40 mg on Days 1, 8, 15 and 22 of each 28-day cycle for subjects who are ≤75 years 
of age. For subjects who are > 75 years of age, the starting dose of DEX is 20 mg on Days 1, 8, 
15 and 22 of each 28-day cycle. Subjects who surpass the age of 75 years while on treatment 
may be switched to the 20 mg dosage based on the Investigator’s best judgement. This treatment 
will continue until PD, unacceptable toxicity or the subject withdraws consent. 
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CC-220 with Dexamethasone (DoubleT)
The potential synergistic antiproliferative activities of IMiDs and DEX have been previously 
established in both in vitro and in vivo (Gandhi, 2010; Imnovid SmPC; Pomalyst PI; Revlimid
PI; Revlimid SmPC; Thalidomide SmPC; Thalomid PI).
CC-220 with Dexamethasone and Daratumumab, Bortezomib, or Carfilzomib
The potential synergistic activities of CC-220 with DEX and DARA, BTZ, or CFZ have been 
observed in preclinical data and are further detailed in Section 1.3.7 below. 
1.3.7.
Rationale for Choice of Combination Compounds 
Please refer to Section 1.2.2, Section 1.3.2, Section 1.3.3, and Section 1.3.4 for information on 
the specific compounds. 
CC-220 with Daratumumab and Dexamethasone 
Daratumumab is a human IgG1k monoclonal antibody that targets CD38, a transmembrane 
receptor with enzymatic activity that is highly and consistently expressed on the surface of 
myeloma cells (Deaglio, 2007). Daratumumab induces directed myeloma cell killing through 
complement-dependent cytotoxicity, antibody-dependent cell cytotoxicity, and other potential 
mechanisms (Lokhorst, 2015). Clinical studies of daratumumab in combination with IMiD 
compounds have shown these combinations to be well tolerated with impressive efficacy in the 
relapsed myeloma setting (Dimopoulos, 2017b; Facon, 2017; Plesner, 2016) and more recently, 
in the newly diagnosed setting (Facon, 2021). Preclinical studies of CC-220 have shown 
remarkable immunomodulatory activity including enhanced IL-2 secretion and granzyme-b 
degranulation in stimulated peripheral blood mononuclear cells when compared to other IMiD 
compounds (Bjorklund, 2016). Furthermore, in co-culture systems using myeloma and immune 
cells, CC-220 has shown to significantly increase the antibody-dependent cellular cytotoxicity 
activity of daratumumab. Based on these preclinical data and the impressive clinical activity of 
daratumumab and IMiD compound combination therapy, the addition of daratumumab to CC-
220 therapy could be a highly effective regimen in newly diagnosed and relapsed/refractory MM, 
and therefore, is chosen for further investigation.
CC-220 with Bortezomib and Dexamethasone
Preclinical data have shown synergistic antimyeloma activity between IMiD compounds and 
bortezomib (Katz, 2018). The tolerability and activity of combination therapy with IMiD 
compounds and bortezomib has also shown very promising results in clinical studies in both the 
front-line and relapsed/refractory MM setting (Richardson, 2018; Richardson, 2010; Richardson, 
2011). CC-220, like IMiD compounds, has cereblon modulating activity that results in the 
proteasome dependent degradation of the transcription factors Aiolos and Ikaros. While the 
mechanism of action of CC-220 and BTZ may suggest antagonism, preclinical studies in 
myeloma cell lines have shown CC-220, like immunomodulatory compounds, has synergistic 
antiproliferative activity in combination with bortezomib (Amatangelo, 2018). Furthermore, CC-
220 treatment has been shown to induce degradation of Aiolos and Ikaros in the presence of 
bortezomib and lead to deeper cell killing in combination with bortezomib than other 
combinations of IMiD compounds and bortezomib. Based on these preclinical data and the 
positive clinical activity of combination therapy with bortezomib and IMiD compounds, the 
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Protocol CC-220-MM-001
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addition of bortezomib to CC-220 therapy could be a highly effective regimen in newly 
diagnosed and relapsed/refractory MM, and therefore, is chosen for further investigation.
CC-220 with Carfilzomib and Dexamethasone
Clinical and preclinical data support the synergistic activity with proteasome inhibitors and 
immunomodulatory compounds. CFZ is approved for the treatment of RRMM with lenalidomide 
and DEX based on the results of the ASPIRE trial (Siegel, 2018). In preclinical models CC-220 
has been shown to induce degradation of Aiolos and Ikaros faster than other immunomodulatory
compounds. The improved potency observed of CC-220 may confer greater efficacy than other 
immunomodulatory compounds in combination with more potent proteasome inhibitors such as 
CFZ. Improved outcomes with CFZ vs BTZ in RRMM suggests the addition of CFZ to CC-220 
therapy could be highly effective in relapsed/refractory MM, and therefore, is chosen for further 
investigation (Dimopoulos, 2016b).
The objective of Cohorts G1 and G2 is to determine the MTD and/or RP2D of CC-220 in 
combination with DEX and CFZ, at the optimal dose and schedule of CFZ. In each cohort, 
different approved CFZ dosing schemes (weekly and twice weekly) will be evaluated by the 
DEC.  
Cohort G1 will implement a weekly regimen of CFZ, based on the results of the A.R.R.O.W. 
study which compared CFZ with DEX once weekly at 70 mg/m² versus twice weekly at 27 
mg/m² in patients with RRMM (Moreau, 2018). In the weekly regimen, CFZ was given as 70 
mg/m² on Days 1, 8, 15, and 22 of a 28-day cycle. Accordingly, Cohort G1 dose level 1 will 
evaluate a starting CFZ dose of 56 mg/m2 on Days 1, 8, 15, 22 and if deemed tolerable by the 
DEC, may be increased to 70 mg/m² in dose level 2. For subsequent dose levels, the DEC will 
determine the appropriate CFZ dose given once weekly in combination with DEX and with 
escalating doses of CC-220.
Cohort G2 may be opened to implement a twice weekly regimen of CFZ, which was 
implemented in the ENDEAVOR and ASPIRE trials (Dimopoulos, 2016b; Siegel, 2018).
ENDEAVOR was a phase 3 trial comparing CFZ with DEX vs BTZ with DEX, using a CFZ 
regimen of 56 mg/m2 given on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. The ASPIRE trial 
compared CFZ with LEN and DEX versus LEN and DEX using a twice weekly CFZ regimen 
given as 27 mg/m2 on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Accordingly, in Cohort G2 
dose level 1, CFZ will be given at 27 mg/m2 on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. If 
tolerated, the next dose level will evaluate CFZ at a dose of 56 mg/m2 on Days 1, 2, 8, 9, 15, and 
16 of a 28-day cycle. For subsequent dose levels, the DEC will determine the appropriate CFZ 
dose given twice weekly in combination with DEX and escalating doses of CC-220.
1.3.8.
Rationale for Pharmacodynamics and Potential Predictive Biomarkers 
Recent research on the mechanism of action of lenalidomide, pomalidomide and thalidomide 
suggest that in tumor cells and T cells, cereblon, a component of an E3 ubiquitin ligase complex, 
is a target for binding by these compounds. CC-220 also binds directly to cereblon, thus resulting 
in induced ubiquitination of the protein substrates Ikaros (encoded by the gene IKZF1) and 
Aiolos (encoded by the gene IKZF3) and degradation of these proteins. Preclinical studies have 
shown that the loss of cereblon or a binding partner, such as DDB1, decreases or eliminates the 
antitumor and immunomodulatory activity of lenalidomide and pomalidomide 
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respectively (Gandhi, 2014; Ito, 2010; Lopez-Girona, 2012; Zhu, 2011). A number of recent 
studies have reported correlation between baseline (pretreatment level of cereblon measured by 
gene expression or by immunohistochemical methods) to clinical outcomes in subjects treated 
with regimens containing lenalidomide, pomalidomide or thalidomide.  
In addition, the measurement of cereblon (and other potential biomarkers, like Ikaros, Aiolos, 
and CD38) and its utility for determining response during treatment with CC-220 (as 
monotherapy, doublet, and triplet therapy) is an open scientific question. Thus, we would like to 
use validated assays for both gene and protein expression and measure baseline and on-treatment 
biomarker levels, to investigate any potential correlation to clinical outcomes. Additionally, we 
will evaluate tumor cytogenetics, gene mutations, and gene expression profiles of MM tumors in 
order to investigate correlations to response and possible identification of patient populations 
more likely to benefit from CC-220 based therapies.
In preclinical studies with lenalidomide and pomalidomide, immune-modulatory effects on T 
cells, natural killer (NK) cells, and monocytes have been observed (Gorgun, 2010; Gandhi, 
2014). Clinical studies in RRMM patients treated with Pom/Dex show an increase in T cells and 
NK cells, along with a decrease in B cells during therapy (Sehgal, 2015).  The effects of CC-220 
treatment on immune cells in myeloma patients is uncertain. Thus, analysis of CC-220 
modulation of immune cell populations, immune cell function and T-cell diversity will also be 
evaluated. 
Results from biomarkers will be evaluated in association with parameters of clinical benefit to 
determine if biomarkers predictive of response or resistance to CC-220 may be identified.  
Statistical analysis will be conducted to determine any correlations with selected markers to 
efficacy and safety parameters including response rate, duration of response, and disease 
progression. In subjects where biomarkers are available during the Treatment phase, changes 
from the baseline will be examined. These data will be associated with the clinical parameters 
noted above to identify potential mechanisms of CC-220 activity. Prognostic markers that 
identify high-risk disease or identify/classify subtypes of disease will also be assessed. Trends 
between CC-220 exposure and indices of response such as relevant Pd biomarkers, efficacy 
endpoints and/or safety endpoints will be explored.
T-cell based therapies are a promising approach for treating MM that have shown success against 
leukemia and lymphoma (Maus, 2014). Chimeric antigen receptors (CARs) T-cells, are T-cells 
engineered to express fusion proteins with an antigen-recognition domain and a T-cell activating 
domain (Sadelain, 2013). Expression of CARs by T-cells redirects the specificity and function of 
these cells and induces their expansion upon repeated antigen exposure in the disease setting.  
Autologous CAR-T cell products with an antigen recognition domain targeting B-cell maturation 
antigen (BCMA), a protein expressed mostly by normal and malignant plasma cells, have 
recently shown great promise in treating high-risk myeloma patients who have run out of 
treatment options (Berdeja, 2017; Brudno, 2018). However, some patient’s disease still 
progresses after receiving BCMA chimeric antigen receptor T-cell therapy (CAR T) therapy, 
despite continued BCMA expression by malignant plasma cells (Ali, 2016). Therefore, 
investigation of strategies to increase CAR-T cell therapy durability are actively ongoing.  
Recent reports have highlighted that variations in individual patient’s T-cell profile during CAR-
T cell product apheresis and injection may be related to the efficacy and durability of CAR-T cell 
immunotherapy (Fraietta, 2018; Xu, 2014). We have observed that treatment with CC-220 
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affects T-cell profiles in patients, including increasing proportions of proliferating CD4+ and 
CD8+ T-cells, increasing proportion of effector memory T-cells and increasing proportion of 
activated T-cells. It is unknown if these changes in T-cells increase the quality of CAR-T product 
produced from MM patients. Therefore, the preclinical efficacy of research use only CAR-T 
products produced from subject’s T-cells before and after treatment with CC-220 will be 
assessed to understand if CC-220 pretreatment improves the anti-MM efficacy of CAR-T 
products against MM cell lines.
1.3.9.
Rationale for Cytogenetic Assessments
The prognosis of and treatment options for MM patients depend on a variety of factors. Strong 
prognostic factors for patients with MM include age/frailty, International Staging System and 
adverse-risk cytogenetics. Chromosomal abnormalities of t(4;14) or del 17p are known to be 
associated with shortened overall and progression-free survival (Fonseca, 2009). More recently, 
the IMWG (International Myeloma Working Group) have published a consensus 
recommendation on high-risk cytogenetic abnormalities including t(4;14), del 17p, t(11;14), 
t(14;20), gain 1q, del 1p, del 13q, and ploidy status (Sonneveld, 2016). While cytogenetic data 
may help identify high-risk/poor prognostic patients, identification of cytogenetic abnormalities 
may vary between different study groups and clinical sites due to differences in processing and 
analysis. These inconsistencies may impede robust analysis of cytogenetic data in studies where 
data is obtained from multiple sites. Standardized central lab processing and analysis of 
cytogenetic data will facilitate robust analysis of the clinical benefit of CC-220 in patients with 
cytogenetically defined high-risk disease where effective treatment options are limited.
1.3.10.
Rationale for Minimal Residual Disease Assessments
Data from several studies of recently approved agents/regimens have demonstrated impressive 
clinical benefits with deep responses and long progression-free survival (PFS) and overall 
survival (OS) in both newly diagnosed multiple myeloma (NDMM) and RRMM. Identifying 
early readouts of clinical benefit for MM patients is now crucial for development of novel 
compounds. Initial minimal residual disease (MRD) data from a study of 52 RRMM patients 
showed that achievement of MRD-negative status prolonged time to progression (Paiva, 2015). 
Recently, two Phase 3 RRMM clinical trials provided the first randomized, controlled, 
prospective evaluation of MRD in this setting (Avet-Loiseau, 2016). Data from the 
POLLUX (Dimopoulos, 2016a) and CASTOR (Palumbo, 2016) trials indicated that the
daratumumab, lenalidomide and dexamethasone (DRd) and daratumumab, bortezomib and 
dexamethasone (DVd) regimens resulted in significantly higher rates of MRD-negative status at 
10-4, 10-5, and 10-6 thresholds as assessed by Adaptive’s ClonoSEQ next generation sequencing
assay (Adaptive Biotechnologies, Seattle, WA, United States) (Avet-Loiseau, 2016). Patients 
who achieved MRD-negative status at 10-5 had fewer PFS events compared to patients who 
were MRD positive. For patients who achieved ≥ complete response (CR), the rate of MRD-
negative status was at least 3-fold higher across all sensitivity thresholds in the DRd/DVd versus 
lenalidomide and dexamethasone (Rd)/bortezomib and dexamethasone (Vd) control arms. These 
data in RRMM are consistent with earlier data in NDMM indicating clinical benefit with 
achievement of MRD-negative status. In addition, these data demonstrated that achievement of 
MRD-negative status predicts similar outcomes independent of treatment regimen received, 
which is consistent with earlier observations from smaller studies in NDMM (Avet-Loiseau, 
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2016; Landgren, 2016). These data suggest that MRD status may be an early readout associated 
with improved clinical outcomes. Additionally, MRD may serve as a tool for monitoring subjects 
as an early indicator of relapse. Therefore, the level of MRD will be evaluated in subjects 
receiving CC-220 and achieving a response of very good partial response (VGPR) or better.
1.3.11.
Rationale for Cohort D Updated Design 
As of 11 January 2019, 58 subjects received CC-220 plus DEX in doses ranging from 0.3 to 1.2 
mg in Cohort B. The median age was 64.5 years (range 33–79), and median number of prior 
regimens was 5 (2–12). Prior therapies included autologous stem cell transplant (79%), LEN 
(100%), pomalidomide (POM) (69%), PIs (100%), and DARA (66%). Median duration of 
therapy was 12+ weeks (range 4–109). Grade 3–4 AEs were reported in 41 (72%) subjects. The 
most frequently occurring Grade 3/4 AEs included neutropenia (26%), anemia (23%), infections 
(19%), and thrombocytopenia (11%). Of the 51 efficacy-evaluable subjects, 16 achieved a PR or 
better (31%), 26 minimal response (MR) or better (51%), and 45 achieved stable disease or 
better (88%). 
Data generated from the dose finding part of this study has reported preliminary favorable 
efficacy and safety of CC-220 plus DEX in heavily pretreated subjects with RRMM who failed 
multiple prior therapies. Once the RP2D is established for Cohort B and expansion is determined 
by the DEC, Part 2 may be initiated to further evaluate the efficacy and safety of CC-220 plus 
DEX in Cohort D. This part of the study will implement a group sequential design (refer to 
Section 3.1 for further details). As of 18 Oct 2019, the DEC has recommended the 1.6 mg dose 
level as the RP2D for CC-220 plus DEX.
1.3.12.
Rationale for Cohort I
B-cell maturation antigen (BCMA), a member of the tumor necrosis factor receptor family, is 
exclusively expressed on the surface of plasmablasts, differentiated plasma cells, malignant 
plasma cells a subset of memory B cells, but is absent in early B cells, hematopoietic stem cells 
and other normal tissues (Laabi, 1994; Novak, 2004). BCMA binds to B-lymphocyte stimulator 
(BLyS), also known as B cell-activating factor (BAFF), and a proliferation-inducing ligand 
(APRIL), both critical proteins supporting the growth and survival of malignant plasma cells in 
MM (Tai, 2016). These data suggest BCMA may be a very promising target for the treatment of 
MM.
Currently, there are multiple BCMA-targeted treatment modalities being investigated to treat 
MM, including: antibody drug conjugates (ADC), bispecific T-cell engagers, CARTs, bispecific 
and bi/trispecific antibodies, as well as cancer vaccines (Cho, 2018). The development of novel 
agents targeting BCMA is ongoing and data from early clinical trials have demonstrated 
significant anti-myeloma activity in heavily pre-treated RRMM subjects. Notably, CAR Ts 
targeting BCMA have demonstrated encouraging results (Raje, 2019). In the 51 subjects who 
received bb2121 as of 17 Dec 2018 with a median of 5.8 months of follow-up, the objective 
response rate was 78.4% (95% confidence interval [CI]: 64.7, 88.7). Twenty subjects (39.2%) 
achieved a confirmed complete response or better. The median duration of response was 10.9 
months (95% CI: 7.5, 13.7). The median progression-free survival was 10.2 months (95% CI: 
5.9, 12). BCMA targeting bispecific T-cell engager (BiTE) immunotherapies have also shown 
promising results, in a phase I dose escalation study of AMG 420 there was a 70% response rate 
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(7/10) with 5 out of 7 responders achieving a sCR at 400 µg/d, the recommended dose for further 
investigation (Topp, 2019).
Despite encouraging results, BCMA-targeted therapy is not curative, and the vast majority of 
subjects will ultimately relapse, thus highlighting the need for effective novel therapies in the 
post-BCMA setting. Cohort I will enroll up to 40 subjects who have received prior BCMA-
targeted therapy to explore the safety and preliminary efficacy of CC-220 plus DEX in this 
patient population. As CAR T therapy is anticipated to be a standard of care option in the future, 
Cohort I targets to enroll a minimum of 40% of subjects with prior BMCA-targeted CAR T 
therapy to ensure adequate representation of this population.
1.3.13.
Rationale for NDMM Cohorts (J1, J2, and K)
For patients with NDMM, the choice of initial therapy is determined by the patient’s age, fitness, 
and the presence of comorbidities (Kumar, 2018; Ludwig, 2014; Moreau, 2017; Palumbo, 2015). 
High-dose chemotherapy followed by ASCT has demonstrated superior outcomes compared with 
other treatment options and is the treatment of choice for patients with NDMM provided they are 
eligible, based on their age, comorbidities and functional status. The current optimal treatment 
paradigm for patients determined to be eligible for ASCT is initial induction therapy followed by 
treatment with high-dose chemotherapy and ASCT, followed by maintenance treatment (with or 
without consolidation therapy). For those patients not considered eligible for ASCT, treatment 
with combination induction regimens including alkylators, proteasome inhibitors, 
immunomodulatory agents, steroids and novel agents are currently considered standard of care. 
Progress has been made in improving the overall survival in NDMM patients. The increase in 
survival has been driven by more effective combination induction regimens composed primarily 
of proteasome inhibitors, immunomodulatory agents and dexamethasone (Kumar, 2017; Moreau, 
2017; Rajkumar, 2016).  
SWOG S0777 was a Phase 3, multicenter, randomized, open-label, active-controlled efficacy 
and safety study of RVd (lenalidomide in combination with bortezomib and dexamethasone)
versus Rd (lenalidomide in combination with dexamethasone) for initial treatment in subjects 
with NDMM without intent for immediate ASCT.  Patients were randomly assigned to receive 6 
months of primary therapy with either RVd (eight 3-week cycles) or Rd (six 4-week cycles), 
each followed by maintenance therapy with Rd until progression or unacceptable toxicity. The 
group treated with RVd showed a significantly longer PFS of 43 versus 30 months (hazard ratio 
[HR], 0.712; 95% CI, 0.56–0.906) and improved median overall survival (OS) of 75 versus 64 
months (HR, 0.709; 95% CI, 0.524–0.959) (Durie, 2017). Based on the significant improvement 
in PFS and OS seen with RVd, this regimen was included in the NCCN clinical practice 
guidelines as a preferred option for the primary treatment of transplant-eligible and non–
transplant-eligible patients with NDMM and in the European Society for Medical Oncology
(ESMO) clinical guidelines as a major treatment regimen in front-line NDMM (Kumar, 2018; 
Moreau, 2017).
The MAIA trial randomly assigned 737 NDMM patients who were ineligible for ASCT to 
receive either daratumumab plus lenalidomide and dexamethasone (DRd) or lenalidomide and 
dexamethasone alone (Rd). Treatment was to continue until the occurrence of disease 
progression or unacceptable side effects. At a median follow-up of 56.2 months, the addition of 
daratumumab to lenalidomide and dexamethasone significantly decreased the risk of disease 
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progression or death (hazard ratio for PFS, 0.53; 95% CI, 0.43 to 0.66; P<0.0001). The 
percentage of patients with a complete response or better was 51% in the DRd group versus 30% 
in the Rd group (P<0.0001). A total of 31% of the patients in the DRd group, as compared with 
10% of the patients in the Rd group had undetectable minimal residual disease at the 10-5
threshold (Facon, 2021). Based on the results from this trial, the DRd regimen is approved in the 
EU (Darzalex SmPC) and the US (Darzalex PI; Darzalex Faspro PI), and listed as a preferred 
regimen (category 1) as primary therapy for non-transplant candidates by the NCCN guidelines 
(NCCN Guidelines, 2021).
Despite a better understanding of the disease biology and the introduction of new and 
mechanistically different therapeutic options, MM is not curable with current therapies; thus, 
there is still a need to develop more efficacious and less toxic treatments for front line treatment 
(Willenbacher, 2018). As described in Section 1.3.7, preclinical studies in myeloma cell lines 
have shown CC-220, like immunomodulatory compounds, has synergistic antiproliferative 
activity in combination with bortezomib (Amatangelo, 2018). CC-220 treatment in combination 
with bortezomib induces deeper degradation of Aiolos and Ikaros and more robust cell killing 
than IMiD compounds in combination with bortezomib. Furthermore, in preclinical models CC-
220 has been shown to induce degradation of Aiolos and Ikaros with faster kinetics than other 
IMiD compounds. As described in Section 1.3.7, CC-220 has also shown to significantly 
increase the antibody-dependent cellular cytotoxicity activity of daratumumab in co-culture 
systems using myeloma and immune cells.
Data generated from the CC-220-MM-001 study has reported favorable tolerability and
promising clinical activity for CC-220Vd in subjects with RRMM.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Similarly, data generated from the study has reported favorable tolerability and promising 
clinical activity for CC-220Dd in subjects with RRMM.
 
 
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Taken together, based on the preclinical synergy data, the positive clinical activity of 
combination therapy with bortezomib and IMiD compounds in the NDMM setting, and on the 
favorable tolerability and encouraging preliminary efficacy of CC-220 plus DEX, the addition of 
bortezomib to CC-220 therapy may represent a highly effective regimen in NDMM subjects who 
are eligible for ASCT and those who are not eligible for ASCT, and therefore, is chosen for 
further investigation. In addition, based on the preclinical data, the clinical activity of 
combination therapy of an IMiD with daratumumab in NDMM and on the favorable tolerability 
of daratumumab and CC-220 plus DEX, the addition of daratumumab to CC-220 therapy may 
represent a highly effective regimen in NDMM subjects who are not eligible for ASCT, and 
therefore, is chosen for further investigation.
1.3.14.
Rationale for Addition of Subcutaneous Daratumumab 
A new formulation of DARA for SC administration was developed to avoid the long infusion 
time and infusion reactions associated with IV administration of DARA. A recombinant human 
hyaluronidase PH20 (rHuPH20) was used to facilitate the SC administration of DARA in order 
to decrease the volume required for SC administration.
The safety and efficacy profile of SC DARA monotherapy was evaluated in COLUMBA, an 
open-label, randomized, non-inferiority Phase 3 study in subjects with RRMM. In this study, 263 
subjects were randomized to receive SC DARA 1800 mg, coformulated with 30,000 units 
hyaluronidase administered subcutaneously, and 259 subjects were randomized to receive 
DARA 16 mg/kg administered intravenously; each administered weekly for Cycles 1 and 2,
every two weeks for Cycles 3 through 6 and every 4 weeks from Cycle 7 onwards. SC DARA 
was shown to be non-inferior to IV DARA in terms of ORR, with both having similar safety 
profiles. In addition, SC DARA had a lower rate of injection-related reactions (IRRs) (Mateos, 
2019).
The SC formulation of DARA in combination with standard MM treatment regimens was also 
investigated in the PLEIADES study, a multi-cohort, open-label, Phase 2 study. In this study, the
safety and efficacy of SC DARA in combination with lenalidomide and DEX (DRd) in RRMM
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subjects with > 1 prior line of therapy and in combination with bortezomib, melphalan, and 
prednisone (DVMP) in NDMM subjects who are ineligible for transplant were evaluated. The 
safety profiles in both cohorts were consistent with those observed with DARA IV. Rates of 
IRRs and injection site reactions were consistent with those observed with SC DARA 
monotherapy in the COLUMBA study. The PK of SC DARA in each regimen was consistent 
with historical data and the immunogenicity of DARA and hyaluronidase were comparable to 
previous reports (Chari, 2019).
As SC DARA is anticipated to be a standard of care option in the future, the combination of CC-
220, SC DARA and DEX will be investigated in this study. Please refer to the current label for 
more information (Darzalex Faspro PI; Darzalex SmPC).
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2.
STUDY OBJECTIVES AND ENDPOINTS
Table 7:
Study Objectives
Primary Objective
The primary objective in Part 1 of the study is to determine the maximum tolerated doses (MTDs) and/or 
recommended Phase 2 doses (RP2Ds) of CC-220 as monotherapy (MonoT), in combination with 
dexamethasone (DEX) (DoubleT), in combination with dexamethasone and daratumumab (CC-220Dd), 
in combination with DEX and bortezomib (CC-220Vd), and in combination with DEX and carfilzomib
(CC-220Kd) in subjects with relapsed and refractory multiple myeloma (RRMM).
The primary objective in Part 2 of the study is to determine the efficacy of CC-220 in combination with 
DEX (DoubleT) in subjects with RRMM in Cohort D, as measured by overall response rate (ORR).
Secondary Objective(s)
The secondary objectives are:

To evaluate the safety of CC-220 as MonoT, DoubleT, CC-220Dd, CC-220Vd, and CC-220Kd in 
subjects with RRMM.

To evaluate the preliminary efficacy and safety of CC-220Vd and CC-220Dd in subjects with 
NDMM, including subjects who are eligible for ASCT and subjects who are not eligible for 
ASCT.

To evaluate additional efficacy parameters of CC-220 in combination with DEX including time-
to-response (TTR), duration of response (DOR), progression-free survival (PFS), and overall 
survival (OS) in subjects with RRMM in Cohort D.

To assess the preliminary efficacy of CC-220 as MonoT, DoubleT, CC-220Dd, CC-220Vd, and 
CC-220Kd in subjects with RRMM in Part 1.

To assess the preliminary efficacy and safety of CC-220 in combination with DEX in subjects 
with RRMM who have received prior B-cell maturation antigen (BCMA)-targeted therapy.

To evaluate the pharmacokinetics (PK) of CC-220 in subjects with RRMM and NDMM.
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Table 7:
Study Objectives (Continued)
Exploratory Objective(s)
The exploratory objectives are:

To explore genomic, molecular and immune biomarkers, including immune activation/exhaustion 
markers and cytokines, for mechanism of action of CC-220, their correlation to clinical outcome 
measures and pharmacodynamics.

To evaluate dose-related immune effects of CC-220.

To evaluate the PK of metabolite M12 in subjects with RRMM.


To evaluate the safety for the combination of CC-220Dd when DARA is administered as 
subcutaneous injection.

In Part 2 of the study,

To explore minimal residual disease (MRD) in subjects who achieve a response of very good 
partial response (VGPR) or better and its correlation to clinical outcome measures in subjects 
with RRMM and NDMM.
Table 8:
Study Endpoints
Endpoint
Name
Description
Timeframe
Primary 
Recommended Dose 
and Regimen in 
Part 1
Establish the maximum tolerated doses 
(MTDs) and/or Recommended Phase 2 doses 
(RP2Ds) of CC-220 monotherapy, in 
combination with DEX, and in combination 
with DEX and daratumumab (CC-220Dd), in 
combination with DEX and bortezomib (CC-
220Vd), and in combination with DEX and 
carfilzomib (CC-220Kd)
Part 1
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Table 8:
Study Endpoints (Continued)
Endpoint
Name
Description
Timeframe
Primary
Overall response rate 
(ORR) in Cohort D
Tumor response, including progressive 
disease (PD) according to the International 
Myeloma Working Group (IMWG) 
Uniform Response Criteria (Kumar, 2016)
in CC-220 in combination with DEX
From first subject 
first dose of IP until 
the last subject is no 
longer evaluable for 
response or has 
progressed
Secondary
Safety
Type, frequency, seriousness and severity 
of adverse events (AEs) (and AEs of 
special interest) and relationship of AEs to 
investigational product
From first subject 
first visit until 28 
days after the last 
subject discontinues 
study treatment
Very good partial 
response or better rate
(VGPR)
Tumor response, including progressive 
disease (PD) according to the International 
Myeloma Working Group (IMWG) 
Uniform Response Criteria (Kumar, 2016) 
for subjects who achieved VGPR or better 
From first subject 
dose of IP until the 
last subject is no 
longer evaluable for 
response or has 
progressed
Overall response rate 
(ORR) 
Tumor response, including progressive 
disease (PD) according to the International 
Myeloma Working Group (IMWG) 
Uniform Response Criteria (Kumar, 2016)
for subjects who achieved partial response 
(PR) or better 
From first subject 
dose of IP until the 
last subject is no 
longer evaluable for 
response or has 
progressed
Time to response 
(TTR)
Time from enrollment to the first 
documentation of response (PR or greater)
From first subject 
dose of IP until the 
last subject is no 
longer evaluable for 
response or has 
progressed
Duration of response 
(DOR)
Time from the first documentation of 
response (PR or greater) to the first 
documentation of PD
From first subject 
dose of IP until the 
last subject is no 
longer evaluable for 
response or has 
progressed
Progression-free 
Survival (PFS)
Time from the first dose of investigational 
product (IP) to the first documentation of 
PD or death from any cause, whichever 
occurs first
From first subject
first dose of IP until 
the last subject 
discontinues study 
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Table 8:
Study Endpoints (Continued)
Endpoint
Name
Description
Timeframe
Overall Survival (OS)
in Part 2 RRMM 
cohorts 
Time from first dose of IP to death due to 
any cause
From first subject 
dose of IP until the 
last subject 
discontinues study 
Pharmacokinetic (PK) 
parameters
PK of CC-220, and as appropriate, its R-
enantiomer CC-17195 in plasma, eg, 
AUC(TAU), Cmax, Tmax
During study 
treatment 
Exploratory
Biomarkers
Evaluate the Pd effects of CC-220 on 
immune cell counts in peripheral blood
During study 
treatment 
Biomarkers
Evaluate modulation of immune responses 
(such as activation/exhaustion makers and 
cytokine secretion), gene expression, 
protein expression and T-cell receptor 
(TCR) clonality in immune cells by CC-
220
During study 
treatment 
Biomarkers
Evaluate correlation of baseline and Pd 
changes in protein expression, gene 
expression, cytogenetics, copy number 
abnormalities and/or mutations in tumor 
cells and tumor microenvironment in the 
bone marrow to CC-220 response or 
resistance  
During study 
treatment
PK parameters
Evaluate the PK of metabolite M12 in 
plasma
During study 
treatment
Biomarkers in Part 2
Evaluate minimal residual disease (MRD)
negativity and duration in subjects who 
achieve a response of very good partial 
response (VGPR) or better and its 
association with clinical outcomes
From first subject 
dose of IP until the 
last subject is no 
longer evaluable for 
response or has 
progressed
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Table 8:
Study Endpoints (Continued)
Endpoint
Name
Description
Timeframe
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3.
OVERALL STUDY DESIGN
3.1.
Study Design
This is a multicenter, multicountry, open-label, Phase 1b/2a dose-escalation study to determine 
the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of CC-220 when 
administered as monotherapy and in combination with other treatments. The study will consist of 
two parts: a dose-escalation portion (Part 1) and dose expansion (Part 2).
In Part 1 dose escalation, RRMM subjects may be enrolled into the following six cohorts: CC-
220 monotherapy (MonoT, Cohort A), in combination with DEX (DoubleT, Cohort B), in 
combination with DEX and IV DARA (CC-220Dd, Cohort E), in combination with DEX and 
BTZ (CC-220Vd, Cohort F), and in combination with DEX and CFZ (CC-220Kd, Cohorts G1 
and G2). 
Once the MTD and/or RP2D is determined in Cohort E (CC-220Dd), 13 subjects will be enrolled 
at this dose level using SC DARA to evaluate the safety and tolerability with the SC formulation. 
The decision to evaluate any additional subjects with the SC formulation will be at the discretion 
of the DEC, based on their review of the data.
In Part 2 dose expansion, the following cohorts may be opened to evaluate efficacy and safety at 
the RP2D: (Cohort C: monotherapy, Cohort D: CC-220 in combination with DEX, Cohort I: 
CC-220 in combination with DEX in RRMM subjects with prior BCMA-targeted therapy,
Cohort J1: CC-220Vd in NDMM subjects who are not eligible for ASCT, Cohort J2: CC-220Vd 
in NDMM subjects who are eligible for ASCT, Cohort K: CC-220Dd in NDMM subjects who 
are not eligible for ASCT). Cohorts J1 and K will evaluate up to 3 dose levels of CC-220 (1.0 
mg, 1.3 mg, 1.6 mg). The decision to evaluate any additional subjects in any of the NDMM dose 
level cohorts will be made in consultation with the DEC, based on their review of the data.
A group sequential design (Jennison, 1999) will be used to evaluate the efficacy and safety of 
CC-220 (at the RP2D of 1.6 mg) in combination with DEX (Cohort D):

Cohort D Stage 1: Following the treatment of 40 subjects, an interim analysis will be 
performed to evaluate the preliminary efficacy of CC-220 plus DEX at the RP2D of 1.6 
mg.

Cohort D Stage 2: If the results from Stage 1 do not cross the futility boundary (see 
Section 9.10), an additional 61 subjects may be treated to confirm the safety and efficacy 
of CC-220 plus DEX at the RP2D of 1.6 mg.
The dose and schedule of DEX for applicable cohorts is detailed in Section 7.2
The starting doses of CC-220 monotherapy in Cohort A and CC-220 in combination with DEX 
in Cohort B are detailed in Table 2; in combination with DEX and IV DARA in Cohort E and in 
combination with DEX and BTZ in Cohort F are detailed in Table 3; and in combination with 
DEX and CFZ in Cohorts G1 and G2 are detailed in Table 4.
Treatment will continue until progressive disease (PD), unacceptable toxicity or withdrawal of 
consent for all cohorts except for Cohort J2 where subjects will receive CC-220Vd for up to 
6 cycles or until PD, unacceptable toxicity or withdrawal of consent, whichever is earlier.
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All subjects who discontinue study treatment in Part 1 or Part 2 of the study for a reason other 
than PD or withdrawal of consent from the study will be followed for response assessment every 
28 days (21 days for Cohort F: CC-220Vd) until PD or a subsequent myeloma regimen has been 
started. Subjects in Cohorts J1 and K will be followed every cycle for the first 2 years and 
thereafter, every 3 months until PD or until a subsequent myeloma regimen has been started. 
Subjects in Cohort J2, following induction and ASCT with or without maintenance, will be 
followed for response assessment during the Post-Treatment Response follow-up every 3 months 
until PD or until a subsequent anti-myeloma regimen has been started.
All RRMM subjects enrolled in Part 2 of the study (Cohorts C, D, and I) will have long-term 
follow-up. Subjects will be contacted every 3 months for 5 years from the date of the last subject 
enrolled in the study (or longer if clinically indicated) to learn of the subject’s death from any 
cause, to continue second primary malignancy (SPM) surveillance, and to collect data on 
subsequent anti-myeloma therapies including date of progression.
The study will be conducted in compliance with the International Council for Harmonisation 
(ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good 
Clinical Practice (GCP) and applicable regulatory requirements.
3.1.1.
Dose Escalation (Part 1)
Subjects who meet all eligibility criteria and have completed all Screening procedures will be 
allocated in parallel to the appropriate treatment cohort, based on eligibility status and on cohort 
slot availability. Enrollment will be accomplished by a validated Interactive Response 
Technology (IRT). The 3+3 design will be utilized to determine the MTD and/or RP2D for CC-
220 as monotherapy (Cohort A: MonoT), in combination with DEX (Cohort B: DoubleT), in 
combination with DEX and IV DARA (Cohort E: CC-220Dd), in combination with DEX and 
BTZ (Cohort F: CC-220Vd), and in combination with DEX and CFZ (Cohorts G1 and G2: CC-
220Kd). Subjects in Cohorts A, B, E, G1 and G2 will have a 28–day treatment cycle and subjects 
in Cohort F will have a 21–day treatment cycle. 
All subjects will be treated in each cohort (Cohorts A, B, E, G1 and G2) and observed for at least 
28 days (21 days for Cohort F) after the first dose of CC-220 before the dose level is escalated in 
the next dose level.
The following dose-escalation rules will be applied in determining the MTD:

Initially 3 subjects will be enrolled into each dose-level cohort (either Cohort A,
Cohort B, Cohort E, Cohort F, Cohort G1, or Cohort G2).

If none of the 3 initial subjects in a dose-level cohort experience a dose-limiting 
toxicity (DLT) (see definition of DLT in Section 3.1.1.2) within the first cycle, 
then enrollment into the next 3-subject dose-level cohort at a higher dose level 
may be initiated.

If 2 or 3 of the 3 initial subjects in a dose-level cohort experience a DLT within 
the first cycle, then the MTD has been exceeded and no further dose escalation is 
needed.
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
If 1 of the 3 initial subjects in a dose-level cohort experiences a DLT within the 
first cycle, then an additional 3 subjects will be enrolled into the same dose-level 
cohort and dose level.
o
If 2 or more subjects in the expanded 6-subject dose-level cohort experience a 
DLT within the first cycle, then the MTD has been exceeded and no further 
dose escalation is needed.
o
If only 1 of the subjects in the expanded 6-subject dose-level cohort 
experiences a DLT within the first cycle, then the next higher dose-level 
cohort may be tested and enrollment of the next 3 subjects at the next higher 
dose-level cohort can be initiated.

The MTD is defined as the previous dose level of the cohort where a DLT is observed 
in at least 2 subjects within the first cycle.

Subjects within a dose-level cohort will be replaced if they are not evaluable for DLT 
during the first cycle due to missed doses for reasons other than DLT:

For Cohort A (MonoT) miss more than 4 doses of CC-220 within the first cycle
(28 days)

For Cohort B (DoubleT) miss more than 4 doses of CC-220 and/or more than 2 
doses of DEX within the first cycle (28 days)

For Cohort E (CC-220Dd) miss more than 4 doses of CC-220, more than 2 doses 
of DEX, and/or more than 1 dose of DARA within the first cycle (28 days)

For Cohort F (CC-220Vd) miss more than 4 doses of CC-220, more than 2 doses 
of DEX, and/or more than 1 dose of BTZ within the first cycle (21 days)

For Cohorts G1 and G2 (CC-220Kd) miss more than 4 doses of CC-220, more 
than 2 doses of DEX, and/or more than 1 dose of CFZ within the first cycle (28 
days)

Discontinue IP for a reason unrelated to a DLT within the first cycle
Dose-limiting toxicity will be assessed to determine MTD during the first treatment cycle. Once 
the MTD and/or RP2D is determined for CC-220 in either Cohort A or Cohort B, subject 
enrollment may begin for Part 2 (expansion). The MTD may be the RP2D. The RP2D may also 
be determined by PK and biomarker data as well as the safety and preliminary efficacy data from 
Part 1, as applicable. The decision to determine the RP2D will be made in consultation with the 
DEC. 
3.1.1.1.
Dose Escalation Committee
Objectives:
In Part 1, the Dose Escalation Committee (DEC) members are responsible for dosing decisions. 
Dosing decisions may include escalations to the next-dose level, de-escalation to a lower dose; 
continuation, delay or termination of dosing, repetition of a dose-level cohort, or expansion of a 
dose-level cohort. At each time, at minimum all clinical and laboratory safety data for a given 
cohort will be reviewed.
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The decision to either evaluate a higher dose level, declare MTD and/or RP2D is determined by 
the DEC. Additional dose levels up to 25% greater than the prior dose level deemed tolerable 
may be explored based on the DEC’s evaluation and recommendation (refer to Section 1.3.6.3).
Members:
The DEC consists of Sponsor team members: Medical Monitor(s), Lead Safety Physician, 
Biostatistician, other functional area representatives as appropriate, Global Study Investigators, 
the IER and site Investigators and/or designees who have enrolled subjects in the given dose-
level cohort will be on the DEC. Responsibilities of this committee are described in the Dose 
Escalation Committee and Independent Expert Reviewer Charter.
3.1.1.2.
Dose-limiting Toxicity
The dose-limiting toxicity (DLT) population will be all subjects who missed no more than 4 
scheduled doses of CC-220, and/or no more than 2 doses of DEX, and/or no more than 1 dose of 
IV DARA (Cohort E) and/or no more than 1 dose of BTZ (Cohort F) and/or no more than 1 dose 
of CFZ (Cohort G1 or Cohort G2) during Cycle 1 for reasons other than DLT. The DLT 
population will be used for analysis of the primary endpoint regarding the determination of the 
MTD. Subjects not evaluable for DLT will be replaced for purposes of adequately assessing 
DLT. Regardless of evaluability for DLT, all subjects receiving any dose of IP will remain in the 
safety database.
For the purpose of determining the MTD for this study, a DLT is defined as any of the following 
events occurring during the first 28 days (21 days for Cohort F) (Cycle 1) (Note – Severity 
grades are defined according to the National Cancer Institute Common Terminology Criteria for 
Adverse Events [NCI CTCAE] v4.0).
Hematologic DLTs

Grade 4 neutropenia (absolute neutrophil count [ANC] <500/μL for >5 days)

Grade 3 neutropenia (ANC < 1,000/μL) with fever ≥38.5°C of any duration

Grade 4 thrombocytopenia (platelet count < 25,000/μL) or Grade 3 thrombocytopenia 
with bleeding or any requirement for platelet transfusion

Any other grade 4 hematologic toxicity, other than anemia, that does not resolve to 
subject’s pretreatment baseline level within 72 hours
Non-hematologic DLTs

Any non-hematological toxicity ≥Grade 3, except for alopecia and nausea controlled 
by medical management

Any treatment interruption greater than 2 weeks due to an AE
While the rules for adjudicating DLTs in the context of dose escalation are specified above, an 
AE not listed above may be defined as a DLT after consultation with the DEC (Section 3.1.1.1). 
3.1.2.
Expansion (Part 2)
All expansion decisions will be determined by the DEC after review of all safety, PK, biomarker 
and preliminary efficacy data, as applicable.
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Cohort C (MonoT)
Once a RP2D from the dose-escalation cohort in Part 1 is determined, up to an additional 24 
subjects may be enrolled into the expansion Cohort C (MonoT).
Following the 08 Nov 2019 DEC review of Cohort A, the 1 mg dose level was deemed tolerable. 
It was agreed that further investigation of CC-220 monotherapy was more appropriate in a newly 
diagnosed MM maintenance setting. Therefore, Cohort C will not be opened.
Cohort D (DoubleT)
Once a RP2D from the dose-escalation cohort in Part 1 is determined, the expansion cohort may 
be initiated. As of 18 Oct 2019, the DEC has recommended the 1.6 mg dose level as the RP2D 
for CC-220 plus DEX. A group sequential design (Jennison, 1999) will be used to evaluate the 
efficacy and safety of CC-220 (at the RP2D of 1.6 mg) plus DEX in Cohort D.
Cohort D Stage 1 

In Stage 1, following the treatment of 40 subjects, an interim analysis will be performed 
to evaluate the preliminary efficacy of CC-220 plus DEX at the RP2D of 1.6 mg.
Cohort D Stage 2

If the results from Stage 1 do not cross the futility boundary (see Section 9.10), an 
additional 61 subjects may be treated to confirm efficacy and safety of CC-220 plus DEX 
at the RP2D of 1.6 mg.
Cohort I (DoubleT Expansion in Post-BCMA RRMM)

Once the RP2D is established for Cohort B (CC-220 plus DEX) and expansion is 
determined by the DEC, this expansion cohort may be initiated. As of 18 Oct 2019, 
the DEC has recommended the 1.6 mg dose level as the RP2D for CC-220 plus DEX.

Up to 40 subjects who have received prior BCMA-targeted therapy may be enrolled 
to explore the safety and preliminary efficacy of CC-220 plus DEX at the RP2D for 
this patient population. A minimum of 40% of the cohort will have prior BCMA-
targeted CAR T therapy. The IRT will be used to monitor the inclusion of these 
subjects.
Cohort J1 (CC-220Vd Expansion in NDMM)

Once the RP2D is established for Cohort F (CC-220Vd) and expansion is determined 
by the DEC, this expansion cohort may be initiated.
 
 
Approximately 75 subjects may be enrolled to explore the safety and preliminary efficacy of up 
to 3 dose levels of CC-220 (1.0 mg, 1.3 mg, and 1.6 mg) in combination with BTZ and DEX in 
NDMM subjects who are not eligible for ASCT. Up to approximately 25 subjects per dose level 
may be enrolled. Additional subjects may be enrolled in any of the dose levels upon consultation 
with the DEC, based on review of the data.
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Cohort J2 (CC-220Vd Expansion in NDMM)

Once the RP2D is established for Cohort F (CC-220Vd) and expansion is determined 
by the DEC, this expansion cohort may be initiated.
Approximately 50 subjects may be enrolled to explore the safety and preliminary efficacy of CC-
220 in combination with BTZ and DEX in NDMM subjects who are eligible for ASCT.
Cohort K (CC-220Dd in NDMM and not eligible for ASCT)

Once the RP2D is established for Cohort E (CC-220Dd) by the DEC (IV DARA), this 
expansion cohort may be initiated. 
 

Approximately 75 subjects may be enrolled to evaluate the safety and preliminary 
efficacy of up to 3 dose levels of CC-220 (1.0 mg, 1.3 mg, and 1.6 mg) in 
combination with SC DARA and DEX in NDMM subjects who are not eligible for 
ASCT. Approximately 25 subjects per dose level may be enrolled. Additional 
subjects may be enrolled in any of the dose levels upon consultation with the DEC, 
based on review of the data.
Any of the cohorts may be removed and/or terminated from the study based on emerging PK, Pd, 
efficacy or safety data, in consultation with the DEC.
During Part 2 of the study, the DEC (including the IER) will continue to review the safety data 
and any other data deemed relevant so that subject safety is ensured. This review, described in 
the Dose Escalation Committee Charter, is in addition to the review by the Safety Management 
Team of all CC-220 safety data and the ongoing review of study data by the clinical team. 
Further details are described in the charter. 
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Figure 2: Overall Study Design
Part 1 – Dose Escalation
RP2D for Established
Part 2 – Dose Expansion
ASCT = autologous stem cell transplant; BCMA = B-cell maturation antigen; BTZ = bortezomib; CC-220Dd = CC-220 + DARA + DEX; CC-220Vd = CC-220 + BTZ + DEX; 
CFZ = carfilzomib; DARA = daratumumab; DEX = dexamethasone; DoubleT = CC-220+DEX combination therapy; IRT = Interactive Response Technology; IV = intravenous; 
MonoT = monotherapy; NDMM= newly diagnosed multiple myeloma; RRMM = relapsed and refractory multiple myeloma; RP2D = recommended Phase 2 dose.
Cohort C 
CC-220 (MonoT)
N = 24
Cohort D 
CC-220 + DEX (DoubleT) 
Stage 1 (N = 40) 
.    
                       Interim Analysis
Screening (Eligibility Check)
Screening (Eligibility Check)
Cohort E
CC-220 + 
DARA+ DEX 
(CC-220Dd)
Cohort F
CC-220 + 
BTZ+ DEX 
(CC-220Vd)
Cohort G2
CC-220 + 
CFZ+ DEX 
(CC-220Kd)
twice weekly
Cohort G1
CC-220 + 
CFZ+ DEX 
(CC-220Kd)
once weekly
Cohort I
CC-220 + DEX   
(DoubleT)
Post-BCMA
N = 40
Cohort J2
CC-220 + BTZ + DEX
(CC-220Vd)
NDMM eligible for 
ASCT
Cohort J1
CC-220 + BTZ + DEX   
(CC-220Vd)
NDMM not eligible for 
ASCT
Cohort K
CC-220 + DARA + DEX
(CC-220Dd)
NDMM not eligible 
for ASCT
Cohort B
CC-220 + 
DEX 
(DoubleT)
Cohort A
CC-220 
(MonoT)
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3.2.
Study Duration for Subjects
The study will consist of the Screening and Treatment phases for the subjects in both Part 1 and 
Part 2 of the study. In Part 2, there is also a Long-term Follow-up phase for RRMM cohorts 
(Cohorts C, D, and I). 
The Screening phase may not exceed a 28-day window prior to the start of IP (Cycle 1 Day 1).
Treatment at each dose level in Part 1 as well as treatment in Part 2 will continue until 
progressive disease (PD), unacceptable toxicity, or the subject withdraws consent for all cohorts 
except Cohort J2 where treatment will continue for up to 6 cycles or until PD, unacceptable 
toxicity or withdrawal of consent, whichever is earlier. 
There will be an End of Treatment (EOT) Visit to collect safety and efficacy assessments. For 
subjects in Cohort J2, the EOT Visit is considered either 3 months (±7 days) post ASCT (prior to 
any maintenance therapy, if applicable) or at any other moment for treatment discontinuation. 
Another visit will be conducted 28 days after the end of treatment to collect safety assessments.
All subjects who discontinue study treatment in Part 1 or Part 2 of the study for a reason other 
than PD or withdrawal of consent from the study will be followed for response assessment every 
28 days (every 21 days for Cohort F) until PD or a subsequent myeloma regimen has been 
started. Subjects in Cohorts J1 and K will be followed every cycle for the first 2 years and 
thereafter, every 3 months until PD or until a subsequent myeloma regimen has been started. 
Subjects in Cohort J2, following induction, ASCT with or without maintenance, will be followed 
for response assessment during the Post-Treatment Response follow-up every 3 months until PD 
or until a subsequent anti-myeloma regimen has been started.
All RRMM subjects in Part 2 (Cohorts C, D, and I) will be contacted every 3 months for 5 years 
from the date of the last subject enrolled in the study to learn of the subject’s death from any 
cause, to continue SPM surveillance, and to collect data on subsequent anti-myeloma therapies 
including date of progression.
3.3.
End of Trial 
The End of Trial is defined as either the date of the last Long-term Follow-up data collection, or 
the date of receipt of the last data point from the last subject that is required for primary, 
secondary and/or exploratory analysis, as prespecified in the protocol, whichever is the later date.
At the conclusion of the study, if the study intervention is not available as an approved treatment
in the local country, participants who continue to demonstrate clinical benefit will be eligible to
receive Sponsor-supplied study intervention. If the study treatment is not available as an
approved and available treatment, study intervention will be provided via an extension of the
study, or a rollover study requiring approval by the responsible Health Authority and ethics
committee, or through another mechanism at the discretion of the Sponsor. The Sponsor reserves
the right to terminate access to the supplied study intervention treatment if any of the following
occur: a) the study is terminated due to safety concerns; b) the development of CC-220 is
terminated for other reasons, including, but not limited to, lack of efficacy and/or not meeting the
study objectives; c) the participant can obtain medication from a government-sponsored or other
health program. In all cases, the Sponsor will follow local regulations.
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4.
STUDY POPULATION
4.1.
Number of Subjects
Approximately 34 subjects in Cohort A and 72 subjects in Cohort B will be treated and evaluated 
in Part 1 for MTD and/or RP2D. Approximately 85 additional subjects will be allocated to one of
the four triplet regimen cohorts (Cohorts E, F, G1 and G2). The actual number of subjects in
dose escalation part (Part 1) will depend on the number of dose levels being tested (based on the 
occurrence of DLT) and may exceed these approximations. In Part 2, up to 341 subjects may be 
enrolled: up to 101 subjects may be enrolled in Cohort D, up to 40 subjects in Cohort I, 
approximately 75 subjects in Cohort J1, approximately 50 subjects in Cohort J2, and 
approximately 75 subjects in Cohort K.
Refer to Table 1 for a summary of each cohort’s eligibility. 
4.2.
Inclusion Criteria
Subjects must satisfy the following criteria to be enrolled in the study:
1. Subject is ≥18 years of age at the time of signing the informed consent form (ICF).
2. Subject must understand and voluntarily sign an ICF prior to any study-related 
assessments/procedures being conducted.
3. Subject is willing and able to adhere to the study visit schedule and other protocol 
requirements.
4. All subjects in RRMM cohorts must have a documented diagnosis of MM and have 
measurable disease defined as:
a.
M-protein (serum and/or urine protein electrophoresis (sPEP or uPEP)): sPEP ≥0.5 
g/dL or uPEP ≥200 mg/24 hours and/or
b. Light chain MM without measurable disease in the serum or urine: serum 
immunoglobulin free light chain ≥ 10 mg/dL (100 mg/L) and abnormal serum 
immunoglobulin kappa lambda free light chain ratio
5. Subjects in Cohorts A, B, C, E, G1, and G2 must have received at least 2 prior myeloma 
regimens (note: induction with or without bone marrow transplant and with or without 
maintenance therapy is considered one regimen). Subjects in Cohort F must have 
received at least 1 prior myeloma regimen. Subjects in Cohorts D and I must have 
received at least 3 prior myeloma regimens.
6. All subjects in RRMM cohorts must have received prior treatment with at least 
2 consecutive cycles of a lenalidomide or pomalidomide-containing regimen. Subjects in 
Cohort D must have received prior treatment with at least 2 consecutive cycles of a 
lenalidomide-containing regimen and at least 2 consecutive cycles of a pomalidomide-
containing regimen.
7. All subjects in RRMM cohorts must have received prior treatment with at least 
2 consecutive cycles of a proteasome inhibitor or a proteasome inhibitor-containing 
regimen.
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8. For Part 2 RRMM cohorts (Cohorts C, D, and I), all subjects must have received prior 
treatment with at least 2 consecutive cycles of a CD38 antibody or a CD38 antibody-
containing regimen.
9. All subjects in RRMM cohorts must have documented disease progression on or within 
60 days from the last dose of their last myeloma therapy. Subjects who had CAR T 
therapy as their last myeloma therapy must have documented disease progression.
10. Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1 or 2.
11. A female of childbearing potential (FCBP) is a female who: 1) has achieved menarche at 
some point, 2) has not undergone a hysterectomy or bilateral oophorectomy, or 3) has not 
been naturally postmenopausal (amenorrhea following cancer therapy does not rule out 
childbearing potential) for at least 24 consecutive months (ie, has had menses at any time 
in the preceding 24 consecutive months) and must:
a. Have two negative pregnancy tests as verified by the Investigator prior to starting 
study treatment. She must agree to ongoing pregnancy testing during the course of 
the study, and after end of study treatment. This applies even if the subject 
practices true abstinence* from heterosexual contact.
b. Either commit to true abstinence* from heterosexual contact (which must be 
reviewed on a monthly basis and source documented) or agree to use, and be able 
to comply with two forms of contraception: one highly effective, and one 
additional effective (barrier) measure of contraception without interruption 28
days prior to starting investigational product, during the study treatment
(including dose interruptions), and for at least 28 days after the last dose of CC-
220, 90 days after the last dose of DARA (for Cohorts E and K), 7 months after 
last dose of BTZ (for Cohorts F, J1 and J2), or 6 months after the last dose of CFZ 
(for Cohorts G1 and G2), whichever is longer. Contraception requirements are 
detailed in Appendix D.
12. Male subjects must:
a.
Practice true abstinence* (which must be reviewed on a monthly basis and source 
documented) or agree to use a condom during sexual contact with a pregnant female 
or a female of childbearing potential while participating in the study, during dose 
interruptions and for at least 90 days following the last dose of study treatment, 
4 months after the last dose of BTZ (for Cohort F, J1 and J2), or 3 months after the 
last dose of CFZ (for Cohorts G1 and G2), whichever is longer, even if he has 
undergone a successful vasectomy. 
* True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. [Periodic 
abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.]
13. Males must agree to refrain from donating sperm while on study treatment, during dose 
interruptions and for at least 90 days following last dose of study treatment.
14. All subjects must agree to refrain from donating blood while on study treatment, during 
dose interruptions and for at least 28 days following the last dose of study treatment.
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15. All male and female subjects must follow all requirements defined in the Pregnancy 
Prevention Program (v5.1). See Appendix D for CC-220 Pregnancy Prevention Plan for 
Subjects in Clinical Trials.
16. Subjects in Cohort D must have received prior treatment with at least 2 consecutive 
cycles of a glucocorticoid-containing regimen.
17. Subjects in Cohort D must be refractory to an immunomodulatory agent, a proteasome 
inhibitor, a glucocorticoid and a CD38 antibody. Refractory is defined as disease that is 
nonresponsive on therapy (failure to achieve minimal response or development of 
progressive disease while on therapy) or progresses within 60 days of last dose.
18. Subjects in Cohort I must have received prior treatment with a BCMA targeted therapy.
Additional Inclusion Criteria for Part 2 Cohorts J1 and J2 (CC-220 + BTZ + DEX in 
NDMM), and K (CC-220 + DARA + DEX in NDMM):
19. Subject must have documented diagnosis with previously untreated symptomatic MM as 
defined by the criteria below (Rajkumar, 2016):

MM diagnostic criteria:

Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or 
extramedullary plasmacytoma*

And any one or more of the following myeloma defining events:
o
one or more of the following myeloma-related organ dysfunction (at least one 
of the following):

[C] Calcium elevation (serum calcium > 0.25 mmol/L [> 1 mg/dL] higher 
than the upper limit of laboratory normal or > 2.75 mmol/L [> 11 mg/dL])

[R] Renal insufficiency (serum creatinine > 2 mg/dl [> 177 μmol/L] or 
creatinine clearance < 40 ml/min)

[A] Anemia (hemoglobin < 10 g/dl or > 2 g/dL below the lower limit of 
laboratory normal)

[B] Bone lesions (lytic or osteopenic) one or more bone lesions on skeletal 
radiography, computed tomography (CT), or positron emission 
tomography (PET)/CT
o
one or more of the following biomarkers of malignancy:

Clonal bone marrow plasma cell percentage* ≥ 60%

Abnormal serum free light-chain (FLC) ratio ≥ 100 (involved kappa) or < 
0.01 (involved lambda) and involved FLC level must be ≥ 100 mg/L 
                                                            
* Clonality should be established by showing κ/λ-light-chain restriction on flow cytometry, immunohistochemistry, 
or immunofluorescence. Bone marrow plasma cell percentage should preferably be estimated from a core biopsy 
specimen; in case of a disparity between the aspirate and core biopsy, the highest value should be used.
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
>1 focal lesion detected by magnetic resonance imaging (MRI) (at least 5 
mm in size)
AND have measurable disease, as assessed by central laboratory, defined by any of the 
following:

Immunoglobulin (Ig)G myeloma: serum M-protein level ≥1.0 g/dL or urine M-
protein level ≥200 mg/24 hours; or

IgA, IgM, IgD, or IgE multiple myeloma: serum M-protein level ≥0.5 g/dL or urine 
M-protein level ≥200 mg/24 hours; or

Light chain multiple myeloma without measurable disease in serum or urine: serum 
FLC ≥100 mg/L and abnormal kappa lambda (κ/λ) ratio
20. Subjects in Cohorts J1 and K are those for who ASCT is not planned for initial therapy or
are not considered by the investigator as eligible for high-dose chemotherapy and 
autologous stem cell transplantation due to:

Age ≥65 years, OR

In subjects <65 years: presence of important comorbid condition(s) likely to have a 
negative impact on tolerability of high-dose chemotherapy with autologous stem cell 
transplantation. 
21. Subjects in Cohort J2 are considered by the investigator as eligible for high-dose 
chemotherapy and autologous stem cell transplantation according to the institution's 
criteria based on age, medical history, cardiac and pulmonary status, overall health and 
condition, co-morbid condition(s), physical examination, and laboratory data.
4.3.
Exclusion Criteria
The presence of any of the following will exclude a subject from enrollment:
1. Subject has any significant medical condition, laboratory abnormality, or psychiatric 
illness that would prevent the subject from participating in the study
2. Subject has any condition including the presence of laboratory abnormalities, which 
places the subject at unacceptable risk if he/she were to participate in the study
3. Subject has any condition that confounds the ability to interpret data from the study
4. Subject has nonsecretory multiple myeloma
5. Subjects with Plasma Cell leukemia or amyloidosis
6. Any of the following laboratory abnormalities

Absolute neutrophil count (ANC) < 1,000/μL

Platelet count < 75,000/μL for Part 1. For Part 2; platelet count < 75,000/μL for 
subjects in whom < 50% of bone marrow nucleated cells are plasma cells; otherwise 
platelet count < 50,000/μL (transfusions are not permitted to achieve minimum 
platelet counts)

Corrected serum calcium > 13.5 mg/dL (> 3.4 mmol/L)
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
Serum glutamic oxaloacetic transaminase (SGOT)/aspartate aminotransferase (AST) 
or serum glutamic pyruvic transaminase (SGPT)/alanine aminotransferase (ALT) 
≥2.0 x upper limit of normal (ULN)

Serum total bilirubin and alkaline phosphatase >1.5 x ULN

Subjects with serious renal impairment (creatinine clearance [CrCl] < 30 mL/min) or 
requiring dialysis would be excluded.
7. Subjects with peripheral neuropathy ≥Grade 2
8. Subjects with gastrointestinal disease that may significantly alter the absorption of 
CC-220
9. Subjects with a prior history of malignancies, other than MM, unless the subject has been 
free of the disease for ≥5 years with the exception of the following noninvasive 
malignancies:

Basal cell carcinoma of the skin

Squamous cell carcinoma of the skin

Carcinoma in situ of the cervix

Carcinoma in situ of the breast

Incidental histological findings of prostate cancer such as T1a or T1b using the 
Tumor/Node/Metastasis (TNM) classification of malignant tumors or prostate cancer 
that is curative
10. Subject has a history of anaphylaxis or hypersensitivity to thalidomide, lenalidomide, 
pomalidomide, DEX, daratumumab (for Cohorts E and K), bortezomib (for Cohorts F, J1 
and J2), or carfilzomib (for Cohorts G1 and G2). Subject has known or suspected 
hypersensitivity to the excipients contained in the formulation of CC-220, DEX, 
daratumumab (for Cohorts E and K), bortezomib (for Cohorts F, J1, and J2), or 
carfilzomib (for Cohorts G1 and G2).
11. Contraindications to the other treatment regimens, as per local prescribing information
12. Subject has received any of the following within the last 14 days of initiating IP:

Plasmapheresis

Major surgery (as defined by the Investigator)

Radiation therapy other than local therapy for MM associated bone lesions

Use of any systemic myeloma drug therapy
13. Subject has been treated with an investigational agent (ie, an agent not commercially 
available) within 28 days or 5 half-lives (whichever is longer) of initiating IP. Not 
applicable for subjects who had CAR T as last prior regimen. 
14. Subject has any one of the following:

Clinically significant abnormal electrocardiogram (ECG) finding at Screening.
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
Congestive heart failure (New York Heart Association Class III or IV)

Myocardial infarction within 12 months prior to starting IP

Unstable or poorly controlled angina pectoris, including the Prinzmetal variant of 
angina pectoris 
15. Subject has current or prior use of immunosuppressive medication within 14 days prior to 
the first dose of IP. The following are exceptions to this criterion:

Intranasal, inhaled, topical or local steroid injections (eg, intra-articular injection)

Systemic corticosteroids at physiologic doses that do not exceed 10 mg/day of 
prednisone or equivalent

Steroids as premedication for hypersensitivity reactions (eg, computed tomography 
[CT] scan premedication)
16. Subject has taken a strong inhibitor or inducer of CYP3A4/5 including grapefruit, St. 
John’s Wort or related products within two weeks prior to dosing and during the course 
of study
17. Subject known to test positive for human immunodeficiency virus (HIV), chronic or 
active hepatitis B, or active hepatitis A or C
18. Subject is unable or unwilling to undergo protocol required thromboembolism 
prophylaxis
19. Subject is a female who is pregnant, nursing or breastfeeding, or who intends to become 
pregnant during the participation in the study
Additional Exclusion Criteria for Cohorts E and K (CC-220 + DARA + DEX):
20. Subject has known chronic obstructive pulmonary disease (COPD) with a forced 
expiratory volume in 1 second (FEV1) 50% of predicted normal. Note that forced 
expiratory testing (FEV1) is required for subjects suspected of having COPD and subjects 
must be excluded if FEV1 is < 50% of predicted normal
21. Subject has received previous allogeneic stem cell transplant; or received autologous 
stem cell transplantation within 12 weeks prior to enrollment
22. Subject has known moderate or severe persistent asthma, or currently has uncontrolled 
asthma of any classification
Additional Exclusion Criteria for Cohorts F, J1 and J2 (CC-220 + BTZ + DEX):
23. Subject has acute diffuse infiltrative pulmonary and pericardial disease
Additional Exclusion Criteria for Cohorts G1 and G2 (CC-220 + CFZ + DEX):
24. Left ventricular ejection fraction (LVEF) < 45% as determined by echocardiogram 
(ECHO) or multigated acquisition (MUGA) scan and/or an ECG with corrected QT 
interval (QTc) of > 470 milliseconds at Screening
25. Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to enrollment
Approved
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EDMS Doc. Number: 25858146 - 20867538
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26. Subject has symptomatic ischemia, pericardial disease, history of severe coronary artery 
disease, sick sinus syndrome, uncontrolled arrhythmias, Grade 3 conduction system 
abnormalities not mitigated by a pacemaker, hypertrophic cardiomyopathy, or restrictive 
cardiomyopathy
27. Subject has mild hepatic impairment defined as elevated bilirubin > 1.0 but < 1.5 x ULN 
or normal bilirubin with any elevation of AST
Additional Exclusion Criteria for Part 2 Cohorts C (MonoT) and D (DoubleT):
28. Previous history of treatment with any gene therapy-based therapeutic for cancer or 
investigational cellular therapy for cancer or BCMA targeted therapy
Additional Exclusion Criteria for Part 2 Cohorts J1 and J2 (CC-220 + BTZ + DEX in 
NDMM), and K (CC-220 + DARA + DEX in NDMM):
29. Previous treatment with anti-myeloma therapy, including treatment for smoldering 
myeloma (does not include radiotherapy, bisphosphonates, or a single short course of 
steroid [ie, less than or equal to the equivalent of dexamethasone 40 mg/day for 4 days; 
such a short course of steroid treatment must not have been given within 14 days of 
initiating study treatment]).
Approved
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v

EDMS Doc. Number: 25858146 - 20867538
CC-220
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CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
5.
TABLE OF EVENTS
Table 9:
Table of Events for Part 1 Cohorts A (monotherapy) and B (CC-220+DEX): 28-day Cycle
Screening
Treatment
Safety Follow-
up
Post-Tx 
Response 
FU
EVENTS
-28 to -1
Cycle 1
Cycle 2 –4
(±2 days for all visits)
≥ Cycle 5 (±2 
days for all 
visits)
EOT
28 days 
after EOT 
(+ 3 d)
Every 28 
days and at 
D/C visit 
(+ 2 d)
D1
D8
D12
D15
D22
D26
D1
D8
D15
D22
D1
D15
STUDY ENTRY AND GENERAL ASSESSMENTS
Informed consent
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Inclusion/exclusion criteria
X
-
-
-
-
-
-
-
-
-
-
-
-
-
IRT registration
X
X
-
-
-
-
-
-
-
-
-
-
-
X
Prior cancer history
X
-
-
-
-
-
-
-
-
-
-
-
-
-
Medical history
X
-
-
-
-
-
-
-
-
-
-
-
-
-
Demographics
X
-
-
-
-
-
-
-
-
-
-
-
-
-
Prior disease history
X
-
-
-
-
-
-
-
-
-
-
-
-
-
Prior disease therapies
X
-
-
-
-
-
-
-
-
-
-
-
-
-
SAFETY ASSESSMENTS
Prior/concomitant medication 
evaluation
X (≤28 
days from 
Screening)
Continuous, until 28 days after last dose of study medication
Prior/concomitant procedures 
evaluation
X (≤28 
days from 
Screening)
Continuous, until 28 days after last dose of study medication
AE (AESI) evaluation
X
Continuous starting after informed consent signature, until 28 days after last dose of study medication
SPM surveillance
X
Continuous starting after informed consent signature, until 28 days after last dose of study medication  
Physical examination (includes VTE 
monitoring and ophthalmologic exam 
if clinically indicated)a, c
X
X
-
-
-
-
-
X
-
-
-
X
-
X
-
-
Approved
12.0
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1.0
v

EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
82
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
Table 9:
Table of Events for Part 1 Cohorts A (monotherapy) and B (CC-220+DEX): 28-day Cycle (Continued)
Screening
Treatment
Safety Follow-
up
Post-Tx 
Response 
FU
EVENTS
-28 to -1
Cycle 1
Cycle 2 –4
(±2 days for all visits)
≥ Cycle 5 (±2 
days for all 
visits)
EOT
28 days 
after EOT 
(+ 3 d)
Every 28 
days and at 
D/C visit 
(+ 2 d)
D1
D8
D12
D15
D22
D26
D1
D8
D15
D22
D1
D15
Vital signs (includes weight)
X
X
X
X
X
X
-
X
X
X
X
X
-
X
X
-
ECG b
X
X
X
And during treatment if clinically indicated
X
-
-
Hematology c, i
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
X
Chemistry c
X
X
X
-
X
X
-
X
X
X
X
X
-
X
-
X
Renal function (CrCL) 
X
X
X
-
X
X
-
X
X
X
X
X
-
X
-
-
Urinalysis
X
Repeated only if clinically indicated
X
-
-
Pregnancy test for FCBP with regular 
or no menstrual cycles
X
X
-10 to -14 days and -24 hours prior to first dose 
weekly for 28 days after first dose, then every 28 days
X
X
-
Pregnancy test for FCBP with 
irregular menstrual cycles
X
X
-10 to -14 days and -24 hours prior to first dose 
weekly for 28 days after first dose, then every 14 days
X
14 and 28 days 
after last dose
-
Pregnancy counseling for all subjects 
k
X
X
-
-
-
-
-
X
-
-
-
X
-
X
-
-
Hepatitis B (HBV) serology local 
testing o
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
EFFICACY AND OTHER ASSESSMENTS
ECOG performance status c
X
X
-
-
-
-
-
X
-
-
-
X
-
X
-
X
Assessment of response (IMWG 
Uniform Response Criteria) d, l
-
-
-
-
-
-
-
X
-
-
-
X
-
X
-
X
Serum and urine protein 
electrophoresis
X
X
-
-
-
-
-
X
-
-
-
X
-
X
-
X
Serum and urine immunofixation e
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Serum free light chain assay
X
X
-
-
-
-
-
X
-
-
-
X
-
X
-
X
Approved
12.0
v
Approved
1.0
v

EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
83
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
Table 9:
Table of Events for Part 1 Cohorts A (monotherapy) and B (CC-220+DEX): 28-day Cycle (Continued)
Screening
Treatment
Safety Follow-
up
Post-Tx 
Response 
FU
EVENTS
-28 to -1
Cycle 1
Cycle 2 –4
(±2 days for all visits)
≥ Cycle 5 (±2 
days for all 
visits)
EOT
28 days 
after EOT 
(+ 3 d)
Every 28 
days and at 
D/C visit 
(+ 2 d)
D1
D8
D12
D15
D22
D26
D1
D8
D15
D22
D1
D15
Quantitative serum immunoglobulin
X
X
-
-
-
-
-
X
-
-
-
X
-
X
-
X
β-2 microglobulin
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
EMP clinical assessment
X
X
-
-
-
-
-
X
-
-
-
X
-
X
-
X
EMP radiological assessment (only 
required if history of or clinical 
indication of EMPs only assessable 
radiographically)
X
-
-
-
-
-
-
Day 1 starting at C3, then every 3 cycles thereafter 
X
-
Xp
Skeletal Survey/CT Scan/MRI (Bone 
lesion) 
X
-
Repeated during treatment if clinically indicated to confirm response or PD
-
Xm
Bone marrow aspirate and/or biopsy 
sampling f
X
- Screening: BMA and, if possible, BMB for local % plasma cells and central cytogenetics and other biomarkers
-C2D15: BMA and if possible BMB at 3-6 hours post dose, for biomarkers 
- BMA and, if possible, BMB at CR confirmation and at PD/treatment discontinuation
- Optional BMA and/or BMB taken at any time point during treatment at request of investigator and prior to 
subsequent myeloma therapy
-
Xn
Whole blood sample for biomarkers g
-
X 
X
-
-
-
C2 and 
C4
-
C2 and 
C4
-
-
C6
X
-
-
Additional whole blood sample for 
biomarkers for selected subjects in 
Cohort B at select US sites (notified 
via IRT) h
-
D1 
and 
D2
-
-
X
-
-
-
-
-
-
-
-
-
-
-
Whole blood samples for PK j
-
-
X
-
X
X
-
-
X
X
X
-
-
-
-
-
COHORT A
Oral CC-220
-
Days 1-21/28-day cycle
-
-
-
Approved
12.0
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EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
84
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
Table 9:
Table of Events for Part 1 Cohorts A (monotherapy) and B (CC-220+DEX): 28-day Cycle (Continued)
Screening
Treatment
Safety Follow-
up
Post-Tx 
Response 
FU
EVENTS
-28 to -1
Cycle 1
Cycle 2 –4
(±2 days for all visits)
≥ Cycle 5 (±2 
days for all 
visits)
EOT
28 days 
after EOT 
(+ 3 d)
Every 28 
days and at 
D/C visit 
(+ 2 d)
D1
D8
D12
D15
D22
D26
D1
D8
D15
D22
D1
D15
COHORT B
Oral CC-220
-
Days 1-21/28-day cycle
-
-
-
Oral DEX
-
Days 1, 8, 15, 22/28-day cycle
-
-
-
VTE prophylaxis
-
C1D1 to EOT
-
-
-
IP (CC-220, DEX, as applicable) 
accountability/compliance
-
X
X
-
X
X
-
X
X
X
X
X
-
X
-
-
Abbreviations: AE = adverse event; AESI = adverse events of special interest; BMA = bone marrow aspirate; BMB = bone marrow biopsy; C = Cycle; CR = complete response; 
CrCL = creatinine clearance; CT = computed tomography; D = Day; D/C = discontinuation; DEX = dexamethasone; ECG = electrocardiogram; ECOG = Eastern Cooperative 
Oncology Group; EMP = extramedullary plasmacytomas; EOT = End of Treatment; FCBP = female of child-bearing potential; FU = follow-up; IMWG = International Myeloma 
Working Group; IRT = Interactive Response Technology; IP = investigational product; MRI = magnetic resonance imaging; PD = progressive disease; Pd = pharmacodynamics; 
PK = pharmacokinetics; SPM = second primary malignancy; sPEP = serum protein electrophoresis; Tx = treatment; uPEP = urine protein electrophoresis; VTE = venous 
thromboembolism.
a Height will be included in the physical examination and only measured at Screening.
b ECG will be taken at time of median Tmax approximately 3-4 hours post first dose on C1D1, C1D8, and at EOT. Also, the ECG will be repeated during treatment if clinically 
indicated.
c On C1D1, safety laboratory assessments must be performed locally, in addition to central laboratory collection, to confirm that the subject continues to meet the required safety 
laboratory values prior to initiating IP.  However, if Screening assessments were performed within 72 hours of C1D1, safety laboratory (hematology and chemistry), physical 
examinations, and ECOG do not need to be repeated at C1D1.
d Refer to Appendix B for IMWG criteria.
e After C1D1, assessment to be taken only if myeloma paraprotein is not detected or too few to quantify in sPEP and uPEP assessments.
f Refer to Table 18 for details on BMA and BMB collection plan.
g Whole blood sample for biomarkers for all subjects: Samples drawn for Pd effects of CC-220 on Aiolos and other Pd biomarkers by protein expression on C1D1 and C1D12. 
Samples drawn for t-cell receptor clonality on C1D1, C2D15, C4D15 and EOT. Samples drawn for Pd effects of CC-220 on T-Cell activation on C1D1 and C1D12. Samples for 
Pd effects of CC-220 on immune cells in peripheral blood and association of baseline levels of these populations with response or resistance to CC-220 on C1D1, C2D1, C2D15, 
C4D1, C4D15, C6D15, and EOT. Samples for pharmacogenomics on C1D1. See Section 6.6.
h For Cohort B, up to 3 subjects in each dose level at selected US sites may be selected for the following assessment (notified via IRT): To evaluate the pharmacodynamic (Pd) 
effects of CC-220 on Aiolos and Ikaros in mononuclear cells with a novel exploratory assay.  Samples taken on C1D1, C1D2 and C1D15. 
i Hematology sample collection contains a lymphocyte panel to support biomarker assessment of Pd effects on T-cell counts, as detailed in Section 6.6.
j Intensive PK samples will be drawn from selected subjects on C1D15 in addition to the samples drawn for sparse PK on all subjects.
k See Appendix D.
Approved
12.0
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EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
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Confidential and Proprietary
85
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
l See Section 6.3.4.
m Skeletal survey will be performed during Post Treatment Response Follow up phase if clinically indicated to confirm response or PD 
n For subjects who enter Post Treatment Response follow up, BMA (and, if possible, BMB) will be collected at confirmed PD instead of treatment discontinuation. 
o All subjects will be tested for hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (antiHBs), and hepatitis B core antibody (antiHBc) locally during screening.
p During Post-Tx Response FU, EMP radiological assessment is required every 3 months for those with a history of or clinical indication of EMPs only assessable 
radiographically.
Approved
12.0
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Approved
1.0
v

EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
86
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
Table 10:
Table of Events for Part 1 Cohort E (CC-220Dd): 28-day Cycle
Screening
Treatment
Safety Follow-
up
Post-Tx 
Response 
FU
EVENTS
-28 to -1
Cycle 1
Cycle 2 –4
(±2 days for all visits)
≥ Cycle 5 (±2 
days for all 
visits)
EOT
28 days 
after EOT 
(+ 3 d)
Every 28 
days and at 
D/C visit 
(+ 2 d)
D1
D8
D12
D15
D22
D26
D1
D8
D15
D22
D1
D15
STUDY ENTRY AND GENERAL ASSESSMENTS
Informed consent
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Inclusion/exclusion criteria
X
-
-
-
-
-
-
-
-
-
-
-
-
-
IRT registration
X
X
-
-
-
-
-
-
-
-
-
-
-
X
Prior cancer history
X
-
-
-
-
-
-
-
-
-
-
-
-
-
Medical history
X
-
-
-
-
-
-
-
-
-
-
-
-
-
Demographics
X
-
-
-
-
-
-
-
-
-
-
-
-
-
Prior disease history
X
-
-
-
-
-
-
-
-
-
-
-
-
-
Prior disease therapies
X
-
-
-
-
-
-
-
-
-
-
-
-
-
SAFETY ASSESSMENTS
Prior/concomitant medication 
evaluation
X (≤28 
days from 
Screening)
Continuous, until 28 days after last dose of study medication
Prior/concomitant procedures 
evaluation
X (≤28 
days from 
Screening)
Continuous, until 28 days after last dose of study medication
AE (AESI) evaluation
X
Continuous starting after informed consent signature, until 28 days after last dose of study medication
SPM surveillance
X
Continuous starting after informed consent signature, until 28 days after last dose of study medication  
Physical examination (includes VTE 
monitoring and ophthalmologic exam 
if clinically indicated)a, c
X
X
-
-
-
-
-
X
-
-
-
X
-
X
-
-
Vital signs (includes weight)r
X
X
X
X
X
X
-
X
X
X
X
X
-
X
X
-
Approved
12.0
v
Approved
1.0
v

EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
87
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
Table 10:
Table of Events for Part 1 Cohort E (CC-220Dd): 28-day Cycle (Continued)
Screening
Treatment
Safety Follow-
up
Post-Tx 
Response 
FU
EVENTS
-28 to -1
Cycle 1
Cycle 2 –4
(±2 days for all visits)
≥ Cycle 5 (±2 
days for all 
visits)
EOT
28 days 
after EOT 
(+ 3 d)
Every 28 
days and at 
D/C visit 
(+ 2 d)
D1
D8
D12
D15
D22
D26
D1
D8
D15
D22
D1
D15
ECG b
X
X
X
And during treatment if clinically indicated
X
-
-
Hematology c, h
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
X
Chemistry c
X
X
X
-
X
X
-
X
X
X
X
X
-
X
-
X
Renal function (CrCL) 
X
X
X
-
X
X
-
X
X
X
X
X
-
X
-
-
Urinalysis
X
Repeated only if clinically indicated
X
-
-
Pregnancy test for FCBP with regular 
or no menstrual cycles
X
X
-10 to -14 days and -24 hours prior to first dose 
weekly for 28 days after first dose, then every 28 days
X
X
-
Pregnancy test for FCBP with 
irregular menstrual cycles
X
X
-10 to -14 days and -24 hours prior to first dose 
weekly for 28 days after first dose, then every 14 days
X
14 and 28 days 
after last dose
-
Pregnancy counseling for all subjects 
j
X
X
-
-
-
-
-
X
-
-
-
X
-
X
-
-
Hepatitis B (HBV) serology local 
testing n
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
HBV DNA local o
X
If indicated, every 12 weeks during treatment, at the EOT Visit, and every 12 weeks for up to 6 months after the last dose of DARA
EFFICACY AND OTHER ASSESSMENTS
ECOG performance status c
X
X
-
-
-
-
-
X
-
-
-
X
-
X
-
X
Assessment of response (IMWG 
Uniform Response Criteria) d, k
-
-
-
-
-
-
-
X
-
-
-
X
-
X
-
X
Serum and urine protein 
electrophoresis
X
X
-
-
-
-
-
X
-
-
-
X
-
X
-
X
Serum and urine immunofixation e
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Serum free light chain assay
X
X
-
-
-
-
-
X
-
-
-
X
-
X
-
X
Approved
12.0
v
Approved
1.0
v

EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
88
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
Table 10:
Table of Events for Part 1 Cohort E (CC-220Dd): 28-day Cycle (Continued)
Screening
Treatment
Safety Follow-
up
Post-Tx 
Response 
FU
EVENTS
-28 to -1
Cycle 1
Cycle 2 –4
(±2 days for all visits)
≥ Cycle 5 (±2 
days for all 
visits)
EOT
28 days 
after EOT 
(+ 3 d)
Every 28 
days and at 
D/C visit 
(+ 2 d)
D1
D8
D12
D15
D22
D26
D1
D8
D15
D22
D1
D15
Quantitative serum immunoglobulin
X
X
-
-
-
-
-
X
-
-
-
X
-
X
-
X
β-2 microglobulin
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
EMP clinical assessment
X
X
-
-
-
-
-
X
-
-
-
X
-
X
-
X
EMP radiological assessment (only 
required if history of or clinical 
indication of EMPs only assessable 
radiographically)
X
-
-
-
-
-
-
Day 1 starting at C3, then every 3 cycles thereafter 
X
-
Xp
Skeletal Survey/CT Scan/MRI (Bone 
lesion) 
X
-
Repeated during treatment if clinically indicated to confirm response or PD
-
Xl
Bone marrow aspirate and/or biopsy 
sampling f
X
- Screening: BMA and, if possible, BMB for local % plasma cells and central cytogenetics and other biomarkers
-C2D15: BMA and if possible BMB at 3-6 hours post dose, for biomarkers 
- BMA and, if possible, BMB at CR confirmation and at PD/treatment discontinuation
- Optional BMA and/or BMB taken at any time point during treatment at request of investigator and prior to 
subsequent myeloma therapy
-
Xm
Whole blood sample for biomarkers g
-
X 
X
-
-
-
C2 and 
C4
-
C2 and 
C4
-
-
C6
X
-
-
Whole blood samples for PK i
-
-
X
-
X
-
-
-
X
X
-
-
-
-
-
-
COHORT E
Oral CC-220
-
Days 1-21/28-day cycle
-
-
-
Oral DEX
-
Days 1, 8, 15, 22/28-day cycle
-
-
-
IV DARA or SC DARA (as 
assigned)q, s
-
C1-2: Days 1, 8, 15, 22; C3-6: Days 1, 15; > C7: Day 1/28-day cycle
-
-
-
Approved
12.0
v
Approved
1.0
v

EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
89
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
Table 10:
Table of Events for Part 1 Cohort E (CC-220Dd): 28-day Cycle (Continued)
Screening
Treatment
Safety Follow-
up
Post-Tx 
Response 
FU
EVENTS
-28 to -1
Cycle 1
Cycle 2 –4
(±2 days for all visits)
≥ Cycle 5 (±2 
days for all 
visits)
EOT
28 days 
after EOT 
(+ 3 d)
Every 28 
days and at 
D/C visit 
(+ 2 d)
D1
D8
D12
D15
D22
D26
D1
D8
D15
D22
D1
D15
VTE prophylaxis
-
C1D1 to EOT
-
-
-
IP (CC-220, DARA, DEX, as 
applicable) accountability/compliance
-
X
X
-
X
X
-
X
X
X
X
X
-
X
-
-
Abbreviations: AE = adverse event; AESI = adverse events of special interest; BMA = bone marrow aspirate; BMB = bone marrow biopsy; C = Cycle; CR = complete response; 
CrCL = creatinine clearance; CT = computed tomography; D = Day; DARA = daratumumab; D/C = discontinuation; DEX = dexamethasone; ECG = electrocardiogram; ECOG = 
Eastern Cooperative Oncology Group; EMP = extramedullary plasmacytomas; EOT = End of Treatment; FCBP = female of child-bearing potential; FU = follow-up; IMWG = 
International Myeloma Working Group; IP = investigational product; IRT = Interactive Response Technology; IV = intravenous; MRI = magnetic resonance imaging; PD = 
progressive disease; PK = pharmacokinetics; Pd = pharmacodynamics; SPM = second primary malignancy; sPEP = serum protein electrophoresis; Tx = treatment; uPEP = urine 
protein electrophoresis; VTE = venous thromboembolism.
a Height will be included in the physical examination and only measured at Screening.
b ECG will be taken at time of median Tmax approximately 3-4 hours post first dose on C1D1, C1D8, and at EOT. Also, the ECG will be repeated during treatment if clinically 
indicated.
c On C1D1, safety laboratory assessments must be performed locally, in addition to central laboratory collection, to confirm that the subject continues to meet the required safety 
laboratory values prior to initiating IP.  However, if Screening assessments were performed within 72 hours of C1D1, safety laboratory (hematology and chemistry), physical 
examinations, and ECOG do not need to be repeated at C1D1.
d Refer to Appendix B for IMWG criteria.
e After C1D1, assessment to be taken only if myeloma paraprotein is not detected or too few to quantify in sPEP and uPEP assessments.
f Refer to Table 18 for details on BMA and BMB collection plan.
g Whole blood sample for biomarkers for all subjects: Samples drawn for Pd effects of CC-220 on Aiolos and other Pd biomarkers by protein expression on C1D1 and C1D12. 
Samples drawn for t-cell receptor clonality on C1D1, C2D15, C4D15 and EOT. Samples drawn for Pd effects of CC-220 on T-Cell activation on C1D1 and C1D12. Samples for 
Pd effects of CC-220 on immune cells in peripheral blood and association of baseline levels of these populations with response or resistance to CC-220 on C1D1, C2D1, C2D15, 
C4D1, C4D15, C6D15, and EOT. Samples for pharmacogenomics on C1D1.  See Section 6.6.
h Hematology sample collection contains a lymphocyte panel to support biomarker assessment of Pd effects on T-cell counts, as detailed in Section 6.6.
i Intensive PK samples will be drawn from selected subjects on C1D8 in addition to the samples drawn for sparse PK on all subjects.
j See Appendix D.
k See Section 6.3.4.
l Skeletal survey will be performed during Post Treatment Response Follow up phase if clinically indicated to confirm response or PD.
m For subjects who enter Post Treatment Response follow up, BMA (and, if possible, BMB) will be collected at confirmed PD instead of treatment discontinuation. 
n All subjects will be tested for hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (antiHBs), and hepatitis B core antibody (antiHBc) locally during screening.
o For subjects with serologic evidence of resolved HBV infection (ie, positive antiHBs or positive antiHBc) at Screening, HBV DNA testing by polymerase chain reaction (PCR)
must be performed locally at screening, every 12 weeks during treatment, at the End of Treatment Visit, and every 12 weeks for up to 6 months after the last dose of DARA. 
Approved
12.0
v
Approved
1.0
v

EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
90
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
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 
p During Post-Tx Response FU, EMP radiological assessment is required every 3 months for those with a history of or clinical indication of EMPs only assessable 
radiographically.
q Once the MTD and/or RP2D is determined in Cohort E (CC-220Dd), an additional 13 subjects will be enrolled at this dose level using SC DARA. See Section 7.2.1.1 for details 
of treatment schedule for SC DARA.
r For SC DARA, vital signs are to be measured at the following time points on C1D1: immediately before SC DARA administration; at the end of SC DARA administration (+ 10
minutes); 30 minutes (± 10 minutes) and 1 hour (± 10 minutes) after the end of SC DARA administration. 
s For SC DARA administration, all subjects will be observed for at least 6 hours after the end of the SC injection during C1D1 and, if deemed necessary by the Investigator, after 
subsequent injections.
Approved
12.0
v
Approved
1.0
v

EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
91
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
Table 11: Table of Events for Part 1 Cohort F (CC-220Vd): 21-day Cycle
Screening
Treatment
Safety 
Follow-
up
Post-Tx 
Response
FU
EVENTS
-28 to -1
Cycle 1
Cycle 2 –4
(±2 days for all visits)
Cycle 5-8 (±2 days for 
all visits)
> Cycle 9 (±2 days 
for all visits)
EOT
28 days 
after 
EOT 
(+ 3 d)
Every 21 
days and 
at D/C 
visit 
(+ 2 d)
D1
D4 D8 D11 D12 D15 D1 D4
D8
D11 D15 D1 D4 D8 D11 D15
D1
D8
D15
STUDY ENTRY AND GENERAL ASSESSMENTS
Informed consent
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Inclusion/exclusion criteria
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
IRT registration
X
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
X
Prior cancer history
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Medical history
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Demographics
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Prior disease history
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Prior disease therapies
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
SAFETY ASSESSMENTS
Prior/concomitant medication 
evaluation
X (≤28 days 
from 
Screening)
Continuous, until 28 days after last dose of study medication
Prior/concomitant procedures 
evaluation
X (≤28 days 
from 
Screening)
Continuous, until 28 days after last dose of study medication
AE (AESI) evaluation
X
Continuous starting after informed consent signature, until 28 days after last dose of study medication
SPM surveillance
X
Continuous starting after informed consent signature, until 28 days after last dose of study medication 
Physical examination (includes VTE 
monitoring and ophthalmologic exam if 
clinically indicated) a,c
X
X
-
-
-
-
-
X
-
-
-
-
X
-
-
-
-
X
-
-
X
-
-
Vital signs (includes weight)
X
X
-
X
-
X
X
X
-
X
-
X
X
-
-
-
-
X
-
-
X
X
-
Approved
12.0
v
Approved
1.0
v

EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
92
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
Table 11:
Table of Events for Part 1 Cohort F (CC-220Vd): 21-day Cycle (Continued)
Screening
Treatment
Safety 
Follow-
up
Post-Tx 
Response 
FU
EVENTS
-28 to -1
Cycle 1
Cycle 2 –4
(±2 days for all visits)
Cycle 5-8 (±2 days for 
all visits)
> Cycle 9 (±2 days 
for all visits)
EOT
28 days 
after 
EOT 
(+ 3 d)
Every 21 
days and 
at D/C 
visit
(+ 2 d)
D1
D4 D8 D11 D12 D15 D1 D4
D8
D11 D15 D1 D4 D8 D11 D15
D1
D8
D15
ECG b
X
X
-
X
And during treatment if clinically indicated
X
-
-
Hematology c, k
X
X
-
X
-
X
X
X
-
X
-
X
X
-
-
-
X
X
-
X
X
-
X
Chemistry c
X
X
-
X
-
-
X
X
-
X
-
X
X
-
-
-
-
X
-
-
X
-
X
Renal function (CrCL) 
X
X
-
X
-
-
X
X
-
X
-
X
X
-
-
-
-
X
-
-
X
-
-
Urinalysis
X
Repeated only if clinically indicated
X
-
-
Pregnancy test for FCBP with regular 
or no menstrual cycles
X
X
-10 to -14 days and -24 hours prior to first dose 
weekly for 21 days after first dose, then every 21 days
X
X
-
Pregnancy test for FCBP with irregular 
menstrual cycles
X
X
-10 to -14 days and -24 hours prior to first dose 
weekly for 21 days after first dose, then every 14 days
X
14 and 28 
days after 
last dose
-
Pregnancy counseling for all subjects i
X
X
-
-
-
-
-
X
-
-
-
-
X
-
-
-
-
X
-
-
X
-
-
Hepatitis B (HBV) serology local 
testing p
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
EFFICACY AND OTHER ASSESSMENTS
ECOG performance status c
X
X
-
-
-
-
-
X
-
-
-
-
X
-
-
-
-
X
-
-
X
-
X
Assessment of response (IMWG 
Uniform Response Criteria) d, j
-
-
-
-
-
-
-
X
-
-
-
-
X
-
-
-
-
X
-
-
X
-
X
Serum and urine protein electrophoresis
X
X
-
-
-
-
-
X
-
-
-
-
X
-
-
-
-
X
-
-
X
-
X
Serum and urine immunofixation e
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Serum free light chain assay
X
X
-
-
-
-
-
X
-
-
-
-
X
-
-
-
-
X
-
-
X
-
X
Quantitative serum immunoglobulin
X
X
-
-
-
-
-
X
-
-
-
-
X
-
-
-
-
X
-
-
X
-
X
Approved
12.0
v
Approved
1.0
v

EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
93
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
Table 11:
Table of Events for Part 1 Cohort F (CC-220Vd): 21-day Cycle (Continued)
Screening
Treatment
Safety 
Follow-
up
Post-Tx 
Response 
FU
EVENTS
-28 to -1
Cycle 1
Cycle 2 –4
(±2 days for all visits)
Cycle 5-8 (±2 days for 
all visits)
> Cycle 9 (±2 days 
for all visits)
EOT
28 days 
after 
EOT 
(+ 3 d)
Every 21 
days and 
at D/C 
visit 
(+ 2 d)
D1
D4 D8 D11 D12 D15 D1 D4
D8
D11 D15 D1 D4 D8 D11 D15
D1
D8
D15
β-2 microglobulin
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
EMP clinical assessment
X
X
-
-
-
-
-
X
-
-
-
-
X
-
-
-
-
X
-
-
X
-
X
EMP radiological assessment (only 
required if history of or clinical 
indication of EMPs only assessable 
radiographically)
X
-
-
-
-
-
-
Day 1 starting at C3, then every 3 cycles thereafter 
X
-
Xq
Skeletal Survey/CT Scan/MRI (Bone 
lesion) 
X
Repeated during treatment if clinically indicated to confirm response or PD
-
Xo
Bone marrow aspirate and/or biopsy 
sampling 
X
- Screening: BMA and, if possible, BMB for local % plasma cells and central cytogenetics and other biomarkers
-C2D11: BMA and if possible BMB at 3-6 hours post dose, for biomarkers 
- BMA and, if possible, BMB at CR confirmation and at PD/treatment discontinuation
- Optional BMA and/or BMB taken at any time point during treatment at request of investigator and prior to 
subsequent myeloma therapy
-
Xn
Whole blood sample for biomarkers for 
all subjects g, h
-
X
-
-
-
X
-
C2 
an
d 
C4
-
-
-
C2 
and 
C4
-
-
-
-
C6
-
-
-
X
-
-
Additional whole blood sample for 
biomarkers for selected subjects at 
select US sites (notified via IRT) l 
-
D1 
and 
D2
-
-
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Whole blood samples for PK m
-
-
-
X
-
-
X
-
-
X
-
X
-
-
-
-
-
-
-
-
-
-
-
COHORT F 
Oral CC-220
-
Days 1-14/21-day cycle
-
-
-
Oral DEX
-
Days 1, 8, 15/21-day cycle
-
-
-
Approved
12.0
v
Approved
1.0
v

EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
94
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
Screening
Treatment
Safety 
Follow-
up
Post-Tx 
Response 
FU
EVENTS
-28 to -1
Cycle 1
Cycle 2 –4
(±2 days for all visits)
Cycle 5-8 (±2 days for 
all visits)
> Cycle 9 (±2 days 
for all visits)
EOT
28 days 
after 
EOT 
(+ 3 d)
Every 21 
days and 
at D/C 
visit 
(+ 2 d)
D1
D4 D8 D11 D12 D15 D1 D4
D8
D11 D15 D1 D4 D8 D11 D15
D1
D8
D15
SC BTZ
-
C1-8: Days 1, 4, 8, 11; > C9: Days 1, 8/21-day cycle
-
-
-
Table 11:
Table of Events for Part 1 Cohort F (CC-220Vd): 21-day Cycle (Continued)
Screening
Treatment
Safety 
Follow-
up
Post-Tx 
Response 
FU
EVENTS
-28 to -1
Cycle 1
Cycle 2 –4
(±2 days for all visits)
Cycle 5-8 (±2 days for 
all visits)
> Cycle 9 (±2 days 
for all visits)
EOT
28 days 
after 
EOT 
(+ 3 d)
Every 21 
days and 
at D/C 
visit 
(+ 2 d)
D1
D4 D8 D11 D12 D15 D1 D4
D8
D11 D15 D1 D4 D8 D11 D15
D1
D8
D15
VTE prophylaxis
-
C1D1 to EOT
-
-
-
IP (CC-220, DEX, BTZ, as applicable) 
accountability/compliance
-
X
-
X
-
-
X
X
-
X
-
X
X
-
-
-
-
X
-
-
X
-
-
Abbreviations: AE = adverse event; AESI = adverse events of special interest; BMA = bone marrow aspirate; BMB = bone marrow biopsy; BTZ = bortezomib; C = Cycle; CR = 
complete response; CrCL = creatinine clearance; CT = computed tomography; DEX = dexamethasone; D = Day; D/C = discontinuation; ECG = electrocardiogram; ECOG = 
Eastern Cooperative Oncology Group; EMP = extramedullary plasmacytomas; EOT = End of Treatment; FCBP = female of child-bearing potential; FU = follow-up; IMWG = 
International Myeloma Working Group; IP = investigational product; IRT = Interactive Response Technology; MRI = magnetic resonance imaging; Pd = pharmacodynamics; PD 
= progressive disease; PK = pharmacokinetics; sPEP = serum protein electrophoresis; SPM = second primary malignancy; SC = subcutaneous; Tx = treatment; uPEP = urine 
protein electrophoresis; VTE = venous thromboembolism.
a Height will be included in the Physical examination and only measured at Screening.
b ECG will be taken at time of median Tmax approximately 3-4 hours post first dose on C1D1, C1D8, and at EOT. Also, the ECG will be repeated during treatment if clinically 
indicated.
c On C1D1, safety laboratory assessments must be performed locally, in addition to central laboratory collection, to confirm that the subject continues to meet the required safety 
laboratory values prior to initiating IP.  However, if Screening assessments were performed within 72 hours of C1D1, safety laboratory (hematology and chemistry), physical 
examinations, and ECOG do not need to be repeated at C1D1.
d Refer to Appendix B for IMWG criteria.
e After C1D1, assessment to be taken only if myeloma paraprotein is not detected or too few to quantify in sPEP and uPEP assessments.
f Screening and C2D11 Bone marrow sampling for biomarkers.
g Whole blood sample for biomarkers for all subjects:Samples drawn for Pd effects on CC-220 on Aiolos and other Pd biomarkers by protein expression on C1D1 and C1D12. 
Samples drawn for t-cell receptor clonality on C1D1, C2D15, C4D15 and EOT. See Section 6.6.
Approved
12.0
v
Approved
1.0
v

EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
95
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
h Additional biomarker sampling for all subjects: Samples drawn for Pd effects of CC-220 on T-cell Activation on C1D1 and C1D12. Samples drawn for Pd effects of CC-220 on 
immune cells in peripheral blood on C1D1, C2D1, C2D15, C4D1, C4D15, C6D15, and EOT. Sample drawn for pharmacogenomics of CC-220 on C1D1. See Section 6.6.
i See Appendix D.
j See Section 6.3.4.
k Hematology sample collection contains a lymphocyte panel to support biomarker assessment of Pd effects on T-cell counts, as detailed in Section 6.6.
l For Cohort F, up to 3 subjects in each dose level at selected US sites may be selected for the following assessment (notified via IRT): To evaluate the pharmacodynamic (Pd) 
effects of CC-220 on Aiolos and Ikaros in mononuclear cells with a novel exploratory assay (C1D1, C1D2, C1D11).
m Intensive PK samples will be drawn from selected subjects C1D8 in addition to the samples drawn for sparse PK on all subjects.
n For subjects who enter Post Treatment Response follow up, BMA (and, if possible, BMB) will be collected at confirmed PD instead of treatment discontinuation. 
o Skeletal survey will be performed during Post Treatment Response Follow up phase if clinically indicated to confirm response or PD.
p All subjects will be tested for hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (antiHBs), and hepatitis B core antibody (antiHBc) locally during screening.
q During Post-Tx Response FU, EMP radiological assessment is required every 3 months for those with a history of or clinical indication of EMPs only assessable 
radiographically.
Approved
12.0
v
Approved
1.0
v

EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
96
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
Table 12:
Table of Events for Part 1 Cohort G1 (CC-220Kd once weekly): 28-day Cycle
Screening
Treatment
Safety 
Follow-up
Post-Tx Response 
FU
EVENTS
-28 to -1
Cycle 1
Cycle 2 –4
(±2 days for all visits)
≥ Cycle 5 
(±2 days for all visits)
EOT
28 days 
after EOT 
(+ 3 d)
Every 28 days and 
at D/C visit (+ 2 d)
D1
D8
D15
D1
D8
D15
D1
D8
D15
STUDY ENTRY AND GENERAL ASSESSMENTS
Informed consent
X
-
-
-
-
-
-
-
-
-
-
-
-
Inclusion/exclusion criteria
X
-
-
-
-
-
-
-
-
-
-
IRT registration
X
X
-
-
-
-
-
-
-
-
X
Prior cancer history
X
-
-
-
-
-
-
-
-
-
-
Medical history
X
-
-
-
-
-
-
-
-
-
-
Demographics
X
-
-
-
-
-
-
-
-
-
-
Prior disease history
X
-
-
-
-
-
-
-
-
-
-
Prior disease therapies
X
-
-
-
-
-
-
-
-
-
-
SAFETY ASSESSMENTS
Prior/concomitant medication 
evaluation
X (≤28 
days from 
Screening)
Continuous, until 28 days after last dose of study medication
Prior/concomitant procedures 
evaluation
X (≤28 
days from 
Screening)
Continuous, until 28 days after last dose of study medication
AE (AESI) evaluation
X
Continuous starting after informed consent signature, until 28 days after last dose of study medication
SPM surveillance
X
Continuous starting after informed consent signature, until 28 days after last dose of study medication 
Physical examination (includes VTE 
monitoring and ophthalmologic exam 
if clinically indicated)a, c
X
X
-
-
X
-
-
X
-
-
X
-
-
Vital signs (includes weight)
X
X
X
X
X
X
X
X
X
X
X
X
-
ECG b
X
X
X
And during treatment if clinically indicated
X
-
-
Approved
12.0
v
Approved
1.0
v

EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
97
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
Table 12:
Table of Events for Part 1 Cohort G1 (CC-220Kd once weekly): 28-day Cycle (Continued)
Screening
Treatment
Safety 
Follow-up
Post-Tx Response 
FU
EVENTS
-28 to -1
Cycle 1
Cycle 2 –4
(±2 days for all visits)
≥ Cycle 5 
(±2 days for all visits)
EOT
28 days 
after EOT 
(+ 3 d)
Every 28 days and 
at D/C visit (+ 2 d)
D1
D8
D15
D1
D8
D15
D1
D8
D15
ECHO/MUGA
X
-
-
-
-
-
-
-
-
-
-
-
-
Hematology c,o
X
X
X
X
X
X
X
X
-
X
X
-
X
Chemistry c
X
X
X
X
X
X
X
X
-
-
X
-
X
Renal function (CrCL) 
X
X
X
X
X
X
X
X
-
-
X
-
-
Urinalysis
X
Repeat only if clinically indicated
X
-
-
Pregnancy test for FCBP with regular 
or no menstrual cycles
X
X
10 to -14 days and -24 hours prior to first dose 
weekly for 28 days after first dose, then every 28 days
X
X
-
Pregnancy test for FCBP with 
irregular menstrual cycles
X
X
-10 to -14 days and -24 hours prior to first dose 
weekly for 28 days after first dose, then every 14 days
X
14 and 28 
days after 
last dose
-
Pregnancy counseling for all subjects 
j
X
X
-
-
X
-
-
X
-
-
X
-
-
Hepatitis B (HBV) serology local 
testing p
X
-
-
-
-
-
-
-
-
-
-
-
-
EFFICACY AND OTHER ASSESSMENTS
ECOG performance status c
X
X
-
-
X
-
-
X
-
-
X
-
X
Assessment of response (IMWG 
Uniform Response Criteria) d, k
-
-
-
-
X
-
-
X
-
-
X
-
X
Serum and urine protein 
electrophoresis
X
X
-
-
X
-
-
X
-
-
X
-
X
Serum and urine immunofixation e
X
-
-
-
-
-
-
-
-
-
-
-
-
Serum free light chain assay
X
X
-
-
X
-
-
X
-
-
X
-
X
Approved
12.0
v
Approved
1.0
v

EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
98
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
Table 12:
Table of Events for Part 1 Cohort G1 (CC-220Kd once weekly): 28-day Cycle (Continued)
Screening
Treatment
Safety 
Follow-up
Post-Tx Response 
FU
EVENTS
-28 to -1
Cycle 1
Cycle 2 –4
(±2 days for all visits)
≥ Cycle 5 
(±2 days for all visits)
EOT
28 days 
after EOT 
(+ 3 d)
Every 28 days and 
at D/C visit (+ 2 d)
D1
D8
D15
D1
D8
D15
D1
D8
D15
Quantitative serum immunoglobulin
X
X
-
-
X
-
-
X
-
-
X
-
X
β-2 microglobulin
X
-
-
-
-
-
-
-
-
-
-
-
-
EMP clinical assessment
X
X
-
-
X
-
-
X
-
-
X
-
X
EMP radiological assessment (only 
required if history of or clinical 
indication of EMPs only assessable 
radiographically)
X
-
-
-
Day 1 starting at C3, then every 3 cycles thereafter
X
-
Xq
Skeletal Survey/CT Scan/MRI (Bone 
lesion) 
X
Repeated during treatment if clinically indicated to confirm response or PD
-
Xl
Bone marrow aspirate and/or biopsy 
sampling f
X
- Screening: BMA and, if possible, BMB for local % plasma cells and central cytogenetics and other 
biomarkers
-C2D15: BMA and if possible BMB at 3-6 hours post dose, for biomarkers 
- BMA and, if possible, BMB at CR confirmation and at PD/treatment discontinuation
- Optional BMA and/or BMB taken at any time point during treatment at request of investigator and prior to 
subsequent myeloma therapy
-
Xm
Whole blood sample for biomarkers g
-
X
-
X
C2 and 
C4
-
C2 and 
C4
-
-
C6
X
-
-
Additional whole blood sample for 
biomarkers for selected subjects at 
select US sites (notified via IRT) h
-
D1 and D2
-
X
-
-
-
-
-
-
-
-
-
Whole blood samples for PK i
-
-
X
X
-
X
X
-
-
-
-
-
-
Approved
12.0
v
Approved
1.0
v

EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
99
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
Table 12:
Table of Events for Part 1 Cohort G1 (CC-220Kd once weekly): 28-day Cycle (Continued)
Screening
Treatment
Safety 
Follow-up
Post-Tx Response 
FU
EVENTS
-28 to -1
Cycle 1
Cycle 2 –4
(±2 days for all visits)
≥ Cycle 5 
(±2 days for all visits)
EOT
28 days 
after EOT 
(+ 3 d)
Every 28 days and 
at D/C visit (+ 2 d)
D1
D8
D15
D1
D8
D15
D1
D8
D15
COHORT G1
Oral CC-220
-
Days 1-21/28-day cycle
-
-
-
Oral DEX
-
Days 1, 8, 15, 22/28-day cycle
-
-
-
IV CFZ
-
Days 1, 8, 15/28-day cycle
-
-
-
Oral and IV hydration n
-
X
As indicated
-
-
-
VTE prophylaxis
-
C1D1 to EOT
-
-
-
IP (CC-220, DEX, CFZ as 
applicable) accountability/compliance
-
X
X
X
X
X
X
X
X
X
X
-
-
Abbreviations: AE = adverse event; AESI = adverse events of special interest; BMA = bone marrow aspirate; BMB = bone marrow biopsy; C = Cycle; CFZ = carfilzomib; CR = 
complete response; CrCL = creatinine clearance; CT = computed tomography; D = Day; D/C = discontinuation; DEX = dexamethasone; ECG = electrocardiogram; ECHO = 
echocardiogram; ECOG = Eastern Cooperative Oncology Group; EMP = extramedullary plasmacytomas; EOT = End of Treatment; FCBP = female of child-bearing potential; FU 
= follow-up; HBV = Hepatitis B virus; IMWG = International Myeloma Working Group; IRT = Interactive Response Technology; MRI = magnetic resonance imaging; PD = 
progressive disease; PK = pharmacokinetics; IP = investigational product; IV = intravenous; MUGA = multiple gated acquisition scan; Pd = pharmacodynamics; SPM = second 
primary malignancy; sPEP = serum protein electrophoresis; Tx = treatment; uPEP = urine protein electrophoresis; VTE = venous thromboembolism.
a Height will be included in the physical examination and only measured at Screening.
b ECG will be taken at time of median Tmax approximately 3-4 hours post first dose on C1D1, C1D8, and at EOT. Also, the ECG will be repeated during treatment if clinically 
indicated.
c On C1D1, safety laboratory assessments must be performed locally, in addition to central laboratory collection, to confirm that the subject continues to meet the required safety 
laboratory values prior to initiating IP.  However, if Screening assessments were performed within 72 hours of C1D1, safety laboratory (hematology and chemistry), physical 
examinations, and ECOG do not need to be repeated at C1D1.
d Refer to Appendix B for IMWG criteria.
e After C1D1, assessment to be taken only if myeloma paraprotein is not detected or too few to quantify in sPEP and uPEP assessments.
f Refer to Table 18 for details on BMA/BMB collection plan.
g Whole blood sample for biomarkers for all subjects: Samples drawn for Pd effects of CC-220 on Aiolos and other Pd biomarkers by protein expression on C1D1 and C1D15. 
Samples drawn for t-cell receptor clonality on C1D1, C2D15, C4D15 and EOT. Samples for Pd effects of CC-220 on immune cells in peripheral blood and association of 
baseline levels of these populations with response or resistance to CC-220 on C1D1, C2D1, C2D15, C4D1, C4D15, C6D15, and EOT. Samples drawn for Pd effects of CC-220 
on T-Cell activation on C1D1 and C1D15. Samples for pharmacogenomics on C1D1. See Section 6.6.
h In Cohort G1, up to 3 subjects in each dose level at select US sites may be selected for the following assessment (notified via IRT): To evaluate the pharmacodynamic (Pd) 
effects of CC-220 on Aiolos and Ikaros in mononuclear cells with a novel exploratory assay on C1D1, C1D2, C1D15. See Section 6.6.
Approved
12.0
v
Approved
1.0
v

EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
100
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
i Intensive PK samples will be drawn from selected subjects (notified via IRT) on C1D8 in addition to the samples drawn for sparse PK on all subjects. See Section 6.5.
j See Appendix D.
k See Section 6.3.4.
l Skeletal survey will be performed during Post Treatment Response Follow up phase if clinically indicated to confirm response or PD.
m For subjects who enter Post Treatment Response Follow up, BMA (and, if possible, BMB) will be collected at confirmed PD instead of treatment discontinuation.
n Oral hydration should start 48 hours prior to C1D1. IV hydration before dosing (recommended) and after (if needed) during Cycle 1. Continue oral and/or IV hydration in 
subsequent cycles if necessary. 
o Hematology sample collection containing a lymphocyte panel to support biomarker assessment. See Section 6.6.
p All subjects will be tested for hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (antiHBs), and hepatitis B core antibody (antiHBc) locally during screening.
q During Post-Tx Response FU, EMP radiological assessment is required every 3 months for those with a history of or clinical indication of EMPs only assessable 
radiographically.
Approved
12.0
v
Approved
1.0
v

EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
101
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
Table 13:
Table of Events for Part 1 Cohort G2 (CC-220Kd twice weekly): 28-day Cycle
Screening
Treatment
Safety 
Follow-up
Post-Tx Response 
FU
EVENTS
-28 to -1
Cycle 1
Cycle 2 –4
(±2 days for all visits)
≥ Cycle 5 
(±2 days for all visits)
EOT
28 days 
after EOT 
(+ 3 d)
Every 28 days and 
at D/C visit (+ 2 d)
D1
D2
D8
D9 D15
D16
D1 D2 D8 D9 D15 D16 D1
D2
D8
D9
D15
D16
STUDY ENTRY AND GENERAL ASSESSMENTS
Informed consent
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Inclusion/exclusion criteria
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
IRT registration
X
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
X
Prior cancer history
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Medical history
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Demographics
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Prior disease history
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Prior disease therapies
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
SAFETY ASSESSMENTS
Prior/concomitant medication 
evaluation
X (≤28 
days from 
Screening)
Continuous, until 28 days after last dose of study medication
Prior/concomitant procedures 
evaluation
X (≤28 
days from 
Screening)
Continuous, until 28 days after last dose of study medication
AE (AESI) evaluation
X
Continuous starting after informed consent signature, until 28 days after last dose of study medication
SPM surveillance
X
Continuous starting after informed consent signature, until 28 days after last dose of study medication 
Physical examination (includes VTE 
monitoring and ophthalmologic exam 
if clinically indicated)a, c
X
X
-
-
-
-
-
X
-
-
-
-
-
X
-
-
-
-
-
X
-
-
Vital signs (includes weight)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
ECG b
X
X
-
X
And during treatment if clinically indicated
X
-
-
Approved
12.0
v
Approved
1.0
v

EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
102
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
Table 13:
Table of Events for Part 1 Cohort G2 (CC-220Kd twice weekly): 28-day Cycle (Continued)
Screening
Treatment
Safety 
Follow-up
Post-Tx Response 
FU
EVENTS
-28 to -1
Cycle 1
Cycle 2 –4
(±2 days for all visits)
≥ Cycle 5 
(±2 days for all visits)
EOT
28 days 
after EOT 
(+ 3 d)
Every 28 days and 
at D/C visit (+ 2 d)
D1
D2
D8
D9 D15
D16
D1 D2 D8 D9 D15 D16 D1
D2
D8
D9
D15
D16
ECHO/MUGA
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Hematology c, o
X
X
-
X
-
X
-
X
-
X
-
X
-
X
-
-
-
X
-
X
-
X
Chemistry c
X
X
-
X
-
X
-
X
-
X
-
X
-
X
-
-
-
-
-
X
-
X
Renal function (CrCL) 
X
X
-
X
-
X
-
X
-
X
-
X
-
X
-
-
-
-
-
X
-
-
Urinalysis
X
Repeat only if clinically indicated
X
-
-
Pregnancy test for FCBP with regular 
or no menstrual cycles
X
X
10 to -14 days and -24 hours prior to first dose 
weekly for 28 days after first dose, then every 28 days
X
X
-
Pregnancy test for FCBP with 
irregular menstrual cycles
X
X
-10 to -14 days and -24 hours prior to first dose 
weekly for 28 days after first dose, then every 14 days
X
14 and 28 
days after 
last dose
-
Pregnancy counseling for all subjects 
j
X
X
-
-
-
-
-
X
-
-
-
-
-
X
-
-
-
-
-
X
-
-
Hepatitis B (HBV) serology local 
testing p
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
EFFICACY AND OTHER ASSESSMENTS
ECOG performance status c
X
X
-
-
-
-
-
X
-
-
-
-
-
X
-
-
-
-
-
X
-
X
Assessment of response (IMWG 
Uniform Response Criteria) d, k
-
-
-
-
-
-
-
X
-
-
-
-
-
X
-
-
-
-
-
X
-
X
Serum and urine protein 
electrophoresis
X
X
-
-
-
-
-
X
-
-
-
-
-
X
-
-
-
-
-
X
-
X
Serum and urine immunofixation e
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Serum free light chain assay
X
X
-
-
-
-
-
X
-
-
-
-
-
X
-
-
-
-
-
X
-
X
Quantitative serum immunoglobulin
X
X
-
-
-
-
-
X
-
-
-
-
-
X
-
-
-
-
-
X
-
X
β-2 microglobulin
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Approved
12.0
v
Approved
1.0
v

EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
103
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
Table 13:
Table of Events for Part 1 Cohort G2 (CC-220Kd twice weekly): 28-day Cycle (Continued)
Screening
Treatment
Safety 
Follow-up
Post-Tx Response 
FU
EVENTS
-28 to -1
Cycle 1
Cycle 2 –4
(±2 days for all visits)
≥ Cycle 5 
(±2 days for all visits)
EOT
28 days 
after EOT 
(+ 3 d)
Every 28 days and 
at D/C visit (+ 2 d)
D1
D2
D8
D9 D15
D16
D1 D2 D8 D9 D15 D16 D1
D2
D8
D9
D15
D16
EMP clinical assessment
X
X
-
-
-
-
-
X
-
-
-
-
-
X
-
-
-
-
-
X
-
X
EMP radiological assessment (only 
required if history of or clinical 
indication of EMPs only assessable 
radiographically)
X
-
-
-
-
-
-
Day 1 starting at C3, then every 3 cycles thereafter 
X
-
Xq
Skeletal Survey/CT Scan/MRI (Bone 
lesion) 
X
Repeated during treatment if clinically indicated to confirm response or PD
-
Xl
Bone marrow aspirate and/or biopsy 
sampling f
X
- Screening: BMA and, if possible, BMB for local % plasma cells and central cytogenetics and other 
biomarkers
-C2D15: BMA and if possible BMB at 3-6 hours post dose, for biomarkers 
- BMA and, if possible, BMB at CR confirmation and at PD/treatment discontinuation
- Optional BMA and/or BMB taken at any time point during treatment at request of investigator and prior to 
subsequent myeloma therapy
-
Xm
Whole blood sample for biomarkers g
-
X
-
-
-
X
-
C2 
and 
C4
-
-
-
C2 
and 
C4
-
-
-
-
-
C6
-
X
-
-
Additional whole blood sample for 
biomarkers for selected subjects at 
select US sites (notified via IRT) h
-
X
X
-
-
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Whole blood samples for PK i
-
-
-
X
-
X
-
-
-
X
-
X
-
-
-
-
-
-
-
-
-
-
Approved
12.0
v
Approved
1.0
v

EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
104
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
Table 13:
Table of Events for Part 1 Cohort G2 (CC-220Kd twice weekly): 28-day Cycle (Continued)
Screening
Treatment
Safety 
Follow-up
Post-Tx Response 
FU
EVENTS
-28 to -1
Cycle 1
Cycle 2 –4
(±2 days for all visits)
≥ Cycle 5 
(±2 days for all visits)
EOT
28 days 
after EOT 
(+ 3 d)
Every 28 days and 
at D/C visit (+ 2 d)
D1
D2
D8
D9 D15
D16
D1 D2 D8 D9 D15 D16 D1
D2
D8
D9
D15
D16
COHORT G2
Oral CC-220
-
Days 1-21/28-day cycle
-
-
-
Oral DEX
-
Days 1, 2, 8, 9, 15, 16, 22, 23/28-day cycle
-
-
-
IV CFZ
-
Days 1, 2, 8, 9, 15, 16/28-day cycle
-
-
-
Oral and IV hydration n
-
X
As indicated 
-
-
-
VTE prophylaxis
-
C1D1 to EOT
-
-
-
IP (CC-220, DEX, CFZ as 
applicable) accountability/compliance
-
X
-
X
-
X
-
X
-
X
-
X
-
X
-
X
-
X
-
X
-
-
Abbreviations: AE = adverse event; AESI = adverse events of special interest; BMA = bone marrow aspirate; BMB = bone marrow biopsy; C = Cycle; CFZ = carfilzomib; CR = 
complete response; CrCL = creatinine clearance; CT = computed tomography; D = Day; D/C = discontinuation; DEX = dexamethasone; ECG = electrocardiogram; ECHO = 
echocardiogram; ECOG = Eastern Cooperative Oncology Group; EMP = extramedullary plasmacytomas; EOT = End of Treatment; FCBP = female of child-bearing potential; FU 
= follow-up; HBV = Hepatitis B virus; IMWG = International Myeloma Working Group; IRT = Interactive Response Technology; MRI = magnetic resonance imaging; PD = 
progressive disease; PK = pharmacokinetics; IP = investigational product; IV = intravenous; MUGA = multiple gated acquisition scan; Pd = pharmacodynamics; SPM = second 
primary malignancy; sPEP = serum protein electrophoresis; Tx = treatment; uPEP = urine protein electrophoresis; VTE = venous Thromboembolism.
a Height will be included in the physical examination and only measured at Screening.
b ECG will be taken at time of median Tmax approximately 3-4 hours post first dose on C1D1, C1D8, and at EOT. Also, the ECG will be repeated during treatment if clinically 
indicated.
c On C1D1, safety laboratory assessments must be performed locally, in addition to central laboratory collection, to confirm that the subject continues to meet the required safety 
laboratory values prior to initiating IP.  However, if Screening assessments were performed within 72 hours of C1D1, safety laboratory (hematology and chemistry), physical 
examinations, and ECOG do not need to be repeated at C1D1.
d Refer to Appendix B for IMWG criteria.
e After C1D1, assessment to be taken only if myeloma paraprotein is not detected or too few to quantify in sPEP and uPEP assessments.
f Refer to Table 18 for details on BMA/BMB collection plan.
g Whole sample for biomarkers for all subjects: Samples drawn for Pd effects of CC-220 on Aiolos and other Pd biomarkers by protein expression on C1D1 and C1D15. Samples 
drawn for t-cell receptor clonality on C1D1, C2D15, C4D15 and EOT. Samples for Pd effects of CC-220 on immune cells in peripheral blood and association of baseline levels 
of these populations with response or resistance to CC-220 on C1D1, C2D1, C2D15, C4D1, C4D15, C6D15, and EOT. Samples drawn for Pd effects of CC-220 on T-Cell 
activation on C1D1 and C1D15. Samples for pharmacogenomics on C1D1. See Section 6.6.
h For Cohort G2, up to 3 subjects in each dose level at select US sites may be selected for the following assessment (notified via IRT): To evaluate the pharmacodynamic (Pd) 
effects of CC-220 on Aiolos and Ikaros in mononuclear cells with a novel exploratory assay on C1D1, C1D2, C1D15. See Section 6.6.
i Intensive PK samples will be drawn from selected subjects (notified via IRT) on C1D8 in addition to the samples drawn for sparse PK on all subjects. See Section 6.5.
j See Appendix D.
Approved
12.0
v
Approved
1.0
v

EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
105
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
k See Section 6.3.4.
l Skeletal survey will be performed during Post Treatment Response Follow up phase if clinically indicated to confirm response or PD.
m For subjects who enter Post Treatment Response Follow up, BMA (and, if possible, BMB) will be collected at confirmed PD instead of treatment discontinuation.
n Oral hydration should start 48 hours prior to C1D1. IV hydration before dosing (recommended) and after (if needed) during Cycle 1. Continue oral and/or IV hydration in 
subsequent cycles if necessary. See Section 7.2.4.
o Hematology sample collection containing a lymphocyte panel to support biomarker assessment. See Section 6.6.
p All subjects will be tested for hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (antiHBs), and hepatitis B core antibody (antiHBc) locally during screening.
q During Post-Tx Response FU, EMP radiological assessment is required every 3 months for those with a history of or clinical indication of EMPs only assessable
radiographically.
Approved
12.0
v
Approved
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v

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Table 14:
Table of Events for Part 2 Cohorts C (monotherapy), D, and I (CC-220+DEX): 28-day Cycle
Screening
Treatment
Safety 
Follow-
up
Post-Tx 
Response 
FU
Long 
Term FU
EVENTS
-28 to -1
Cycle 1
Cycle 2-4
(±2 days for all visits)
≥Cycle 5
(±2 days for all 
visits)
EOT
28 days 
after 
EOT 
(+ 3 d)
Every 28 
days and at 
D/C visit 
(+ 2 d)
Every 3 
months 
for 5
years
D1
D8
D15
D1
D15
D1
STUDY ENTRY AND GENERAL ASSESSMENTS
Informed consent
X
-
-
-
-
-
-
-
-
-
-
Inclusion/exclusion criteria
X
-
-
-
-
-
-
-
IRT registration
X
X
-
-
-
-
-
X
Prior cancer history
X
-
-
-
-
-
-
-
Medical historyp
X
-
-
-
-
-
-
-
Demographics
X
-
-
-
-
-
-
-
Prior disease history
X
-
-
-
-
-
-
-
Prior disease therapies
X
-
-
-
-
-
-
-
SAFETY ASSESSMENTS
Prior/concomitant medication evaluation
X (≤28 
days from 
Screening)
Continuous, until 28 days after last dose of study medication
-
Prior/concomitant procedures evaluation
X (≤28 
days from 
Screening)
Continuous, until 28 days after last dose of study medication
-
AE (AESI) evaluation
X
Continuous starting after informed consent signature, until 28 days after last dose of study medication
-
SPM surveillance
X
Continuous starting after informed consent signature, until the end of the 5-year Long-term Follow-up phase
Physical examination (includes VTE 
monitoring and ophthalmologic exam if 
clinically indicated) a, c
X
X
-
-
X
-
X
X
-
-
-
Vital signs (includes weight)
X
X
X
X
X
X
X
X
X
-
-
Approved
12.0
v
Approved
1.0
v

EDMS Doc. Number: 25858146 - 20867538
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Table 14:
Table of Events for Part 2 Cohorts C (monotherapy), D, and I (CC-220+DEX): 28-day Cycle (Continued)
Screening
Treatment
Safety 
Follow-
up
Post-Tx 
Response 
FU
Long 
Term FU
EVENTS
-28 to -1
Cycle 1
Cycle 2-4
(±2 days for all visits)
≥ Cycle 5
(±2 days for all 
visits)
EOT
28 days 
after 
EOT 
(+ 3 d)
Every 28 
days and at 
D/C visit  
(+ 2 d)
Every 3 
months 
for 5
years
D1
D8
D15
D1
D15
D1
ECG b
X
X
X
And during treatment if clinically indicated
X
-
-
-
Hematology c
X
X
X
X
X
X
X
X
-
X
-
Chemistry c
X
X
X
X
X
X
X
X
-
X
-
Renal function (CrCl)
X
X
X
X
X
X
X
X
-
-
-
Urinalysis
X
Repeated only if clinically indicated
X
-
-
-
Pregnancy test for FCBP with regular or 
no menstrual cycles
X
X
-10 to -14 days and -24 hours prior to first dose 
weekly for 28 days after first dose, then every 28 days
X
X
-
-
Pregnancy test for FCBP with irregular 
menstrual cycles
X
X
-10 to -14 days and -24 hours prior to first dose 
weekly for 28 days after first dose, then every 14 days
X
14 and 28 
days after 
last dose
-
-
Pregnancy counseling for all subjects i
X
X
-
-
X
-
X
X
-
-
-
EFFICACY AND OTHER ASSESSMENTS
ECOG performance status c
X
X
-
-
X
-
X
X
-
X
-
Assessment of response (IMWG Uniform 
Response Criteria) d, j
-
-
-
-
X
-
X
X
-
X
-
Serum and urine protein electrophoresis
X
X
-
-
X
-
X
X
-
X
-
Serum and urine immunofixation e
X
-
-
-
-
-
-
-
-
-
-
Serum free light chain assay
X
X
X
X
X
-
X
X
-
X
-
Quantitative serum immunoglobulin
X
X
-
-
X
-
X
X
-
X
-
β-2 microglobulin
X
-
-
-
-
-
-
-
-
-
-
Approved
12.0
v
Approved
1.0
v

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Table 14:
Table of Events for Part 2 Cohorts C (monotherapy), D, and I (CC-220+DEX): 28-day Cycle (Continued)
Screening
Treatment
Safety 
Follow-
up
Post-Tx 
Response 
FU
Long 
Term FU
EVENTS
-28 to -1
Cycle 1
Cycle 2-4
(±2 days for all visits)
≥ Cycle 5
(±2 days for all 
visits)
EOT
28 days 
after 
EOT 
(+ 3 d)
Every 28 
days and at 
D/C visit  
(+ 2 d)
Every 3 
months 
for 5
years
D1
D8
D15
D1
D15
D1
EMP clinical assessment
X
X
-
-
X
-
X
X
-
X
-
EMP radiological assessment (only 
required if history of or clinical 
indication of EMPs only assessable 
radiographically)
X
-
-
-
Day 1 starting at C3, then every 3 cycles 
thereafter 
X
-
X q
-
Skeletal Survey/CT Scan/MRI (Bone 
lesion)
X
Repeated during treatment if clinically indicated to confirm response or PD
-
X n
-
Bone marrow aspirate and/or biopsy 
sampling k
X
- Screening: BMA and if possible BMB for local % plasma cells and central 
cytogenetics and other biomarkers
-C2D15: BMA and if possible BMB at 3-6 hours post dose, for biomarkers 
- BMA and if possible BMB at CR confirmation and at PD/treatment discontinuation
- BMA at 6, 12, 18, 24 months from C1D1 and yearly thereafter after achieving a 
response of VGPR or better until disease progression for MRD
- Optional BMA and/or BMB taken at any time point during treatment at request of 
investigator and prior to subsequent myeloma therapy
-
X m
-
Whole blood sample for biomarkers for 
all subjects g
-
X
-
X
C2 
C2 
C6D15
X
-
-
-
Additional whole blood sample for 
biomarkers for selected subjects at select 
US sites in Cohort D (notified via IRT) l
-
D1 and 
D2
-
X
C2
C2
-
-
-
-
-
Additional whole blood sample and 
BMA for 5 selected subjects in Cohort D 
at one pre-identified US site o
X
-
X
-
-
C2
-
-
-
-
-
Approved
12.0
v
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1.0
v

EDMS Doc. Number: 25858146 - 20867538
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Confidential and Proprietary
109
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
Table 14:
Table of Events for Part 2 Cohorts C (monotherapy), D, and I (CC-220+DEX): 28-day Cycle (Continued)
Screening
Treatment
Safety 
Follow-
up
Post-Tx 
Response 
FU
Long 
Term FU
EVENTS
-28 to -1
Cycle 1
Cycle 2-4
(±2 days for all visits)
≥ Cycle 5
(±2 days for all 
visits)
EOT
28 days 
after 
EOT 
(+ 3 d)
Every 28 
days and at 
D/C visit  
(+ 2 d)
Every 3 
months 
for 5
years
D1
D8
D15
D1
D15
D1
Whole blood samples for PK for Cohorts 
C and D h
-
-
-
X
-
X
-
-
-
-
-
Whole blood samples for PK for Cohort 
Ih
-
-
-
X
-
C2
-
-
-
-
-
Survival
-
-
-
-
-
-
-
-
-
-
X
Subsequent myeloma therapies including 
date of progression
-
-
-
-
-
-
-
-
-
-
X
COHORT C
Oral CC-220
-
Days 1-21/28-day cycle
-
-
-
-
COHORT D and I
Oral CC-220
-
Days 1-21/28-day cycle
-
-
-
-
Oral DEX
-
Days 1, 8, 15, 22/28-day cycle
-
-
-
-
VTE prophylaxis
-
C1D1 to EOT
-
-
-
-
IP (CC-220, DEX as applicable) 
accountability/compliance
-
X
X
X
X
X
X
X
-
-
-
Abbreviations: AE = adverse event; AESI = adverse events of special interest; BMA = bone marrow aspirate; BMB = bone marrow biopsy; 
 C = Cycle; CR = complete response; CrCL = creatinine clearance; CT = computed tomography; D = Day; D/C = discontinuation; DEX = dexamethasone; ECG = 
electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EMP = extramedullary plasmacytomas; EOT = End of Treatment; FCBP = female of child-bearing potential; 
FU = follow-up; IMWG = International Myeloma Working Group; IRT = Interactive Response Technology; IP = investigational product; MRD = minimal residual disease; MRI = 
magnetic resonance imaging; PD = progressive disease; Pd = pharmacodynamics; PK = pharmacokinetics; SPM = second primary malignancy; sPEP = serum protein 
electrophoresis; Tx = treatment; uPEP = urine protein electrophoresis; VGPR = very good partial response; VTE = venous thromboembolism.
a Height will be included in the Physical examination and only measured at Screening.
Approved
12.0
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b ECG will be taken at time of median Tmax approximately 3-4 hours post first dose on C1D1, C1D8, and at EOT. Also, the ECG will be repeated during treatment if clinically 
indicated.
c On C1D1, safety laboratory assessments must be performed locally, in addition to central laboratory collection, to confirm that the subject continues to meet the required safety 
laboratory values prior to initiating IP.  However, if Screening assessments were performed within 72 hours of C1D1, safety laboratory (hematology and chemistry), physical 
examinations, and ECOG do not need to be repeated at C1D1.
d Refer to Appendix B for IMWG criteria.
e After C1D1, assessment to be taken only if myeloma paraprotein is not detected or too few to quantify in sPEP and uPEP assessments.
g Whole blood sample for biomarkers for all subjects: samples drawn for Pd effects of CC-220 on T-Cell Activation on C1D1, C1D15. Samples for Pd effects of CC-220 on 
immune cells in peripheral blood and association of baseline levels of these populations with response or resistance to CC-220 on C1D1, C2D1, C2D15, C6D15, EOT. Samples 
for pharmacogenomics on C1D1.  See Section 6.6.
h Intensive PK samples will be drawn from selected subjects on C1D15 (for Cohorts C and D) in addition to the samples drawn for sparse PK on all subjects. For Cohort I, no 
intensive PK samples will be drawn from subjects.
i See Appendix D.
j See Section 6.3.4.
k Refer to Table 18 for details on BMA and BMB collection plan.
l Additional whole blood sample for biomarkers for select subjects at select US sites in Cohort D (notified via IRT if subject will be participating in one or more): Samples 
collected on C1D1, C2D1, C2D15 
.  Samples collected on C1D1, C1D2, and C1D15 to evaluate Pd effect on 
CC-220 on Aiolos and Ikaros with novel assay. See Section 6.6.
m For subjects who enter Post Treatment Response follow up, BMA (and, if possible, BMB) will be collected at confirmed PD instead of EOT. 
n Skeletal survey will be performed during Post Treatment Response Follow up phase if clinically indicated to confirm response or PD.  
o Cohort D subjects from one selected US site: samples collected on screening, C1D8, C2D15 to evaluate time-matched concentration of CC-220 in peripheral blood and tumor 
microenvironment and assess the correlation between concentration, pharmacodynamic changes in tumor microenvironment, and outcome measures. See Section 6.6.
p For subjects in Cohort D, this will include data on subject’s prior CAR T cell candidacy.
q During Post-Tx Response FU, EMP radiological assessment is required every 3 months for those with a history of or clinical indication of EMPs only assessable 
radiographically.
Approved
12.0
v
Approved
1.0
v

EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
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Confidential and Proprietary
111
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
Table 15:
Table of Events for Part 2 Cohort J1 (CC-220Vd in NDMM and not eligible for ASCT)
Screening
Treatment 
Safety 
Follow-
up
Post-Tx
Response 
FUm
EVENTS
-28 to -1
Cycle 1(21-day cycle) 
±2 days for all visits
Cycles 2 –8 (21-day cycle)
±2 days for all visits
Cycles 9-29
(28-day cycle) 
±2 days for all visits
> Cycle 30 (28-
day cycle) ±7 days 
for all visits
EOT
28 days 
after 
EOT 
(+ 3 d)
Every 28 
days and 
at D/C 
visit      
(+ 2 d)
D1
D4
D8
D11
D1
D4
D8
D11
D1
D1
STUDY ENTRY AND GENERAL ASSESSMENTS
Informed consent
X
-
-
-
-
-
-
-
-
-
-
-
-
-
Inclusion/exclusion criteria
X
-
-
-
-
-
-
-
-
-
-
-
IRT registration
X
X
-
-
-
-
-
-
-
-
-
X
Prior cancer history
X
-
-
-
-
-
-
-
-
-
-
-
Medical history
X
-
-
-
-
-
-
-
-
-
-
-
Demographics
X
-
-
-
-
-
-
-
-
-
-
-
Prior disease history
X
-
-
-
-
-
-
-
-
-
-
-
Prior disease therapies
X
-
-
-
-
-
-
-
-
-
-
-
SAFETY ASSESSMENTS
Prior/concomitant medication 
evaluation
X (≤28 
days from 
Screening)
Continuous, until 28 days after last dose of study medication
Prior/concomitant procedures 
evaluation
X (≤28 
days from 
Screening)
Continuous, until 28 days after last dose of study medication
AE (AESI) evaluation
X
Continuous starting after informed consent signature, until 28 days after last dose of study medication
SPM surveillance
X
Continuous starting after informed consent signature, until 28 days after last dose of study medication 
Physical examination (includes VTE 
monitoring and ophthalmologic exam if 
clinically indicated)
a, c
X
X
-
-
-
X
-
-
-
X
X
X
-
-
Vital signs (includes weight)
X
X
X
X
X
X
X
X
X
X
X
X
X
-
Approved
12.0
v
Approved
1.0
v

EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
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Confidential and Proprietary
112
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
Table 15:
Table of Events for Part 2 Cohort J1 (CC-220Vd in NDMM and not eligible for ASCT) (Continued)
Screening
Treatment 
Safety 
Follow-up
Post-Tx 
Respons
e FUm
EVENTS
-28 to -1
Cycle 1(21-day cycle) 
±2 days for all visits
Cycles 2 –8 (21-day cycle)
±2 days for all visits
Cycles 9-29 
(28-day cycle) 
±2 days for all visits
> Cycle 30 (28-
day cycle) ±7 days 
for all visits
EOT
28 days 
after 
EOT 
(+ 3 d)
Every 28 
days and 
at D/C 
visit      
(+ 2 d)
D1
D4
D8
D11
D1
D4
D8
D11
D1
D1
ECG b
X
X
-
X
And during treatment if clinically indicated
X
-
-
Hematology c 
X
X
-
X
-
X
-
X
-
X
X
X
-
-
Chemistry c
X
X
-
X
-
X
-
X
-
X
X
X
-
-
Renal function (CrCL) 
X
X
-
X
-
X
-
X
-
X
X
X
-
-
Urinalysis
X
Repeated only if clinically indicated
X
-
-
Pregnancy test for FCBP with regular 
or no menstrual cycles
X
X
-10 to -14 days and -24 hours prior to first dose 
weekly for 21 days after first dose, then every 21 days from cycle 1 to 8, then every 28 days
thereafter
X
X
-
Pregnancy test for FCBP with irregular 
menstrual cycles
X
X
-10 to -14 days and -24 hours prior to first dose 
weekly for 21 days after first dose, then every 14 days
X
14 & 28 
days after 
last dose
-
Pregnancy counseling for all subjects h
X
X
-
-
-
X
-
-
-
X
X
X
-
-
EFFICACY AND OTHER ASSESSMENTS
ECOG performance status c
X
X
D1 of Cycle 3, 6, 9, 12 for year 1; every 6th cycle thereafter 
X
-
X
Assessment of response (IMWG 
Uniform Response Criteria) d, i
-
-
-
-
-
X
-
-
-
X
C30 & every 3 
cycles thereafter
X
-
X
Serum and urine protein electrophoresis
X
X
-
-
-
X
-
-
-
X
C30 & every 3 
cycles thereafter
X
-
X
Serum and urine immunofixation e
X
-
-
-
-
-
-
-
-
-
-
-
-
-
Serum free light chain assay
X
X
-
-
X
X
-
-
-
X
C30 & every 3 
cycles thereafter
X
-
X
Quantitative serum immunoglobulin
X
X
-
-
-
X
-
-
-
X
C30 & every 3 
cycles thereafter
X
-
X
Approved
12.0
v
Approved
1.0
v

EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
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Confidential and Proprietary
113
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
Table 15:
Table of Events for Part 2 Cohort J1 (CC-220Vd in NDMM and not eligible for ASCT) (Continued)
Screening
Treatment
Safety 
Follow-
up
Post-Tx 
Response 
FUm
EVENTS
-28 to -1
Cycle 1
±2 days for all visits
Cycles 2 –8 (21-day 
cycle)
±2 days for all visits
Cycles 9-29
(28-day cycle) 
±2 days for all visits
> Cycle 30 (28-
day cycle) ±7 days 
for all visits
EOT
28 days 
after 
EOT 
(+ 3 d)
Every 28 
days and 
at D/C 
visit      
(+ 2 d)
D1
D4
D8
D11
D1 D4
D8
D11
D1
D1
β-2 microglobulin
X
-
-
-
-
-
-
-
-
-
-
-
-
-
EMP clinical assessment
X
X
-
-
-
X
-
-
-
X
X
X
-
X
EMP radiological assessment (only 
required if history of or clinical 
indication of EMPs only assessable 
radiographically)
X
-
-
-
-
Day 1 starting at C3, then every 3 cycles thereafter if clinically indicated
X
-
Xl
Skeletal Survey/CT Scan/MRI (Bone 
lesion) 
X(within 60 
days prior 
to first dose
is 
acceptable)
Repeated during treatment if clinically indicated to confirm response or PD
-
Xk
Bone marrow aspirate and/or biopsy 
sampling f
X
- Screening: BMA and, if possible, BMB for local % plasma cells and central cytogenetics and other biomarkers
- C2D11: BMA and if possible BMB at 3-6 hours post dose, for biomarkers
- BMA and, if possible, BMB at CR confirmation and at PD/treatment discontinuation
- BMA at C7D1 and 12, 18, 24 months from C1D1 and yearly thereafter after achieving a response of VGPR or better 
until disease progression for MRD
- Optional BMA and/or BMB taken at any time point during treatment at request of investigator and prior to 
subsequent myeloma therapy
-
Xj
Whole blood sample for biomarkers g
-
X
-
-
X
-
-
C4 
and 
C8
-
-
-
X
-
-
Whole blood samples for PK 
-
-
-
X
-
-
-
C2
-
-
-
-
-
-
COHORT J1
Oral CC-220
-
Cycles 1 – 8: Days 1-14/21-day cycle
Cycle > 9: Days 1-21/28-day cycle
-
-
-
Approved
12.0
v
Approved
1.0
v

EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
114
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
Table 15:
Table of Events for Part 2 Cohort J1 (CC-220Vd in NDMM and not eligible for ASCT) (Continued)
Screening
Treatment
Safety 
Follow-
up
Post-Tx 
Response 
FUm
EVENTS
-28 to -1
Cycle 1
±2 days for all visits
Cycles 2 –8 (21-day 
cycle)
±2 days for all visits
Cycles 9-29
(28-day cycle)
±2 days for all visits
> Cycle 30 (28-
day cycle) ±7 days 
for all visits
EOT
28 days 
after 
EOT 
(+ 3 d)
Every 28 
days and 
at D/C 
visit
(+ 2 d)
D1
D4
D8
D11
D1 D4
D8
D11
D1
D1
Oral DEX
-
Cycles 1 – 8: Days 1, 2, 4, 5, 8, 9, 11,12/21-day cycle
Cycle > 9: Days 1, 8, 15, 22/28-day cycle
-
-
-
SC BTZ
-
Cycles 1 - 8: Days 1, 4, 8, 11/21-day cycle
-
-
-
VTE prophylaxis
-
C1D1 to EOT
-
-
-
IP (CC-220, DEX, BTZ, as applicable) 
accountability/compliance
-
X
-
X
-
X
-
X
-
X
X
X
-
-
Abbreviations: AE = adverse event; AESI = adverse events of special interest; ASCT = autologous stem cell transplant; BMA = bone marrow aspirate; BMB = bone marrow 
biopsy; BTZ = bortezomib; C = Cycle; CR = complete response; CrCL = creatinine clearance; CT = computed tomography; DEX = dexamethasone; D = Day; D/C = 
discontinuation; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EMP = extramedullary plasmacytomas; EOT = End of Treatment; FCBP = female of 
child-bearing potential; FU = follow-up; IMWG = International Myeloma Working Group; IP = investigational product; IRT = Interactive Response Technology; MRD = minimal 
residual disease; MRI = magnetic resonance imaging; NDMM = newly diagnosed multiple myeloma; Pd = pharmacodynamics; PD = progressive disease; PK = pharmacokinetics; 
sPEP = serum protein electrophoresis; SPM = second primary malignancy; SC = subcutaneous; Tx = treatment; uPEP = urine protein electrophoresis; VGPR = very good partial 
response; VTE = venous thromboembolism.
a Height will be included in the Physical examination and only measured at Screening.
b ECG will be taken at time of median Tmax approximately 3-4 hours post first dose on C1D1, C1D8, and at EOT. Also, the ECG will be repeated during treatment if clinically 
indicated.
c On C1D1, safety laboratory assessments must be performed locally, in addition to central laboratory collection, to confirm that the subject continues to meet the required safety 
laboratory values prior to initiating IP.  However, if Screening assessments were performed within 72 hours of C1D1, safety laboratory (hematology and chemistry), physical 
examinations, and ECOG do not need to be repeated at C1D1.
d Refer to Appendix B for IMWG criteria.
e From C1D1, assessment to be taken only if myeloma paraprotein is not detected or too few to quantify in sPEP and uPEP assessments.
f Screening and C2D11 Bone marrow sampling for biomarkers.
g Whole blood sample for biomarkers for all subjects: Samples drawn for Pd effects of CC-220 on T-cell Activation on C1D1 and C1D11. Samples drawn for Pd effects of CC-
220 on immune cells in peripheral blood on C1D1, C4D8, C8D8, and EOT. Sample drawn for pharmacogenomics of CC-220 on C1D1. See Section 6.6.
h See Appendix D.
i See Section 6.3.4.
j For subjects who enter Post Treatment Response follow up, BMA (and, if possible, BMB) will be collected at confirmed PD instead of treatment discontinuation. 
k Skeletal survey will be performed during Post Treatment Response Follow up phase if clinically indicated to confirm response or PD.
l During Post-Tx Response FU, EMP radiological assessment is required every 3 months for those with a history of or clinical indication of EMPs only assessable
radiographically.
m All subjects who discontinue study treatment for a reason other than PD or withdrawal of consent from the study will enter the Post Treatment Response Follow Up phase and 
will be followed for response assessment every 28 days until PD or until subsequent myeloma regimen has been started.
Approved
12.0
v
Approved
1.0
v

EDMS Doc. Number: 25858146 - 20867538
CC-220
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Confidential and Proprietary
115
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
Table 16:
Table of Events: Part 2 Cohort J2 (CC-220Vd in NDMM and Eligible for ASCT): 21-day Cycle
Events
Screening 
Period
Treatment Period
Follow-up Period
-28 to -1
Cycles 1-6 
Induction
(±2 days)
Post-
induction/Pre-
ASCT b
(±7 days)
Post-ASCT/Pre-
maintenance 
(monthly up to 3 
months post-
ASCT) c
(±7 days)
EOT d
(≤ 7 days 
from Tx 
D/C)
28 days 
after 
EOT e
(±3 d)
Post-Tx 
Response 
FU every 3 
months f
(±7 d)
Post-Tx 
Response FU 
D/C
(±3 d)
D1
D4, D8, 
D11
STUDY ENTRY AND GENERAL ASSESSMENTS
Informed consent
X
-
-
-
-
-
-
-
-
Inclusion/Exclusion criteria
X
-
-
-
-
-
-
-
-
IRT registration
X
X
-
-
-
X
-
-
-
Prior cancer history 
X
-
-
-
-
-
-
-
-
Medical history
X
-
-
-
-
-
-
-
-
Demographics
X
-
-
-
-
-
-
-
-
Prior disease history
X
-
-
-
-
-
-
-
-
Prior disease therapies
X
-
-
-
-
-
-
-
-
SAFETY ASSESSMENTS
Prior/concomitant medication and 
procedures evaluation
X (≤28 days 
from 
Screening)
Continuous until 28 days after the last dose of induction treatment
-
-
-
AE (AESI) evaluation g
Continuous, starting after informed consent signature, until 28 days after the last dose of 
induction treatment
-
-
-
SPM surveillance
Continuous, starting after informed consent signature, until 28 days after the last dose of 
induction treatment
-
-
-
Physical examination (includes VTE 
monitoring and ophthalmologic exam if 
clinically indicated) a
X
X
-
X
X
X
-
-
-
Vital signs (including weight)
X
X
X
X
X
X
X
-
-
Height
X
-
-
-
-
-
-
-
-
Approved
12.0
v
Approved
1.0
v

EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
116
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
Table 16:
Table of Events: Part 2 Cohort J2 (CC-220Vd in NDMM and Eligible for ASCT): 21-day Cycle (Continued)
Events
Screening 
Period
Treatment Period
Follow-up Period
-28 to -1
Cycles 1-6 Induction
(±2 days)
Post-
induction/Pre-
ASCT b
(±7 days)
Post-ASCT/Pre-
maintenance 
(monthly up to 3 
months post-
ASCT) c
(±7 days)
EOT d
≤ 7 days 
from Tx 
D/C
28 days 
after 
EOT e
(±3 d)
Post-Tx 
Response 
FU every 3 
months f
(±7 d)
Post-Tx 
Response FU 
D/C
(±3 d)
D1
D4, D8, 
D11
ECG
X
C1D1 
C1D8
If clinically indicated
X
-
-
-
Hematology a
X
X
X
X
X
X
X
-
-
Chemistry a
X
X
X
X
X
X
X
-
-
Renal function (CrCl) h
X
X
X
X
X
X
X
-
-
Urinalysis
X
If clinically indicated
X
-
-
-
Pregnancy test for FCBP with regular or 
no menstrual cycles
-10 to -14 days and -24 hours prior to first dose, 
weekly for the first cycle (C1D8, C1D15), then Day 1 of every cycle thereafter (starting with 
C2D1), at treatment discontinuation and 28 days following the last dose of CC-220
-
-
Pregnancy test for FCBP with irregular 
menstrual cycles
-10 to -14 days and -24 hours prior to first dose, 
weekly for the first cycle (C1D8, C1D15), then every 14 days thereafter (starting with C2D1), at 
treatment discontinuation and 14 and 28 days following the last dose of CC-220
-
-
Pregnancy counseling i
X
X
-
X
-
X
-
-
-
EFFICACY and OTHER ASSESSMENTS
ECOG Performance status a
X
X
-
X
X
X
-
X
X
Assessment of response (IMWG Uniform 
Response Criteria) j
-
C2 
onward
s
-
X
X
X
-
X k
X k
Serum and urine protein electrophoresis
X
X
-
X
X
X
-
X k
X k
Serum and urine immunofixation q
X
-
-
-
-
-
-
-
-
Serum free light chains assay
X
X
C1D11
X
X
X
-
X k
X k
Quantitative serum immunoglobulin
X
X
-
X
X
X
-
X k
X k
Approved
12.0
v
Approved
1.0
v

EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
117
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
Table 16:
Table of Events: Part 2 Cohort J2 (CC-220Vd in NDMM and Eligible for ASCT): 21-day Cycle (Continued)
Events
Screening 
Period
Treatment Period
Follow-up Period
-28 to -1
Cycles 1-6 
Induction
(±2 days)
Post-
induction/Pre-
ASCT b
(±7 days)
Post-ASCT/Pre-
maintenance 
(monthly up to 3 
months post-
ASCT) c
(±7 days)
EOT d
≤ 7 days 
from Tx 
D/C
28 days 
after 
EOT e
(±3 d)
Post-Tx 
Response 
FU every 3 
months f
(±7 d)
Post-Tx 
Response FU 
D/C
(±3 d)
D1
D4, D8, 
D11
β-2 microglobulin
X
-
-
-
-
-
-
-
-
EMP clinical assessment
X
X
-
X
X
X
-
X k
X k
EMP radiological assessment (only 
required if history of or clinical indication 
of EMPs only assessable radiographically)
l
X
C4
-
X
3 months after 
ASCT
X
-
If clinically indicated as per 
Institutional SOC and to 
confirm PD k
Skeletal Survey/CT Scan/MRI (Bone 
lesion)m
X
(within 60 
days prior to 
first dose is 
acceptable)
Repeated during treatment if clinically indicated to confirm PD
-
If indicated to confirm PD
Bone marrow aspirate and/or biopsy 
sampling n
- Screening: BMA and, if possible, BMB for local % plasma cells, central cytogenetics 
and other central biomarkers
- BMA and, if possible, BMB at CR confirmation and at PD/treatment discontinuation
-BMA for MRD at C4D1 of induction or end of induction, whichever comes first after 
achieving VGPR and 100 days post ASCT if achieved VGPR or better
-Optional BMA and/or BMB taken at any time point during treatment at request of 
investigator and prior to subsequent myeloma therapy
-
If indicated as per Institutional 
SOC
Whole blood sample for biomarkers all 
subjects o
-
C1D1
C1D11, 
C4D8
-
-
X
-
-
-
Whole blood sample for PK
-
-
C1D8,
C2D8
-
-
-
-
-
-
Approved
12.0
v
Approved
1.0
v

EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
118
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
Table 16:
Table of Events: Part 2 Cohort J2 (CC-220Vd in NDMM and Eligible for ASCT): 21-day Cycle (Continued)
Events
Screening 
Period
Treatment Period
Follow-up Period
-28 to -1
Cycles 1-6 
Induction
(±2 days)
Post-
induction/Pre-
ASCT b
(±7 days)
Post-ASCT/Pre-
maintenance 
(monthly up to 3 
months post-
ASCT) c
(±7 days)
EOT d
≤ 7 days 
from Tx 
D/C
28 days 
after 
EOT e
(±3 d)
Post-Tx 
Response 
FU every 3 
months f
(±7 d)
Post-Tx 
Response FU 
D/C
(±3 d)
D1
D4, D8, 
D11
STUDY TREATMENT (CC-220, BTZ, DEX)
Oral CC-220
-
Days 1-14/21-day 
cycle
-
-
-
-
-
-
Oral DEX
-
Days 1, 2, 4, 5, 8, 9, 
11, 12/21-day cycle
-
-
-
-
-
-
Subcutaneous BTZ p
-
X
X
-
-
-
-
-
-
VTE prophylaxis
-
C1D1 to EOT
-
-
-
-
-
-
IP (CC-220, BTZ, DEX) 
accountability/compliance
-
X
X
-
-
Xr
-
-
-
Abbreviations: AE = adverse event; ASCT = autologous stem cell transplant; BMA = bone marrow aspirate; BMB = bone marrow biopsy; BTZ = bortezomib; C = cycle; CR = 
complete response; CrCl = creatinine clearance; CT = computed tomography; D = day; D/C = discontinuation; DEX = dexamethasone; ECG = electrocardiogram; ECOG = Eastern 
Cooperative Oncology Group; EMP = extramedullary plasmacytoma; EOT = end of treatment; FCBP = female of childbearing potential; FU = follow-up; IMWG = International 
Myeloma Working Group; IRT Interactive Response Technology; MRD = minimal residual disease; MRI = magnetic resonance imaging; NDMM = newly diagnosed multiple 
myeloma; PD = progressive disease; Pd = pharmacodynamic; PK = pharmacokinetics; SAE = serious adverse event; SOC = standard of care; sPEP = serum protein 
electrophoresis; SPM =second primary malignancy; Tx D/C = treatment discontinuation; uPEP = urine protein electrophoresis; VGPR = very good partial response; VTE = venous 
thromboembolism.
a On C1D1, safety laboratory assessments must be performed locally, in addition to central laboratory collection, to confirm that the subject continues to meet the required safety 
laboratory values prior to initiating IP.  However, if Screening assessments were performed within 72 hours of C1D1, safety laboratory (hematology and chemistry), physical 
examinations, and ECOG do not need to be repeated at C1D1.
b The post-induction/pre-ASCT visit should be performed at a minimum of 4 weeks after completion of the last induction cycle.
c The post-ASCT/pre-maintenance visits should be done monthly from the date of ASCT and the last visit performed 3 months ± 7 days after the ASCT.
d The EOT visit should be performed for all subjects at 3 months ±7 days post ASCT (prior to any maintenance therapy), or at moment of induction treatment discontinuation. 
e The 28-day safety follow-up visit after EOT is only required for subjects who do not continue with an ASCT.
f The Post-Tx Response FU visits will be done every 3 months following EOT. Only efficacy and response assessments will be performed during these visits. Subjects will 
continue to be followed in the Post-Tx Response FU phase until PD or until a subsequent anti-myeloma regimen has been started.
g All SAEs made known to the Investigator at any time after 28 days after the last dose of induction treatment, that are suspected of being related to induction treatment will be 
recorded.
h Estimation of renal function will be assessed using the 24-hour urine creatinine clearance, or CrCl calculated based on the Cockcroft-Gault formula or the CrCL directly 
calculated from the 24-hour urine collection method.
Approved
12.0
v
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1.0
v

EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
119
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
i Pregnancy counseling at the post-induction/pre-ASCT is only required for subjects who continue with an ASCT. Subjects who do not continue with an ASCT will perform 
pregnancy counseling at the EOT Visit. 
j Per IMWG Uniform Response Criteria all response categories and progressive disease require 2 consecutive assessments. 
k Efficacy assessments during the Post-Tx Response FU will be done locally as per the Institutional SOC. 
l EMPs assessable radiographically by CT or MRI. 
m Skeletal survey is done locally and can be performed by X-ray, CT or MRI provided the same modality will be used for future assessments.
n The 100 day post-ASCT BMA for MRD in subjects that have achieved VGPR or better may be performed +/- 1 week.
o Biomarker sampling for all subjects: Samples drawn for Pd effects of CC-220 on T-cell Activation on C1D1 and C1D11. Samples drawn for Pd effects of CC-220 on immune 
cells in peripheral blood on C1D1, C4D8 and EOT (end of induction). Sample drawn for pharmacogenomics of CC-220 on C1D1. See Section 6.6.
p BTZ doses should be given at least 72 hours apart.
q From C1D1, assessment to be taken only if myeloma paraprotein is not detected or too few to quantify in sPEP and uPEP assessments.
r IP accountability/compliance to be performed at the end of induction.
Approved
12.0
v
Approved
1.0
v

EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
120
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
Table 17:
Table of Events for Part 2 Cohort K (CC-220Dd): 28-day Cycle
Screening
Treatment
Safety Follow-
up
Post-Tx 
Response 
FUp
EVENTS
-28 to -1
Cycle 1
(±2 days for all visits)
Cycle 2
(±2 days for all visits)
Cycle 3-6
(±2 days for all 
visits)
≥ Cycle 
7 (±2 
days 
for all 
visits)
> Cycle 
26 (±7 
days 
for all 
visits)
EOT
28 days 
after EOT 
(+ 3 d)
Every 28 
days and at 
D/C visit 
(+ 2 d)
D1
D8
D15
D22
D1
D8
D15
D22
D1
D15
D1
D1
STUDY ENTRY AND GENERAL ASSESSMENTS
Informed consent
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Inclusion/exclusion criteria
X
-
-
-
-
-
-
-
-
-
-
-
-
-
IRT registration
X
X
-
-
-
-
-
-
-
-
-
-
-
X
Prior cancer history
X
-
-
-
-
-
-
-
-
-
-
-
-
-
Medical history
X
-
-
-
-
-
-
-
-
-
-
-
-
-
Demographics
X
-
-
-
-
-
-
-
-
-
-
-
-
-
Prior disease history
X
-
-
-
-
-
-
-
-
-
-
-
-
-
Prior disease therapies
X
-
-
-
-
-
-
-
-
-
-
-
-
-
SAFETY ASSESSMENTS
Prior/concomitant medication 
evaluation
X (≤ 28 
days from 
Screening)
Continuous, until 28 days after last dose of study medication
Prior/concomitant procedures 
evaluation
X (≤ 28 
days from 
Screening)
Continuous, until 28 days after last dose of study medication
AE (AESI) evaluation
X
Continuous starting after informed consent signature, until 28 days after last dose of study medication
SPM surveillance
X
Continuous starting after informed consent signature, until 28 days after last dose of study medication 
Physical examination (includes VTE 
monitoring and ophthalmologic exam 
if clinically indicated)a, c
X
X
-
-
-
X
-
-
-
X
-
X
X
X
-
-
Approved
12.0
v
Approved
1.0
v

EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
121
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
Table 17:
Table of Events for Part 2 Cohort K (CC-220Dd): 28-day Cycle (Continued)
Screening
Treatment
Safety Follow-
up
Post-Tx 
Response 
FUp
EVENTS
-28 to -1
Cycle 1
(±2 days for all visits)
Cycle 2
(±2 days for all visits)
Cycle 3-6
(±2 days for all 
visits)
≥ Cycle 
7 (±2 
days 
for all 
visits)
> Cycle 
26 (±7 
days 
for all 
visits)
EOT
28 days 
after EOT 
(+ 3 d)
Every 28 
days and at 
D/C visit 
(+ 2 d)
D1
D8
D15
D22
D1
D8
D15
D22
D1
D15
D1
D1
Vital signs (includes weight) n
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
ECG b
X
X
-
And during treatment if clinically indicated
X
-
-
Hematology c
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
Chemistry c
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
Renal function (CrCL) 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
Urinalysis
X
Repeated only if clinically indicated
X
-
-
Pregnancy test for FCBP with regular 
or no menstrual cycles
X
X
-10 to -14 days and -24 hours prior to first dose 
weekly for 28 days after first dose, then every 28 days
X
X
-
Pregnancy test for FCBP with 
irregular menstrual cycles
X
X
-10 to -14 days and -24 hours prior to first dose 
weekly for 28 days after first dose, then every 14 days
X
14 and 28 days 
after last dose
-
Pregnancy counseling for all 
subjectsg
X
X
-
-
-
X
-
-
-
X
-
X
X
X
-
-
Hepatitis B (HBV) serology local 
testing k
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
HBV DNA local l
X
If indicated, every 12 weeks during treatment, at the EOT Visit, and every 12 weeks for up to 6 months after the last dose of DARA 
EFFICACY AND OTHER ASSESSMENTS
ECOG performance status c
X
X
-
-
-
-
-
-
-
D1 of Cycle 3, 6, 9, 12 for year 1; 
every 6th cycle thereafter
X
-
X
Approved
12.0
v
Approved
1.0
v

EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
122
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
Table 17:
Table of Events for Part 2 Cohort K (CC-220Dd): 28-day Cycle (Continued)
Screening
Treatment
Safety Follow-
up
Post-Tx 
Response 
FUp
EVENTS
-28 to -1
Cycle 1
(±2 days for all visits)
Cycle 2
(±2 days for all visits)
Cycle 3-6
(±2 days for all 
visits)
≥ Cycle 
7 (±2 
days 
for all 
visits)
> Cycle 
26 (±7 
days for 
all visits)
EOT
28 days 
after EOT 
(+ 3 d)
Every 28 
days and at 
D/C visit 
(+ 2 d)
D1
D8
D15
D22
D1
D8
D15
D22
D1
D15
D1
D1
Assessment of response (IMWG 
Uniform Response Criteria) d, h 
-
-
-
-
-
X
-
-
-
X
-
X
C26 & 
every 3 
cycles 
thereafter
X
-
X
Serum and urine protein 
electrophoresis
X
X
-
-
-
X
-
-
-
X
-
X
C26 & 
every 3 
cycles 
thereafter
X
-
X
Serum and urine immunofixation e
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Serum free light chain assay
X
X
-
X
-
X
-
-
-
X
-
X
C26 & 
every 3 
cycles 
thereafter
X
-
X
Quantitative serum immunoglobulin
X
X
-
-
-
X
-
-
-
X
-
X
C26 & 
every 3 
cycles 
thereafter
X
-
X
β-2 microglobulin
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
EMP clinical assessment
X
X
-
-
-
X
-
-
-
X
-
X
X
X
-
X
EMP radiological assessment (only 
required if history of or clinical 
indication of EMPs only assessable 
radiographically)
X
-
-
-
-
-
-
-
-
Day 1 starting at C3, then every 3 
cycles thereafter
X
-
Xm
Approved
12.0
v
Approved
1.0
v

EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
123
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
Table 17:
Table of Events for Part 2 Cohort K (CC-220Dd): 28-day Cycle (Continued)
Screening
Treatment
Safety Follow-
up
Post-Tx 
Response 
FUp
EVENTS
-28 to -1
Cycle 1
(±2 days for all visits)
Cycle 2
(±2 days for all visits)
Cycle 3-6
(±2 days for all 
visits)
≥ Cycle 
7 (±2 
days 
for all 
visits)
> Cycle 
26 (±7 
days for 
all visits)
EOT
28 days 
after EOT 
(+ 3 d)
Every 28 
days and at 
D/C visit 
(+ 2 d)
D1
D8
D15
D22
D1
D8
D15
D22
D1
D15
D1
D1
Skeletal Survey/CT Scan/MRI (Bone 
lesion) 
X(within 
60 days 
prior to 
first dose 
is 
acceptable
)
Repeated during treatment if clinically indicated to confirm response or PD
-
Xi
Bone marrow aspirate and/or biopsy 
sampling f
X
- Screening: BMA and, if possible, BMB for local % plasma cells and central cytogenetics and other biomarkers
-C2D15: BMA and if possible BMB at 3-6 hours post dose, for biomarkers 
- BMA and, if possible, BMB at CR confirmation and at PD/treatment discontinuation
BMA at 6, 12, 18, 24 months from C1D1 and yearly thereafter after achieving a response of VGPR or better until 
disease progression for MRD
- Optional BMA and/or BMB taken at any time point during treatment at request of investigator and prior to 
subsequent myeloma therapy 
-
Xj
Whole blood sample for biomarkers
-
X 
X
-
X
-
X
-
-
C6
-
-
X
-
-
Whole blood samples for PK 
-
-
-
X
-
-
-
X
-
-
-
-
-
-
-
-
COHORT K
Oral CC-220
-
Days 1-21/28-day cycle
-
-
-
Oral DEX
-
Days 1, 8, 15, 22/28-day cycle
-
-
-
SC DARAo
-
C1-2: Days 1, 8, 15, 22; C3-6: Days 1, 15; > C7: Day 1/28-day cycle
-
-
-
VTE prophylaxis
-
C1D1 to EOT
-
-
-
IP (CC-220, DARA, DEX, as 
applicable) accountability/compliance
-
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
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Abbreviations: AE = adverse event; AESI = adverse events of special interest; BMA = bone marrow aspirate; BMB = bone marrow biopsy; C = Cycle; CR = complete response; 
CrCL = creatinine clearance; CT = computed tomography; D = Day; DARA = daratumumab; D/C = discontinuation; DEX = dexamethasone; ECG = electrocardiogram; ECOG = 
Eastern Cooperative Oncology Group; EMP = extramedullary plasmacytomas; EOT = End of Treatment; FCBP = female of child-bearing potential; FU = follow-up; HBV = 
hepatitis B virus; IMWG = International Myeloma Working Group; IP = investigational product; IRT = Interactive Response Technology; MRD = minimal residual disease; MRI 
= magnetic resonance imaging; PD = progressive disease; PK = pharmacokinetics; SC = subcutaneous; sPEP = serum protein electrophoresis; SPM = second primary malignancy; 
Tmax = time to maximum plasma concentration; Tx = treatment; uPEP = urine protein electrophoresis; VGPR = very good partial response; VTE = venous thromboembolism.
a Height will be included in the physical examination and only measured at Screening.
b ECG will be taken at time of median Tmax approximately 3-4 hours post first dose on C1D1, and at EOT. Also, the ECG will be repeated during treatment if clinically indicated.
c On C1D1, safety laboratory assessments must be performed locally, in addition to central laboratory collection, to confirm that the subject continues to meet the required safety 
laboratory values prior to initiating IP.  However, if Screening assessments were performed within 72 hours of C1D1, safety laboratory (hematology and chemistry), physical 
examinations, and ECOG do not need to be repeated at C1D1.
d Refer to Appendix B for IMWG criteria.
e From C1D1, assessment to be taken only if myeloma paraprotein is not detected or too few to quantify in sPEP and uPEP assessments.
f Refer to Table 18 for details on BMA and BMB collection plan.
g See Appendix D.
h See Section 6.3.4.
i Skeletal survey will be performed during Post Treatment Response Follow up phase if clinically indicated to confirm response or PD.
j For subjects who enter Post Treatment Response follow up, BMA (and, if possible, BMB) will be collected at confirmed PD instead of treatment discontinuation. 
k All subjects will be tested for hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (antiHBs), and hepatitis B core antibody (antiHBc) locally during screening.
l For subjects with serologic evidence of resolved HBV infection (ie, positive antiHBs or positive antiHBc) at Screening, HBV DNA testing by polymerase chain reaction (PCR) 
must be performed locally at screening, every 12 weeks during treatment, at the End of Treatment Visit, and every 12 weeks for up to 6 months after the last dose of DARA. 
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 
m During Post-Tx Response FU, EMP radiological assessment is required every 3 months for those with a history of or clinical indication of EMPs only assessable 
radiographically.
n For SC DARA, vital signs are to be measured at the following time points on C1D1: immediately before SC DARA administration; at the end of SC DARA administration (+ 10 
minutes); 30 minutes (± 10 minutes) and 1 hour (± 10 minutes) after the end of SC DARA administration.
o For SC DARA administration, all subjects will be observed for at least 6 hours after the end of the SC injection during C1D1 and, if deemed necessary by the Investigator, after 
subsequent injections.
p All subjects who discontinue study treatment for a reason other than PD or withdrawal of consent from the study will enter the Post Treatment Response Follow Up phase and 
will be followed for response assessment every 28 days until PD or until subsequent myeloma regimen has been started.
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Protocol CC-220-MM-001
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6.
PROCEDURES
Any questions regarding the protocol should be directed to the Celgene Medical Monitor or 
designee. 
6.1.
Screening Period
Screening evaluations will be performed centrally for all subjects to determine study eligibility. 
These evaluations must be completed within 28 days of first dosing unless noted otherwise 
below. The Celgene Medical Monitor or designee must be contacted if there is a discrepancy 
between central safety laboratory results and local safety laboratory results. Upon review of the 
local laboratory results, the Celgene Medical Monitor or designee may deem the subject eligible 
for the study if all other eligibility criteria are satisfied. 
Any questions regarding subject eligibility should be directed to the Celgene Medical Monitor or 
designee. Waivers to the protocol will not be granted during the conduct of this trial, under any 
circumstances.
Tests that may result in dose interruption and/or reduction should also be performed locally to 
allow for treatment-related decisions during subject visits. All results from local laboratories 
used in treatment decisions or AE reporting must be entered as an unscheduled visit into the 
electronic case report form (eCRF). Screening laboratory values must demonstrate subject 
eligibility, but may be repeated within the Screening window, if necessary. Platelet transfusions 
or granulocyte colony-stimulating factor (GCSF) should not be administered during Screening to 
enable eligible laboratory values.
The following will be performed at Screening as specified in the Table of Events, after informed 
consent has been obtained:

Interactive Response Technology (IRT) registration

Demographics (initials, age, sex, race, and if allowed by local regulations, ethnicity, 
initials and date of birth will be collected in the eCRF and/or IRT systems)

Prior disease history (if available, the date of initial diagnosis, staging at time of 
diagnosis, cytogenetics at diagnosis to be collected)

Prior disease therapies: includes surgery, radiation, systemic or any other therapy for 
MM

Complete medical history (all relevant medical conditions diagnosed/ occurring prior 
to Screening should also be included)

Prior and concomitant procedures evaluation (including all procedures occurring ≤ 28 
days before Screening)

Prior and concomitant medication evaluation (including those taken ≤ 28 days before 
Screening, except for those taken for MM). 

Physical examination including height (at Screening only), and assessment for 
potential venous thromboembolism events (VTEs) (must be source documented only)
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EDMS Doc. Number: 25858146 - 20867538
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
Vital signs (including weight, blood pressure, temperature, and heart rate)

ECOG performance status

12-lead electrocardiogram (ECG) 

Efficacy assessment/ tumor evaluation (see Section 6.3). 

Hematology panel including lymphocyte panel and complete blood count (CBC) with 
differential, including red blood cell (RBC) count, hemoglobin, hematocrit, white 
blood cell (WBC) count (with differential), and platelet count. These assessments will 
be performed at a central laboratory; however, laboratory tests performed locally that 
are used for eligibility in cases of discrepancy between central safety laboratory 
results and local safety laboratory results or that result in dose interruption and/or 
reduction must be recorded in the eCRF.

Chemistry panel including sodium, potassium, calcium, corrected serum calcium, 
chloride, blood urea nitrogen (BUN), creatinine, glucose, albumin, total protein, 
alkaline phosphatase, bilirubin (total and direct), aspartate aminotransferase/serum 
glutamic oxaloacetic transaminase (AST/SGOT), alanine aminotransferase/serum 
glutamic pyruvic transaminase (ALT/SGPT), lactate dehydrogenase (LDH), 
magnesium, bicarbonate, lipase, gamma glutamyl transferase (GGT), uric acid, 
triglycerides, cholesterol, amylase, and phosphate. These assessments will be 
performed at a central laboratory; however, laboratory tests performed locally that are
used for eligibility in cases of discrepancy between central safety laboratory results 
and local safety laboratory results or that result in dose interruption and/or reduction 
must be recorded in the eCRF.

Estimation of renal function will be assessed using the 24-hour urine creatinine 
clearance, or CrCL calculated based on the Cockcroft-Gault formula or the CrCL 
directly calculated from the 24-hour urine collection method. Cockcroft-Gault 
formula: CrCL (mL/min) = (140-age) (weight [kg])/(72 (serum creatinine [mg/dL])); 
for females, the formula is multiplied by 0.85.

Urinalysis (a urine dipstick may be used)

Pregnancy test is required for all female subjects of childbearing potential. Serum 
beta human chorionic gonadotropin (β-hCG) pregnancy test (with a sensitivity of at 
least 25 mIU/mL) must be performed at Screening within 10 to 14 days prior to the 
start of CC-220. The second pregnancy test must be performed within 24 hours prior 
to the start of CC-220. A urine (or serum) pregnancy test will be performed to assess 
subject eligibility within 24 hours prior to the first administration of IP (CC-220 
monotherapy or CC-220 plus DEX combination therapy).

Counseling about pregnancy precautions and the potential risks of fetal exposure 
must be conducted and documented in the source notes (see Appendix D). For Cohort 
J2, pregnancy counseling at the post-induction/pre-ASCT is only required for subjects 
who continue with an ASCT. Subjects who do not continue with an ASCT will 
perform pregnancy counseling at the EOT Visit.
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
Bone marrow aspirate/biopsy for cytogenetics (fluorescence in situ hybridization 
[FISH]), percent plasma cells, and biomarkers and in Part 2 of the study including a 
sample for MRD assessment.

Adverse event assessment, including SPM surveillance, begins when the subject signs 
the informed consent form

Local hepatitis panel: hepatitis B surface antigen (HBsAg), hepatitis B surface 
antibody (antiHBs), hepatitis B core antibody (antiHBc) and if applicable hepatitis B 
virus (HBV) DNA testing by PCR. Refer to the Table of Events for further details
(Table 9, Table 10, Table 11, Table 12, Table 13, and Table 17as applicable).

ECHO/MUGA for Cohorts G1 and G2. Refer to Table 12 and Table 13.
6.2.
Treatment Period
The subject will begin treatment upon confirmation of eligibility. The subject must start 
treatment within 28 days of signing the informed consent form (ICF) and will be allocated by 
IRT to an appropriate cohort, depending on his/her eligibility and on the cohort slot availability. 
After Cycle 1, for all subsequent visits, an administrative window of ± 2 days is permitted. On 
Cycle 1 Day 1 (C1D1), safety laboratory assessments must be drawn for the central lab and 
performed locally to confirm that the subject continues to meet the required safety laboratory 
values prior to initiating IP. However, if Screening assessments were performed within 72 hours 
of C1D1, safety laboratory for the central lab and physical examinations need not be repeated at 
C1D1.  
Treatment cycles are 28 days in duration for all cohorts with the exception of Cohorts F, J1(first 
8 cycles) and J2 (CC-220Vd), which are 21 days in duration. Further details can be found in 
Section 7.2.
The following evaluations will be performed at the frequency specified in the Table of Events
(Table 9, Table 10, Table 11, Table 12, Table 13, Table 14, Table 15, Table 16, and Table 17 as 
applicable). The evaluations should be performed unless otherwise specified.

IRT Registration (C1D1)

Concomitant medications evaluation

Concomitant procedures evaluation

Adverse event (including AEs of special interest [AESI] and SPM surveillance) 
evaluation (continuously). Note in Cohort J2, all SAEs made known to the 
Investigator at any time after 28 days after the last dose of induction treatment, that 
are suspected of being related to induction treatment will be recorded.

Physical examination including assessment for ECOG performance status, potential 
VTEs (source documented only)

Vital signs including weight

Hematology panel 

Chemistry panel (including renal function [CrCl])
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
12-lead ECGs 

Efficacy assessment (see Section 6.3)

Response assessment in accordance with IMWG criteria (Day 1 of each cycle starting 
with Cycle 2). Subjects in Cohorts J1and K will be followed every cycle for the first 2 
years and thereafter, every 3 months until PD or until a subsequent myeloma regimen 
has been started. Subjects in Cohort J2, following induction, ASCT with or without 
maintenance, will be followed for response assessment during the Post-Treatment 
Response follow-up every 3 months until PD or until a subsequent anti-myeloma 
regimen has been started.

Urine (or serum) pregnancy test for FCBP (prior to dosing on Day 1 of every cycle). 
For cycle 1, pregnancy testing will occur weekly, then at Day 1 for each subsequent 
cycle. For FCBP with irregular menstrual cycles, pregnancy testing will be weekly for 
cycle 1, and biweekly for each subsequent cycle.

Counseling about pregnancy precautions and the potential risks of fetal exposure for 
subjects receiving CC-220 (see Appendix D)

Continuous thromboembolism prophylaxis treatment 

Bone marrow aspirate/biopsy and blood sampling for biomarkers (see Section 6.3.1),
percent plasma cells and in Part 2 of the study, MRD assessment (see Table 18 for 
details)

Blood sampling for biomarker assessments (see Section 6.6)

Blood sampling for PK assessments (see Section 6.5)

Blood sampling for immunogenicity assessments (see Section 6.6)

IP (CC-220, DEX, BTZ, DARA, and CFZ as applicable) accountability/compliance

Urinalysis if clinically indicated

Ophthalmological examination if clinically indicated

For Cohorts E and K subjects, HBV DNA by PCR (local testing) every 12 weeks if 
indicated and applicable (see Table 10 and Table 17)

 
 
6.2.1.
End of Treatment Visit
An end of treatment (EOT) evaluation will be performed for subjects who are withdrawn from 
treatment for any reason within 7 days after the decision to permanently discontinue treatment 
has been made. For subjects in Cohort J2 who will not undergo an ASCT for whatever reason, an 
EOT Visit should be performed. For those subjects in Cohort J2 who undergo an ASCT, the EOT 
Visit should be performed three months (± 7 days) after the transplant.  
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The following evaluations will be performed as specified in the Schedule of Events (Table 9,
Table 10, Table 11, Table 12, Table 13, Table 14, Table 15, Table 16 and Table 17 as 
applicable):

IRT registration

Physical examination including ECOG performance status and VTE monitoring 
(source documented only)

Vital signs including weight

Concomitant medications evaluation (monitored for 28 days after the last dose of CC-
220)

Concomitant procedures evaluation (monitored for 28 days after the last dose of CC-
220)

Adverse event (including AESIs and SPM) evaluation (monitored through 28 days 
after the last dose of IP) 

Counseling about pregnancy precautions and the potential risks of fetal exposure for 
subjects who received CC-220 (see Appendix D)

Response assessment in accordance with IMWG criteria

12-lead ECG

Urinalysis 

Hematology panel

Chemistry panel (including CrCL)

BMA/BMB if treatment discontinuation is due to PD for biomarkers (see 
Section 6.3.1) and percent plasma cells

Whole blood sample collection for biomarkers

Urine or serum pregnancy test for FCBP

Ophthalmological examination if clinically indicated

IP accountability/compliance

Efficacy assessment will be performed according to the schedule defined in the 
Schedule of Events (Table 9, Table 10, Table 11, Table 12, Table 13, Table 14,
Table 15, Table 16 and Table 17 as applicable), and does not need to be performed 
specifically for the EOT visit except as specified in Section 6.3.

For Cohorts E and K subjects, HBV DNA by PCR (local testing) at EOT and every 
12 weeks for up to 6 months after the last dose of DARA, if indicated/applicable (see
Table 10, and Table 17)

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6.2.2.
28-Day Post Treatment Visit
The following assessments will be performed at this visit 28 days after the EOT visit (+/- 3 
days):

Urine or serum pregnancy test for FCBP. Additionally, for FCBP with irregular 
menstrual cycles, a urine or serum pregnancy test will be performed 14 days after 
treatment discontinuation.

Follow up on any ongoing AEs at time of IP discontinuation

Vital signs and weight
6.2.3.
Post Treatment Response Assessment
Subjects who discontinue study treatment in Part 1 or Part 2 of the study for a reason other than 
PD or withdrawal of consent from the study will be followed for response assessment every 28 
days (or 21 days for Cohort F subjects) until PD or a subsequent myeloma regimen has been 
started. Concomitant medications, concomitant procedures and adverse event (including AESIs 
and SPM) evaluations will continue to be collected for subjects who enter this follow up phase.
Additionally, subjects in Cohort J2, following induction, ASCT with or without maintenance, 
will be followed for response assessment every 3 months until PD or until a subsequent anti-
myeloma regimen has been started. For Cohort J2, these efficacy assessments every 3 months 
will be done locally. Subjects are expected to have a visit at the time of discontinuation from the 
Post Treatment Response Assessment follow-up period.
6.2.4.
Long-term Follow-up
Part 2 RRMM subjects (Cohorts C, D, and I) will have long-term follow-up. Subjects will be 
contacted every 3 months to collect data on survival, SPM status, and subsequent anti-myeloma 
therapies including date of progression for at least 5 years after the date of the last subject 
enrolled into the study. Cause of death is to be recorded on the eCRF. 
6.3.
Efficacy Assessment 
All laboratory assessments for efficacy will be performed centrally.
If Screening assessments are performed within 72 hours of C1D1, efficacy laboratory 
assessments need not be repeated at C1D1.

Serum protein electrophoresis (sPEP) and urine protein electrophoresis (uPEP) tests 
(performed on 24-hour urine collection) are required at Screening, on Day 1 of each 
cycle, at the EOT Visit, and at the Post-Treatment Response Follow Up visits (for 
subjects who enter this phase).

For Cohort J1 and K: at Screening, on Day 1 from Cycle 1 to Cycle 30 (Cohort 
J1), on Day 1 from Cycle 1 to Cycle 26 (Cohort K) (ie, first ~ 2 years) and 
thereafter, every 3 months (done locally) until PD or until a subsequent myeloma 
regimen has been started.
Approved
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EDMS Doc. Number: 25858146 - 20867538
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Protocol CC-220-MM-001
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
For Cohort J2: at Screening, on Day 1 from Cycle 1 to 6, pre-ASCT, monthly 
post-ASCT, at the EOT Visit and then every 3 months (done locally) during the 
Post-Treatment Response Follow Up visits.

Serum and urine immunofixation tests are required at Screening and will be triggered 
to be performed whenever M-protein is undetectable or too few to quantify in both 
sPEP and uPEP assays.

For Cohorts J1 and K: at Screening, on Day 1 from Cycle 1 to Cycle 30 (Cohort 
J1), on Day 1 from Cycle 1 to Cycle 26 (Cohort K) (ie, first 2 years) and 
thereafter, every 3 months (done locally) until PD or until a subsequent myeloma 
regimen has been started.

For Cohort J2: at Screening, on Day 1 from Cycle 1 to 6, pre-ASCT, monthly 
post-ASCT, at the EOT Visit and then every 3 months (done locally) during the 
Post-Treatment Response Follow Up visits.

Quantitative serum immunoglobulin assessment includes IgG, immunoglobulin A 
(IgA), immunoglobulin M (IgM), immunoglobulin E (IgE) and immunoglobulin D 
(IgD). Immunoglobulin E or IgD will only be drawn on Day 1 of each cycle, at the 
EOT Visit, and during the Post-Treatment Response Follow Up visits (for subjects 
who enter this phase) for subjects who demonstrate MM subtype IgE and IgD at 
Screening.

For Cohorts J1 and K: at Screening, on Day 1 from Cycle 1 to Cycle 30 (Cohort 
J1), on Day 1 from Cycle 1 to Cycle 26 (Cohort K) (ie, first ~ 2 years) and 
thereafter, every 3 months (done locally) until PD or until a subsequent myeloma 
regimen has been started.

Cohort J2: at Screening, on Day 1 from Cycle 1 to 6, pre-ASCT, monthly post-
ASCT, at the EOT Visit and then every 3 months (done locally) during the Post-
Treatment Response Follow Up visits.

Serum free light chain assay is required at Screening, on Day 1 of each cycle, at the 
EOT Visit, and at the Post-Treatment Response Follow Up Visits (for subjects who 
enter this phase). For Part 2 subjects, an additional serum free light chain assay is 
required on Day 8, and Day 15 of Cycle 1 for RRMM Cohorts C, D and I. 

For Cohort J1: at Screening, on C1D11, on Day 1 from Cycle 1 to Cycle 30 (ie 
first ~ 2 years) and thereafter, every 3 months (done locally) until PD or  until a 
subsequent myeloma regimen has been started.

Cohort J2: at Screening, on C1D11, on Day 1 from Cycle 1 to 6, pre-ASCT, 
monthly post-ASCT, at the EOT Visit and then every 3 months (done locally) 
during the Post-Treatment Response Follow Up visits. 

For Cohort K: at Screening, on C1D15, on Day 1 from Cycle 1 to Cycle 26 (ie 
first ~ 2 years) and thereafter, every 3 months (done locally) until PD or until a 
subsequent myeloma regimen has been started.

Assessment of clinically assessable extramedullary plasmacytomas (EMPs) at 
Screening, Day 1 of each cycle and at the EOT Visit
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
Assessment of radiographically assessable EMPs at Screening, Day 1 of every 3rd
cycle after Screening and at the EOT Visit

β-2 microglobulin at Screening only.
Daratumumab detection on serum immunofixation has been demonstrated in subjects treated 
with DARA and may interfere with the traditional IMWG criteria of negative serum 
immunofixation for CR or stringent complete response (sCR). To mitigate this interference, a 
reflex assay that utilizes anti-idiotype antibody to bind DARA and confirm its interference on 
serum immunofixation will be performed. For subjects in Cohorts E with VGPR, and a negative 
endogenous M-protein by sPEP, reflex serum immunofixation testing will be performed centrally
to confirm the presence of DARA on serum immunofixation.
6.3.1.
Bone Marrow Aspirate and/or Biopsy
A BMA and, if possible, BMB is mandatory at the following time points:

At Screening, BMA and, if possible, BMB for percent plasma cells, cytogenetics 
(FISH), biomarkers assessments and in Part 2 of the study minimal residual disease 
(MRD) testing.

During treatment:

Only applicable for approximately 5 Cohort D subjects at one pre-identified US 
site: a C1D8 BMA may be taken for PK/Pd assessments. 

BMA and, if possible, BMB at C2D15 for biomarker assessments (C2D11 for 
Cohorts F and J1 subjects)

BMA and, if possible, BMB at the time of confirmed first complete response 
(CR) for biomarker assessments and percent plasma cells (by IMWG criteria, see
Appendix B) and in Part 2 of the study, MRD assessment on BMA.

In Part 2 of the study, BMA for MRD assessment:
o
For Cohorts C, D, I, and K: At 6, 12, 18, 24 months from C1D1 and yearly 
thereafter after achieving a response of VGPR or better until disease 
progression
o
For Cohort J1: At C7D1 and 12, 18, 24 months from C1D1 and yearly 
thereafter after achieving a response of VGPR or better until disease 
progression
o
For Cohort J2: At C4D1 of induction or end of induction, whichever comes 
first, and 100 days post-transplant after achieving VGPR or better

BMA and, if possible, BMB at time of confirmed PD/treatment discontinuation 
for biomarker assessments and percent plasma cells. Collection of this sample 
may be up to the time preceding the start of subsequent myeloma treatment after 
IP discontinuation. 
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A BMA and/or BMB is optional at the following time points

BMA and/or BMB taken at any time during the study at the request of 
investigator will have samples processed for biomarker assessments and percent 
plasma cells and in Part 2 of the study, MRD assessments if the subject has a 
response of VGPR or better and has not progressed.
The analysis of BMA/BMB for percentage of plasma cells will be performed locally. The bone 
marrow (BM) samples for cytogenetics (FISH), biomarkers will be submitted to a central 
laboratory. Bone marrow aspirate samples for MRD assessment collected at Screening will be 
submitted to a central laboratory and samples collected at VGPR, CR or any time during this 
response will be submitted to both a central laboratory (for next-generation sequencing analysis 
of MRD) and a specialized laboratory (for next-generation flow cytometry analysis of MRD).
The BMA and/or BMB collection sample plan is further outlined in Table 18 below.
Table 18:
Bone Marrow Aspirate and/or Biopsy Sample Collection Plan 
Study 
Phase 
Type
Visit
Sample 
Assessmentsb
Part 1 
Mandatory
Screening
BMA (and, if 
possible, BMB)
Percent plasma cells 
Cytogenetics (FISH)
Biomarkers assessments
Mandatory
C2D15
(C2D11 for 
Cohort F)
BMA (and, if 
possible, BMB)
Biomarker assessments 
Mandatory
At CR confirmation
BMA (and, if 
possible, BMB)
Percent plasma cells (by IMWG 
criteria)
Biomarker assessments
Optional
During study: any 
time requested by 
investigator (prior 
to start of 
subsequent 
myeloma therapy)
BMA and/or BMB
Percent plasma cells 
Biomarker assessments
Mandatory
Treatment 
discontinuation/time 
of confirmed PD a
BMA (and, if 
possible, BMB)
Percent plasma cells 
Biomarker assessments
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EDMS Doc. Number: 25858146 - 20867538
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Table 18:
Bone Marrow Aspirate and/or Biopsy Sample Collection Plan (Continued)
Study 
Phase 
Type
Visit
Sample 
Assessmentsb
Part 2
Mandatory
Screening
BMA 
(and, if 
possible, 
BMB)
Percent plasma cells 
Cytogenetics (FISH) 
Biomarkers assessments
MRD 
Mandatory 
(only 
applicable for 
one pre-
identified US 
site) c
C1D8 
BMA
Pharmacokinetic/pharmacodynamic
assessments
Mandatory for 
C, D, I, J1 and 
K (not 
required for 
J2)
C2D15 for C, D, I and K
C2D11 for Cohort J1
BMA 
(and, if 
possible, 
BMB)
Biomarker assessments
Mandatory
At CR confirmation
BMA 
(and, if 
possible, 
BMB)
Percent plasma cells (by IMWG 
criteria)
Biomarker assessments
MRD on BMA 
Mandatory for 
Cohorts C, D, 
I, and K
During treatment: at 6, 
12, 18 and 24 months 
from C1D1 and yearly 
thereafter after achieving 
a response of VGPR or 
better until disease 
progression
BMA
MRD
Mandatory for 
Cohort J1
During treatment: at 
C7D1 and 12, 18 and 24 
months from C1D1 and 
yearly thereafter after 
achieving a response of 
VGPR or better until 
disease progression
BMA
MRD
Mandatory for 
Cohort J2
C4D1 of induction or end 
of induction, whichever 
comes first, after 
achieving VGPR or 
better
BMA
MRD
Mandatory for 
Cohort J2
100 days post ASCT if 
achieved VGPR or better 
+/- 7 days
BMA
MRD
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Table 18:
Bone Marrow Aspirate and/or Biopsy Sample Collection Plan (Continued)
Study 
Phase 
Type
Visit
Sample 
Assessmentsb
Part 2 
Optional
During study: any time 
requested by investigator 
(prior to start of 
subsequent myeloma 
therapy)
BMA 
and/or
BMB
Percent plasma cells 
Biomarker assessments
MRD (if VGPR or better)
Mandatory
Treatment 
discontinuation/time of 
confirmed PDa
BMA 
(and, if 
possible, 
BMB)
Percent plasma cells 
Biomarker assessments
Abbreviations: ASCT = autologous stem cell transplant; BMA = bone marrow aspirate; BMB = bone marrow 
biopsy; CR = complete response; FISH = fluorescence in situ hybridization; IMWG = International Myeloma 
Working Group; MRD = minimal residual disease; PD = progressive disease; US = United States; VGPR= very 
good partial response.
a Collection of this sample may be up to the time preceding the start of subsequent myeloma treatment after 
treatment discontinuation. For subjects who enter Post-Treatment Response Follow up, the collection of this 
sample will be at the time of confirmed PD, not at treatment discontinuation. 
b All biomarker assessments will be submitted to a central laboratory with the exception of percent plasma cells for 
all subjects in Part 1 and Part 2 and cytogenetics for a subset of subjects in Part 1, which will be performed at the 
local laboratory. MRD assessments by next-generation flow cytometry will be submitted to a specialized 
laboratory.
c Assessment only applicable for approximately 5 subjects enrolled in Cohort D at one pre-identified US site.
6.3.2.
Bone Lesion Assessment
Bone lesion assessment by x-ray (skeletal survey), CT Scan or MRI will be performed at 
Screening and when clinically indicated. Bone lesion assessments will also be performed when 
clinically indicated for subjects who enter the Post-Treatment Response Follow up Phase. The 
same method (x-ray, CT Scan or MRI) should be used throughout the study. All films will be 
analysed locally by the site Investigator/Radiologist. If a bone lesion assessment by x-ray, CT 
Scan or MRI was performed within 60 days prior to C1D1, it may be used for the Screening 
assessment.
If assessment is done by x-ray, the following are the minimum plain radiological films required 
for the skeletal (bone) survey:

Lateral skull

Anterior/posterior (AP) and lateral cervical spine

AP and lateral thoracic spine

AP and lateral lumbar spine

AP chest

AP pelvis

AP upper extremities, shoulder to elbow

AP lower extremities, hip to knee
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Other radiological films may be necessary to view symptomatic areas of known pre-existing 
lesions in skeletal regions not included in the films above.
6.3.3.
Extramedullary Plasmacytoma Assessments
Clinical assessment for EMPs will be performed at Screening, on Day 1 of every cycle, at the 
EOT Visit, and at the Post-Treatment Response Follow Up visits if applicable. In addition, for 
Cohort J2, EMP assessments will be done pre-ASCT, monthly post-ASCT, at the EOT Visit and 
then every 3 months during the Post-Treatment Response Follow-up visits.
For EMPs that are only assessable radiographically (by x-ray and/or conventional [spiral] 
CT/magnetic resonance imaging [MRI] scan), scans are required at Screening, at Cycle 3 Day 1, 
every 3 cycles thereafter (Cycle 6 Day 1, Cycle 9 Day 1, etc.) during treatment and at the EOT 
Visit and when clinically indicated to confirm a response or PD. EMP assessments will also be 
performed for subjects who enter the Post-Treatment Response Follow up Phase. For Cohort J2, 
EMP assessments will be done at Cycle 4 Day 1, pre-ASCT, post-ASCT (3 months after ASCT), 
at the EOT Visit, during the Post-Treatment Response Follow up visits if clinically indicated. 
The radiographic modality used at Screening (eg, x-ray) will be repeated at each assessment time 
point throughout the study. All scans will be reviewed locally.
6.3.4.
Assessment of Response
Starting from Cycle 2, response will be assessed by the Investigator using the International 
Myeloma Working Group (IMWG) Uniform Response Criteria (Kumar, 2016) (see 
Appendix B) at every cycle starting at Cycle 2 on Day 1, and at the EOT Visit. Additionally, 
subjects who discontinue study treatment for a reason other than PD or withdrawal from the 
study will be followed every 28 days (or 21 days for Cohort F) for response assessment until PD 
or the start of a subsequent myeloma regimen. Accordingly, IMWG response will continue to be 
assessed at the Safety Follow Up visit and the Post-Treatment Response Follow Up visits for 
these subjects, as applicable. Subjects in Cohort J2, following induction, response assessment 
will be done pre-ASCT, monthly post-ASCT, at the EOT Visit, every 3 months during the Post-
Treatment Response Follow-up and at the Post-Treatment Response Discontinuation Visit.  
Response must be based on the central laboratory data to ensure consistency across investigative 
sites. For Cohorts J1 and K, central laboratory will be used for response assessment from Cycle 1 
to Cycle 30 (Cohort J1), or from Cycle 1 to Cycle 26 (Cohort K) (ie, first ~2 years) and 
thereafter, local laboratory will be used for response assessment every 3 months until PD or until 
a subsequent myeloma regimen has been started. For Cohort J2, local laboratory will be used for 
response assessment every 3 months during the Post-Treatment Response Follow Up visits.
NOTE: IMWG Uniform Response Criteria requires 2 consecutive assessments for all response 
categories and progressive disease except for radiographic or bone marrow assessments.
6.3.5.
Independent Response Committee (IRC) Assessment
Investigator response assessments will be used to determine the efficacy outcome throughout the 
study. An Independent Response Committee (IRC) may also be set up to review efficacy data 
from Part 2 RRMM Cohorts C, D, and/or I. The IRC will determine the tumor response to 
therapy based on the IMWG uniform Response Criteria as well as time of response (including 
PD) for each subject. 
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The IRC will adjudicate efficacy data according to the IRC Charter.
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6.5.
Pharmacokinetics 
Cohorts A and B
All subjects will participate in sparse PK as a participant in the main study. Both intensive and 
sparse PK samples will be collected to evaluate CC-220, and as appropriate, its R-enantiomer 
CC-17195 in plasma. The pharmacologically active metabolite, M12, will also be quantified in 
an exploratory manner. At each timepoint, approximately 6 mL of blood will be collected.
Sparse PK Sampling
All subjects will have sparse PK samples collected.
Pharmacokinetic blood samples will be collected in subjects at the following time points:

Cycles 1-4, Days 8, 15, 22: one pre-dose sample per visit.
Intensive PK Sampling
A subset of subjects will be selected to participate in the intensive PK assessment. In addition to 
the sparse PK sampling, frequent collection of PK blood samples will be performed in 
approximately 2 subjects per dose level (a total of 8 subjects at the minimum). Samples will be 
collected at the following time points:

Cycle 1, Day 15: 1, 2, 3, 4, 6, 8 hours and 24 hours after administration of CC-220.

The IRT will be used to monitor inclusion of a minimum of 2 intensive PK 
participants per dose group.
Cohorts C and D
All subjects will participate in sparse PK as a participant in the main study. Both intensive and 
sparse PK samples will be collected to evaluate the concentrations of CC-220 in plasma. At each 
time point, approximately 3 mL of blood will be collected.
Sparse PK Sampling
All subjects will have sparse PK samples collected.
Pharmacokinetic blood samples will be collected in subjects at the following time points:

Cycles 1-4, Day 15: one pre-dose sample per visit.
Intensive PK Sampling
In addition to the sparse PK sampling, frequent collection of PK blood samples will be 
performed in approximately 10 subjects enrolled. Samples will be collected at the following 3 
time points:

Cycle 1, Day 15: 1 timepoint at 2 h, 1 timepoint between 4-8 h, and 1 timepoint at 24 
hours after administration of CC-220.

The IRT will be used to monitor inclusion of a minimum of 10 intensive PK 
participants 
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Cohorts E, F, G1, and G2
All subjects will participate in sparse PK as a participant in the main study. Both intensive and 
sparse PK samples will be collected to evaluate CC-220 in plasma. At each time point, 
approximately 3 mL of blood will be collected.
Sparse PK Sampling
All subjects will have sparse PK samples collected.
Pharmacokinetic blood samples will be collected in subjects at the following time points:

Cycles 1-4, Days 8, 15: one pre-dose sample per visit.
Intensive PK Sampling
A subset of subjects will be selected to participate in the intensive PK assessment. In addition to 
the sparse PK sampling, frequent collection of PK blood samples will be performed in 
approximately 1 subject per dose level of each cohort. Samples will be collected at the following 
3 time points:

Cycle 1, Day 8: 1 timepoint at 2 h, 1 timepoint between 4-8 h, and 1 timepoint at 24 
hours after administration of CC-220.

The IRT will be used to monitor inclusion of the minimum required intensive PK 
participants per dose group.
Cohorts I and K 
All subjects will participate in sparse PK as a participant in the main study. Only sparse PK
samples will be collected to evaluate the concentrations of CC-220 in plasma. At each time 
point, approximately 3 mL of blood will be collected.
Sparse PK Sampling
All subjects will have sparse PK samples collected.
Pharmacokinetic blood samples will be collected in subjects at the following time points:

Cycles 1-2, Day 15: 1 timepoint at pre-dose and 1 timepoint at 2 hours after 
administration of CC-220.
There is no intensive sampling in Cohorts I and K.
Cohorts J1 and J2
All subjects will participate in sparse PK as a participant in the main study. Only sparse PK 
samples will be collected to evaluate the concentrations of CC-220 in plasma. At each time 
point, approximately 3 mL of blood will be collected.
Sparse PK Sampling
Pharmacokinetic blood samples will be collected in subjects at the following time points:

Cycles 1-2, Day 8: 1 timepoint at pre-dose and 1 timepoint at 2 hours after 
administration of CC-220.
There is no intensive sampling in Cohorts J1 and J2.
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Pharmacokinetic samples should be collected within the following collection windows:

-30 to -5 minutes for the pre-dose sample

± 10 minutes for the samples collected at time points of 1 to 4 hours

± 20 minutes for the samples collected at the time point of between 6 and 8 hours

± 5 hours for the sample collected at the time point of 24 hours (this sample must be 
collected prior to the second dose)
The CC-220 concentration in plasma will be determined. Specific details regarding the 
collection, processing, storage, and shipment of PK samples will be provided in a separate 
document.
On all PK visits, subjects must bring their CC-220 to the study center and CC-220 must be 
administered to subjects at the study center after the collection of the pre-dose PK blood sample.  
Subjects will be asked to report the date and time of their last CC-220 dose (prior to the current 
study visit day) to the study staff during their visit at the study center.  Dosing and sample 
collection information including CC-220 dose level, dosing date, dosing time (24-hour clock), 
and actual PK blood sampling time (24-hour clock) should be accurately documented on the 
appropriate eCRF pages.
6.6.
Biomarkers, Pharmacodynamics and Pharmacogenomics
The changes of each biomarker will be determined by comparing the levels of biomarkers in pre-
treatment and post-treatment samples and, where possible, correlate these with PK findings and 
tumor response over time.  
If Celgene determines, during the conduct of the study, that a Pd measurement is not reliable or 
informative, the sites will be notified, via an administrative letter, that this Pd sample should no 
longer be collected. 
Full details of all statistical analyses and modeling for these outcomes will be described in the 
statistical analysis plan and final study report.
The following will be mandatory in dose escalation (Part 1) and not collected in expansion 
(Part 2)

To evaluate the pharmacodynamic (Pd) effects of CC-220 on Aiolos and other Pd 
biomarkers (by protein expression) in peripheral blood cell components including 
mononuclear cells and secreted cytokines.
Blood collection time points:

C1D1 – pre-dose, 3, 5 hours post dose

C1D12 – pre-dose, 3, 5 hours post dose. For Cohorts G1 and G2, this assessment 
will be performed on C1D15. Note, in all cohorts, the acceptable window for this 
assessment is C1D11 to C1D15.
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
To explore TCR (T-cell receptor) clonality in peripheral blood. 
Blood collection time points:

C1D1– pre-dose

C2D15– pre-dose

C4D15– pre-dose

IP discontinuation (EOT)

To explore Pd effects of CC-220 on T-cell counts in peripheral blood. This 
lymphocyte subset panel is obtained from existing hematology sampling; no 
additional sampling is required. 
Blood collection time points for all Cohorts except Cohorts F, G1 and G2:

Cycles 1 Days 1, 8, 12, 15, 22, 26– pre-dose

Cycles 2-4 Days 1, 8, 15, 22– pre-dose

Cycles 5+ Days 1, 15– pre-dose
Blood collection timepoints for Cohort F:

Cycles 1 Days 1, 8, 12, 15– pre-dose when applicable

Cycles 2-4 Days 1, 8, 15– pre-dose when applicable

Cycles 5+ Days 1, 15– pre-dose when applicable
Blood collection timepoints for Cohorts G1 and G2:

Cycles 1-4 Days 1, 8, 15– pre-dose

Cycles 5+ Days 1, 15– pre-dose

For Cohorts B, G1, and G2, up to 3 subjects in each dose level at select US sites may 
be selected for the following assessment: To evaluate the pharmacodynamic (Pd) 
effects of CC-220 on Aiolos and Ikaros in mononuclear cells with a novel exploratory 
assay. The IRT will be used to monitor inclusion of these participants.
Blood collection time points:

C1D1 – pre-dose, 3, 6 hours post dose

C1D2 – pre-dose

C1D15 – pre-dose, 3 hours post dose

For Cohort F, up to 3 subjects in each dose level at select US sites may be selected 
for the following assessment: To evaluate the pharmacodynamic (Pd) effects of CC-
220 on Aiolos and Ikaros in mononuclear cells with a novel exploratory assay. The 
IRT will be used to monitor inclusion of these participants.
Blood collection time points:

C1D1 – pre-dose, 3, 6 hours post dose
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
C1D2 – pre-dose

C1D11 – pre-dose, 3 hours post dose
The following will be mandatory in dose escalation (Part 1) and mandatory in expansion 
(Part 2)

To explore the pharmacodynamic (Pd) effects of CC-220 on T-Cell Activation in 
peripheral blood
Blood collection time points:

C1D1 – pre-dose, 3, 5 hours post dose

C1D12 – pre-dose, 3, 5 hours post dose. For Cohorts C, D, G1, G2 and K this 
assessment will be performed on C1D15. For Cohorts J1 and J2, this assessment will 
be performed on C1D11. Note, in all cohorts, the acceptable window for this 
assessment is C1D11 to C1D15.

To explore the Pd effects of CC-220 on immune cell populations in peripheral blood 
and association of baseline levels of these populations with response or resistance to 
CC-220
Blood collection time points for Cohorts A, B, E, F, G1, and G2:

C1D1 – pre-dose

C2D1 – pre-dose

C2D15 – pre-dose

C4D1 – pre-dose

C4D15 – pre-dose

C6D15– pre-dose

At IP discontinuation (EOT)
Blood collection time points for Cohorts C, D, I and K: 

C1D1 – pre-dose

C2D1 – pre-dose

C2D15 – pre-dose

C6D15– pre-dose 

EOT
Blood collection time points for Cohort J1:

C1D1 – pre-dose

C4D8– pre-dose

C8D8– pre-dose 

EOT
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Blood collection time points for Cohort J2:

C1D1 – pre-dose

C4D8 – pre-dose

EOT

To explore pharmacogenomics of CC-220 response
Blood collection time point:

C1D1 – pre-dose

To explore the association of CC-220 response or resistance to baseline levels and Pd 
changes in protein expression, gene expression, cytogenetics, copy number 
abnormalities and/or mutations in tumor cells and tumor microenvironment in the 
bone marrow
BMA/BMB collection time points (Please refer to Table 18 for details on BMA/BMB 
sample collection plan):

Screening BMA (and, if possible, BMB)

C2D15 – 3-6 hours post dose BMA (and, if possible, BMB). (C2D11 for Cohort F
and Cohort J1)

Confirmatory BMA (and, if possible, BMB) for complete response (CR)

Optional BMA and/or BMB taken at any time requested by investigator during 
the study period

BMA (and, if possible, BMB) taken at the time of PD/treatment discontinuation
or any time after PD and before the start of subsequent myeloma therapy 
The following will be mandatory in expansion (Part 2) only.

To explore the effects of CC-220 on minimal residual disease (MRD) negativity in 
subjects achieving a response of VGPR or better and who have not progressed.
BMA collection time points (Please refer to Table 18 for details on BMA/BMB 
sample collection plan):

Screening

Confirmatory BMA (and, if possible, BMB) for complete response (CR)

To evaluate the duration of MRD negativity and changes in MRD status in 
responding subjects, a BMA after achieving response of VGPR or better until disease 
progression. Please refer to Table 18 for details on timepoints.

Only applicable for approximately 20 subjects enrolled in Cohort D at select US 
sites: To evaluate the pharmacodynamic (Pd) effects of CC-220 on Aiolos and Ikaros 
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in mononuclear cells with a novel exploratory assay. The IRT will be used to monitor 
inclusion of these participants.
Blood collection time points:

C1D1 – pre-dose, 3, 6 hours post dose

C1D2 – pre-dose

C1D15 – pre-dose, 3 hours post dose

Only applicable for approximately 20 subjects enrolled in Cohort D at select US 
sites:
 
 The IRT will be used to monitor inclusion of these participants.
Blood collection time points:

C1D1 – pre-dose

C2D1 – pre-dose

C2D15 – pre-dose

Only applicable for approximately 5 subjects enrolled in Cohort D at one pre-
identified US site: To evaluate time-matched concentration of CC-220 in peripheral 
blood and tumor microenvironment and assess the correlation between concentration, 
pharmacodynamic changes in tumor microenvironment, and outcome measures. The 
IRT will be used to monitor inclusion of these participants.
BMA and blood collection timepoints:

Screening

C1D8 – 3-6 hours post dose

C2D15 – 3-6 hours post dose
 
Full details of all statistical analyses for biomarkers will be described in a separate biomarker
study report.
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7.
DESCRIPTION OF STUDY TREATMENTS
7.1.
Description of Investigational Product(s)
CC-220

CC-220 has a chemical name of 2,6-piperidinedione, 3-[1,3-dihydro-4-[[4-(4-
morpholinylmethyl)phenyl]methoxy]-1-oxo-2H-isoindol-2-yl]-, (3S)-, hydrochloride 
(1:1).  It has a molecular weight of 485.96.
CC-220 will be supplied by Celgene Corporation in formulated capsules and will be 
labeled appropriately as investigational material. 
Dexamethasone

Subjects enrolled in countries where DEX is commercially available may obtain 
commercially available product through their local hospital pharmacy or licensed 
distributer.

Celgene will provide DEX for countries where supplies are not commercially 
available, or not readily available, or not provided per regulation.

Please refer to local prescribing information for more details on available 
formulations, preparation, storage conditions (eg, refrigeration), the approved 
indications, known precautions, warnings, and adverse reactions of dexamethasone 
(see current version of prescribing information). The DEX dosing schedule and dose 
adjustments to be followed for this study are described in Section 7.3.2.
Intravenous (IV) Daratumumab

Subjects enrolled in countries where IV DARA is commercially available may obtain 
commercially available product through their local hospital pharmacy or licensed 
distributer.

Celgene will provide IV DARA for countries where supplies are not commercially 
available, or not readily available, or not provided per regulation.

Please refer to local prescribing information for more details on available 
formulations, preparation, storage conditions (eg, refrigeration), the approved 
indications, known precautions, warnings, and adverse reactions of IV DARA (see 
current version of prescribing information). The IV DARA dosing schedule and dose 
adjustments to be followed for this study are described in Section 7.3.3 and the 
Protocol Summary Table 3.
Subcutaneous (SC) Daratumumab

Subjects enrolled in countries where SC DARA is commercially available may
obtain commercially available product through their local hospital pharmacy or 
licensed distributer.

Celgene will provide SC DARA for countries where supplies are not commercially 
available, or not readily available, or not provided per regulation.
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
Please refer to local prescribing information for more details on available 
formulations, preparation, storage conditions (eg, refrigeration), the approved 
indications, known precautions, warnings, and adverse reactions of SC DARA (see 
current version of prescribing information). The SC DARA dosing schedule and dose 
adjustments to be followed for this study are described in Section 7.3.3 and the 
Protocol Summary Table 3.
Bortezomib

Subjects enrolled in countries where BTZ is commercially available may obtain 
commercially available product through their local hospital pharmacy or licensed
distributer.

Celgene will provide BTZ for countries where supplies are not commercially 
available, or not readily available, or not provided per regulation.

Please refer to local prescribing information for more details on available 
formulations, preparation, storage conditions (eg, refrigeration), the approved 
indications, known precautions, warnings, and adverse reactions of bortezomib (see 
current version of prescribing information). The bortezomib dosing schedule and dose 
adjustments to be followed for this study are described in Section 7.3.4 and the 
Protocol Summary Table 3.
Carfilzomib

Subjects enrolled in countries where CFZ is commercially available may obtain 
commercially available product through their local hospital pharmacy or licensed 
distributer.

Celgene will provide CFZ for countries where supplies are not commercially 
available, or not readily available, or not provided per regulation.

Please refer to local prescribing information for more details on available 
formulations, preparation, storage conditions (eg, refrigeration), the approved 
indications, known precautions, warnings, and adverse reactions of carfilzomib (see 
current version of prescribing information). The carfilzomib dosing schedule and 
dose adjustments to be followed for this study are described in Section 7.3.5 and 
Protocol Summary Table 4.
7.2.
Treatment Administration and Schedule
The first day of IP dosing (CC-220) is considered Day 1 of a cycle for all cohorts, including 
triplet regimen cohorts. Capsules of CC-220 will be taken by mouth (PO) with or without food.
7.2.1.
Treatment Schedule 
7.2.1.1.
Part 1 (Dose Escalation)
Cohort A (MonoT)
Subjects who have been allocated to Cohort A will receive CC-220 monotherapy (MonoT).
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
Oral CC-220 at dose specified by cohort dose level from Day 1-21 of each 28-day 
cycle.

Subjects who have confirmed PD (by IMWG criteria) on MonoT may have DEX 
added to CC-220. The subject’s dose of CC-220 will not be higher than the dose of 
CC-220 used in combination with DEX in Cohort B that has been determined to be 
safe.  The site will be informed of the dose of CC-220 to which DEX will be added.
Cohort B (DoubleT)
Subjects who have been allocated to Cohort B will receive CC-220 in combination with DEX 
(DoubleT)

Oral CC-220 at dose specified by cohort dose level from Day 1-21 of each 28-day 
cycle

For subjects ≤ 75 years old, oral DEX 40 mg on Days 1, 8, 15, and 22 of each 28-day 
cycle. For subjects >75 years old, DEX will be administered at 20 mg on Days 1, 8, 
15, and 22 of each 28-day cycle. Subjects who surpass the age of 75 years while on 
treatment may be switched to the 20 mg dosage based on the investigator’s best 
judgement.
Cohort E (CC-220Dd)
Subjects who have been allocated to Cohort E will receive CC-220 in combination with DARA
and DEX 

Oral CC-220 at dose specified by cohort dose level from Day 1-21 of each 28-day 
cycle

Intravenous (IV) DARA administered at a dose of 16 mg/kg for:

Cycles 1 and 2 on Days 1, 8,15, 22 of each 28-day cycle

Cycles 3 to 6 on Days 1, 15 of each 28-day cycle

Cycles ≥7 on Day 1 of each 28-day cycle

For subjects ≤ 75 years old, oral DEX 40 mg on Days 1, 8, 15, and 22 of each 28-day 
cycle. For subjects >75 years old, DEX will be administered at 20 mg on Days 1, 8, 
15, and 22 of each 28-day cycle. Subjects who surpass the age of 75 years while on 
treatment may be switched to the 20 mg dose based on the investigator’s judgement.
Once the MTD and/or RP2D is determined in Cohort E (CC-220Dd), subjects will be enrolled at 
this dose level using SC DARA.

Oral CC-220 at the MTD/RP2D from Days 1-21 of each 28-day cycle

SC DARA administered at a dose of 1800 mg over 3 to 5 minutes for:

Cycles 1 and 2 on Days 1, 8, 15 and 22 of a 28-day cycle

Cycles 3 to 6 on Days 1 and 15 of a 28-day cycle

Cycles ≥7 on Day 1 of a 28-day cycle
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
For subjects ≤ 75 years old, oral DEX 40 mg on Days 1, 8, 15, and 22 of each 28-day 
cycle. For subjects >75 years old, DEX will be administered at 20 mg on Days 1, 8, 
15, and 22 of each 28-day cycle. Subjects who surpass the age of 75 years while on 
treatment may be switched to the 20 mg dose based on the investigator’s judgement.
Cohort F (CC-220Vd)
Subjects who have been allocated to Cohort F will receive CC-220 in combination with BTZ and
DEX

Oral CC-220 at dose specified by cohort dose level from Day 1-14 of each 21-day 
cycle

Subcutaneous (SC) BTZ administered at a starting dose of 1.3 mg/m2:

Cycles 1 to 8 on Days 1, 4, 8, 11 of each 21-day cycle

Cycles ≥ 9 on Days 1, 8 of each 21-day cycle
Bortezomib doses must be at least 72 hours apart.

For subjects ≤ 75 years old, oral DEX 40 mg on Days 1, 8, and 15 of each 21-day 
cycle. For subjects >75 years old, DEX will be administered at 20 mg on Days 1, 8, 
and 15 of each 21-day cycle. Subjects who surpass the age of 75 years while on 
treatment may be switched to the 20-mg dose based on the investigator’s judgement.
Cohort G1 (CC-220Kd)
Subjects who have been allocated to Cohort G1 will receive CC-220 in combination with once 
weekly CFZ and DEX

Oral CC-220 at dose specified by cohort dose level from Day 1-21 of each 28-day 
cycle

Intravenous (IV) CFZ administered at a starting dose of 20 mg/m2 on C1D1; and at a 
dose specified by cohort dose level thereafter (refer to Table 4):

Days 1, 8, 15 of each 28-day cycle

Oral DEX on Days 1, 8, 15, and 22 of each 28-day cycle

For subjects ≤ 75 years old, the DEX dose will be 40 mg. For subjects > 75 years 
old, the DEX dose will be 20 mg. 

Administer DEX 30 minutes to 4 hours before CFZ.
Cohort G2 (CC-220Kd)
Subjects who have been allocated to Cohort G2 will receive CC-220 in combination with twice 
weekly CFZ and DEX

Oral CC-220 at dose specified by cohort dose level from Day 1-21 of each 28-day 
cycle

Intravenous (IV) CFZ administered at a starting dose of 20 mg/m2 on C1D1; and at a 
dose level specified by cohort dose level thereafter (refer to Table 4):
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
Days 1, 2, 8, 9, 15, 16 of each 28-day cycle

Oral DEX on Days 1, 2, 8, 9, 15, 16, 22, 23 of each 28-day cycle

The DEX dose will be 20 mg.

Administer DEX 30 minutes to 4 hours before CFZ
7.2.1.2.
Part 2 (Expansion)
Cohort C (MonoT)
Subjects who have been allocated to Cohort C will receive CC-220 monotherapy (MonoT).

Oral CC-220 at RP2D from Day 1-21 of each 28-day cycle

Subjects who have confirmed PD (by IMWG criteria) on MonoT may have DEX 
added to their current dose of CC-220. The subject’s dose of CC-220 will not be 
higher than the dose used in Cohort B that has been determined to be safe. If MTD 
has been reached in Cohort B, the RP2D of CC-220 will be used when DEX is added.
Cohort D (DoubleT)
Subjects who have been allocated to Cohort D will receive CC-220 in combination with DEX

Oral CC-220 at RP2D from Day 1-21 of each 28-day cycle

Oral DEX 40 mg on Days 1, 8, 15, and 22 of each 28-day cycle. For subjects > 75 
years old, DEX will be administered at 20 mg on Days 1, 8, 15, and 22 of each 28-
day cycle. Subjects who surpass the age of 75 years while on treatment may be 
switched to the 20 mg dosage based on the Investigator’s best judgement.
Cohort I (DoubleT in prior BCMA Targeted Therapy)
Subjects who have been enrolled to Cohort I will receive CC-220 in combination with DEX

Oral CC-220 at RP2D from Day 1-21 of each 28-day cycle

Oral DEX 40 mg on Days 1, 8, 15, and 22 of each 28-day cycle. For subjects > 75 
years old, DEX will be administered at 20 mg on Days 1, 8, 15, and 22 of each 28-
day cycle. Subjects who surpass the age of 75 years while on treatment may be 
switched to the 20 mg dosage based on the Investigator’s best judgement.
Cohort J1 (CC-220Vd in NDMM)
Subjects who have been enrolled to Cohort J1 will receive CC-220 in combination with BTZ and 
DEX.

Oral CC-220 at 1.0 mg, 1.3 mg or 1.6 mg as follows:

Cycles 1 to 8 on Days 1-14 of each 21-day cycle

Cycles > 9 on Days 1-21 of each 28-day cycle

Subcutaneous (SC) BTZ administered at a starting dose of 1.3 mg/m2:

Cycles 1 to 8 on Days 1, 4, 8, 11 of each 21-day cycle. Bortezomib doses must be 
at least 72 hours apart
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
Oral DEX administered as follows:

Cycles 1 to 8, 20 mg (≤ 75 years old) or 10 mg (> 75 years old) on Days 1, 2, 4, 5, 
8, 9, 11 and 12 of each 21-day cycle

Cycles > 9, 40 mg (≤ 75 years old) or 20 mg (> 75 years old) on Days 1, 8, 15, 
and 22 of each 28-day cycle 
Cohort J2 (CC-220Vd in NDMM)
Subjects who have been enrolled to Cohort J2 will receive CC-220 in combination with BTZ and 
DEX as induction treatment for up to 6 cycles.

Oral CC-220 at RP2D from Day 1-14 of each 21-day cycle

Subcutaneous (SC) BTZ administered at a starting dose of 1.3 mg/m2:

Cycles 1 to 6 on Days 1, 4, 8, 11 of each 21-day cycle. Bortezomib doses must be 
at least 72 hours apart.

Oral DEX dosed at 20 mg/day (≤ 75 years old) or 10 mg/day (> 75 years old) for:

Cycles 1 to 6 on Days 1, 2, 4, 5, 8, 9, 11 and 12 of a 21-day cycle 

Mobilization of hematopoietic stem cells as per Institutional’s standard practice and 
subsequent apheresis

After 4 to 6 cycles of induction, subjects may undergo ASCT as per Institutional’s 
standard of practice 

Maintenance regimen or observation as per Institutional’s standard practice until PD 
or a subsequent anti-myeloma regimen has been started 
Cohort K (CC-220Dd)
Subjects who have been allocated to Cohort K will receive CC-220 in combination with DARA 
and DEX 

Oral CC-220 at 1.0 mg, 1.3 mg or 1.6 mg from Days 1-21 of each 28-day cycle

SC DARA administered at a dose of 1800 mg over 3 to 5 minutes for:

Cycles 1 and 2 on Days 1, 8, 15 and 22 of a 28-day cycle

Cycles 3 to 6 on Days 1 and 15 of a 28-day cycle

Cycles ≥7 on Day 1 of a 28-day cycle

For subjects ≤ 75 years old, oral DEX 40 mg on Days 1, 8, 15, and 22 of each 28-day 
cycle. For subjects >75 years old, DEX will be administered at 20 mg on Days 1, 8, 
15, and 22 of each 28-day cycle. Subjects who surpass the age of 75 years while on 
treatment may be switched to the 20 mg dose based on the investigator’s judgement.
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7.2.2.
Dexamethasone
Refer to the full prescribing information and labeling for DEX contained in the respective current 
prescribing information, SmPC, or equivalent document for the specific region/country.
7.2.3.
Daratumumab
Refer to the full prescribing information and labeling for DARA contained in the respective 
current PI, SmPC, or equivalent document for the specific region/country. It should be noted that 
DARA interferes with blood group compatibility testing and cross matching for up to 6 months 
after the last DARA administration (due to drug-mediated positive indirect antiglobulin test).
Guidance on pre- and post-administration medications for injection reaction prophylaxis in 
relation to DARA dosing is given in Table 19 and can be used in conjunction with the site’s 
standard of care for DARA administrations. Investigators should refer to the current DARA PI or 
SmPC for guidelines on the management of infusion or injection-related reactions (Darzalex PI; 
Darzalex Faspro PI; Darzalex SmPC).
Table 19:
Daratumumab Pre- and Post-administration Medications
Time point
Medication
Subjects NOT Receiving DEX
As Part Of Study Regimen
Subjects Receiving 
DEX As Part Of 
Study Regimen
Pre-administration (~1 
hr prior to every 
DARA 
administration)
oral montelukast
(if approved and 
available)
per Investigator discretion prior 
to first administration
per Investigator 
discretion prior to 
first administration
IV corticosteroid 
methylprednisolone 100 mg or 
equivalent dose of an 
intermediate-acting or long-
acting corticosteroid (refer to
Table 20 for conversion table).
Following the second 
administration, the dose of 
corticosteroid may be reduced 
(methylprednisolone 60 mg 
intravenously)
not applicable
a
oral antipyretics 
acetaminophen 650 to 1000 mg
b
acetaminophen 650 
to 1000 mg
oral or IV 
antihistamine 
diphenhydramine 25 to 50 mg or 
equivalentb
diphenhydramine 25 
to 50 mg or 
equivalent
Post-administration
medication 
(1st and 2nd day after 
every DARA 
administration)
oral corticosteroid
c
20 mg methylprednisolone or 
equivalent dose of a 
corticosteroid in accordance 
with local standards 
Not applicablea, d
DARA = daratumumab; DEX = dexamethasone; IV = intravenous.
a Not applicable since dexamethasone is already given as part of the study treatment, see Section 7.2.1.
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b If necessary, oral pre-administration medications may be administered at the subject’s home on the day of 
administration, provided they are given within 3 hours prior to the administration.
c For subjects with a history of obstructive pulmonary disorder, consider prescribing post-administration
medications such as short and long-acting bronchodilators, and inhaled corticosteroids. Following the first four 
administrations, if the subject experiences no major infusion or injection reactions, these additional inhaled post-
administration medications may be discontinued. 
d For subjects receiving dexamethasone ≤ 20 mg/week (> 75 years or with DEX dose reduced) and given as pre-
administration medication, may receive low-dose methylprednisolone (≤20 mg) orally (or equivalent in 
accordance with local standards) for the prevention of delayed infusion or injection-related reactions, as clinically 
indicated.
Table 20:
Conversion Table for Glucocorticoid Dose
Medication
Oral or Intravenous Dose (mg)
Dexamethasone
0.75
Hydrocortisone
20
Methylprednisolone
4
Prednisolone
5
Prednisone
5
7.2.3.1.
Subcutaneous Daratumumab 
Subcutaneous DARA will be provided as a fixed-dose of 1800 mg DARA and 30,000 units 
hyaluronidase per 15 mL (120 mg and 2000 units/mL).
Daratumumab (1800 mg) will be administered via SC injection by manual push over 3 to 5
minutes in the abdominal subcutaneous tissues in left/right locations, alternating between 
individual doses. All subjects will be observed for at least 6 hours after the end of the SC 
injection during Cycle 1 Day 1 and, if deemed necessary by the Investigator, after subsequent 
injections. Reasons for continued observation on subsequent DARA injections may include but 
are not limited to the following: 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), subjects with IRRs with 
first injection of study drug, or subjects with a decreased condition on day of dosing compared to 
the prior dosing day. 
For further details regarding storage, preparation and administration, please refer to the current 
approved prescribing information and labeling. 
7.2.3.1.1. Management of Injection-site and Injection-related Reactions
7.2.3.1.1.1. Injection-related Reactions
If an IRR develops, then DARA administration should be temporarily interrupted. Subjects who 
experience AEs during DARA administration must be treated for their symptoms. Subjects 
should be treated with acetaminophen (paracetamol), antihistamine, or corticosteroids, as needed. 
Intravenous saline may be indicated. For bronchospasm, urticaria, or dyspnea, subjects may 
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require antihistamines, oxygen, corticosteroids, or bronchodilators. For hypotension, subjects 
may require vasopressors. In the event of a life-threatening IRR (which may include pulmonary 
or cardiac events) or an anaphylactic reaction, DARA should be discontinued.  
7.2.3.1.1.2. Injection-related Reactions of Grade 1 or Grade 2
If the Investigator assesses a Grade 1 or 2 IRR AE to be related to administration of study drug, 
then the DARA administration should be paused. When the subject's condition is stable, DARA
administration may be restarted at the Investigator's discretion. 
If the subject experiences a Grade 2 or higher event of laryngeal edema, or a Grade 2 or higher 
event of bronchospasm that does not respond to systemic therapy and does not resolve within 6 
hours from onset, then the subject must be permanently discontinued from DARA treatment.
7.2.3.1.1.3. Injection-related Reactions of Grade 3 or Higher
For IRR AEs (other than laryngeal edema or bronchospasm) that are Grade 3, the DARA
administration must be stopped, and the subject must be observed carefully until resolution of the
AE or until the intensity of the event decreases to Grade 1, at which point the DARA 
administration may be restarted at the Investigator’s discretion.
If the intensity of the AE returns to Grade 3 after restart of the DARA administration, then the 
subject must be permanently discontinued from DARA treatment.
For IRR AEs that are Grade 4, the DARA administration must be stopped and the subject
permanently discontinued from DARA treatment.
7.2.3.1.1.4. Recurrent Injection-related Reactions
If a Grade 3 IRR (or Grade 2 or higher event of laryngeal edema, or a Grade 2 or higher event of 
bronchospasm) recurs during or within 24 hours after a subsequent DARA administration, the 
subject must be permanently discontinued from all DARA treatments.
7.2.4.
Carfilzomib
Refer to the full prescribing information and labeling for CFZ contained in the respective current 
PI, SmPC, or equivalent document for the specific region/country.
Guidance on pre-infusion and post-infusion medications for infusion reaction prophylaxis in 
relation to CFZ dosing is provided and can be used in conjunction with the site’s standard of care 
for CFZ infusions:

At least 48 hours before C1D1, oral hydration to be given as follows: 30 mL/kg/day 
(approximately 6 to 8 cups of liquid per day) continuing up to the time of treatment. 
Oral hydration may be continued in Cycle 2 and beyond as per Investigator’s 
discretion.

Intravenous hydration with 250 to 500 mL of normal saline or other appropriate IV 
fluid to be given immediately prior to CFZ during Cycle 1 and at the Investigator’s 
discretion in Cycle 2 and onwards. 

Carfilzomib to be given as an IV infusion over approximately 30 minutes. Subjects to 
remain at the site under observation for at least 1 hour following each dose of CFZ in 
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Cycle 1. Post dose IV hydration (between 250 to 500 mL normal saline or other 
appropriate IV fluid) as needed may be given. It is recommended to use no more than 
750 mL IV fluids as a combination of pre- and post-dose hydration.  Subjects to be 
monitored periodically during this period for evidence of fluid overload. 
7.3.
Dose Reduction and Interruption
Dosing interruptions and reductions are permitted throughout the study.  Subjects will be 
evaluated for adverse events at each visit with the NCI CTCAE (version 4.0) used as a guide for 
the grading of severity. Dosing is to be modified in subjects who experience a DLT as described 
in Section 3.1.1.2. 
In the event of any CC-220 dose reduction for a subject, the site staff must contact the IRT to 
record the new dose level and obtain the new IP assignment.
Dose delays for CC-220 of more than 28 days for any reason should be discussed with the 
Medical Monitor.
Cohorts B, D, and I (DoubleT)

If CC-220 dosing is withheld, then DEX dosing must also be withheld.

If CC-220 is permanently discontinued, then the subject must be permanently
discontinued from all study medications.

If DEX is withheld or permanently discontinued, CC-220 may be continued
Cohorts E and K (CC-220Dd)

If DARA dosing is withheld or permanently discontinued, then CC-220 and DEX dosing 
may still be continued

If CC-220 dosing is withheld during a cycle, then DARA and DEX dosing may still be 
continued at the discretion of the treating physician.

If CC-220 dosing is permanently discontinued, then the subject must be permanently 
discontinued from all study medications. 

If DEX dosing is withheld or permanently discontinued, then CC-220 and DARA dosing 
may still be continued.

If DARA and DEX dosing is withheld or permanently discontinued, then CC-220 dosing 
may still be continued.

If CC-220 and DEX dosing is withheld during a cycle, then DARA dosing may still be 
continued.

If CC-220 and DEX dosing is permanently discontinued, then the subject must be 
permanently discontinued from all study medications.

If CC-220 and DARA dosing is withheld, then DEX must also be withheld.  
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Cohorts F, J1, and J2 (CC-220Vd)

If BTZ dosing is withheld or permanently discontinued, then CC-220 and DEX dosing 
may still be continued

If CC-220 dosing is withheld during a cycle, then BTZ and DEX dosing may still be 
continued at the discretion of the treating physician.

If CC-220 dosing is permanently discontinued, then the subject must be permanently 
discontinued from all study medications.

If DEX dosing is withheld or permanently discontinued, then CC-220 and BTZ dosing 
may still be continued.

If BTZ and DEX dosing is withheld or permanently discontinued, then CC-220 dosing 
may still be continued.

If CC-220 and DEX dosing is withheld during a cycle, then BTZ dosing may still be 
continued.

If CC-220 and DEX dosing is permanently discontinued, then the subject must be 
permanently discontinued from all study medications.

If CC-220 and BTZ dosing is withheld, then DEX must also be withheld.  
Cohorts G1 and G2 (CC-220Kd)

If CFZ dosing is withheld or permanently discontinued, then CC-220 and DEX dosing 
may still be continued

If CC-220 dosing is withheld during a cycle, then CFZ and DEX dosing may still be 
continued at the discretion of the treating physician.  

If CC-220 dosing is permanently discontinued, then the subject must be permanently 
discontinued from all study medications.

If DEX dosing is withheld or permanently discontinued, then CC-220 and CFZ dosing 
may still be continued.

If CFZ and DEX dosing is withheld or permanently discontinued, then CC-220 dosing 
may still be continued.

If CC-220 and DEX dosing is withheld during a cycle, then CFZ dosing may still be 
continued.

If CC-220 and DEX dosing is permanently discontinued, then the subject must be 
permanently discontinued from all study medications.

If CC-220 and CFZ dosing is withheld, then DEX must also be withheld.
7.3.1.
Dose Modification Instructions for CC-220
Instructions for CC-220 dose interruptions and reductions are provided in Table 21 and Table 22, 
which outlines the dose reduction steps for CC-220. 
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Table 21:
Dose Modification Instructions for CC-220
Toxicity
Dose Modification
Hematologic Toxicity
Neutropenia
Grade 4 neutropenia (ANC < 500/μL) 
or Febrile neutropenia (fever ≥38.5°C
and ANC < 1,000/μL)
Stop the dose for the remainder of the CC-220 treatment cycle
If the subject was not receiving GCSF therapy for given cycle 
(not permitted during Cycle 1 for Cohorts A and B only), 
initiate GCSF therapy
On Day 1 of the next cycle, the dose of CC-220 may be 
maintained if neutropenia was the only CC-220-related toxicity 
requiring a dose modification and GCSF treatments are 
continued. ANC must return to ≥1,000/μL to resume dosing.
Grade 4 thrombocytopenia (platelet 
count <25,000/μL) or Grade 3 
thrombocytopenia with bleeding or 
any requirement for a platelet 
transfusion
Stop the dose for the remainder of the CC-220 treatment cycle
Decrease by one dose level when restarting treatment when 
platelet count returns to ≥50,000/μL
Non-Hematologic Toxicity
Rash = Grade 3
Withhold dose of CC-220 for remainder of cycle.
Decrease by one dose level CC-220 when treatment is restarted 
(rash must be resolved or improved to ≤Grade 1 before dose 
resumption).
Rash = Grade 4 or Blistering
Permanently discontinue IP.
Thrombosis/embolism ≥Grade 3
Stop the dose of CC-220 for remainder of cycle
Anticoagulation therapy should be adapted based on the clinical 
and investigational results.
Decrease by one dose level of CC-220 when restarting 
treatment 
Peripheral neuropathy = Grade 3
Stop the dose of CC-220 for remainder of cycle
Decrease CC-220 by one dose level when restarting treatment 
(neuropathy must resolve to ≤Grade 1)
Peripheral neuropathy = Grade 4
Discontinue the subject from IP
Non-Hematologic Toxicity
Other ≥ Grade 3 CC-220-related
adverse eventsa, b
Withhold dose for remainder of cycle.  Decrease by one dose 
level when dosing resumed at next cycle (adverse event must be 
resolved or improved to ≤Grade 2 before restarting dosing).
ANC = absolute neutrophil count; GCSF = granulocyte colony-stimulating factor; IP = investigational product.
a For Grade 3 or 4 AEs that are not considered to be related to CC-220, the Investigator should consult with the 
Celgene Medical Monitor for dose interruptions and reductions.
b Not applicable to Second Primary Malignancies (SPMs) where dosing modification is at the discretion of the 
Investigator and in consideration of any SPM-related procedures/therapy.
To initiate a new cycle of CC-220, the absolute neutrophil count must be ≥1,000 μL/mL with or 
without granulocyte colony-stimulating factor (G-CSF) (not permitted during Cycle 1 for Cohort 
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A and B only), the platelet count must be ≥50,000/μL, and non-hematologic AEs must be 
resolved or improved as outlined in Table 21.
If recovery from toxicities is prolonged and CC-220 dose withholding is beyond 14 days, then 
the dose of CC-220 should be decreased by one dose level when dosing is resumed in the new 
cycle.
Dose delays of more than 28 days for any reason should be discussed with the Medical Monitor.
Dose level reductions will follow the dose levels in Part 1. No dose re-escalation is permitted for 
CC-220.
Table 22:
Dose Level Reduction (DLR) for CC-220
Starting Dose Level
Part 1
DLR-1
DLR-2
DLR-3
0.3 mg
0.15 mg
--
--
0.45 mg
0.3 mg
0.15 mg
--
0.6 mg
0.45 mg
0.3 mg
0.15 mg
0.75 mg
0.6 mg
0.45 mg
0.3 mg
0.9 mg
0.75 mg
0.6 mg
0.45 mg
1 mg
0.9 mg
0.75 mg
0.6 mg
Subsequent dose levels
Reductions will be made in one dose level decreases
Part 2
1.6 mg
1.3 mg
1.0 mg
0.75 mg
1.3 mg 
1.0 mg 
0.75 mg
-
1.0 mg 
0.75 mg
-
-
Treatment with CC-220 should be discontinued if the subject is unable to tolerate 0.15 mg dose. 
Treatment with CC-220 may continue if DEX is discontinued. The Celgene Medical Monitor 
should be contacted in cases where subjects require more than 3 dose level reductions.
7.3.2.
Dose Modification Instructions for Dexamethasone
Table 23 details instructions for DEX dose interruptions and reductions and Table 24 outlines the 
dose reduction steps for DEX; however, dose withholding/resumption decision is at the treating 
physician’s discretion per the full prescribing information and labeling in the respective current 
US prescribing information, EU SmPC, or equivalent document for the specific region/country.
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Table 23:
Dose Modification for Dexamethasone-related Toxicities
Toxicity
Dexamethasone Dose Reduction
Dyspepsia = Grade 1-2
Maintain dose and treat with histamine blockers (H2) or 
equivalent.  Decrease by one dose level if symptoms persist.
Dyspepsia ≥ Grade 3
Withhold dose until symptoms are controlled.  Add H2 blocker or 
equivalent and decrease one dose level when dosing is resumed.
Edema ≥ Grade 3
Use diuretics as needed and decrease dose by one dose level.
Confusion or mood alteration ≥ 
Grade 2
Withhold dose until symptoms resolve.  When dosing is resumed, 
decrease dose by one dose level.
Muscle weakness (steroid 
myopathy) ≥ Grade 2
Withhold dose until muscle weakness ≤ Grade 1.  When dosing is 
resumed, decrease dose by one dose level.
Hyperglycemia ≥ Grade 3
Decrease dose by one dose level.  Treat with insulin or oral 
hypoglycemic agents as needed.
Acute pancreatitis
Discontinue dexamethasone from treatment regimen.
Other ≥ Grade 3 dexamethasone-
related adverse events
Stop dexamethasone dosing until the adverse event resolves to ≤ 
Grade 2. Decrease by one dose level when dosing is resumed.
If recovery from toxicities is prolonged and DEX dosing withholding is beyond 14 days, then the 
dose of DEX will be decreased by one dose level when dosing is resumed in the new cycle. 
Table 24:
Dose Level Reduction for Dexamethasone 
Starting Dose Level
40 mg
20 mg
10 mg
Dose Level Reduction -1
20 mg
12 mg
6 mg
Dose Level Reduction -2 
10 mg
8 mg
4 mg
Dexamethasone should be discontinued if the subject is unable to tolerate 10 mg if ≤75 years old 
or 8 mg if > 75 years old unless subject’s starting dose level is 10 mg. Dexamethasone is to be 
discontinued if CC-220 is discontinued.
No dose re-escalation of DEX is permitted.
7.3.3.
Dose Modification Instructions for Daratumumab
For dose modification instructions for DARA, refer to the full prescribing information.
The criteria for a dose delay are:

Grade 4 hematologic toxicity, except for Grade 4 lymphopenia; 

Grade 3 or higher thrombocytopenia with bleeding;

Grade 3 or 4 febrile neutropenia;

Grade 3 or 4 neutropenia with infection;

Grade 3 or 4 non-hematologic toxicities with the following exceptions:

Grade 3 nausea or Grade 3 vomiting that responds to antiemetic treatment,
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
Grade 3 diarrhea that responds to antidiarrheal treatment,

Grade 3 fatigue or asthenia that lasts for < 7 days after the last administration of
DARA.
DARA treatment should be resumed when the toxicity has resolved to ≤ Grade 2, with the 
exception that Grade 2 laryngeal edema or Grade 2 bronchospasm must be fully recovered. If 
DARA administration does not commence within the pre-specified window (Table 10, and 
Table 17) of the scheduled administration date, then the dose will be considered a missed dose.
Administration may resume at the next planned dosing date. A missed dose will not be made up.
For subjects who are diagnosed with HBV reactivation while on treatment, study treatment 
should be interrupted until the infection is adequately controlled. If the benefits outweigh the 
risks, study treatment may be resumed with concomitant antiviral prophylaxis as per local 
standard of care. Consult a liver disease specialist as clinically indicated. Primary antiviral 
prophylaxis is permitted as per local standard of care.
Table 25:
Daratumumab-related Toxicity Management
Cycles
Dosing Frequency
Missed Dose
Dosing Resumption
1 and 2
Weekly (Days 1, 8, 15, 22)
> 3 days
Next planned weekly dosing date
3 to 6
Biweekly (Days 1, 15)
> 7 days
Next planned biweekly dosing date
>7
Every 4 weeks (Day 1)
> 14 days
Next planned every 4-week dosing date
Any dose held for more than 28 days due to toxicity may result in permanent discontinuation of 
DARA unless continuation is approved by the medical monitor. Dose delays of more than 28 
days for any reason should be discussed with the Medical Monitor.
7.3.3.1.
Daratumumab Interruption or Missed Doses
Dose delay of 3 days or more from the planned date of administration for any reason other than 
toxicities suspected to be related to DARA should be brought to the attention of the Medical 
Monitor at the earliest possible time.
The Celgene Medical Monitor should be informed of any subjects missing ≥3 consecutive 
planned doses of DARA for reasons other than toxicity. In Cycle 1, for subjects being evaluated 
for DLTs in Cohort E (IV DARA), subject cannot miss any more than 1 dose of DARA for 
reasons other than drug-related AE to be considered DLT evaluable.
7.3.4.
Dose Modification Instructions for Bortezomib
Table 26 details instructions for BTZ dose interruptions and reductions and Table 27 outlines the 
dose reduction levels for BTZ; however, dose modification decisions for BTZ will be at the 
treating physician’s discretion per the full prescribing information and labeling in the respective 
current US Prescribing Information, EU SmPC, or equivalent document for the specific 
region/country.
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Table 26:
Bortezomib Dose Modification
Toxicity
Bortezomib Dose Modification
≥ Grade 3 non-
hematological toxicity 
(excluding neuropathy)
Withhold bortezomib until the symptoms of the toxicity have resolved, 
bortezomib therapy may be reinitiated at reduced bortezomib dosing by 
1 dose level
Grade 4 hematological 
toxicity
Withhold bortezomib until the symptoms of the toxicity have resolved, 
bortezomib therapy may be reinitiated at reduced bortezomib dosing by 
1 dose level
Grade 1 neuropathy without 
pain or loss of function
No action
Grade 1 neuropathy with 
pain or Grade 2 neuropathy
Reduce bortezomib dosing by one level
Grade 2 neuropathy with 
pain or Grade 3 neuropathy
Withhold bortezomib until toxicity resolves, bortezomib therapy may be 
reinitiated at a reduced dose level of 0.7 mg/m2 and change treatment 
schedule to once per week (Days 1 and 8 of a 21-day cycle)
Grade 4 neuropathy
Permanently discontinue study treatment
Table 27:
Dose Level Reductions for Bortezomib
Starting Dose Level
Bortezomib
Dose Levela
(Cycle 1-8:  Days 1, 4, 8, 11 of a 21-day cycle
Cycle ≥ 9:  Days 1, 8 of a 21-day cycle)
Starting Dose
1.3 mg/m2
Dose Level -1
(25% reduction from starting dose)
1 mg/m2
Dose Level -2 
(25% reduction from dose level -1)
0.7 mg/m2
a Cycle ≥ 9 only applicable for Cohort F.
The minimum permitted dose level for bortezomib is 0.7 mg/m2.  No dose re-escalation is 
permitted for bortezomib.
7.3.5.
Dose Modification Instructions for Carfilzomib
Table 28 details instructions for CFZ dose interruptions and reductions.
Table 29 outlines the dose reduction levels for CFZ; however, dose modification decisions for 
CFZ will be at the treating physician’s discretion per the full prescribing information and 
labeling in the respective current PI, SmPC, or equivalent document for the specific 
region/country.
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Table 28:
Carfilzomib Dose Modifications
Toxicity
Carfilzomib Dose Modification
Hematologic Toxicity
Neutropenia
Grade 4 Neutropenia (ANC < 500/μL)
Withhold the carfilzomib dose. Continue at the 
same dose level if the ANC recovers to ≥500/μL. 
For subsequent ANC levels < 500/μL, follow the 
same as above and consider reducing the dose by 
1 dose level when restarting carfilzomib.
Febrile neutropenia 
(Fever > 38.5°C or 2 consecutive readings > 38°C
for 2 hours and ANC < 500/μL)
Withhold the carfilzomib dose.
Continue at the same dose level if the ANC 
recovers to baseline and the fever resolves.
Thrombocytopenia
If platelet count < 10,000/μL or evidence of 
bleeding with thrombocytopenia
Withhold the carfilzomib dose. Continue at same 
dose level if platelets recover to ≥10,000/μL
and/or bleeding is controlled.
For subsequent platelet levels < 10,000/μL, 
withhold dose and consider reducing dose by 1 
dose level when restarting carfilzomib.
Non-Hematologic Toxicity
Renal Toxicity
Serum creatinine ≥ 2x baseline or CrCl
< 15 mL/min or CrCl ≤ 50% of baseline or need 
for hemodialysis
Withhold the carfilzomib dose and continue 
monitoring renal function (serum creatinine or 
creatinine clearance).
If attributable to carfilzomib, resume when renal
function has recovered to within 25% of baseline;
start at 1 dose level reduction.
If not attributable to carfilzomib, dosing may be
resumed at the discretion of the investigator.
For subjects on hemodialysis receiving 
carfilzomib, the dose is to be administered after 
the hemodialysis procedure.
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Table 28:
Carfilzomib Dose Modifications (Continued)
Toxicity
Carfilzomib Dose Modification
Hepatic Dysfunction and Related Investigations
Mild to moderate liver dysfunction defined as 2 
consecutive values, at least 28 days apart, of:
1) total bilirubin (> 33% direct) > 1x 
ULN to < 3x ULN
             OR
2) an elevation of AST and/or ALT with 
normal bilirubin 
Grade 3 elevation in ALT and/or AST (> 5xULN)
Grade 3 elevation in total bilirubin
Drug-induced hepatotoxicity (attributable to
carfilzomib)
25% dose reduction. Dose may be re-escalated if 
liver function tests return to normal and drug-
induced hepatotoxicity is excluded.
Hold carfilzomib until resolution to baseline.
Monitor any abnormality weekly.  Resume 
carfilzomib with a 25% dose reduction if drug-
induced hepatotoxicity is excluded.
Hold carfilzomib until resolution to baseline.  
Monitor total bilirubin and direct bilirubin 
weekly. Upon resolution of total bilirubin to 
normal, resume carfilzomib dosing with a 25% 
dose reduction if drug induced hepatotoxicity is 
excluded.
Discontinue carfilzomib
Any other drug-related non-hematologic toxicity 
≥ Grade 3
Withhold the carfilzomib dose until resolved or 
returned to baseline. Consider restarting at 1 dose 
level reduction. Please refer to full prescribing 
information and labeling in the respective 
current PI, SmPC, or equivalent document for 
the specific region/country.
Abbreviations: ALT = alanine transaminase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; 
CrCl = creatinine clearance; PI = prescribing information; SmPC = summary of product characteristics; ULN = 
upper limit of normal.
For any dose held for more than 28 days due to toxicity, subjects may be required to permanently 
discontinue CFZ unless continuation is approved by the medical monitor. Dose delays of more 
than 28 days for any reason should be discussed with the Medical Monitor.
Table 29:
Dose Level Reductions for Carfilzomib
Starting Dose Level
Carfilzomib 
Dose Level
Carfilzomib Dose 
Level
Carfilzomib Dose 
Level
Starting Dose
70 mg/m2
56 mg/m2
27 mg/m2 
Dose Level -1
56 mg/m2
45 mg/m2
20 mg/m2
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Table 29:
Dose Level Reductions for Carfilzomib (Continued)
Starting Dose Level
Carfilzomib 
Dose Level
Carfilzomib Dose 
Level
Carfilzomib Dose 
Level
Dose Level -2
45 mg/m2
36 mg/m2
15 mg/m2 a
Dose Level -3
36 mg/m2 a
27 mg/m2 a
-
Note: infusion times remain unchanged during dose reduction(s).
a If toxicity persists, carfilzomib therapy should be discontinued.
7.4.
Overdose
Overdose, as defined for this protocol, refers to CC-220 (oral), DEX (oral), DARA (IV and SC), 
BTZ (SC), and CFZ (IV) dosing.
On a per dose basis, an overdose is defined as the following amount over the protocol-specified 
dose of CC-220, DEX, DARA, BTZ, or CFZ assigned to a given subject, regardless of any 
associated adverse events or sequelae.

For CC-220 and DEX (oral), any amount over the protocol-specified dose

For DARA (IV and SC) and CFZ (IV), 10% over the protocol-specified dose

For BTZ (SC), 10% over the protocol-specified dose
On a schedule or frequency basis, an overdose is defined as any amount more frequent than the 
protocol-required schedule or frequency. On an infusion rate basis, an overdose is defined as any 
rate faster than the protocol-specified rate.
Complete data about drug administration, including any overdose, regardless of whether the 
overdose was accidental or intentional, should be reported in the electronic case report form 
(eCRF). See Section 10.1 for the immediate reporting of adverse events associated with 
overdose.
7.4.1.
CC-220 Overdose
There is no information available about the appropriate dose of CC-220 in humans nor is there 
any available information regarding overdose. There is no experience in the management of 
human CC-220 overdose. In the event of overdose, subjects should be managed by symptomatic 
and supportive care. Please refer to the IB for full information.
7.5.
Method of Treatment Assignment
Subjects will be allocated via IRT to an appropriate cohort based on eligibility status and on 
cohort availability. Slots will be assigned for Part 1 cohorts. Sites will have up to 2 weeks to 
identify a subject, obtain informed consent and begin the screening process. If no subject is 
identified within 2 weeks from the time of slot assignment, the site must contact the Medical 
Monitor or designee, or the slot may be reassigned.
The Celgene Medical Monitor or designee will review specific eligibility criteria for all screened 
subjects prior to allocation via IRT.
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An IRT system will be used to track subject assignments to the cohorts and dose levels as well as 
subjects who are assigned to participate in the intensive PK and/or Pd sample collection.
Once MTD and/or RP2D has been reached in Cohort A, Cohort B, Cohort E, or Cohort F in Part 
1, IRT allocations may continue to the expansion phases of the study in that cohort even if the 
MTD and/or RP2D has not yet been achieved in the other cohorts of Part 1.
Enrollment of NDMM subjects in Cohort J1 at the 1.6 mg dose level  will start according to 
Protocol Amendment No. 9. Upon approval of Protocol Amendment No. 10, subjects will be 
allocated evenly into all open J1 and K dose level cohorts. Subjects will be allocated to each dose 
level based on a fixed sequence via the IRT.
7.6.
Packaging and Labeling
The label(s) for Celgene-supplied IP may include but is not limited to Sponsor name, address and 
telephone number, the protocol number, name, dosage form and strength (where applicable), 
amount of IP per container, lot number, expiry date (where applicable), medication 
identification/kit number, dosing instructions, storage conditions, and required caution 
statements and/or regulatory statements as applicable. Additional information may be included 
on the approved drug label as applicable per local regulations.
7.7.
Investigational Product Accountability and Disposal 
Celgene (or designee) will review with the Investigator and relevant site personnel the process 
for investigational product return, disposal, and/or destruction including responsibilities for the 
site versus Celgene (or designee).
7.8.
Investigational Product Compliance
Accurate recording of all IP administration (CC-220, DEX, DARA, BTZ, and CFZ) will be made 
in the appropriate section of the subject’s eCRF and source documents. The Investigator or 
designee is responsible for accounting for all study-specific treatment either administered or in 
their custody during the course of the study.
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8.
CONCOMITANT MEDICATIONS AND PROCEDURES
Over the course of this study, additional medications may be required to manage aspects of the 
disease state of the subjects, including side effects from IPs or disease progression. Antibiotics 
(including those for prophylactic use) may be administered at the discretion of the Investigator. 
Other supportive care, including but not limited to analgesics, antihistamines, and/or antiemetic
medications, may be administered at the discretion of the Investigator. 
All concomitant treatments, including blood and blood products, used from 28 days prior to first 
dose of IP until 28 days after the last dose of IP must be reported on the eCRF. 
Subjects must check with study personnel before initiating the use of prescribed or over-the-
counter medications during the study. Medication doses and treatment regimens should remain 
generally stable throughout the course of the study.
In the event a subject requires a surgical or invasive procedure during the course of the study, the 
Celgene Medical Monitor or designee must be contacted to discuss whether or not the subject is 
eligible to continue.
For information regarding other drugs that may interact with CC-220 and DEX and affect its 
metabolism, pharmacokinetics, or excretion, please see the IB and/or local prescribing 
information.
8.1.
Permitted Concomitant Medications and Procedures
Subjects with myeloma-associated bone disease may receive bisphosphonate therapy prior to 
study entry. The use of bisphosphonates is permitted throughout the study.
Platelet/RBC transfusions and hematopoietic growth factors are also permitted during the study. 
Granulocyte colony-stimulating factor (GCSF) and similar hematopoietic growth factors are 
encouraged to prevent neutropenia and to support neutrophil recovery. However, prophylactic 
use of platelet transfusions or GCSF to prevent a potential DLT during Cycle 1 should be 
avoided in Cohorts A and B unless deemed medically necessary by the treating physician for 
subject safety. Use of GCSF is permitted during Cycle 1 for Cohorts E, F, G and Part 2 subjects 
per local standard of care and Investigator discretion. 
8.2.
Prohibited Concomitant Medications and Procedures
The following medications are considered exclusionary during the study. The Celgene Medical 
Monitor or designee must be notified if a subject receives any of these medications during the 
study.
a.
The prophylactic use of hematopoietic growth factors or platelet transfusions to 
prevent a potential DLT during Cycle 1 should be avoided in Cohorts A and B unless 
deemed medically necessary by the treating physician for subject safety; however, it 
is permitted at the Investigator’s discretion after a subject completes the first cycle or 
within the first cycle if a hematological DLT has already been declared for that 
subject. Use of GCSF is permitted during Cycle 1 for Cohorts E, F, G and Part 2
subjects per site standard of care and Investigator discretion. Subjects who fail 
absolute neutrophil count or platelet eligibility criteria at Screening should not be 
retested for the study after being treated with GCSF or platelet transfusion(s).
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b. Any anticancer therapy including investigational therapy 
c.
Any concurrent chemotherapy, radiotherapy (except palliative radiotherapy), 
immunotherapy, biologic or hormonal therapy for cancer treatment.
d. Immunosuppressive medications including, but not limited to systemic corticosteroids 
at doses exceeding 10 mg/day of prednisone or equivalent. Use of 
immunosuppressive medications for the management of CC-220-related AEs or in 
subjects with contrast allergies is acceptable. Use of corticosteroids for DARA pre-
administration and post-administration is acceptable. In addition, use of inhaled, 
topical, intranasal corticosteroids or local steroid injection (eg, intra-articular 
injection) is permitted. Temporary use of corticosteroids for concurrent illnesses (eg, 
food allergies, CT scan contrast hypersensitivity, pneumonia, etc.) are acceptable 
upon discussion and agreement with the Medical Monitor.
e.
Medications that are strong inhibitors or inducers of CYP3A4/5 are prohibited. Of 
note, any antibiotics/antifungals listed as strong inhibitors or inducers of CYP3A4/5 
should be avoided and replaced by alternate treatment. In general, azole antifungals 
such as itraconazole as well as antibiotics clarithromycin and rifampin should be 
avoided. Also, grapefruit, St. John’s Wort, and related products are prohibited while 
participating in this study. Please refer to Table 30 for a list of medications that are 
strong inhibitors or inducers of CYP3A4/5. Please note this list is not exhaustive. If 
there are any questions regarding whether a medication is a strong CYP3A4/5 
inhibitor or inducer, please contact the Celgene Medical Monitor or designee.  
For subjects receiving CC-220Vd, caution should be exercised when bortezomib is combined 
with CYP3A4 and CYP2C19 substrates.
Table 30:
Medications that are CYP3A4/5 Strong Inhibitors and Inducers
Drug Class
Generic Name
CYP3A4/5 Strong Inhibitors
Human Immunodeficiency Virus (HIV)
Protease Inhibitor
Atazanavir
Indinavir
Darunavir
Lopinavir
Saquinavir
Nelfinavir
Ritonavir and ritonavir containing coformulations
Antihepaciviral (NS 3/4A) Protease 
Inhibitor 
Boceprevir
Telaprevir
Ombitasvir-paritaprevir- ritonavir
Ombitasvir-paritaprevir- ritonavir plus dasabuvir
CYP450 Inhibitor 
Cobicistat and cobicistat containing coformulations
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Table 30:
Medications that are CYP3A4/5 Strong Inhibitors and Inducers (Continued)
Drug Class
Generic Name
Azole Antifungal
Itraconazole
Ketoconazole
Posaconazole
Voriconazole
Macrolide antibiotic 
Telithromycin
Clarithromycin
Antiprogestin
Mifepristone
Serotonin Reuptake Inhibitor
Nefazodone
Phosphatidylinositol 3-kinase inhibitor 
Idelalisib
CYP3A4/5 Strong Inducers
Anticonvulsant 
Carbamazepine
Fosphenytoin
Phenytoin
Phenobarbital
Primidone
Antineoplastic/Antiandrogen 
Enzalutamide
Apalutamide
Antineoplastic agent
Mitotane
Cystic fibrosis agent 
Lumacaftor
Antitubercular 
Rifampin (rifampicin)
Herbal
St. John’s wort
8.3.
Required Concomitant Medications and Procedures

Thromboembolism prophylaxis consisting of low-dose aspirin, low molecular weight 
heparin, or other equivalent antithrombotic or anticoagulant will be given to all subjects 
as part of the study. 

Antiviral prophylaxis: Subjects in Cohort E (CC-220Dd), Cohort F (CC-220Vd), 
Cohorts G1 and G2 (CC-220Kd), J1(CC-220Vd) and J2 (CC-220Vd), and Cohort K (CC-
220Dd) must initiate antiviral prophylaxis to prevent herpes virus infection. Subjects in 
Cohorts E and K (CC-220Dd) must start therapy within 1 week of starting DARA and 
continue for 3 months following last dose of DARA.
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
Infusion or injection reaction prophylaxis: Guidance on pre-administration and post-
administration medications for infusion or injection reaction prophylaxis in relation to 
DARA dosing is detailed in Table 19.
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9.
STATISTICAL CONSIDERATIONS
9.1.
Overview
This is a Phase 1b/2a, multicenter, open-label, dose-escalation study to determine the MTD and 
or RP2D, assess the safety, tolerability, PK and efficacy of CC-220 as monotherapy and in 
combination with other treatments in subjects with MM.
All analyses will be done by cohort and dose level, as necessary and applicable. No statistical 
test will be performed to compare different dose levels or cohorts. For subjects who are treated 
with CC-220 in combination with DEX following confirmed PD in the monotherapy cohort, 
efficacy and safety information during the combination treatment period will be summarized
separately. Details on the statistical analyses will be given in the statistical analysis plan (SAP).
9.2.
Study Population Definitions
The following analysis populations will be used:
Full Analysis Population:  includes all subjects enrolled into this study regardless of whether or 
not they receive study treatment.
Safety Population:  includes all enrolled subjects who take at least one dose of study treatment.
All safety analyses will be based on this population.
DLT Evaluable Population: includes all subjects from the Safety Population who meet the 
minimum exposure criterion and have sufficient safety evaluations or experience a DLT during 
the first treatment cycle.
Efficacy Evaluable Population:  includes all enrolled subjects who take at least one dose of study 
treatment and have measurable disease at baseline and at least one post-baseline response 
assessment.
Patient Reported Outcome (PRO) Evaluable Population: includes all subjects who complete their 
baseline PRO questionnaires and have at least one post-baseline measurement in the safety
population. All analyses of PRO data will be based on the PRO Evaluable population. 
Pharmacokinetic Population:  includes all subjects who receive at least one dose of study 
treatment and have measurable plasma concentration data. All analysis of PK data will be based 
on the PK population and subjects will be analyzed according to treatment group. 
9.3.
Sample Size and Power Considerations
In the MTD and/or RP2D determination part of the study (Part 1), a 3+3 design will be used to 
determine the MTD and/or RP2D level for CC-220 cohort (MonoT), CC-220 + DEX cohort 
(DoubleT), CC-220 + DARA + DEX (CC-220Dd), CC-220 + BTZ + DEX (CC-220Vd), and 
CC-220 + CFZ + DEX (CC-220Kd). Approximately 34 subjects will be enrolled for Cohort A 
and approximately 72 subjects will be enrolled for Cohort B. Approximately 85 additional 
subjects will be allocated to one of the four triplet regimen cohorts. Additional subjects may be 
enrolled into a dose-level cohort, as determined by the DEC. The actual number of subjects will 
depend on the number of dose levels being tested and may exceed these approximations.
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In Part 2 of the study, for Cohort C, a sample size of 24 at the MTD and/or RP2D level based on 
clinical consideration may be enrolled to obtain the preliminary efficacy information of the 
treatment. If the observed response rate is 20% at the final analysis, the two-sided 95% 
confidence intervals will be 20%±16%. 
The primary objective of Cohort D is to determine the efficacy of CC-220 plus DEX (Cohort D) 
in subjects with RRMM, as measured by ORR, which is defined as the proportion of subjects 
with a partial response (PR) or better. The sample size is calculated based on a group sequential 
design (Jennison, 1999) for a one-sample binomial test with normal approximation. One interim 
analysis for futility at 40% information and one final analysis are planned. The null hypothesis is 
ORR ≤ 12% and the alternative hypothesis is ORR > 12%. Assuming a treatment benefit of ORR 
≥ 24%, a sample size of 101 subjects would provide 90% power at a one-sided 0.025 alpha level 
(Sample size calculation used EAST version 6.4).
In Cohort I, up to 40 subjects will be enrolled to explore the safety profile and preliminary 
efficacy of CC-220 + DEX in the post BCMA treatment patient population. An objective 
response rate (ORR) of 20% is considered as minimum clinically meaningful in this heavily 
pretreated patient population with prior BCMA-targeted therapy exposure. Bayesian continuous 
monitoring method will be applied to monitor the objective response rate (ORR).
For Cohorts J1, J2, and K the very good partial response or better (≥ VGPR) rate is considered an 
important and clinically relevant efficacy parameter to explore the treatment effect for NDMM 
patient population (Durie, 2018; Facon, 2018). In the SWOG S0777 study, the ≥ VGPR rate in 
NDMM subjects not eligible for ASCT following 8 cycles of RVd is 57%. In the IFM2009 
study, the ≥ VGPR rate in NDMM subjects eligible for ASCT following 4 cycles of RVd 
induction therapy is 57% (IFM 2009 and SWOG S0777 Clinical Study Reports; Data on File). In 
the MAIA study, the  ≥ VGPR rate in NDMM subjects not eligible for transplant following DRd 
(daratumumab in combination with lenalidomide and dexamethasone) treatment is 81% at a 
median follow-up of 56.2 months (Facon, 2021). A sample size of approximately 50 subjects in 
Cohort J2 and approximately 75 subjects each for Cohorts J1 and K (with up to approximately 25 
subjects in each of the three CC-220 dose levels) is considered clinically adequate to explore the 
preliminary efficacy, safety, and PK profile of CC-220Vd and CC-220Dd in this patient 
population. 
9.4.
Subject Disposition
Subject disposition (analysis population allocation, entered, discontinued, along with primary 
reason for discontinuation) will be summarized using frequency and percent by cohort and dose 
level and follow-up phases.
Protocol deviations will be summarized using frequency tabulations by dose cohort and 
deviation.
9.5.
Background and Demographic Characteristics
Age, height, weight, and other continuous baseline disease characteristics will be summarized 
using descriptive statistics, while gender, race, and other categorical variables will be provided 
using frequency tabulations.
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9.6.
Medical History
Medical history data will be summarized using frequency tabulations by the Medical Dictionary 
for Regulatory Activities (MedDRA) Version 18 or higher by system organ class and preferred 
term.
9.7.
Concomitant Medications and Procedures
All concomitant medications and procedures documented during the study will be summarized 
using frequency tabulations. The Anatomical Therapeutic Chemical coding scheme of the World 
Health Organization will be used to group medications into relevant categories for these 
tabulations.
9.8.
Efficacy Analysis
All efficacy analyses will be summarized using the Safety population. Supportive efficacy 
analyses will also be performed using the Efficacy Evaluable (EE) Population.
An IRC may also be set up to review efficacy data from Part 2 Cohorts C, D, and/or I. The IRC 
will determine the tumor response to therapy based on the IMWG uniform Response Criteria as 
well as time of response (including PD) for each subject. The IRC will adjudicate efficacy data 
according to the IRC Charter.
9.8.1.
Overall Response Rate (ORR)
The overall response rate (ORR) is defined as the proportion of subjects with best response of PR 
or better during the trial without administration of myeloma therapy other than study treatment.
The ORR with 95% confidence interval (CI) together with the proportions in each response 
category based on the IMWG Uniform Response Criteria (ie, Stringent Complete Response 
[sCR], Complete Response [CR], Very Good Partial Response [VGPR], Partial Response [PR],
Minimal Response [MR], Stable Disease [SD], and Progressive Disease [PD]) will be examined. 
Efficacy Evaluable Population will also be used for sensitivity response analysis (see 
Appendix B).
For Part 2 Cohort D, the ORR will be analyzed based on a one-sample binomial test. The null 
hypothesis ORR ≤ 12% will be tested by a one-sided binominal test (normal approximation) with 
a type I error of 0.025 (one-sided).
9.8.2.
Very Good Partial Response or Better Rate
The very good partial response or better (≥VGPR) rate is defined as the proportion of subjects 
with best response of VGPR or better during the trial without administration of myeloma therapy 
other than study treatment. The ≥VGPR rate with 95% confidence interval (CI) together with the 
proportions in each response category based on the IMWG Uniform Response Criteria will be 
presented for NDMM cohorts (Cohorts J1, J2 and K).
9.8.3.
Time to Response (TTR)
Time to response is defined as the time from the first dose date of study treatment to the first date 
of documented response (PR or better). Time to response will be summarized for responders 
using descriptive statistics by cohort and dose level. 
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9.8.4.
Response Duration (DoR)
Duration of response is defined as time from the earliest date of documented response (PR or 
better) to the earliest date of disease progression per IMWG Uniform Response Criteria or death, 
whichever occurred first. Subjects who do not have progression of disease or death will be 
censored on the last adequate response assessment date. Duration of response for responders will 
be summarized using Kaplan-Meier estimates by cohort and dose level as appropriate.
9.8.5.
Progression-free Survival (PFS)
Progression-free Survival is defined as time from the first dose date of study treatment to first 
documentation of PD, or death due to any cause, whichever occurs first. Subjects who do not 
have a PFS event will be censored on the last adequate response assessment date. PFS will be 
summarized using Kaplan-Meier estimates by cohort and dose level as appropriate.
9.8.6.
Overall Survival (OS)
Overall survival is defined as time from first dose of study treatment to time of death due to any 
cause. Subjects who are still alive will be censored at the date last known alive or the data cut-off 
date (if applicable), whichever is earlier. OS will be summarized using Kaplan-Meier estimates 
by cohort and dose level as appropriate.
9.9.
Safety Analysis
All safety analyses will be conducted using the Safety population. All analyses will be presented 
by cohort and dose level. Adverse events will be coded according to the Medical Dictionary for 
Regulatory Activities (MedDRA) version 18 or higher. The intensity of AEs will be graded 
according to the NCI CTCAE Version 4.0.
Treatment-emergent AEs are defined as any AE occurring or worsening on or after the first dose 
of study treatment and up to 28 days after the date of last dose of the study treatment (CC-220,
DEX, DARA, BTZ, or CFZ as applicable). If a subject experienced the same AE multiple times, 
then the event was counted only once and by the greatest severity. Treatment-emergent AEs, 
(TEAEs) leading to permanent study treatment discontinuation, TEAEs leading to dose 
reduction/interruption, TEAEs related to study treatment, serious adverse events (SAEs) and 
TEAEs leading to death will be summarized by system organ class, and preferred term for each 
cohort and dose level. A summary of TEAEs with NCI CTCAE Grade 3 or higher, as well as the 
most frequent preferred terms, will be provided. A summary of TEAEs by dosing cycle based on 
onset date will also be provided. If a subject experiences the same preferred term multiple times, 
then the event will be counted only once and by greatest severity. All death and reasons for death 
will be summarized. Death within 28 days after the last dose of study treatment will be 
summarized separately. A summary of DLTs by dose cohort will also be provided.
Clinical laboratory values will be graded according to NCI CTC version 4.0 for applicable tests. 
Shift from baseline to the worst grade observed during the treatment for selected laboratory 
results will be provided.
For vital signs, summary statistics (N, Mean, Standard Deviation, Median, Minimum, and 
Maximum) of observed values and change from baseline will be presented. 
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The overall ECG interpretation will be summarized by presenting the number and percentage of 
subjects with ‘Normal’, ‘Abnormal, not clinically significant’ and ‘Abnormal, clinically 
significant’ readings. Shift from baseline to worst during the treatment in the overall ECG 
interpretation will be displayed in cross–tabulations. 
Graphical displays will be provided where useful to assist in the interpretation of results.
9.10.
Interim Analysis
One interim analysis for Cohort D is planned at 40% information reached, ie, the interim analysis 
will be performed at approximately the first 40 treated subjects. The results of the interim 
analysis will be used for futility assessment only, for which a stopping boundary will be applied 
based on a beta spending function of gamma distribution with gamma = -2. The one-sided p-
value to reject the alternative hypothesis (for futility) is p ≥ 0.656, which is corresponding to ≤ 
10% observed response rate at the time of interim analysis (assuming 40% information at interim 
analysis, may be adjusted according to actual percent of information available).
Bayesian continuous monitoring method will be applied to monitor the ORR for futility of 
Cohort I after enrollment of 21 subjects. Assume a relatively weak prior of Beta (0.2, 0.8) for 
ORR, which will allow the accruing data to dominate the posterior distribution of ORR, if the 
posterior probability of ORR is less than or equal to 20% and is greater than 0.8, then this cohort 
will be stopped for futility. Otherwise, treatment will continue, and enrollment will continue to 
up to 40 subjects to explore the safety profile and assess the preliminary efficacy for this patient 
population. The following stopping rule will be applied, accounting for subjects already enrolled 
in the study.
Table 31:
Stopping Rules for Cohort I
Number of Subjects
Number of Responses to Stop for Futility 
1-20
No futility stopping
21
<= 2
22-27
<= 3
28-33
<= 4
34-39
<=5
9.11.
Other Topics
9.11.1.
Pharmacokinetic Analysis
Pharmacokinetic measures are incorporated into the study to assess the extent of systemic 
exposure, and to explore the relationship between CC-220 and clinical response, provided data is 
sufficient. Blood samples for PK will be collected at selected visits from all subjects. PK 
parameters area under the plasma concentration-time curve from time zero to tau, where tau is 
the dosing interval (AUC[TAU]), maximum plasma concentration of drug (Cmax), time to Cmax
(Tmax), apparent total plasma clearance (CLT/F), concentration at the end of a dosing interval 
(Ctau), trough observed plasma concentration (Ctrough), Enantiomer ratio (ER_Cmax, 
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ER_AUC) and metabolite ratio to parent (MR_Cmax, MR_AUC) will be estimated from 
CC-220, CC17195 and M12 versus time data using noncompartmental analysis, as appropriate. 
Descriptive statistics will be provided for CC-220, CC17195 and M12 concentrations and PK 
parameters, and the results will be presented in tabular and graphic form as appropriate.
9.11.2.
Exploratory Analysis 
Exploratory analysis will be performed based on the exploratory objectives of the study. 
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10.
ADVERSE EVENTS
10.1.
Monitoring, Recording and Reporting of Adverse Events
An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen 
in a subject during the course of a study. It may be a new intercurrent illness, a worsening 
concomitant illness, an injury, or any concomitant impairment of the subject’s health, including 
laboratory test values (as specified by the criteria in Section 10.3), regardless of etiology. Any 
worsening (ie, any clinically significant adverse change in the frequency or intensity of a pre-
existing condition) should be considered an AE. A diagnosis or syndrome should be recorded on 
the AE page of the eCRF rather than the individual signs or symptoms of the diagnosis or 
syndrome. 
Abuse, withdrawal, sensitivity or toxicity to an investigational product should be reported as an 
AE. Overdose, accidental or intentional, whether or not it is associated with an AE, should be 
reported on the overdose eCRF. (See Section 7.4 for the definition of overdose.) Any sequela of 
an accidental or intentional overdose of an investigational product should be reported as an AE 
on the AE eCRF. If the sequela of an overdose is an SAE, then the sequela must be reported on 
an SAE report form and on the AE eCRF. The overdose resulting in the SAE should be 
identified as the cause of the event on the SAE report form and eCRF but should not be reported 
as an SAE itself.
In the event of overdose, the subject should be monitored as appropriate and should receive 
supportive measures as necessary.  There is no known specific antidote for CC-220, DARA, 
BTZ, CFZ or DEX overdose. Actual treatment should depend on the severity of the clinical 
situation and the judgment and experience of the treating physician.
All subjects will be monitored for AEs during the study.  Assessments may include monitoring 
of any or all of the following parameters:  the subject’s clinical symptoms, laboratory, 
pathological, radiological or surgical findings, physical examination findings, or findings from 
other tests and/or procedures.
All AEs will be recorded by the Investigator from the time the subject signs informed consent
until 28 days after the last dose of IP as well as those SAEs made known to the Investigator at 
any time thereafter that are suspected of being related to CC-220, DARA, BTZ, CFZ or DEX, as 
applicable. AEs and SAEs will be recorded on the AE page of the eCRF and in the subject’s 
source documents.  All SAEs must be reported to Celgene Drug Safety within 24 hours of the 
Investigator’s knowledge of the event by facsimile, or other appropriate method, using the SAE 
Report Form, or approved equivalent form.  
10.2.
Evaluation of Adverse Events
A qualified Investigator will evaluate all AEs as to: 
10.2.1.
Seriousness 
An SAE is any AE occurring at any dose that:

Results in death;
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
Is life-threatening (ie, in the opinion of the Investigator, the subject is at immediate 
risk of death from the AE);

Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length of stay);

Results in persistent or significant disability/incapacity (a substantial disruption of the 
subject’s ability to conduct normal life functions);

Is a congenital anomaly/birth defect;

Constitutes an important medical event.
Important medical events are defined as those occurrences that may not be immediately life-
threatening or result in death, hospitalization, or disability, but may jeopardize the subject or 
require medical or surgical intervention to prevent one of the other outcomes listed above.  
Medical and scientific judgment should be exercised in deciding whether such an AE should be 
considered serious.
Events not considered to be SAEs are hospitalizations for:

a standard procedure for protocol therapy administration.  However, hospitalization or 
prolonged hospitalization for a complication of therapy administration will be 
reported as an SAE. 

routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition.

the administration of blood or platelet transfusion as routine treatment of studied 
indication.  However, hospitalization or prolonged hospitalization for a complication 
of such transfusion remains a reportable SAE.

a procedure for protocol/disease-related investigations (eg, surgery, scans, endoscopy, 
sampling for laboratory tests, bone marrow sampling).  However, hospitalization or 
prolonged hospitalization for a complication of such procedures remains a reportable 
SAE.

hospitalization or prolongation of hospitalization for technical, practical, or social 
reasons, in absence of an AE.

a procedure that is planned (ie, planned prior to start of treatment on study); must be 
documented in the source document and the eCRF.  Hospitalization or prolonged 
hospitalization for a complication remains a reportable SAE.

an elective treatment of or an elective procedure for a pre-existing condition, 
unrelated to the studied indication, that has not worsened from baseline. 

emergency outpatient treatment or observation that does not result in admission, 
unless fulfilling other seriousness criteria above.
If an AE is considered serious, both the AE page/screen of the eCRF and the SAE Report Form 
must be completed.
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For each SAE, the Investigator will provide information on severity, start and stop dates, 
relationship to the IP (CC-220, DARA, BTZ, CFZ DEX, as applicable), action taken regarding 
the IP, and outcome.
10.2.2.
Severity/Intensity
For both AEs and SAEs, the Investigator must assess the severity/ intensity of the event. 
The severity/intensity of AEs will be graded based upon the subject’s symptoms according to the 
current active minor version of the Common Terminology Criteria for Adverse Events (CTCAE, 
Version 4.0);
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40
AEs that are not defined in the CTCAE should be evaluated for severity/intensity according to 
the following scale:

Grade 1 = Mild – transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required

Grade 2 = Moderate – mild to moderate limitation in activity, some assistance may be 
needed; no or minimal medical intervention/therapy required

Grade 3 = Severe – marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalization is possible

Grade 4 = Life-threatening – extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, hospitalization or hospice 
care probable

Grade 5 = Death - the event results in death
Seriousness, not severity, serves as a guide for defining regulatory obligations.
10.2.3.
Causality
The Investigator must determine the relationship between the administration of the IP (CC-220, 
DARA, BTZ, CFZ, DEX to be assessed separately) and the occurrence of an AE/SAE as Not 
Suspected or Suspected as defined below:
Not suspected:
a causal relationship of the adverse event to CC-220, DARA, 
BTZ, CFZ, or DEX administration is unlikely or remote, or 
other medications, therapeutic interventions, or underlying 
conditions provide a sufficient explanation for the observed 
event.
Suspected:
there is a reasonable possibility that the administration of CC-
220, DARA, BTZ, CFZ or DEX caused the adverse event.  
‘Reasonable possibility’ means there is evidence to suggest a 
causal relationship between CC-220, DARA, BTZ, CFZ, or 
DEX and the adverse event.
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Causality should be assessed and provided for every AE/SAE based on currently available 
information.  Causality is to be reassessed and provided as additional information becomes 
available.
If an event is assessed as suspected of being related to a comparator, ancillary or additional IP 
that has not been manufactured or provided by Celgene, please provide the name of the 
manufacturer when reporting the event.
10.2.4.
Duration
For both AEs and SAEs, the Investigator will provide a record of the start and stop dates of the 
event.
10.2.5.
Action Taken
The Investigator will report the action taken with CC-220, DARA, BTZ, CFZ or DEX as a result 
of an AE or SAE, as applicable (eg, discontinuation, interruption, or dose reduction of CC-220, 
DARA, BTZ, CFZ or DEX, as appropriate) and report if concomitant and/or additional 
treatments were given for the event. 
10.2.6.
Outcome
The Investigator will report the outcome of the event for both AEs and SAEs.
All SAEs that have not resolved upon discontinuation of the subject’s participation in the study 
must be followed until recovered (returned to baseline), recovered with sequelae, or death (due to 
the SAE).
10.3.
Abnormal Laboratory Values
An abnormal laboratory value is considered to be an AE if the abnormality:

results in discontinuation from the study;

requires treatment, reduction/ interruption of IP (CC-220, DARA, BTZ, CFZ or 
DEX) dose, or any other therapeutic intervention; or

is judged to be of significant clinical importance, eg, one that indicates a new disease 
process and/or organ toxicity, or is an exacerbation or worsening of an existing 
condition.
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness criterion 
need to be documented as a serious adverse event.
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis 
or syndrome should be recorded on the AE page/screen of the eCRF.  If the abnormality was not 
a part of a diagnosis or syndrome, then the laboratory abnormality should be recorded as the AE. 
If possible, the laboratory abnormality should be recorded as a medical term and not simply as an 
abnormal laboratory result (eg, record thrombocytopenia rather than decreased platelets).
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10.4.
Pregnancy
All pregnancies or suspected pregnancies occurring in either a female subject of childbearing 
potential or female partner of a male subject are immediately reportable events.
In the event of a pregnancy occurring in a female subject of child bearing potential or female 
partner of the male subject, Celgene Drug Safety will follow up with the clinical investigator 
each trimester of the pregnancy and for 1 year following the birth of the infant (if applicable). 
Please reference the informed consent (permission) forms for data collection regarding the 
pregnancy of a female subject participating in a Celgene sponsored study, the pregnancy of a 
female partner of a male subject participating in a Celgene sponsored study and the pregnancy of 
a nonsubject pregnant female. In all scenarios, data collection will occur each trimester of the 
pregnancy and for 1 year after the birth of the infant (if applicable).
The exposure of any nonsubject pregnant female (eg, caregiver, pharmacist, study coordinator or 
monitor) to CC-220 is also an immediately reportable event.
Females of childbearing potential are instructed to practice two forms of reliable contraception. 
One must be a highly effective method and one additional effective (barrier) method without 
interruption, 28 days prior to starting IP, throughout the entire duration of treatment, during dose 
interruptions and for at least 28 days after the last dose of CC-220 or 90 days after the last dose 
of DARA (for Cohorts E and K), or 7 months after the last dose of BTZ (for Cohorts F, J1, and 
J2), or 6 months after the last dose of CFZ (for Cohorts G1 and G2), whichever is longer.  See
Appendix D for the CC-220 Pregnancy Prevention Plan.
10.4.1.
Females of Childbearing Potential
Pregnancies and suspected pregnancies (including elevated β-hCG or positive pregnancy test in a 
female subject of childbearing potential regardless of disease state) occurring while the subject is 
on IP, or within 28 days of the subject’s last dose of CC-220 or within 90 days after last dose of 
DARA, or within 7 months after the last dose of BTZ, or within 6 months after the last dose of 
CFZ, whichever occurs later, are considered immediately reportable events.  Investigational 
product is to be discontinued immediately and the subject instructed to return any unused portion 
of the IP to the Investigator. The pregnancy, suspected pregnancy, or positive pregnancy test 
must be reported to Celgene Drug Safety immediately by email, phone or facsimile, or other 
appropriate method, using the Pregnancy Initial Report Form, or approved equivalent form.  
The female subject should be referred to an obstetrician-gynecologist, preferably one 
experienced in reproductive toxicity for further evaluation and counseling.
The Investigator will follow the female subject until completion of the pregnancy, and must 
notify Celgene Drug Safety immediately about the outcome of the pregnancy (either normal or 
abnormal outcome) using the Pregnancy Follow-up Report Form, or approved equivalent form.
In the event of a pregnancy occurring in a female subject of childbearing potential, Celgene will 
follow up with the clinical investigator each trimester of the pregnancy and for 1 year following 
the birth of the infant (if applicable). Any follow-up information or outcome information must be 
reported to Celgene Drug Safety immediately.
If the outcome of the pregnancy was abnormal (eg, spontaneous abortion), the Investigator 
should report the abnormal outcome as an AE.  If the abnormal outcome meets any of the serious 
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criteria, it must be reported as an SAE to Celgene Drug Safety by facsimile, or other appropriate 
method, within 24 hours of the Investigator’s knowledge of the event using the SAE Report 
Form, or approved equivalent form.
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs.  In addition, any infant death after 28 days that the Investigator suspects is 
related to the in utero exposure to the IP should also be reported to Celgene Drug Safety by 
facsimile, or other appropriate method, within 24 hours of the Investigator’s knowledge of the 
event using the SAE Report Form, or approved equivalent form.
10.4.2.
Male Subjects
If a female partner of a male subject taking IP becomes pregnant, the male subject taking IP
should notify the Investigator, and the pregnant female partner should be advised to call her 
healthcare provider immediately.  
The event must also be reported to Celgene Drug Safety immediately by facsimile, or other 
appropriate method, using the Initial Pregnancy Report Form, or approved equivalent form. In 
the event, of a pregnancy occurring in a female partner of the male subject, Celgene will follow 
up with the clinical investigator each trimester of the pregnancy and for 1 year following the 
birth of the infant (if applicable). Any follow-up information or outcome information must be 
reported to Celgene Drug Safety immediately.
10.5.
Reporting of Serious Adverse Events
Any AE that meets any criterion for an SAE requires the completion of an SAE Report Form in 
addition to being recorded on the AE page/screen of the eCRF. All SAEs must be reported to 
Celgene Drug Safety within 24 hours of the Investigator’s knowledge of the event by facsimile, 
or other appropriate method (eg, via email), using the SAE Report Form, or approved equivalent 
form. This instruction pertains to initial SAE reports as well as any follow-up reports.
The Investigator is required to ensure that the data on these forms is accurate and consistent.  
This requirement applies to all SAEs (regardless of relationship to the IP) that occur during the 
study (from the time the subject signs informed consent until 28 days after the last dose of IP) or 
any SAE made known to the Investigator at any time thereafter that are suspected of being 
related to IP. Serious adverse events occurring prior to treatment (after signing the ICF) will be 
captured.
The SAE report should provide a detailed description of the SAE and include a concise summary 
of hospital records and other relevant documents. If a subject died and an autopsy has been 
performed, copies of the autopsy report and death certificate are to be sent to Celgene Drug 
Safety as soon as these become available. Any follow-up data should be detailed in a subsequent 
SAE Report Form, or approved equivalent form, and sent to Celgene Drug Safety.  
Where required by local legislation, the Investigator is responsible for informing the Institutional 
Review Board/Ethics Committee (IRB/EC) of the SAE and providing them with all relevant 
initial and follow-up information about the event. The Investigator must keep copies of all SAE 
information on file including correspondence with Celgene and the IRB/EC.
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10.5.1.
Safety Queries
Queries pertaining to SAEs will be communicated from Celgene Drug Safety to the site via 
facsimile or electronic mail. The response time is expected to be no more than five (5) business 
days. Urgent queries (eg, missing causality assessment) may be handled by phone.
10.6.
Expedited Reporting of Adverse Events
For the purpose of regulatory reporting, Celgene Drug Safety will determine the expectedness of 
events suspected of being related to CC-220 based on the IB.
In the US, all suspected unexpected serious adverse reactions (SUSARs) will be reported in an 
expedited manner in accordance with 21 CFR 312.32.
For countries within the European Economic Area (EEA), Celgene or its authorized 
representative will report in an expedited manner to Regulatory Authorities and Ethics 
Committees concerned, SUSARs in accordance with Directive 2001/20/EC and the Detailed 
Guidance on collection, verification and presentation of adverse reaction reports arising from 
clinical trials on investigational products for human use (ENTR/CT3) and also in accordance 
with country-specific requirements.  
For the purpose of regulatory reporting in the EEA, Celgene Drug Safety will determine the 
expectedness of events suspected of being related to the other IPs (DEX, DARA, BTZ and/or 
CFZ as applicable) based on the SmPC.
Events of disease progression for the disease under study (including deaths due to disease 
progression for indications that are considered to be fatal) will be assessed as expected adverse 
events and will not be reported as expedited safety reports to regulatory authorities.
Celgene or its authorized representative shall notify the Investigator of the following 
information:

Any AE suspected of being related to the use of IP in this study or in other studies 
that is both serious and unexpected (ie, SUSAR);

Any finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or carcinogenicity.
Where required by local legislation, the Investigator shall notify his/her IRB/EC promptly of 
these new serious and unexpected AE(s) or significant risks to subjects.
The Investigator must keep copies of all pertinent safety information on file including 
correspondence with Celgene and the IRB/EC. (See Section 14.3 for record retention 
information).
Celgene Drug Safety Contact Information:
For Celgene Drug Safety contact information, please refer to the Serious Adverse Event Report 
Form Completion Guidelines or to the Pregnancy Report Form Completion Guidelines.
10.7.
Adverse Events of Special Interest
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding the safety profile of the Investigational Product, CC-220, and may require close 
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monitoring and rapid communication by the Investigator to the Sponsor. An AESI may be 
serious or nonserious. The rapid reporting of AESIs allows ongoing surveillance of these events 
in order to characterize and understand their association with the use of this investigational 
product.
Further information on potential risks (eg, presenting symptoms) can be found in the current 
version of the IB including guidelines for their evaluation and treatment.
10.7.1.
Second Primary Malignancies (SPMs)
Second primary malignancies (SPMs) will be monitored as events of interest and must be 
reported as serious adverse events regardless of the treatment cohort the subject is in. This 
includes any second primary malignancy, regardless of causal relationship to IP occurring at any 
time for the duration of the study, from the time of signing the ICF until the end of the 5-year 
Long-term Follow-up phase.  Events of second primary malignancy are to be reported using the 
SAE report form and must be considered “Important Medical Events” if no other serious criteria 
apply; these events must also be documented in the appropriate page(s) of the eCRF (ie, AE and 
SPM eCRF) and subject’s source documents.  Documentation on the diagnosis of the SPM must 
be provided at the time of reporting as an SAE (eg, any confirmatory histology or cytology 
results, X- rays, CT scans, etc.).
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11.
DISCONTINUATIONS
11.1.
Treatment Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the 
investigational product(s):

Progressive Disease

Adverse Event

Withdrawal by subject

Death

Lost to follow-up

Other (to be specified on the eCRF)
The reason for discontinuation of treatment should be recorded in the eCRF and in the source 
documents.
The decision to discontinue a subject from treatment remains the responsibility of the treating 
physician, which will not be delayed or refused by the Sponsor.  However, prior to discontinuing 
a subject, the Investigator may contact the Medical Monitor and forward appropriate supporting 
documents for review and discussion.
11.2.
Study Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the 
study:

Screen failure

Adverse event

Withdrawal by subject

Death

Lost to follow-up

Other (to be specified on the eCRF)
The reason for study discontinuation should be recorded in the eCRF and in the source 
documents.
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12.
EMERGENCY PROCEDURES
12.1.
Emergency Contact
In emergency situations, the Investigator should contact the responsible Clinical Research 
Physician/Medical Monitor or designee by telephone at the number(s) listed on the Emergency 
Contact Information page of the protocol (after title page).
In the unlikely event that the Clinical Research Physician/Medical Monitor or designee cannot be 
reached, please contact the global Emergency Call Center by telephone at the number listed on 
the Emergency Contact Information page of the protocol (after title page). This global 
Emergency Call Center is available 24 hours a day and 7 days a week. The representatives are 
responsible for obtaining your call-back information and contacting the on-call Celgene/contract 
research organization Medical Monitor, who will then contact you promptly.
Note: The back-up 24-hour global emergency contact call center should only be used if you are 
not able to reach the Clinical Research Physician(s) or Medical Monitor or designee for 
emergency calls. 
12.2.
Emergency Identification of Investigational Products
This is an open-label study; therefore, IP will be identified on the package labeling.
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13.
REGULATORY CONSIDERATIONS
13.1.
Good Clinical Practice
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that Celgene, its authorized representative, 
and Investigator abide by Good Clinical Practice (GCP), as described in International Council for
Harmonisation (ICH) Guideline E6 and in accordance with the general ethical principles outlined 
in the Declaration of Helsinki. The study will receive approval from an IRB/EC prior to 
commencement. The Investigator will conduct all aspects of this study in accordance with 
applicable national, state, and local laws of the pertinent regulatory authorities.
13.2.
Investigator Responsibilities
Investigator responsibilities are set out in the ICH Guideline for Good Clinical Practice and in 
the local regulations. Celgene staff or an authorized representative will evaluate and approve all 
Investigators who in turn will select their staff.
The Investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, amendments, study treatments, as well as study-related duties and functions, 
including obligations of confidentiality of Celgene information. The Investigator should maintain 
a list of Sub-investigators and other appropriately qualified persons to whom he or she has 
delegated significant study-related duties.
The Investigator is responsible for keeping a record of all subjects who sign an informed consent 
form (ICF) and are screened for entry into the study. Subjects who fail screening must have the 
reason(s) recorded in the subject’s source documents.
The Investigator, or a designated member of the Investigator’s staff, must be available during 
monitoring visits to review data, resolve queries and allow direct access to subject records (eg, 
medical records, office charts, hospital charts, and study-related charts) for source data 
verification. The Investigator must ensure timely and accurate completion of eCRFs and queries.
The information contained in the protocol and amendments (with the exception of the 
information provided by Celgene on public registry websites) is considered Celgene confidential 
information. Only information that is previously disclosed by Celgene on a public registry 
website may be freely disclosed by the Investigator or its institution, or as outlined in the Clinical 
Trial Agreement. Celgene protocol, amendment and IB information is not to be made publicly 
available (for example on the Investigator’s or their institution’s website) without express written 
approval from Celgene. Information proposed for posting on the Investigator’s or their
institution’s website must be submitted to Celgene for review and approval, providing at least 5 
business days for review.
At the time results of this study are made available to the public, Celgene will provide 
Investigators with a summary of the results that is written for the lay person. The Investigator is 
responsible for sharing these results with the subject and/or their caregiver as agreed by the 
subject.
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13.3.
Subject Information and Informed Consent
The Investigator must obtain informed consent of a subject and/or a subject’s legal representative 
prior to any study related procedures.
Documentation that informed consent occurred prior to the study subject’s entry into the study 
and of the informed consent process should be recorded in the study subject’s source documents 
including the date. The original ICF signed and dated by the study subject and by the person 
consenting the study subject prior to the study subject’s entry into the study, must be maintained 
in the Investigator’s study files and a copy given to the study subject. In addition, if a protocol is 
amended and it impacts on the content of the informed consent, the ICF must be revised. Study 
subjects participating in the study when the amended protocol is implemented must be re-
consented with the revised version of the ICF. The revised ICF signed and dated by the study 
subject and by the person consenting the study subject must be maintained in the Investigator’s 
study files and a copy given to the study subject.
13.4.
Confidentiality
Celgene affirms the subject's right to protection against invasion of privacy and to be in 
compliance with ICH and other local regulations (whichever is most stringent). Celgene requires 
the Investigator to permit Celgene's representatives and, when necessary, representatives from 
regulatory authorities, to review and/or copy any medical records relevant to the study in 
accordance with local laws.
Should direct access to medical records require a waiver or authorization separate from the 
subject’s signed ICF, it is the responsibility of the Investigator to obtain such permission in 
writing from the appropriate individual.
13.5.
Protocol Amendments
Any amendment to this protocol must be approved by the Celgene Clinical Research 
Physician/Medical Monitor. Amendments will be submitted to the IRB/EC for written approval.  
Written approval must be obtained before implementation of the amended version occurs.  The 
written signed approval from the IRB/EC should specifically reference the Investigator name, 
protocol number, study title and amendment number(s) that is applicable. Amendments that are 
administrative in nature do not require IRB/IEC approval but will be submitted to the IRB/IEC 
for information purposes.
13.6.
Institutional Review Board/Independent Ethics Committee Review 
and Approval
Before the start of the study, the study protocol, ICF, and any other appropriate documents will 
be submitted to the IRB/EC with a cover letter or a form listing the documents submitted, their 
dates of issue, and the site (or region or area of jurisdiction, as applicable) for which approval is 
sought. If applicable, the documents will also be submitted to the authorities in accordance with 
local legal requirements.
Investigational product can only be supplied to an Investigator by Celgene or its authorized 
representative after documentation on all ethical and legal requirements for starting the study has 
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been received by Celgene or its authorized representative. This documentation must also include 
a list of the members of the IRB/EC and their occupation and qualifications. If the IRB/EC will 
not disclose the names, occupations and qualifications of the committee members, it should be 
asked to issue a statement confirming that the composition of the committee is in accordance 
with GCP. For example, the IRB General Assurance Number may be accepted as a substitute for 
this list. Formal approval by the IRB/EC should mention the protocol title, number, amendment 
number (if applicable), study site (or region or area of jurisdiction, as applicable), and any other 
documents reviewed. It must mention the date on which the decision was made and must be 
officially signed by a committee member. Before the first subject is enrolled in the study, all 
ethical and legal requirements must be met.
The IRB/EC and, if applicable, the authorities, must be informed of all subsequent protocol 
amendments in accordance with local legal requirements. Amendments must be evaluated to 
determine whether formal approval must be sought and whether the ICF should also be revised.
The Investigator must keep a record of all communication with the IRB/EC and, if applicable, 
between a Coordinating Investigator and the IRB/EC. This statement also applies to any 
communication between the Investigator (or Coordinating Investigator, if applicable) and 
regulatory authorities.
Any advertisements used to recruit subjects for the study must be reviewed by Celgene and the 
IRB/EC prior to use.  
13.7.
Ongoing Information for Institutional Review Board/ Ethics 
Committee
If required by legislation or the IRB/EC, the Investigator must submit to the IRB/EC:

Information on serious or unexpected adverse events as soon as possible; 

Periodic reports on the progress of the study;

Deviations from the protocol or anything that may involve added risk to subjects.
13.8.
Termination of the Study
Celgene reserves the right to terminate this study prematurely at any time for reasonable medical 
or administrative reasons. Any premature discontinuation will be appropriately documented 
according to local requirements (eg, IRB/EC, regulatory authorities, etc).
At the conclusion of the study, if the study intervention is not available as an approved treatment 
in the local country, participants who continue to demonstrate clinical benefit will be eligible to 
receive Sponsor-supplied study intervention. If the study treatment is not available as an 
approved and available treatment, study intervention will be provided via an extension of the 
study, or a rollover study requiring approval by the responsible Health Authority and ethics 
committee, or through another mechanism at the discretion of the Sponsor. The Sponsor reserves 
the right to terminate access to the supplied study intervention treatment if any of the following 
occur: a) the study is terminated due to safety concerns; b) the development of CC-220 is 
terminated for other reasons, including, but not limited to, lack of efficacy and/or not meeting the 
study objectives; c) the participant can obtain medication from a government-sponsored or other 
health program. In all cases, the Sponsor will follow local regulations. In addition, the 
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Investigator or Celgene has the right to discontinue a single site at any time during the study for 
medical or administrative reasons such as:

Unsatisfactory enrollment;

GCP noncompliance;

Inaccurate or incomplete data collection;

Falsification of records;

Failure to adhere to the study protocol.
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14.
DATA HANDLING AND RECORDKEEPING
14.1.
Data/Documents
The Investigator must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the investigational product are complete, accurate, filed and 
retained. Examples of source documents include: hospital records; clinic and office charts; 
laboratory notes; memoranda; subject’s diaries or evaluation checklists; dispensing records; 
recorded data from automated instruments; copies or transcriptions certified after verification as 
being accurate copies; microfiche; x-ray film and reports; and records kept at the pharmacy, and 
the laboratories, as well as copies of eCRFs or CD-ROM.
14.2.
Data Management
Data will be collected via eCRF and entered into the clinical database per Celgene standard 
operating procedures (SOPs). This data will be electronically verified through use of 
programmed edit checks specified by the clinical team. Discrepancies in the data will be brought 
to the attention of the clinical team, and investigational site personnel, if necessary. Resolutions 
to these issues will be reflected in the database. An audit trail within the system will track all 
changes made to the data.
14.3.
Record Retention
Essential documents must be retained by the Investigator according to the period of time outlined 
in the clinical trial agreement. The Investigator must retain these documents for the time period 
described above or according to local laws or requirements, whichever is longer. Essential 
documents include, but are not limited to, the following:

Signed ICFs for all subjects;

Subject identification code list, screening log (if applicable), and enrollment log;

Record of all communications between the Investigator and the IRB/EC;

Composition of the IRB/EC;

Record of all communications between the Investigator, Celgene, and their authorized 
representative(s);

List of Sub-investigators and other appropriately qualified persons to whom the 
Investigator has delegated significant study-related duties, together with their roles in 
the study, curriculum vitae, and their signatures;

Copies of CRFs (if paper) and of documentation of corrections for all subjects;

IP accountability records;

Record of any body fluids or tissue samples retained;

All other source documents (subject records, hospital records, laboratory records, 
etc.); 
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
All other documents as listed in Section 8 of the ICH consolidated guideline on GCP 
(Essential Documents for the Conduct of a Clinical Trial).
The Investigator must notify Celgene if he/she wishes to assign the essential documents to 
someone else, remove them to another location or is unable to retain them for a specified period.  
The Investigator must obtain approval in writing from Celgene prior to destruction of any 
records. If the Investigator is unable to meet this obligation, the Investigator must ask Celgene 
for permission to make alternative arrangements. Details of these arrangements should be 
documented. 
All study documents should be made available if required by relevant health authorities. 
Investigator or institution should take measures to prevent accidental or premature destruction of 
these documents.
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15.
QUALITY CONTROL AND QUALITY ASSURANCE
All aspects of the study will be carefully monitored by Celgene or its authorized representative 
for compliance with applicable government regulations with respect to current GCP and SOPs.
15.1.
Study Monitoring and Source Data Verification
Celgene ensures that appropriate monitoring procedures are performed before, during and after 
the study. All aspects of the study are reviewed with the Investigator and the staff at a study 
initiation visit and/or at an Investigators’ Meeting. Prior to enrolling subjects into the study, a 
Celgene representative will review the protocol, eCRFs, procedures for obtaining informed 
consent, record keeping, and reporting of AEs/SAEs with the Investigator. Monitoring will 
include on-site visits with the Investigator and his/her staff as well as any appropriate 
communications by mail, email, fax, or telephone. During monitoring visits, the facilities, 
investigational product storage area, eCRFs, subject’s source documents, and all other study 
documentation will be inspected/reviewed by the Celgene representative in accordance with the 
Study Monitoring Plan.
Accuracy will be checked by performing source data verification that is a direct comparison of 
the entries made onto the eCRFs against the appropriate source documentation. Any resulting 
discrepancies will be reviewed with the Investigator and/or his/her staff. Any necessary 
corrections will be made directly to the eCRFs or via queries by the Investigator and/or his/her 
staff. Monitoring procedures require that informed consents, adherence to inclusion/exclusion 
criteria and documentation of SAEs and their proper recording be verified. Additional 
monitoring activities may be outlined in a study-specific monitoring plan.
15.2.
Audits and Inspections
In addition to the routine monitoring procedures, a Good Clinical Practice Quality Assurance 
unit exists within Celgene. Representatives of this unit will conduct audits of clinical research 
activities in accordance with Celgene SOPs to evaluate compliance with Good Clinical Practice 
guidelines and regulations.
The Investigator is required to permit direct access to the facilities where the study took place, 
source documents, eCRFs and applicable supporting records of study subject participation for 
audits and inspections by IRB/ECs, regulatory authorities (eg, FDA, EMA, Health Canada) and 
company authorized representatives. The Investigator should make every effort to be available 
for the audits and/or inspections. If the Investigator is contacted by any regulatory authority 
regarding an inspection, he/she should contact Celgene immediately.
15.3.
Product Quality Complaint
Issues that call into question IMP safety, purity, potency, quality and identity (eg, evidence of 
suspected tampering of product) must be reported as soon as possible to your study Clinical Trial 
Monitor and/or Clinical Trial Manager or designee. Report an issue or concern with all Sponsor
supplied investigational medicinal product (IMP), non-investigational medicinal product (NIMP) 
or auxiliary medicinal product (AxMP) suspected to have occurred before the product was 
transferred to the responsibility of the investigational site (eg, during manufacturing, packaging 
and labeling, storage, and/or distribution). 
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This includes suspected quality issues of components co-packaged with the drug, labelling, and 
IMP device/drug combination products, and medical devices.  
In the event of a suspected product quality issue, the immediate action to be taken by site is to 
quarantine the affected product. Do not dispose of the product unless retention presents a risk to 
personnel (eg, cytotoxic, risk of injury from broken glass or sharps). When reporting, provide as 
much product information as possible. Suspected IMP quality issues will be investigated and a 
response will be provided back to the investigational site.
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16.
PUBLICATIONS
As described in Section 13.2, all protocol- and amendment-related information, with the 
exception of the information provided by Celgene on public registry websites, is considered 
Celgene confidential information and is not to be used in any publications. Celgene protocol-
related information proposed for use in a publication must be submitted to Celgene for review 
and approval, and should not be utilized in a publication without express written approval from 
Celgene, or as described in the Clinical Trial Agreement.
Celgene will ensure Celgene-sponsored studies are considered for publication in the scientific 
literature in a peer-reviewed journal, irrespective of the results. At a minimum, this applies to 
results from all Phase 3 clinical studies, and any other study results of significant medical 
importance. This also includes results relating to investigational medicines whose development 
programs have been discontinued.
Study results may also be presented at one or more medical congresses, and may be used for 
scientific exchange and teaching purposes. Additionally, this study and its results may be 
submitted for inclusion in all appropriate health authority study registries, as well as publication 
on health authority study registry websites, as required by local health authority regulations.
Eligibility for external authorship, as well as selection of first authorship, will be based on 
several considerations, including, but not limited to, contribution to protocol development, study 
recruitment, data quality, participation in data analysis, participation in study steering committee 
(when applicable) and contribution to abstract, presentation and/or publication development.
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17.
REFERENCES
 
 
Agarwal A, Chow E, Bhutani M, Voorhees PM, Friend R, Usmani SZ. Practical considerations 
in managing relapsed multiple myeloma. Clin Lymphoma Myeloma Leuk. 2017;17(2):69-77.
Ali SA, Shi V, Maric I, Wang M, Stroncek DF, Rose JJ, et al. T cells expressing an anti-B-cell 
maturation antigen chimeric antigen receptor cause remissions of multiple myeloma. Blood.
2016 Sep 29;128(13):1688-700.
Amatangelo M, Bjorklund CC, Kang J, Polonskaia A, Viswanatha S, Thakurta A. Iberdomide 
(CC-220) has Synergistic Anti-Multiple Myeloma Activity in Combination with both 
Bortezomib and Dexamethasone, or in combination with Daratumumab in vitro. Blood. 
2018;132(Suppl 1):1935.
Avet-Loiseau H, Casneuf T, Chiu C, Laubach J, Lee J, Moreau P, et al. Evaluation of Minimal 
Residual Disease (MRD) in Relapsed/Refractory Multiple Myeloma (RRMM) Patients Treated 
with Daratumumab in Combination with Lenalidomide Plus Dexamethasone or Bortezomib Plus 
Dexamethasone. Blood. 2016; 128(22):246.
Benboubker L, Dimopoulos MA, Dispenzieri A, Catalano J, Belch AR, Cavo M, et al. 
Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med. 
2014 Sep 4;371(10):906-17.
Berdeja J, Lin Y, Raje N, Munshi N, Siegel D, Liedtke M, et al. Durable Clinical Responses in 
Heavily Pretreated Patients with Relapsed/Refractory Multiple Myeloma: Updated Results from 
a Multicenter Study of bb2121 Anti-Bcma CAR T Cell Therapy. Blood. 2017; 130 (Suppl 1): 
740.
Bjorklund C, Kang J, Lu L, Amatangelo M, Chiu H, Hagner P, et al. CC-122 Is a Cereblon 
Modulating Agent That Is Active in Lenalidomide-Resistant and Lenalidomide/Dexamethasone-
Double-Resistant Multiple Myeloma Pre-Clinical Models. Blood. 2016;128(Suppl 1):1592.
Botta C, Ciliberto D, Rossi M, Staropoli N, Cucè M, Galeano T, et al. Network meta-analysis of 
randomized trials in multiple myeloma: efficacy and safety in relapsed/refractory patients. Blood 
Advances. 2017 Feb 28;1(7):455-66.
Brudno JN, Maric I, Hartman SD, Rose JJ, Wang M, Lam N, et al. T Cells Genetically Modified 
to Express an Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor Cause Remissions of 
Poor-Prognosis Relapsed Multiple Myeloma. J Clin Oncol. 2018 Aug 1;36(22):2267-80.
Chari A, San-Miguel J, McCarthy H, Suzuki K, Hungria VT, Sureda AS, et al. Subcutaneous 
Daratumumab Plus Standard Treatment Regimens in Patients with Multiple Myeloma across 
Lines of Therapy: Pleiades Study Update. Blood. 2019; 134 (Supplement_1): 3152. 
Cho SF, Anderson KC, Tai YT. Targeting B Cell Maturation Antigen (BCMA) in Multiple 
Myeloma: Potential Uses of BCMA-Based Immunotherapy. Front Immunol. 2018 Aug 
10;9:1821.
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18.
APPENDICES
Appendix A:
Table of Abbreviations
Table 32:
Abbreviations and Specialist Terms
Abbreviation or 
Specialist Term
Explanation
ADC
Antibody drug conjugate
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase 
ANC
Absolute neutrophil count
antiHBs
Hepatitis B surface antibody
antiHBc
Hepatitis B core antibody
AP
Anterior/posterior
AST
Aspartate aminotransferase 
ASCT
Autologous stem cell transplant 
AUC
Area under the curve
AxMP
Auxiliary medicinal product
β-hCG
Serum beta human chorionic gonadotropin
BAFF
B-cell-activating factor
BCMA
B-cell maturation antigen
BiTE
bispecific T-cell engager 
BLyS
B lymphocyte stimulator
BMA
Bone marrow aspirate
BMB
Bone marrow biopsy
BTZ
Bortezomib
C
Cycle
CAR T
Chimeric Antigen Receptor T-cell Therapy
CC-220Dd
CC-220 + daratumumab + dexamethasone
CC-220Vd
CC-220 + bortezomib + dexamethasone
CC-220Kd
CC-220 + carfilzomib + dexamethasone
CFZ
Carfilzomib
CI
Confidence interval
CLT/F
Apparent total plasma clearance
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Table 32:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
Cmax
Maximum plasma concentration of drug
CNS
Central nervous system
COPD
Chronic obstructive pulmonary disease
CR
Complete response
CrCl
Creatinine clearance
CT
Computed tomography
Ctau
Concentration at the end of a dosing interval
CTCAE
Common Terminology Criteria for Adverse Events
Ctrough
Trough observed plasma concentration
CYP
Cytochrome
D
Day
DARA
Daratumumab
DDB1
Deoxyribonucleic acid damage binding protein 1
DLBCL
Diffuse large B cell lymphoma
DEC
Dose Escalation Committee
DEX
Dexamethasone
DLT
Dose-limiting toxicity
DNA
Deoxyribonucleic acid
DoubleT
Combination treatment with 2 drugs
DRd
Daratumumab, lenalidomide, and dexamethasone
DVd
Daratumumab, bortezomib, and dexamethasone
DVMP
Daratumumab, bortezomib, melphalan, and prednisone
EC
Ethics Committee
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EEA
European Economic Area
EFD
Embryofetal development
EMP
Extramedullary plasmacytoma
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Table 32:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
 
EOT
End of treatment
ER_AUC
Enantiomer ratio of AUC
ER_Cmax
Enantiomer ratio of Cmax
ESMO
European Society for Medical Oncology
EU
European Union
FCBP
Female of childbearing potential
FDA
Food and Drug Administration
FEV1
Forced expiratory volume in 1 second
FISH
Fluorescence in situ hybridization
FLC
Free light chain
GCP
Good Clinical Practice
GCSF
Granulocyte colony stimulating factor
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus 
hERG 
Human ether à go go related gene
HMCL
Human multiple myeloma cell lines
HR
Hazard ratio
IB
Investigator Brochure
IC50
Half maximal inhibitory concentration
ICF
Informed consent form
ICH
International Council for Harmonisation
IER
Independent Expert Reviewer
IFN-γ
Interferon-gamma
IgA
Immunoglobulin A
IgD
Immunoglobulin D
IgE
Immunoglobulin E
IgG
Immunoglobulin G
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Table 32:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
IgM
Immunoglobulin M
IL-2
Interleukin-1
IKZF1
Ikaros family zinc finger 1
IKZF3
Ikaros family zinc finger 3
IMiD®
Immunomodulatory compounds
IMP
Investigational medicinal product
IMWG
International Myeloma Working Group
IP
Investigational product
IRB
Institutional Review Board
IRC
Independent Response Committee
IRR
Infusion or injection-related reactions
IRT
Interactive Response Technology
IV
Intravenous 
LEN
Lenalidomide
MedDRA
Medical Dictionary for Regulatory Activities
MM
Multiple myeloma
MonoT
monotherapy
MR
Minimal response
MR_AUC
Metabolite ratio of AUC to parent
MR_Cmax
Metabolite ratio of Cmax to parent
MRD
Minimal residual disease
MTD
Maximum tolerated dose
MUGA
Multi-gated acquisition scan
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NDMM
Newly diagnosed multiple myeloma
NF-kB
Nuclear factor-kappa B
NGS
Next generation sequencing
NIMP
Non-investigational medicinal product
NK
Natural killer
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Table 32:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
NOAEL
No-observed-adverse-effect-level
NOEL
No-observed-effect-level
ORR
Overall response rate
OS
Overall survival
PCR
Polymerase chain reaction
Pd
Pharmacodynamic
PD
Progressive disease
PET
Positron emission tomography
PFS
Progression-free survival
P-gp
Permeability glycoprotein
PI
Package insert/prescribing information
PI
Proteasome inhibitor
PK
Pharmacokinetics
POM
Pomalidomide
PQC
Product quality complaint
PR
Partial response
PRO
Patient Reported Outcome
QD
Once daily
RBC
Red blood cell count
RP2D
Recommended Phase 2 dose
RRMM
Relapsed and refractory multiple myeloma
RVd
Lenalidomide in combination with bortezomib and dexamethasone
SAE
Serious adverse event
SAP
Statistical analysis plan
sCR
Stringent complete response
SGOT
Serum glutamic oxaloacetic transaminase 
SGPT
Serum glutamic pyruvic transaminase
SmPC
Summary of Product Characteristics
SOP
Standard operating procedure
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Table 32:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
sPEP
Serum protein electrophoresis
SPM
Second primary malignancy
SC
Subcutaneous
SUSAR
Suspected unexpected serious adverse reaction
t1/2
Terminal-phase elimination half-life
TCR
T-cell receptor
TEAE
Treatment-emergent adverse event
Tmax
Time to maximum plasma concentration of drug
TNF-α
Tumor necrosis factor-alpha
ULN
Upper limit of normal
uPEP
Urine protein electrophoresis
US
United States 
VGPR
Very good partial response
VTE
Venous thromboembolism
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Appendix B: International Myeloma Working Group Uniform Response 
Criteria 2016
Table 33:
International Myeloma Working Group Uniform Response Criteria
Response 
Category
Response Criteria*
MRD response Criteria (requires a complete response)
Sustained 
MRD-
negative
MRD negativity in the marrow (NGF or NGS, or both) and by imaging as defined 
below, confirmed minimum of 1 year apart. Subsequent evaluations can be used to 
further specify the duration of negativity (eg, MRD-negative at 5 years) †
Flow MRD-
negative
Absence of phenotypically aberrant clonal plasma cells by NGF‡ on bone marrow 
aspirates using the EuroFlow standard operation procedure for MRD detection in 
multiple myeloma (or validated equivalent method) with a minimum sensitivity of 1 
in 105 nucleated cells or higher
Sequencing 
MRD-
negative
Absence of clonal plasma cells by NGS on bone marrow aspirate in which presence 
of a clone is defined as less than two identical sequencing reads obtained after DNA 
sequencing of bone marrow aspirates using the LymphoSIGHT platform (or validated 
equivalent method) with a minimum sensitivity of 1 in 105 nucleated cells§ or higher
Imaging plus 
MRD-
negative
MRD negativity as defined by NGF or NGS plus disappearance of every area of 
increased tracer uptake found at baseline or a preceding PET/CT or decrease to less 
mediastinal blood pool SUV or decrease to less than that of surrounding normal 
tissue¶
Standard IMWG response criteria
Stringent 
Complete 
Response 
(sCR)
Complete response (CR) as defined below, plus
Normal serum free light chain (FLC) ratio** and
Absence of clonal plasma cells by immunohistochemistry (κ/λ ratio ≤4:1 or ≥1:2 for κ 
and λ patients, respectively, after counting ≥100 plasma cells)††
Complete 
Response 
(CR)
Negative immunofixation of serum and urine and
Disappearance of any soft tissue plasmacytomas and
< 5% plasma cells in bone marrow aspirates
In patients in whom the only measurable disease is by serum FLC levels: CR in such 
patients indicates a normal FLC ratio of 0.26 to 1.65 in addition to CR criteria listed 
above. 
Very Good 
Partial 
Response 
(VGPR)
Serum and urine M-protein detectable by immunofixation but not on electrophoresis 
or
90% or greater reduction in serum M-protein plus urine M-protein level <100 mg per 
24 hours
In patients in whom the only measurable disease is by serum FLC levels: VGPR in 
such patients requires a > 90% decrease in the difference between involved and 
uninvolved FLC levels.
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Table 33:
International Myeloma Working Group Uniform Response Criteria
(Continued)
Response 
Category
Response Criteria*
Partial 
Response 
(PR)
≥ 50% reduction of serum M-Protein and reduction in 24-hour urinary M-protein by ≥ 
90% or to < 200 mg per 24 hours
If the serum and urine M-protein are not measurable, a ≥ 50% decrease in the 
difference between involved and uninvolved FLC levels is required in place of the M-
protein criteria.
If serum and urine M-protein are unmeasurable, and the serum free light chain assay 
is also unmeasurable, a ≥ 50% reduction in plasma cells is required in place of M-
protein, provided baseline bone marrow plasma cell percentage was ≥ 30%
In addition to these criteria, if present at baseline, a ≥50% reduction in the size 
measured by sum of the products (SPD) §§ of the maximal perpendicular diameters of 
soft tissue plasmacytomas is also required
Stable 
Disease (SD)
Not meeting criteria for CR, VGPR, MR, PR, or progressive disease (PD)
Progressive 
disease (PD)
¶¶  ||||
Requires only one of the following:
Increase of 25% from lowest response value in any of the following:

Serum M-component (absolute increase must be ≥ 0.5 g/dL), and/or

Urine M-component (absolute increase must be ≥ 200 mg/24 h), and/or
Only in patients without measurable serum and urine M-protein levels: the difference 
between involved and uninvolved FLC levels (absolute increase must be ≥ 10 mg/dL)
Only in patients without measurable serum and urine M protein levels and without 
measurable disease by FLC levels, bone marrow plasma cell percentage (absolute 
increase must be ≥ 10%)
Appearance of a new lesion(s), ≥ 50% increase from nadir in SPD§§ of > 1 lesion, or 
≥ 50% increase in the longest diameter of a previous lesion > 1 cm in short axis;
≥ 50% increase in circulating plasma cells (minimum of 200 cells per μL) if this is the 
only measure of disease
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Table 33:
International Myeloma Working Group Uniform Response Criteria
(Continued)
Response 
Category
Response Criteria*
Clinical 
Relapse
Clinical relapse requires one or more of the following criteria:
Direct indicators of increasing disease and/or end organ dysfunction (CRAB features) 
related to the underlying clonal plasma-cell proliferative disorder. It is not used in 
calculation of time to progression or progression-free survival but is listed as 
something that can be reported optionally or for use in clinical practice;
Development of new soft tissue plasmacytomas or bone lesions (osteoporotic 
fractures do not constitute progression);
Definite increase in the size of existing plasmacytomas or bone lesions. A definite 
increase is defined as a 50% (and ≥1 cm) increase as measured serially by the SPD§§
of the measurable lesion;
Hypercalcaemia (> 11 mg/dL);
Decrease in hemoglobin of ≥ 2 g/dL not related to therapy or other non-myeloma-
related conditions;
Rise in serum creatinine by 2 mg/dL or more from the start of the therapy and 
attributable to myeloma;
Hyperviscosity related to serum paraprotein
Relapse from 
complete 
response (to 
be used only 
if the 
endpoint is 
disease-free 
survival)
Any one or more of the following criteria:
Reappearance of serum or urine M-protein by immunofixation or electrophoresis;
Development of ≥ 5% plasma cells in the bone marrow;
Appearance of any other sign of progression (ie, new plasmacytoma, lytic bone 
lesion, or hypercalcaemia see above)
Relapse from 
MRD 
negative (to 
be used only 
if the 
endpoint is 
disease-free 
survival) 
Any one or more of the following criteria:
Loss of MRD negative state (evidence of clonal plasma cells on NGF or NGS, or 
positive imaging study for recurrence of myeloma);
Reappearance of serum or urine M-protein by immunofixation or electrophoresis;
Development of ≥ 5% plasma cells in the bone marrow;
Appearance of any other sign of progression (ie, new plasmacytoma, lytic bone 
lesion, or hypercalcaemia)
Minimal 
Response 
(MR)
≥ 25% but ≤ 49% reduction of serum M-protein and reduction in 24-hour urine M-
protein by 50%-89%
In addition to the above criteria, if present at baseline, ≥50% reduction in the size 
(SPD) §§ of soft tissue plasmacytomas is also required 
Refer to IMWG criteria for specific details (Kumar, 2016).
For MRD assessment, the first bone marrow aspirate should be sent to MRD (not for morphology) and this sample should 
be taken in one draw with a volume of minimally 2 mL (to obtain sufficient cells), but maximally 4–5 mL to avoid 
haemodilution. IMWG = International Myeloma Working Group. MRD = minimal residual disease. NGF = next-
generation flow. NGS = next-generation sequencing. FLC = free light chain. M-protein = myeloma protein. SPD = sum of 
the products of the maximal perpendicular diameters of measured lesions. CRAB features = calcium elevation, renal 
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failure, anaemia, lytic bone lesions. FCM = flow cytometry. SUVmax = maximum standardised uptake value. MFC = 
multiparameter flow cytometry. 18F-FDG PET = 18F-fluorodeoxyglucose PET. ASCT = autologous stem cell 
transplantation.
*
All response categories require two consecutive assessments made any time before starting any new therapy; for MRD 
there is no need for two consecutive assessments, but information on MRD after each treatment stage is recommended 
(eg, after induction, high-dose therapy/ASCT, consolidation, maintenance). MRD tests should be initiated only at the 
time of suspected complete response. All categories of response and MRD require no known evidence of progressive 
or new bone lesions if radiographic studies were performed. However, radiographic studies are not required to satisfy 
these response requirements except for the requirement of FDG PET if imaging MRD-negative status is reported. 
†
Sustained MRD negativity when reported should also annotate the method used (eg, sustained flow MRD-negative, 
sustained sequencing MRD-negative).
‡
Bone marrow MFC should follow NGF guidelines. The reference NGF method is an eight-colour two-tube approach, 
which has been extensively validated. The two-tube approach improves reliability, consistency, and sensitivity because 
of the acquisition of a greater number of cells. The eight-colour technology is widely available globally and the NGF 
method has already been adopted in many flow laboratories worldwide. The complete eight-colour method is most 
efficient using a lyophilised mixture of antibodies which reduces errors, time, and costs. 5 million cells should be 
assessed. The FCM method employed should have a sensitivity of detection of at least 1 in 105 plasma cells. 
§
DNA sequencing assay on bone marrow aspirate should use a validated assay such as LymphoSIGHT (Sequenta). 
¶
Criteria used by Zamagni and colleagues, and expert panel (IMPetUs; Italian Myeloma criteria for PET Use). Baseline 
positive lesions were identified by presence of focal areas of increased uptake within bones, with or without any 
underlying lesion identified by CT and present on at least two consecutive slices. Alternatively, an SUVmax=2·5 
within osteolytic CT areas >1 cm in size, or SUVmax=1·5 within osteolytic CT areas ≤1 cm in size were considered 
positive. Imaging should be performed once MRD negativity is determined by MFC or NGS. ||Derived from 
international uniform response criteria for multiple myeloma. Minor response definition and clarifications derived from 
Rajkumar and colleagues. When the only method to measure disease is by serum FLC levels: complete response can be 
defined as a normal FLC ratio of 0·26 to 1·65 in addition to the complete response criteria listed previously. Very good 
partial response in such patients requires a ≥90% decrease in the difference between involved and uninvolved FLC 
levels. All response categories require two consecutive assessments made at any time before the institution of any new 
therapy; all categories also require no known evidence of progressive or new bone lesions or extramedullary 
plasmacytomas if radiographic studies were performed. Radiographic studies are not required to satisfy these response 
requirements. Bone marrow assessments do not need to be confirmed. Each category, except for stable disease, will be 
considered unconfirmed until the confirmatory test is performed. The date of the initial test is considered as the date of 
response for evaluation of time dependent outcomes such as duration of response. 
** All recommendations regarding clinical uses relating to serum FLC levels or FLC ratio are based on results obtained 
with the validated Freelite test (Binding Site, Birmingham, UK). 
†† Presence/absence of clonal cells on immunohistochemistry is based upon the κ/λ/L ratio. An abnormal κ/λ ratio by 
immunohistochemistry requires a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting presence of 
an abnormal clone is κ/λ of >4:1 or <1:2. 
‡‡ Special attention should be given to the emergence of a different monoclonal protein following treatment, especially in 
the setting of patients having achieved a conventional complete response, often related to oligoclonal reconstitution of 
the immune system. These bands typically disappear over time and in some studies have been associated with a better 
outcome. Also, appearance of monoclonal IgG κ in patients receiving monoclonal antibodies should be differentiated 
from the therapeutic antibody. §§Plasmacytoma measurements should be taken from the CT portion of the PET/CT, or 
MRI scans, or dedicated CT scans where applicable. For patients with only skin involvement, skin lesions should be 
measured with a ruler. Measurement of tumour size will be determined by the SPD. 
¶¶ Positive immunofixation alone in a patient previously classified as achieving a complete response will not be 
considered progression. For purposes of calculating time to progression and progression-free survival, patients who 
have achieved a complete response and are MRD-negative should be evaluated using criteria listed for progressive 
disease. Criteria for relapse from a complete response or relapse from MRD should be used only when calculating 
disease-free survival. 
|||| In the case where a value is felt to be a spurious result per physician discretion (eg, a possible laboratory error), that 
value will not be considered when determining the lowest value.
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Appendix C:
ECOG Performance Status
Table 34:
ECOG Performance Status
Grade
ECOG
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up 
and about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Dead
Source (Oken, 1982).
Eastern Cooperative Oncology Group, Robert Comis, MD, Group Chair.
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Appendix D: CC-220 Pregnancy Prevention Plan for Subjects in Clinical 
Trials
1. CC-220 PREGNANCY PREVENTION PLAN FOR SUBJECTS IN CLINICAL TRIALS
1.1.
The Pregnancy Prevention Plan (PPP) (v5.1) applies to all subjects receiving CC-220 
within a clinical trial. The following PPP documents are included: 
•
The CC-220 Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth 
Control Methods document (Section 2) provides the following information:
•
Potential risks to the fetus associated with CC-220 exposure
•
Definition of female of childbearing potential (FCBP)/female not of childbearing potential 
(FNCBP)
•
Requirements for counseling of all subjects receiving CC-220 about pregnancy precautions 
and the potential risks of fetal exposure to CC-220
•
Acceptable birth control methods for both female subjects of childbearing potential and male 
subjects receiving CC-220 in the study
•
Pregnancy testing requirements for subjects receiving CC-220 who are FCBP
1.2.
The CC-220 Education and Counseling Guidance Document for each gender (female and 
male; Section 1 and Section 2 respectively) must be completed and signed by a trained counselor 
at the participating clinical center prior to each dispensing of CC-220. A copy of this document 
must be maintained in the subject’s records for each dispense.
1.3.
The CC-220 Information Sheet (Section 3) will be given to each subject receiving CC 
220. The subject must read this document prior to starting CC-220 and each time the subject 
receives a new supply of CC-220.
2. CC-220 RISKS OF FETAL EXPOSURE, PREGNANCY TESTING GUIDELINES AND 
ACCEPTABLE BIRTH CONTROL METHODS
2.1.
Risks Associated with Pregnancy
CC-220 was found to cause birth defects in experimental animals (rat and rabbit). CC-220 is an 
analogue of thalidomide. Thalidomide is a known human teratogen that causes severe life-
threatening human birth defects. If CC-220 is taken during pregnancy, it may cause birth defects 
or death to an unborn baby. Therefore, a pregnancy prevention program must be followed.
2.2.
Definition of Females of Childbearing Potential
A FCBP is a female who: 1) has achieved menarche at some point, 2) has not undergone a 
hysterectomy or bilateral oophorectomy or 3) has not been naturally postmenopausal 
(amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 
consecutive months (ie, has had menses at any time in the preceding 24 consecutive months).
2.3.
Definition of Females Not of Childbearing Potential
Females who do not meet the above definition of FCBP should be classified as FNCBP.
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2.4.
Counseling
2.4.1.
Females of Childbearing Potential
For a FCBP, CC-220 is contraindicated unless all of the following are met (ie, all FCBP must be 
counseled concerning the following risks and requirements prior to the start of CC-220): 
•
She understands the potential teratogenic risk to the unborn child
•
She understands the need for effective contraception, without interruption, 28 days before 
starting CC-220, throughout the entire duration of CC-220, during dose interruptions and for at 
least 28 days after the last dose of CC-220
•
She understands and agrees to inform the Investigator if a change or stop of method of 
contraception is needed
•
She must be capable of complying with effective contraceptive measures
•
She is informed and understands the potential consequences of pregnancy and the need to 
notify her study doctor immediately if there is a risk of pregnancy
•
She understands the need to commence CC-220 as soon as it is dispensed following a 
negative pregnancy test
•
She understands and accepts the need to undergo pregnancy testing based on the frequency 
outlined in this plan (Section 2.6) and in the Informed Consent
•
She acknowledges she understands the hazards CC-220 can cause to an unborn fetus and the 
necessary precautions associated with the use of CC-220.
•
The Investigator must ensure that a FCBP:
•
Complies with the conditions of the pregnancy prevention plan, including confirmation that 
she has an adequate level of understanding
•
Acknowledges the aforementioned requirements.
2.4.2. Females Not of Childbearing Potential
For a FNCBP, CC-220 is contraindicated unless all of the following are met (ie, all FNCBP must 
be counseled concerning the following risks and requirements prior to the start of CC-220): 
•
She acknowledges she understands the hazards CC-220 can cause to an unborn fetus and the 
necessary precautions associated with the use of CC-220.
2.4.3. Males
In a 9-month toxicity study in monkeys given CC-220 at doses higher than the highest dose 
planned for this study, male monkeys had a decrease in the amount of sperm producing cells. It 
is not known at this time if this finding can be reversed or at what time after the start of CC-220 
treatment this decrease will occur. It is not known if there might be a similar effect in men taking 
CC-220 and how this will affect their ability to father children. There were no observable effects 
in male sex organs in monkeys that received more than the highest dose given to humans. There 
were no effects of CC-220 in the sex organs of female monkeys.
Therefore, male subjects taking CC-220 must meet the following conditions (ie, they must be 
counseled concerning the following risks and requirements prior to the start of CC-220):
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•
Understand the potential teratogenic risk if engaged in sexual activity with a pregnant female 
or a FCBP
•
Understand the need for the use of a condom even if he has had a vasectomy, if engaged in 
sexual activity with a pregnant female or a FCBP
•
Understand the potential teratogenic risk if the subject donates semen or sperm.
•
Understand that the effects on fertility are currently unknown, therefore all family planning 
options and/or alternatives should be thoroughly discussed with the study doctor prior to 
receiving CC-220.
2.5.
Contraception
2.5.1. Female Subjects of Childbearing Potential
Females of childbearing potential enrolled in this protocol must agree to use two reliable forms 
of contraception simultaneously or to practice complete abstinence (True abstinence is 
acceptable when this is in line with the preferred and usual lifestyle of the subject. Periodic 
abstinence [eg, calendar, ovulation, symptothermal or post ovulation methods] and withdrawal 
are not acceptable methods of contraception.) from heterosexual contact during the following 
time periods related to this study: 1) for at least 28 days before starting CC-220; 2) while taking 
CC-220; 3) during dose interruptions; and 4) for at least 28 days after the last dose of CC-220. 
The two methods of reliable contraception must include one highly effective method and one 
additional effective (barrier) method. If the below contraception methods are not appropriate for 
the FCBP, she must be referred to a qualified provider of contraception methods to determine the 
medically effective contraception method appropriate to the subject. The following are examples 
of highly effective and additional effective methods of contraception:
Examples of highly effective methods:
•
Intrauterine device (IUD)
•
Hormonal (birth control pills, injections, implants, levonorgestrel-releasing intrauterine 
system [IUS], medroxyprogesterone acetate depot injections, ovulation inhibitory progesterone-
only pills [eg, desogestrel])
•
Tubal ligation
•
Partner’s vasectomy
Examples of additional effective methods:
•
Male condom
•
Diaphragm
•
Cervical Cap
Implants and levonorgestrel-releasing intrauterine systems are associated with an increased risk 
of infection at the time of insertion and irregular vaginal bleeding. Prophylactic antibiotics 
should be considered particularly in subjects with neutropenia. 
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2.5.2. Male Subjects
Subjects must either:
1. practice complete abstinence (true abstinence), which is acceptable when this is in line 
with the preferred and usual lifestyle of the subject. Periodic abstinence (eg, calendar, 
ovulation, symptothermal or post-ovulation methods) and withdrawal are not acceptable 
methods of contraception, or
2. agree to use a condom during sexual contact with a pregnant female or a FCBP while 
taking CC-220, including during dose interruptions, and for at least 90 days following the 
last dose of CC-220, even if he has undergone a successful vasectomy. 
2.6.
Pregnancy Testing
Medically supervised pregnancy tests with a minimum sensitivity of 25 mIU/mL must be 
performed for FCBP.
Females of childbearing potential must have two negative pregnancy tests (sensitivity of at least 
25 mIU/mL) prior to starting CC-220. The first pregnancy test must be performed within 10 to 
14 days prior to the start of CC-220 and the second pregnancy test must be performed within 24 
hours prior to the start of CC-220. The subject may not receive CC-220 until the study doctor has 
verified that the results of these pregnancy tests are negative.
Females of childbearing potential with regular or no menstrual cycles must agree to have 
pregnancy tests weekly for the first 28 days of study participation and then every 28 days while 
taking CC-220, at study discontinuation, and at Day 28 following the last dose of CC-220. 
Females of childbearing potential with irregular menstrual cycles must agree to have pregnancy 
tests weekly for the first 28 days of study participation and then every 14 days while taking CC 
220, at study discontinuation, and at Days 14 and 28 following the last dose of CC-220.  
2.7.
Pregnancy Precautions for CC-220 Use
2.7.1. Before Starting CC-220
2.7.1.1.
Female Subjects of Childbearing Potential
Females of childbearing potential must have two negative pregnancy tests (sensitivity of at least 
25 mIU/mL) prior to starting CC-220. The first pregnancy test must be performed within 10 to 
14 days prior to the start of CC-220 and the second pregnancy test must be performed within 24 
hours prior to the start of CC-220. The subject may not receive CC-220 until the study doctor has 
verified that the results of these pregnancy tests are negative.
Females of childbearing potential must use two reliable forms of contraception simultaneously, 
or practice complete abstinence (True abstinence is acceptable when this is in line with the 
preferred and usual lifestyle of the subject. Periodic abstinence [eg, calendar, ovulation, 
symptothermal or post-ovulation methods] and withdrawal are not acceptable methods of 
contraception.) from heterosexual contact for at least 28 days before starting CC-220.
2.7.1.2.
Male Subjects
Subjects must agree to practice complete abstinence (True abstinence is acceptable when this is 
in line with the preferred and usual lifestyle of the subject. Periodic abstinence [eg, calendar, 
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ovulation, symptothermal or post ovulation methods] and withdrawal are not acceptable methods 
of contraception.) or agree to use a condom during sexual contact with a pregnant female or a 
FCBP while taking CC-220, during dose interruptions and for at least 90 days following the last 
dose of CC-220, even if he has undergone a successful vasectomy. 
2.7.2. During and After Study Participation
2.7.2.1.
Female Subjects
•
Females of childbearing potential with regular or no menstrual cycles must agree to have 
pregnancy tests weekly for the first 28 days of study participation and then every 28 days while 
taking CC-220, at study discontinuation, and at Day 28 following the last dose of CC-220. 
•
Females of childbearing potential with irregular menstrual cycles must agree to have 
pregnancy tests weekly for the first 28 days of study participation and then every 14 days while 
taking CC-220, at study discontinuation, and at Days 14 and 28 following the last dose of CC-
220.  
•
At each visit, the Investigator must confirm with the FCBP that she is continuing to use two 
reliable methods of birth control if not committing to complete abstinence, or confirm 
commitment to complete abstinence.
•
If a FCBP considers the need to change or to stop a method of contraception, the Investigator 
must be notified immediately.
•
Counseling about pregnancy precautions and the potential risks of fetal exposure must be 
conducted at a minimum of every 28 days. 
•
If pregnancy or a positive pregnancy test does occur in a subject, CC-220 must be 
immediately discontinued.
•
Pregnancy testing and counseling must be performed if a subject misses her period or if her 
pregnancy test or her menstrual bleeding is abnormal. CC-220 must be discontinued during this 
evaluation.
•
Females must agree to abstain from breastfeeding while taking CC-220 and for at least 28 
days after the last dose of CC-220.
2.7.2.2.
Male Subjects
•
Must practice complete abstinence (True abstinence is acceptable when this is in line with the 
preferred and usual lifestyle of the subject. Periodic abstinence [eg, calendar, ovulation, 
symptothermal or post ovulation methods] and withdrawal are not acceptable methods of 
contraception) or use a condom during sexual contact with a pregnant female or a FCBP while 
receiving CC-220, during dose interruptions and for at least 90 days following the last dose of 
CC-220, even if he has undergone a successful vasectomy.
•
Must not donate semen or sperm while receiving CC-220, during dose interruptions or for at 
least 90 days following the last dose of CC-220.
•
Counseling about pregnancy precautions and the potential risks of fetal exposure must be 
conducted at a minimum of every 28 days.
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Protocol CC-220-MM-001
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Confidential and Proprietary
219
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
•
If pregnancy or a positive pregnancy test does occur in the partner of a male subject while 
taking CC-220, the Investigator must be notified immediately.
2.7.3. Additional Precautions
•
Subjects should be instructed to never give CC-220 to another person.
•
Subjects should be instructed to return any unused capsules to the study doctor.
•
Subjects should not donate blood while receiving CC-220, during dose interruptions and for 
at least 28 days following the last dose of CC-220.
•
No more than a 28 day CC-220 supply may be dispensed to a subject. 
1. CC-220 EDUCATION AND COUNSELING GUIDANCE DOCUMENT FOR FEMALE 
SUBJECTS
To be completed prior to each dispensing of CC-220.
Protocol Number: ____________________________________________
Subject Name (Print): __________________ DOB: _____/_____/_____ (dd/mmm/yyyy)
Check one risk category:
•
FCBP (Female of childbearing potential): a female who: 1) has achieved menarche (first 
menstrual cycle) at some point, 2) has not undergone a hysterectomy (the surgical removal of the 
uterus) or bilateral oophorectomy (the surgical removal of both ovaries) or 3) has not been 
naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing 
potential) for at least 24 consecutive months (ie, has had menses at any time during the preceding 
24 consecutive months)
•
NOT FCBP
Female of Childbearing Potential:
1. I have verified and counseled the subject regarding the following:
•
Potential risk of fetal exposure to CC-220: CC-220 was found to cause birth defects in 
experimental animals (rat and rabbit). A teratogenic potential of CC-220 in humans cannot be 
ruled out. If CC-220 is taken during pregnancy, it may cause birth defects or death to any unborn 
baby. Females are advised to avoid pregnancy while taking CC-220. Females of childbearing 
potential must agree not to become pregnant while taking CC-220. 
•
That the required pregnancy tests performed are negative.
•
The subject confirmed that she is using TWO reliable methods of birth control at the same 
time, or complete abstinence (True abstinence is acceptable when this is in line with the 
preferred and usual lifestyle of the subject. Periodic abstinence [eg, calendar, ovulation, 
symptothermal or post ovulation methods] and withdrawal are not acceptable methods of 
contraception.) from heterosexual contact (at least 28 days prior to receiving CC-220, while 
receiving CC-220, during dose interruptions and for at least 28 days after the last dose of CC-
220). 
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CC-220
Protocol CC-220-MM-001
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Confidential and Proprietary
220
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One highly effective method and one additional method of birth control must be used AT THE 
SAME TIME. The following are examples of highly effective and additional effective methods 
of contraception:
-
Examples of highly effective methods:
o
Intrauterine device (IUD)
o
Hormonal (birth control pills, injections, implants, levonorgestrel-releasing intrauterine 
system [IUS], medroxyprogesterone acetate depot injections, ovulation inhibitory progesterone-
only pills [eg, desogestrel])
o
Tubal ligation
o
Partner’s vasectomy
-
Examples of additional effective methods:
o
Male condom
o
Diaphragm
o
Cervical Cap
•
The subject confirmed that even if she has amenorrhea she must comply with advice on 
contraception.
•
Pregnancy tests before, during administration of CC-220 and at the last dose of CC 220, even 
if the subject agrees not to have reproductive heterosexual contact.
•
Frequency of pregnancy tests to be done:
-
Two pregnancy tests will be performed prior to receiving CC-220, one within 10 to 14 days, 
and a second within 24 hours of the start of CC-220.
-
Every week during the first 28 days of this study and a pregnancy test every 28 days while 
the subject is taking CC-220 if menstrual cycles are regular. 
-
Every week during the first 28 days of this study and a pregnancy test every 14 days while 
the subject is taking CC-220 if menstrual cycles are irregular.
-
If the subject missed a period or has unusual menstrual bleeding.  
-
When the subject is discontinued from the study and at Day 28 after CC-220 discontinuation 
if menstrual cycles are regular. If menstrual cycles are irregular, pregnancy tests will be done at 
discontinuation from the study and at Days 14 and 28 after the last dose of CC-220.
•
The subject confirmed that she will stop taking CC-220 immediately in the event of 
becoming pregnant and to call her study doctor as soon as possible. 
•
The subject confirmed that she has not and will not breastfeed a baby while taking CC-220 
and for at least 28 days after the last dose of CC-220.
•
The subject has not and will never share CC-220 with anyone else.
•
The subject has not and will not donate blood while taking CC-220, during dose interruptions 
and for at least 28 days after the last dose of CC-220.
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EDMS Doc. Number: 25858146 - 20867538
CC-220
Protocol CC-220-MM-001
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Confidential and Proprietary
221
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
•
The subject has not and will not break, chew, or open CC-220 capsules at any point.
•
The subject confirmed that she will return unused CC-220 capsules to the study doctor.
2. I have provided the CC-220 Information Sheet to the subject.
Female Not of Childbearing Potential (Natural Menopause for at Least 24 Consecutive Months, a 
Hysterectomy, or Bilateral Oophorectomy):
1. I have verified and counseled the subject regarding the following:
•
Potential risk of fetal exposure to CC-220: CC-220 was found to cause birth defects in 
experimental animals (rat and rabbit). A teratogenic potential of CC-220 in humans cannot be 
ruled out. If CC-220 is taken during pregnancy, it may cause birth defects or death to any unborn 
baby.
•
The subject has not and will never share CC-220 with anyone else.
•
The subject has not and will not donate blood while taking CC-220, during dose interruptions 
and for at least 28 days after the last dose of CC-220.
•
The subject has not and will not break, chew, or open CC-220 capsules at any point.
•
The subject confirmed that she will return unused CC-220 capsules to the study doctor.
2. I have provided the CC-220 Information Sheet to the subject.
Do Not Dispense CC-220 if:
•
The subject is pregnant.
•
No pregnancy tests were conducted for a FCBP.
•
The subject states she did not use TWO reliable methods of birth control (unless practicing 
complete abstinence from heterosexual contact) at least 28 days prior to receiving CC-220, while 
receiving CC-220 and during dose interruptions.
•
The subject stated that she has or does not want to adhere to pregnancy precautions outlined 
within this PPP.
Counselor Name (Print): ____________________
Counselor Signature: _______________________ Date: _____/_____/_____(dd/mmm/yyyy)
**Maintain a copy of the Education and Counseling Guidance Document in the subject’s 
records.**
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Protocol CC-220-MM-001
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Confidential and Proprietary
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2. CC-220 EDUCATION AND COUNSELING GUIDANCE DOCUMENT FOR MALE 
SUBJECTS
To be completed prior to each dispensing of CC-220.
Protocol Number: ____________________________________________
Subject Name (Print): __________________ DOB: _____/_____/_____ (dd/mmm/yyyy)
1. I have verified and counseled the subject regarding the following:
•
Potential risk of fetal exposure to CC-220: CC-220 was found to cause birth defects in 
experimental animals (rat and rabbit). A teratogenic potential of CC-220 in humans cannot be 
ruled out. If CC-220 is taken during pregnancy, it may cause birth defects or death to any unborn 
baby.
•
The subject confirmed that he has practiced complete abstinence (True abstinence is 
acceptable when this is in line with the preferred and usual lifestyle of the subject. Periodic 
abstinence [eg, calendar, ovulation, symptothermal or post ovulation methods] and withdrawal 
are not acceptable methods of contraception.) or used a condom when engaging in sexual contact 
(including those who have had a vasectomy) with a pregnant female or FCBP, while taking CC-
220, during dose interruptions and for at least 90 days after the last dose of CC-220.
•
The subject confirmed that he has not impregnated his female partner while in the study.
•
The subject confirmed that he will notify his study doctor if his female partner becomes 
pregnant and the female partner of a male subject taking CC-220 confirmed that she will call her 
healthcare provider immediately if she becomes pregnant.
•
The subject has not and will never share CC-220 with anyone else.
•
The subject confirmed that he has not donated and will not donate semen or sperm while 
taking CC-220 or during dose interruptions and that he will not donate semen or sperm for at 
least 90 days after the last dose of CC-220.
•
The subject has not and will not donate blood while taking CC-220, during dose interruptions 
and for at least 28 days after the last dose of CC-220.
•
The subject has not and will not break, chew, or open CC-220 capsules at any point.
•
The subject confirmed that he will return unused CC-220 capsules to the study doctor.
2. I have provided the CC-220 Information Sheet to the subject.
Do Not Dispense CC-220 if:
•
The subject stated that he has or does not want to adhere to pregnancy precautions outlined 
within this PPP.
Counselor Name (Print): ____________________
Counselor Signature: _______________________ Date: _____/_____/_____ (dd/mmm/yyyy)
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EDMS Doc. Number: 25858146 - 20867538
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Protocol CC-220-MM-001
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**Maintain a copy of the Education and Counseling Guidance Document in the subject’s records.**
3. CC-220 INFORMATION SHEET 
For subjects enrolled in clinical research studies 
Please read this CC-220 Information Sheet before you start taking CC-220 and each time you get 
a new supply. This CC-220 Information Sheet does not take the place of an informed consent to 
participate in clinical research or talking to your study doctor or healthcare provider about your 
medical condition or your treatment.  
What is the most important information I should know about CC-220?
1. CC-220 may cause birth defects (deformed babies) or death of an unborn baby. CC 220 is 
similar to the medicine thalidomide. It is known that thalidomide causes life threatening birth 
defects. CC-220 was found to cause birth defects in experimental animals (rat and rabbit). CC-
220 has not been tested in pregnant women but may cause birth defects.
If you are a female who is able to become pregnant:
•
Do not take CC-220 if you are pregnant or plan to become pregnant
•
You must practice complete abstinence from sexual contact with a male or use two reliable, 
separate forms of effective birth control at the same time: 
-
for 28 days before starting CC-220
-
while taking CC-220 
-
during breaks (dose interruptions) of CC-220 
-
for at least 28 days after the last dose of CC-220 
•
You must have pregnancy testing done at the following times:
-
within 10 to 14 days prior to the first dose of CC-220
-
24 hours prior to the first dose of CC-220 
-
weekly for the first 28 days
-
if you have regular menstrual periods: every 28 days after the first month 
-
if you have irregular menstrual periods: every 14 days after the first month
-
if you miss your period or have unusual menstrual bleeding
-
28 days after the last dose of CC-220 (14 and 28 days after the last dose if menstrual 
periods are irregular)
•
Stop taking CC-220 if you become pregnant while taking CC-220
-
If you suspect you are pregnant at any time during the study, you must stop CC 220 
immediately and immediately inform your study doctor. Your study doctor will report all 
cases of pregnancy to Celgene Corporation.
•
Do not breastfeed while taking CC-220 and for at least 28 days after the last dose of CC-220
•
The study doctor will be able to advise you how to get additional advice on contraception.
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If you are a female not able to become pregnant:
In order to ensure that an unborn baby is not exposed to CC-220, your study doctor will confirm 
that you are not able to become pregnant.
If you are a male:
In a 9-month study in monkeys given CC-220 at doses higher than the highest dose in planned 
lupus and multiple myeloma studies in humans, male monkeys had a decrease in the amount of 
sperm producing cells. It is not known at this time if this finding can be reversed or at what time 
after start of CC-220 treatment this decrease will occur. It is not known if there might be a 
similar effect in men taking CC-220 and how this might affect their ability to father children. 
There were no observable effects in male sex organs in monkeys that received more than the 
highest dose given to humans. There were no effects of CC-220 in the sex organs of female 
monkeys. 
•
Subjects (including those who have had a vasectomy) must practice complete abstinence or 
must use a condom during sexual contact with a pregnant female or a female that can become 
pregnant:
-
While you are taking CC-220 
-
During breaks (dose interruptions) of CC-220 
-
For at least 90 days after the last dose of CC-220
•
Male subjects should not donate sperm or semen while taking CC-220, during breaks (dose 
interruptions) and for at least 90 days after the last dose of CC-220. 
•
If you suspect that your partner is pregnant any time during the study, you must immediately 
inform your study doctor. The study doctor will report all cases of pregnancy to Celgene 
Corporation. Your partner should call their healthcare provider immediately if they become 
pregnant.
2. All subjects:
•
Do not share CC-220 with other people. It must be kept out of the reach of children and 
should never be given to any other person.
•
Do not donate blood while you take CC-220, during breaks (dose interruptions) and for at 
least 28 days after the last dose of CC-220. 
•
Do not break, chew, or open CC-220 capsules at any point.
•
You will get no more than a 28-day supply of CC-220 at one time.
•
Return unused CC-220 capsules to your study doctor.
Additional information is provided in the informed consent form and you can ask your study 
doctor for more information.
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EDMS Doc. Number: 25858146 - 20867538
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Protocol CC-220-MM-001
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CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
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Appendix F:
Risk/Benefit Assessment
In the RRMM cohorts, participants have already relapsed after or been refractory to the three 
major classes of treatment in multiple myeloma: immunomodulatory drugs (IMiDs), proteasome 
inhibitors, and anti-CD38 antibodies. Clinical outcomes in patients who failed treatment with 
these drugs are poor, with a median PFS between 3 to 4 months. These patients represent a 
population with high unmet medical need and novel therapies, especially ones that can add the 
convenience of oral administration, are greatly needed by these patients.
In NDMM progress has been made in improving the overall survival of patients. The increase in 
survival has been driven by more effective combination induction regimens composed primarily
of combination regimens containing proteasome inhibitors, IMiDs, and more recently with the 
addition of a CD38-directed cytolytic antibody. However, despite a better understanding of the 
disease biology and the introduction of new and mechanistically different therapeutic options, 
MM is not curable with current therapies; thus, there remains a need to develop more efficacious 
and less toxic therapies for front-line treatment. IMiDs are a core component of these regimens
in NDMM, and CC-220, a more potent cereblon-modulating agent with potentially better 
immunomodulatory properties, may confer further benefit to these patients.
The safety and tolerability profile of the IMiDs lenalidomide and pomalidomide has been well 
characterized through the extensive use of these drugs in MM. Given the similar mechanism of 
action, the safety and tolerability profile of CC-220 is anticipated to have common features with 
these IMiDs. This extensive prior experience with IMiDs was used to support the design and 
safety monitoring of this study. Additionally, the study CC-220-MM-001 has required close 
monitoring of participants’ safety throughout via frequent visits during the clinical trial, and 
participants are encouraged to contact the Investigator if an intercurrent illness develops between 
study visits.
Testing for COVID-19 to inform decisions about clinical care during the study should follow 
local standard practice. The effectiveness and safety risk for the currently approved COVID-19 
vaccines in RRMM participants, who are taking the study drugs in this trial, is unknown. 
Therefore, the Investigator and participant should carefully weigh the benefit to risk ratio prior to 
making the decision to give an approved COVID-19 vaccine during the Treatment Phase of this 
study. Investigators are encouraged to contact the Sponsor Medical Monitor to discuss any 
questions related to the selection or administration of COVID-19 vaccines.
Risk Assessment 
Actual clinical risks of combination treatment are unknown but anticipated clinical risks may 
include some combination of the known clinical risks observed in each of the monotherapies and 
as noted in the IBs for CC-220, and approved, country-specific package inserts for bortezomib, 
daratumumab, carfilzomib, and dexamethasone. Human safety data, as detailed above, have 
shown all compounds to be safe and tolerable at the RP2Ds for CC-220 and at the approved 
doses and schedules of bortezomib, daratumumab, carfilzomib, and dexamethasone.
The potential risks of clinical significance and mitigation strategies associated with the use each 
of the novel combinations in this trial are presented in Table 35.
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More detailed information about the known and expected benefits and risks and reasonably 
anticipated AEs of CC-220, bortezomib, daratumumab, carfilzomib, and dexamethasone may be 
found in the respective IB or approved, country-specific package inserts for each compound.
Table 35:
Risk Assessment
Potential Risk of Clinical 
Significance
Summary of 
Data/Rationale for Risk
Mitigation Strategy
Study interventions
Hematologic toxicity (eg, 
neutropenia, anemia, 
thrombocytopenia)
CC-220 IB
Daratumumab USPI
Bortezomib USPI
Carfilzomib USPI
Exclusion Criteria (Section 4.3).
Dose modification or interruptions per guidelines in 
Section 7.3.
G-CSF, red blood cell and platelet transfusions per 
Investigator discretion.
Skin and subcutaneous tissue
toxicity (eg, rash)
CC-220 IB
Daratumumab USPI
Bortezomib USPI
Dexamethasone USPI
Exclusion Criteria (Section 4.3).
Dose modification or interruptions per guidelines in 
Section 7.3
Vascular (eg, VTE, 
hypertension)
CC-220 IB
Daratumumab USPI
Bortezomib USPI
Carfilzomib USPI
Dexamethasone USPI
Exclusion Criteria (Section 4.3).
Dose modification or interruptions per guidelines in 
Section 7.3
Hyperglycemia
CC-220 IB
Carfilzomib USPI
Dexamethasone USPI
Exclusion Criteria (Section 4.3).
Dose modification or interruptions per guidelines in 
Section 7.3
Gastroenterological toxicity 
(eg, diarrhea, nausea, 
vomiting, colitis, and 
gastrointestinal perforation)
CC-220 IB
Daratumumab USPI
Bortezomib USPI
Carfilzomib USPI
Dexamethasone USPI
Exclusion Criteria (Section 4.3).
Dose modification or interruptions per guidelines in 
Section 7.3
General disorders and 
administration site conditions 
(eg, fatigue, febrile 
neutropenia, pyrexia)
CC-220 IB
Daratumumab USPI
Bortezomib USPI
Carfilzomib USPI
Dexamethasone USPI
Exclusion Criteria (Section 4.3). 
Dose modification or interruptions per guidelines in 
Section 7.3
Increased risk of infection
CC-220 IB
Daratumumab USPI
Bortezomib USPI
Dexamethasone USPI
Dose modification or interruptions per guidelines in 
Section 7.3
Metabolism and nutrition 
disorders (eg, decreased 
appetite)
CC-220 IB
Daratumumab USPI
Bortezomib USPI
Carfilzomib USPI
Dexamethasone USP
Dose modification or interruptions per guidelines in 
Section 7.3
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Table 35:
Risk Assessment (Continued)
Potential Risk of Clinical 
Significance
Summary of 
Data/Rationale for Risk
Mitigation Strategy
Respiratory, thoracic, and 
mediastinal disorders (eg, 
ILD, pneumonitis, dyspnea)
CC-220 IB
Daratumumab USPI
Bortezomib USPI
Carfilzomib USPI
Dexamethasone USPI
Exclusion Criteria (Section 4.3). Dose modification or 
interruptions per guidelines in Section 7.3
Musculoskeletal and 
connective tissue toxicity (eg, 
pain)
CC-220 IB
Daratumumab USPI
Carfilzomib USPI
Dexamethasone USPI
Dose modification or interruptions per guidelines in 
Section 7.3
Developmental toxicity
CC-220 IB
Inclusion Criteria (Section 4.2), Exclusion Criteria 
(Section 4.3), Pregnancy Surveillance (Section 10.4), 
Pregnancy Prevention Plan (Appendix D)
Second primary malignancy
(SPM)
CC-220 IB
Exclusion Criteria (Section 4.3), SPM Surveillance 
(Section 10.7.1)
Study Procedures
Bone marrow aspirate/biopsy 
(eg, pain, infection)
Not applicable
Per institutional protocol / Investigator discretion
Phlebotomy (eg, pain, 
ecchymosis, bleeding, 
syncope, infection)
Other (if applicable)
Allergy to contrast agent (eg, 
allergic reaction or 
anaphylaxis)
Not applicable
Prophylaxis and/or treatment per institutional protocol / 
Investigator discretion
Abbreviations: AE = adverse event; G-CSF = granulocyte colony-stimulating factor; IB = Investigator’s Brochure; 
ILD = interstitial lung disease; SPM = second primary malignancy; USPI = United States Prescribing Information; 
VTE = venous thromboembolic event.
The global coronavirus disease 2019 (COVID-19) pandemic has been identified as a potential risk 
to clinical trial participants in general. Immunocompromised patient populations such as
those with MM, may be more susceptible to infections, including SARS-CoV-2 infections. In
addition, the potential impact of study treatments administration on the frequency or severity
of SARS- CoV-2 infections in participants with MM are currently unknown. Participants with
recent or acute SARS-CoV-2 infections will be excluded or delay start of treatment as defined
per Investigator. If a participant has a confirmed SARS-CoV-2 infection while on study
treatment, dose delay or interruption of study treatment is per Investigator discretion.  
Benefit Assessment 
Immunomodulatory compounds are a key component in the treatment of multiple myeloma. CC-
220 increased potency and unique pharmacokinetic properties may result in improved efficacy 
and tolerability over other cereblon-modulating agents. Although benefits may be hypothesized
based on mechanisms of action and/or preclinical observations, actual clinical benefits to patients
with RRMM have not been established. As noted previously, this population of RRMM
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CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
participants may have a median PFS of 3 to 4 months and would benefit from novel, efficacious 
therapeutics. It is expected that a large portion of the population of RRMM patients eligible for 
this trial will be amenable to treatment with a combination therapy to be evaluated within this
clinical trial that may further extend the lives of these patients. NDMM patients may have a 
benefit with the use of a more potent cereblon-modulating agent like CC-220 in commonly used 
first-line combination regimens. 
Overall Benefit/Risk Conclusion
Taking into account the measures taken to minimize risk to participants in this study, the potential 
risks identified in association with the novel therapeutic combinations defined in this protocol are 
justified by the anticipated benefits that may be afforded to participants with RRMM and 
NDMM.
The Sponsor will evaluate the risk/benefit profile of the study on an ongoing basis in consultation 
with the DEC. This evaluation will be based on all available data – with particular attention to:
(i) AEs or other safety trends in this or any other clinical study of the therapeutic agents evaluated
in this protocol whose character, severity, and/or frequency suggest that participants would be 
exposed to an unreasonable and significant risk of illness or injury; (ii) new nonclinical data
suggesting unreasonable and significant risk of illness or injury.
If such evaluation suggests that the risk/benefit profile of the study has become unfavorable to 
participants, the Sponsor will pause enrollment and/or treatment until further evaluation of data, 
and interaction with the appropriate Health Authority(ies) can take place on potential actions. Such 
actions may include (but are not limited to) study continuation, substantial amendment, or 
termination of the study.
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Celgene Signing Page
This is a representation of an electronic record that was signed electronically in Livelink.
This page is the manifestation of the electronic signature(s) used in compliance with
the organizations electronic signature policies and procedures.
UserName: 
Title:  
Date: Thursday, 06 January 2022, 01:07 PM   Eastern Daylight Time
Meaning: Approved, no changes necessary.
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EDMS Doc. Number: 25858146 - 20971704
CC-220
Summary of Changes CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
4
CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
1. One of the main purposes of this amendment is the addition of Cohort K with the goal to
investigate CC-220Dd combination regimen in subjects with newly diagnosed multiple
myeloma (NDMM) who are transplant non-eligible.
The rationale for the addition of this cohort is supported by the preclinical data showing
the synergy of this combination, the established clinical activity of combination therapy
with daratumumab and immunomodulatory compounds (IMiDs) in the NDMM setting,
and on the favorable tolerability and encouraging preliminary efficacy of CC-220 in
combination with daratumumab and dexamethasone in relapsed and refractory multiple
myeloma (RRMM). Refer to Protocol Section 1.3.13 for further details. Thus, the
addition of daratumumab to CC-220 therapy may represent a highly effective regimen in
NDMM subjects who are not eligible for autologous stem cell transplant (ASCT), and
therefore, is chosen for further investigation.
Revised sections: Protocol Summary; Section 1.3.6.4 Rationale for Dose Levels in
NDMM Cohorts J1 and K; Section 1.3.6.5 Schedule; Section 1.3.13 Rationale for
NDMM Cohorts (J1, J2 and K); Section 3.1 Study Design; Section 3.1.2 Expansion (Part
2); Figure 2; Section 3.2 Study Duration for Subjects; Section 4 Study Population;
Section 5 Table 17; Section 6.2 Treatment Period; Section 6.3 Efficacy Assessment;
Section 7.2.1.2 Part 2 (Expansion); Section 7.3 Dose Reduction and Interruption; Section
7.3.1 Table 22; Section 7.5 Method of Treatment Assignment; Section 8.3 Required
Concomitant Medications and Procedures; Section 9.1 Overview; Section 9.3 Sample
Size and Power Considerations; Section 9.8.2 Very Good Partial Response or Better
Rate; Section 10.4 Pregnancy
2.
An additional revision is the incorporation of 3 different CC-220 dose levels (1.0 mg, 1.3
mg, and 1.6 mg) in NDMM expansion Cohort J1 and newly added Cohort K.
Approximately 75 subjects (up to approximately 25 subjects per dose level) will be
enrolled. These doses were selected based on data available from both CC-220Vd
(Cohort F) and CC-220Dd (Cohort E) in subjects with RRMM. In both Cohorts F and E,
doses of CC-220 up to 1.6 mg have been investigated and considered safe and well
tolerated by the Dose Escalation Committee. Based on an additional analysis showing
clinical and pharmacodynamic activity of lower doses of CC-220 in these combinations,
doses in this interval were selected for further investigation in subjects with NDMM who
are not eligible for transplant. Refer to Protocol Section 1.3.6.4 for further details.
Revised sections: Protocol Summary; Protocol Summary Table 3; Section 1.3.6.4.
Rationale for Dose Levels in NDMM Cohorts J1 and K; Section 1.3.13 Rationale for
NDMM Cohorts (J1, J2 and K); Section 3.1 Study Design; 3.1.2 Expansion (Part 2);
Section 3 Figure 2; Section 4.1 Number of Subjects; Section 7.2.1.2. Part 2 (Expansion);
Section 7.3.1 Table 22; Section 7.5 Method of Treatment Assignment; Section 9.3
Sample Size and Power Considerations
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CC-220
Summary of Changes CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
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CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
3.
 
  
Revised sections: Protocol Summary; Section 3.1.2 Expansion (Part 2)
4.
 
 
  
Revised sections: Protocol Summary; Section 3.1.2 Expansion (Part 2)
5.
A revision was made to the laboratory exclusion criterion #6 to reflect the limited effect 
of renal function on CC-220 pharmacokinetics (PK). The role of renal impairment (RI) 
on CC-220 PK was assessed by an integrated population pharmacokinetic (PopPK) 
analysis including heathy subjects and patients with relapsed and refractory multiple 
myeloma. Creatinine clearance (CrCl: 36.2 to 234 mL/min) was not a statistically 
significant covariate in the final PopPK model and the data suggested that mild/moderate 
RI (CrCl ≥ 30 to < 90 mL/min) is unlikely to impact CC-220 PK. Additionally, based on 
the human radiolabeled absorption, distribution, metabolism, and excretion (ADME)
study, the intact CC-220 only accounted for 16% and 11% of dose in urine and feces, 
respectively, indicating the absorbed drug is extensively metabolized and excreted mostly 
as metabolites with nearly equal contribution from urinary and fecal excretion routes.
The update was made as follows: 

Exclusionary criterion #6 was modified to update the exclusionary CrCl value to <30 
mL/min (previously <45 mL/min)
Revised section: Section 4.3 Exclusion Criteria
6. A revision was made to the inclusion criterion #20 to include subjects for who ASCT is 
not planned for initial therapy.
Revised sections: Protocol Summary; Section 4.2 Inclusion Criteria
7. The protocol objectives have been updated to reflect the modifications to Cohort J1 and 
addition of Cohort K.
Revised sections: Protocol Summary; Section 2 Table 7
8. Modifications were made to existing biomarker assessments to reflect the addition of 
Cohort K.
Revised sections: Protocol Summary; Section 6.6 Biomarkers, Pharmacodynamics and 
Pharmacogenomics
9. Modifications were made to existing PK assessments to reflect the addition of Cohort K. 
Additional edits were made to provide further clarification to PK endpoints. 
Revised sections: Protocol Summary; Section 2 Table 8; Section 6.5 Pharmacokinetics; 
Section 9.11.1 Pharmacokinetic Analysis 
10. The protocol was updated to include a Risk/Benefit Assessment for CC-220.
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EDMS Doc. Number: 25858146 - 20971704
CC-220
Summary of Changes CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
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CC-220-MM-001 Amendment 10 Final: 05 Jan 2022
Added section: Appendix F
11. Language was revised to provide further clarity regarding investigational product (IP) 
supply at the end of the study.
Revised sections: Protocol Summary; Section 3.3 End of Trial; Section 13.8 Termination 
of the Study
12. The protocol was updated to reflect updated reporting for Product Quality Complaint. 
Revised section: Section 15.3 Product Quality Complaint
13. The Rationale section has been updated to include updated indications for daratumumab 
and bortezomib.
Revised sections: Section 1.3.2 Daratumumab; Section 1.3.3 Bortezomib
14. The Permitted Concomitant Medications and Procedures section was modified to clarify 
the use of granulocyte colony-stimulating factor (GCSF) and similar hematopoietic 
growth factors to prevent or treat neutropenia. 
Revised section: Section 8.1 Permitted Concomitant Medications and Procedures
15. The amendment also includes other minor clarifications and corrections.
16. Contact details were added for the Medical Monitors 
 and
.
17. Additional references were added.
Revised section: Section 17 References
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EDMS Doc. Number: 24824423 - 20971704
CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
3
CC-220-MM-001 Amendment 9 Final: 08 Jul 2020
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
1. Subcutaneous daratumumab (SC DARA) has recently been approved in the United States 
(US) and European Union, and is anticipated to be a standard of care option in the future. 
For this reason, once the recommended Phase 2 dose (RP2D) is determined in Cohort E 
(CC-220 + daratumumab + dexamethasone [CC-220Dd]) utilizing intravenous DARA,
13 subjects will be enrolled at this dose level using SC DARA to evaluate its safety and 
tolerability when combined with CC-220 and dexamethasone. 
Revised sections: Protocol Summary; Protocol Summary Table 3; Section 1.3.2 
Daratumumab; Section 1.3.14 Schedule; Section 1.3.14 Rationale for Addition of 
Subcutaneous Daratumumab; Section 2 Table 7; Section 3.1 Study Design; Section 4.1 
Number of Subjects; Section 5 Table 10; Section 7.1 Description of Investigational 
Product(s); Section 7.2.1.1 Part 1 (Dose Escalation); Section 7.2.3 Daratumumab; Section 
7.2.3 Table 18; Section 7.2.3.1 Subcutaneous Daratumumab; Section 7.2.3.1.1
Management of Injection-site and Injection-related Reactions; Section 7.2.3.1.1.1
Injection-related Reactions; Section 7.2.3.1.1.2 Injection-related Reactions of Grade 1 or 
Grade 2; Section 7.2.3.1.1.3 Injection-related Reactions of Grade 3 or Higher; Section 
7.2.3.1.1.4 Recurrent Injection-related Reactions; Section 7.4 Overdose
2. The protocol has been updated throughout to reflect the RP2D of 1.6 mg for CC-220 plus 
DEX, based on the 18 Oct 2019 Dose Escalation Committee recommendation.  
Revised sections: Protocol Summary; Protocol Summary Table 2; Section 1.3.11 
Rationale for Cohort D Updated Design; Section 3.1 Study Design; Section 3.1.2 
Expansion (Part 2); Section 7.3.1 Table 21
3. The protocol has been updated to reflect that Cohort C monotherapy (Part 2) will no 
longer be opened. Following the 08 Nov 2019 Dose Escalation Committee review of 
Cohort A, the 1 mg dose level was deemed tolerable and it was agreed that further 
investigation of CC-220 monotherapy was more appropriate in a newly diagnosed 
multiple myeloma maintenance setting. This will be evaluated in a separate protocol.
Revised sections: Protocol Summary; Section 3.1.2 Expansion (Part 2); Section 4.1 
Number of Subjects
4. The protocol objectives have been updated to correctly reflect study cohorts.
Revised sections: Protocol Summary; Section 2 Table 7
5. A modification was made to existing biomarker assessments:
The number of subjects enrolled in Cohort D at select US sites, in which the 
pharmacodynamic (Pd) effects of CC-220 on Aiolos and Ikaros in mononuclear cells will 
be evaluated, was increased to approximately N=20.
Revised sections: Protocol Summary; Section 6.6 Biomarkers, Pharmacodynamics and 
Pharmacogenomics
6. The background section has been updated.
Revised sections: Section 1.2.1.1 Mechanism of Action of CC-220
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EDMS Doc. Number: 24824423 - 20971704
CC-220
Protocol CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
4
CC-220-MM-001 Amendment 9 Final: 08 Jul 2020
7. The International Myeloma Working Group (IMWG) Uniform Response Criteria is 
updated to the current 2016 criteria (Kumar, 2016).
Revised sections: Table 8 Study Endpoints; Section 6.3.4 Assessment of Response;
Section 9.8.3 Time to Response (TTR); Section 9.8.4 Response Duration (DoR); Section 
17 References; Appendix B International Myeloma Working Group Uniform Response 
Criteria 2016
8. The amendment also includes other minor clarifications and corrections.
9. Contact details were added for the Medical Monitors 
 and
 
.
10.
11. Additional references were added.
Revised section: Section 17 References
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EDMS Doc. Number: 24163254 - 20971704
CC-220
Summary of Changes CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
4
CC-220-MM-001 Amendment 8 Final:  04 Oct 2019
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
1. The primary purpose of this protocol amendment is the implementation of the following 
three expansion cohorts: CC-220 + dexamethasone (DEX) in relapsed refractory multiple 
myeloma subjects who have progressed following B-cell maturation antigen (BCMA)
therapy (Cohort I), CC-220 + bortezomib + DEX in newly diagnosed multiple myeloma
subjects (NDMM) not eligible for autologous stem cell transplantation (ASCT) (Cohort 
J1), and CC-220 + bortezomib + DEX in NDMM subjects eligible for ASCT (Cohort J2).
Accordingly, the study title is revised to “A Phase 1B/2A Multicenter, Open-label, Dose-
escalation Study to Determine the Maximum Tolerated Dose, Assess the Safety, 
Tolerability, Pharmacokinetics, and Efficacy of CC-220 as Monotherapy and in 
Combination with Other Treatments in Subjects with Multiple Myeloma”. 
Revised sections: Protocol Summary; Table 1; Table 2; Table 3; Section 1.1 Disease 
Background; Section 1.3.13 Rationale for NDMM Cohorts (J1 and J2); Section 1.3.6.4 
Schedule; Section 2 Study Objectives and Endpoints; Table 7; Table 8; Section 3.1 Study 
Design; Section 3.1.2 Expansion (Part 2); Figure 2; Section 4.2 Inclusion Criteria;
Section 4.3 Exclusion Criteria; Table 14; Table 15; Table 16; Section 9.3 Sample Size 
and Power Considerations
2. The rationale for the addition of the transplant non-eligible NDMM (Cohort J1) and the 
transplant eligible NDMM (Cohort J2) is supported by the preclinical synergy data, the 
positive clinical activity of combination therapy with bortezomib and immunomodulatory 
compounds (IMiD) in the NDMM setting, and on the favorable tolerability and 
encouraging preliminary efficacy of CC-220 + DEX.
Despite a better understanding of the disease biology and the introduction of new and 
mechanistically different therapeutic options (refer to Protocol Section 1.3.13), multiple 
myeloma (MM) is not curable with current therapies; thus, there is still a need to develop 
more efficacious and less toxic treatments for front line treatment (Willenbacher, 2018). 
As described in Protocol Section 1.3.7, preclinical studies in myeloma cell lines have 
shown CC-220, like immunomodulatory compounds, to have synergistic antiproliferative 
activity in combination with bortezomib (Amatangelo, 2018). CC-220 treatment in 
combination with bortezomib also induces degradation of Aiolos and Ikaros to a greater 
depth and leads to deeper cell killing than IMiD compounds in combination with 
bortezomib. Further, in preclinical models CC-220 has been shown to induce degradation 
of Aiolos and Ikaros with faster kinetics than other IMiD compounds.
As of 15 April 2019, a total of 101 subjects were enrolled in the CC-220-MM-001 study; 
26 subjects in the Cohort A (CC-220 monotherapy, from 0.3 to 1 mg), 66 subjects in 
Cohort B (CC-220 + DEX, from 0.3 to 1.3 mg), 6 subjects in Cohort E (CC-220Dd, from 
1 to 1.1 mg), and 3 subjects in Cohort F (CC-220Vd, 1 mg). The maximum tolerated dose 
(MTD) and/or recommended Phase 2 dose (RP2D) was not yet reached in any cohort. In 
subjects receiving CC-220 + DEX, the median age was 65 years (range 33 to 79), and 
median number of prior regimens was 5 (range 2 to12). Prior therapies included
autologous stem cell transplantation (79%), lenalidomide (100%), pomalidomide (68%), 
proteasome inhibitor (100%), and CD38 monoclonal antibody (74%).  Clinical activity 
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EDMS Doc. Number: 24163254 - 20971704
CC-220
Summary of Changes CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
5
CC-220-MM-001 Amendment 8 Final:  04 Oct 2019
was observed across all CC-220 + DEX dose levels with an ORR of 32%, a clinical 
benefit rate of 49%, and a disease control rate of 85%. The ORR was 35% and 30% in 
IMiD agent-refractory and daratumumab and pomalidomide-refractory subjects, 
respectively. CC-220 + DEX showed a favorable safety profile, with Grade 3/4 
neutropenia, infections, and thrombocytopenia, occurring in 29%, 26%, and 12% of 
subjects, respectively. Grade 3/4 fatigue, neuropathy and gastrointestinal disorders 
occurred in 0%, 1% of subjects, 3% of subjects, respectively. Thus far, data generated 
from the dose finding part of the study has reported preliminary favorable efficacy and 
safety of CC-220 + DEX in heavily pretreated subjects with relapsed and refractory 
multiple myeloma (RRMM) who failed multiple prior therapies (Lonial, 2019).
Taken together, based on the preclinical synergy data, the positive clinical activity of 
combination therapy with bortezomib and IMiD compounds in the NDMM setting, and 
on the favorable tolerability and encouraging preliminary efficacy of CC-220 + DEX, the 
addition of bortezomib to CC-220 therapy may represent a  highly effective regimen in 
NDMM subjects who are eligible for ASCT and those who are not eligible for ASCT, 
and therefore, is chosen for further investigation.
Revised sections: Protocol Summary; Table 1; Table 3; Section 1.1 Disease Background;
Section 1.3.6.4 Schedule; Section 1.3.13. Rationale for NDMM Cohorts (J1 and J2);
Section 2 Study Objectives and Endpoints; Table 7; Table 8; Section 3.1 Study Design;
Section 3.1.2 Expansion (Part 2); Figure 2; Section 4.2 Inclusion Criteria; Section 4.3 
Exclusion Criteria; Table 14; Table 15; Table 16; Section 9.3 Sample Size and Power 
Considerations
3. Another major rationale for the amendment is the addition of Cohort I (CC-220 + DEX in 
RRMM subjects who have progressed following BCMA) therapy. Currently, there are 
multiple BCMA-targeted treatment modalities being investigated to treat MM, including: 
antibody drug conjugates (ADC), bispecific T-cell engagers, Chimeric Antigen Receptor 
T-cell Therapies (CAR T), bispecific and bi/trispecific antibodies, as well as cancer 
vaccines. (Shih-Feng Cho, 2018). The development of novel agents targeting BCMA is 
ongoing and data from early clinical trials have demonstrated significant anti-myeloma 
activity in heavily pre-treated RRMM subjects (Raje, 2019; Topp, 2019).
Despite encouraging results, BCMA-targeted therapy is not curative, and the vast 
majority of subjects will ultimately relapse, thus highlighting the need for effective novel 
therapies in the post-BCMA setting. Cohort I will enroll up to 40 subjects who have 
received prior BCMA-targeted therapy to explore the safety and preliminary efficacy of 
CC-220 + DEX in this patient population. As CAR T therapy is anticipated to be a 
standard of care option in the future, Cohort I targets to enroll a minimum of 40% of 
subjects with prior BCMA-targeted CAR T therapy to ensure adequate representation of 
this population.
Revised sections: Protocol Summary; Table 1; Table 3; Section 1.1 Disease Background;
Section 1.3.12 Rationale for Cohort I; Section 2 Study Objectives and Endpoints; Table 
7; Table 8; Section 3.1 Study Design; Section 3.1.2 Expansion (Part 2); Figure 2; Section 
4.2 Inclusion Criteria; Section 4.3 Exclusion Criteria; Table 14; Section 1.3.6.4 Schedule;
Section 9.3 Sample Size and Power Considerations
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EDMS Doc. Number: 24163254 - 20971704
CC-220
Summary of Changes CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
6
CC-220-MM-001 Amendment 8 Final:  04 Oct 2019
4. Several revisions are made to the study population, primarily to reflect the addition of 
Cohorts I, J1 and J2 to Part 2. 
Updates to account for the addition of Cohort I are as follows: 

Inclusion criteria #4 is amended to clarify the measurable disease criteria applicable 
for RRMM subjects. The prior myeloma regimen requirements, which are outlined in 
inclusion criteria #5, #6, #7, #8, and #18 are amended to specify RRMM cohorts 
and/or to account for the addition of Cohort I. Inclusion criteria #9 is amended to 
specify that RRMM subjects who had CAR T therapy as their last myeloma therapy 
must have documented disease progression. Clarification is added to exclusion 
criteria #13 that the 28 days or 5 half-lives washout period from treatment with an 
investigational agent is not applicable for subjects who received CAR T as last prior 
regimen.
Updates to account for the addition of Cohorts J1 and J2 are as follows: 

Additional inclusion criteria #19, #20, and #21 are incorporated to reflect diagnostic 
and measurable disease criteria for NDMM Cohorts J1 and J2. Exclusion criteria #10
and #23 are amended to account for addition of Cohorts J1 and J2.  Additional 
exclusion criteria #29 is incorporated to exclude any prior anti-myeloma therapy.
Additional revisions are made to the laboratory exclusion criterion #6 to reflect the 
expected organ and bone marrow function of the multiple myeloma patient population. 
The changes are further supported by data generated from the dose finding part of this 
study, which has reported favorable safety of CC-220 + DEX (please refer to further 
details presented in Section 1.3.13).

Updates are made to exclusion criteria #6 to amend platelet counts for subjects in Part 
2 to < 75,000/μL for subjects in whom < 50% of bone marrow nucleated cells are 
plasma cells; otherwise platelet count <50,000/μL. Creatinine clearance requirements 
are updated from 50 ml/min to 45 ml/min.
Other changes include inclusion criteria #11 and #12 contraception requirements for 
bortezomib which were updated to align with the latest Velcade® prescribing information
and to include Cohorts J1 and J2. A clarification is made to the cardiac history in
exclusion criteria #26.
Revised sections: Protocol Summary; Table 1; Section 4.2 Inclusion Criteria; Section 4.3 
Exclusion Criteria
5. Primary, secondary, and exploratory objectives and endpoints are updated primarily to 
reflect the addition of the NDMM cohorts. The study endpoint table is modified to reflect 
the addition of a ≥Very Good Partial Response rate secondary endpoint. Additional minor 
modifications were made to objectives and endpoints to specify applicability to certain 
cohorts.  
Revised section: Protocol Summary; Section 2 Study Objectives and Endpoints; Table 7;
Table 8; Section 6.6 Biomarkers, Pharmacodynamics and Pharmacogenomics; Section 
9.8.2 Very Good Partial Response or Better Rate
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EDMS Doc. Number: 24163254 - 20971704
CC-220
Summary of Changes CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
7
CC-220-MM-001 Amendment 8 Final:  04 Oct 2019
6. The number of planned subjects is updated primarily to reflect the addition of Cohorts I, 
J1, and J2.
Up to 40 total subjects may be enrolled to Cohort I. 
Approximately 100 total subjects (50 subjects each) may be enrolled to Cohorts J1 and 
J2. Sample size assumptions are further described in Protocol Section 9.3.
Revised sections: Protocol Summary; Section 1.3.12 Rationale for Cohort I; Section 
1.3.13 Rationale for NDMM Cohorts (J1 and J2); Section 3.1.2 Expansion (Part 2);
Section 4.1 Number of Subjects; Section 9.3 Sample Size and Power Considerations
7. Response assessment requirements during treatment period is amended to specify that 
subjects in J1 will be followed every cycle for the first 2 years and thereafter, every 
3 months until Progressive disease (PD) or a until a subsequent myeloma regimen has 
been started. Subjects in Cohort J2, following induction, ASCT with or without 
maintenance, will be followed for response assessment during the Post-Treatment 
Response follow-up every 3 months until PD or until a subsequent anti-myeloma regimen 
has been started.
End of treatment visit is amended to specify for subjects in Cohort J2 who will not 
undergo an ASCT for whatever reason, an end of treatment (EOT) Visit should be 
performed. For those subjects in Cohort J2 who undergo an ASCT, the EOT Visit should 
be performed three months after the transplant.  
Follow-up criteria for Cohort J1 is added to include every cycle for the first 2 years and 
thereafter, every 3 months until PD or a until a subsequent myeloma regimen has been 
started. Follow-up criteria for Cohort J2 is added to include subject follow-up for 
response assessment following induction, ASCT with or without maintenance every 
3 months until PD or until a subsequent anti-myeloma regimen has been started whereby 
a Post-Treatment Response Follow Up Discontinuation visit will be performed. 
Long-term follow-up criteria in Part 2 is amended to include Cohort I.
Revised sections: Protocol Summary; Table 14; Table 15; Table 16; Section 3.1 Study 
Design; Section 3.2 Study Duration for Subjects; Section 6.2 Treatment Period; Section 
6.2.1 End of Treatment Visit; Section 6.2.3 Post Treatment Response Assessment;
Section 6.2.4 Long-term Follow-up; Section 6.3 Efficacy Assessment; Section 6.3.3 
Extramedullary Plasmacytoma Assessments; Section 6.3.4 Assessment of Response
8. Table 14 is updated to include Cohort I (CC-220 + DEX in post-BCMA RRMM). 
Table 15 is created for Cohort J1 (CC-220Vd in NDMM not eligible for ASCT). 
Table 16 is created for Cohort J2 (CC-220Vd in NDMM eligible for ASCT). 
A clarification is added to Tables 9, 10, 11, 12, 13, 14 and 15 that during Post-Treatment 
Response Follow-up an extramedullary plasmacytoma (EMP) radiological assessment is 
only required every 3 months for those with a history of or clinical indication of EMPs 
only assessable radiographically.
Revised sections: Tables 9, 10, 11, 12, 13,14, 15, and 16
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CC-220
Summary of Changes CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
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CC-220-MM-001 Amendment 8 Final:  04 Oct 2019
9. The pharmacokinetic assessments section is revised to include both the sparse and 
intensive collection plan for Cohorts I, J1, and J2. 
Revised sections: Protocol Summary; Table 14; Table 15; Table 16; Section 6.5 
Pharmacokinetics
10. Several revisions are made to the existing biomarker collection plan primarily to reflect 
the addition of Cohorts I, J1, and J2. 
The bone marrow aspirate collection plan for minimal residual disease assessment is 
modified to include 6, 12, 18, and 24 months from C1D1 and yearly thereafter after 
achieving a response of VGPR or better until disease progression for Cohorts C, D, and I. 
For Cohort J1, the following bone marrow aspirate (BMA) collection plan is 
implemented: C7D1, 12, 18, 24 months from C1D1 and yearly thereafter after achieving 
a response of VGPR or better until disease progression. For Cohort J2 the following 
BMA collection plan for minimal residual disease (MRD) assessment is implemented:
C4D1 of induction or end of induction, whichever comes first, after achieving VGPR or 
better and 100 days post-ASCT.
Additional modifications are made to existing biomarker assessments to include Cohorts 
I, J1 and J2.
Revised sections: Protocol Summary; Section 6.3.1 Bone Marrow Aspirate and/or 
Biopsy; Section 6.6 Biomarkers, Pharmacodynamics and Pharmacogenomics; Table 7;
Table 8; Table 14; Table 15; Table 16; Table 17
11. Descriptions of treatment administration and schedule are modified to include Cohorts I, 
J1, and J2.  
Revised sections: Section 7.2 Treatment Administration and Schedule
12. Concomitant medications section is modified to clarify granulocyte colony stimulating 
factor (GCSF) use during the study. 
Revised sections: Section 8.1 Permitted Concomitant Medications and Procedures;
Section 8.2 Prohibited Concomitant Medications and Procedures
13. The statistical plan, sample size, and study population definitions are amended to include 
Cohorts I, J1 and J2. Verbiage describing the Bayesian continuous monitoring method to 
monitor overall response rate (ORR) for futility and stopping rules for Cohort I is 
presented. 
The definition of very good partial response or better (> VGPR) rate is added.
Revised sections: Table 30; Section 9 Statistical Considerations; Section 9.3 Sample Size 
and Power Considerations; Section 9.8.2 Very Good Partial Response or Better Rate;
9.10 Interim Analysis
14. Additional references are added. 
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EDMS Doc. Number: 24163254 - 20971704
CC-220
Summary of Changes CC-220-MM-001
Celgene Corporation
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CC-220-MM-001 Amendment 8 Final:  04 Oct 2019
Revised section: Section 17 References
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EDMS Doc. Number: 23668701 - 20971704
CC-220
Summary of Changes CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
4
CC-220-MM-001 Amendment 7 Final:  23 Apr 2019
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
1. The primary purpose of this protocol amendment is the implementation of the following
two triplet safety cohorts: CC-220 + dexamethasone (DEX) + weekly carfilzomib (CFZ)
(Cohort G1) and CC-220 + DEX + twice weekly CFZ (Cohort G2). Accordingly, the
study title is revised to “A Phase 1b/2a Multicenter, Open-label, Dose-escalation Study to
Determine the Maximum Tolerated Dose, Assess the Safety, Tolerability,
Pharmacokinetics, and Efficacy of CC-220 Monotherapy and in Combination with Other
Treatments in Subjects with Relapsed and Refractory Multiple Myeloma”. The basis for
the combination with CFZ is supported by pre-clinical and clinical data that demonstrate
the synergistic activity with proteasome inhibitors and immunomodulatory compounds.
Improved outcomes with CFZ compared to bortezomib in relapsed and refractory
multiple myeloma (RRMM) suggests the addition of CFZ to CC-220 therapy could be
highly effective in RRMM, and therefore, is chosen for further investigation.
A 3+3 dose escalation design, which is currently utilized for existing Part 1 cohorts, will
also be utilized to establish the maximum tolerated dose and/or recommended phase 2
dose (MTD/RP2D) of CC-220 when administered in combination with DEX and CFZ.
The primary objective is revised to include determination of the MTD/RP2D of CC-220
in combination with DEX and CFZ in subjects with RRMM. The secondary objectives
are also revised to include both Cohorts G1 and G2 in the evaluation of safety and in the
evaluation of preliminary efficacy. Consequently, the endpoints are modified to include
these two additional cohorts, where applicable.
Revised section: Protocol Summary, Table 1, Table 4, Section 2 Study Objectives and
Endpoints, Table 7, Table 8, Section 3.1 Study Design, Section 3.1.1 Dose Escalation
(Part 1), Section 3.1.1.2 Dose-limiting Toxicity, Figure 2, Section 4.2 Inclusion Criteria,
Table 12, Table 13, Section 4.3 Exclusion Criteria, Section 1.3.5 Carfilzomib, Section
1.3.7.2 Dose of CC-220 in Triplet Regimens (Cohorts E, F, G1 and G2), Section 1.3.7.4
Schedule, Section 1.3.8. Rationale for Choice of Combination Compounds, Section 9.3
Sample Size and Power Considerations.
2. The amendment also implements a group sequential design to evaluate the efficacy and
safety of CC-220 in combination with DEX in Cohort D. Once the RP2D is established
for Cohort B and expansion is determined by the Dose Escalation Committee (DEC), Part
2 will be initiated to further evaluate the efficacy and safety of CC-220 plus DEX in
Cohort D. This part of the study will implement a group sequential design, where a
limited number of subjects will be enrolled in Stage 1 to ensure a sufficient efficacy
signal is seen prior to potentially enrolling additional subjects in Stage 2.
The rationale for this change is supported by data generated from the dose finding part of
this study, which has reported favorable preliminary efficacy and safety of CC-220 in
combination with DEX in heavily pretreated subjects with RRMM who failed multiple
prior therapies. As of 11 January 2019, 58 subjects received CC-220 plus DEX in doses
ranging from 0.3 to 1.2 mg in Cohort B. The median age was 64.5 years (range 33–79),
and median number of prior regimens was 5 (2–12). Prior therapies included autologous
stem cell transplant (79%), lenalidomide (100%), pomalidomide (69%), proteasome
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EDMS Doc. Number: 23668701 - 20971704
CC-220
Summary of Changes CC-220-MM-001
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CC-220-MM-001 Amendment 7 Final:  23 Apr 2019
inhibitors (100%), and daratumumab (66%). Median duration of therapy was 12+ weeks 
(range 4–109). Grade 3–4 AEs were reported in 41 (72%) subjects. The most frequently 
occurring Grade 3/4 AEs included neutropenia (26%), anemia (23%), infections (19%), 
and thrombocytopenia (11%). Of the 51 efficacy-evaluable subjects, 16 achieved a partial 
response or better (31%), 26 minimal response or better (51%), and 45 achieved stable 
disease or better (88%).
For this reason, a primary objective was added for Part 2 to determine the efficacy of CC-
220 in combination with DEX in subjects with RRMM, as measured by overall response 
rate (ORR). Secondary objectives were amended to include evaluation of additional 
efficacy parameters of CC-220 in combination with DEX, including time-to-response 
(TTR), duration of response (DOR), progression-free survival (PFS), and overall survival
(OS) in subjects with RRMM. Accordingly, endpoints are modified, where applicable. 
Revised sections: Protocol Summary, Table 1, Section 1.3.12. Rationale for Cohort D 
Updated Design, Section 2 Study Objectives and Endpoints, Table 9, Section 3.1 Study 
Design, Section 3.1.2 Expansion (Part 2), Figure 2, Section 4.2 Inclusion Criteria, Section 
4.3 Exclusion Criteria, Section 9 Statistical Considerations, Section 9.10 Interim 
Analysis.
3. Several revisions are made to the study population, primarily to reflect the addition of 
Cohorts G1 and G2 and to reflect the modifications to Part 2. 
Updates to account for the addition of Cohorts G1 and G2 are as follows:

Inclusion criteria #5 is amended to specify subjects in these cohorts must also 
have 2 prior regimens. The male and female contraception requirements, which 
are outlined in inclusion criteria #11 and #12, are updated in accordance with the 
latest carfilzomib prescribing information. Exclusion criteria #10 is revised to 
account for the addition of Cohorts G1 and G2. Exclusion criteria #24, #25, #26 
and #27 are incorporated to reflect safety parameter exclusions for carfilzomib.
Updates to account for the modifications to Part 2 are as follows:

Inclusion criteria #5, #6, and #16 are modified to update the prior exposure 
requirements for Cohort D. Subjects in this cohort are now required to receive at
least three prior therapies including lenalidomide, pomalidomide, a proteasome 
inhibitor, a glucocorticoid and a CD38 antibody. Inclusion criterion #17 is added 
to require subjects in Cohort D be refractory to an immunomodulatory agent, a 
proteasome inhibitor, a glucocorticoid, and a CD38 antibody. Refractory is 
defined as disease that is nonresponsive on therapy (failure to achieve minimal 
response or development of progressive disease while on therapy) or progresses 
within 60 days of last dose. Exclusion criterion #28 is added to exclude subjects 
with prior history of treatment with gene therapy-based therapeutic for cancer or 
investigational cellular therapy for cancer or B-cell maturation antigen (BCMA)
targeted therapy from Cohorts C and D.
Other changes include the additions of exclusion criteria #23 to exclude subjects with 
acute diffuse infiltrative pulmonary and pericardial disease in accordance with the latest 
bortezomib prescribing information and exclusion criteria #11 to generally exclude 
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EDMS Doc. Number: 23668701 - 20971704
CC-220
Summary of Changes CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
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CC-220-MM-001 Amendment 7 Final:  23 Apr 2019
subjects with contraindications to other treatment regimens, as per local prescribing 
information. 
Revised sections: Protocol Summary, Table 1, Section 4.2 Inclusion Criteria, Section 4.3 
Exclusion Criteria.
4. The dose increments for all Part 1 dose escalation cohorts is modified to allow up to a
25% increase in dose from the prior dose level, as determined by the Dose Escalation 
Committee. In the present study, at doses above 0.9 mg, dosing ascends in increments of 
0.1 mg. Based on estimated pharmacokinetic (PK) parameters from this study’s data, 
historical data variability, and the less than 10% increases in dose, clinically significant 
differences in exposure are not being achieved with 0.1 mg dose escalations. In addition, 
based on the preliminary data generated from the dose finding part of the present study 
thus far, CC-220 as monotherapy and in combination with DEX appears to be generally 
well tolerated in heavily pretreated subjects with RRMM who failed multiple prior 
therapies. Therefore, based on the totality of the data, dose increases of up to 25% are 
implemented for subsequent dose level explorations. The rationale for the modification in 
dose increment increase is further detailed in in Section 1.3.7.3.
Revised section: Protocol Summary, Table 2, Table 3, Table 4, Section 1.3.7.3 Rationale 
for Dose Increments in Dose Escalation, Figure 1, Table 5, Table 6, Section 3.1.1.1 Dose 
Escalation Committee.
5. The number of planned subjects is updated primarily to reflect the addition of Cohorts G1 
and G2 and to reflect the modifications to the design of Cohort D.

Approximately 36 total subjects may be enrolled to Cohorts G1 and G2. The actual 
number of subjects will depend on the number of dose levels being tested (based on 
the occurrence of dose-limiting toxicity [DLT]) and may exceed these 
approximations.

In Cohort D, Stage 1, following the treatment of 40 subjects, an interim analysis will 
be performed to evaluate the preliminary efficacy of CC-220 plus DEX at the RP2D.
If the results from Stage 1 does not cross the futility boundary, an additional 61 
subjects may be treated to confirm the efficacy and safety of CC-220 plus DEX at the 
RP2D.
Further, the number of subjects in Cohort A is modified to 34 subjects and in Cohort B to 
72 subjects. As of 11 January 2019, the MTD/RP2D of CC-220 has not yet been reached 
at the dose levels studied in either cohort. Two DLTs, a Gr 3 lower respiratory tract 
infection and Gr 4 neutropenia, were observed in Cohort A at the 0.75 and 0.9 mg dose 
levels, respectively. One DLT of Gr 4 sepsis was observed in Cohort B at the 1.2 mg dose 
level. Consequently, 3 additional subjects were enrolled into each cohort dose level per 
the protocol DLT/MTD definition criteria. No further DLTs were observed, thus dose 
escalation in both cohorts is ongoing. The actual number of subjects in dose escalation 
part (Part 1) will depend on the number of dose levels being tested (based on the 
occurrence of DLT) and may exceed these approximations. 
Revised sections: Protocol Summary, Section 3.1.1 Dose Escalation (Part 1), Section 4.1 
Number of Subjects, Section 9.3 Sample Size and Power Considerations.
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EDMS Doc. Number: 23668701 - 20971704
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Summary of Changes CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
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CC-220-MM-001 Amendment 7 Final:  23 Apr 2019
6.
Revised sections: Protocol Summary, Section 2 Study Objectives and Endpoints, Table 7, 
Table 8, Table 14, Section 6.2 Treatment Period, Section 6.2.1 End of Treatment Visit,
 
 Section 9 Statistical Considerations, 
 
.
7. Part 2 of the study may incorporate an independent response committee (IRC) to review 
efficacy data. The IRC will review efficacy data in accordance with the IRC Charter. 
Revised sections: Protocol Summary, Section 6.3.5 Independent Response Committee 
(IRC) Assessment, Section 9.8 Efficacy Analysis.
8. The long-term follow-up criteria for Part 2 cohorts (Cohort C and Cohort D) are modified 
to include subject contact every 3 months for 5 years from the date of the last subject 
enrollment in the study, or longer if clinically indicated. Subjects will be followed to 
collect the following information: survival, subsequent anti-myeloma therapies including 
date of progression, and second primary malignancies (SPM).
 
Revised sections: Protocol Summary, Section 2 Study Objectives and Endpoints, Table 7, 
Table 8, Section 3.1 Study Design, Section 3.2 Study Duration for Subjects, Table 14, 
Section 6.2.4 Long-term Follow-up, 
 
9. Primary, secondary, and exploratory are updated to reflect the changes in the study. The 
study endpoint table is modified to reflect the appropriate timeframes for all primary, 
secondary, and exploratory endpoints.
Revised section: Protocol Summary, Section 2 Study Objectives and Endpoints, Table 7, 
Table 8, Table 9.
10. Multiple Table of Events are created to provide cohort specific information and improve 
clarity for sites. Table 9 is created for Part 1 Cohorts A (monotherapy) and B (CC-
220+DEX). Table 10 is created for Part 1 Cohort E (CC-220Dd). Table 11 for Part 1 
Cohort F (CC-220Vd) is updated to reflect relevant protocol changes. Table 12 is created 
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EDMS Doc. Number: 23668701 - 20971704
CC-220
Summary of Changes CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
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CC-220-MM-001 Amendment 7 Final:  23 Apr 2019
for Part 1 Cohort G1 (CC-220Kd). Table 13 is created for Part 1 Cohort G2 (CC-220Kd). 
Table 14 is created for Part 2 Cohort C (monotherapy) and Cohort D (CC-220+DEX).
Revised section: Tables 9, 10, 11, 12, 13, and 14.
11. Phosphate testing is now included in the chemistry panel that is utilized during the 
screening period, treatment period, and end of treatment visit.
Revised section: Section 6.1 Screening Period, Section 6.2 Treatment Period, Section 
6.2.1 End of Treatment Visit
12. A local hepatitis panel is incorporated during screening for all subjects. In addition, 
hepatitis B virus (HBV) DNA testing by polymerase chain reaction (PCR) is added to 
Cohort E subjects who have an indication for testing, as detailed in Table 10 (Table of 
Events for CC-220Dd) in accordance with updated daratumumab (DARA) safety 
information in the prescribing information (PI) and Summary of Product Characteristics
(SmPC). 
Revised section: Tables 9, 10, 11, 12, 13, and 14, Section 6.1 Screening Period, Section 
6.2 Treatment Period, Section 6.2.1 End of Treatment Visit.
13. An echocardiogram/multi-gated acquisition scan (ECHO/MUGA) is incorporated during 
screening for all subjects in Cohorts G1 and G2 in accordance with the safety 
considerations for carfilzomib.
Revised section: Table 12, Table 13, Section 6.1 Screening Period.
14. The pharmacokinetic assessments section is revised to include both the sparse and 
intensive collection plan for Cohorts G1 and G2. Additionally, the number of subjects 
undergoing intensive PK in Cohorts C and D is modified to approximately 10 subjects in 
each cohort.
Revised section: Protocol Summary, Table 12, Table 13, Table 14, Section 6.5 
Pharmacokinetics.
15. Several revisions are made to the existing biomarker collection plan to reflect the 
addition of Cohorts G1 and G2. Additional modifications are made to various timepoints 
to account for cohort specific dosing schedules. Other modifications include the removal 
of the lymphocyte panel to explore T-cell counts from Part 2.
New biomarker assessments are introduced for a subset of patients at select United States 
(US) sites. An assessment to evaluate the pharmacodynamic (Pd) effects of CC-220 on 
Aiolos and Ikaros using a novel exploratory assay is added for Cohorts B, D, F, G1, and 
G2. At one pre-identified US site, time-matched bone marrow aspirate (BMA) and whole 
blood will be collected to analyze PK/Pd in approximately 5 subjects in Cohort D.  
Lastly, an assessment
 
will be performed on approximately 20 
subjects in Cohort D. Accordingly, changes were made to the study’s exploratory 
objectives
 
. Rationale for the CAR-T cell products assay is outlined in Section 1.3.9.
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EDMS Doc. Number: 23668701 - 20971704
CC-220
Summary of Changes CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
9
CC-220-MM-001 Amendment 7 Final:  23 Apr 2019
Revised sections: Protocol Summary, Section 1.3.9 Rationale for Pharmacodynamics and 
Potential Predictive Biomarkers, Section 2 Study Objectives and Endpoints, Table 7, 
Table 8, Tables 9, 10, 11, 12, 13, and 14, Section 6.3.1 Bone Marrow Aspirate and/or 
Biopsy, Table 15, Section 6.6 Biomarkers, Pharmacodynamics and Pharmacogenomics.
16. Rationale and explanation for the DARA reflex assay is added.
Revised section: Section 6.3 Efficacy Assessment.
17. Descriptions of treatment administration, schedule and supply/sourcing are added for 
CFZ.  Section 7.2.4 is added to provide guidance on pre-infusion and post-infusion 
medications for infusion reaction prophylaxis in relation to CFZ dosing.
Revised sections: Section 7.1 Description of Investigational Product, Section 7.2 
Treatment Administration and Schedule, Section 7.2.4 Carfilzomib.
18. Table 18 clarifies that following a dose interruption, the dose of CC-220 may be 
maintained based on Investigator’s discretion if neutropenia was the only CC-220-related 
toxicity requiring a dose modification and GCSF treatments are continued. This is 
consistent with experience and practice with other drugs of class (eg, pomalidomide) 
given bone marrow involvement by disease may worsen cytopenias early in treatment. 
The use of growth factors in early cycles without dose reduction was fairly common in 
pomalidomide studies and in practice and is supported by the literature (Expert panel 
consensus statement on the optimal use of pomalidomide in relapsed and refractory 
multiple myeloma. MA Dimopoulos, X Leleu, A Palumbo, P Moreau, M Delforge, M 
Cavo, et al. Leukemia (2014) 28, 1573–1585).
Revised sections: Table 18 Dose Reduction Instructions for CC-220.
19. The text for dose level reductions for CC-220 in Part 2 is updated to clarify dose level 
reductions may be in one dose level decrease or as determined by the dose escalation 
committee. 
Revised section: Section 7.3.1 Dose Modification Instructions for CC-220, Table 19.
20. Dose modification instructions for daratumumab are updated to reflect the suggestions in 
the latest prescribing information, per PI and SmPC.
Revised section: Section 7.3.3 Dose Modification Instructions for Daratumumab, Table 
22.
21. Dose reduction and interruption instructions are added for Cohorts G1 and G2. Dose 
modification and dose level reduction instructions are added for CFZ.
Revised section: Section 7.3 Dose Reduction and Interruption, Section 7.3.5 Dose 
Modification Instructions for Carfilzomib, Table 25, Table 26.
22. Verbiage for overdose, method of treatment assignment, and investigational product 
compliance is updated to account for the addition of Cohort G1 and Cohort G2. The 
definition of overdose is detailed for all study treatments. 
Revised sections: Section 7.4 Overdose, Section 7.5 Method of Treatment Assignment, 
Section 7.8 Investigational Product Compliance 
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EDMS Doc. Number: 23668701 - 20971704
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Summary of Changes CC-220-MM-001
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CC-220-MM-001 Amendment 7 Final:  23 Apr 2019
23. The pregnancy language is updated to include CFZ.
Revised Section: Section 4.2 Inclusion Criteria, Section 10.4 Pregnancy.
24. Concomitant medications section is updated to include CFZ antiviral prophylaxis as a
required medication. A sentence was added to highlight that CYP2C19 substrates should
be utilized with caution for subjects in Cohort F (CC-220+DEX+BTZ) due to BTZ’s
effect on the CYP2C19 enzyme.
Revised section: Section 8.2 Prohibited Concomitant Medications and Procedures,
Section 8.3 Required Concomitant Medications and Procedures.
25. The statistical plan, sample size, and study population definitions are amended to include
Cohorts G1 and G2. Verbiage describing the Full Analysis population and the DLT
Evaluable population are updated. A description of the Patient Reported Outcomes
Evaluable population is presented. The definitions of overall response rate (ORR), time to
response (TTR), response duration (DoR), progression-free survival (PFS), and overall
survival (OS) are updated.
A description of the group sequential design that will be utilized for Cohort D is
presented. An interim analysis in Cohort D is described.
Revised section: Section 9 Statistical Considerations.
26. Additional references are added.
Revised section: Section 17 References.
27. Additional terms are added to the Table of Abbreviations.
Revised section: Table 28.
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EDMS Doc. Number: 22950613 - 20971704
CC-220
Summary of Changes CC-220-MM-001
Celgene Corporation
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CC-220-MM-001 Amendment 6 Final:  27 Aug 2018
1.
JUSTIFICATION FOR AMENDMENT
1. The primary purpose of this amendment is the implementation of the following two 
triplet safety cohorts: CC-220 + daratumumab (DARA) + dexamethasone (DEX) (Cohort 
E) and CC-220 + bortezomib (BTZ) + DEX (Cohort F). A 3+3 dose escalation design, 
which is currently utilized for Cohorts A and B, will also be utilized to establish the 
MTD/RP2D of CC-220 when administered in combination with these agents. 
Consequently, the study title is revised to “A Phase 1b/2a Multicenter, Open-label, Dose-
Escalation Study to Determine the Maximum Tolerated Dose, Assess the Safety and 
Tolerability, Pharmacokinetics and Preliminary Efficacy of CC-220 Monotherapy, in 
Combination with Dexamethasone, and in Combination with Dexamethasone and 
Daratumumab or Bortezomib in Subjects with Relapsed and Refractory Multiple 
Myeloma”. The primary objective is revised as follows “determine the maximum 
tolerated doses (MTDs) and/or recommended Phase 2 doses (RP2Ds) of CC-220 as 
monotherapy (MonoT), in combination with dexamethasone (DEX) (DoubleT), and in 
combination with dexamethasone and daratumumab (C220Dd TripleT) or bortezomib 
(C220Vd TripleT) in subjects with relapsed and refractory multiple myeloma (RRMM)”. 
The secondary objectives are also revised to include TripleT cohorts in the evaluation of 
safety and in the evaluation of preliminary efficacy. Accordingly, the endpoints are
modified to include TripleT cohorts, where applicable. 
Revised sections: Protocol Summary, Section 2 Table 3 Study Objectives and Table 4 
Endpoints, Section 3.1 Study Design and Figure 1 Overall Study Design, 
2. The description of the study design is amended to incorporate Cohorts E and F into the 
dose escalation phase of the study (Part 1). The number of allowable missed doses for 
DARA and BTZ impacting criteria for dose-limiting toxicity (DLT) evaluability is
defined for these new cohorts. It is also clarified that the determination of RP2D may be 
based on safety, pharmacokinetic (PK), biomarker, and preliminary efficacy, as 
applicable.
Revised sections: Protocol Summary, Section 3.1 Study Design and Figure 1 Overall 
Study Design
3. Several revisions are made to the study population, primarily to reflect the 
implementation of TripleT cohorts. The number of planned subjects is updated
accordingly. Inclusion Criterion #5 is modified to allow subjects who have received at 
least 1 prior regimen into Cohort F. Inclusion Criterion #4 is modified to include subjects 
with light chain multiple myeloma without measurable disease in the serum or urine: 
serum immunoglobulin free light chain ≥ 10 mg/dL (100 mg/L) and abnormal serum 
immunoglobulin kappa lambda free light chain ratio. Exclusion Criteria # 20, 21, and 22 
are added to reflect safety parameter exclusions for Cohort E. Additionally, Inclusion 
Criteria # 11, 12, 13, and 14 and Exclusion Criteria # 5, 10, and 11 were revised, 
primarily to account for the addition of the TripleT cohorts. 
Revised sections: Protocol Summary, Section 4.1 Number of Subjects, Section 4.2 
Inclusion Criteria, Section 4.3 Exclusion Criteria
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Summary of Changes CC-220-MM-001
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CC-220-MM-001 Amendment 6 Final:  27 Aug 2018
4. Multiple myeloma epidemiology data is updated to include incidence and mortality data 
from 2016.
Revised section: Section 1.1 Disease Background
5. In Section 1.3.3, the background information on DARA is updated to include the latest 
regulatory approvals in the United States (US) and in the European Union (EU) and to 
reflect the Darzalex® Prescribing Information (PI) for the US and Summary of Product 
Characteristics (SmPC) for the EU.
Revised section: Section 1.3.3 Anti-CD38 Therapy
6. Section 1.3.4 is added to provide background information on BTZ from the Velcade® PI 
for the US and SmPC for the EU.
Added section: Section 1.3.4 Bortezomib
7. The rationale for the starting dose of CC-220 in TripleT cohorts and for the 28-day cycle 
in Cohort E and the 21-day cycle in Cohort F is added.  
Revised section: Section 1.3.6 Rationale for Dose, Schedule and Regimen Selection
8. The rationale for the choice of combination of CC-220 with DEX and DARA or BTZ is 
added. Details from preclinical data in conjunction with data supporting the clinical 
activity of DARA and BTZ with IMiDs (immunomodulatory compounds) combination 
therapy are provided.
Revised section: Section 1.3.7 Rationale for Choice of Combination Compounds
9. Revisions are made to the rationale for pharmacodynamics and potential predictive 
markers section to include CD38 as a biomarker for further exploration in this study. 
Revised section: Section 1.3.8 Rationale for Pharmacodynamics and Potential Predictive 
Biomarkers
10. Table 5 (Table of Events) is modified to include Cohort E. Table 6 is created to reflect 
assessments on a 21-day schedule for Cohort F. Additionally, a Post-Treatment Response 
Follow-up phase is added to the Table of Events to outline the continued collection of 
response assessments in subjects with a minimal response (MR) or better who 
discontinue study treatment in Part 1 or Part 2 of the study for a reason other than 
progressive disease (PD) or withdrawal of consent from the study.
Revised sections: Table of Events: Tables 5 and 6 
11. The screening assessments section is updated to specify that the Celgene Medical 
Monitor or designee must be contacted if there is a discrepancy between central safety 
laboratory results and local safety laboratory results. Upon review of the local laboratory 
results, the Celgene Medical Monitor or designee may deem the subject eligible for the 
study if all other eligibility criteria are satisfied.  
Revised section: Section 6.1 Screening Period
12. An additional serum free light chain assay is added to Day 8 and Day 15 of Cycles 1 to 4
for Part 2 to align the current study’s analyses of this data with that of other studies.  
Revised section: Table of Events: Table 5 and Section 6.3 Efficacy Assessment
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EDMS Doc. Number: 22950613 - 20971704
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Summary of Changes CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
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CC-220-MM-001 Amendment 6 Final:  27 Aug 2018
13. The pharmacokinetic assessments section is revised to include the sampling plan for 
Cohorts E and F, as well as to provide revisions and clarifications to the existing 
sampling plan for Cohorts C and D for both sparse and intensive collection. 
Revised sections: Protocol Summary Overview of Pharmacokinetic Assessments, Table 
of Events: Tables 5 and 6, Section 6.4 Pharmacokinetics
14. The biomarker collection plan is modified to include an additional assessment for 
evaluation of the pharmacodynamic (Pd) effects of CC-220 on Aiolos and Ikaros in 
mononuclear cells with a novel exploratory assay. Further, an additional timepoint is
added at C6D15 to the existing assessments of Pd effects of CC-220 on immune cell 
populations to further observe evolution of response over time.  Additional clarifications 
are made to the blood collection time points for Cohort F which has a 21-day treatment 
cycle. Lastly, revisions and clarifications are made to existing assessments, including 
clarification of when the collection of a bone marrow aspirate (BMA) and/or bone 
marrow biopsy (BMB) is mandatory and clarification of which assessments are 
mandatory in Part 1 versus Part 2 of the study. Table 7 is added to summarize and outline 
the BMA/BMB sample collection plan.  
Revised sections: Protocol Summary Overview of Biomarkers for Pharmacodynamic 
Assessments, Table of Events: Tables 5 and 6, Section 6.3.1 Bone Marrow Aspirate 
and/or Biopsy, Section 6.5 Biomarkers, Pharmacodynamics and Pharmacogenomics
15. Additional strengths of CC-220 capsules are added. Details of the excipients of the gel
formulation have been removed to allow more flexibility in usage of a different capsule 
formulation.
Revised sections: Protocol Summary and Section 7.1 Description of Investigational 
Product(s)
16. Descriptions of treatment administration; schedule and supply/sourcing are added for 
DARA and BTZ.  Table 8 is added to provide guidance on pre-infusion and post-infusion 
medications for infusion reaction prophylaxis in relation to DARA dosing. Table 9 
provides conversion for glucocorticoid doses to aid with the various glucocorticoids that 
may be used for pre-infusion and post-infusion across different institutions.  
Revised sections: Section 7.1 Description of Investigational Product(s) and Section 7.2 
Treatment Administration and Schedule
17. Dose reduction and interruption instructions are added for Cohorts B, D, E and F. Criteria 
for dose delay and guidance for DARA-related toxicity management are provided. Dose
modification and dose level reductions are also added for BTZ. A footnote was added to 
the dose modification table for CC-220 to clarify that dose modification instructions are 
not applicable for > Grade 3 Second Primary Malignancies, where dosing modification is 
at discretion of the Investigator.
Revised section: Section 7.3
18. Verbiage for overdose, method of treatment assignment, investigational product
compliance, and adverse events has been updated to account for the addition of Cohort E 
and Cohort F. 
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EDMS Doc. Number: 22950613 - 20971704
CC-220
Summary of Changes CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
6
CC-220-MM-001 Amendment 6 Final:  27 Aug 2018
Revised sections: Section 7.4 Overdose, Section 7.5 Method of Treatment Assignment, 
Section 7.8 Investigational Product Compliance, Section 10 Adverse Events
19. The pregnancy language has been updated to include DARA and BTZ.
Revised Section: Section 10.4 Pregnancy
20. Concomitant medications section has been updated to include DARA pre-infusion and
post-infusion and antiviral prophylaxis as required medications. Table 17 is added to
outline the list of medications that are CYP3A4/5 strong inhibitors and inducers. A
sentence was also added to highlight that antibiotics (including prophylaxis use) may be
administered.
Revised section: Section 8 Concomitant Medications and Procedures
21. The statistical plan, sample size and study population definitions are amended to include
Cohorts E and F.  Further, the verbiage describing the exploratory analyses was
simplified to indicate details will be presented in the statistical analysis plan.
Revised section: Section 9.2 Study Population Definitions, Section 9.3 Sample Size and
Power Considerations and Section 9.11.2 Exploratory Analysis
22. Additional terms were added to the Table of Abbreviations.
Revised section: Section 18, Table 18
23. Additional references are added to Section 17 References.
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EDMS Doc. Number: 22621318 - 20971704
CC-220
Summary of Changes CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
3
CC-220-MM-001 Amendment 5 Final:  04 Apr 2018
1.
JUSTIFICATION FOR AMENDMENT
1. The primary purpose of this amendment results from preliminary data reported by the 
Celgene Translational Development team showing changes of T lymphocytes at the 
higher doses of CC-220. Consequently, an additional exploratory objective, “To evaluate 
dose-related immune effects of CC-220”, has been added to the protocol. To support this 
objective, a lymphocyte panel containing CD4/CD8 counts will be added to the already 
scheduled hematology sampling. An additional hematology sample will be drawn on Day 
15 of each cycle from Cycle 5 onward. No additional blood will be required at each 
sampling.
Revised sections: Protocol Summary Exploratory Objectives, Overview of 
Biomarkers for Pharmacodynamic Assessments, Section 1.3.7, Section 2 Table 2, 
Section 2 Table 3, Section 5 Table 4, Section 6.1, Section 6.5, Section 9.11.2
2. To further understand the association between response and residual disease status, 
another exploratory objective has been added, “In Part 2 of the study, to explore minimal 
residual disease (MRD) in subjects who achieve a very good partial response (VGPR) or 
better and its correlation to clinical outcome measures”. To support this objective, all 
subjects enrolled in Part 2 of the study will have a Screening bone marrow aspirate
sample taken and stored. If the subject achieves a VGPR or better, another bone marrow 
aspirate sample will be taken and the two samples then analyzed.  If a subject achieves a 
MRD negative state, a bone marrow aspirate sample will be collected every six months 
until progression of disease (PD) to determine the duration of the MRD negative state. A 
rationale for MRD assessments has been added.
Revised sections: Protocol Summary Exploratory Objectives, Protocol Summary 
Overview of Key Efficacy Assessments, Protocol Summary Overview of Biomarkers for 
Pharmacodynamic Assessments, Section 1.3.9, Section 2 Table 2, Section 2 Table 3, 
Section 5 Table 4, Section 6.1, Section 6.2, Section 6.3.1, Section 6.5, Section 9.11.2
3. An existing exploratory objective has been edited to include immune activation/
exhaustion markers and cytokines.
Revised sections: Protocol Summary Exploratory Objectives, Section 2 Table 2, Section 
2 Table 3, Section 9.11.2
4. Cytogenetic data is collected at Screening for all subjects enrolled. These data are 
reported by local labs at the investigative sites. To enable consistent and complete results, 
a central laboratory will be used for this analysis.
Revised sections: Section 5 Table 4, Section 6.3.1
5. A rational for cytogenetic assessments has been added.
Revised section: 1.3.8
6. The section Overview of Biomarkers for Pharmacodynamic Assessments has been 
expanded to provide greater clarity of what markers are being studied and the sample 
collection time points:
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EDMS Doc. Number: 22621318 - 20971704
CC-220
Summary of Changes CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
4
CC-220-MM-001 Amendment 5 Final:  04 Apr 2018
Revised sections: Protocol Summary Overview of Biomarkers for Pharmacodynamic 
Assessments, Section 6.5
7. The following statement was added to assist investigator’s in the management of dosing
their elderly subjects greater than 75 years with dexamethasone, “Subjects who surpass
the age of 75 years while on treatment may be switched to the 20 mg once daily (QD)
dosage based on the investigator’s best judgement”.
Revised sections: Protocol Summary, Section 1.3.5.3, Section 3.1, Section 7.2.1, Section
7.2.2
8. References have been updated to support the new objectives and additional text for the
rational of cytogenetic assessment.
Revised section: Section 1.3.7 Section 1.3.8, Section 1.3.9, Section 17
9. The eligibility criteria regarding contraception have been updated in line with the current
Pregnancy Prevention Plan.
Revised section: Section 4.2 Inclusion Criteria #11 and #12
10. Additional information has been provided on the prescribing information for
dexamethasone.
Revised section: Section 7.1
11. The Method of Treatment Assignment has been edited to provide a more efficient
process.
Revised section: Section 7.5
12. The Concomitant Medications and Procedures was updated to include analgesics,
antihistamines and/or antibiotic medications for use during the study at the discretion of
the investigator.
Revised section: Section 8
13. The Prohibited Concomitant Medications and Procedures was updated to provide further
information of prohibited medications that are strong inhibitors or inducers of CYP3A/5.
Revised section: Section 8.2
14. A new section was included to provide sites with information regarding product quality
complaints
Revised section: Section 15.3
The amendment also includes other minor clarifications or corrections:

The Study Design of Part 2 (Expansion) section has been corrected to include dosing
with dexamethasone in Cohort D.

Revised section: Protocol Summary

A label of cohort study treatment was added to Part 2 of Table 1.

Revised section: Protocol Summary
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EDMS Doc. Number: 22621318 - 20971704
CC-220
Summary of Changes CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
5
CC-220-MM-001 Amendment 5 Final:  04 Apr 2018

Timeframes have been added to all study endpoints.

Revised section: Section 2 Table 3

A sentence was corrected to indicate all subjects with a minimal response or better 
who discontinue study treatment for a reason other than PD will be followed for 
response assessment every 28 days until PD or a new myeloma regimen has been 
started. 

Revised sections: Protocol Summary, Sections 3.1, 3.2

A sentence was edited to provide clarity regarding the need to record all local tests 
that determined a dose interruption and/or reduction of study treatment.

Revised section: Section 6.1

Within the section of Efficacy Analysis, a subsection was relabeled for greater clarity.

Revised section: 9.8.1

Additional abbreviations were added to the Table of Abbreviations

Revised sections: Section 18 Table 9, Section 1.3.9, Section 15.3
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EDMS Doc. Number: 22217357 - 20971704
CC-220
Summary of Changes CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
3
CC-220-MM-001 Amendment #4 FINAL: 03 Oct 2017
1.
JUSTIFICATION FOR AMENDMENT
1. The primary purpose of this amendment is to provide additional dose-level cohorts to 
extend the planned dose escalation during Part 1 of this study.  All dose levels have been 
enrolled with no safety concerns or dose-limiting toxicities observed. Further dose levels 
are necessary to determine the maximum tolerated dose (MTD) and/or recommended 
Phase 2 dose (RP2D).
Revised sections: Protocol Summary, Figure 1, Section 7.3.1 Table 6
2. In the Part 2 expansion phase of the study, subjects will be required to have been treated 
with an anti-CD38 therapy in addition to lenalidomide or pomalidomide and a 
proteasome inhibitor to be eligible for this study. These changes have been made to more 
fully understand the efficacy profile of CC-220 in patients with advanced relapsed and 
refractory multiple myeloma (RRMM).
Revised sections: Protocol Summary, Section 1.3.3, Section 4.2
3. Study endpoints have been changed to include progression-free survival and overall 
survival for the subjects enrolled in Part 2 of the study to further evaluate the preliminary 
efficacy of CC-220 as monotherapy and in combination with dexamethasone in subjects 
with RRMM. These changes have been made to more fully understand the efficacy 
profile of CC-220 in patients with advanced RRMM.
Revised sections: Protocol Summary, Section 2, Figure 1, Table 4, Section 6.2.4, Section 
9.8.4, Section 9.8.5
4. A long-term follow-up period of 2 years has been added to the length of the study to 
collect data for the overall survival endpoint and to include second primary malignancy 
(SPM) surveillance.
Revised sections: Protocol Summary, Section 3.2, Section 3.3, Figure 1, Table 4, Section 
6.2.4, Section 10.7.1
5. Several biomarker assessments that were optional in Part 1 or optional in Part 2 are now 
mandatory in both Parts 1 and 2.  Additionally 2 sample collections were added to the 
immunophenotyping study to provide greater understanding of the data being collected.
Revised sections: Protocol Summary, Section 5 Table 4, Section 6.5
6. The pregnancy section has been updated with new information released from the Global 
Risk Management Pregnancy Prevention Plan.
Revised sections: Section 10.4, Section 10.4.1, Section 10.4.2 
7. The size of the subject population to be enrolled for Cohort C and Cohort D was adjusted. 
Previously, the planned analysis would include the subjects treated at the recommended 
Phase 2 dose (RP2D) in Part 1 to be added to these cohorts in Part 2. This has been 
changed and the full planned population of subjects for analysis will be enrolled for these 
cohorts.
Revised sections: Protocol Summary, Section 3.1.2, Section 4.1, Section 9.3
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EDMS Doc. Number: 22217357 - 20971704
CC-220
Summary of Changes CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
4
CC-220-MM-001 Amendment #4 FINAL: 03 Oct 2017
The amendment also includes some other minor clarifications or corrections:

Reference to the MTD as determining the start of treatment with the RP2D in Part 2
of the study has been edited to read, MTD/RP2D since the RP2D may be achieved
based on safety, pharmacokinetic (PK) and biomarker data prior to observing the
MTD.

Revised sections: Protocol Summary, Section 1.3.5.1, Section 2, Section 9.3

Clarification of creatinine clearance methods to determine eligibility and to measure
creatinine clearance throughout the study.

Revised sections: Section 4.3, Section 6.1

Description of Investigational Product – There has been an addition of two
formulated capsules to accommodate the new dose escalating schedule.

Revised sections: Protocol Summary, Section 7.1

Additional changes were made to the statistical section to further clarify data to be
collected and analyzed.

Revised sections: Section 9.1, Section 9.4, Section 9.7

The definition of the end of trial has been adjusted to accommodate the addition of
the long-term follow-up phase of the study.

Revised sections: Protocol Summary, Section 3.3
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EDMS Doc. Number: 21745329 - 20971704
CC-220
Summary of Changes CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
3
CC-220-MM-001 Amendment 3 Final:  17 Mar 2017
1.
JUSTIFICATION FOR AMENDMENT
This amendment is primarily being generated to provide updated information available with the 
publication of the Investigator’s Brochure (IB) version 7. Section 6.3.6.1 Use in Pregnancy was 
revised to change the length of time that sexually active males must agree to use protocol-
specified contraceptive methods after the last dose of investigational product from at least 28 
days to at least 90 days after the last CC-220 dose. Changing the duration of use of contraceptive 
methods by male subjects from at least 28 days to at least 90 days after the last CC-220 dose 
aligns with no donation of sperm/semen by male subjects for at least 90 days after the last CC-
220 dose (as stated in Section 6.3.6.1). In either case, a male subject who completed a CC-220 
dose regimen presents the same risk of male-mediated developmental toxicity to the conceptus of 
a female sexual partner. The duration of at least 90 days for male contraception use is chosen 
based on the duration of one spermatogenic cycle in men and the residence time for unejaculated 
sperm. The 90-day duration for male contraception use after the last CC-220 dose would be 
considered sufficient to avoid risk to the conceptus of a female sexual partner.
In addition, this opportunity was used to include in the amendment the evaluation of the 
pharmacokinetic (PK) metabolite M12 as an exploratory objective of the study, include the 
evaluation of CC-220’s R-enantiomer CC-17195 in the PK analysis, to more accurately address 
the assessment of duration of response study endpoint, insert regulatory review changes 
requested by the Medicines and Healthcare Products Regulatory Agency (MHRA), changes to 
the inclusion and exclusion criteria, change to the timing of the electrocardiogram (ECG) at 
steady state and to generally bring greater clarity and consistency to some sections. 
Significant changes included in this amendment are summarized below:

Inclusion of the PK metabolite M12 was added as an exploratory objective of the 
study
Revised sections: Protocol Summary, Table 2: Study Objectives, Table 3: Study Endpoints,
Section 6.4 Pharmacokinetics, and Section 9.9.2 Exploratory Analysis

Clarification of the duration of response endpoint assessment
To address the duration of response endpoint, all subjects with a minimal response (MR) or 
better who discontinue study treatment in Part 1 or Part 2 of the study for a reason other than 
progressive disease (PD) will be followed for response assessment every 28 days until PD or a 
new myeloma regimen has been started. 
Revised sections: Protocol Summary, Section 3.1 Study Design, Section 3.2 Study Duration for 
Subjects, Table 4: Table of Events and Section 6.3.4 Assessment of Response
Added section: Section 6.2.3 Post Treatment Response Assessment

Removal of specific information regarding clinical experience
The development of CC-220 is a dynamic process with ongoing studies resulting in changes to 
data. Consequently, the specific information about studies has been deleted and readers are 
referred to the IB for detailed and current information. Dose and safety summaries from these 
studies are still available in Section 1.3.4.1.
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EDMS Doc. Number: 21745329 - 20971704
CC-220
Summary of Changes CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
4
CC-220-MM-001 Amendment 3 Final:  17 Mar 2017
Revised sections: Section 1.2.1.5 Clinical Experience and Section 1.3.4.1 Dose 

Change to the Table of Events
The protocol includes an ECG assessment at Cycle 1 Day 7 after the first dose at steady state. 
This assessment has proven to be burdensome to the subjects who have to make a trip to the 
investigative site for the sole purpose of an ECG. Consequently, after consultation with the 
pharmacokineticist and the United States (US) Food and Drug Administration (FDA), the 
assessment has been moved to Cycle 1 Day 8 after the first dose at steady state. This will 
eliminate the need for the subject to make an additional trip to the investigative site and provide 
the safety data intended for this assessment. 
Revised section: Table 4: Table of Events

Change to Inclusion Criteria
o
A correction was made to inclusion criterion number 13. Subjects must agree to 
refrain from donating blood while on CC-220, during dose interruptions and for at 
least 28 days following the last dose of CC-220. The previous version stated 90 
days.
Revised section: Section 4.2 Inclusion Criteria

Changes to the Exclusion Criteria
o
The exclusion criterion (number 6) prohibiting a subject from participating in the 
study if their hemoglobin is <8 g/dL (<4.9 mmol/L) was removed since it is 
widely acknowledged that anemia is a hallmark of advanced multiple myeloma, 
the population being tested in this study. Further, anemia is not a dose-limiting 
toxicity in this study. Other sections were adjusted based on this change (eg, 
permitted and prohibited medications)
Revised sections: Section 4.3 Exclusion Criteria, Section 6.1 Screening Period, Section 8.1
Permitted Concomitant Medications and Procedures, and Section 8.2 Prohibited Concomitant 
Medications and Procedures
o
The exclusion criterion (number 13) prohibiting subjects from participating in the 
study if they have been treated with an investigational agent within 28 days or 5 
half-lives (whichever is longer) of initiating IP has been clarified so that the term 
“investigational” is understood to be an agent being studied and for which the 
safety profile is not well developed.  This differs from a commercially available 
agent that has been developed and has a known safety profile.
Revised section: Section 4.3 Exclusion Criteria
o
The exclusion criterion (number 16) has been edited to include grapefruit, St. 
John’s Wort or related products within two weeks (changed from one week) prior 
to dosing and during the course of the study. This change is subsequent to a drug-
drug interaction (DDI) study that showed that exposures of CC-220 change with 
alterations in CYP3A4. This change aligns with other studies being conducted 
with CC-220 in other indications. 
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EDMS Doc. Number: 21745329 - 20971704
CC-220
Summary of Changes CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
5
CC-220-MM-001 Amendment 3 Final:  17 Mar 2017
Revised sections: Section 4.3 Exclusion Criteria and Section 8.2 Prohibited Concomitant 
Medications and Procedures

Timing of pregnancy tests has been adjusted for consistency
It was noted that the timing of pre-study pregnancy tests was not aligned with the directions 
given in Appendix D.
Revised section: Section 6.1 Screening Period

Clarification of CC-220 Dose-level Reductions
Table 6 has been expanded to clarify that subjects receiving CC-220 at higher doses are eligible 
to receive more than 2 dose reductions.
Revised section: Table 6: Dose-Level Reduction (DLR) for CC-220

Dose-limiting toxicity (DLT) Evaluable Population clarified
To make the DLT definition consistent with other sections of the protocol, this definition was 
edited to include that subjects who miss more than 4 scheduled doses of CC-220 and/or 2 doses 
of dexamethasone (DEX) during Cycle 1 for reasons other than drug-related adverse events 
(AEs) will not be included in the DLT population. 
Revised section: Section 9.2 Study Population Definitions

Regulatory Considerations - Protocol Amendments
A request has been made by the MHRA that a statement be placed in the protocol that substantial 
protocol amendments would be submitted to national Competent Regulatory Authorities (as 
applicable) and approval must be obtained before implementation of the amended version 
occurs.
Revised section: Section 13.5 Protocol Amendments

Update to the CC-220 Pregnancy Prevention Plan for Subjects in Clinical Trials
o
Based on new data published in the Investigator’s Brochure version 7, a statement 
has been added to inform subjects that CC-220 was found to cause birth defects in 
experimental animals (rat and rabbit). 
Revised section: Appendix D
o
Based on new data published in the Investigator’s Brochure version 7, a statement 
has been added to inform male subjects that a 9-month toxicity study in monkeys 
indicates that there was a decrease in the amount of sperm producing cells. It is 
not known if this is reversible or what time after the start of CC-220 treatment this 
decrease will occur. It is not known if there might be a similar effect in men 
taking CC-220 and how this will affect their ability to father children. There were 
no observable effects in male sex organs in monkeys that received more than the 
highest dose given to humans.  There were no effects of CC-220 in the sex organs 
of female monkeys. 
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EDMS Doc. Number: 21745329 - 20971704
CC-220
Summary of Changes CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
6
CC-220-MM-001 Amendment 3 Final:  17 Mar 2017
o
The requirement for male subjects to practice birth control after the last dose of
CC-220 has been increased from 28 days to 90 days to account for the duration of
one spermatogenic cycle in men and the residence time for unejaculated sperm.
Revised sections: Appendix D, Section 4.2 Inclusion Criteria
The amendment also includes minor corrections:

The text, US and Canada, has been changed to North America since Canada is not
participating in Part 1 of this study but may participate in Part 2.

Clarification was made that the R-enantiomer (and not an active metabolite) would be
analyzed as appropriate.

The contact information for the Medical Monitor was updated.

The International Conference on Harmonisation (ICH) was updated to read
International Council for Harmonisation (ICH).

Cytogenetic (FISH) testing has been changed to indicate that the analysis will be done
by a local laboratory and not by a central laboratory.

Abbreviations and Specialist Terms were updated.
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EDMS Doc. Number: 21328865 - 20971704
CC-220
Summary of Changes CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
3
CC-220-MM-001 : 25 Aug 2016
1.
JUSTIFICATION FOR AMENDMENT
This amendment is being generated to add to the prohibited concomitant medications during 
study participation medications that are strong inhibitors or inducers of CYP3A/5 as well as 
grapefruit and related products. 
In addition, the role of an Independent Expert Review has been added to the Dose Escalation 
Committee (DEC) in Part 1, and in Part 2 of the study to ensure a robust review of safety during 
the expansion phase of this study where CC-220 as monotherapy and in combination with 
dexamethasone will be used at the recommended Phase 2 dose determined in Part 1 of the study.
Significant changes included in this amendment are summarized below:

Inclusion of strong inhibitors or inducers of CYP3A/5 as well as grapefruit and
related products to the prohibited concomitant medications
Exclusion criterion 16 of the protocol states that subjects who have taken a strong inhibitor or 
inducer of CYP3A4/5 at least one week prior to dosing with the intention of taking them during
the course of the study and grapefruit or related products one week prior to dosing with the 
intention to eat these products throughout the study are excluded.  This amendment adds such 
medications, grapefruit and related products to the prohibited concomitant medications and 
procedures listed in Section 8.2.
Revised section: Section 8.2

Addition of an Independent Expert Reviewer to the study
The role of an Independent Expert Reviewer (IER) has been added to Part 1 of the study as part 
of the DEC and in Part 2 of the study to ensure subject safety. The review performed by the IER 
is dictated in the Dose Escalation Committee and Independent Expert Reviewer Charter.
Revised section: Protocol Summary, Section 3.1.1.1
Added: Section 3.1.3
The amendment also includes minor corrections:

The Clinical Research Physician representing the EU has been added to the members
of the DEC in Section 3.1.1.1.

The Independent Expert Reviewer (IER) has been added to the List of Abbreviations.
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EDMS Doc. Number: 20971242 - 20971704
CC-220
Summary of Changes CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
3
CC-220-MM-001 Amendment 1:  05 May 2016
1.
JUSTIFICATION FOR AMENDMENT
This amendment is being generated to provide greater clarity to the pregnancy prevention 
requirements for this study, clinical pharmacology, and CC-220 dosing of monotherapy cohorts 
at the time of progressive disease. Additional clarifications have been made to pharmacokinetic 
and biomarker analyses and sampling.
Significant changes included in this amendment are summarized below:

Inclusion of a contraception requirement in the protocol inclusion criteria
The protocol has been amended to add the requirement that any study subject who is a female of 
child bearing potential shall practice two forms of reliable contraception. One must be a highly 
effective method and one an additional effective (barrier) method. An additional eligibility 
criterion was added to require that both male and female subjects must follow all requirements 
defined in the Pregnancy Prevention Program.
Revised sections: Section 4.2 

Addition of the CC-220 Pregnancy Prevention Plan for Subjects in Clinical 
Trials as a fixed appendix to the protocol
Appendix D has been added to the protocol providing the full text of the CC-220 Pregnancy 
Prevention Plan for Subjects in Clinical Trials.
Revised sections: Section 4.2; Section 5; Section 6.1; Section 6.2; Section 10.4 Pregnancy; 
Appendix D

Additional pregnancy caution
A statement was added to the section on pregnancy and reporting of pregnancies, suspected 
pregnancies or exposure of any pregnant female to CC-220.
Revised section: 10.4 Pregnancy

Clarification on the dosing of CC-220 for monotherapy cohorts at the time of PD
Clarifying statements regarding the dose of CC-220 to be administered for subjects in the 
monotherapy cohorts who experience progression of disease and have the option of adding 
dexamethasone. The investigator will contact the Medical Monitor and be informed of the dose 
of CC-220 that is to be administered in this setting.
Revised sections: Protocol Summary, Study Design; Section 1.3.4.3; Section 3.1 Study Design; 
Section 7.2.1; Section 7.2.2

Table of Events has been corrected
The Table of Events has been edited to more clearly show the pharmacokinetic sampling time 
points. Footnote “i” has been edited to indicate that intensive pharmacokinetic (PK) samples will 
be drawn on Cycle 1/Day 15 along with sparse PK samples.
Revised section: Section 5, Table 4; Section 5, Table 4 footnote ‘i’
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EDMS Doc. Number: 20971242 - 20971704
CC-220
Summary of Changes CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
4
CC-220-MM-001 Amendment 1:  05 May 2016

CC-220 Food Effect
A statement was added to indicate that there is no food effect associated with CC-220 dosing.
Revised section: Section 7.2

Characterization of the elimination half-life of CC-220
The schedule of intensive PK sampling has been altered to demonstrate the requested 
characterization of elimination half-life of CC-220. Also, changes have been made to the text to 
clarify that subjects participating in intensive PK sampling will also participate in sparse PK 
sampling.
Revised sections:  Protocol Summary; Section 5, Table 4, footnote ‘i’; Section 6.4

Addition of further PK analyses
The analyses of metabolites M12 and CC-17195 have been added to the PK parameters being 
studied in this protocol.
Revised section: Protocol Summary; Section 2, Table 3; Section 6.4 

Addition of electrocardiogram (ECG) assessments 
The Table of Events has been updated to include ECG assessments at the maximal concentration 
of CC-220 (Day 1, 3-4 hours post first dose) and after the first dose at steady state (Cycle 1/Day 
7). This is in addition to the scheduled ECGs at Screening and at End of Treatment. ECGs will 
also be conducted if clinically indicated.
Revised section: Section 5, Table 4 footnote “b”

Correction of biomarker collection time points and biomarker definition
Pharmacodynamic time points for Cycle 1 Day 1 and Cycle 1 Day 12 at 1.5 hours has been 
changed to 3 hours. The Table of Events was updated to include the phrase “BMA and/or BMB”, 
and footnote ‘f’ was revised.  Analysis definitions of biomarkers were updated. Samples for 
testing bone marrow aspirate (BMA) and bone marrow biopsy (BMB)s were adjusted. 
Revised section: Protocol Summary; Section 5, Table 4 footnote “f”; Section 6.3.1; Section 6.5
The amendment also includes several other minor clarifications and corrections:

Table 1 was revised for clarity.

Correction of footnote “c” for Table 4, Table of Events

Frequency of assessments for serum and urine immunofixation tests was corrected 
(Section 5; Table 4; Section 6.3 )

Clarification of Immunoglobulin D (IgD) and immunoglobulin E (IgE) sample 
collection (Section 6.3)

Text change in Section 3.1 to remove redundancy

Two corrections made in Section 7.5 Method of Treatment Assignment:
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EDMS Doc. Number: 20971242 - 20971704
CC-220
Summary of Changes CC-220-MM-001
Celgene Corporation
Confidential and Proprietary
5
CC-220-MM-001 Amendment 1:  05 May 2016
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An Interactive Response Technology (IRT) system will be used to track subjects 
who are assigned to participate in the intensive PK sample collection.  There is no 
substudy in this protocol.

When both cohorts are open in Part 2, the IRT will assign subjects in a 1:2 ratio.
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