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

1. Subject is >=18 years of age 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 at least 3 prior myeloma 
regimens.


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

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), or 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.

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 last 
dose of study treatment.

15. All male and female subjects must follow all requirements defined in the 
Pregnancy Prevention Program. 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
* >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 (*/*) ratio

20. Subjects in Cohorts J1 and K are those for who ASCT (autologous stem cell 
transplant) 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 his

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) · 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 (creatine 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 · 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 with 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
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]).