A Study to Determine Dose and Tolerability 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 (MM)

Subjects assigned to CC-220 monotherapy, who develop progressive disease (PD) will have the
option to receive DEX in addition to CC-220 after consultation with the Medical Monitor. The
dose of CC-220 will not be higher than the dose of CC-220 used in combination with
dexamethasone in Cohort B that has been determined to be safe. Progressive disease must be
confirmed in accordance with international myeloma working group (IMWG) criteria.

The starting dose of DEX will be 40 mg for subjects who are ≤75 years of age and 20 mg for
subjects who are >75 years of age, given once weekly. 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. 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. For Cohorts E and F, the starting dose level of CC-220, dose
level 1, is one dose level below the maximum dose for Cohort B that has been determined to be
safe by the dose escalation committee (DEC) at the start of enrollment for both cohorts. For
Cohort E in addition to CC-220 and DEX, daratumumab will be administered intravenously (IV)
at a 16mg/kg dose. For Cohort F in addition to CC-220 and DEX, bortezomib will be
administered subcutaneous (SC) at a 1.3mg/m2 dose.

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 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.

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.

The initiation of Part 2 will begin when the RP2D is established in Part 1 in either Cohort A
or Cohort B. Either cohort may begin once the RP2D is determined for each cohort
independently during 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 Independent Expert Reviewer will review safety data and any other data deemed relevant
so that subject safety is ensured.

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. Subjects must have a documented diagnosis of Multiple myeloma (MM) and have measurable
disease defined as:

1. M-protein (serum and/or urine protein electrophoresis (sPEP) or (uPEP): sPEP ≥0.5
g/dL or uPEP ≥200 mg/24 hours and/or

2. 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.

5. Subjects in Cohorts A to E 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

6. All subjects must have received prior treatment with at least 2 consecutive cycles of
a lenalidomide or pomalidomide-containing regimen

7. All subjects 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 (Cohort C and Cohort D), all subjects must have received prior treatment
with at least 2 consecutive cycles of an anti-CD38 therapy or an anti-CD38-containing
regimen

9. All subjects must have documented disease progression on or within 60 days from the
last dose of their last myeloma therapy

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 not had menses
at any time in the preceding 24 consecutive months) and must:

1. 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.

2. 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 or 90 days after the last dose of DARA (for Cohort E) or BTZ (for Cohort
F). 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,
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
treatment.

15. All male and female subjects must follow all requirements defined in the Pregnancy
Prevention Program (v5.1).

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 or oligosecretory 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

- 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 Upper Limit of Normal (ULN)

- Subjects with serious renal impairment (24-hour creatinine clearance [CrCl] <50
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 Cohort E), or bortezomib (for Cohort F)

11. Subject has known or suspected hypersensitivity to the excipients contained in the
formulation of CC-220, DEX, daratumumab (for Cohort E), or bortezomib (for Cohort F)

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
investigational product (IP)

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 Cohort E (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