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)

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