Inclusion Criteria:

• Documented newly diagnosed multiple myeloma
  • At least 25% of patients accrued should be high risk as defined by IMWG or mSMART criteria.
• Patient should be deemed transplant eligible.
• Patients may not have had more than 1 cycle of prior induction therapy.
• Subjects must satisfy the following criteria to be enrolled in the study:
  • Subject is ≥ 18 years of age at the time of signing the informed consent form (ICF).
  • Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.
  • Subject is willing and able to adhere to the study visit schedule and other protocol requirements.
• Subjects must have a documented diagnosis of MM and have measurable disease defined as:
  • M-protein (serum and/or urine protein electrophoresis (sPEP or uPEP)): sPEP≥0.5 g/dL or uPEP ≥ 200 mg/24 hours and/or
  • 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
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1 or 2.
• A female of childbearing potential (FCBP) is a female who:
  • has achieved menarche at some point,
  • has not undergone a hysterectomy or bilateral salpingectomy, or
  • 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:
    • 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.
    • 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
• Male subjects must:
  • 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 [e.g. calendar, 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 he has undergone a successful vasectomy.
• 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.
• 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.
• All male and female subjects must follow all requirements defined in the Pregnancy Prevention Program.
  • Note: A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.

Exclusion Criteria:

• Subject has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study
• 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
• Subject has any condition that confounds the ability to interpret data from the study
• Subject has nonsecretory or oligosecretory multiple myeloma
• Subjects with Plasma Cell leukemia or amyloidosis (with the exception of isolated marrow involvement).
• 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) ≥ 2.5 x upper limit of normal (ULN)
  • Serum total bilirubin, direct bilirubin, and alkaline phosphatase ≥ 1.5 x ULN
  • Subjects with serious renal impairment ([CrCl] < 50 mL/min) or requiring dialysis would be excluded
• Subjects with peripheral neuropathy ≥ Grade 2
• Subjects with gastrointestinal disease that may significantly alter the absorption of CC-220
• 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
• Subject has a history of anaphylaxis or hypersensitivity to thalidomide, lenalidomide, or pomalidomide
• Contraindications to the other treatment regimens, as per local prescribing information
• 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
• 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
• Subject has any one of the following:
  • Active congestive heart failure (New York Heart Association Class III to IV), symptomatic ischemia, uncontrolled arrhythmias, screening ECG with corrected QT interval (QTc) of > 470 msec, pericardial disease, or myocardial infarction within 4 months prior to randomization.
  • Unstable or poorly controlled angina pectoris, including the Prinzmetal variant of angina pectoris
• 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)
  • Glucocorticoid therapy within 14 days prior to randomization that exceeds a cumulative dose of 160 mg of dexamethasone or equivalent dose of other corticosteroids.
  • Steroids as premedication for hypersensitivity reactions (eg, computed tomography [CT] scan premedication)
• 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
• Subject known to test positive for human immunodeficiency virus (HIV), uncontrolled or active viral hepatitis.
• Subject is unable or unwilling to undergo protocol required thromboembolism prophylaxis
• Subject is a female who is pregnant, nursing or breastfeeding, or who intends to become pregnant during the participation in the study, or who will not agree to comply with contraceptive requirements or pregnancy monitoring requirements
• Left ventricular ejection fraction (LVEF) < 40% as determined by echocardiogram (ECHO)
• Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to enrollment. Uncontrolled hypertension is defined as: where blood pressure exceeds ≥ 160 mmHg systolic or ≥ 100 mmHg diastolic when taken in accordance with the European Society of Hypertension/European Society of Cardiology 2018 guidelines