This is a phase II study to evaluate the efficacy and safety of different doses of iberdomide continuous therapy as maintenancetreatment after transplant.

This is a phase II study with two parallel cohorts of newly diagnosed multiple myeloma (NDMM) patients in at least partial response (PR) after induction with proteasome inhibitors (PIs) plus IMIDs and single or double ASCT Subjects will receive two dose levels of Iberdomide, they will be evaluated for efficacy and safety. In case, in one cohort will be registered unacceptable toxicity, a third cohort will be opened. Subjects will receive treatment until progression, intolerance or unacceptable toxicity. Subsequently subjects will be followed for 24 months. The maximum number of subjects is 130 for cohort 1 and 2, 160 in case a third cohort will be opened.

Inclusion Criteria:

• Subjects with newly diagnosed MM, requiring therapy due to the presence of CRAB symptoms or myeloma defining events and measurable disease (sPEP >0.5 g/dL and/or uPEP > 200 mg/24h and/or FLC involved > 10 mg/dL with abnormal FLC ratio) before induction therapy with a PI and IMID-containing regimen-

• Subjects with complete baseline evaluation at the time of diagnosis according to revised International Staging System (R-ISS) (cytogenetic profile, ISS and LDH)

• Subjects treated with proteasome inhibitor plus immunomodulatory drug-based induction (3-6 cycles), followed by single or double autologous stem cell transplant (ASCT) with melphalan as condItioning regimen +/- consolidation.

• Subjects within 12 months from diagnosis and 120 days after last ASCT, who achieved at least a partial response (PR) after ASCT, according to IMWG criteria

• Subjects willing and able to follow the trial procedures

• Subjects must understand and voluntary sign an ICF prior to any study related assessment/procedurs being conducted

• Age ≥18 years

• ECOG performance status 0-1

• 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 (i.e., has 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, 90 days after the last dose of cyclophosphamide, whichever is longer. Contraception requirements are detailed in Appendix H.

• 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.]

• 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 (v5.1). See Appendix I for CC-220 Pregnancy Prevention Plan for Subjects in Clinical Trials.

• Subject agree to refrain from donating blood while on iberdomide, during dose interruption and for at least 28 days following the last iberdomide dose

• Baseline values:

ANC ≥1.0 x 109/L without use of growth factors; PLTs≥75 x109/L (transfusions within 14 days from Day1 cycle 1 to achieve this cut off are not allowed); Hb >8 g/dL (transfusions within 14 days from Day1 cycle 1 to achieve this cut off are not allowed); • Life expectancy ≥ 3 months

Exclusion Criteria:

• • Systemic AL amyloidosis or plasma cell leukemia (>2.0x109/L circulating plasma cells by standard differential) or Waldenstrom's macroglobulinemia

  • Subject has known meningeal involvement of multiple myeloma
  • History of active malignancy during the past 5 years, except squamous cell and basal cell carcinomas of the skin and carcinoma in situ of the cervix or breast and incidental histologic finding of prostate cancer (T1a or T1b using the TNM [tumor, nodes, metastasis] clinical staging system) or prostate cancer that is cured, or malignancy that in the opinion of the local investigator, with concurrence with the principal investigator, is considered cured with minimal risk of recurrence within 3 years.
  • Subject with any one of the following: clinically significant abnormal electrocardiogram (ECG) findings at screening; congestive heart failure (New York Heart Association Class III or IV); myocardial infarction within 12 months prior to starting iberdomide; unstable or poorly controlled angina pectoris, including Prinzmetal variant; clinically significant pericardial disease
  • Peripheral neuropathy of ≥grade 2.
  • Subject has any concurrent severe and/or uncontrolled medical condition or psychiatric disease that is likely to interfere with study procedures or results, or that in the opinion of the investigator would constitute a hazard for participating in this study or that confounds the ability to interpret data from the study.
  • Subjects with gastrointestinal disease that may significantly alter the absorption of iberdomide
  • Subject with known history of anaphylaxis or hypersensitivity to thalidomide, lenalidomide, pomalidomide
  • Subject with known or suspected hypersensitivity to excipients contained in the formulation of iberdomide
  • Subjects has current or prior use of immunosuppressive medication within 14 days prior to starting therapy with iberdomide (exceptions are intranasal, inhaled, topical or local steroids injections; systemic corticosteroids at doses not exceeding 10 mg/day of prednisone or equivalent; steroids as premedication for hypersensitivity reactions)
  • Subject has taken a strong inhibitor or inducer of CYP3A4/5 including grapefruit, St John's wort or related products within 2 weeks prior to dosing and during the course of study
  • Subject known to test positive for HIV or have active hepatitis A, B or C
  • Subjects 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
  • Baseline lab values:

• Creatinine clearance ≤30 ml/min.

• Significant hepatic dysfunction (total bilirubin > 1.5x ULN or AST/ALT > 2.5x ULN), or > 3.0 mg/dL for subjects with documented Gilbert's syndrome unless related to myeloma

• Corrected serum calcium>13.5 mg/dL (3.4 mmol/L) • Any clinical condition at screening that would preclude subject from completing the study