Inclusion Criteria:

• Age ≥ 18 years at the time of signing the informed consent form (ICF).
• Previously untreated multiple myeloma or have received no more than one cycle of any anti-myeloma treatment regimen.
  • NOTE: Prior radiation therapy for the treatment of solitary plasmacytoma is permitted. Prior therapy with clarithromycin, DHEA, anakinra, pamidronate or zoledronic acid is permitted. Any additional agents not listed must be approved by the Principal Investigator.
• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0, 1 or 2.
• THe following laboratory values obtained ≤ 14 days prior to registration:
  • Hemoglobin ≥ 8.0 g/dL;
  • Absolute neutrophil count (ANC) ≥1000/mm^3;
  • Platelet count ≥ 75,000/mm^3;
  • Total bilirubin ≤ 1.5 x ULN (exception for Gilbert’s syndrome);
  • Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤ 2 x ULN and alkaline phosphatase ≤ 1.5 x ULN;
  • PT/INR/aPTT ≤ 1.5 x ULN OR if patient is receiving anticoagulant therapy and INR or aPTT is within target range of therapy.
  • Calculated creatinine clearance ≥ 50 ml/min using the Cockcroft-Gault formula below:
  • Cockcroft-Gault Equation:
  • Creatinine clearance for males =       (140 - age)(weight in kg)
  •                                                            (  72)(serum creatinine in mg/dL)
  • Creatinine clearance for females =    (140 - age)(weight in kg)(0.85)
  •                                                           (  72)(serum creatinine in mg/dL)
• Negative pregnancy test done ≤ 7 days prior to registration, for persons of childbearing potential only. Note: A person of childbearing potential (PCBP) is a person who:
  • has achieved menarche at some point;
  • has not undergone a hysterectomy or bilateral oophorectomy; or
  • 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:
    • Have 2 negative pregnancy tests as verified by the Investigator prior to starting study treatment and 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; AND
    • 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, and for at least 28 days after the last dose of Iberdomide (90 days after the last dose of daratumumab, 7 months after last dose of bortezomib, whichever is longer.
      • NOTE: Non-childbearing potential is defined as follows (by other than medical reasons):
        • ≥ 45 years of age and has not had menses for > 24 months.
• • Patients who have been amenorrhoeic for < 2 years without history of a hysterectomy and oophorectomy must have a follicle stimulating hormone value in the postmenopausal range upon screening evaluation.
  • Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure.
• Willingness to follow Pregnancy Prevention Program requirements:
• Persons of childbearing potential must agree to use a contraceptive method that is highly effective (with a failure rate of < 1% per year), preferably with low user dependency, during the intervention period and for at least 7 months after the last dose of study intervention. These patients must also agree not to donate eggs (ova, oocytes) for the purpose of reproduction during this period.
• Persons able to father a child must agree that during the treatment intervention period and for 6 months after the last dose of study treatment (to allow for clearance of any altered sperm), the participant will:
  • Refrain from donating sperm while on study treatment, during dose interruptions and for at least 90 days following last dose of study treatment, PLUS either:
    • Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent; OR
    • Must agree to use contraception/barrier such as a male condom (even if they have undergone successful vasectomy), and when having sexual intercourse with a person of childbearing potential who is not currently pregnant his partner will use an additional highly effective contraceptive method with a failure rate of < 1% per year.
• Provide written informed consent.
• Negative hepatitis B test (defined by a negative test for hepatitis B surface antigen [HBsAg], or antibodies to hepatitis B surface and/or core antigens [antiHBs or antiHBc).
  • NOTE: Participants with serologic findings suggestive of HBV vaccination (antiHBs positivity as the only serologic marker) AND a known history of prior HBV vaccination do not need to be tested for HBV DNA by PCR. Those who are PCR positive will be excluded from the study.
• Willingness to provide mandatory bone marrow specimens for correlative research.
• Willing and able to adhere to the study visit schedule and other protocol requirements. Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study).
• Willing 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.

Eligibility last updated 2/18/22. Questions regarding updates should be directed to the study team contact.