COMbination Regimens in MM Post AHCT to elimiNate MRD Utilizing IbERdomide

Inclusion Criteria:

1. Age >18 years with no upper age limit

2. Confirmation of newly diagnosed multiple myeloma (MM) with 1-2 prior regimensutilized in induction that included an immunomodulatory agent (IMiD) and aproteasome inhibitor (PI) combined or in different regimens

3. Eastern Cooperative Oncology Group (ECOG) performance status 0-2

4. Prior AHCT 100-180 days prior to initiation of protocol-directed therapy

5. MRD ≥ 10^-5 by clonoSEQ® NGS platform, determined 60-120 days after AHCT as part ofthe usual care.

6. No prior disease progression (either before or since AHCT)

7. Overall response (i.e post-AHCT compared to historical baseline prior to initiationof any therapy for MM) ≥ PR.

8. Measurable disease at the time of the initial diagnosis (i.e. prior to starting anytherapy for MM) meeting at least one of the following criteria:

• Serum monoclonal (M) protein ≥1.0 g/dl

• 200 mg of M protein/24h in the urine

• Difference between involved and uninvolved free light chain ≥10 mg/dL andabnormal kappa to lambda ratio.

9. Adequate hepatic function evidenced by AST and ALT ≤ 3 x ULN and bilirubin ≤ 1.5ULN.

10. Adequate bone marrow function evidenced by platelets ≥ 75,000 /mm3 (withouttransfusion of platelets in the prior 7 days) and absolute neutrophil count ≥ 1,000/mm3.

11. Creatinine clearance (CrCl) ≥ 40 mL/minute within 28 days prior to start of therapyeither measured or calculated using standard Cockcroft and Gault formula (availablein https://www.kidney.org/professionals/KDOQI/gfr_calculatorCoc ).

12. Females of childbearing potential (FCBP) must have two negative pregnancy tests asverified by the investigator and agree to ongoing pregnancy testing and to practicecontraception during treatment. Male subjects must agree to practice contraceptionand refrain from donating sperm during treatment.

13. In line with the higher incidence of MM in Blacks, and to address the historicalunderrepresentation of ethnical minorities in MM trials, at least 25% of theenrolled patients will be of ethnical minorities.

14. Written informed consent in accordance with federal, local, and institutionalguidelines.

Exclusion Criteria:

1. Diagnosis of amyloidosis, POEMS, Waldenstrom's macroglobulinemia, plasma cellleukemia or smoldering multiple myeloma (i.e. never evolved to active myeloma).

2. Major surgery or radiotherapy within 28 days of starting protocol-directedtreatment.

3. Acute active infection requiring treatment within 14 days of startingprotocol-directed treatment.

4. Current or prior involvement of central nervous system by multiple myeloma.

5. MM refractory to prior CD38 monoclonal antibody therapy and/or to carfilzomib (priorexposure allowed). Refractoriness here is defined as not achieving at least a PR ina regimen containing the agent or disease progression < 60 days from last dose ofthe agent.

6. Pregnant or lactating females.

7. Seropositive for hepatitis B (defined by a positive test for hepatitis B surfaceantigen [HBsAg]). Subjects with resolved infection (ie, subjects who are HBsAgnegative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/orantibodies to hepatitis B surface antigen [anti-HBs]) must be screened usingreal-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNAlevels. Those who are PCR positive will be excluded. EXCEPTION: Subjects withserologic findings suggestive of HBV vaccination (anti-HBs positivity as the onlyserologic marker) AND a known history of prior HBV vaccination, do not need to betested for HBV DNA by PCR.

8. Seropositive for hepatitis C (except in the setting of a sustained virologicresponse [SVR], defined as aviremia at least 12 weeks after completion of antiviraltherapy).

9. Unstable angina or myocardial infarction within 4 months prior to startingprotocol-directed treatment, NYHA Class II, III or IV heart failure, uncontrolledangina, history of severe coronary artery disease, severe uncontrolled ventriculararrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemiaor Grade 3 conduction system abnormalities unless subject has a pacemaker.

10. A prolongation of QT interval on screening electrocardiogram (ECG) as defined bycorrected QT interval (QTc) > 480 ms using Fridericia's QT correction formula.

11. Cerebrovascular disease manifested as prior stroke at any time or TIA in the 12months prior to initiation of therapy.

12. Uncontrolled hypertension (per investigator assessment, despite optimal medicalmanagement)

13. Diagnosis of interstitial lung disease

14. Nonhematologic malignancy within the past 3 years with the exception of a)adequately treated basal cell carcinoma, squamous cell skin cancer, or localizedthyroid cancer; b) carcinoma in situ of the cervix or breast; c) prostate cancer ofGleason Grade 6 or less with stable prostate-specific antigen levels; or d) cancerconsidered cured by surgical resection or unlikely to impact survival during theduration of the study, such as localized transitional cell carcinoma of the bladderor benign tumors of the adrenal or pancreas.

15. Significant neuropathy (Grades 3-4, or Grade 2 with pain) within 28 days prior tostarting protocol-directed treatment.

16. For regimen B - Known history of allergy to Captisol® (a cyclodextrin derivativeused to solubilize carfilzomib).

17. Contra indication or intolerance to required supportive care medications (Aspirinand Acyclovir)

18. Concomitant use of strong inhibitors or inducers of CYP3A4, P-gp, or BCRP, or BCRPsubstrate with a narrow therapeutic index, for at least 14 days or 5 half-lives (whichever is shorter). (consulthttps://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers )

19. Any other clinically significant medical disease or condition that, in theInvestigator's opinion, may interfere with protocol adherence or a subject's abilityto give informed consent Diagnosis of amyloidosis, POEMS, Waldenstrom'smacroglobulinemia.