NDMM Patients Candidates for ASCT Comparing Extended VRD Plus vs. Isa-VRD vs. Isa-V-Iberdomide

Inclusion Criteria:

1. Patient is, in the investigator's opinion, willing and able to comply with theprotocol requirements.
2. Patient must be able to understand the study procedures.
3. Patient has given voluntary written informed consent before performance of anystudyrelated procedure non part of normal medical care, with the understanding thatconsent may be withdrawn by the patient at any time without prejudice to their futuremedical care.
4. Newly diagnosed multiple myeloma patient who requires start active treatment accordingto the 2014 IMWG criteria, namely clonal bone marrow plasma cells ≥10% orbiopsy-proven bony or extramedullary plasmacytoma and any one or more of the followingmyeloma defining events: evidence of end organ damage that can be attributed to theunderlying plasma cell proliferative disorder, specifically: Hypercalcaemia, Anaemia,Renal Insufficiency, or Bone lesions (one or more osteolytic lesions on skeletalradiography, CT, or PET-CT), and any one or more of the following biomarkers: clonalBMPC% ≥60%, i/u free light ratio ≥100 or > 1 focal lesions on MRI or PET/CT) [LancetOncol. 2014;15(12): e538-e548].
5. Patient must have a measurable secretory disease defined as either serum monoclonalprotein of ≥ 0,5 g/dl or urine monoclonal (light chain) protein ≥ 200 mg/24 h. Forpatients whose disease is only measurable by serum FLC, the involved FLC should be ≥ 10mg/dL (100 mg/L), with an abnormal serum FLC ratio.
6. Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of ≤
8. Patient must be ≤ 65 years of age.
9. Patient must have adequate organ function, defined as follows:

• Absolute neutrophil count (ANC) ≥1.0 X 109/L without G-CSF use in the prior 7days
• Hemoglobin ≥8.0 g/dL (prior red blood cell (RBC) transfusion or recombinant humanerythropoietin use is permitted)
• Platelets ≥ 75 x 109/L in participants in whom <50% of bone marrow nucleatedcells are plasma cells and ≥ 50×109/L in participants in whom ≥50% of bone marrownucleated cells are plasma cells (without transfusion support or thrombopoietinreceptor agonist within 7 days before the laboratory test).
• Calcium Corrected serum calcium ≤13.5 mg/dL (≤3.4 mmol/L); or free ionizedcalcium ≤6.5 mg/dL (≤1.6 mmol/L).
• Total bilirubin ≤2 X ULN
• ALT ≤2.5 X ULN
• AST ≤2.5 X ULN
• Renal: eGFRa: ≥40 mL/min/ 1.73 m2
• Cardiac: LVEF (echo) ≥ 50%

9. Female patient: contraceptive use should be consistent with local regulationsregarding the methods of contraception for those participating in clinical studies. Afemale patient is eligible to participate if she is not pregnant or breastfeeding, andat least one of the following conditions applies:

• Is not a woman of childbearing potential (WOCBP), i.e., fertile, followingmenarche and until becoming post-menopausal unless permanently sterile. Permanentsterilization methods include hysterectomy, bilateral salpingectomy and bilateraloophorectomy OR
• Is a WOCBP and
• She understands the potential teratogenic risk to the unborn child
• She understands the need for effective contraception as stated in theprotocol, without interruption, 28 days before starting study treatment,throughout the entire duration of study treatment, during dose interruptionsand for at least 28 days after the last dose of study treatment.
• She understands and agrees to inform the Investigator if a change or stop ofmethod of contraception is needed.
• She must be capable of complying with effective contraceptive measures.
• She is informed and understands the potential consequences of pregnancy andthe need to notify her study doctor immediately if there is a risk ofpregnancy.
• She understands the need to commence study treatment as soon as it isdispensed following a negative pregnancy test.
• She understands and accepts the need to undergo pregnancy testing based onthe frequency outlined in this plan and in the Informed Consent.
• She acknowledges she understands the hazards iberdomide or lenalidomide cancause to an unborn fetus and the necessary precautions associated with theuse of study drugs. The Investigator must ensure that a WOCBP: i) Complies with the conditions of thepregnancy prevention plan, including confirmation that she has an adequate level ofunderstanding. ii) Acknowledges the aforementioned requirements. A WOCBP must have a negative highly sensitive serum pregnancy test (as required bylocal regulations) within 72 hours before the first dose of study drug. Nonchildbearing potential is defined as follows (by other than medical reasons):
• Has not achieved menarche at some point.
• Has undergone a hysterectomy or bilateral oophorectomy.
• Has been naturally postmenopausal (amenorrhea following cancer therapy does notrule out childbearing potential) for at least 24 consecutive months (ie, has hadmenses at any time in the preceding 24 consecutive months).

10. Male patient: contraceptive use should be consistent with local regulations regardingthe methods of contraception for those participating in clinical studies. Male patient is eligible to participate if he agrees to the following from the time offirst dose of study until 6 months after the last dose of iberdomide or lenalidomideto allow for clearance of any altered sperm:

• Understand the potential teratogenic risk if engaged in sexual activity with apregnant female or a WOCBP.
• Understand the need for the use of a condom even if he has had a vasectomy, ifengaged in sexual activity with a pregnant female or a FCBP
• Understand the potential teratogenic risk, so the subject should not donate semenor sperm.. Understand that the effects on fertility are currently unknown,therefore all family planning options and/or alternatives should be thoroughlydiscussed with the study doctor prior to receiving iberdomide.

11. All prior treatment-related toxicities (defined by National Cancer Institute- CommonToxicity Criteria for Adverse Events (NCI-CTCAE), version 5.0 must be ≤ Grade 1 at thetime of enrolment except for alopecia.

Exclusion Criteria:

1. Patient has a diagnosis of primary amyloidosis, monoclonal gammopathy of undeterminedsignificance (MGUS), smoldering multiple myeloma (SMM), plasma cell leukemia or activePOEMS syndrome at the time of screening.
2. Patient has had clinical evidence of central nervous system (CNS) or pulmonaryleukostasis, disseminated intravascular coagulation, or CNS multiple myeloma.
3. Prior history of malignancies, other than multiple myeloma (except for basal orsquamous cell carcinoma of the skin, carcinoma in situ of the cervix or the breast),unless the patient has been free of the disease for ≥ 5 years.
4. Any serious medical condition that places the subject at an unacceptable risk if he orshe participates in this study; subjects with conditions requiring chronic steroid orimmunosuppressive treatment, such as rheumatoid arthritis, multiple sclerosis and/orlupus, that likely need additional steroid or immunosuppressive treatments in additionto the study treatment.
5. Pregnant or breastfeeding females.
6. Men and women of reproductive potential who are not using effective contraceptivemethods (double barrier method, intrauterine device, oral contraception).
7. Patient is simultaneously enrolled in other interventional clinical trial.
8. Patient has used an investigational drug within 28 days or five half-lives, whicheveris longer, preceding the first dose of study drug.
9. Patient must not have received prior radiotherapy (except localized palliativeradiotherapy for pain, palliation or fracture) within 2 weeks of start of studytherapy. Participants must have recovered from all radiation-related toxicities, notrequire corticosteroids, and not have had radiation pneumonitis.
10. Major surgery (except kyphoplasty) ≤ 4 weeks prior to initiating protocol therapy.
11. Patient has peripheral neuropathy or neuropathic pain grade 1 with pain or ≥2, asdefined by the National Cancer Institute Terminology Criteria for Adverse Events (NCICTCAE) Version 5.0.
12. Patient evidence of cardiovascular risk including any of the following:

• Myocardial infarction within 6 months before randomization, or an unstable oruncontrolled disease/condition related to or affecting cardiac function (eg,unstable angina, congestive heart failure, New York Heart Association ClassIII-IV).
• Uncontrolled cardiac arrhythmia.
• Screening 12-lead ECG showing a baseline interval QTcF> 470 msec (exception:subjects with pacemaker).
• Patients with uncontrolled hypertension.

13. Patients who have current unstable liver or biliary disease defined by the presence ofascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices,persistent jaundice, or cirrhosis. Note: Stable chronic liver disease (includingGilbert's syndrome or asymptomatic gallstones) or hepatobiliary involvement ofmalignancy is acceptable if otherwise meets entry criteria.
14. Presence of active renal condition (infection, requirement for dialysis or any othercondition that could affect patient's safety). Participants with isolated proteinuriaresulting from MM are eligible, provided they fulfil inclusion criteria.
15. Evidence of active mucosal or internal bleeding.
16. Any serious medical condition or psychiatric illness that would interfere inunderstanding of the informed consent form.
17. Uncontrolled endocrine diseases (i.e. diabetes mellitus, hypothyroidism orhyperthyroidism) (i.e. requiring relevant changes in medication within the last month,or hospital admission within the last 3 months).
18. Patient with acute diffuse infiltrative pulmonary disease and/or pericardial disease.
19. Patient with severe chronic obstructive pulmonary disease (COPD) or asthma with forcedexpiratory volume in the first minute (FEV1) less than 50%.
20. History of interstitial lung disease or ongoing interstitial lung disease.
21. Subject has gastrointestinal disease that may significantly alter the absorption ofiberdomide and/or other oral study treatment.
22. Patient has an active infection requiring systemic antibiotic, antiviral, orantifungal treatment at the time of starting treatment.
23. Patient has known HIV infection.
24. Patient has positive hepatitis B surface antigen (HBsAg), or hepatitis B core antibody (HBcAb) at screening or within 3 months prior to first dose of study treatment.
25. Patient has positive hepatitis C antibody test result or positive hepatitis C RNA testresult at screening or within 3 months prior to first dose of study treatment. Note:Participants with positive Hepatitis C antibody due to prior resolved disease can beenrolled, only if a confirmatory negative Hepatitis C RNA test is obtained. Note:Hepatitis RNA testing is optional and participants with negative Hepatitis C antibodytest are not required.
26. Patient require concurrent administration of a strong inhibitor or inducer ofcytochrome P450 (CYP3A4/5) (including within 14 days of initiating study treatment).
27. Patient has a known immediate or delayed hypersensitivity reaction or idiosyncraticreactions to iberdomide or drugs chemically related to iberdomide.
28. Patient has a known immediate or delayed hypersensitivity reaction or idiosyncraticreactions to isatuximab or drugs chemically related to isatuximab, hypersensitivityreactions, or idiosyncratic reactions to other molecular antibodies.
29. Patient has a known immediate or delayed hypersensitivity reaction or idiosyncraticreactions to lenalidomide or dexamethasone or drugs chemically related to lenalidomideor dexamethasone.