Iberdomide-dexamethasone Alone or in Combination With Standard MM Treatment Regimens in Transplant Ineligible Newly Diagnosed Patients.

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performance of anystudy-related procedure nor part of normal medical care, with the understanding thatconsent may be withdrawn by the patient at any time without prejudice to their futuremedical care.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 ≥65 years or younger but non-transplanteligible who requires start active treatment according to the IMWG published in 2014.
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/L (100 mg/dl), with an abnormal serum FLC ratio.
6. Patient is defined as non-frail or frail using the modified-IMWG scale (APPENDIX 5).Frailty score according to the modified-IMWG scale will be collected before startingthe treatment in order to ensure 30% of the patients are frail.
7. Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
8. Patient must be ≥ 18 years of age
9. Patient must have adequate organ function,
10. Female childbearing potential patient (FCBP) criteria: contraceptive use should beconsistent with local regulations regarding the methods of contraception for thoseparticipating in clinical studies. A female patient is eligible to participate if she is not pregnant or breastfeeding,and at least one of the following conditions applies:

• Is not a female of childbearing potential (FNCBP) OR
• Is a FCBP and
• She understands the potential teratogenic risk to the unborn child
• She understands the need for effective contraception, without interruption, 28 days before starting study treatment, throughout the entire duration ofstudy treatment, during dose interruptions and for at least 3 months afterthe 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
• She acknowledges she understands the hazards study drugs can cause to anunborn fetus and the necessary precautions associated with the use of studydrugs. The Investigator must ensure that a FCBP:
• Complies with the conditions of the pregnancy prevention plan, includingconfirmation that she has an adequate level of understanding
• Acknowledges the aforementioned requirements. A FCBP must have a negative highlysensitive serum pregnancy test (as required by local regulations) within 24 hoursbefore the first dose of study drug(s). Non-childbearing 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).

11. 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 during doseinterruptions and for at least 3 months following the last dose of iberdomide to allowfor clearance of any altered sperm:

• Understand the potential teratogenic risk if engaged in sexual activity with apregnant female or a FCBP
• 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 if the subject donates semen or sperm.
• Understand that the effects on fertility are currently unknown, therefore allfamily planning options and/or alternatives should be thoroughly discussed withthe study doctor prior to receiving study drugs.

12. 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. Patient has invasive malignancies other than disease under study, unless the secondmalignancy has been medically stable for at least 2 years and, in the opinion of theprincipal investigators, will not affect the evaluation of the effects of clinicaltrial treatments on the currently targeted malignancy. Participants with curativelytreated non-melanoma skin cancer may be enrolled without a 2-year restriction.
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 andlupus, that likely need additional steroid or immunosuppressive treatments in additionto the study treatment.
5. Pregnant or breastfeeding females.
6. Patient is simultaneously enrolled in other interventional clinical trial.
7. Received plasmapheresis within 7 days prior to the first dose of study drug.
8. Patient has received prior radiotherapy within 2 weeks of start of study therapy.Participants must have recovered from all radiation-related toxicities, not requirecorticosteroids, and not have had radiation pneumonitis. A 1-week washout is permittedfor palliative radiation (≤2 weeks of radiotherapy) to non-central nervous system (CNS) disease.
9. Patient has a known immediate or delayed hypersensitivity reaction or idiosyncraticreactions to iberdomide or drugs chemically related to iberdomide, or any of theexcipients contained in the formulation of the study treatment.
10. Patient has a known immediate or delayed hypersensitivity reaction or idiosyncraticreactions to daratumumab or drugs chemically related to daratumumab, or any of theexcipients contained in the formulation of the study treatment.
11. Participant has a known immediate or delayed hypersensitivity reaction or idiosyncrasyto other monoclonal antibodies.
12. Patient has a known immediate or delayed hypersensitivity reaction or idiosyncraticreactions to dexamethasone or drugs chemically related to dexamethasone, or any of theexcipients contained in the formulation of the study treatment.
13. Major surgery (except kyphoplasty) ≤ 4 weeks prior to initiating protocol therapy.
14. Patient has peripheral neuropathy or neuropathic pain grade ≥2, as defined by theNational Cancer Institute Terminology Criteria for Adverse Events (NCI CTC AE) Version 5.0.
15. Patient evidence of cardiovascular risk including any of the following:

• QTcF interval QTcF > 480 msec (the QT interval values must be corrected for heartrate by Fridericia's formula [QTcF])
• Evidence of current clinically significant uncontrolled arrhythmias, includingclinically significant ECG abnormalities such as 2nd degree (Type II) or 3rddegree atrioventricular (AV) block.
• History of myocardial infarction, acute coronary syndromes (including unstableangina), coronary angioplasty, or stenting or bypass grafting within six monthsof Screening.
• Class III or IV heart failure as defined by the New York Heart Associationfunctional classification system [NYHA, 1994]
• Uncontrolled hypertension, defined as an average systolic blood pressure ≥ 160mmHg or diastolic ≥ 100 mmHg despite optimal treatment.

16. Patient has 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
17. 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
18. Evidence of active mucosal or internal bleeding.
19. Any serious medical condition or psychiatric illness that would interfere inunderstanding of the informed consent form.
20. 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).
21. Patients with acute diffuse infiltrative pulmonary disease and/or pericardial disease.
22. Patients with severe chronic obstructive pulmonary disease (COPD) or asthma withforced expiratory volume in the first minute (FEV1) less than 50%.
23. History of interstitial lung disease or ongoing interstitial lung disease.
24. Patient has an active infection requiring antibiotic, antiviral, or antifungaltreatment
25. Participant has known HIV infection
26. Patient has presence of hepatitis B surface antigen (HBsAg), or hepatitis B coreantibody (HBcAb) at screening or within 3 months prior to first dose of studytreatment. aa.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 to also undergo Hepatitis C RNA testing.