Iberdomide, Daratumumab, Bortezomib, and Dexamethasone for Treatment of Newly Diagnosed Multiple Myeloma, IDEAL Study

Inclusion Criteria:

• Age >= 18 years at the time of signing the informed consent form (ICF)

• Previously untreated active/symptomatic multiple myeloma or have received no morethan one cycle of any anti-myeloma treatment regimen for active/symptomatic myeloma

• NOTE: Prior radiation therapy for the treatment of solitary plasmacytoma ispermitted. Prior therapy with clarithromycin, dehydroepiandrosterone (DHEA),anakinra, pamidronate or zoledronic acid is permitted. Any additional agentsnot listed must be approved by the principal investigator

• Measurable disease

• Serum M-protein ≥0.5 g/dL

• Urine M-protein ≥200 mg in a 24-hour collection

• Serum Free Light Chain level ≥ 10 mg/dL provided the free light chain ratio isabnormal

• Measurable plasmacytoma [at least one lesion that has a single diameter of ≥2cm on positron emission tomography (PET)-computed tomography (CT) scan]

• Bone marrow plasma cells≥30%

• Patients with IgA myeloma in whom serum protein electrophoresis is deemedunreliable, due to co-migration of normal serum proteins with the para proteinin the beta region, may be considered eligible as long as total serum IgA levelis elevated above normal range.

• For patients with extramedullary disease (EMD) measurable by CT or MRI or theCT portion of the PET/CT: Must have at least one lesion that has a singlediameter of ≥2 cm. Skin lesions can be used if the area is ≥2cm in at least onediameter and measured with a ruler.

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2

• Hemoglobin >= 8.0 g/dL (obtained =< 14 days prior to registration)

• Absolute neutrophil count (ANC) >= 1000/mm^3 (obtained =< 14 days prior toregistration)

• Platelet count >= 75,000/mm^3 (obtained =< 14 days prior to registration)

• Total bilirubin =< 1.5 x upper limit of normal (ULN) (Exception for Gilbert'ssyndrome) (obtained =< 14 days prior to registration)

• Alanine aminotransferase (ALT) and aspartate transaminase (AST) =< 2 x ULN andalkaline phosphatase =< 1.5 x ULN (obtained =< 14 days prior to registration)

• Prothrombin time (PT)/international normalized ratio (INR)/activated partialthromboplastin time (aPTT) =< 1.5 x ULN OR if patient is receiving anticoagulanttherapy and INR or aPTT is within target range of therapy (obtained =< 14 days priorto registration)

• Calculated creatinine clearance >= 50 ml/min using the Cockcroft-Gault formula (obtained =< 14 days prior to registration)

• Negative pregnancy test done =< 7 days prior to registration, for persons ofchildbearing potential only. Note: A person of childbearing potential (PCBP) is aperson who: 1) has achieved menarche at some point, 2) has not undergone ahysterectomy or bilateral oophorectomy, or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) forat least 24 consecutive months (i.e., has had menses at any time in the preceding 24consecutive months) and must:

• Have 2 negative pregnancy tests as verified by the Investigator prior tostarting study treatment and must agree to ongoing pregnancy testing during thecourse of the study, and after end of study treatment. This applies even if thesubject practices true abstinence from heterosexual contact. AND

• Either commit to true abstinence from heterosexual contact (which must bereviewed on a monthly basis and source documented) or agree to use, and be ableto comply with two forms of contraception: one highly effective, and oneadditional effective (barrier) measure of contraception without interruption 28days prior to starting investigational product, during the study treatment, andfor at least 28 days after the last dose of Iberdomide (90 days after the lastdose of daratumumab, 7 months after last dose of bortezomib whichever islonger).

• NOTE: Non-childbearing potential is defined as follows (by other than medicalreasons):

• >= 45 years of age and has not had menses for > 24 months

• Patients who have been amenorrhoeic for < 2 years without history of ahysterectomy and oophorectomy must have a follicle stimulating hormonevalue in the postmenopausal range upon screening evaluation

• Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation.Documented hysterectomy or oophorectomy must be confirmed with medicalrecords of the actual procedure or confirmed by an ultrasound. Tuballigation 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 thatis highly effective (with a failure rate of < 1% per year), preferably with lowuser dependency, during the intervention period and for at least 7 months afterthe last dose of study intervention. These patients must also agree not todonate eggs (ova, oocytes) for the purpose of reproduction during this period

• Persons able to father a child must agree that during the treatmentintervention period and for 6 months after the last dose of study treatment (toallow for clearance of any altered sperm), the participant will:

• Refrain from donating sperm while on study treatment, during doseinterruptions and for at least 6 months following last dose of studytreatment, PLUS either:

• Be abstinent from heterosexual intercourse as their preferred andusual lifestyle (abstinent on a long term and persistent basis) andagree to remain abstinent, OR,

• Must agree to use contraception/barrier such as a male condom (evenif they have undergone successful vasectomy), and when having sexualintercourse with a person of childbearing potential who is notcurrently pregnant his partner will use an additional highlyeffective 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 surfaceantigen [HBsAg], or antibodies to hepatitis B surface and/or core antigens [antiHBsor antiHBc)

• NOTE: Participants with resolved hepatitis B infection (i.e.., subjects who areHBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must bescreened using real-time polymerase chain reaction (PCR) measurement ofhepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excludedfrom the study.

• NOTE: Participants with serologic findings suggestive of hepatitis B virus (HBV) vaccination (antiHBs positivity as the only serologic marker) AND a knownhistory of prior HBV vaccination do not need to be tested for HBVdeoxyribonucleic acid (DNA) by polymerase chain reaction (PCR). Those who arePCR 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 protocolrequirements. Willing to return to enrolling institution for follow-up (during theActive Monitoring Phase of the study)

• Willing to refrain from donating blood while on study treatment, during doseinterruptions and for at least 28 days following the last dose of study treatment

Exclusion Criteria:

• Monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, orAL amyloidosis

• Any of the following because this study involves an agent that has known genotoxic,mutagenic and teratogenic effects:

• Pregnant persons

• Nursing persons

• Men or women of childbearing potential who are unwilling to employ adequatecontraception

• Receiving any other concurrent chemotherapy, or any ancillary therapy consideredinvestigational

• NOTE: Bisphosphonates are considered to be supportive care rather than therapyand are thus allowed while on protocol treatment

• Known to be human immunodeficiency virus (HIV) positive, known or suspected activehepatitis C infection or seropositive for hepatitis B (defined by a positive testfor hepatitis B surface antigen [HBsAg]) at screening or within 3 months prior tofirst dose of study treatment.

• NOTE: Participants with resolved hepatitis B infection (i.e.., subjects who areHBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must bescreened using real-time polymerase chain reaction (PCR) measurement ofhepatitis B virus (HBV) DNA levels. Those who are PCR positive will beexcluded.

• EXCEPTION: subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of priorHBV vaccination, do not need to be tested for HBV DNA by PCR

• Uncontrolled intercurrent illness including, but not limited to:

• Ongoing or active infection (defined as infection undergoing treatment)

• Active mucosal or internal bleeding,

• Social situations that would limit compliance with study requirements (including drug addiction)

• Known gastrointestinal disease (including difficulty swallowing) orgastrointestinal procedure that could interfere with the oral absorption ortolerance of iberdomide or dexamethasone

• Unstable liver or biliary disease defined by the presence of ascites,encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices,persistent jaundice, or cirrhosis. NOTE: Stable non-cirrhotic chronic liverdisease (including Gilbert's syndrome or asymptomatic gallstones) orhepatobiliary involvement of malignancy is acceptable if otherwise meets entrycriteria

• Active renal condition (infection, requirement for dialysis or any othercondition that could affect participant's safety). NOTE: Participants withisolated proteinuria resulting from MM are eligible, provided they fulfilinclusion criteria

• Evidence of cardiovascular disease risk, as defined by any of the following:

• Evidence of current clinically significant uncontrolled arrhythmias, includingclinically significant ECG abnormalities such as 2nd degree (Mobitz Type II) or 3rd degree atrioventricular (AV) block

• History of myocardial infarction, acute coronary syndromes (including unstableangina), coronary angioplasty, or stenting or bypass grafting within three (3)months of Screening

• Class III or IV heart failure as defined by the New York Heart Associationfunctional classification system

• Uncontrolled hypertension

• History of life-threatening ventricular arrhythmias

• Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volumein 1 second (FEV1) 50% of predicted normal. Note that forced expiratory testing (FEV1) is required for subjects suspected of having COPD and subjects must beexcluded if FEV1 is < 50% of predicted normal

• Known moderate or severe persistent asthma, or currently has uncontrolled asthma ofany classification

• Acute diffuse infiltrative pulmonary and pericardial disease

• Unable or unwilling to undergo protocol required thromboembolism prophylaxis

• Has taken a strong inhibitor or inducer of CYP3A4/5 including grapefruit, St. John'sWort or related products =< 14 days prior to registration

• Known allergy to any of the study medications, their analogues or excipients in thevarious formulations

• Major surgery =< 14 days prior to registration

• Plasmapheresis =< 14 days prior to registration

• Has been treated with an investigational agent (i.e., an agent not commerciallyavailable) =< 28 days or 5 half-lives (whichever is longer) prior to registration

• Any serious medical or psychiatric illness that could, in the investigator'sopinion, potentially interfere with the completion of treatment according to thisprotocol

• Radiotherapy =< 14 days prior to registration

• NOTE: If the involved field is small, 7 days will be considered a sufficientinterval between treatment and administration of the iberdomide

• More than 1 prior cycle of an antimyeloma therapy or corticosteroids for thetreatment of active / symptomatic multiple myeloma by SLiMCRAB criteria

• NOTE: Prior corticosteroid use for the treatment of non-malignant disorders ispermitted

• Other co-morbidity which would interfere with patient's ability to participate intrial, e.g. uncontrolled infection, uncompensated heart or lung disease

• Peripheral neuropathy >= grade 3 on clinical examination or grade 2 with pain duringthe screening period

• Corrected serum calcium > 13.5 mg/dL (> 3.4 mmol/L)

• Gastrointestinal disease that may significantly alter the absorption of iberdomide

• History of anaphylaxis or hypersensitivity to thalidomide, lenalidomide,pomalidomide, or pegfilgrastim / biosimilars

• The subject has a planned or received immunization with a live or live attenuatedvaccine =< 8 weeks prior to registration

• History of prior malignancies, other than MM, unless the subject has been free ofthe disease for >= 5 years with the exception of the following noninvasivemalignancies:

• Basal cell carcinoma of the skin

• Squamous cell carcinoma of the skin

• Carcinoma in situ of the cervix

• Carcinoma in situ of the breast

• Incidental histological findings of prostate cancer such as T1a or T1b usingthe Tumor/Node/Metastasis (TNM) classification of malignant tumors or prostatecancer that is curative