Isa-KRd vs KRd in Newly Diagnosed Multiple Myeloma Patients Eligible for Autologous Stem Cell Transplantation (IsKia TRIAL)

Inclusion Criteria:

• Patient with newly diagnosed multiple myeloma and eligible to ASCT.

• Patient is, in the investigator's opinion, willing and able to comply with the studyvisits and procedures required per protocol.

• Patient has provided written informed consent in accordance with federal, local, andinstitutional guidelines prior to initiation of any study-specific activities orprocedures. Subject does not have kind of condition that, in the opinion of theInvestigator, may compromise the ability of the subject to give written informedconsent and patient is, in the investigator(s) opinion, willing and able to complywith the protocol requirements.

• Monoclonal plasma cells in the bone marrow ≥10% or presence of a biopsy provenplasmacytoma and documented multiple myeloma satisfying at least one of the calcium,renal, anemia, bone (CRAB) criteria or biomarkers of malignancy criteria:

• CRAB criteria:

• Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than upper limit ofnormal (ULN) or >2.75 mmol/L (>11 mg/dL)

• Renal insufficiency: creatinine clearance <40mL/min or serum creatinine >177 μmol/L (>2 mg/dL)

• Anemia: hemoglobin >2 g/dL below the lower limit of normal or hemoglobin <10g/dL

• Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, orPET-CT

• Biomarkers of Malignancy:

• Clonal bone marrow plasma cell percentage ≥60%

• Involved: uninvolved serum FLC ratio ≥100

• >1 focal lesion on magnetic resonance imaging (MRI) studies

• Patient is 18 - 70 years old and is eligible for autologous stem celltransplantation

• Patient has measurable disease as defined by any one of the following:

• Serum monoclonal paraprotein (M-protein) level ≥1.0 g/dL or urine M-proteinlevel ≥200 mg/24 hours; or

• Light chain multiple myeloma without measurable disease in the serum or theurine: Serum immunoglobulin FLC ≥10 mg/dL and abnormal serum immunoglobulinkappa lambda FLC ratio.

• Life expectancy ≥ 3 months

• ECOG status ≤2

• Clinical laboratory values meeting the following criteria during the ScreeningPhase:

• Adequate hepatic function, with serum (alanine aminotransferase) ALT ≤ 2.5times the upper limit of normal (ULN), AST (aspartate transaminase) ≤ 2.5 x theULN

• Serum direct bilirubin ≤ 1.5 ULN) (except in subjects with congenitalbilirubinemia, such as Gilbert syndrome, direct bilirubinemia ≤ 1.5 ULN)

• Absolute neutrophil count (ANC) ≥ 1.0 × 109/L

• Platelet count ≥ 75× 109/L (≥ 50× 109/L if myeloma involvement in the bonemarrow is > 50%) and no platelet infusion in the 1 week prior to screeningplatelet count

• Creatinine clearance (CrCl) ≥ 30 mL/minute. Creatinine clearance should becalculated using eGFR (Modified Diet in Renal Disese [MDRD])

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

• LVEF ≥ 40%. 2-D transthoracic echocardiogram (ECHO) is the preferred method ofevaluation. Multigated Acquisition Scan (MUGA) is acceptable if ECHO is notavailable.

• Females of childbearing potential (FCBP)* complies with the conditions of thePregnancy Prevention Plan, including confirmation that she has an adequate level ofunderstanding and must agree to ongoing pregnancy testing and to practicecontraception or true abstinence. FCBP must use a highly effective and an additionalbarrier contraception method simultaneously for 4 weeks before starting therapy,during treatment and dose interruptions and for 5 months after the last dose ofstudy drugs.

• Male subjects must agree to practice contraception if sexually active with FCBPduring the treatment and for 5 months after the last dose of study drugs. Males mustagree to refrain from donating sperm for at least 90 days after the last dose ofcarfilzomib and for at least 5 months after the last dose of isatuximab.

• *Note 1: a FCBP is a woman who:

• has achieved menarche at some time point,

• has not undergone a hysterectomy or bilateral oophorectomy or,

• has not 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).

• Note 2: true abstinence is acceptable when this is in line with the preferred andusual lifestyle of the patient. Periodic abstinence (eg, calendar, ovulation,symptothermal, post-ovulation methods) and withdrawal are not acceptable methods ofcontraception.

Exclusion Criteria:

• Previous treatment with anti-myeloma therapy (does not include radiotherapy,biphosphonates, or a single short course of steroid ≤ to the equivalent ofdexamethasone 40 mg/day for 4 days).

• Patients with non-secretory MM unless serum free light chains are present and theratio is abnormal or a plasmacytoma with minimum largest diameters of > 2 cm.

• Patients with plasma cell leukemia, amyloidosis, Waldenstrom Disease, POEMS syndrome

• Meningeal involvement of multiple myeloma

• Patient ineligible for autologous transplantation

• Pregnant or lactating females

• Acute active infection requiring treatment (systemic antibiotics, antivirals, orantifungals) within 14 days prior to randomization

• Known human immunodeficiency virus infection (HIV)

• Active hepatitis A, B or C infection. Hepatitis C infection (subjects with hepatitisC that achieve a sustained virologic response after antiviral therapy are allowed),or hepatitis B infection (subjects with hepatitis B surface antigen or core antibodythat achieve sustained virologic response with antiviral therapy are allowed). Teststo be performed if required per local country regulations. In fact it is notpossible to avoid the risk of virological reactivation with the study treatments.

• Unstable angina or myocardial infarction within 4 months prior to randomization,NYHA Class III or IV heart failure, uncontrolled angina, uncontrolled hypertension, (Uncontrolled hypertension, defined as an average systolic blood pressure ≥ 160 mmHgor diastolic ≥ 100 mmHg despite optimal treatment (measured following EuropeanSociety of Hypertension/European Society of Cardiology 2013 guidelines), pulmonaryembolia, 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

• Non-hematologic malignancy within the past 3 years with the exception of a)adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroidcancer; b) carcinoma in situ of the cervix or breast; c) prostate cancer of GleasonGrade 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

• Significant neuropathy (Grades 3-4, or Grade 2 with pain) within 14 days prior torandomization as defined by National Cancer Institute Common Toxicity Criteria (NCICTCAE) 5.0

• Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilizecarfilzomib) and to PS80; prior hypersensitivity to sucrose, histidine (as base andhydrochloride salt), or any of the components (active substance or excipients) ofstudy treatments that are not amenable to premedication with steroids, or H2blockers, that would prohibit further treatment with these agents.

• Contraindication to any of the required concomitant drugs or supportive treatments,including hypersensitivity to all anticoagulation and antiplatelet options,antiviral drugs, or intolerance to hydration due to preexisting pulmonary or cardiacimpairment

• 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

• Pregnant or breastfeeding woman or woman who intends to become pregnant during theparticipation in the study. FCBP unwilling to prevent pregnancy by the use of 2reliable methods of contraception for ≥4 weeks before the start of study treatment,during treatment (including dose interruptions), and for at least 28 days followingdiscontinuation of study lenalidomide, or 30 days following discontinuation ofcarfilzomib or for 5 months after discontinuation of isatuximab treatment, whicheveroccurs last,

• Male participants who disagree to practice true abstinence or disagree to use acondom during sexual contact with a pregnant woman or a FCBP while participating inthe study, during dose interruptions, and for at least 28 days followingdiscontinuation of study lenalidomide, or 30 days following discontinuation ofcarfilzomib, or for 5 months after discontinuation of isatuximab treatment,whichever occurs last, even if he has undergone a successful vasectomy.