Inclusion Criteria:
* Subject must be at least 18 years of age.
* Subject must have documented multiple myeloma satisfying the CRAB criteria and measurable disease defined as:
* Monoclonal plasma cells in the bone marrow ≥10% or presence of a biopsy-proven Plasmacytoma.
* Measurable disease as defined by any of the following:
* IgG myeloma: Serum monoclonal paraprotein (M-protein) level ≥.5 g/dL or urine M-protein level ≥200 mg/24 hours; or
* IgA, IgM, or IgD multiple myeloma: serum M-protein level ≥0.25 g/dL or urine M-protein level ≥200 mg/24 hours; or
* Light chain multiple myeloma: Serum immunoglobulin free light chain ≥10 mg/dL and abnormal serum immunoglobulin kappa lambda free light chain ratio.
* Sixty percent or greater clonal plasma cells on bone marrow examination.
* Serum involved / uninvolved free light chain ratio of 100 or greater, provided the absolute level of the involved free light chain is at least 100 mg/L (a patient's "involved" free light chain - either kappa or lambda - is the one that is above the normal reference range; the uninvolved light chain is the one that typically is in, or below, the normal range).
* More than one focal lesion on magnetic resonance image (MRI) that is at least 5 mm or greater in size.
* Newly diagnosed and considered candidate for high-dose chemotherapy with stem cell transplant.
* Subject must have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2.
* Subject must have pretreatment clinical laboratory values meeting the following criteria during the Screening Phase:
* hemoglobin ≥ 7.5 g/dL (≥ mmol/L; prior RBC transfusion or recombinant human erythropoietin use is permitted);
* absolute neutrophil count ≥1.0 x 109/L (granulocyte colony stimulating factor \[GCSF\] use is permitted);
* platelet count ≥70 x 109/L for subjects in whom \<50% of bone marrow nucleated cells are plasma cells; otherwise platelet count \>50 × 109/L (transfusions are not permitted to achieve this minimum platelet count)
* aspartate aminotransferase (AST) ≤2.5 x upper limit of normal (ULN);
* alanine aminotransferase (ALT) ≤2.5 x ULN;
* total bilirubin ≤2.0 x ULN, except in subjects with congenital bilirubinemia, such as Gilbert syndrome (direct bilirubin ≤2.0 x ULN)
* creatinine clearance ≥30 mL/min
* corrected serum calcium ≤14 mg/dL (≤3.5 mmol/L); or free ionized calcium \<6.5 mg/dL (\<1.6 mmol/L).
* Women of childbearing potential must commit to either abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously. This includes one highly effective form of contraception (tubal ligation, intrauterine device \[IUD\], hormonal \[birth control pills, injections, hormonal patches, vaginal rings or implants\] or partner's vasectomy) and one additional effective contraceptive method (male latex or synthetic condom, diaphragm, or cervical cap). Contraception must begin 4 weeks prior to dosing. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy or bilateral oophorectomy.
* A man who is sexually active with a woman of childbearing potential must agree to use a latex or synthetic condom, even if they had a successful vasectomy. All men must also not donate sperm during the study, for 4 weeks after the last dose of lenalidomide, for 90 days after the last dose of carfilzomib, and for 4 months after the last dose of isatuximab.
* A woman of childbearing potential must have 2 negative serum or urine pregnancy tests at Screening, first within 10 to 14 days prior to dosing and the second within 24 hours prior to dosing.
* Each subject (or their legally acceptable representative) must sign an informed consent form (ICF) indicating that he or she understands the purpose of and procedures required for the study and are willing to participate in the study. Subject must be willing and able to adhere to the prohibitions and restrictions specified in this protocol, as referenced in the ICF.
Exclusion Criteria:
* Any potential subject who meets any of the following criteria will be excluded from participating in the study.
* Subject has a diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined significance, or smoldering multiple myeloma. Monoclonal gammopathy of undetermined significance is defined by presence of serum M-protein \<3 g/dL; absence of lytic bone lesions, anemia, hypercalcemia, and renal insufficiency related to the M-protein; and (if determined) proportion of plasma cells in the bone marrow of 10% or less. Smoldering multiple myeloma is defined as asymptomatic MM with absence of related organ or tissue impairment end organ damage.
* Subject has a diagnosis of Waldenström's disease, or other conditions in which IgM M-protein is present in the absence of a clonal plasma cell infiltration with lytic bone lesions
* Subject has prior or current systemic therapy or SCT for MM, with the exception of an emergency use of a short course (equivalent of dexamethasone 40 mg/day for a maximum 4 days) of corticosteroids before treatment.
* Subject has a history of malignancy (other than MM) within 5 years before the date of enrollment (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy that in the opinion of the investigator, with concurrence with the sponsor's medical monitor, is considered cured with minimal risk of recurrence within 5 years).
* Subject has had radiation therapy within 14 days of enrollment.
* Subject has had plasmapheresis within 28 days of enrollment.
* Subject is exhibiting clinical signs of meningeal involvement of MM.
* Subject has known chronic obstructive pulmonary disease (COPD) (defined as a forced expiratory volume \[FEV\] in 1 second \<60% of predicted normal), persistent asthma, or a history of asthma within the last 2 years (intermittent asthma is allowed). Subjects with known or suspected COPD or asthma must have a FEV1 test during screening.
* Subject is known to be seropositive for history of human immunodeficiency virus (HIV) or known to have active hepatitis B or hepatitis C.
* Subject has any concurrent medical or psychiatric condition or disease (eg, active systemic infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary disease) that is likely to interfere with the study procedures or results, or that in the opinion of the investigator, would constitute a hazard for participating in this study.
* Subject has clinically significant cardiac disease, including:
* myocardial infarction within 1 year before enrollment, or an unstable or uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina, congestive heart failure, New York Heart Association Class III-IV;
* uncontrolled cardiac arrhythmia (National Cancer Institute Common Terminology Criteria for Adverse Events \[NCI CTCAE\] Version 4 Grade ≥2) or clinically significant ECG abnormalities;
* screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia's formula (QTcF) \>470 msec.
* uncontrolled hypertension
* Subject has known allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal antibodies or human proteins, or their excipients (refer to respective package inserts or IB) or known sensitivity to mammalian-derived products.
* Subject has plasma cell leukemia (according to World Health Organization \[WHO\] criterion: ≥20% of cells in the peripheral blood with an absolute plasma cell count of more than 2 × 109/L) or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes).
* Subject is known or suspected of not being able to comply with the study protocol (eg, because of alcoholism, drug dependency, or psychological disorder). Subject has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (eg, compromise the well-being) or that could prevent, limit, or confound the protocol specified assessments.
* Subject is a woman who is pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study within 30 days after the last dose of lenalidomide or carfilzomib, or within 4 months after the last dose of isatuximab. Or, subject is a man who plans to father a child while enrolled in this study, within 4 weeks after the last dose of lenalidomide, within 90 days of the last dose of carfilzomib, or within 4 months after the last dose of isatuximab.
* Subject has had major surgery within 2 weeks before enrollment or has not fully recovered from surgery, or has surgery planned during the time the subject is expected to participate in the study. Kyphoplasty or vertebroplasty is not considered major surgery.
* Subject has received an investigational drug (including investigational vaccines) or used an invasive investigational medical device within 4 weeks before enrollment or is currently enrolled in an interventional investigational study.
* Subject has contraindications to required prophylaxis for deep vein thrombosis and pulmonary embolism.
* Incidence of gastrointestinal disease that may significantly alter the absorption of oral drugs.
* Peripheral neuropathy ≥ Grade 2 on clinical examination during the screening period.
* Systemic treatment with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin), strong inhibitors of CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobartital), or use of Ginkgo biloba, St. John's wort within 14 days before the first dose of study treatment.
