Isatuximab in Combination With Rd Compared to Rd in Elderly Patients (Aged ≥70 Years) With NDMM

Inclusion Criteria:

* Age ≥ 70 years
* Able to provide written informed consent in accordance with federal, local, and institutional guidelines
* Patients must have newly diagnosed, symptomatic multiple myeloma with evidence of measurable disease (assessed within 21 days prior to randomization)

  * Serum M protein ≥0.5 g/dL measured using serum protein immunoelectrophoresis and/or
  * Urine M protein ≥200 mg/24 hours measured using urine protein immunoelectrophoresis and/or
  * In subjects without detectable serum or urine M-protein, serum free light chain (SFLC) ≥100 mg/L (involved light chain) and an abnormal FLC ratio
* No prior treatment for multiple myeloma
* Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-2
* Patients at cardiac risk (NYHA \>ll) or pre-existing coronary heart disease, or any other clinically relevant cardiac complication) should be scheduled for a baseline ECHO and can only be included if the LVEF is \>40%
* Adequate organ and bone marrow function within the 21 days prior to randomization defined by:

  * Bilirubin \< 2 times the upper limit of normal (ULN), Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \< 3 times the ULN
  * absolute neutrophil count (ANC) ≥ 750/mm3 (growth factor support for max 3 days allowed to achieve this value)
  * Hemoglobin \>8.0 g/dL (Use of erythropoietic stimulating factors and red blood cell \[RBC\] transfusion per institutional guidelines is allowed, however the most recent RBC transfusion may not have been done within 7 days prior to obtaining screening hemoglobin.)
  * Platelet count \>50,000/mm3
  * Calculated or measured creatinine clearance (CrCl) of ≥30 mL/min; Calculation should be based on the MDRD formula (age, gender, black/non- black, weight, height)

Exclusion Criteria:

* ECOG status \>2
* Patients unlikely to tolerate Rd
* Waldenström macroglobulinemia
* POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
* Plasma cell leukemia (\> 2.0 x 10\^9/L circulating plasma cells by standard differential)
* Myelodysplastic syndrome
* Smoldering Myeloma and MGUS
* Second malignancy within the past 5 years except:

  * Adequately treated basal cell or squamous cell skin cancer
  * Carcinoma in situ of the cervix
  * Prostate cancer ≤ Gleason score 6 with stable prostate-specific antigen (PSA over 12 months)
  * Ductal breast carcinoma in situ with full surgical resection (i.e., negative margins)
  * Treated medullary or papillary thyroid cancer
  * Other tumors with low risk of recurrence/metastases and/or early stage R0 surgery
* History of or current amyloidosis
* Glucocorticoid therapy within the 14 days prior to randomization that exceeds an accumulated dose of 160 mg dexamethasone or 1000 mg prednisone
* Extended field radio therapy (more than 3 fields) within the 21 days prior to randomization
* Contraindication to isatuximab, dexamethasone, lenalidomide or any of the required concomitant drugs or supportive treatments, including hypersensitivity to antiviral drugs
* Active congestive heart failure (New York Heart Association \[NYHA\] Class III or IV), symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention, acute diffuse infiltrative pulmonary disease, pericardial disease, or myocardial infarction within 4 months prior to enrolment
* Active infection within the 14 days prior to randomization requiring systemic antibiotics and/or antiviral therapy
* Uncontrolled hypertension or uncontrolled diabetes despite medication
* Significant neuropathy (Grade 2 with pain or Grade 3 or higher) within the 14 days prior to randomization
* Known cirrhosis
* Known human immunodeficiency virus (HIV) seropositivity or active hepatitis C or hepatitis B infection (subjects with past hepatitis B virus \[HBV\] infection or resolved HBV infection defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen \[anti HBc\] antibody test are eligible; subjects positive for hepatitis C virus \[HCV\] antibody are eligible only if polymerase chain reaction \[PCR\] is negative for HCV RNA.)
* Participation in another interventional study within the 28 days prior to randomization
* Major surgery (except kyphoplasty) within the 28 days prior to randomization
* Any other clinically significant medical disease or social condition that, in the Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent, be compliant with study procedures, or provide accurate information.