Inclusion Criteria:

1. Adult patients 18 to 70 years old, with newly diagnosed symptomatic (according to the revised 2014 IMWG criteria as summarized in Appendix A) myeloma. Patients must have measurable disease at diagnosis defined by any of the following:

* Serum M-protein ≥1 g/dL (for IgA ≥0.5 g/dL) or urine M-protein ≥200 mg/24 hours
* For oligosecretory myeloma, involved serum free light chain (FLC) level ≥10 mg/dL, provided serum FLC ratio is abnormal
* For non-secretory myeloma, \> 1 focal lesions measurable by imaging
2. Subjects must have high-risk myeloma defined as followed:

* R-ISS stage II or III patients (Appendix B)
* ISS stage III (Appendix B)
* ≥ 3 copies +1q21 in patients with ISS Stage II/III or R-ISS Stage II/III
* Presence of del(17p) cytogenetic abnormality regardless of ISS/R-ISS Stage
* Presence of at least 2 high-risk genetic abnormalities \[del(17p), t(4;14), t(14;16), t(14;20), +1q21\] regardless of ISS/R-ISS stage
3. English and non-English speaking patients are eligible.
4. Karnofsky performance score of at least 70% and/or ECOG PS ≤2
5. Underwent ASCT using a conditioning regimen consisting of single agent Melphalan or a Busulfan and Melphalan with adequate cell count recovery after transplant without the need for growth factor support or transfusions within 7 days from the lab test

* Absolute neutrophil count (ANC) ≥1000 /µL
* Hemoglobin ≥8 g/dL
* Platelet count ≥50,000 /µL
6. Patients must have achieved partial response (PR) or better prior to starting maintenance therapy.
7. Adequate major organ system function as demonstrated by:

* Serum creatinine clearance equal or more than 30 ml/min (calculated with Cockcroft- Gault formula).
* Total bilirubin equal or less than 2.0 mg/dL (equal or less than 3.0 mg/dL for patients with Gilbert's disease).
* ALT or AST equal or less than 3 times the upper normal for adults.
8. Patient or patient's legal representative, parent(s) or guardian should provide written Internal Review Board (IRB)-approved informed consent.
9. Female patients included must not be pregnant or lactating. Females of childbearing potential must have (before starting treatment) a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10-14 days prior to and again within 24 hours prior to starting Isatuximab and with each cycle of study treatment. Females of childbearing potential must refrain from becoming pregnant and commit to either apply highly effective method of birth control (two reliable methods of birth control) or continue abstinence from heterosexual intercourse during study period and for at least 5 months after last dose of Isatuximab. Patients who receive Lenalidomide should continue to follow REVLIMID REMSTM requirements.
10. Men of reproductive potential must agree to follow accepted birth control methods and refrain from sperm donation for the duration of the study and for at least 5 months after last dose of Isatuximab. Patients who receive Lenalidomide should continue to follow REVLIMID REMSTM requirements.

Exclusion Criteria

1. Progression of myeloma, as defined by the IMWG criteria (Appendix C), prior to initiation of maintenance therapy
2. Patients receiving any other investigational agents within 14 days or 5 half-lives of the investigational drug prior to initiation of study intervention. Exceptions can be granted after discussing with PI.
3. History of allergic reactions attributed to compounds of similar chemical or biologic composition to any of the study drugs. Hypersensitivity or history of intolerance to steroids, mannitol, pregelatinized starch, sodium stearyl fumarate, histidine (as base and hydrochloride salt), arginine hydrochloride, poloxamer 188, sucrose or any of the other components of study intervention that are not amenable to premedication with steroids and H2 blockers or would prohibit further treatment with these agents.
4. Known hypersensitivity or desquamating rash to either thalidomide or lenalidomide.
5. Participants must not have an active infection requiring treatment.
6. Participants must not have an uncontrolled intercurrent illness including, but not limited to, an uncontrolled hypertension (systolic \>170, diastolic \>100 despite antihypertensive therapy), symptomatic congestive heart failure (Class III or IV as defined by the New York Heart Association (NYHA) functional classification system), acute coronary syndrome, liver cirrhosis, and/or cognitive impairments/psychiatric illness/social situations that would limit compliance with study requirements. PI is the final arbiter of this criterion.
7. Major surgery within 4 weeks before initiating study treatment.
8. HIV-positive patients and/or active hepatitis A, B or C infections.