Isatuximab With or Without Lenalidomide in Patients With High Risk Smoldering Multiple Myeloma (ISAMAR)

This is a multi-center, open label, phase II study designed to evaluate the efficacy of isatuximab with or without lenalidomide when given to patients with high risk smoldering multiple myeloma.

Inclusion Criteria: -Risk factors for progression to multiple myeloma in patients with smoldering multiple myeloma (SMM) have been identified and include: percentage of bone marrow involvement by plasma cells, monoclonal spike in blood, serum free light chains in blood, presence or absence of immunoparesis in blood, percentage of normal versus abnormal plasma cells in the bone marrow compartment by using standard flow cytometry techniques and gene expression profiling of plasma cells obtained from a bone marrow aspirate. Patients must have histologically confirmed SMM based on the following criteria. Both criteria must be met: 1. Serum monoclonal protein (IgG or IgA) ≥ 3 g/dL or urinary monoclonal protein ≥ 500 mg per 24 hours and/or clonal bone marrow plasma cells 10-60% 2. Absence of myeloma defining events or amyloidosis Additionally, patients must meet criteria for high risk of progression to multiple myeloma by PETHEMA criteria (patients must have at least 2 risk factors present) (11): * ≥95% abnormal plasma cells/total plasma cells in bone marrow compartment. (This is measured as a percentage of the total abnormal versus normal plasma cells in the bone marrow compartment using standard flow cytometry of the bone marrow aspirate. Having ≥95% abnormal plasma cells/total plasma cells constitutes a risk factor for progression to multiple myeloma by PETHEMA criteria) * Immunoparesis (This term refers to the patient having low uninvolved immunoglobulins in peripheral blood, for example if a patient has IgA smoldering multiple myeloma, then either having a low IgM and/or low IgG will qualify as a risk factor for progression to multiple myeloma) \*2 of 2 risk factors: high risk for progression at a rate of 72% at 5 years * Creatinine clearance (CrCl) ≥ 40 ml/min. CrCl will be calculated using the Modification of Diet in Renal Disease (MDRD) equation. * Age ≥ 18 years. Because no dosing or adverse event data are currently available on the use of isatuximab in patients \0.25 mmol/L (\>1 mg/dL) higher than the upper limit of normal or \> 2.75 mmol/L (\> 11 mg/dL) 2. Renal Insufficiency: creatinine clearance \< 50 ml/min or serum creatinine \> 2 mg/dL 3. Anemia: hemoglobin value \1 focal lesions on MRI studies (each focal lesion must be 5 mm or more in size) * Bisphosphonates are permitted, including pamidronate, zoledronic acid, alendronate, ibandronate, risedronate. * Treatment with corticosteroids is not permitted, unless the patient is on a stable chronic dose of inhaled steroids to treat respiratory diseases or on stable chronic steroid replacement therapy for endocrinology disorders. * Radiotherapy is not permitted. * Prior or concurrent treatment for smoldering multiple myeloma with chemotherapy agents approved for the treatment of smoldering multiple myeloma or CD38 drugs is not permitted. * Plasma cell leukemia * Pregnant or lactating females. Because there is a potential risk for adverse events in nursing infants secondary to treatment of the mother with isatuximab, breastfeeding should be discontinued if the mother is treated with isatuximab. These potential risks may also apply to other agents used in this study. * Active hepatitis B or C infection * Known HIV infection * Intolerance to infused protein products, sucrose, histidine or polysorbate 80 * Concurrent treatment with other anti-cancer therapy is not permitted * Patients must not have uncontrolled intercurrent illness including hypertension, symptomatic congestive heart failure, unstable angina, uncontrolled cardiac arrhythmia. Patients should not have New York Heart Association classification III or IV heart failure at baseline. * Uncontrolled intercurrent illness including but not limited to active infection or psychiatric illness/social situations that would compromise compliance with study requirements * Contraindication to any concomitant medication, including pre-medications or hydration given prior to therapy * Major surgery within 1 month prior to enrollment * Patients with pre-existing pulmonary uncontrolled disease will be excluded. Uncontrolled refers to patients having had at least one hospitalization due to pulmonary disease (for example, asthma, chronic obstructive pulmonary disease) within the 6 months prior to enrollment in the study. Patients with previous history of pneumonitis will be excluded. * Recruitment Strategies * Patients that are seen in clinic at MD Anderson, Memorial Sloan Kettering Cancer Center and Mount Sinai meeting eligibility criteria will be screened for the protocol * Other participant sources will be from outside physician referrals. * Our outside physician referral network has a high representation of minorities.