The purpose of this study is to test the safety of short course Daratumumab in combination with lenalidomide and to find out what effects, if any, short course Daratumumab in combination with lenalidomide has on people and their risk of multiple myeloma. The study is also designed to test the amount of remaining myeloma cells in your body after treatment with daratumumab which is known as minimal residual disease (MRD).

Inclusion Criteria:

• Patients with a diagnosis of Multiple Myeloma who have achieved a VGPR or better (based on best response) after induction with or without consolidation therapy/ HDT ASCT
• MRD positive at screening by flow cytometry
• Additionally, patients who were previously MRD negative after induction therapy with/without consolidative HDT/ASCT and have turned MRD positive (by flow cytometry) based on bone marrow done at screening and do not have any evidence of progressive disease are eligible
• Patients must be on standard of care lenalidomide maintenance therapy for at least 6 months at the time of study enrollment
• Patient can be receiving bisphosphonate therapy per the treating oncologist's discretion
• Creatinine clearance ≥45 ml/min using the Cockcroft-Gault method, MDRD, or CKD-EPI formula. If the calculated CrCl based on Cockcroft-Gault method, MDRD, or CKD-EPI is <45 mL/min, patient will have a 24 hr urine collection to measure CrCl.
• Age ≥18 years
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Male or female patient who accepts and is able to use recognized effective contraception (oral contraceptives, IUCD, barrier method of contraception in conjunction with spermicidal jelly) throughout the study when relevant.
• Absolute neutrophil count (ANC) ≥1.0 x 10^9/L, hemoglobin ≥8 g/dL, and platelet count ≥75 x 10^9/L. No transfusion or growth factor support for one week prior to labs.
• Adequate hepatic function, with bilirubin < 1.5 x the ULN, and AST and ALT < 2.5 x ULN

Exclusion Criteria:

• Patients with a diagnosis of MM not achieving a VGPR or better to the most recent therapy.

• Patients with a diagnosis of MM who are MRD Negative by flow cytometry

• Patients must not have measurable disease at the time of enrollment. Measurable disease is defined as follows

  • Serum monoclonal protein > 0.5 gm/dL
  • Urine monoclonal protein > 200 mg/24 hours
  • Involved serum free light chain > 10 mg/dL

• Pregnant or lactating females

• Uncontrolled hypertension or diabetes

• Has significant cardiovascular disease with NYHA Class III or IV symptoms, or hypertrophic cardiomegaly, or restrictive cardiomegaly, or myocardial infarction within 3 months prior to enrollment, or unstable angina, or unstable arrhythmia

• Uncontrolled intercurrent illness including but not limited to active infection or psychiatric illness/social situations that would compromise compliance of study requirements

• Active infection requiring treatment within two weeks prior to first dose

• Contraindication to any concomitant medication, including antivirals, anticoagulation prophylaxis, tumor lysis prophylaxis, or hydration given prior to therapy

• Major surgery within 1 month prior to enrollment

• Previous therapy with daratumumab or other anti-CD38 monoclonal antibodies

• History of other malignancy (apart from basal cell carcinoma of the skin, or in situ cervix carcinoma) except if the patient has been free of symptoms and without active therapy during at least 5 years

• Active hepatitis B or C infection

• Subject is:

  • seropositive for human immunodeficiency virus (HIV)
  • seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (ie, subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR. seropositive for hepatitis C (except in the setting of a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy).

Up to 1 year