Registration Step 1 - Study Entry Post-Induction and Pre-Maintenance

• Except where otherwise indicated below that test is required in a shorter timeframe, all tests for establishing baseline disease status must be completed within 60 days prior to registration. All test results must be documented on the Baseline Tumor Assessment Form for Multiple Myeloma and the Onstudy Form.

Inclusion Criteria:

• Patients must have had a confirmed diagnosis of symptomatic multiple myeloma that required systemic induction therapy prior to autologous stem cell transplantation (ASCT). Patients with smoldering myeloma are not eligible. Patients with purely nonsecretory MM as measured by electrophoresis and immunofixation and the absence of Bence Jones proteins in the urine are not eligible.
• Patients must have measurable M protein in the serum (defined as ≥ 0.5g/dL) or urine (defined as ≥ 200 mg/24h). Patients with plasma cell leukemia are not eligible. Patients with disease measurable by serum light chain assay alone are eligible (defined as ≥ 100 mg/L on involved light chain).
• Patients must not have any organ involvement by amyloidosis or evidence of amyloidosis related organ dysfunction.
• Patients must not have progressive disease at any time prior to registration.
• Patients must not be refractory to either lenalidomide or daratumumab/rHuPH20. 
• Patients must not be intolerant to either lenalidomide or daratumumab/rHuPH20.
• Patients must have initiated induction therapy within 12 months prior to registration Step 1 and have received at least two cycles of induction therapy.
• Patients must be registered to Step 1 prior to registration to Step 2. Registration to Step 1 may take place prior to or after autologous stem cell transplant (ASCT), but after completion of induction therapy.
• Patients must not have received any investigational agents within 14 days prior to registration.
• Patients must be willing and able to take DVT prophylaxis (aspirin, low molecular weight heparin, warfarin, or equivalent oral anticoagulation).
• Patients must be ≥ 18 and ≤ 75 years of age at time of registration to Step 1.
• Patients must have history and physical exam within 28 days prior to registration.
• Patients must have Zubrod Performance Status ≤ 2.
• Patients must have evidence of adequate renal function, as defined by:
  • creatinine clearance (CrCl) ≥ 30 mL/min., as measured by a 24-hour urine collection, or estimated by the Cockcroft and Gault formula; or
  • serum creatinine < 2.5 mg/dL. Values must be obtained within 28 days prior to registration. Estimated creatinine clearance = (140 - age) x wt (kg) x 0.85 (if female) 72 x creatinine (mg/dl).
• Patients must have adequate hepatic function defined by the following within 42 days prior to registration:
  • Total bilirubin ≤ 1.5 x IULN (institutional upper limit of the norm); AND
  • AST and ALT ≤ 3.0 x IULN o. Patients must not have chronic obstructive pulmonary disease with a forced expiratory volume in 1 second (FEV1) < 50% of predicted normal. FEV1 is required for patients suspected of having chronic obstructive pulmonary disease and are not eligible if FEV1 is < 50% of predicted normal. p. Patients must not have moderate or severe persistent asthma within the past 2 years and must not have currently uncontrolled asthma of any classification.
• Patients must meet one of the following criteria:
  • Be acceptable for transplant per institutional guidelines and the criteria evidencing this must be documented on the S1803 Onstudy Form; OR
  • Note that these are guidelines and not required criteria.)
  • Have completed autologous stem cell transplant within 180 days prior to registration.
• Patients must not have had prior autograft or allograft, or prior organ transplant requiring immunosuppressive therapy.
• Patient’s with human immunodeficiency virus (HIV) are eligible providing they are on effective antiretroviral therapy and have undetectable viral load at their most previous viral load test and within 6 months prior to registration.
• Patients must not have known allergy to any of the study drugs.
• Patients with uncontrolled bacterial, viral or fungal infections (currently taking medication and with progression or no clinical improvement) at time of enrollment are not eligible.
• Patients must not have known central nervous system (CNS) involvement with multiple myeloma, defined as CSF positivity for plasma cells at any time or a parenchymal CNS plasmacytoma at time of enrollment. Lumbar puncture is not required.
• Patients must not be seropositive for hepatitis C (except in the setting of sustained virologic response, defined as undetectable viral load at least 12 weeks after completion of antiviral therapy). HCV testing is only required if clinically indicated or if the patient has a history of HCV.
• Patients must be able to take and swallow oral medication (capsules) whole. Patients may not have any known impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of study drug (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
• No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years. 
• Patients must not have any uncontrolled intercurrent illness including (not limited to):
  • Symptomatic CHF (NYHA III/IV), unstable angina pectoris or coronary angioplasty, or stenting within 6 months prior to registration, Unstable cardiac arrhythmia (ongoing cardiac dysrhythmias of NCI CTCAE v5.0 Grade ≥ 2), intracardiac defibrillators, known cardiac metastases, or abnormal cardiac valve morphology (≥ Grade 3), or known psychiatric illness that would limit study compliance.
• For patients who have not yet received transplant:
  • Patients must be willing and able to return to the transplant center for their assigned treatment after randomization. Note that patients need not have a direct relationship with the transplant center in order to register.
• Patients must submit specimens for MRD.  Note that patients are not ineligible based solely on archival specimens being unavailable.
• Patients must be offered participation in specimen banking for future research. 
• Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines.
• As a part of the OPEN registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system.

Exclusion Criteria:

• Patients with smoldering myeloma are not eligible. Patients with purely non-secretory MM as measured by electrophoresis and immunofixation and the absence of Bence Jones proteins in the urine are not eligible. Patients must have measurable M protein in the serum (defined as ≥ 0.5g/dL) or urine (defined as ≥ 200 mg/24h). Patients with plasma cell leukemia are not eligible.
• Patients must not have any organ involvement by amyloidosis or evidence of amyloidosis related organ dysfunction.
• Patients must not have progressive disease at any time prior to registration.
• Patients must not be refractory to either lenalidomide or daratumumab/rHuPH20.
• Patients must not be intolerant to either lenalidomide or daratumumab/rHuPH20.
• Patients must not have received any investigational agents within 14 days prior to registration.
• Patients must not have chronic obstructive pulmonary disease with a forced expiratory volume in 1 second (FEV1) < 50% of predicted normal. FEV1 is required for patients suspected of having chronic obstructive pulmonary disease and are not eligible if FEV1 is < 50% of predicted normal.
• Patients must not have moderate or severe persistent asthma within the past 2 years and must not have currently uncontrolled asthma of any classification.
• Patients must not have had prior autograft or allograft, or prior organ transplant requiring immunosuppressive therapy.
• Patients must not have known allergy to any of the study drugs.
• Patients with uncontrolled bacterial, viral or fungal infections (currently taking medication and with progression or no clinical improvement) at time of enrollment are not eligible.
• Patients must not have known central nervous system (CNS) involvement with multiple myeloma, defined as CSF positivity for plasma cells at any time or a parenchymal CNS plasmacytoma at time of enrollment. Lumbar puncture is not required.
• Patients must not be seropositive for hepatitis C (except in the setting of sustained virologic response, defined as undetectable viral load at least 12 weeks after completion of antiviral therapy). HCV testing is only required if clinically indicated or if the patient has a history of HCV.
• No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years.
• Patients must not have any uncontrolled intercurrent illness including (not limited to): Symptomatic CHF (NYHA III/IV), unstable angina pectoris or coronary angioplasty, or stenting within 6 months prior to registration, Unstable cardiac arrhythmia (ongoing cardiac dysrhythmias of NCI CTCAE v5.0 Grade ≥ 2), intra-cardiac defibrillators, known cardiac metastases, or abnormal cardiac valve morphology (≥ Grade 3), or known psychiatric illness that would limit study compliance.

Registration Step 2 - First Randomization (Post-ASCT, Pre-Maintenance)

Inclusion Criteria:

• Patients must have completed ASCT within 180 days prior to registering to Step 2.
• Patients must not have received any other maintenance therapy post-ASCT and prior to Step 2 registration.
• Patients must not have had progressive disease between induction and registration to Registration Step 2.
• Patients must have one of the following performed within 60 days prior to registration for disease assessment: diagnostic quality skeletal survey, whole body CT scan, MRI, or PET.
• Patients must have Zubrod Performance Status ≤ 2 f. Patients must have adequate bone marrow function as evidenced by platelets ≥ 75,000/mm^3 and ANC ≥ 1,000/mm^3 within 28 days prior to first randomization:
• Patients must have adequate hepatic function defined by the following within 28 days prior to first randomization:
  • Total bilirubin ≤ 1.5 x IULN (institutional upper limit of the norm) AND 2. AST and ALT ≤ 3.0 x IULN.
• Patients must have evidence of adequate renal function, as defined by creatinine clearance (CrCl) ≥ 30 mL/min., as measured by a 24-hour urine collection, or estimated by the Cockcroft and Gault formula, or have a serum creatinine < 2.5 mg/dL within 28 days prior to first randomization. Estimated creatinine clearance = (140 - age) x wt (kg) x 0.85 (if female) 72 x creatinine (mg/dl).
• All ASCT-related toxicities must have recovered to ≤ Grade 1 (except for alopecia, fatigue and amenorrhea) prior to first randomization. 
• Mucositis and gastrointestinal symptoms must have resolved to ≤ Grade 1.
• Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10-14 days prior to registration. FCBP must agree to have a second pregnancy test within 24 hours prior to starting Cycle 1. Further, FCBP must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control: one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before starting lenalidomide. FCBP must also agree to ongoing pregnancy testing and must agree to not become pregnant for at least 3 months after the last dose of study treatment. A FCBP is a female who:
  • has achieved menarche (first menstrual cycle) at some point;
  • has not undergone a hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries); or
  • has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time during the preceding 24 consecutive months). Men must agree to use a latex condom during sexual contact with a FCBP, even if they have had a successful vasectomy, during the study treatment and for 3 months after the last dose of study treatment.
• Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines.

Exclusion Criteria:

• Patients must not have received any other maintenance therapy post-ASCT and prior to Step 2 registration.
• Patients must not have had progressive disease between induction and registration to Registration Step 2.

Registration Step 3 - Second Randomization (Post 24 Months Maintenance)

Inclusion Criteria:

• Patients must have completed 24 cycles of protocol maintenance with either lenalidomide or lenalidomide + daratumumab/rHuPH20.
• Patients must have 24-month MRD by NGS test results available and must be MRD negative. Patients whose PCR results are indeterminable will be considered to have positive results.
• Patients must be in very good partial remission (VGPR) or better by IMWG response criteria.