S1803, Lenalidomide +/- Daratumumab/rHuPh20 as Post-ASCT Maintenance for MM w/MRD to Direct Therapy Duration

Registration Step 1 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 (SeeSection 4.1) that required systemic induction therapy prior to autologous stem celltransplantation (ASCT).

• Patients with disease measurable by serum light chain assay alone are eligible (defined as >/= 100 mg/L on involved light chain).

• Patients must be registered to Step 1 prior to registration to Step 2. Registrationto Step 1 may take place prior to or after autologous stem cell transplant (ASCT),but after completion of induction therapy.

• Patients must have initiated induction therapy within 12 months prior toregistration Step 1 and have received at least two cycles of induction therapy.

• Patients must be willing and able to take DVT prophylaxis (aspirin, low molecularweight 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 (1) creatinineclearance (CrCl) >/= 30 mL/min., as measured by a 24-hour urine collection, orestimated by the Cockcroft and Gault formula, or (2) serum creatinine < 2.5 mg/dL.Values must be obtained within 28 days prior to registration.

• Patients must have adequate hepatic function defined by the following within 42 daysprior to registration:

• Total bilirubin </=1.5 x IULN (institutional upper limit of the norm) AND

• AST and ALT </=3.0 x IULN

• Patients must meet one of the following criteria:

• Be acceptable for transplant per institutional guidelines and the criteriaevidencing this must be documented on the S1803 Onstudy Form. (See Appendix 18.3 for standard transplant eligibility guidelines. Note that these areguidelines and not required criteria.) OR

• Have completed autologous stem cell transplant within 180 days prior toregistration (see also Section 5.2a).

• Patient's with human immunodeficiency virus (HIV) are eligible providing they are oneffective antiretroviral therapy and have undetectable viral load at their mostprevious viral load test and within 6 months prior to registration.

• Patients must be able to take and swallow oral medication (capsules) whole. Patientsmay not have any known impairment of gastrointestinal function or gastrointestinaldisease that may significantly alter the absorption of study drug (e.g. ulcerativedisease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or smallbowel resection).

• For patients who have not yet received transplant: Patients must be willing and ableto return to the transplant center for their assigned treatment after randomization.Note that patients need not have a direct relationship with the transplant center inorder to register.

• Patients must submit specimens for MRD as outlined in Section 15.1. See Section 15.1for further information, including specimen submission timepoints. Note thatpatients are not ineligible based solely on archival specimens being unavailable.

• Patients must be offered participation in specimen banking for future research. Withpatient's consent, specimens must be submitted as outlined in Section 15.2.

• Patients must be informed of the investigational nature of this study and must signand give written informed consent in accordance with institutional and federalguidelines.

• As a part of the OPEN registration process (see Section 13.3 for OPEN accessinstructions) the treating institution's identity is provided in order to ensurethat the current (within 365 days) date of institutional review board approval forthis study has been entered in the system.

Exclusion Criteria

• Patients with smoldering myeloma are not eligible. Patients with purelynon-secretory MM as measured by electrophoresis and immunofixation and the absenceof Bence Jones proteins in the urine are not eligible. Patients must have measurableM protein in the serum (defined as >/= 0.5g/dL) or urine (defined as >/= 200mg/24h). Patients with plasma cell leukemia are not eligible.

• Patients must not have any organ involvement by amyloidosis or evidence ofamyloidosis 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 toregistration.

• Patients must not have chronic obstructive pulmonary disease with a forcedexpiratory volume in 1 second (FEV1) < 50% of predicted normal. FEV1 is required forpatients suspected of having chronic obstructive pulmonary disease and are noteligible if FEV1 is < 50% of predicted normal.

• Patients must not have moderate or severe persistent asthma within the past 2 yearsand must not have currently uncontrolled asthma of any classification.

• Patients must not have had prior autograft or allograft, or prior organ transplantrequiring immunosuppressive therapy.

• Patients must not have known allergy to any of the study drugs.

• Patients with uncontrolled bacterial, viral or fungal infections (currently takingmedication and with progression or no clinical improvement) at time of enrollmentare not eligible.

• Patients must not have known central nervous system (CNS) involvement with multiplemyeloma, defined as CSF positivity for plasma cells at any time or a parenchymal CNSplasmacytoma at time of enrollment. Lumbar puncture is not required.

• Patients must not be seropositive for hepatitis C (except in the setting ofsustained virologic response, defined as undetectable viral load at least 12 weeksafter completion of antiviral therapy). HCV testing is only required if clinicallyindicated or if the patient has a history of HCV.

• No other prior malignancy is allowed except for the following: adequately treatedbasal cell or squamous cell skin cancer, in situ cervical cancer, adequately treatedStage I or II cancer from which the patient is currently in complete remission, orany other cancer from which the patient has been disease free for three years.

• Patients must not have any uncontrolled intercurrent illness including (not limitedto): Symptomatic CHF (NYHA III/IV), unstable angina pectoris or coronaryangioplasty, or stenting within 6 months prior to registration, Unstable cardiacarrhythmia (ongoing cardiac dysrhythmias of NCI CTCAE v5.0 Grade >/= 2),intra-cardiac defibrillators, known cardiac metastases, or abnormal cardiac valvemorphology (>/= Grade 3), or known psychiatric illness that would limit studycompliance.

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 have one of the following performed within 60 days prior toregistration for disease assessment: diagnostic quality skeletal survey, whole bodyCT scan, MRI, or PET.

• Patients must have Zubrod Performance Status </= 2

• Patients must have adequate bone marrow function as evidenced by platelets >/= 75,000/mm3 and ANC >/= 1,000/mm3 within 28 days prior to first randomization:

• Patients must have adequate hepatic function defined by the following within 28 daysprior to first randomization:

• Total bilirubin </=1.5 x IULN (institutional upper limit of the norm) AND AST andALT </=3.0 x IULN

• Patients must have evidence of adequate renal function, as defined by creatinineclearance (CrCl) >/= 30 mL/min., as measured by a 24-hour urine collection, orestimated by the Cockcroft and Gault formula, or have a serum creatinine < 2.5 mg/dLwithin 28 days prior to first randomization.

• 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 urinepregnancy test with a sensitivity of at least 25 mIU/mL within 10-14 days prior toregistration.

• FCBP must agree to have a second pregnancy test within 24 hours prior to startingCycle 1. Further, FCBP must either commit to continued abstinence from heterosexualintercourse or begin TWO acceptable methods of birth control: one highly effectivemethod and one additional effective method AT THE SAME TIME, at least 28 days beforestarting lenalidomide. FCBP must also agree to ongoing pregnancy testing and mustagree to not become pregnant for at least 3 months after the last dose of studytreatment.

• Men must agree to use a latex condom during sexual contact with a FCBP, even if theyhave had a successful vasectomy, during the study treatment and for 3 months afterthe last dose of study treatment.

• Patients must be informed of the investigational nature of this study and must signand give written informed consent in accordance with institutional and federalguidelines.

Exclusion Criteria:

• Patients must not have received any other maintenance therapy post-ASCT and prior toStep 2 registration.

• Patients must not have had progressive disease between induction and registration toRegistration Step 2. (See Section 10.1b).

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

Inclusion Criteria:

• Patients must have completed 24 cycles of protocol maintenance with eitherlenalidomide or lenalidomide + daratumumab/rHuPH20.

• Patients must have 24-month MRD by NGS test results available and must be MRDnegative. Patients whose PCR results are indeterminable will be considered to havepositive results.

• Patients must be in very good partial remission (VGPR) or better by IMWG responsecriteria (see Section 10.1b).