SWOG S1803

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.

• Patients must have had a confirmed diagnosis of symptomatic multiple myeloma (See Section 4.1) that required systemic induction therapy prior to autologous stem cell transplantation (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. Registration to 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 to registration Step 1 and have received at least two cycles of induction therapy.
• 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 (1) creatinine clearance (CrCl) >/= 30 mL/min., as measured by a 24-hour urine collection, or estimated 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 days prior 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 criteria evidencing this must be documented on the S1803 Onstudy Form. (See Appendix 18.3 for standard transplant eligibility guidelines. Note that these are guidelines and not required criteria.) OR
  • Have completed autologous stem cell transplant within 180 days prior to registration (see also Section 5.2a).
• 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 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).
• 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 as outlined in Section 15.1. See Section 15.1 for further information, including specimen submission timepoints. Note that patients are not ineligible based solely on archival specimens being unavailable.
• Patients must be offered participation in specimen banking for future research. With patient'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 sign and give written informed consent in accordance with institutional and federal guidelines.
• As a part of the OPEN registration process (see Section 13.3 for OPEN access instructions) 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.

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 to registration for disease assessment: diagnostic quality skeletal survey, whole body CT 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 days prior to first randomization:
• Total bilirubin </=1.5 x IULN (institutional upper limit of the norm) AND 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.
• 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.
• 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.

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 (see Section 10.1b).