This phase II trial tests daratumumab given at a reduced frequency with lenalidomide for maintenance therapy for the cost effective treatment of patients with multiple myeloma post stem cell transplant. Darzalex Faspor (also known as Daratumumab-hyaluronidase) is a combination of two drugs used alone or with other drugs to treat adults with certain types of multiple myeloma or light chain amyloidosis. Daratumumab binds to a protein called CD38, which is found on some types of immune cells and cancer cells, including myeloma cells. Daratumumab may block CD38 and help the immune system kill cancer cells. Hyaluronidase allows daratumumab to be given by injection under the skin. Daratumumab and hyaluronidase can be given in less time than daratumumab alone, which is given as an infusion. Lenalidomide may stop or slow cancer cells by blocking the growth of new blood vessels necessary for tumor growth. Daratumumab-hyaluronidase is typically given every 4 weeks per standard of care. Giving it every 8 weeks for the first year followed by every 16 weeks for years 2 through 4 in combination with lenalidomide may be equally as effective and reduce costs and treatment visits for patients with multiple myeloma post stem cell transplant.

Inclusion Criteria:

• Signed and dated written informed consent
• Male or female newly diagnosed multiple myeloma (NDMM) patients 18 to 70 years old on the day of signing informed consent who had ASCT with post-ASCT response of partial response (PR) or better as defined by International Myeloma Working Group (IMWG). The induction regimen should include a proteasome inhibitors (PI), immunomodulatory drugs (IMiD) and anti-CD38 monoclonal antibody
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
• Patients with high-risk and international staging system (ISS) stage-III disease in 15% of the intent to treat population. Patients with 1q gain, 1p deletion, del17p, t[4;14], or t[14;16] by fluorescence in situ hybridization [FISH] will be categorized as having high risk disease
• Absolute neutrophil count, ≥ 1.0 × 10^9/L
• Platelets ≥ 75,000/μL
• Hemoglobin level ≥ 7.5 g/dL
• Total bilirubin < 1.5 times institutional upper limit of normal (ULN) (if patient has known history of Gilbert's syndrome, total bilirubin will not be used as an exclusion criteria)
• Corrected serum calcium, ≤ 14.0 mg/dL (≤ 3.5 mmol/L)
• Platelet count, ≥ 50 × 10^9/L (≥ 50 × 10^9/L if ≥ 50% of the bone marrow was infiltrated with multiple myeloma [MM] cells)
• Alanine aminotransferase and aspartate aminotransferase levels < 2.5 times the upper limit of normal
• Creatinine clearance ≥ 30 mL/min (per institutional standard)
• 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
• Patients must not be pregnant due to potential harm to the fetus from daratumumab and lenalidomide. All patients of childbearing potential must have a negative test result via blood test or urine study with a sensitivity of at least 50 mIU/mL within 10-14 days prior to the first dose of lenalidomide and again within 24 hours prior to the first dose of lenalidomide. Patients of childbearing potential must also agree to ongoing pregnancy testing while on treatment. A patient of childbearing potential is defined as anyone, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: * 1) has achieved menarche at some point, * 2) has not undergone a hysterectomy or bilateral oophorectomy, or * 3) 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 in the preceding 24 consecutive months). Patients of childbearing potential must either abstain from sexual intercourse for the duration of their participation in the study or agree to use TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME for * 1) at least 28 days before starting study treatment; * 2) while participating in the study; * 3) during dose interruptions; and * 4) for at least 3 months after the last dose of protocol treatment. Patients must also agree to not breastfeed during this same time period. Men must agree to either abstain from sexual intercourse for the duration of their participation in the study or use a latex condom during sexual contact with a partner of childbearing potential while participating in the study and for 3 months after the last dose of lenalidomide even if they have had a successful vasectomy. Patients must also agree to abstain from donating sperm, even if they have had a successful vasectomy, or eggs while on study treatment and for 3 months after the last dose of protocol. Patients must agree to abstain from donating blood during study participation and for at least 28 days after last dose of lenalidomide

Exclusion Criteria:

• All patients with concomitant amyloidosis or plasma cell leukemia
• Patient is pregnant or breastfeeding
• Has received a live vaccine within 30 days prior to first dose of study treatment. * Examples of prohibited live vaccines include but are not limited to: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, bacillus Calmette-Guérin (BCG), and typhoid vaccine. * Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (for example FluMist® Quadrivalent [Influenza Vaccine Live, Intranasal, MedImmune]) are live attenuated vaccines and are not allowed. COVID-19 vaccines that are messenger ribonucleic acid (mRNA) based which do not use live virus are allowed
• Is currently participating in or within 4 weeks prior to receiving first dose of study treatment in a study of an investigational agent or investigational device. * Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose or last exposure to the previous investigational agent or investigational device
• Diagnosis of immunodeficiency; or is receiving systemic steroid therapy exceeding 10 mg daily prednisone equivalent dose (=10mg is acceptable); or has received any other form of immunosuppressive therapy within 7 days prior to first dose of study treatment
• Known additional malignancy that is progressing or has required active treatment within the past 3 years prior to first dose of study treatment. * Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (for example, in situ cervical cancer or breast carcinoma, superficial bladder cancer, or carcinoma in situ of the prostate) that have undergone potentially curative therapy are not excluded
• Radiographically detectable (even if asymptomatic and/or previously treated) central nervous system metastases and/or carcinomatous meningitis as assessed by local site investigator and radiology review
• Recipient of previous allogeneic tissue/solid organ transplant
• Known severe hypersensitivity (≥ grade 3) to drug daratumumab or lenalidomide
• History of myocarditis or pericarditis or other known underlying heart disease that is clinically significant by investigator judgment (for example, cardiomyopathy, congestive heart failure with New York Heart Association [NYHA] functional classification III or IV, symptomatic arrhythmia not controlled by medication, unstable angina, history of acute myocardial infarction). History of cerebrovascular accident (including transient ischemic attack [TIA]) within the past 6 months (24 weeks) prior to starting study treatment
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection/sepsis, or psychiatric illness/social situations that would limit compliance with study requirements
• Active autoimmune disease with immunodeficiency as a clinical component (for example, rheumatoid arthritis, systemic lupus erythematosus [SLE], ulcerative colitis, Crohn's disease, multiple sclerosis [MS], ankylosing spondylitis)
• Recognized immunodeficiency disease including cellular immunodeficiencies; hypogammaglobulinemia or dysgammaglobulinemia; or acquired, hereditary, or congenital immunodeficiencies
• Known conditions associated with immunosuppression such as uncontrolled HIV/AIDS, leukemia, lymphoma, generalized malignancy, solid organ transplant recipient, or allogeneic hematopoietic stem cell transplant recipient
• Gastrointestinal disease that may significantly alter the absorption of oral drugs
• Unable or unwilling to undergo antithrombotic prophylactic treatment