STEP 0: Patient must be >= 18 years of age

STEP 0 - Patient must have the ability to understand and the willingness to sign an informed consent document. Patients with impaired decision-making capacity (IDMC) who have a legally authorized representative (LAR) or caregiver and/or family member available will also be eligible

STEP 0 - Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2 (PS 3 allowed if secondary to pain)

STEP 0 - Patient must have suspected or confirmed newly diagnosed multiple myeloma (MM) by International Myeloma Working Group (IMWG) criteria and must not have received more than one cycle of treatment.
* NOTE: Patient does not need to have bone marrow evaluation prior to Step 0 pre-registration. Bone marrow evaluation may be deferred to after Step 0 pre-registration to confirm presence of > 10% clonal bone marrow plasma cells per IMWG criteria

STEP 0 - Patient must be considered ineligible for autologous stem cell transplantation by the treating physician, or willing to delay stem cell transplantation until first relapse or later. 
* NOTE: Stem cell collection is allowed on study

STEP 0 - Patient must agree to register to the mandatory Celgene Revlimid Risk Evaluation and Mitigation Strategy (REMS) program and be willing and able to comply with the requirements of the Revlimid REMS program

STEP 0 - Patient must not have any known allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal antibodies or human proteins, or their excipients (refer to respective package inserts or Investigator's Brochure), or known sensitivity to mammalian-derived products

STEP 0 - Patient must be able to undergo diagnostic bone marrow aspirate following preregistration if not performed previously. If the bone marrow aspirate was performed previously, archival bone marrow aspirate smears (3-5) or FFPE slides/scrolls from the clot section (5-10) must be available for clonoSEQ® Assay.
* NOTE: Bone marrow aspirate specimen, or an acceptable alternative, (high disease specimen – at least 5% disease) (i.e.: FFPE slides/scrolls from the clot section, or bone marrow aspirate smears) must be submitted to Adaptive Biotechnologies for clonoSEQ® Assay. Decalcified specimens (core) or whole blocks are not acceptable.
* NOTE: Adaptive Biotechnologies will release results to the diagnostic portal from the Clonality (ID) test within fourteen (14) days of receipt and reconciliation of fresh bone marrow specimen to the submitting institution
* NOTE: If clonoSEQ Assay was performed previously as part of standard of care, results can be used for Step 1 registration

STEP 1 - Patient must meet all eligibility criteria in STEP 0 with exception of the last criterion

STEP 1 - Institution must have received the Clonality (ID) test results from Adaptive Biotechnologies and dominant sequences must have been identified

STEP 1 - Patient must have standard risk MM as defined by the Revised International Staging System (R-ISS) stage I or II
* NOTE: R-ISS stage is based on serum beta2 microglobulin, albumin and lactate dehydrogenase (LDH) levels along with presence of chromosomal abnormalities (CA) detected by interphase fluorescent in situ hybridization (iFISH). Presence of del(17p), t(4;14), and/or t(14;16) is considered high risk and absence of these, including any other findings, are standard risk
* R-ISS stage
** Stage I: ISS stage I [beta2 macroglobulin < 3.5 mg/L, albumin > 3.5 g/dL] AND standard-risk CA AND normal LDH (=< upper limit of normal)
** Stage II: Not R-ISS stage I or III
** Stage III: ISS stage III [beta2 macroglobulin > 5.5 mg/L] AND high-risk CA OR high LDH (> upper limit of normal) [patients with R-ISS stage III are ineligible]

STEP 1 - Patient must have measurable or evaluable disease as defined by having one or more of the following, obtained within 28 days prior to Step 1 registration:
* >= 1 g/dL monoclonal protein (M-protein) on serum protein electrophoresis
* >= 200 mg/24 hours of monoclonal protein on a 24-hour urine protein electrophoresis
* Involved free light chain >= 10 mg/dL or >= 100 mg/L AND abnormal serum immunoglobulin kappa to lambda free light chain ratio (< 0.26 or > 1.65)
* Monoclonal bone marrow plasmacytosis >= 30% (evaluable disease)

STEP 1 - Patient must have a serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP), and serum free light chain (FLC) assay performed within 28 days prior to Step 1 registration. In addition, a bone marrow biopsy and/or aspirate is required within 28 days prior to Step 1 registration if measurable disease is only present in bone marrow. Otherwise, a bone marrow examination must have been performed within 90 days prior to Step 1 registration).
* NOTE: UPEP (on a 24-hour collection) is required, no substitute method is acceptable. Urine must be followed monthly if the baseline urine M-spike is >= 200 mg/24 hr. Please note that if both serum and urine M-components are present, both must be followed in order to evaluate response
* NOTE: The serum free light chain test is required to be done if the patient does not have measurable disease in the serum or urine. Measurable disease in the serum is defined as having a serum M-spike >= 1 g/dL. Measurable disease in the urine is defined as having a urine M-spike >= 200 mg/24 hr

STEP 1 - Calculated creatinine clearance > 30 mL/min (obtained =< 14 days prior to Step 1 registration)

STEP 1 - Absolute neutrophil count (ANC) >= 1000/mm^3 (obtained =< 14 days prior to Step 1 registration)

STEP 1 - Untransfused platelet count >= 75,000/mm^3 (obtained =< 14 days prior to Step 1 registration)

STEP 1 - Hemoglobin >= 8.0 g/dL (obtained =< 14 days prior to Step 1 registration)

STEP 1 - Total bilirubin =< 1.5 x ULN (institutional upper limit of normal) (obtained =< 14 days prior to Step 1 registration)

STEP 1 - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN (obtained =< 14 days prior to Step 1 registration)

STEP 1 - Patient must have received no more than one cycle (28 days or less) of prior chemotherapy and no more than 160 mg of prior dexamethasone (or equivalent dose of prednisone) for treatment of symptomatic myeloma. Prior radiation therapy to symptomatic lesions is allowed provided there are no residual toxicity related to radiation and blood counts meet the study requirements. Radiation treatment must be completed at least 14 days prior to Step 1 registration
* NOTE: Patients who have received prior treatment for smoldering multiple myeloma (SMM) are eligible, except those who have received prior treatment with lenalidomide in combination with an anti-CD38 monoclonal antibody

STEP 1 - Patient must not be pregnant or breast-feeding due to the potential harm and teratogenic effects to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used. All patients of childbearing potential must have a blood test or urine study with a sensitivity of at least 25 mIU/mL within 10-14 days prior to Step 1 registration to rule out pregnancy 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 protocol treatment. A patient of childbearing potential is defined as anyone, regardless of whether they have undergone tubal ligation, who meets the following criteria: 
* Has achieved menarche at some point,
* Has not undergone a hysterectomy or bilateral oophorectomy; 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 in the preceding 24 consecutive months)

STEP 1 - Patients of childbearing potential must not expect to conceive children by using accepted and effective method(s) of contraception [for this protocol defined as the use of 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 protocol 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] OR by practicing true abstinence from sexual intercourse for the duration of their participation in the study (periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception). Patients must not expect to father children by practicing true abstinence from sexual intercourse for the duration of their participation in the study (periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods and withdrawal are not acceptable methods of contraception] OR use a latex condom during sexual contact with a partner of child bearing potential while participating in the study and for at least 3 months after the last dose of protocol treatment 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 donating eggs while on study treatment and for 3 months after the last dose of protocol treatment. All patients must agree to abstain from donating blood during study participation and for at least 28 days after the last dose of protocol treatment

STEP 1 - Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of Step 1 registration are eligible for this trial

STEP 1 - For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated

STEP 1 - Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load

STEP 1 - Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial

STEP 1 - Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better. Patients must not have evidence of current uncontrolled cardiovascular conditions, including hypertension, cardiac arrhythmias, congestive heart failure, unstable angina, or myocardial infarction within 6 months prior to Step 1 registration

STEP 1 - Patient must not have peripheral neuropathy >= grade 2 on clinical examination or grade 1 with pain at time of Step 1 registration

STEP 1 - Patient must not have any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially interfere with the completion of treatment according to this protocol

STEP 1 - Patient may have a history of current or previous deep vein thrombosis (DVT) or pulmonary embolism (PE) but must be willing to take some form of anti-coagulation as prophylaxis if they are not currently on full-dose anticoagulation

STEP 1 - Patients with a history of chronic obstructive pulmonary disease (COPD) must have FEV1 testing done within 28 days prior to Step 1 registration and the forced expiratory volume in 1 second (FEV1) must be > 50% of predicted normal

STEP 1 - Patient must not have moderate or severe persistent asthma within the past 2 years, or uncontrolled asthma of any classification
* NOTE: Patients who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed to register

STEP 1 - Patient must not receive any other concurrent chemotherapy, or any ancillary therapy considered investigational while on this protocol
* NOTE: Bisphosphonates are considered to be supportive care rather than therapy, and are thus allowed while on protocol treatment

STEP 2 - Institution must have received Tracking (MRD) test results from Adaptive Biotechnologies

STEP 2: Patient must be MRD positive after induction. Patients with post-induction status of MRD negative or MRD indeterminate will not be eligible for randomization.  
Post-Induction MRD Status Definitions: Negative versus Positive versus Indeterminate 
* MRD Negative Status defined as:
** Serum Immunofixation = Negative
AND
** Urine Immunofixation = Negative
AND
** ClonoSEQ® MRD Assay Report states either:
*** No Residual Sequences Detected’, 0 Residual Clonal Cells AND Total Nucleated Cells ≥ 100,000 Cells
OR
*** (+) Residual Sequences Detected’ AND < 10 Residual Clonal Cells Per Million Nucleated Cells
OR
*** Residual Sequences Detected’ (without a [+] sign to the left of the word ‘Residual’) with ‘**’Sequences detected below Limit of Detection (LOD); frequency too low to enable consistent MRD determination across samples AND < 10 Residual Clonal Cells per Million Nucleated Cells.
* MRD Positive Status defined as:
** Serum Immunofixation = Positive
OR
** Urine Immunofixation = Positive
OR
** ClonoSEQ® MRD Assay Report states either:
** ‘(+) Residual Sequences Detected’ AND ≥ 10 Residual Clonal Cells per Million Nucleated Cells
OR
** ‘Residual Sequences Detected’ [without a (+) sign to the left of the word ‘Residual’] with ‘**’Sequences detected below Limit of Detection (LOD); frequency too low to enable consistent MRD determination across samples AND ≥ 10 Residual Clonal Cells per Million Nucleated Cells
MRD Indeterminate Status defined as:
*** ClonoSEQ® MRD Assay Report states either:
*** ‘No Results Available’ this sample failed the quality control criteria despite multiple sequencing attempts, or there was a problem processing the test
OR
*** ‘No Residual Sequences Detected,‘ 0 Residual Clonal Cells AND Total Nucleated Cells < 100,000 Cells
OR
*** All other scenarios that cannot be classified as MRD-negative or MRD-positive

STEP 2 - Patient must have completed the Step 1 Induction phase of this protocol without experiencing progression

STEP 2 - Patient must be registered to Step 2 within 8 weeks of completing Step 1 Induction Treatment, counting from last day of completion of last cycle

STEP 2 - Patient must not have received any non-protocol therapy outside of the assigned Step 1 Induction treatment including stem cell transplant

STEP 2 - Patient must have an ECOG performance status (PS) of 0-2 (PS 3 allowed if secondary to pain)

STEP 2 - Any adverse event(s) related to Step 1 Induction Treatment must have resolved to grade 2 or less

STEP 2 - Hemoglobin >= 8 g/dL (obtained within 14 days prior to Step 2 randomization)

STEP 2 - Platelet count >= 50,000/mm^3 (obtained within 14 days prior to Step 2 randomization)

STEP 2 - Absolute neutrophil count (ANC) >= 1000/mm^3 (obtained within 14 days prior to Step 2 randomization)

STEP 2 - Calculated creatinine clearance >= 30 mL/min (obtained within 14 days prior to Step 2 randomization)

STEP 2 - Total bilirubin =< 1.5 x ULN (Institutional upper limit of normal) (obtained within 14 days prior to Step 2 randomization)

STEP 2 - ALT and AST < 3 x ULN (obtained within 14 days prior to Step 2 randomization)

STEP 2 - Patient must not be pregnant or breast-feeding due to the potential harm and teratogenic effects to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used. All patients of childbearing potential must have a blood test or urine study with a sensitivity of at least 25 mIU/mL within 10-14 days prior to Step 2 randomization to rule out pregnancy 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 protocol treatment. A patient of childbearing potential is defined as anyone, regardless of whether they have undergone tubal ligation, who meets the following criteria: 
* Has achieved menarche at some point, 
* Has not undergone a hysterectomy or bilateral oophorectomy; 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 in the preceding 24 consecutive months).

STEP 2 - Patients of childbearing potential must not expect to conceive children by using accepted and effective method(s) of contraception [for this protocol defined as the use of 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 protocol 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] OR by practicing true abstinence from sexual intercourse for the duration of their participation in the study (periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception). Patients must not expect to father children by practicing true abstinence from sexual intercourse for the duration of their participation in the study (periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods and withdrawal are not acceptable methods of contraception] OR use a latex condom during sexual contact with a partner of child bearing potential while participating in the study and for at least 3 months after the last dose of protocol treatment 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 donating eggs while on study treatment and for 3 months after the last dose of protocol treatment. All patients must agree to abstain from donating blood during study participation and for at least 28 days after the last dose of protocol treatment

PRIMARY OBJECTIVE:
I. To determine if bortezomib, daratumumab and hyaluronidase-fihj (daratumumab-hyaluronidase) subcutaneous (SC), lenalidomide and dexamethasone (Btz-DRd) consolidation followed by daratumumab-hyaluronidase SC and lenalidomide (DR) maintenance after standard induction therapy with daratumumab-hyaluronidase SC, lenalidomide and dexamethasone (DRd) results in superior overall survival compared to DRd consolidation followed by DR maintenance, in patients who are minimal residual disease (MRD) positive after induction.

SECONDARY OBJECTIVES:
I. To determine if Btz-DRd consolidation followed by DR maintenance after standard induction therapy with DRd results in superior progression-free survival compared to DRd consolidation followed by DR maintenance in patients who are MRD positive after induction.
II. To describe the incidence of toxicities during induction and compare the incidence of toxicities during consolidation and maintenance between Btz-DRd and DRd arms.
III. To assess the improvement in MRD negative rate with consolidation among patients who are MRD positive after induction.
IV. To evaluate best response on induction, consolidation, and maintenance.

PATIENT REPORTED OUTCOMES (PRO) OBJECTIVES (EXPLORATORY):
I. To quantify the extent to which the addition of bortezomib to DRd over consolidation treatment contributes to neuropathy and associated physical and functional impairments. 
II. To evaluate the rate of resolution of neurotoxicity and associated physical and functional impairments following completion of consolidation therapy.
III. To investigate the relationship between MRD status change and patient reported health-related quality of life outcomes.
IV. To evaluate attributes of select patient reported treatment-emergent symptomatic adverse events (PRO- Common Terminology Criteria for Adverse Events [CTCAE]) longitudinally and compare responses with provider-reported adverse events.
V. To tabulate PRO compliance and completion rates.

IMAGING OBJECTIVES:
I. To evaluate the association between post-induction fludeoxyglucose F-18 (18F-FDG) positron emission tomography (PET)/computed tomography (CT) and patient outcomes (overall survival [OS] and progression-free survival [PFS]) for patients who are MRD-positive after 9 cycles of induction therapy. (Primary Imaging Objective)
II. To compare overall survival with the addition of bortezomib to consolidation DRd therapy among post-induction 18F-FDG PET/CT-positive and 18F-FDG PET/CT-negative subgroups. (Secondary Imaging Objective)
III. To evaluate the ability of baseline 18F-FDG PET/CT to predict post-induction depth of response as measured by MRD assessment. (Secondary Imaging Objective)
IV. To evaluate the ability of post-induction 18F-FDG PET/CT to predict MRD conversion post-consolidation. (Secondary Imaging Objective)
V. To utilize 18F-FDG PET/CT, standard risk factors and clinical data to identify distinct subgroups with differing patient outcomes (PFS and OS). (Exploratory Imaging Objective)

OUTLINE:
ARM A (INDUCTION): All patients receive standard induction therapy comprising the following: daratumumab-hyaluronidase subcutaneously (SC) on days 1, 8, 15, and 22 of cycles 1-2, days 1 and 15 of cycles 3-6, and day 1 of cycles 7-9, lenalidomide orally (PO) daily on days 1-21, and dexamethasone PO on days 1, 8, 15, and 22. Treatment repeats every 28 days for 9 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow biopsy and/or aspirate and blood and urine sample collection throughout the study. Patients also receive18F-FDG intravenously (IV) and undergo PET/CT during screening and on study. 

After completion of standard induction therapy, patients who are MRD positive are randomized to 1 of 2 arms. 

ARM B:
CONSOLIDATION: Patients receive bortezomib SC on days 1, 8, and 15, daratumumab SC on day 1, lenalidomide PO daily on days 1-21, and dexamethasone PO on days 1, 8, 15, and 22. Treatment repeats every 28 days for 9 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow biopsy and/or aspirate and blood and urine sample collection throughout the study. Patients also receive 18F-FDG IV and undergo PET/CT during screening and on study. 

MAINTENANCE: Patients receive lenalidomide PO daily on days 1-21 and daratumumab-hyaluronidase SC on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM C: 
CONSOLIDATION: Patients receive daratumumab-hyaluronidase SC on day 1, lenalidomide PO daily on days 1-21, and dexamethasone PO on days 1, 8, 15, and 22. Treatment repeats every 28 days for 9 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow biopsy and/or aspirate and blood and urine sample collection throughout the study. Patients also receive 18F-FDG IV and undergo PET/CT during screening and on study. 

MAINTENANCE: Patients receive lenalidomide PO daily on days 1-21, and daratumumab-hyaluronidase SC on day 1. Cycles repeats every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months if less than 2 years from study entry, every 6 months if 2-5 years from study entry, then annually for up to 15 years from study entry.