Inclusion Criteria:
* Patients must have documented newly diagnosed multiple myeloma satisfying standard International Myeloma Working Group (IMWG) diagnostic criteria within 28 days prior to registration for participants with no prior therapy, or within 28 days prior to initiation of first induction cycle for participants who had prior therapy
* Clonal bone marrow plasma cells ≥ 10% or biopsy-proven bony or extramedullary plasmacytoma and any one or more of the following CRAB features (myeloma-defining events) or biomarkers of malignancy:
* Myeloma defining events (as per IMWG criteria for the diagnosis of multiple myeloma):
\*\* Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically (one or more of the following):
* \[C\] Calcium (Hypercalcemia: serum calcium \> 0.25 mmol/L (\> 1 mg/dL) higher than the upper limit of normal (ULN) or \> 2.75 mmol/L (\> 11 mg/dL)
* \[R\] Renal insufficiency: Renal insufficiency: creatinine clearance \< 40 mL/min (measured or estimated by validated equations) or serum creatinine \> 177 µmol/L (\> 2 mg/dL)
* \[A\] Anemia: hemoglobin value \> 2 g/dL below the upper limit of normal, or a hemoglobin value \< 10 g/dL
* \[B\] Bone lesions: one or more osteolytic lesions on skeletal radiography, CT or 18F-fluorodeoxyglucose PET with CT
* Biomarkers of malignancy:
* Clonal bone marrow plasma cell percentage ≥ 60% (clonality should be established by showing κ/λ light chain restriction on flow cytometry, immunohistochemistry or immunofluorescence. Bone marrow plasma cell percentage should preferably be estimated from a core biopsy specimen; in case of disparity between the aspirate and core biopsy, the highest value should be used
* Involved:uninvolved serum free light chain (FLC) ratio \> 100. The involved FLC must be ≥ 100 mg/L (these values are based on the serum Freelite assay \[The Binding Site Group Birmingham, United Kingdom \[UK\])
* \> 1 focal lesion on MRI studies (each focal lesion must be ≥ 5 mm in size) \*\*\*\* If bone marrow has less than 10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement
* Measurable disease as defined by any of the following:
\* Serum M-protein ≥ 1.0 g/dL (≥ 0.5 g/dL if immunoglobulin A \[IgA\], IgD, IgE or IgM myeloma) or urine M-protein ≥ 200 mg/24 hours
* Light chain myeloma without measurable disease in the urine: involved serum free light chain ≥ 10 mg/dL with abnormal serum kappa/lambda ratio)
* Participants must have whole body imaging within 60 days prior to registration. The recommended method of imaging is PET/CT; a low-dose whole body CT scan or whole-body MRI should be done only if a PET/CT scan cannot be done or is not feasible. The scan must be completed prior to initiation of any treatment for multiple myeloma, with the exception of localized palliative radiation therapy
* In concordance with the International Myeloma Society/IMWG Consensus Recommendations, patients with high-risk multiple myeloma (HRMM) are excluded. HRMM is defined as having at least one of these abnormalities:
* del(17p), with a cut-off of \> 20% clonal fraction, and/or TP53 mutation;
* An IgH translocation including t(4;14), t(14;16), or t(14;20) along with 1q+ and/or del(1p32);
* Monoallelic del(1p32) along with 1q+ or biallelic del(1p32); or
* ß2-microglobulin ≥ 5.5 mg/L with normal creatinine (\< 1.2 mg/dL) \*\* In addition, patients with plasma cell leukemia, polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) or concomitant light chain amyloidosis are excluded
* Revised International Staging System (R-ISS) information (obtained at diagnosis) will be collected for staging and data collection purposes only
* Stage I
\*\* All of the following:
\*\*\* ß2-microglobulin \< 3.5 mg/L
* Serum albumin ≥ 3.5 g/dL
* Normal lactate dehydrogenase (LDH)
* No del(17p), t(4;14), or t(14;16) by fluorescence in situ hybridization (FISH)
* Stage II
\*\* Neither stage I nor stage III
* Stage III \*\* Both of the following:
* ß2-microglobulin ≥ 5.5 mg/L
* Elevated LDH and/or del(17p), t(4;14), or t(14;16) by FISH
* Participants may receive up to one cycle of therapy prior to enrollment. If a patient receives ≥ 75% of 1 cycle of protocol identical DaraRVd, this will be considered cycle 1 of protocol induction. Any patient who receives less than 75% of 1 cycle of DaraRVd or non-protocol therapy will still be eligible but will be treated per protocol. If protocol identical therapy is initiated prior to enrollment, this treatment is not continued but rather treatment is dictated per protocol
* Participants may be receiving chronic corticosteroids if they are being given for disorders other than multiple myeloma
* For patients who previously received lenalidomide and/or daratumumab for a diagnosis of smoldering myeloma, disease progression to active myeloma cannot have occurred while on treatment and a washout period of ≥ 12 months is required
* Radiation therapy is permitted prior to study entry, during screening and during cycles 1-2 of induction as needed for management of lytic bone disease
* Patients with a prior or concurrent malignancy whose natural history of treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
* Age 18 to 75 years
* Able to tolerate melphalan 200 mg/m2 as per the physician's discretion
* Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2
* Absolute neutrophil count (ANC) ≥ 1,000/mm\^3
* Platelet count ≥ 75,000/mm\^3 for subjects in whom \< 50% of bone marrow nucleated cells are plasma cells; otherwise platelet count ≥ 50,000/mm\^3
* Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (except for participants with history of Gilbert Syndrome where total bilirubin must be ≤ 5 x ULN)
* Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) ≤ 3 x upper limit of normal (ULN)
* Calculated (Calc.) creatinine clearance ≥ 30 mL/min
* Not pregnant and not nursing, because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown
\* A female of childbearing potential is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months)
* Women of childbearing potential (WOCBP):
\*\*\* Must use a contraceptive method that is highly effective (with a failure rate of \< 1% per year), preferably with low user dependency during the intervention period and for at least 5 months after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention
\*\*\* Must have a negative highly sensitive serum pregnancy test (as required by the lenalidomide Risk Evaluation and Mitigation Strategies \[REMS\]) within 24 hours before the first dose of study intervention and agree to use a highly effective method of contraception during the study and for 5 months after the last dose of lenalidomide
\*\*\* The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with a nearly undetected pregnancy
* Must have a negative highly sensitive serum pregnancy test ≤ 5 days prior to registration
* Non-childbearing potential is defined as follows (by other than medical reasons):
* ≥ 45 years of age and has not had menses for \> 1 year
* Patients who have been amenorrhoeic for \< 2 years without history of a hysterectomy and oophorectomy must have a follicle stimulating hormone value in the postmenopausal range upon screening evaluation
* Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure
* Male patients must agree to use an adequate method of contraception for the duration of the study and for 90 days afterwards
* Male participants: contraceptive use should be consistent with the lenalidomide REMS regarding the methods of contraception:
* Male participants are eligible to participate if they agree to the following during the intervention period and for 6 months after the last dose of study treatment to allow for clearance of any altered sperm:
* Refrain from donating sperm
PLUS either:
* Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent OR
* Must agree to use contraception/barrier as detailed below:
* Agree to use a male condom, even if they have undergone a successful vasectomy, and female partner to use an additional highly effective contraceptive method with a failure rate of \< 1% per year as when having sexual intercourse with a woman of childbearing potential (including pregnant females)
* Patients with known HIV infection on effective anti-retroviral therapy with undetectable viral load within 6 months prior to registration are eligible for this trial
* For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
* 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
* 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
* Participants must not have evidence of greater than or equal to grade 3 peripheral neuropathy prior to study registration
* Participants must not have uncontrolled blood pressure within 14 days prior to registration, to be determined by treating physician
* Participants must not have known allergies to any of the study drugs or intolerance to monoclonal antibodies or human proteins
* Participants must not have had a major surgery within 14 days prior to cycle 1, day 1 and be fully recovered from any prior surgery prior to registration. Note-kyphoplasty is not considered a major surgery
* Participants must not have a known or uncontrolled chronic obstructive pulmonary disease with prior testing resulting in a forced expiratory volume in 1 second (FEV1) \< 50% of predicted normal
Exclusion Criteria:
N/A
