Patient must be ≥ 18 years of age

Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
* NOTE: ECOG performance status 3 patients are eligible if attributable to pathological fractures and/or cancer-related bone pain

Patient must have multiple myeloma and meet BOTH of the following criteria for the original diagnosis of myeloma following the International Myeloma Working Group (IMWG) myeloma diagnostic criteria within 90 days prior to randomization
* Bone marrow plasmacytosis with ≥ 10% plasma cells or sheets of plasma cells or biopsy proven plasmacytoma
** Tissue biopsy of any bone lesion or extramedullary plasmacytoma if applicable (positive/negative for clonal plasma cells)
* Any one or more of the following myeloma-defining events:
** Anemia (hemoglobin value of > 2 g/dL below the lower limit of normal, or a hemoglobin value < 10 g/dL)
** Hypercalcemia (serum calcium > 1 mg/dL higher than the upper limit of normal or > 11 mg/dL)
** Bone disease (one or more osteolytic lesions on skeletal radiography, CT, or fludeoxyglucose F-18 [FDG]-PET/CT)  
** Renal dysfunction (creatinine clearance < 40 mL/min or serum creatinine > 2 mg/dL)
** Clonal bone marrow plasma cells (BMPCs) ≥ 60% 
** Involved: uninvolved serum free light chain ratio ≥ 100
** > 1 focal lesions on MRI studies ≥ 5 mm  
** NOTE: Patients with smoldering myeloma (serum m protein ≥ 3 gm/dL or bone marrow plasma cells ≥ 10% plus no evidence of anemia, hypercalcemia, lytic bone lesions or renal dysfunction) and monoclonal gammopathy of undetermined significance (serum m protein < 3 gm/dL and bone marrow plasma cells < 10% plus no evidence of anemia, hypercalcemia, lytic bone lesions or renal dysfunction) are not eligible

Patient must have newly diagnosed (within the last 90 days) light chain cast nephropathy (LCCN) defined as patients with > 1 g/dl proteinuria with < 10% albuminuria, and/or an involved serum free light chain (FLC) concentration > 150 mg/dL

Patient must have new onset of renal failure (within the last 90 days). Patient must have met one of the following criteria:
* Any serum creatinine who have an estimated glomerular filtration rate (eGFR) of < 40 ml/min/1.73  m^2 calculated with the Modification of Diet in Renal Disease (MDRD) formula
* Serum creatinine > 2 mg/dL
* On dialysis
* NOTE: eGFR must be < 50 ml/min/1.73  m^2 if eligible based on serum creatinine level and/or dialysis

Patient may have received myeloma targeting therapy including any of the following: Cyclophosphamide, bortezomib and/or dexamethasone, as long as it was no more than one cycle AND the last dose administered was within 30 days prior to randomization
 NOTE: There is no washout period required

Patient may have received plasma exchange to treat LCCN within 30 days prior to randomization

Patient must not have been exposed to any prior or currently be on any anti-CD38 monoclonal antibodies

Patients who have received prior investigational drug (including investigational vaccine) or invasive investigational medical device for any indication must have recovered from clinically significant adverse events prior to randomization

Patient must not have current or prior exposure to focal radiation therapy within 14 days prior to randomization with the exception of palliative radiotherapy for symptomatic management but not on measurable extramedullary plasmacytoma

Patient must have serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP), and serum free light chain (FLC) assays performed within 28 days prior to randomization. In addition, a bone marrow biopsy and/or aspirate and/or tissue biopsy of any bone lesion or extramedullary plasmacytoma is required to be performed within 28 days prior to randomization
* NOTE: UPEP (on a 24 hour collection) is required, no substitute method is acceptable. Urine must be followed monthly if the baseline urine monoclonal protein (M)-spike is ≥ 200 mg/24 hr. If both serum and urine M-components are measurable, both must be followed in order to confirm response
* NOTE: The serum free light chain test is required to be done monthly if the patient does not have measurable disease in the serum or urine

Hemoglobin ≥ 7.5 g/dL (≥ 4.65 mmol/L) (obtained < 28 days prior to randomization)
* Use of prior red blood cell (RBC) transfusion or recombinant human erythropoietin use is permitted

Absolute neutrophil count (ANC) > 1000 mcL (obtained < 28 days prior to randomization)

Platelets > 75,000 mcL (obtained < 28 days prior to randomization)
* Prior platelet transfusion is permitted

Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (obtained ≤ 28 days prior to randomization)

Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase [SGPT]) ≤ 3 x institutional ULN (obtained ≤ 28 days prior to randomization)

Patient must not be pregnant or breast-feeding due to the potential harm 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 within 14 days prior to randomization to rule out pregnancy
* 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)

Patient must not expect to conceive or father children by using accepted and effective method(s) of contraception or by abstaining from sexual intercourse for the duration of their participation in the treatment phase of the study. Patients of childbearing potential must agree to continue contraceptive measures for at least 1 year after the last dose of Arm A protocol treatment and for at least 7 months after the last dose of Arm B protocol treatment. Patients who can father children with partners who could become pregnant must agree to continue contraceptive measures for at least 4 months after the last dose of protocol treatment. Patient must not donate eggs (ova, oocytes) or sperm while on protocol treatment and for 4 weeks after the last dose of daratumumab-hyaluronidase

Patient must have the ability to understand and the willingness to sign a written 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 considered eligible

Patients with a history of respiratory disease within the past 2 years (i.e. chronic obstructive pulmonary disease, moderate or severe persistent asthma) must have a forced expiratory volume in 1 second (FEV1) ≥ 50% of predicted normal (obtained within ≤ 28 days prior to randomization) to be eligible. Patients with current uncontrolled asthma of any classification are not eligible

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 II or better

Patients with a history of human immunodeficiency virus (HIV) must be on effective anti-retroviral therapy with an undetectable viral load within 6 months of randomization to be 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. Patients who completed treatment for hepatitis C at least 6 months prior to randomization and have no detectable circulating HCV are eligible

Patient must not have grade 3 or 4 peripheral neuropathy at the time of randomization

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

Patient must not have amyloid light-chain (AL) amyloidosis (amyloid light chain or primary amyloidosis), plasma cell leukemia, or central nervous system (CNS) involvement

Patient must not have known allergies, hypersensitivity, or intolerance to boron or mannitol, sorbitol, corticosteroids, monoclonal antibodies or human proteins, or their excipients

PRIMARY OBJECTIVE:
I. To determine whether incorporation of daratumumab-hyaluronidase into the treatment algorithm for newly diagnosed light chain cast nephropathy (LCCN) will improve efficacy measured by renal response rates (RRR) per International Myeloma Working Group (IMWG) renal response criteria over 4 cycles of treatment.

SECONDARY OBJECTIVES:
I. To evaluate the safety profile of daratumumab-hyaluronidase replacing cyclophosphamide in combination with bortezomib and dexamethasone and to compare treatment-related grades 3-5 adverse event rates based on Common Terminology Criteria for Adverse Events (CTCAE) criteria.
II. To evaluate the myeloma response per IMWG uniform response criteria over 4 cycles of therapy.
III. To evaluate progression-free and overall survival.

EXPLORATORY OBJECTIVES:
I. To characterize renal function over time.
II. To assess stem cell mobilization initiation and collection yield in patients eligible for autologous stem cell transplant (ASCT) who undergo mobilization.
III. To assess rate of eligible patients undergoing ASCT.
IV. To assess treatment exposure and adherence.
V. To assess the association of renal impairment stage at baseline and renal response with survival outcomes.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive dexamethasone orally (PO) or intravenously (IV) on days 1-4, 8, 15, and 22 of cycle 1 and on days 1, 8, 15 and 22 of cycles 2-4, cyclophosphamide PO or IV on days 1, 8, 15, and 22 of each cycle and bortezomib subcutaneously (SQ) on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicities. Patients also undergo urine and blood sample collection, positron emission tomography (PET)/computed tomography (CT) or whole body magnetic resonance imaging (MRI), and bone marrow biopsy and aspiration throughout the study. Additionally, patients may undergo CT of the chest, abdomen and pelvis as clinically indicated.

ARM B: Patients receive dexamethasone PO or IV on days 1-4, 8, 15, and 22 of cycle 1 and on days 1, 8, 15, and 22 of cycles 2-4, daratumumab-hyaluronidase SQ over 3-5 minutes on days 1, 8, 14 and 22 of cycles 1 and 2, and on days 1 and 15 of cycles 3 and 4, and bortezomib SQ on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo urine and blood sample collection, PET/CT or whole body MRI, and bone marrow biopsy and aspiration throughout the study. Additionally, patients may undergo CT of the chest, abdomen and pelvis as clinically indicated.

After completion of study treatment, patients are followed every 3 months for years 1 and 2, then every 6 months for years 3-10 from the date of randomization.