The goal of this study is to assess the efficacy of induction treatment with daratumumab-hyaluronidase (dara SC) with cyclophosphamide, bortezomib, and dexamethasone (Dara-CyBorD) for four cycles in patients with newly diagnosed multiple myeloma who have new onset renal failure. This study will also investigate the difference responses in African American (AA) patients versus non-African American patients.

The primary questions this study aims to answer are:

1. To evaluate the very good partial response rate (VGPR) after 4 cycles of Dara-CyBord.
2. To evaluate the renal response rate (RRR) after 4 cycles of Dara-CyBord.

Acute renal impairment (RI) is a myeloma emergency. Diagnosis should be established as fast as possible, and antimyeloma therapy should be started immediately after confirmation of the diagnosis to restore renal function rapidly. The incidence of RI at diagnosis ranges from 20% to 50%. Patients with RI had more advanced disease than the others, a lower response rate to treatment than those with normal renal function, and shorter survival. Overall survival is significantly longer among those with baseline CrCl ≥30 mL per minute than those with CrCl <30 mL per minute.

This is a prospective, interventional pilot study for patients with newly diagnosed multiple myeloma (NDMM) who have new onset renal failure. The study will implement a planned enrollment strategy to focus on the African American (AA) patient population, with an accrual goal of 50% of all participants. All participants will be assigned to receive induction treatment with daratumumab-hyaluronidase (dara SC) with cyclophosphamide, bortezomib, and dexamethasone (Dara-CyBorD) for four cycles of 28 days, followed by restaging with repeat PET-CT, bone marrow evaluation, and myeloma serological testing. After induction with Dara-CyBorD, further treatment as per standard guidelines will be determined at the physician's discretion based on transplant eligibility to either an additional 2 cycles of Dara-CyBorD followed by maintenance therapy (if transplant ineligible) or autologous stem cell transplantation (ASCT) followed by maintenance therapy (if transplant eligible). Maintenance therapy will consist of lenalidomide with dara SC for 2 years. Participants will be followed every three months for up to 2 years per the standard guidelines or until disease progression or the start of a new line of therapy to assess the duration of response.

The use of novel antimyeloma agents resulted in a substantial increase in the survival of patients with MM with RI. MM patients with RI are generally excluded from clinical trials. Clinical trials for MM patients with RI are an unmet need. Bortezomib-based regimens remain the cornerstone of the management of myeloma-related RI, with high-dose dexamethasone, with the addition of a conventional chemotherapy agent (cyclophosphamide).

Inclusion Criteria:

1. Patients must have had a confirmed new diagnosis of MM following revised IMWG criteria.
2. Patients must have Zubrod/ECOG Performance Status ≤ 2.
3. Patients must have renal insufficiency. Renal insufficiency is defined as eCrCl < 60 mL/min (using Cockcroft-Gault Equation for Cr Cl) and/or necessitating dialysis
4. must not have known allergies to any of the study drugs. Must have adequate organ function.
5. International normalized ratio (INR) and prothrombin time (PT) ≤1.5 × ULN. Activated partial thromboplastin time (aPTT) ≤1.5 × ULN.

Exclusion Criteria:

• 1. Known seropositive for: human immunodeficiency virus (HIV), Hepatitis B, or Hepatitis C.

  2. Known Chronic obstructive pulmonary disease (COPD). 3. Known Moderate or severe persistent asthma within the past 2 years, or uncontrolled asthma of any classification.

  4. Known Clinically significant heart disease is defined as: myocardial infarction within 6 months before enrollment, or unstable or uncontrolled disease/condition related to or affection cardiac function.

  5. Women who are pregnant, breastfeeding, or planning to become pregnant while enrolled in this study.

  6. Patients with grade 3 or 4 peripheral neuropathy 7. Patients with other active malignancies that require concurrent treatment 8. Known CNS involvement or plasma cell leukemia, or AL amyloidosis 9. Participants with active infection requiring systemic therapy 10. Has known substance abuse disorders that would interfere with cooperation with the requirements of the study.