Inclusion Criteria:

1. Documented multiple myeloma satisfying the International Myeloma Working Group (IMWG) diagnostic criteria36 (evidence of myeloma defining event attributed to underlying plasma cell disorder) with measurable disease defined as:

   1. Clonal plasma cells in the bone marrow ≥ 10% or presence of a biopsy proven plasmacytoma

   2. Measurable disease within the past 4 weeks defined by any of the following:

      • IgG myeloma: Serum monoclonal protein ≥ 1.0 g/dL or urine monoclonal protein ≥ 200 mg/24 hr; or
      • IgA, IgM, IgD, IgE multiple myeloma: serum M-protein ≥ 0.5 g/dL or urine monoclonal protein ≥ 200 mg/24 hr; or
      • Light chain multiple myeloma: Involved serum immunoglobulin free light chain ≥ 10 mg/dL AND abnormal serum free kappa/lambda light chain ratio
      • Measurable plasmacytomas seen on imaging (≥ 1 lesion that has a single diameter ≥ 2 cm). If this is the primary marker of measurable disease, patients will need a biopsy at screening.
      • Bone marrow plasma cells ≥ 30% as determined by CD138 immunohistochemistry staining.

2. Standard risk multiple myeloma - excluding patients with high risk cytogenetic abnormality (HRCA) according to the IMS/IMWG 2024 Consensus Definition:

   1. TP53 mutation and/or del(17p) with cancer clonal function (CCF) >20% by analyses conducted on CD138+ purified cells
   2. t(4;14), t(14;16), or t(14;20) co-occurring with +1q (gain/amp 1q) and/or del(1p)
   3. Monoallelic del(1p32) with +1q or biallelic del(1p32)
   4. High Beta-2 microglobulin (>5.5 mg/dL) with normal creatinine (<1.2 mg/dL)

3. Newly diagnosed patient considered a candidate for high-dose chemotherapy and autologous stem cell transplant

   a. For patients who received one complete cycle of Dara-RVd at MSK, patients can enter treatment at cycle 2 at the discretion of treating investigator and PI

4. Age ≥18 years.
5. Eastern Cooperative Oncology Group (ECOG) performance status 0-2

6. Have adequate organ and hematologic function:

   1. Hemoglobin ≥ 7.5 g/dL (prior RBC transfusion or recombinant human erythropoietin use is permitted);
   2. Absolute neutrophil count (ANC) ≥ 1.0 x 109/L (G-CSF use is permitted);
   3. Platelet count ≥ 75 x 109/L
   4. Creatinine Clearance ≥ 30 ml/min. CrCl can be measured or estimated using Cockcroft-Gault method, MDRD, or CKD-EPI formula
   5. Total bilirubin ≤ 2 x ULN (≤ 3 x ULN if documented Gilbert's syndrome);
   6. AST ≤ 2.5 x ULN;
   7. ALT ≤ 2.5 x ULN
7. All study participants must be able to tolerate one of the following thromboprophylaxis strategies: aspirin, low molecular weight heparin or warfarin (coumadin) or alternative anti-coagulant.
8. All study participants must be able to tolerate one of the following thromboprophylaxis strategies: aspirin, low molecular weight heparin or warfarin (Coumadin), or direct-acting oral anticoagulants (DOACs).
9. All study participants must be registered into the mandatory REMS® program and be willing and able to comply with the requirements of REMS®, including compliance with contraception methods (Appendix A).

Exclusion Criteria:

1. Patients who have received > 1 cycle of prior treatment or concurrent systemic therapy for multiple myeloma (excluding corticosteroids or radiation therapy)). For patients who received one complete cycle of Dara-RVd at MSK, patients can enter treatment at cycle 2 at the discretion of treating investigator and PI
2. Patients with diagnosis of plasma cell leukemia, primary light chain amyloidosis, monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes), Waldentröm's macroglobulinemia
3. History of another active primary malignancy within 2 years prior to enrollment, except for adequately treated basal cell carcinoma or squamous cell skin cancer or carcinoma in situ.

4. Significant, uncontrolled comorbid conditions that is likely to interfere with the study procedures or results, or that in the opinion of the investigator, would constitute a hazard for participating in the study. Examples include, but are not limited to

   1. Chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) < 50% of predicted normal. Note that FEV1 testing is required for participants suspected of having COPD and participants must be excluded if FEV1 is < 50% of predicted normal.
   2. Moderate or severe persistent asthma within the past 2 years or uncontrolled asthma of any classification. Note that participants who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed to participate.
   3. Infiltrative pulmonary disease
   4. Active autoimmune disease requiring systemic immunosuppressive therapy within 6 months before start of study treatment. Exception of vitiligo, type 1 diabetes, and prior autoimmune thyroiditis that is currently euthyroid
   5. Disabling psychiatric conditions (e.g., alcohol or drug abuse)., severe dementia, or altered mental status
   6. Known history of human immunodeficiency virus (HIV)
   7. Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]).

   i. Subjects with resolved infection (i.e., subjects who are HBsAg negative with antibodies to total hepatitis B core antigen [anti-HBc] with or without the presence of hepatitis B surface antibody [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded.

   ii. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of HBV vaccination, do not need to be testing for HBV DNA by PCR.

   h. Seropositive for hepatitis C i. Except in the setting of a sustained virologic response [SVR], defined as a viremia at least 12 weeks after completion of antiviral therapy.

   i. Clinically significant cardiac disease, including: i. Myocardial infarction within 6 months before enrollment, or unstable or uncontrolled disease/condition related to or affection cardiac function (e.g., unstable angina, congestive heart failure, New York Heart Association Class III-IV) ii. Uncontrolled cardiac arrhythmia

5. Pregnant or lactating patients
6. Unwilling to give written, informed consent, unwilling to participate, or unable to comply with the protocol for the duration of the study