Dara-RVd Induction for Newly Diagnosed Multiple Myeloma With Autologous Stem Cell Transplantation

• Daratumumab (Biological): Daratumumab is a CD38-directed cytolytic antibody indicated for the treatment of adults with multiple myeloma. 1800 mg will be given subcutaneously according to its standard package insert schedule.
• Lenalidomide (Drug): Lenalidomide will be administered, once daily orally on Days 1-21 of a 28-day
• Bortezomib (Drug): Bortezomib is a proteasome inhibitor indicated for the treatment of adult patients with multiple myeloma, will be given subcutaneously once weekly on days 1, 8, and 15 of every 28 day cycle.
• Dexamethasone (Drug): Dexamethasone is a glucocorticoid.

Primary outcomes

• The rate of achievement of bone marrow minimal residual disease (MRD) negativity [At completion of stem cell transplantation (60 days)]: The rate of achievement of bone marrow minimal residual disease (MRD) negativity will be defined as the percentage of subjects achieving MRD negativity as determined by next-generation flow cytometry.

Secondary outcomes

• Progression Free Survival (PFS ) [Up to 2 years]: PFS will be defined as the time from the start of study treatment until progression per revised Uniform Response Criteria by the International Myeloma Working Group (IMWG) or death from any cause. Complete response (CR): Negative immunofixation of serum and urine, the disappearance of soft tissue plasmacytomas, and <5% plasma cells in bone marrow (BM). Stringent complete response (sCR): CR plus normal free light chains (FLC) ratio and absence of clonal plasma cells in BM biopsy. Very good partial response (VGPR):-Serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M component plus urine M component <100/24h. Partial response (PR) ≥50% reduction of serum M-protein \& reduction in 24-hour (24h) urinary M-protein by ≥90% or to <200 mg/24h and if present at baseline, a ≥ 50% reduction in the size soft tissue plasmacytomas.
• Stringent complete response (sCR) [At completion of stem cell transplantation (60 days)]: Stringent complete response (sCR) will be defined according to the standard International Myeloma Working Group (IMWG) response criteria for multiple myeloma. Complete response (CR): Negative immunofixation of serum and urine, the disappearance of soft tissue plasmacytomas, and <5% plasma cells in bone marrow (BM). Stringent complete response (sCR): CR plus normal free light chains (FLC) ratio and absence of clonal plasma cells in BM biopsy. Very good partial response (VGPR):-Serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M component plus urine M component <100/24h. Partial response (PR) ≥50% reduction of serum M-protein \& reduction in 24-hour (24h) urinary M-protein by ≥90% or to <200 mg/24h and if present at baseline, a ≥ 50% reduction in the size soft tissue plasmacytomas.
• Overall Survival (OS) [Up to 2 years]: OS will be defined as the time from the start of treatment to death from any cause.
• Therapeutic discontinuation [Up to 2 years]: Therapeutic discontinuation will be defined as a treatment discontinuation of all drugs for any reason.
• Time to first response [Up to 2 years]: Time to first response will be defined as time from the start of study treatment until the first achievement of at least a partial response (PR) by IMWG criteria or better. Complete response (CR): Negative immunofixation of serum and urine, the disappearance of soft tissue plasmacytomas, and <5% plasma cells in bone marrow (BM). Stringent complete response (sCR): CR plus normal free light chains (FLC) ratio and absence of clonal plasma cells in BM biopsy. Very good partial response (VGPR):-Serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M component plus urine M component <100/24h. Partial response (PR) ≥50% reduction of serum M-protein \& reduction in 24-hour (24h) urinary M-protein by ≥90% or to <200 mg/24h and if present at baseline, a ≥ 50% reduction in the size soft tissue plasmacytomas.
• Time to best response [Up to 2 years]: The time to best response will be defined as the time from the start of study treatment until the time at which a patient's best response according to IMWG criteria is achieved. Complete response (CR): Negative immunofixation of serum and urine, the disappearance of soft tissue plasmacytomas, and <5% plasma cells in bone marrow (BM). Stringent complete response (sCR): CR plus normal free light chains (FLC) ratio and absence of clonal plasma cells in BM biopsy. Very good partial response (VGPR):-Serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M component plus urine M component <100/24h. Partial response (PR) ≥50% reduction of serum M-protein \& reduction in 24-hour (24h) urinary M-protein by ≥90% or to <200 mg/24h and if present at baseline, a ≥ 50% reduction in the size soft tissue plasmacytomas.
• Maximum depth of response (from PR to CR, including sCR) [Up to 2 years]: The maximum depth of response (from PR to CR, including sCR) will be determined based on IMWG criteria. Complete response (CR): Negative immunofixation of serum and urine, the disappearance of soft tissue plasmacytomas, and <5% plasma cells in bone marrow (BM). Stringent complete response (sCR): CR plus normal free light chains (FLC) ratio and absence of clonal plasma cells in BM biopsy. Very good partial response (VGPR):-Serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M component plus urine M component <100/24h. Partial response (PR) ≥50% reduction of serum M-protein \& reduction in 24-hour (24h) urinary M-protein by ≥90% or to <200 mg/24h and if present at baseline, a ≥ 50% reduction in the size soft tissue plasmacytomas.
• Overall response rate (ORR) [Up to 2 years]: ORR will be defined as the percentage of subjects achieving a partial response (PR) or better according to IMWG criteria. Complete response (CR): Negative immunofixation of serum and urine, the disappearance of soft tissue plasmacytomas, and <5% plasma cells in bone marrow (BM). Stringent complete response (sCR): CR plus normal free light chains (FLC) ratio and absence of clonal plasma cells in BM biopsy. Very good partial response (VGPR):-Serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M component plus urine M component <100/24h. Partial response (PR) ≥50% reduction of serum M-protein \& reduction in 24-hour (24h) urinary M-protein by ≥90% or to <200 mg/24h and if present at baseline, a ≥ 50% reduction in the size soft tissue plasmacytomas.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Written informed consent was obtained to participate in the study and HIPAA authorization for release of personal health information. Subjects are willing and able to comply with study procedures based on the judgment of the investigator.
2. Age ≥18 years at the time of consent.
3. Eastern Cooperative Oncology Group (ECOG) ≤ 2
4. Subjects with Multiple Myeloma.

Exclusion Criteria:

1. Active infection requiring systemic therapy or other serious infection within 14 days prior to study treatment.
2. Pregnant or breastfeeding.

• Samuel M Rubinstein, MD, MSCI, Principal investigator, UNC Lineberger Comprehensive Cancer Center