A Systematic Review of Daratumumab Based Four Drug Regimen for Newly Diagnosed Multiple Myeloma in Phase III Clinical Trials
Authors: Neupane Karun , Ahmed Zahoor , Khan Amna , Ashraf Rabia , Shahzad Moazzam , Nabeel Shaha , Akbar Arshia , Javed Saad , Abdullah Syed Maaz , Faizan Unaiza , Anwer Faiz 
Published: November 2020

Introduction:
Daratumumab (Dara) is a human an IgG1k monoclonal antibody that targets the CD38 which is overexpressed in the malignant cells of multiple myeloma (MM). Its use has been approved for use as a single agent as well as in combination therapy for the treatment of both newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM). This review highlights the efficacy and safety of Dara in the four-drug regimen in NDMM patients (pts).
Methods:
We conducted a literature search using four databases (PubMed, Embase, Cochrane, and Clinicaltrials.gov). Our search strategy included Medical Subject Headings (MeSH terms) and keywords for multiple myeloma and daratumumab including trade names and generic names from the date of inception to June 2020. After excluding review articles, duplicates, and non-relevant articles, we included three phase III trials out of 588 articles reporting Dara addition to the standard of care four drug regimens for NDMM pts.
Results:
A total of 1998 patients were enrolled and evaluated in three-phase III randomized controlled trials. A total of 997 patients were evaluated in the Dara group and 1001 patients were evaluated in the control group. Total 1292 were transplant eligible and 706 patients were transplant ineligible. Transplant eligible
Moreau et al. (2019) studied the efficacy of Dara + bortezomib (V) + thalidomide (T) + dexamethasone (d) vs VTd in newly diagnosed MM (NDMM) pts (n=1085) in CASSIOPEIA phase III trial. Addition of Dara to VTd group showed marked improvement in progression-free survival (PFS): 93% vs 85% at 18 months (hazard ratio (HR) 0.42 [0.34-0.51]; p&lt;0.0001), and overall response rate (ORR) of 92.6% in Dara + VTd group as compared to 89.9% in VTd group (CI: 95%, P&lt;0.0001). Minimal residual disease (MRD) negative status (10-⁵ sensitivity threshold, assessed by multiparametric flow cytometry) in bone marrow was 64% in Dara using VTd vs 44% in the VTd group (P&lt;0.0001).
Vorhees et al. (2020) reported addition of Dara to lenolidamide (R), and Vd in GRIFFIN study in NDMM patients (n= 207). Addition of Dara to VRd resulted in improved PFS: 95.8% ((95% CI, 89.2- 98.4) vs 89.8% ((95% CI, 77.1-95.7) at 24 months), and ORR of 99% (Odd's ratio (OR) 8.75 with 95% CI: 1.08-71.01; p=0.0160) in Dara + VRd group vs VRd group (91.8%). MRD status in bone marrow was also higher in Dara group as compared to control group (51% vs 20.4%) (p&lt;0.0001). Transplant ineligible
Mateos et al. (2018) reported the role of Dara + V + melphalan (M) + prednisone (P) vs VMP in NDMM pts (n=706) in a phase III trial (Alcyone). Addition of Dara to VMP group showed marked improvement in PFS: 63% vs 36 at 24 months (HR: 0.47, 95% CI 0.33-0.67, p&lt;0.0001), and ORR: 90.9% vs 73.9%, respectively. MRD negative status in bone marrow was observed higher with Dara compared to without Dara using VMP (28% vs 7%) (p&lt;0.0001).
Significant toxicities in phase III trials mainly included pancytopenias and opportunistic infections (Table 2).
Conclusion:
NDMM treatment with Dara in four-drug regimens (VTd, VMP, VRd) has shown promising outcomes with improved efficacy and higher negative MRD status, providing a benchmark for future studies.

Disclosures
Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.