Efficacy and Safety of Daratumumab-Based Quadruplet Therapy Vs Non-Daratumumab-Based Triplet Therapy in Newly Diagnosed Multiple Myeloma Patients: A Systematic Review and Meta-Analysis
Authors: Osama Muhammad , Haris Khan Muhammad , Tahir Ammara , Hussain Amna , Ali Aizaz , Khan Safeena , Hasan Malik Bilal , Alam Intikhab , Khan Zeeshan , Afridi Abdullah , Gul Amna , Ur Rehman Mohammad Ebad , Iftikhar Ahmad , Husnain Muhammad , Anwer Faiz 
Published: December 2024

Introduction: Multiple Myeloma (MM) involves the clonal proliferation of plasma cells and is the second most common hematologic malignancy, with a five-year Overall Survival (OS) rate of 48.5%. National Comprehensive Cancer Network (NCCN) guidelines v4.2024 recommend triple therapy regimens as preferred induction therapy in both Transplant-Eligible (TE) and Transplant-Ineligible (TIE) patients. However, quadruplet therapy regimens comprising a CD 38 monoclonal antibody like daratumumab have been introduced, leading to a higher Minimal Residual Disease (MRD) negativity and deeper responses, translating into longer Progression-Free Survival (PFS). This study compares the efficacy and safety of daratumumab-based quadruplet therapy regimens with standard triplet therapy regimens in NDMM patients.

Methods: We conducted a comprehensive electronic search of PubMed, Embase, Cochrane Database of Systemic Reviews, and clinicaltrial.gov up to July 1, 2024, using relevant MeSH terms and keywords for “Multiple Myeloma” and “Daratumumab”. Inclusion criteria encompassed randomized controlled trials (RCTs) comparing daratumumab-based quadruplet therapy versus non-daratumumab-based triplet therapy in NDMM patients. Primary efficacy outcomes focused on PFS and stringent complete response (sCR). Secondary outcomes included overall response rate (ORR), complete response (CR), complete response or better (≥CR), very good partial response rate (VGPR), very good partial response rate or better (≥VGPR), negative MRD, and safety profiles. Subgroup analyses based on TE, and TIE were performed. The Mantel-Haenszel technique with a random effects model was used in The Review Manager (RevMan, Version 5.4) for data analysis.

Results: Six RCTs meeting inclusion criteria were identified from 2365 screened studies, involving 3,048 patients (1,562 in the daratumumab group and 1,486 in the non-daratumumab group). Among these, three RCTs were conducted in TE-MM patients (2,001 patients), and three in TIE-MM patients (1,047 patients). Median patient's age ranged from 59 to 75.9 years, with 43.8% female representation. Daratumumab-based therapy demonstrated significantly higher sCR rates (35.1% vs. 22.2%, RR 1.66, 95% CI 1.34-2.05; P &lt; 0.00001), with TE-MM (RR 1.50 CI 1.34-1.67; P &lt; 0.00001) and TIE-MM (RR 2.73 CI 1.85-4.04; P &lt; 0.00001) showing notable improvements. PFS was also significantly better with daratumumab (HR 0.48, 95% CI 0.41-0.56; P &lt; 0.00001), including in TE-MM (HR 0.43 CI 0.34-0.54; P &lt; 0.00001) and TIE-MM (HR 0.52 CI 0.42-0.65; P &lt; 0.00001). Secondary outcomes were all significantly improved in the DARA group except for VGPR and Progressive disease which were comparable among the two groups. Subgroup analysis of sCR on cytogenetic risk basis in TE-MM trials showed better outcomes in standard-risk patients (RR 1.56, 95% CI 1.28-1.91) compared to high-risk patients (RR 0.83, 95% CI 0.52-1.34), with a significant subgroup difference (P = 0.02).

Among the adverse events neutropenia (RR 1.42, CI 1.04-1.92; P = &lt;0.00001) in the hematological adverse events, whereas diarrhea (RR 1.11., CI 1.00-1.22; P = 0.05), pneumonia (RR 2.08, CI 1.52-2.86; P&lt;0.00001), URTI (RR 1.54, CI 1.26-1.88; P&lt;0.0001), pyrexia (RR1.18, CI 1.02-1.36; P=0.02), and cough (RR 1.75, CI 1.38-2.22; P&lt;0.00001) in the non-hematological adverse events were significantly higher in the DARA compare to the non- DARA group.

Conclusion: The use of daratumumab-based quadruplet therapy regimens in NDMM has shown significant improvement in sCR, and PFS, and has led to higher rates of MRD negativity compared to triplet therapy regimens. Although there is a higher incidence of adverse events (both hematological and non-hematological), the enhanced efficacy and clinical outcomes, including reduced relapse rates, support the use of daratumumab-based quadruplet therapy regimens for treating NDMM patients in both transplant-eligible (TE) and transplant-ineligible (TIE) groups.