Efficacy and Safety of Daratumumab Based Regimens for Multiple Myeloma: A Systematic Review and Meta-Analysis
Authors: Abu Zar Muhammad , Kamal Ahmad , Khan Ali Younas , Malik Saad Ullah , Malik Mustafa Nadeem , Rafae Abdul , Durer Ceren , Durer Seren , Selene Insija Ilyas , Qureshi Anum , Jose Jemin Aby , Fazeel Hafiz Muhammad , Shah Zunairah , Rehman Muhammad Adil , Anwer Faiz 
Published: October 2019

Abstract
Introduction: Daratumumab is a human IgGκ monoclonal antibody targeting CD38 that has been approved for the treatment of multiple myeloma (MM). We performed a meta-analysis of trials with daratumumab to find its efficacy and safety.
Materials and Methods: Extensive literature search of Medline, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov on 5/07/2018 identified a total of 1596 articles. Fourteen articles (n = 1439) met the inclusion criteria, eleven in the relapsed and refractory multiple myeloma (RRMM) and three in the newly diagnosed multiple myeloma (NDMM) group (Table 1). A meta-analysis was performed using STATA version 15 and inter study heterogeneity was calculated using I² statistic.
Results: The overall response rate (ORR) was 69% (95% CI: 51-84%) and very good partial response or better (≥VGPR) was 40% (95% CI: 22-60%) in RRMM patients. In a subgroup analysis with three, two and single drug regimen, ORR was 85% (95% CI: 77-92%), 30% (95% CI: 21-40%) and 31% (95% CI: 24-39%) respectively in RRMM patients. The hazard ratio (HR) for progression free survival (PFS) with daratumumab based regimens was 0.35 (95% CI: 0.26-0.45) as compared to non-daratumumab based regimens in two randomized controlled trials (RCTs). The most effective regimen, in terms of PFS for RRMM patients with a median of a single previous line of therapy was daratumumab with lenalidomide with dexamethasone (24-months PFS rate: 68%) in the POLLUX trial (Dimopoulos et al., 2017). The ORR was 97% (95% CI: 92-100%) and ≥VGPR rate was 64% (95% CI: 44-83%) in NDMM patients (Figure 1). In the only available RCT for NDMM patients, the HR for PFS was 0.50 (95% CI: 0.38-0.65) (Mateos et al., 2017).
Incidence of neutropenia was 30% (95% CI: 16-46%) and thrombocytopenia was 25% (95% CI: 15-37%). While the incidence of anemia was 17% (95% CI: 13-21%). Incidence of ≥ grade 3 non-hematologic treatment emergent adverse effects (TEAEs) were as follows: pneumonia (11.3-12%), hypertension (8-12%) and fatigue (4-12.5%). In daratumumab and non-daratumumab based regimens ≥ grade 3 infusions related reactions occurred in 5% of the patients. In the three RCTs, these hematologic (≥ grade 3) TEAEs were comparable as neutropenia occurred in 36.86% vs 29.57%, thrombocytopenia in 30% vs 29% and anemia in 16.67% vs 19% respectively. Patients on daratumumab based regimens who discontinued treatment due to TEAEs were 8.56% vs 9.93% on non-daratumumab based regimens in the three RCTs which shows that most of the treatment discontinuations was due to other drugs in the regimen.
Conclusion: Our results suggest that daratumumab containing regimen is more effective than non-daratumumab based regimens for RRMM and NDMM patients. Three drug daratumumab based regimens are more effective when compared to two drug or daratumumab monotherapy regimens. The safety profile of daratumumab is favorable, which makes it an extremely useful drug. Despite limited data in NDMM patients, daratumumab based regimens appear to be highly effective. Further prospective randomized trials are needed to compare various daratumumab based regimens.

Disclosures
No relevant conflicts of interest to declare.