Efficacy of daratumumab combination regimen in patients with multiple myeloma: A combined analysis of phase III randomized controlled trials

Abstract The use of the CD38 monoclonal antibody daratumumab in combination with standard myeloma chemotherapy regimens has been studied extensively in recent years. We undertook an updated meta‐analysis of phase III randomized controlled trials (RCT) to determine the efficacy of daratumumab combination regimens. The relative risk for progression was significantly lower in daratumumab‐treated cohorts (HR 0.46, 95% CI 0.38‐0.55) and this was consistent across newly diagnosed and relapsed cases. No statistically significant improvement was identified in newly diagnosed patients with high‐risk cytogenetics and this group remains a therapeutic challenge.


INTRODUCTION
Multiple myeloma (MM) is a hematological malignancy characterized by monoclonal proliferation of abnormal plasma cells, which accounts for one percent of all cancers worldwide [1]. MM remains incurable and complicated by end-organ damage, including anemia, hypercalcemia, renal dysfunction, and lytic lesions in the bone [2]. MM ultimately progresses or relapses and remains a therapeutic challenge [3]. Over the past two decades, proteasome inhibitors (PI) and immunomodulatory drugs (IMiDs) have improved survival in patients with MM [4]. Introducing novel agents has recently become the hallmark of a therapeutic paradigm shift in the management of newly diagnosed MM (NDMM) and relapsed or refractory MM (RRMM), in both transplant -eligible and -ineligible patients [5]. Daratumumab is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that can bind to CD38 on the surface of myeloma cells and lead to cell lysis [6]. Studies  treatment of MM. We undertook an updated meta-analysis of phase III randomized controlled trials (RCT) to determine the efficacy of daratumumab combination regimens in patients with NDMM and RRMM.

METHODS
The systematic review was performed as per the Cochrane Handbook for Systematic Reviews and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [7]. We performed systematically a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts up to 30 th April 2020 using the keywords "multiple myeloma AND daratumumab," OR "plasma cell disorder AND daratumumab." The references of all potential studies were also reviewed for any additional relevant studies. We limited the search to "humans" and "randomised controlled trials." All studies written in English or non-English languages were obtained. The studies that were eligible to be included in the meta-analysis had to conform with the following characteristics: phase III RCTs utilizing daratumumab in patients with newly diagnosed/untreated multiple myeloma or relapsed/refractory multiple myeloma.
The primary outcome of our meta-analysis was progression-free survival (PFS). The secondary outcome was the overall response rate (ORR), including stringent complete response (sCR), complete response (CR), and MRD negativity (molecular response). We summarized the characteristic features of incorporated studies in Table 1 [  [14]. A "P-value" of <.05 was considered significant and I 2 > 50% is considered substantially heterogeneous. An HR < 1.0 or RR < 1.0 was in favor of daratumumab. The risk of bias for each study was evaluated by Cochrane RevMan 5.3 software. Five main salient biases (selection bias, performance bias, detection bias, attrition bias, reporting bias, and others) were categorized and were rated as low, high, or unclear risk [14]. Publication bias was assessed by funnel plots.

RESULTS
The I 2 statistic showed some heterogeneity among RCTs and the random-effects model was applied to provide a more conservative result. The pooled HR for overall PFS was statistically significant at .46 (95% CI: 0.38-0.55; P < .00001) Figure 1A. The pooled HR for PFS was calculated for each subset; NDMM in Figure 1B (HR, 0.54; 95% CI: 0.46-0.63; P < .00001) and RRMM in Figure 1C (HR, 0.44; 95% CI: 0.30-0.64; P < .0001). Although the pooled HR for PFS was significant in standard-risk cytogenetic NDMM cohort in Figure 1D

DISCUSSION
Daratumumab is an anti-CD38 monoclonal antibody that lyses abnormal plasma cells through direct cytotoxicity to the cell and complement activation [6] as well as an immunomodulatory effect [15]. The antitumor effect of daratumumab can be enhanced by the addition of immunomodulatory drugs such as lenalidomide [6]. Recently, there have been several studies comparing the efficacy and safety of daratumumab combination regimens with non-daratumumab based antimyeloma therapies.
Our meta-analysis showed that daratumumab combination regimens yielded better PFS than control arms in both NDMM and RRMM. Despite the consistency of our findings, some caution should be used in their interpretation. First, the studies used different standard combination regimens, trial design, and methodology, which might confound the analysis. Second, the overall survival data are still immature for a few trials and we used the abstract data for the CANDOR trial. Individual patient data pooled meta-analysis would provide more detailed and accurate analyses and confirm our findings. Lastly, translating clinical trial data into the real-world setting is of paramount importance.

CONCLUSION
Our meta-analysis showed that daratumumab combination regimens significantly improved PFS, ORR, CR, and sCR, and MRD negativity

CONFLICTS OF INTEREST AND SOURCE OF FUNDING
Gavin Preston has received honoraria or meeting sponsorship from Abbvie, Janssen-Cilag, and Takeda, and has attended meetings sponsored by Celgene, Roche, Bristol-Myers-Squibb, Novartis, Gilead, Pfizer, and Napp pharmaceuticals. Jane Tighe has received educational support and travel for meetings from Amgen, Celgene, Sanofi Aventis, Takeda, and Janssen over the years. We had no financial support for this project.