Tolerability in Patients with Multiple Myeloma Treated with Daratumumab: A Systematic Review and Meta-Analysis of Phase III Randomized Controlled Trials

Abstract

Introduction: Multiple myeloma, which accounts for 1% of all cancers, is a hematologic cancer in which clonal plasma-cell proliferation leads to complications and death. Over the recent years, it has shown that the introduction of novel agents, including daratumumab and the incorporation of proteasome inhibitors and immunomodulatory drugs has improved outcomes in patients with multiple myeloma. Daratumumab is a human, CD38-targeting, IgG1κ monoclonal antibody with direct antitumor effects and an immunomodulatory component and has recently shown to improve survival in patients with multiple myeloma. However, there are considerable safety concerns. The purpose of our study is to determine the risk of TD and deaths due to treatment-related adverse events (TRAE) in patients with multiple myeloma treated with daratumumab. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2019. Phase III RCTs utilizing daratumumab in patients with multiple myeloma were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR), and risk difference (RD) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Random effects model was applied. Results: Five phase III RCTs with a total of 3,547 patients with multiple myeloma were eligible. Studies compared daratumumab (D) + bortezomib (V) + melphan (M) + prednisone (P) vs VMP, D + lenalidomide (R) + dexamethasone (d) vs Rd, DVd vs Vd, DVd + thalidomide (T) vs VTd and DRd vs Rd. The randomization ratio was 1:1 in all studies. Daratumumab was utilized in relapsed and refractory multiple myeloma in the POLLUX study (n= 564) and the CASTOR study (n= 480) and as first-line treatment for patients with multiple myeloma in the ALCYONE study (n= 700), the CASSIOPEIA study (n= 1085) and the MAIA study (n= 737). The I2 statistic for heterogeneity was 39, suggesting some heterogeneity among RCTs. TD due to TRAE was noted in 120 (6.77%) vs 179 (10.08%) in control group with RR of 0.68 (95% CI: 0.51 -0.91; P = 0.0009) and RD of -0.03 (95% CI: -0.06 to 0.00; P = 0.02). TD due to infection/ pneumonia was reported in 0.95% vs 0.73% in control group (RR, 1.19; 95% CI: 0.42 -3.34; P = 0.75). Treatment-related deaths were 64 (3.61%) in daratumumab arm vs 77 (4.34%) in control arm. The pooled RR was not statistically significant at 0.86 (95% CI: 0.59 -1.25; P = 0.43). Conclusions: The rate of discontinuation of trial treatment due to adverse events was significantly lower in the daratumumab group (6.77%) than in the control arm (10.08%) with RR of 0.68, favoring daratumumab combination regimen. Furthermore, there was no significant difference in the treatment discontinuation due to pneumonia or infection and treatment-related deaths due to TRAE in the daratumumab group, compared to control arm. Disclosures No relevant conflicts of interest to declare.

Risk of Infections Associated with the Use of Monoclonal Antibodies in Multiple Myeloma (MM)

“…In fact, as regards infectious diseases, the FAERS suggests a significant association between daratumumab-based regimens and multiple opportunistic infections [4] and pivotal randomized phase 3 clinical trials documented that the rates of infectious complications, in particular respiratory tract infections including viral complications, are higher in the anti-CD38 mAbs combination with IMiDs or PIs plus dexamethasone group than IMiDs or PIs and dexamethasone alone. In the same line, a recent metanalysis of clinical trials [39], pooling five randomized phase 3 studies (ALCYONE, MAIA, CASSIOPEIA, CASTOR and POLLUX), confirmed that the incidence of TD due to infection/pneumonia was slightly higher with daratumumab than in the control group (0.95% vs 0.73%); conversely, the rates of TD due to treatment-emergent adverse events (TEAEs) (6.77% vs 10.08%) and treatment-related deaths (3.61% vs 4.34%) were significantly lower in the daratumumab group than in the control arm. In contrast to anti-CD38 mAbs, the addition of elotuzumab with IMiDs did not result in a higher incidence of treatment-related neutropenia and pneumonia [36][37][38].…”

“…Despite these clinical observations, to analyze the severity and outcomes of infectious disease with daratumumab vs comparators, some questions need to be asked. Firstly, it is very interesting to observe that, although grade ≥3 infections (25.7% vs 19.0%) and pneumonia (9.3% s 5.7%) [5] were reported more frequently in the anti-CD38 mAbs group than in the control group, the incidence of serious AEs and the incidence of infections leading to death were similar compared with control arms [39]. The safety profile of quadruplet regimens is similar to those of triplet regimens and there is no evidence of additional significant toxicities [6,[9][10][11][12][13].…”