Meta-Analysis of Randomized Controlled Trials to Evaluate the Incidence of Pneumonia, Upper Respiratory Tract Infections and Febrile Neutropenia in Patients with Multiple Myeloma Treated with Isatuximab

Abstract

Introduction Multiple myeloma is a cancer of plasma cell and accounts for approximately 13% of all haematologic malignancies. Isatuximab is an anti CD38 IgG1 monoclonal antibody which binds to and kills myeloma cells through antibody-dependent cellular-mediated cytotoxicity, complement-dependent cytotoxicity, antibody-dependent cellular phagocytosis, and direct induction of apoptosis. The incorporation of isatuximab to standard treatment in patients with relapsed refractory multiple myeloma (RRMM) has shown to significantly improve efficacy, with notable toxicities. We performed a combined analysis of randomized controlled trials (RCT) to determine the risk of pneumonia and upper respiratory tract infections (URTIs) and febrile neutropenia in patients with RRMM treated with isatuximab. Methods We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 30 th, 2023. Phase III RCTs utilizing isatuximab in patients with relapsed or refractory multiple myeloma that mention pneumonia, URTIs and febrile neutropenia as adverse effects were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Random effects model was applied. Results A total of 600 patients with RRMM from 2 phase III RCTs (ICARIA-MM and IKEMA) were eligible. ICARIA-MM and IKEMA compared isatuximab (I) + pomalidomide (P) + dexamethasone (d) vs Pd, and isatuximab (I) + Carfilzomib (K) + dexamethasone (d) vs Kd respectively. The randomization ratios were 1:1 in ICARIA-MM, and 3:2 in IKEMA studies. The I 2 statistic for heterogeneity was 0, suggesting homogeneity among RCT. The incidence of any-grade pneumonia was 30.1% in study group vs 25.8% in control group (RR, 1.19; 95% CI: 0.91 - 1.54; P=0.20). High-grade pneumonia rate was nearly 4% higher in isatuximab group compared to control arm but RR was not statistically significant at 1.26 (95% CI: 0.90 - 1.75; P = 0.18). More events of any-grade URTIs were reported in study arm (36.8%) versus 23.2% in control arm with RR of 1.55 (95% CI: 1.20- 2.01; P = 0.0008). The incidence of high-grade URTIs was low in both groups: 3.3% in study group versus 1.47% in control arm (RR, 2.25; 95% CI: 0.72 - 6.98; P = 0.16). Febrile neutropenia was noted in 20 (6%) of patients in study group compared to 5 (1.8%) in control group with RR of 3.52 (95% CI: 1.40- 8.83; P = 0.007). Conclusions Our meta-analysis showed that the addition of isatuximab to standard anti-myeloma regimen contributed to higher incidence of any-grade URTIs and febrile neutropenia in patients with RRMM, with RR of 1.55 for any-grade URTIs and RR of 3.5 for febrile neutropenia. However, risks of high-grade URTIs, any-grade and high-grade pneumonia were found to be statistically not significant between the two groups. Early recognition and proper supportive care are required to improve any-grade URTIs and febrile neutropenia.