Updated Meta-Analysis of Phase III Randomized Controlled Trials (RCTs) to Evaluate the Incidence of Pneumonia, Upper Respiratory Tract Infections (URTIs) and Venous Thromboembolism (VTE) in Patients with Multiple Myeloma Treated with Isatuximab

Introduction

Multiple myeloma is a hematologic malignancy characterized by the clonal proliferation of malignant plasma cells in the bone marrow, constituting approximately 13% of all hematologic malignancies. Isatuximab is a monoclonal antibody targeting the CD38 protein on myeloma cells, causing cell death through various immune-mediated mechanisms. Clinical trials have shown that adding Isatuximab to standard regimens for multiple myeloma significantly enhances efficacy but introduces some notable toxicities. The purpose of this study is to determine the risk of pneumonia, URTIs, and VTE in patients with MM treated with isatuximab.

Methods

We conducted a comprehensive literature search using MEDLINE, EMBASE, and COCHRANE databases from inception through July 22nd, 2024. Phase III RCTs utilizing isatuximab in newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM) mentioning pneumonia, URTIs, and VTE as adverse effects were included. 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 1044 patients from 3 Phase III RCTs (ICARIA-MM, IKEMA, IMROZ) were eligible for evaluation of pneumonia and URTIs incidence. A total of 1403 patients from 3 phase III RCTs (IKEMA, IMROZ, GMMG-HD7) were eligible for evaluation of VTE incidence. ICARIA-MM and IKEMA involved RRMM patients, while IMROZ and GMMG-HD7 involved NDMM patients. ICARIA-MM compared isatuximab (I) + pomalidomide (P) + dexamethasone (d) vs Pd with a 1:1 randomization ratio, while IKEMA compared isatuximab (I) + carfilzomib (K) + dexamethasone (d) vs. Kd with a 3:2 randomization ratio. IMROZ and GMMG-HD7 both compared isatuximab (I) + bortezomib (V) + lenalidomide (R) + dexamethasone (d) vs VRd with a randomization ratio of 3:2 and 1:1 respectively. The incidence of any-grade pneumonia was 30.1% in the isatuximab group vs 23.2% in the control group (RR, 1.31; 95% CI: 1.06 - 1.61; P=0.01), the risk difference (RD) is 0.08 [0.02, 0.13]. High-grade pneumonia incidence in the isatuximab group compared to the control was 20.1% vs 15.3% (RR, 1.38 [1.06-1.81]; P=0.02), RD is 0.06 [0.02-0.11]. More events of any-grade URTIs were reported in the isatuximab arm 35.5% vs 27.7% in the control arm (RR 1.31; 95% CI: 0.96-1.78; P=0.09) with a RD of 0.08 ([0.00-0.17]; P=0.06). High-grade URTIs incidence was 2.2% in the isatuximab arm vs 1.8% in the control arm (RR, 1.28 [0.53-3.13]; P=0.58), RD of high-grade URI was 0.00 [-0.01-0.02]. The incidence of VTE was not statistically different between two groups; 4.67% in the isatuximab arm vs 3.96% in the control arm with an RR of 1.04 (95% CI: 0.65-1.68; P=0.87) and a RD of 0.00 (-0.01-0.01; P=0.71).

Conclusions

Our meta-analysis revealed that adding isatuximab to the standard anti-myeloma regimen increased the incidence of any-grade or high-grade pneumonia and any-grade URTIs in both RRMM and NDMM patients. The risk of high-grade URTIs was not statistically significantly different between the two groups. The incidence of VTE was similar between the isatuximab and control groups. Timely identification and effective supportive care are crucial to manage these adverse events.