Tolerability, Incidence of Second Primary Skin Malignancies and Diarrhea in Patients with Relapsed Refractory Multiple Myeloma Treated with Isatuximab: A Systematic Review and Meta-Analysis of Phase III Randomized Controlled Trials
Authors: Htut Thura Win , Han Myat Min , Myat Yin Mon , Thein Kyaw Zin 
Published: December 2023

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. Isatuximab is a human, CD38-targeting, IgG1 monoclonal antibody with direct antitumor effects, and an immunomodulatory component, resulting in apoptosis of myeloma cells. Over the recent years, it has shown that the addition of isatuximab to proteasome inhibitors and immunomodulatory drugs has improved outcomes in patients with relapsed or refractory multiple myeloma (RRMM). However, there are considerable safety concerns. The purpose of our study is to determine the risks of second primary skin malignancy, diarrhea, treatment emergent serious adverse events (SAE) and treatment discontinuation due to treatment emergent adverse events (TEAE) 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 second primary skin malignancy, diarrhea, treatment emergent serious adverse events and treatment discontinuation 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. Second primary skin malignancy was reported in 16 of patients (4.9%) treated with isatuximab based combination treatment compared to 7 (2.6%) but RR was not statistically significant at 1.79 (95% CI: 0.74 - 4.31; P = 0.19). More events of any-grade diarrhea were noted in study arm (36.2%) compared to 26.9% in control arm with RR of 1.31 (95% CI: 1.03 - 1.67; P=0.03) but RR for high-grade diarrhea was not statistically significant at 1.26 (95% CI: 0.42 - 3.82; P = 0.68). TD due to TEAE was noted in 40 patients (12.2%) in study group vs 43 (15.9%) in control group with RR of 0.76 (95% CI: 0.51 -1.13; P = 0.17). Treatment emergent SAEs were reported in 71.4% vs 60.1 % in control group (RR, 1.19; 95% CI: 1.06-1.34; P = 0.004).
Conclusions
Our meta-analysis showed that there was no significant difference in the treatment discontinuation due to adverse events in patients with RRMM treated with isatuximab combination regimen, compared to control arm although rate of treatment emergent SAEs and any-grade diarrhea were slightly higher in the isatuximab-treated arm than the control arm. Furthermore, differences in the risks of second primary skin malignancy and high-grade diarrhea were found to be statistically not significant between study and control arms. Further studies and longer follow up are required to determine the actual relationship of second primary skin malignancies. In addition, close observation and supportive care is essential to improve treatment-emergent SAEs.