Updated Meta-Analysis of Phase III Randomized Controlled Trials (RCTs) to Evaluate the Incidence of Second Primary Malignancies (SPMs) in Patients with Multiple Myeloma (MM) Treated with Isatuximab

Introduction:

The management of multiple myeloma has experienced significant advancements in recent years.The isatuximab combination regimens are becoming the standard of care nowadays for both newly diagnosed (ND) and relapsed/refractory (RR) MM. However, it is crucial to consider all potential risks, particularly the risk of second primary malignancies (SPMs). The purpose of this meta-analysis is to further investigate the risk of SPMs in patients with MM treated with isatuximab.

Methods:

We conducted a comprehensive systematic literature search using MEDLINE, EMBASE, and cochrane databases from inception through July 22nd, 2024. Phase III RCTs utilizing isatuximab in patients with either RRMM or NDMM that report SPMs were included in the analysis. We reported the total number of SPMs including both solid and non-solid malignancy. We performed a subgroup analysis regarding the incidence of SPMs in the first-line treatment setting (NDMM) and second-line treatment setting (RRMM). 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 1704 patients from 4 phase III RCTs were eligible (1104 patients with NDMM from GMMG-HD7 and IMROZ trials + 600 patients with RRMM from IKEMA and ICARIA-MM trials). ICARIA-MM and IKEMA compared isatuximab (I) + pomalidomide (P) + dexamethasone (d) vs Pd, and isatuximab (I) + Carfilzomib (K) + dexamethasone (d) vs Kd respectively. IMROZ and GMMG-HD7 both compared isatuximab (I) + bortezomib (V) + lenalidomide (R) + dexamethasone (d) vs VRd. Randomization ratios were 1:1 in ICARIA-MM and GMMG-HD7 studies, and 3:2 in IKEMA and IMROZ studies. Overall, the incidence of SPMs was 6.50% in the isatuximab group vs 4.22% in the control group (RR, 1.39; 95% CI: 0.83-2.33; P=0.21), (risk difference [RD], 0.02; 95% CI: -0.01-0.05; P=0.24). In the subgroup analysis, the results were also not statistically significant. In the NDMM cohort, incidence of SPMs was 5.38% (isatuximab group) vs 3.92% (control group) (RR, 1.16; 95% CI: 0.48-2.80; P=0.74), (RD, 0.01; 95% CI: -0.04-0.06); P=0.67). In the RRMM cohort, incidence of SPMs was 8.51% (isatuximab group) vs 4.79% (control group) (RR, 1.75; 95% CI: 0.70-4.35; P=0.23), (RD, 0.04; 95% CI: -0.00-0.07; P=0.05).

Conclusion:

This meta-analysis shows no increased risk of SPMs overall in patients with NDMM or RRMM treated with isatuximab. Further investigations and long term follow up with close surveillance of those patients on the studies are needed to monitor for any developing malignancies in the future and define the actual relation and definitive incidence.

Thein:OMNI-Oncology: Honoraria; Onviv Expert Network: Honoraria; Targeted Oncology: Honoraria; Eisai: Honoraria; Advisory Board for Eisai: Membership on an entity's Board of Directors or advisory committees; Aptitude Health: Honoraria; Curio Science: Honoraria.