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Background CAR-T therapy is an effective immunotherapy for hematologic malignancies. However, patients may experience long-term adverse events including second primary malignancies (SPMs), which significantly impact long-term survival and mortality. This systematic review and meta-analysis aimed to determine the frequency and subtype distribution of SPMs following CAR-T therapy in patients with leukemia, lymphoma, and myeloma.Methods MEDLINE, Embase, Web of Science, and Cochrane CENTRAL databases were searched. SPM cases were extracted, malignancies were adjudicated, and point estimates for SPMs were calculated using a random-effects model.Results A total of 25 clinical trials and 13 real-world studies comprising 15,244 patients were included, identifying 640 SPMs. With a median follow-up of 22.9 months, the overall SPM incidence was 4.2% (95% CI 3.91%–4.53%). Meta-regression confirmed that follow-up duration, bridging therapies,lymphodepleting chemotherapy regimen, and lines of prior therapy were independent study-level risk factors for SPM. Secondary CAR + T cell cancers were identifies. SPM subtype analysis revealed hematologic malignancies as the most common (35.9%), followed by solid tumors (18.4%) and nonmelanoma skin cancer (13.8%). AML and MDS predominated among hematologic SPMs. SPM distribution varied by disease type and CAR-T product.Conclusions This study indicates SPM is a clinically relevant long-term adverse event requiring vigilance in CAR-T recipients.The incidence warrants close monitoring.the underlying risk factors and pathogenesis merit further investigation.