Background: Non-invasive low-grade urothelial carcinoma (UC) carries a very low risk of distant metastasis and such tumors are typically managed with localized therapies. These tumors also appear to be biologically distinct from high-grade invasive urothelial carcinoma, with unique molecular signatures and driver mutations. The efficacy of systemic therapy including platinum-based chemotherapy, immune checkpoint inhibitors (CPI), and FGFR blocking agents in non-invasive low-grade tumors has not been assessed. Results: A 68-year-old woman with history of high-dose chemotherapy followed by autologous stem cell transplant (SCT) for treatment of breast cancer developed a renal mass 22 years later. She underwent a left nephroureterectomy, which revealed non-invasive low-grade UC (pTa). Surveillance cystoscopy after 21 months showed non-invasive low-grade UC of the bladder. Shortly thereafter, she was discovered to have bilateral “cannon-ball” pulmonary metastasis and mediastinal lymphadenopathy, with biopsy of a lung lesion demonstrating metastatic low-grade UC. Foundation Medicine next generation sequencing (NGS) demonstrated an FGFR3 S249C mutation. She was treated with platinum-based chemotherapy, achieving a partial treatment response. She was subsequently initiated on CPI, but developed rapid disease progression in the lungs and new bony metastasis, with a bone biopsy confirming metastatic low-grade UC. She then rapidly deteriorated and passed away. Conclusion: We report a unique case of clinically-aggressive metastatic non-invasive low-grade UC arising in a patient post autologous SCT. Molecular tumor profiling in this rare setting is crucial to assist with optimal selection of systemic therapy.