Background: Prior studies have shown an increased risk of SPM in melanoma, however there is limited data on the incidence of SPM following the 2011 approvals of immune checkpoint (ipilimumab) and BRAF (vemurafenib) inhibitors, which have become standard of care. We present data comparing SPM rates before and after introduction of these agents for advanced cutaneous melanoma. Methods: Adult melanoma patients with regional or distant metastases were identified from SEER-18 database and divided into cohorts: 2005-2010 and 2011-2016. SPM was defined as tumors diagnosed ≥6 months from diagnosis of the primary cancer. SEER*stat was used to calculate SPM by multiple primary standardized incidence ratio based on observed (O) and expected (E) cases. The expected numbers of new cancers of specific types were estimated by assuming that incidence rates for new primary tumors corresponded to sex, age, and calendar time–specific SEER rates for similar invasive primary cancers and applying those rates to the accumulated person-years (PYR) of observation. Excess absolute risk (EAR) of malignancy per 10,000 PYR at risk was calculated as ([O − E]/PYR) × 10,000. Results: As shown in the table, from before 2005-2010, 421 of 7991 patients (5.2%) with advanced melanoma had 444 SPM (O/E ratio 2.2, 95% CI 1.9-2.4, P< 0.0001, EAR 157). In comparison, from 2011-2016, 527 of 9341 patients (5.6%) developed 584 SPM (O/E ratio 2.5, 95% CI 2.3-2.7, P< 0.0001, EAR 193). Incidence of AML, myeloma, and pancreatic cancer increased in 2005-2010, while soft tissue malignancies increased from 2011-2016. The incidence of thyroid, brain, and small bowel tumors increased in both groups from 2005-2016. Conclusions: There is a distinct pattern as well as increased latency of SPM in patients with advanced melanoma in the era of immune checkpoint and BRAF inhibitors. We speculate that reduction in chemotherapy use, augmentation of immunosurveillance, and inhibition of oncogenic pathways may impact the pathogenesis of SPM.