Australia has one of the highest incidences of melanoma in the world and it has been referred to as our national cancer. Survival rates for melanoma are poor if not caught early. Recently, understanding of the molecular events that dominate the landscape of early disease has benefited from genomic sequencing, but how melanoma evolves into its metastatic and lethal form is poorly understood. To help rectify this, a rapid autopsy program, CASCADE (CAncer tiSsue Collection After DEath) was established at the Peter MacCallum Cancer Centre that provides multi-region sampling of metastases from patients at time of death. We obtained sequencing data from more than 70 samples from 13 patients, including WES and WGS. The matricial nature of this dataset prompted us to apply an analysis approach that builds on existing methods and makes use of the multiple samples from each patient. Our analysis reveals striking patterns in the evolution of lethal melanoma. While early melanomas have large numbers of single nucleotide variants, we generally observed limited subsequent SNV and indel gain. Rather, evolution was dominated by large-scale copy number change including a remarkable level of loss of heterozygosity in some patients. In one case, multicore sampling revealed spatial heterogeneity in copy number of the primary tumour. Patterns of copy number change hinted that two mutational processes, aneuploidy and genome doubling, were operating universally. To test this we developed a novel method that models these mechanisms using branching processes. Our findings in lethal melanoma suggest possible biomarkers that might be useful clinically in challenging settings where patients present significant clinical heterogeneity such as stage III disease. We are further developing these using a training set of 55 sequencing datasets from primary disease.