Timing the Initiation of Multiple Myeloma

The evolution and progression of multiple myeloma (MM) and its precursors over time is poorly understood. Here, we investigated the landscape and timing of mutational processes shaping MM evolution in a large cohort of 89 whole genomes and 973 exomes. Eight processes were identified, including a new mutational signature associated with exposure to alkylating agents. Reconstructing the chronological activity of each mutational signature, we estimated that initial transformation of a germinal center B-cell usually occurred during the first 2-3 decades of life. From there the transformed cells followed one of four main trajectories to MM, each reflecting a distinct order of mutational processes driving tumor evolution. Our findings provide a framework to study the etiology of MM and explore strategies for prevention and early detection.