Accelerated single cell seeding in relapsed multiple myeloma
Heather Landau, Venkata D. Yellapantula, Benjamin Diamond, Even H. Rustad, Kylee Maclachlan, Gunes Gundem, Juan S. Medina-Martínez, Juan Arango Ossa, Max F. Levine, Yangyu Zhou, Rajya Kappagantula, Priscilla Baez, Marc A. Attiyeh, Alvin P. Makohon-Moore, Lance Zhang, Eileen M. Boyle, Cody Ashby, Patrick Blaney, Minal Patel, Yanming Zhang, Ahmet Doǧan, David J. Chung, Sergio Giralt, Oscar Lahoud, Jonathan U. Peled, Michael Scordo, Gunjan L. Shah, Hani Hassoun, Neha Korde, Alexander M. Lesokhin, Sydney X. Lu, Sham Mailankody, Urvi A. Shah, Eric L. Smith, Malin Hultcrantz, Gary A. Ulaner, Frits van Rhee, Gareth J. Morgan, Ola Landgren, Elli Papaemmanuil, Christine A. Iacobuzio–Donahue, Francesco Maura
Abstract
Multiple myeloma (MM) progression is characterized by the seeding of cancer cells in different anatomic sites. To characterize this evolutionary process, we interrogated, by whole genome sequencing, 25 samples collected at autopsy from 4 patients with relapsed MM and an additional set of 125 whole exomes collected from 51 patients. Mutational signatures analysis showed how cytotoxic agents introduce hundreds of unique mutations in each surviving cancer cell, detectable by bulk sequencing only in cases of clonal expansion of a single cancer cell bearing the mutational signature. Thus, a unique, single-cell genomic barcode can link chemotherapy exposure to a discrete time window in a patient's life. We leveraged this concept to show that MM systemic seeding is accelerated at relapse and appears to be driven by the survival and subsequent expansion of a single myeloma cell following treatment with high-dose melphalan therapy and autologous stem cell transplant.