Accelerated single cell seeding in relapsed multiple myeloma

Heather J Landau; Venkata Yellapantula; Benjamin T Diamond; Even H Rustad; Kylee H Maclachlan; Gunes Gundem; Juan Medina-Martinez; Juan Arango Ossa; Max F Levine; Yangyu Zhou; Rajya Kappagantula; Priscilla Baez; Marc Attiyeh; Alvin Makohon-Moore; Lance Zhang; Eileen M Boyle; Cody Ashby; Patrick Blaney; Minal Patel; Yanming Zhang; Ahmet Dogan; David J Chung; Sergio Giralt; Oscar B Lahoud; Jonathan U Peled; Michael Scordo; Gunjan Shah; Hani Hassoun; Neha S Korde; Alexander M Lesokhin; Sydney Lu; Sham Mailankody; Urvi Shah; Eric Smith; Malin L Hultcrantz; Gary A Ulaner; Frits van Rhee; Gareth J Morgan; Ola Landgren; Elli Papaemmanuil; Christine Iacobuzio-Donahue; Francesco Maura

doi:10.1038/s41467-020-17459-z

Accelerated single cell seeding in relapsed multiple myeloma

Nat Commun. 2020 Jul 17;11(1):3617. doi: 10.1038/s41467-020-17459-z.

Authors

Heather J Landau^#^{1

2}, Venkata Yellapantula^#^{3

4}, Benjamin T Diamond⁴, Even H Rustad⁴, Kylee H Maclachlan⁴, Gunes Gundem³, Juan Medina-Martinez³, Juan Arango Ossa³, Max F Levine³, Yangyu Zhou³, Rajya Kappagantula⁵, Priscilla Baez⁵, Marc Attiyeh⁵, Alvin Makohon-Moore⁵, Lance Zhang⁵, Eileen M Boyle⁶, Cody Ashby⁷, Patrick Blaney⁶, Minal Patel⁸, Yanming Zhang⁹, Ahmet Dogan¹⁰, David J Chung^{1

2}, Sergio Giralt^{1

2}, Oscar B Lahoud^{1

2}, Jonathan U Peled^{1

2}, Michael Scordo^{1

2}, Gunjan Shah^{1

2}, Hani Hassoun^{2

4}, Neha S Korde^{2

4}, Alexander M Lesokhin^{2

4}, Sydney Lu^{2

4}, Sham Mailankody^{2

4}, Urvi Shah^{2

4}, Eric Smith^{2

4}, Malin L Hultcrantz^{2

4}, Gary A Ulaner¹¹, Frits van Rhee⁷, Gareth J Morgan⁶, Ola Landgren^{2

4}, Elli Papaemmanuil³, Christine Iacobuzio-Donahue⁵, Francesco Maura¹²

Affiliations

¹ Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
² Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
³ Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁴ Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁵ Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁶ NYU Perlmutter Cancer Center, New York, NY, USA.
⁷ Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
⁸ Center for Hematological Malignancies, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁹ Cytogenetics Laboratory, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁰ Hematopathology Service, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹¹ Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹² Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. [email protected].

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Combined Chemotherapy Protocols / administration & dosage
Antineoplastic Combined Chemotherapy Protocols / adverse effects*
Cell Survival / drug effects
Cell Survival / genetics
Clonal Evolution / drug effects*
Disease Progression
Dose-Response Relationship, Drug
Hematopoietic Stem Cell Transplantation / adverse effects*
Humans
Male
Melphalan / administration & dosage
Melphalan / adverse effects
Middle Aged
Multiple Myeloma / diagnostic imaging
Multiple Myeloma / genetics
Multiple Myeloma / pathology*
Multiple Myeloma / therapy
Mutation / drug effects
Neoplasm Invasiveness / genetics
Neoplasm Invasiveness / pathology
Neoplasm Recurrence, Local / diagnostic imaging
Neoplasm Recurrence, Local / genetics
Neoplasm Recurrence, Local / pathology*
Neoplasm Recurrence, Local / therapy
Positron Emission Tomography Computed Tomography
Single-Cell Analysis
Spatio-Temporal Analysis
Transplantation, Autologous / adverse effects
Whole Genome Sequencing

Substances

Melphalan

Abstract

Publication types

MeSH terms

Substances

Grants and funding