Clonal hematopoiesis is associated with adverse outcomes in multiple myeloma patients undergoing transplant

Tarek H Mouhieddine; Adam S Sperling; Robert Redd; Jihye Park; Matthew Leventhal; Christopher J Gibson; Salomon Manier; Amin H Nassar; Marzia Capelletti; Daisy Huynh; Mark Bustoros; Romanos Sklavenitis-Pistofidis; Sabrin Tahri; Kalvis Hornburg; Henry Dumke; Muhieddine M Itani; Cody J Boehner; Chia-Jen Liu; Saud H AlDubayan; Brendan Reardon; Eliezer M Van Allen; Jonathan J Keats; Chip Stewart; Shaadi Mehr; Daniel Auclair; Robert L Schlossman; Nikhil C Munshi; Kenneth C Anderson; David P Steensma; Jacob P Laubach; Paul G Richardson; Jerome Ritz; Benjamin L Ebert; Robert J Soiffer; Lorenzo Trippa; Gad Getz; Donna S Neuberg; Irene M Ghobrial

doi:10.1038/s41467-020-16805-5

Clonal hematopoiesis is associated with adverse outcomes in multiple myeloma patients undergoing transplant

Nat Commun. 2020 Jun 12;11(1):2996. doi: 10.1038/s41467-020-16805-5.

Authors

Tarek H Mouhieddine^{1

2

3}, Adam S Sperling^{1

2}, Robert Redd⁴, Jihye Park^{1

3}, Matthew Leventhal³, Christopher J Gibson¹, Salomon Manier^{1

5

6}, Amin H Nassar^{1

7}, Marzia Capelletti¹, Daisy Huynh¹, Mark Bustoros^{1

2

3}, Romanos Sklavenitis-Pistofidis^{1

2

3}, Sabrin Tahri^{1

2

3}, Kalvis Hornburg¹, Henry Dumke¹, Muhieddine M Itani⁸, Cody J Boehner¹, Chia-Jen Liu¹, Saud H AlDubayan¹, Brendan Reardon¹, Eliezer M Van Allen¹, Jonathan J Keats⁹, Chip Stewart⁴, Shaadi Mehr¹⁰, Daniel Auclair¹⁰, Robert L Schlossman¹, Nikhil C Munshi¹, Kenneth C Anderson¹, David P Steensma¹, Jacob P Laubach¹, Paul G Richardson¹, Jerome Ritz¹, Benjamin L Ebert^{1

2

3}, Robert J Soiffer¹, Lorenzo Trippa^{1

11}, Gad Getz^{3

8}, Donna S Neuberg⁴, Irene M Ghobrial^{12

13

14}

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA.
² Harvard Medical School, Boston, MA, 02115, USA.
³ Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
⁴ Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, 02115, USA.
⁵ Department of Hematology, CHU, Univ. Lille, 59000, Lille, France.
⁶ INSERM UMR-S1172, 59000, Lille, France.
⁷ Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA.
⁸ Massachusetts General Hospital, Boston, MA, 02114, USA.
⁹ Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ, 85004, USA.
¹⁰ Multiple Myeloma Research Foundation, Norwalk, CT, 06851, USA.
¹¹ Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.
¹² Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA. irene_ghobrial@dfci.harvard.edu.
¹³ Harvard Medical School, Boston, MA, 02115, USA. irene_ghobrial@dfci.harvard.edu.
¹⁴ Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. irene_ghobrial@dfci.harvard.edu.

Abstract

Multiple myeloma (MM) is a plasma-cell neoplasm that is treated with high-dose chemotherapy, autologous stem cell transplant (ASCT) and long-term immunomodulatory drug (IMiD) maintenance. The presence of somatic mutations in the peripheral blood is termed clonal hematopoiesis of indeterminate potential (CHIP) and is associated with adverse outcomes. Targeted sequencing of the stem cell product from 629 MM patients treated by ASCT at the Dana-Farber Cancer Institute (2003-2011) detects CHIP in 136/629 patients (21.6%). The most commonly mutated genes are DNMT3A, TET2, TP53, ASXL1 and PPM1D. Twenty-one from fifty-six patients (3.3%) receiving first-line IMiD maintenance develop a therapy-related myeloid neoplasm (TMN). However, regardless of CHIP status, the use of IMiD maintenance associates with improved PFS and OS. In those not receiving IMiD maintenance, CHIP is associated with decreased overall survival (OS) (HR:1.34, p = 0.02) and progression free survival (PFS) (HR:1.45, p < 0.001) due to an increase in MM progression.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Aged, 80 and over
Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
DNA (Cytosine-5-)-Methyltransferases / genetics
DNA Methyltransferase 3A
DNA-Binding Proteins / genetics
Dioxygenases
Female
Hematopoiesis / genetics*
Hematopoietic Stem Cell Transplantation / methods*
Humans
Male
Middle Aged
Multiple Myeloma / genetics
Multiple Myeloma / therapy*
Mutation*
Progression-Free Survival
Proto-Oncogene Proteins / genetics
Transplantation, Autologous
Tumor Suppressor Protein p53 / genetics
Young Adult

Substances

DNA-Binding Proteins
DNMT3A protein, human
Proto-Oncogene Proteins
Tumor Suppressor Protein p53
Dioxygenases
TET2 protein, human
DNA (Cytosine-5-)-Methyltransferases
DNA Methyltransferase 3A

Abstract

Publication types

MeSH terms

Substances

Grants and funding