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

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

doi:10.1038/s41467-020-16805-5

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.

Highlights

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
Not all patients benefit from ASCT and it can be associated with significant long-term toxicities including cytopenias and therapy-related myeloid neoplasms (TMN), a risk that is further increased by the use of lenalidomide maintenance[2,3,4]
clonal hematopoiesis of indeterminate potential (CHIP) is defined as the presence of characteristic leukemia-associated somatic mutations in hematopoietic cells that occur at a variant allele fraction (VAF) of at least 0.02 in the absence of diagnostic criteria for hematological neoplasms[9]

Summary

Introduction

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 standard of care for fit newly diagnosed patients in the United States is induction chemotherapy with a combination of a proteasome inhibitor and immunomodulatory drug (IMiD) followed by high dose melphalan chemotherapy and autologous stem cell transplantation (ASCT). This is typically followed by IMiD maintenance until disease progression. Not all patients benefit from ASCT and it can be associated with significant long-term toxicities including cytopenias and therapy-related myeloid neoplasms (TMN), a risk that is further increased by the use of lenalidomide maintenance[2,3,4]. The presence of CHIP has been reported in patients with MM, but that study was not powered to assess a relationship between CHIP and clinical outcomes[22]

Methods

Results

Conclusion