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

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.

Haematopoietic ageing through the lens of single-cell technologies

“…The increased occurrence of clonal haematopoiesis is one of the signs of haematopoietic ageing ( Arends et al, 2018 ; Jaiswal et al, 2014 ). Several studies have investigated the impact of clonal haematopoiesis on the outcome of HSC transplantation therapy ( Frick et al, 2019 ; Gibson et al, 2017 ; Mouhieddine et al, 2020 ; Ortmann et al, 2019 ). However, the implications of clonal haematopoiesis for stem cell transplantation are difficult to identify owing to the high degree of mutational heterogeneity present within the genetically distinct subclones ( Park et al, 2019 ).…”

Monoclonal Gammopathy of Undetermined Significance (MGUS)—Not So Asymptomatic after All

“…Potentially clonal hematopoiesis may co-exist with MGUS [95]. Recent studies on the presence of CHIP in MM report a prevalence of 22% [96]. Whether this extends to MGUS and correlates with the risk of CVD is not known.…”

Clonal Hematopoiesis of Indeterminate Potential as a Novel Risk Factor for Donor-Derived Leukemia

“…Surprisingly, mutations in other CHIP-associated genes, such as DNMT3A , TET2 , and ASXL1 , were observed but were not associated with inferior outcomes, implying that specific CHIP-associated mutations may be more susceptible to the autologous transplant environment ( Husby et al., 2020 ). Similarly, in patients undergoing autologous transplantation for multiple myeloma, CHIP correlated with decreased survival and increased multiple myeloma progression, indicating that CHIP can modulate multiple types of hematological malignancy ( Mouhieddine et al., 2020 ). Autologous transplantation in CHIP patients is also associated with late non-relapse mortality, demonstrating that CHIP-associated mutations have diverse effects on transplant outcomes ( Slavin et al., 2019 ).…”

“… Patients with mutations in DNA damage repair genes exhibited worse overall survival and increased intensive care admissions. Mouhieddine et al. (2020) 629 multiple myeloma patients 58 years autologous 21 CHIP patients developed MDS or AML after transplant.…”