Clonal Hematopoiesis Prevalence and Mutational Spectrum in Patients with Plasma Cell Disorders at the Time of Diagnosis and Its Impact on Clinical Features, Cardiovascular Complications, and Survival

Abstract

Introduction: Multiple myeloma (MM) most commonly occurs in older individuals with median age at diagnosis of 70 years. Clonal hematopoiesis (CH) also increases with age with 10-15% prevalence in individuals older than 70. CH has been analyzed in patients with plasma cell disorders (PCD). A single institution study detected CH in 21.6% of MM patients at the time of autologous transplant and CH was associated with poor survival in those that did not receive maintenance therapy with immunomodulatory drug (IMiD) (Mouhieddine et al, Nat. Comm., 2020). In newly diagnosed MM patients, CH was detected in 10.2% patients and prevalence increased with time from diagnosis (Mouhieddine et al, Blood, 2021, S1). More recently, a population-based study in older adults with median age 91 yrs showed CH prevalence of 9.7% in MGUS patients (Da Via et al, Blood advances, 2022). The prevalence of CH in other PCDs including smoldering myeloma (SM), and Amyloidosis (AM) have not been reported. We therefore conducted a study to identify CH prevalence in a spectrum of PCD patients at the time of diagnosis and examined the association of CH with clinical features and outcomes. Methods: Patients diagnosed with PCD who consented to our biorepository protocol who had samples collected at diagnosis were eligible for inclusion in the study. We performed next generation sequencing (NGS) to identify mutations associated with myeloid neoplasm using Archer Core Myeloid VarientPlex panel plus PPM1D and GNAS for a total of 39 genes. In order to detect very low frequency variants, 250 ng of DNA was used as input, cycling conditions for both PCR steps were modified, and 15-20M reads/sample were targeted. Variants were called using the Archer Analysis Bioinformatics Suite variant calling pipeline. ICD 9 and 10 diagnosis codes were used to identify cardiovascular comorbidities. Categorical outcomes were summarized with frequencies and proportions and modeled with logistic regression. Overall survival was evaluated with Cox proportional hazards regression. Results: 228 subjects with a diagnosis of a PCD were included. CH was identified in 10.5% (24/228) of subjects using 2% variant alle frequency (VAF). When we included VAF of 1% or greater, CH prevalence increased to 17.5% (40/228, Figure 1A). The most common CH clones identified were DNMT3A (24), TET2 (8), KRAS (4), U2AF1 (2), TP53 (2), and PPM1D (2). 30 pts had 1 mutation, 8 had 2, and 2 patients had 3 CH clones. Median age at sample collection was 70 yrs in the CH group compared to 63 yrs in the no CH group (p<.001.) Prevalence of CH was not significantly different among races with 18.5% (29/157) in Caucasians vs 15.4% (10/65) in Africans Americans (p=.87). CH was more common in males than females [22.3% (25/112) vs 12.9% (15/106) p=.08] and more prevalent in MM patients, 27.5% (25/91), compared to 14.6% (8/55) in SM, 9.5% (6/63) in MGUS and 5.3% (1/19) in AM patients. The difference in CH prevalence by Dx was significantly different (p=.012). The prevalence of CH increased linearly as PCD progressed from MGUS to SM to MM. CH prevalence was 4.5 times higher in MM patients compared to MGUS patients after adjusting for age and gender (Figure 1B). Evaluating several cardiovascular comorbidities, two showed significant association with CH. The rate of atrial fibrillation was 30% (12/40) in patients with CH compared to 15% (28/188) in no CH pts (p=0.037), and the atherosclerosis was reported in 20% (8/40) in patients with CH vs 8% (15/188) in patients without CH (p=0.038). Among MM patients, with median follow up of 45.5 mo, overall survival was not significantly different between the CH group and no-CH group [HR 0.65 (0.17-2.55, p=.54), adjusted for age, gender, and cytogenetic risk level]. Conclusion: The spectrum of CH mutations in PCD patients was similar to that found in age associated CH. As expected, CH in our PCD population was more prevalent in older patients and in males but was not associated with race. Notably, the prevalence of CH increased in PCD patients with increasing disease severity, MGUS to SM to MM, even when adjusted for age. CH was associated with more A Fib and atherosclerosis in PCD patients, but overall survival was not significantly different for CH patients in the MM subgroup. Our data indicate an increase in CH prevalence with PCD disease progression highlighting the need for additional studies to evaluate the factors responsible. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal