Prevalence and Clinical Implications of Germline Variants in Multiple Myeloma Patients
Authors: Kubicki Tadeusz , Millan Kaina , Pula Anna , Raeder Henry , Hauck Quinn , Bhagwat Manoj , Barton Jude , Awe Eyitayo , Das Soma , Del Gaudio Daniela , Wu Sulin , Wen Frank , Cooperrider Jennifer H , Derman Benjamin A , Jakubowiak Andrzej J , Drazer Michael W 
Published: December 2024

Introduction
Epidemiologic observations and genetic studies suggest an inherited susceptibility to multiple myeloma (MM) occurs in some patients. Several candidate genes for hereditary MM risk have been identified, but the prevalence of pathogenic/likely pathogenic (P/LP) germline variants in genes associated with hereditary cancer syndromes and related disorders remains understudied. One ASH abstract estimated 8.8% of patients with MM carry P/LP variants in hereditary cancer genes (Thibaud, ASH 2021). Considering the postulated role of immune stimulation in MM pathogenesis, we hypothesized that additional variants associated with immunological disorders and/or hereditary hematopoietic disorders may also be important for MM predisposition. Therefore, we determined the prevalence of P/LP variants in genes related to hereditary cancer, hematopoietic, and immune syndromes in a large, multi-institutional cohort of MM patients, the CoMMpass dataset.
Methods
DNA was extracted from non-tumor tissue (peripheral blood), and whole exome sequencing (WES) was performed. After alignment and duplicate calling, the GVCF workflow by GATK4.4 was used to call germline variants using HaplotypeCaller. Single nucleotide polymorphisms (SNPs) and insertions/deletions (indels) were quality filtered based on GATK Best Practices. Filtered variants were functionally annotated using Funcotator's curated germline data source. The resulting variants were manually validated, and pathogenicity was determined using the ClinVar database. Clinical characteristics were obtained from the IA22 CoMMpass dataset. The study group and intragroup associations were examined using the Chi-square or Fisher's exact test. The Kaplan-Meier method and Cox proportional hazards models were used for univariate and multivariate survival analyses. When applicable, the Bonferroni method was applied to adjust for multiple testing. Survival was compared using the log-rank test. Stepwise selection was used to determine the optimal multivariate model.
Results
We identified 137 P/LP germline variants in 130 patients out of 972 included in this analysis (13.4%). Six patients carried two P/LP variants, and one patient carried three different variants. TNFRSF13B was the most commonly mutated gene (24 patients, 2.5%), followed by MUTYH (21 patients, 2.2%), APC (9 patients, 1.0%), TTR (8 patients, 1.0%), and CHEK2 (8 patients, 1.0%).
The median age of the 130 patients with germline MM predisposition was 63 years (range: 32-86), compared to 63 (27-89) in other patients (p=0.9). There were no differences between the groups in terms of sex (46% female vs 38%, p=0.15), race (78% White, 15% Black vs 76% and 17%, p=0.49), or family history of cancer (62% vs 55%, p=0.21).
In terms of disease characteristics, 71% of patients with germline MM predisposition had at least one high-risk cytogenetic abnormality by FISH-seq [del(17p), amp(1q), del(1p), t(4:14), t(14:16), t(14:20)], compared to 61% of patients without germline predisposition (p=0.04). ISS stage III disease was present in 25% of patients with germline MM predisposition and in 27% of the remaining patients (p=0.6). Patients with P/LP variants had significantly better progression-free survival (PFS) after first-line therapy, with a median of 49.1 months vs 35.0 months [HR=0.73 (95%CI: 0.57-0.94), p=0.01]. This PFS benefit remained significant in multivariable analysis [HR=0.69 (0.53-0.89), p=0.005] after adjusting for cytogenetic risk [HR=1.52 (1.27-1.83), p&lt;0.001], ISS stage III [HR=1.62 (1.34-1.94), p&lt;0.001], and use of first-line ASCT [HR=0.43 (0.36-0.51), p&lt;0.001]. There were no differences in overall survival between the two groups [median not reached in both groups, HR=0.82 (0.6-1.13), p=0.2].
Conclusions
We found 13.4% of patients with MM carried P/LP germline variants when analyzed with an extended panel of genes. This is higher than prior reports. We identified TNFRSF13B, which causes hereditary immunodeficiency, as the most frequently mutated gene in this cohort of patients. Presence of P/LP variants was associated with a significant PFS benefit. Further studies are needed to better elucidate the impact of these P/LP germline variants on myeloma biology, treatment response, and prognosis.