First-degree relatives of multiple myeloma (MM) patients are at increased risk for MM, but the contribution of pathogenic germline variants (PGVs) in hereditary cancer genes to MM risk and outcomes is not well characterized. To address this, we analyzed germline exomes in two independent cohorts of 895 and 786 MM patients. PGVs were identified in 8.6% of the discovery cohort and 11.5% of the replication cohort, with a notable presence of high or moderate-penetrance PGVs (PGV-As) in DNA repair genes (3.6% and 4.1%, respectively). PGVs in BRCA1 (OR=3.9, FDR<0.01) and BRCA2 (OR=7.0, FDR<0.001) were significantly enriched in MM patients compared to 134,187 healthy controls. Five of the eight BRCA2 PGV carriers exhibited tumor-specific copy number loss in BRCA2, suggesting somatic loss of heterozygosity. PGV-As were associated with younger age at diagnosis, personal or familial cancer history, and longer progression-free survival after upfront high-dose melphalan and autologous stem cell transplant (p<0.01).

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Supplementary data

Supplementary Table 1

SUPPLEMENTARY TABLE 1: Clinical Characteristics by Cohort

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Supplementary Table 2

SUPPLEMENTARY TABLE 2: PGV Classification and Allele Count by Cohort

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Supplementary Table 3

SUPPLEMENTARY TABLE 3: Per-Gene PGV Counts and Gene Pathway Enrichments

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Supplementary Table 4

SUPPLEMENTARY TABLE 4: Comprehensive characterization of PGV-B/C carriers with multiple myeloma

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Supplementary Table 5

SUPPLEMENTARY TABLE 5: Comparative Per-gene PGV-A Burden Analysis in Multiple Myeloma Cohorts versus Non-Cancer gnomAD Control Populations

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Supplementary Table 6

SUPPLEMENTARY TABLE 6: Comparative Per-gene PGV-B Burden Analysis in Multiple Myeloma Cohorts versus Non-Cancer gnomAD Control Populations

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Supplementary Table 7

SUPPLEMENTARY TABLE 7: Comparative Per-variant PGV-C Burden Analysis in Multiple Myeloma Cohorts versus Non-Cancer gnomAD Control Populations

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Supplementary Table 8

SUPPLEMENTARY TABLE 8: Assessment of Loss of Heterozygosity (LOH) in Carriers of PGVs in BRCA1 and BRCA2

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Supplementary Table 9

SUPPLEMENTARY TABLE 9: Matching Study Identifiers for MM patients included in the Discovery cohort to Publicly Available MMRF CoMMpass IDs

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Supplementary Table 10

SUPPLEMENTARY TABLE 10: Sema4 Hereditary Cancer (HC) Gene Panel Composition

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Supplementary Figure 1

SUPPLEMENTARY FIGURE 1: Output of Cox Proportional Hazards Model for Multivariate PFS1 Analysis in HDM-ASCT Recipients with MM (Combined Cohort)

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Supplementary Figure 2

SUPPLEMENTARY FIGURE 2: Overall Survival (OS) in PGV-A carriers vs non-carriers

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Supplementary Figure 3

SUPPLEMENTARY FIGURE 3: PFS1 and OS in PGV-B/C carriers vs non-carriers (combined cohort)

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Supplementary Figure 4

SUPPLEMENTARY FIGURE 4: Concordance of Genetically-Determined Ancestry and Self-Reported Race in a subset of patients from the Discovery Cohort (MMRF CoMMpass dataset)

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