SUPPLEMENTARY TABLE 2: PGV Classification and Allele Count by Cohort

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

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

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

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

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

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

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

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

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

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

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

SUPPLEMENTARY TABLE 1: Clinical Characteristics by Cohort

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

10619 Background: Our research has shown that 10% of multiple myeloma (MM) patients harbor pathogenic or likely-pathogenic germline variants (PGVs) in cancer predisposition genes, with a significant enrichment observed in BRCA1/2 genes. PGVs are notably more common in younger MM patients and those with a personal or familial cancer history. This study presents our experience in referring plasma cell disorder (PCD) patients at increased risk for carrying PGVs, due to either clinical history or suspicious tumor NGS findings, for genetic counseling and subsequent germline testing. Methods: This retrospective study reviewed patient records from our institution's PCD clinic, focusing on those referred for a genetic evaluation between 2020 and 2024 due to suspected cancer predisposition. We compiled demographic and clinical data for these patients, reasons for referral, and cancer history of patients and their families. The uptake of germline testing, identified mutations, and subsequent recommendations for advanced cancer surveillance and prevention, including cascade testing, were also analyzed. Germline testing utilized targeted hereditary cancer panels from five companies and was conducted on DNA samples extracted from peripheral blood, saliva/buccal swabs, or skin biopsies. Results: 52 PCD patients underwent a genetic evaluation and were included in this review, comprising 31 MM, 9 smoldering MM, and 12 MGUS cases. Median age at the time of referral was 63, and 54% of patients were female. Racial composition was 62% White, 15% Black/African-American, 12% Hispanic, 2% Asian, with 10% undisclosed. 8 patients were referred due to suspicious findings in tumor NGS, while the rest were referred due to clinical suspicion. A personal history of cancer was reported by 19 patients (37%), and 49 had a first- or second-degree relative with cancer (94%). 38 patients (73%) underwent germline testing, of which 15 (39%) harbored PGVs (11 had MM, 4 had smoldering MM). 8 PGV carriers had well-established founder variants. The remaining 7 had PGVs in genes including BRCA2 (n=3), PALB2 (n=1), BLM (n=1), SMAD4 (n=1) and NTHL1 (n=1). Of note, all 8 referred for suspicious findings in tumor NGS were confirmed to harbor PGVs. All PGV-positive patients were recommended for cascade testing and enhanced cancer screening. Conclusions: Our findings indicate a 39% PGV detection rate in PCD patients referred for genetic evaluation, underscoring the potential benefit of implementing screening guidelines in this population. PGV detection led to recommendations for intensified surveillance and cascade testing in all cases, impacting both patients and their families. The discovery of BRCA2PGVs in 20% (3/15) of cases reinforces its potential role as a predisposition gene in MM, corroborating our prior findings.

Abstract First-degree relatives of patients with multiple myeloma are at increased risk for the disease, but the contribution of pathogenic germline variants (PGV) in hereditary cancer genes to multiple myeloma risk and outcomes is not well characterized. To address this, we analyzed germline exomes in two independent cohorts of 895 and 786 patients with multiple myeloma. 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 (associated with autosomal dominant cancer predisposition) 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 patients with multiple myeloma when compared with 134,187 healthy controls. Five of the eight BRCA2 PGV carriers exhibited tumor-specific copy number loss in BRCA2, suggesting somatic loss of heterozygosity. PGVs associated with autosomal dominant cancer predisposition 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 transplantation (P < 0.01). Significance: Our findings suggest up to 10% of patients with multiple myeloma may have an unsuspected cancer predisposition syndrome. Given familial implications and favorable outcomes with high-dose melphalan and autologous stem-cell transplantation in high-penetrance PGV carriers, genetic testing should be considered for young or newly diagnosed patients with a personal or family cancer history. See related commentary by Walker, p. 375

Benefits and limitations in using NCCN guidelines to distinguish TP53 CH from mosaic LFS.

Pathogenic variants in CDH1 are known to be associated with hereditary diffuse gastric cancer and lobular breast cancer syndrome (HDGC-LBC) as well as blepharocheilodontic syndrome 1 (BCD1). Potential genotype/phenotype correlations have been investigated suggesting that variants causing HDGC-LBC and BCD1 may be distinct, however, there are also families with variants in CDH1 with evidence of both HDGC-LBC and clefting. There is no current consensus on the cancer risks and surveillance guidelines for patients with BCD1 due to variants in the CDH1 gene.

Etiological links to multiple myeloma (MM) remain poorly understood, though emerging evidence suggests a significant hereditary component. This review integrates current literature on inherited factors contributing to MM risk, synthesizing both epidemiologic and genomic data. We examine familial clustering patterns, assess genome-wide association studies (GWAS) that reveal common genetic variants linked to MM, and explore rare, high-penetrance variants in key susceptibility genes. Additionally, we advocate for routine germline screening in high-risk MM populations, particularly those with a strong family history of cancer, a personal history of cancer, or early-onset disease. By elucidating the inherited influences on MM predisposition, this review seeks to inform future research and refine risk assessment strategies in this population.

Introduction: Our research has shown that ~10% of multiple myeloma (MM) patients harbor pathogenic or likely-pathogenic germline variants (PGVs) in cancer predisposition genes, with a significant enrichment observed in BRCA1/2 genes (Thibaud et al, Blood Cancer Discovery, 2024). PGVs were notably more common in younger MM patients and those with a personal or familial cancer history. Based on these findings, we developed a clinical pathway with genetic counselors to facilitate germline and cascade testing for these patients, as well as for those with suspicious tumor NGS findings. Whether this referral strategy focused on high-risk subgroups of plasma cell disorder (PCD) patients is an effective measure to identify individuals and families with PGVs has not been established. Methods: This retrospective study reviewed patient records from our institution's PCD clinic, focusing on those referred for a genetic evaluation between 2020 and 2024 due to suspected cancer predisposition. We compiled demographic and clinical data for these patients, reasons for referral, and cancer history of patients and their families. The uptake of germline testing, identified mutations, and subsequent recommendations for advanced cancer surveillance and prevention, including cascade testing, were also analyzed. Germline testing utilized commercial targeted hereditary cancer panels from five companies and was conducted on DNA samples extracted from peripheral blood, saliva/buccal swabs, or skin biopsies. Results: 72 PCD patients underwent a genetic evaluation and were included in this review, comprising 46 MM, one plasma cell leukemia (PCL), 10 smoldering MM and 15 MGUS cases. Median age at the time of referral was 65 (range 37-88), and 53% of patients were female. Racial composition was 65% White, 17% non-Hispanic Black, 14% Hispanic, 3% Asian, 1% Other. Thirteen patients (18%) were referred due to suspicious findings in tumor NGS, while the rest were referred due to clinical suspicion. A personal history of cancer was reported by 33 patients (46%), and 62 patients (86%) had a first/second-degree relative with cancer. 52 of the evaluated patients (72.2%) have completed germline testing to date, of which 20 (38.5%) have been found to harbor PGVs (15 with MM, 1 with PCL and 4 with smoldering MM). Relative to our previously cited independent study, which detected 167 PGVs in 1681 MM patients (9.9%), this represents a significant enrichment (OR 5.7 [95% CI 3.2-10.1], p<0.01 by Fisher's exact test), suggesting that targeted testing in high-risk subgroups of PCD patients can enhance PGV detection rates. Notably, of the 13 patients referred for suspicious findings in tumor NGS, all were confirmed to harbor PGVs. 8 of 20 PGV carriers had well-established low-penetrance founder variants (4 APC c.3920T>A; 2 CHEK2 c.1283C>T; 1 CHEK2 c.470T>C; 1 MUTYH c.1187G>A), while the remaining 12 had moderate/high-penetrance PGVs in BRCA2 (n=4), PALB2 (n=2), BRCA1 (n=1), CDKN2A (n=1), BLM (n=1), SMAD4 (n=1), ATM (n=1) and NTHL1 (n=1). Eight of 20 PGV carriers (40%) reported a prior cancer history (2 each for female breast, colon and thyroid cancer; 1 ovarian; 1 melanoma). Family history of cancer was reported by 19 of 20 PGV carriers, with most common types being breast (n=8), pancreatic (n=8), colon (n=5) and prostate (n=3). Ten additional tested patients in whom PGVs were not detected had variants of unknown significance, including 2 in BRCA2. Of the 20 evaluated PCD patients who have not completed germline testing to date, 4 have collected samples but are pending results, 8 deferred testing without providing a reason, 5 were lost to follow-up, 2 expired prior to sample collection, and 1 deferred citing affordability concerns. All PGV carriers have been advised to undergo cascade testing and enhanced cancer screening. One BRCA2 PGV carrier underwent prophylactic total abdominal hysterectomy and bilateral salpingo-oophorectomy following her results. Conclusion: Our findings indicate a 36% PGV detection rate in PCD patients referred for genetic evaluation, underscoring the potential benefit of implementing screening guidelines in this population. PGV detection led to recommendations for intensified surveillance and cascade testing in all cases, impacting both patients and their families. The discovery of BRCA2 PGVs in 20% (4 out of 20) of cases reinforces its potential role as a predisposition gene in MM, corroborating our prior findings.