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.

Disclosures

Richard:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Steering Committee, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Gracell Therapeutics: Other: Steering Committee, Research Funding; C4 Therapeutics: Research Funding; Heidelberg Pharma: Research Funding. Richter:Johnson & Johnson - Janssen: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau; Pfizer: Consultancy; Karyopharm: Consultancy; Sanofi: Consultancy, Speakers Bureau; Takeda: Consultancy; Genentech: Consultancy; AbbVie: Consultancy; Regeneron: Consultancy; Adaptive Biotechnologies: Speakers Bureau. Sanchez:Janssen Pharmaceuticals: Consultancy, Honoraria, Research Funding. Rodriguez:Amgen, Celgene, Janssen, BMS, Teneobio: Research Funding; Amgen, BMS, Janssen, Karyopharm, Sanofi, Artiva: Consultancy; BMS, Janssen, Sanofi, Artiva: Membership on an entity's Board of Directors or advisory committees. Rossi:Adaptive, BMS, Janssen, Karyopharm, JNJ, and Sanofi: Consultancy. Cho:Takeda: Research Funding; BMS: Research Funding; MMRF: Current Employment; Genentech Roche: Research Funding. Jagannath:Janssen, BMS, Caribou, Legend Biotech, Regeneron, Takeda, Sanofi, Posieda Therapeutics, GRAIL: Consultancy; IMS and SOHO: Membership on an entity's Board of Directors or advisory committees. Balwani:Disc Medicine: Consultancy, Other: Principal Investigator on clinical trial.

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