Abstract Pathogenic germline variants (PGVs) are present in ~10 % of unselected multiple myeloma (MM) cases (Thibaud et al., Blood Cancer Discovery 2024). Germline testing to detect such variants is rarely incorporated into MM care, largely because no formal screening guidelines have been established. Consequently, individuals with plasma cell disorders (PCD) who exhibit well-recognized indicators of inherited risk frequently remain untested, missing clinically actionable information that could guide surveillance strategies, cascade testing of family members, and sometimes therapy. To address this gap, we evaluated whether targeted germline testing based on clinical and genomic risk indicators increases the detection of PGVs. We retrospectively identified patients with PCDs who underwent cancer genetic counseling (CGC) at our institution between 2010-2025. Referrals were initiated by treating providers based on clinical suspicion of hereditary cancer (HC), informed by personal or family history of malignancy, or tumor next-generation sequencing (NGS) findings suggestive of germline origin. Germline DNA was collected via peripheral blood, saliva, or skin biopsy, and analyzed using CLIA-certified multigene HC panels. Clinical and genomic data were extracted from the electronic health record. The primary outcome was the detection rate of PGVs. 118 patients with PCDs were referred for CGC. Most referrals (103/118, 87%) were based on personal or family history of cancer, while the remaining 15 (13%) were prompted by tumor NGS findings. Median age at referral was 63 years (range 22–88), and 59% of patients were female. The cohort was racially diverse: 65% White, 21% Black, 12% Hispanic, and 2% Other. A personal history of cancer was documented in 53% of patients, and 90% reported a first-or second-degree relative with malignancy. Germline testing was completed in 103 patients (87%), including 57 with MM, 19 with SMM, and 27 with MGUS. Among these, 32 (31%) were found to harbor a PGV in a HC gene. Stratified by disease stage, PGVs were identified in 40% of MM cases (23/57), 32% of SMM cases (6/19), and 11% of MGUS cases (3/27). The prevalence in MM patients represented a 6-fold increase compared to a previously published unselected cohort (9.9%) (OR of 6.1, 95% CI 3.5–10.6, p = 4.2 × 10⁻⁹). When precursor conditions were grouped, PGVs were significantly more common in MM than in SMM/MGUS combined (23/57 vs 9/46; OR 2.78, 95% CI 1.10–6.84; p = 0.032), suggesting enrichment in more advanced disease stages. 21 of 32 PGVs (66%) were in high-penetrance cancer susceptibility genes. The most frequently altered gene was BRCA2 (7), followed by BRCA1 (3), ATM (2), DIS3 (2), and PALB2 (2); single events were observed in BLM, CDKN2A, FH, NTHL1, and SMAD4. The remaining 11 PGVs (34%) were low-penetrance variants in APC (5), CHEK2 (5), and MUTYH (1). Among BRCA2 PGV carriers, 3 of 7 (43%) had tumor monosomy 13. Given the gene's location at 13q12.3, this finding raises the possibility of somatic loss of the wild-type allele. Similar evidence was observed in our prior study (Thibaud et al., Blood Cancer Discovery 2024), where 5/8 BRCA2 PGV carriers exhibited tumor-specific copy number loss, suggestive of loss of heterozygosity. Cancers with biallelic BRCA2 inactivation have shown sensitivity to PARP inhibitors in other settings, pointing to a rationale for evaluating it in BRCA2-mutated MM. Clinical features among PGV carriers included a second malignancy in 14 individuals, most commonly colorectal (4), breast (4), and thyroid cancer (3). A first-degree family history of cancer was reported in 30 carriers, with the most frequent associated malignancies being breast (13), gynecologic (9), pancreatic (7), colon (6), prostate (6), hematologic malignancies other than MM (6), lung (6) and MM (5). Variants of uncertain significance were reported in 32 patients, the most commonly affected genes were POT1, DICER1, and ATM. PGVs were identified in 31% of referred PCD patients and 40% of those with MM, a 6-fold increase compared to the unselected cohort. PGVs were significantly more frequent in symptomatic disease, supporting a stage- and risk-informed approach to referral. These findings show that selecting MM patients for germline testing based on clinical and genomic features substantially increases the likelihood of identifying actionable variants, and support the development of formal screening guidelines and cascade testing strategies in this setting.
Rosal et al. (Mon,) studied this question.