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    Myeloma Genomics and Microenvironment and immune profiling

    Category: Myeloma Genomics and Microenvironment and immune profiling

    Referral of Select Multiple Myeloma Patients for Genetic Evaluation Leads to 5-Fold Increase in Pathogenic Germline Variant Detection

    (PA-224) Referral of Select Multiple Myeloma Patients for Genetic Evaluation Leads to 5-Fold Increase in Pathogenic Germline Variant Detection

    Wednesday, September 17, 2025
    Introduction: In a prior analysis of 1,681 unselected multiple myeloma (MM) patients, we showed that ~10% carry pathogenic germline variants (PGVs) in hereditary cancer (HC) genes (Thibaud et al, Blood Cancer Discovery 2024). PGV detection offers a powerful tool for reducing cancer burden through tailored, family-centered prevention strategies. However, germline testing is not routinely performed in MM & no guidelines exist to define who should be tested. To guide future testing recommendations, we evaluated whether selective referral of PCD patients with HC risk indicators increases PGV detection relative to unselected cohorts

    Methods:

    We retrospectively reviewed patients with PCDs referred for genetic counseling & germline testing at our institution between 2010 & 2025. Referrals were made at the discretion of treating physicians, based on clinical suspicion due to personal or family history of cancer and/or the presence of mutations in tumor NGS suggestive of germline origin. PGVs were identified through CLIA-certified multigene HC panels. Clinical & genomic data were extracted from the electronic health record. The primary outcome was PGV detection rate.

    Results: 115 PCD patients had a genetic evaluation by a certified genetic counselor. 101 were referred based on personal/family cancer history & 14 due to suspicious tumor NGS findings. Median age at referral was 64 (range 22–88) & 41% were male. 66% were White, 20% Black, 11% Hispanic & 3% Other. 61 patients (53%) had a personal history of other cancers & 104 (90%) had a first- or second-degree relative with cancer. 100 referred patients completed germline testing (87%), including 55 with MM, 18 smoldering MM (SMM) & 27 MGUS. 29 tested patients (29%) carried PGVs associated with HC: 20 MM (36% of all MM cases), 5 SMM (28% of all SMM cases) & 3 MGUS (11% of all MGUS cases). Compared to our previously published unselected MM cohort with a 9.9% PGV prevalence, the 36% detection rate in this selected MM subgroup represents a highly significant enrichment (OR 5.2, 95% CI 2.9–9.2, p=2.8×10⁻⁷). 18 of 29 PGVs were in high-penetrance HC genes, including BRCA2 (6), BRCA1 (3), PALB2 (2) & 7 others. The remaining 11 PGVs were low-penetrance founder variants in APC (5), CHEK2 (5) & MUTYH (1). 2 additional MM patients, not included in above calculations, were incidentally found to carry clinically actionable PGVs unrelated to cancer risk (long QT syndrome & hypertrophic cardiomyopathy). 13 PGV carriers (45%) had a personal history of cancer, most commonly colon (4), breast (3) & thyroid (3). 28 PGV carriers had a first-degree relative with cancer (97%), most frequently breast (13), gynecologic (9) & pancreatic (7).

    Conclusions:

    1 in 3 MM patients referred for suspected cancer predisposition carried a clinically actionable PGV, representing a fivefold enrichment over unselected MM cases. These findings highlight the feasibility & clinical utility of targeted germline screening in MM. A prospective study is underway to inform future testing guidelines.