Session: 651. Myeloma: Biology and Pathophysiology, excluding Therapy: Poster I
Hematology Disease Topics & Pathways:
multiple myeloma, Adult, Diseases, smoldering myeloma, Technology and Procedures, Plasma Cell Disorders, Lymphoid Malignancies, Study Population, genomics, genetic profiling, Clinically relevant, molecular testing, NGS
Methods: DNA Library preparations were performed from CD138+ cells (76 MM) and 4 MM cell lines according to Illumina TruSeq protocol and sequenced at a depth of 1000x using a custom designed mutation panel. Variants were called by six somatic variant callers and correlates with patient clinical data were assessed.
Results: A total of 376 mutations were identified within 63 patients (325) and 4 cell lines (51); no mutations were identified in 13 patients. ATM was the most mutated gene and KRAS had the highest number of mutations per kilobase. Forty three patients harbored 1-4 mutations, 12 patients harbored 5-9, and 8 patients harbored ≥10 mutations. Progression-free survival (PFS) was found to be significantly reduced in patients harboring high-severity mutations (frame shift, splice site, and stop altering mutations) (n =15 HR = 2.85; 95% CI: 1.3-6.35; p = 0.01). We also assessed mutations by the pathogenicity scoring algorithms rfPred, SIFT, MutationTaster, Polyphen2, and FATHMM-FX, as well as SPLICEAI which predicts splicing impacts of mutations. FATHMM-FX was the only algorithm to identify mutations that define a group with significantly altered PFS (n = 5; HR = 6.7; 95% CI: 2.5-18; p < 0.001). We then combined these indicators to define high-risk patients such that a patient is considered high risk if they harbor one or more mutations that are high-severity or predicted by FATHMM-FX to be pathogenic. Of the 376 in our cohort, 23 were high-risk markers, 19 of which were in patient samples. This classified 16 of 76 patients as high risk which had significantly reduced PFS (n = 16; HR = 3.5; 95% CI: 1.6-7.6; p = 0.002) (Fig. 1 A-B). Notably, 2 high risk mutations were found in 3 patients, one of whom had plasma cell leukemia (PCL) and the other progressed to PCL. This group had a markedly reduced PFS (n = 3; HR = 16; 95% CI: 2.9-83; p = 0.001) (Fig. 1 C-D). Additionally, focal copy-number alterations (CNVs) were probed from panel data, and patients harboring 2 or more focal CNVs had significantly reduced PFS (n = 10, HR = 3.2, 95% CI: 1-9.1, p = 0.043). Combining focal CNV and mutation risk identified 24 patients with significantly reduced PFS (HR = 4.2; 95% CI: 1.9-9.1; p < 0.001) (Fig. 1 E-F). Harboring a high-risk mutation or more than one focal CNV was independent of age, ISS stage, Beta-2 microglobulin, serum albumin, LDH, and bone marrow plasma cell burden. Of 48 fluorescent in situhybridization (FISH) assessed patients, 12 had ‘high risk’ FISH findings, none of whom had severe mutations though 1 harbored two focal CNVs. Of the 36 patients standard-risk by FISH, 12 had high-risk mutations, and 5 had more than one panel identified focal CNV. Combined, these identified 15 high-risk patients in the FISH standard-risk group which had significantly reduced PFS (HR = 3.7; 95% CI: 1.1-12; p = 0.031) (Fig. 1 G-H).
Conclusion: Our custom mutation panel demonstrates novel findings that independently redefine prognosis in multiple myeloma in our cohort of Nova Scotian patients.
Disclosures: Forward: Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Calgene: Membership on an entity's Board of Directors or advisory committees; IMV: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Astellas: Research Funding; IMV: Research Funding; Merck: Research Funding; Seattle Genetics: Research Funding. White: Karyopharm: Honoraria; Antengene: Honoraria; GSK: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Sanofi: Honoraria; Amgen: Honoraria.
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