Genome-Wide Association Study Identifies Novel Loci Associated with Survival in Multiple Myeloma

Background: Multiple myeloma (MM) is a hematologic malignancy characterized by the clonal proliferation of plasma cells in the bone marrow. The survival of MM patients has improved dramatically with overall survival (OS) doubling over the last two decades. Improved survival from MM is attributable to the introduction of autologous stem cell transplantation (ASCT) and novel anti-myeloma agents, such as immunomodulatory drugs and proteasome inhibitors. The current expected median survival of MM ranges from 5 to 8 years, which exceeds 10 to 15 years in certain patient populations such as those with standard risk and early stage. Despite these improvements, MM remains incurable, and considerable heterogeneity in the survival outcomes persists among MM patients. It is well recognized that germline variation plays an important role in cancer development and progression. Genome-wide association studies (GWAS) have identified over 20 susceptibility loci for MM. However, genetic risks affecting MM OS remain unclear.

Methods: We performed a GWAS analysis of MM survival in 617 patients enrolled from the Medical College of Wisconsin (MCW) Tissue Bank. Genomic DNA extracted from buffy coat samples were genotyped on the Illumina Infinium Global Screening Array. After standard quality control (QC), 548,895 single nucleotide polymorphisms (SNPs) were used for imputation against the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) reference panel (version R2). Post-imputation QC was conducted by excluding SNPs with imputation quality score < 0.3. The association between SNPs and OS was assessed using Cox proportional hazards model implemented in R, with adjustment of age, sex, race, Revised International Staging System (RISS) stage and top principal components. Associations were considered as statistically significant at P values < 5.0 × 10^-8.

Results: Among 617 patients, 255 died during follow-up, with the median follow-up time of 106 months (standard deviation, s.d. 56 months) and median survival time of 73 months (s.d. 51 months). The quantile-quantile (QQ) plot indicated no evidence for hidden substructure or cryptic relatedness in the GWAS (λ=1.06). A total of 9,849,852 common SNPs with minor allele frequency (MAF) ≥ 1% that passed QC were used for survival analysis. We identified 8 loci that were significantly associated with OS. They are 3p12.2 (rs146838946 near LINC02008, hazard ratio [HR] = 3.97, 95% confidence interval [CI] = 2.49-6.33; P = 6.92 × 10^-9), 5q33.1 (rs115818338 in ENSG00000286749, HR = 3.99, 95% CI = 2.43-6.55, P = 4.18 × 10^-8), 5q35.1 (rs142465985 near LOC105377714, HR = 5.77, 95% CI = 3.10-10.7, P = 2.98 × 10^-8), 7p12.2 (rs17133726 near SPMIP7, HR = 8.06, 95% CI = 4.0-16.2, P = 5.10 × 10^-9), 8q22.2 (rs537660173 in LOC124901991, HR = 6.46, 95% CI = 3.45-12.1, P = 5.73 × 10^-9), 9q21.13 (rs35198294 near RORB, HR = 8.07, 95% CI = 4.04-16.1, P = 3.36 × 10^-9), 12q24.31 (rs148548146 in PITPNM2, HR = 5.82, 95% CI = 3.11-10.9, P = 3.32 × 10^-8), and 15q26.1 (rs2238345 in SLCO3A1, HR = 7.79, 95% CI = 3.85-15.8, P = 1.17 × 10^-8).

Conclusion: This study identifies eight novel loci that are associated with OS in MM, contributing to the body of research into the effect of genetic factors on clinical outcomes. Future research exploring gene expression, pathway enrichment analysis and potential drug targets can elucidate their functional roles in the pathophysiology and clinical progression of MM.

D'Souza:Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Caelum: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Prothena: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron: Research Funding; Takeda: Research Funding. Dhakal:Medical College of Wisconsin: Current Employment; Karyopharm: Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Acrellx: Research Funding; Genentech: Consultancy, Honoraria; Carsgen: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Sanofi: Research Funding; Janssen: Honoraria, Research Funding, Speakers Bureau; C4 therapeutics: Research Funding.