Myeloma Genomics and Microenvironment and immune profiling

Examining the role of XRCC1 and BRCA1 gene variants on survival and treatment response in patients with multiple myeloma from South America and Spain

P-214: Examining the role of XRCC1 and BRCA1 gene variants on survival and treatment response in patients with multiple myeloma from South America and Spain

Friday, September 27, 2024

David Garrido, MD

Hematology fellowship
Hospital de Clínicas Dr. Manuel Quintela
Montevideo, Montevideo, Uruguay

Introduction: Multiple Myeloma (MM) shows differences in epidemiology, clinical evolution, and genetics among different populations. This variation could influence treatment outcomes. We hypothesize that single nucleotide variants (SNVs) in DNA repair genes could impact treatment outcomes.

Aims: To analyze the association between SNVs BRCA1 rs799917 and XRCC1 rs2548 with treatment response, overall survival (OS), and progression-free survival (PFS) in MM patients undergoing high-dose melphalan (HDM) and autologous stem cell transplantation (ASCT) as first-line consolidative therapy.

Methods: This retrospective study included 222 newly diagnosed MM patients (median age: 54.3 years; 45% females) from Uruguay (12.2%), Argentina (5.4%), and Spain (82.4%). Response rate, overall survival (OS), and progression-free survival (PFS) were evaluated. DNA was purified from peripheral blood or bone marrow samples. In Uruguay and Argentina, genotyping of SNVs was performed by conventional PCR and Sanger sequencing, whereas in Spain was performed by allelic discrimination with TaqMan probes in an ABI PRISM 7500 Sequence detection system. Statistical analysis was performed using SPSS v.26 and R 4.3.2 software.

Results: MM subtypes were IgG 57.7%, IgA 23.4%, and other 18.9% with a risk staging: ISS-2 35% and ISS-3 22.7%. Bortezomib-based regimens (BBR) were used in 28.4%. Pre-ASCT responses included: complete response 20.6%, very good partial response (VGPR) 11%, partial response (PR) 45%, and < PR 23.4%.

Genotypic frequencies for rs25487 (n=179): AA 30.7%, AG 46.4%, GG 22.9%; allelic: G 46.1%, A 53.9%. For rs799917 (n=210): GG 20%, AG 77.6%, AA 2.4%; allelic: G 58.8%, A 41.2%. The genotypic frequencies among the three countries were significantly different for both SNVs.

The median OS (mOS) and PFS (mPFS) for the whole group were 7.52 years (y) and 2.8y, respectively. Factors significantly affecting 10y-OS included ISS, pre-transplant response, and use of BBR.

The rates of ≥VGPR according to the SNVs were rs799917 AG/AA 29.7% and GG 45.2% (p >0.05), and rs25487 AA 25%, AG 34.1, and GG 56.1% (p< 0.01).

No significant differences in 10y-OS rates for rs799917 AG/AA: 42.6% and GG: 49.2%. Similarly, for 10y-PFS of this SNV, AG/AA 12.9%, while GG 21.3%. For rs25487 AA, 10y-OS 35.7%, AG 47.0%, and GG 68.9%. Likewise, for 10y-PFS, we observed AA 22.1%, AG 12.4%, and GG 12.6%.

No significant difference regarding ISS frequency among genotypes. However, rs25487 GG had a higher proportion of BBR (p< 0.05).

Conclusions: Our findings demonstrate a notable increase in pretransplant ≥VGPR rates for patients carrying rs25487 GG genotype. SNVs XRCC1 rs25487 and BRCA1 rs799917 exhibited non-significant differences in OS and PFS, in agreement with previous studies. While these results hint at the potential impacts of XRCC1 rs25487 on patient outcomes, other variables underlying the clinical phenotype and cofounders must be considered for predictive accuracy.
Funding. IMS and Paula and Rodger Ridney Foundation.