P-343: Evaluation of single nucleotide variants in BRCA1, CDKN1A, TP53BP, and XRCC1 in multiple myeloma patients undergoing hematopoietic stem cell transplantation. Association with clinical outcomes

Introduction: High-dose melphalan (HDM) followed by autologous hematopoietic stem cell transplantation (ASCT) remains the standard upfront treatment for transplant-eligible multiple myeloma (MM) patients. However, clinical responses to this strategy are highly variable. We hypothesize that single nucleotide variants (SNVs) in DNA repair genes may influence clinical outcomes in the transplant setting.

Aims: To determine the association of SNV in CDKN1A (rs1801270), TP53BP1 (rs560191), BRCA1 (rs4986850, rs1799949, and rs799917), and XRCC1 (rs25487) genes, with the response and progression-free survival (PFS) in patients with MM treated with HDM as pre-transplant conditioning

Methods: An observational, analytic, and retrospective study, including adult patients with active MM, diagnosed at the Hospital de Clínicas (HC), Uruguay, and Hospital Posadas, Argentina, who received HDM and ASCT as consolidation therapy either frontline or second-line. Evaluated outcomes included response rate and PFS. DNA was purified from peripheral blood or bone marrow. Genotyping of SNVs was performed by conventional PCR and Sanger sequencing. Statistical analysis was performed with SPSS v.26 at p< 0.05.

Results: We included 34 MM patients with a median age of 53.5 years at diagnosis, 64.7% males, and 35.3% females. The frequency of MM types was 61.8% IgG, 23.6% IgA, and 14.7% light chain myeloma. Risk groups included 26.5% ISS1, 44.1% ISS2, and 29.4% ISS3. Bortezomib-based regimens were used in 97.1%. Six patients received ASCT as second-line consolidation therapy. The median PFS for the whole group was 29.2 months. In patients receiving ASCT as first-line consolidation therapy, a ≥CR after transplantation, and ISS-1 were associated with improved PFS, achieving 48.9 months (p < 0.01) and 54.1 months (p < 0.01), respectively. The frequency of ≥CR before and after ASCT was 26.5% and 52.9%, respectively.
The allele frequencies found were rs25487 G 75%, A 25%; rs799917 C 56.4%, T 43.6%; rs4986850 G 89.7%, A 10.3%; rs1799949 G 63.2%, A 36.8%; rs1801270 C 73.5%, A 26.5%; and rs560191 G 77.9%, C 22.1%. No significant differences were found between observed genotype frequencies and those predicted from the Hardy-Weinberg equilibrium. Higher CR rates after the first ASCT were associated with CDKN1A rs1801270 CC (73.3%) and TP53BP1 rs560191 GC/CC (70%) genotypes. Patients with homozygous genotype for BRCA1 rs799917 TT had a significantly lower median PFS compared to CT/CC carriers (p < 0.01) which was similar in patients receiving ASCT only as first-line consolidation (48.9 months vs 16.7 months, p=0.1)

Conclusions: These preliminary results would indicate that homozygosity for the alternative BRCA1 rs799917 T allele would be associated with treatment failure. To our knowledge, this is the first study evaluating the impact of single nucleotide variants (SNVs) in DNA repair genes in the HDM-ASCT clinical outcomes in Latin America, Further studies are required to validate our results.