Background: Clinical outcomes for multiple myeloma are highly variable. Inherited genetic variants of immune regulatory genes can modulate disease susceptibility and clinical outcomes. The germline variant CTLA4 rs231775 polymorphism may alter T-cell function and affect clinical outcomes. Methods: We conducted a retrospective single-center study including 156 consecutive myeloma patients who underwent first-line ASCT. The patients were stratified according to the CTLA4 rs231775 genotype and disease stage (ISS I–III). Results: The CTLA4 rs231775 AA genotype was associated with inferior PFS in ISS I–II and superior PFS in ISS III. In the multivariate analysis, the CTLA4 rs231775 AA genotype emerged as a potential risk factor in ISS I-II and a potential protective factor in ISS III. Conclusions: This germline CTLA4 polymorphism may serve as biomarker to refine post-transplant risk stratification and enable personalized treatment management.

Background/Objectives: Therapeutic options for patients with relapsed and refractory multiple myeloma (RRMM) have advanced substantially in recent years. In particular, T-cell-engaging therapies, including chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies (bsAbs), have emerged as highly effective treatment modalities. However, data on predictive biomarkers for response to these therapies remain limited. Patients currently receiving T-cell-engaging therapies are typically heavily pretreated and frequently exhibit clonal hematopoiesis. Clonal hematopoiesis, especially involving PPM1D mutations, may adversely affect the efficacy of T-cell-engaging therapies. Methods: We conducted a retrospective, single-center study including 27 patients with RRMM who were treated with bsAbs (teclistamab, elranatamab, or talquetamab) between June 2022 and September 2025 and for whom genetic material was available before bsAB treatment. We evaluated the impact of PPM1D mutations on treatment response, progression-free survival (PFS), and overall survival (OS). Results: The prevalence of PPM1D mutations in our cohort was 27%. Compared with patients without PPM1D mutations, mutation carriers showed a trend toward less deep remissions and demonstrated significantly inferior 6-month PFS (43% vs. 85%, p = 0.0272) and 6-month OS (57% vs. 90%, p = 0.0473). Conclusions: These findings suggest that PPM1D mutations may represent a promising biomarker in patients with RRMM treated with bsAbs. Larger, prospective studies are warranted to validate and further elucidate these observations.

Background: BCMA-targeted Chimeric Antigen Receptor (CAR) T-cell therapy has revolutionized the treatment of Relapsed/Refractory Multiple Myeloma (RRMM). However, the disease is not curable and progression after CAR T-cell treatment remains a challenge. Clonal hematopoiesis, specifically mutations in the DNA damage response gene PPM1D, has been linked to therapy resistance and inferior survival in lymphoma patients undergoing cellular therapy. The impact of PPM1D mutations on MM patient outcome after CAR T-cell therapy remains undefined. Methods: We conducted a retrospective single-center study of 83 patients with RRMM patients treated with idecabtagene vicleucel or ciltacabtagene autoleucel between 2022 and 2025. Next-generation sequencing was performed on peripheral blood mononuclear cells collected prior to CAR T-cell infusion to identify PPM1D exon 6 mutations (variant allele frequency > 0.01). We analyzed associations between mutational status, clinical characteristics, toxicity, and survival. Results: PPM1D mutations were detected in 14.5% (12/83) of patients. PPM1D-mutated patients had fewer prior autologous stem cell transplantation compared to wild-type patients (50% vs. 82%, p = 0.02) and presented more advanced disease burden and adverse prognostic features (R-ISS stage III 58% vs. 20%, p = 0.05). Notably, PPM1D status did not impact initial efficacy; complete remission rates were comparable between groups (67% vs. 69%). However, PPM1D mutations were significantly associated with inferior progression-free survival (PFS) (median PFS: 6 months vs. 16 months, p = 0.04). Regarding toxicity, the mutated subgroup exhibited significantly higher rates of grade ≥2 cytokine release syndrome and a trend toward increased neurotoxicity (25% vs. 7%). Conclusions: PPM1D clonal hematopoiesis is frequent in RRMM and despite deep initial responses, patients harboring PPM1D mutations face a significantly higher risk of early relapse. PPM1D mutations may serve as a biomarker for poor durability of response and should be further evaluated in larger, prospective trials.

Background: Brexu-cel is an established CD19-directed CAR-T cell therapy for relapsed or refractory mantle cell lymphoma, but clinical outcomes are heterogeneous, and germline determinants of response are poorly defined. Methods: We investigated the clinical impact of the CD19 single-nucleotide polymorphism rs2904880 on treatment outcome after brexu-cel CAR-T cell therapy by analyzing genotype-outcome associations in a retrospective single-center cohort of patients with relapsed or refractory mantle cell lymphoma treated with this CAR-T cell therapy. Results: Overall survival varied according to CD19 polymorphism, with improved survival of patients carrying the V174 homozygous genotype compared with L174V heterozygotes. Conclusions: The germline CD19 polymorphism may have implications for future risk stratification after brexu-cel CAR-T cell therapy in mantle cell lymphoma, but requires validation in larger, multicenter cohorts.

Background: Germline variants of immune-regulatory genes may affect immune checkpoint functions, disease susceptibility, disease features, and treatment response in acute myeloid leukemia. Methods: We analyzed the prevalence and potential impact of the PDCD1 gene variant rs6710479 in AML patients eligible for high-dose chemotherapy and autologous hematopoietic stem cell transplantation as consolidation treatment in first complete remission. Results: The PDCD1 rs6710479 was prevalent at elevated minor allele frequencies (MAF 0.52) in AML patients, compared to the allele frequencies reported for the European population (MAF 0.43). Baseline blood count profiles differed across PDCD1 genotypes, suggesting a link between PDCD1 rs6710479 and disease-associated levels of thrombocytopenia and leukocytosis. Conclusion: The germline PDCD1 rs6710479 variant may associate with AML disease risk and specific hematological disease features.

Background: Glofitamab is a bispecific antibody engaging CD3 on T-cells and CD20 on B-cells. Glofitamab is approved for the treatment of relapsed, refractory diffuse large B-cell lymphoma (R/R DLBCL). Lymphocyte-activation gene 3 (LAG3) and T-lymphocyte-associated protein 4 (CTLA4) are immune checkpoint receptors with inhibitory effects on T-cell activity. There are several common germline variants of both receptor genes. Methods: Here, we evaluate clinical outcomes in R/R DLBCL patients treated with glofitamab according to the single-nucleotide polymorphisms LAG3 rs870849 and CTLA4 rs231775. Results: While there was no apparent association of CTLA4 genotype with glofitamab treatment outcomes, significant differences emerged in LAG3 rs870849 carriers with extended progression-free and overall survival in homozygous LAG3 T455, intermediate PFS and OS in heterozygous LAG3 I455T, and short PFS and OS in homozygous LAG3 I455 carriers. Conclusions: LAG3 rs870849 may be a prognostic response marker in R/R DLBCL treated with glofitamab.