The Clinical Relevance of Selected Cytokines in Newly Diagnosed Multiple Myeloma Patients
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ABSTRACT:
SUBMITTER: Mielnik M
PROVIDER: S-EPMC10669681 | biostudies-literature | 2023 Nov
REPOSITORIES: biostudies-literature
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Project description:Multiple myeloma (MM) is a malignant plasma cell neoplasm with complex biology and heterogenous course. Interferon regulatory factor 4 (IRF4) transcription factor, important key developmental stages of hematopoiesis, represents an excellent potential therapeutic target. The present work aimed to investigate the expression status of IRF4 in the diagnostic bone marrow biopsy (BMB) cores of MM patients. This prospective study included 62 newly diagnosed MM patients. The expression of IRF4 was assessed in the BMB by immunohistochemistry (IHC). The data were correlated to the patients' clinico-pathological features, response to treatment and survival rates. IRF4 expression was observed in 50% of MM patients (31/62). IRF-4 positive patients were more frequently male patients (P = 0.018), have immunoglobulin heavy chain (IgH) translocations (P = 0.05) and tended to present with a higher platelets count (P = 0.07). Multiple myeloma patients presenting with urine M-protein had worse overall survival (OS) than negative cases (P = 0.012). Normocellular BM aspirate (BMA) was associated with better OS than hypercellular and hypocellular BMA (P = 0.006). Patchy distribution of plasma cells in BMB was associated with better disease-free survival (DFS) while diffuse infiltration had the worst (P = 0.019). Of note, after treatment, MM patients had significantly lower percentage of BMA plasma cells, platelet count, β2 microglobulin and creatinine levels (P = 0.037, < 0.001, 0.022 and 0.026, respectively). Had higher albumin level (P = 0.007), compared to initial investigations. No significant association was found between IRF4 expression and the patients'clinical outcomes. Patterns of plasma cells distribution in BMB, BMA cellularity and urine M-protein are prognostically relevant in MM.Supplementary informationThe online version contains supplementary material available at 10.1007/s12288-023-01628-3.
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Project description:Clonal hematopoiesis (CH) at time of autologous stem cell transplant (ASCT) has been shown to be associated with decreased overall survival (OS) and progression-free survival (PFS) in patients with multiple myeloma not receiving immunomodulatory drugs (IMiD). However, the significance of CH in newly diagnosed patients, including transplant ineligible patients, and its effect on clonal evolution during multiple myeloma therapy in the era of novel agents, has not been well studied. Using our new algorithm to differentiate tumor and germline mutations from CH, we detected CH in approximately 10% of 986 patients with multiple myeloma from the Clinical Outcomes in MM to Personal Assessment of Genetic Profile (CoMMpass) cohort (40/529 transplanted and 59/457 non-transplanted patients). CH was associated with increased age, risk of recurrent bacterial infections and cardiovascular disease. CH at time of multiple myeloma diagnosis was not associated with inferior OS or PFS regardless of undergoing ASCT, and all patients benefited from IMiD-based therapies, irrespective of the presence of CH. Serial sampling of 52 patients revealed the emergence of CH over a median of 3 years of treatment, increasing its prevalence to 25%, mostly with DNMT3A mutations.SignificanceUsing our algorithm to differentiate tumor and germline mutations from CH mutations, we detected CH in approximately 10% of patients with newly diagnosed myeloma, including both transplant eligible and ineligible patients. Receiving IMiDs improved outcomes irrespective of CH status, but the prevalence of CH significantly rose throughout myeloma-directed therapy.
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Project description:Risk stratification of multiple myeloma (MM) at diagnosis is critical. We examined the ability of hematopoietic indices including mean corpuscular volume (MCV), hemoglobin (Hgb), and platelet (Plt) to predict outcomes. This was a retrospective study of patients treated at Mayo Clinic between January 2004 and April 2018. We incorporated three variables (Hgb < 10 g/dL, Plt < 150 × 109 /L, and MCV > 96 fL), assigning a score of 1 to each. We identified 1540 newly diagnosed MM patients, of whom 707 (46%) had a score of 0, 513 (33%) had a score of 1, 260 (17%) had a score of 2, and 60 (4%) had a score of 3. The score risk stratified patients into four groups with differing survivals. The median PFS was 32.3 months for score 0, 24.8 months for score 1, 21.7 months for score 2, and 18.3 months for score 3, for P < .001. The median OS was 80.7 months for score 0, 59.9 months for score 1, 51.7 months for score 2, and 31.3 months for score 3, P < .0001. Predictors of OS on the multivariable analysis were age ≥ 65 (HR, 1.93; P < .0001), R-ISS stage (1-2 vs 3) (HR, 0.48; P < .0001), and hematopoietic score (0-2 vs 3) (HR, 0.51; P = .006). A hematopoietic score can predict survival in newly diagnosed myeloma patients.
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Project description:A subanalysis of the GIMEMA-MMY-3006 trial was performed to characterize treatment-emergent peripheral neuropathy (PN) in patients randomized to thalidomide-dexamethasone (TD) or bortezomib-TD (VTD) before and after double autologous transplantation (ASCT) for multiple myeloma (MM). 236 patients randomized to VTD and 238 to TD were stratified according to the emergence of grade ≥2 PN. Gene expression profiles (GEP) of CD138+ plasma cells were analyzed from 122 VTD-treated patients. The incidence of grade ≥2 PN was 35% in the VTD arm and 10% in the TD arm (p<0.001). PN resolved in 88% and 95% of patients in VTD and TD groups, respectively. Rates of complete/near complete response, progression-free and overall survival were not adversely affected by emergence of grade ≥2 PN. Baseline characteristics were not risk factors for PN, while GEP analysis revealed the deregulated expression of genes implicated in cytoskeleton rearrangement, neurogenesis and axonal guidance. In conclusion, in comparison with TD, incorporation of VTD into ASCT was associated with a higher incidence of PN which, however, was reversible in most of the patients and did not adversely affect their outcomes nor their ability to subsequently receive ASCT. GEP analysis suggests an interaction between myeloma genetic profiles and development of VTD-induced PN.
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