Timing of treatment of smoldering myeloma: early treatment.
Ontology highlight
ABSTRACT:
SUBMITTER: Mateos M
PROVIDER: S-EPMC6234377 | biostudies-other | 2018 Nov
REPOSITORIES: biostudies-other
Similar Datasets
Project description:The evolution and progression of multiple myeloma and its precursors over time is poorly understood. Here, we investigate the landscape and timing of mutational processes shaping multiple myeloma evolution in a large cohort of 89 whole genomes and 973 exomes. We identify eight processes, including a mutational signature caused by exposure to melphalan. Reconstructing the chronological activity of each mutational signature, we estimate that the initial transformation of a germinal center B-cell usually occurred during the first 2nd-3rd decades of life. We define four main patterns of activation-induced deaminase (AID) and apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) mutagenesis over time, including a subset of patients with evidence of prolonged AID activity during the pre-malignant phase, indicating antigen-responsiveness and germinal center reentry. Our findings provide a framework to study the etiology of multiple myeloma and explore strategies for prevention and early detection.
| S-EPMC7174344 | biostudies-literature
Project description: Not available
| S-EPMC9907188 | biostudies-literature
Project description: Not available
| S-EPMC7948301 | biostudies-literature
Project description:PurposeSmoldering multiple myeloma (SMM) is a rare asymptomatic plasma cell disorder. Even with emerging therapeutic approaches and risk stratification, the optimal time to treat SMM remains controversial. This meta-analysis aimed to compare early treatment with deferred treatment of SMM, especially high-risk SMM.MethodsEarly treatment was defined as treatment immediately after diagnosis. Deferred treatment was initiated after progression. The primary outcome was progression. Secondary outcomes were mortality, response, and safety. PubMed, EMBASE, Medline, Cochrane, and ClinicalTrials.gov databases were searched from January 1990 to March 2019. Randomized controlled trials (RCTs) comparing early treatment with deferred treatment in SMM patients were eligible. Risk ratios (RRs) with 95% confidence interval (CI) were pooled.ResultsEight RCTs covering 885 SMM patients were included. Considering all the different treatment approaches, early treatment significantly decreased progression of SMM (RR=0.53, 95% CI 0.33-0.87, P=0.01). In subgroup analysis, melphalan plus prednisone (RR=0.22, 95% CI 0.08-0.64, P=0.005) and immuno-modulatory drugs (RR=0.43, 95% CI 0.31-0.59, P<0.00001) significantly reduced progression. However, neither mortality nor response rate was significantly affected by early treatment. In terms of high-risk SMM patients, early treatment significantly decreased both progression (RR=0.51, 95% CI 0.37-0.70, P=0.0001) and mortality (RR=0.53, 95% CI 0.29-0.96, P=0.04). Frequently seen adverse events were infection, constipation, asthenia, and second primary malignancy. A remarkably elevated risk of constipation was associated with early treatment using immuno-modulatory agents (RR=4.43, 95% CI 2.14-9.12, P<0.0001). Second primary malignancy was significantly increased with early treatment (RR=4.13, 95% CI 1.07-15.97, P=0.04). No significant difference was identified in infection or asthenia.ConclusionThese findings suggest that early treatment could decrease progression and mortality of high-risk SMM patients with a tolerable safety profile.
| S-EPMC6595476 | biostudies-literature
Project description:PurposeWhether patients with smoldering multiple myeloma (SMM) needed to receive early interventional treatment remains controversial. Herein, we conducted a meta-analysis comparing the efficacy and safety of early treatment over deferred treatment for patients with SMM.MethodsMEDLINE and Cochrane Library were searched to May 2014 for randomized controlled trials (RCTs) that assessed the effect of early treatment over deferred treatment. Primary outcome measure was mortality, and secondary outcome measures were progression, response rate, and adverse events.ResultsOverall, 5 trials including 449 patients were identified. There was a markedly reduced risk of disease progression with early treatment (Odds Ratio [OR] = 0.13, 95% confidence interval [CI] = 0.07 to 0.24). There were no significant differences in mortality and response rate (OR = 0.85, 95% CI = 0.45 to 1.60, and OR = 0.63, 95% CI = 0.32 to 1.23, respectively). More patients in the early treatment arm experienced gastrointestinal toxicities (OR = 10.02, 95%CI = 4.32 to 23.23), constipation (OR = 8.58, 95%CI = 3.20 to 23.00) and fatigue or asthenia (OR = 2.72, 95%CI = 1.30 to 5.67). No significant differences were seen with the development of acute leukemia (OR = 2.80, 95%CI = 0.42 to 18.81), hematologic cancer (OR = 2.07, 95%CI = 0.43 to 10.01), second primary tumors (OR = 3.45, 95%CI = 0.81 to 14.68), nor vertebral compression (OR = 0.18, 95%CI = 0.02 to 1.59).ConclusionsEarly treatment delayed disease progression but increased the risk of gastrointestinal toxicities, constipation and fatigue or asthenia. The differences on vertebral compression, acute leukemia, hematological cancer and second primary tumors were not statistically significant. Based on the current evidence, early treatment didn't significantly affect mortality and response rate. However, further much larger trials were needed to provide more evidence.
| S-EPMC4184905 | biostudies-literature
Project description:The treatment of multiple myeloma has changed dramatically in the past decade. The increase in the number of active agents has generated numerous possible drug combinations that can be used in the first-line and relapsed settings. As a result, there is considerable confusion about the choice of regimens for initial therapy, role of transplantation in the era of new drugs, end points for therapy, and the role of maintenance therapy. A hotly debated area is whether treatment approaches should achieve cure or disease control, which impacts greatly on the treatment strategy employed. This article provides an update on the treatment of multiple myeloma, with a focus on recent advances, newly diagnosed disease, role of transplantation and maintenance therapy. A synthesized approach to the treatment of myeloma is presented, along with a discussion of key paradigms that need to be challenged.
| S-EPMC3773461 | biostudies-literature
Project description:Multiple myeloma is the most common indication for high-dose chemotherapy and autologous stem cell transplantation (ASCT), and lenalidomide maintenance after transplant is now standard. Although lenalidomide doubles progression-free survival, almost all patients eventually relapse. Posttransplant immunotherapy to improve outcomes after ASCT therefore has great merit but first requires delineation of the dynamics of immune reconstitution. We evaluated lymphocyte composition and function after ASCT to guide optimal timing of immunotherapy and to identify potential markers of relapse. Regulatory T cells (Treg) decline as CD8(+) T cells expand during early lymphocyte recovery after ASCT, markedly reducing the Treg:CD8(+) effector T-cell ratio. These CD8(+) T cells can respond to autologous dendritic cells presenting tumor antigen in vitro as early as day +12 after transplant, becoming antigen-specific cytolytic T-lymphocyte effectors and thereby demonstrating preservation of cellular reactivity. CD4(+) and CD8(+) T cells express the negative regulatory molecules, CTLA-4, PD-1, LAG-3, and TIM-3, before and after ASCT. A subpopulation of exhausted/senescent CD8(+) T cells, however, downregulates CD28 and upregulates CD57 and PD-1, characterizing immune impairment and relapse after ASCT. Relapsing patients have higher numbers of these cells at +3 months after transplant, but before detection of clinical disease, indicating their applicability in identifying patients at higher risk of relapse. PD-1 blockade also revives the proliferation and cytokine secretion of the hyporesponsive, exhausted/senescent CD8(+) T cells in vitro. Collectively, these results identify T-cell exhaustion/senescence as a distinguishing feature of relapse and support early introduction of immunotherapy to stimulate antitumor immunity after ASCT.
| S-EPMC4703436 | biostudies-literature
Project description:DNA replication enables genetic inheritance across the kingdoms of life. Replication occurs with a defined temporal order known as the replication timing (RT) programme, leading to organization of the genome into early- or late-replicating regions. RT is cell-type specific, is tightly linked to the three-dimensional nuclear organization of the genome1,2 and is considered an epigenetic fingerprint3. In spite of its importance in maintaining the epigenome4, the developmental regulation of RT in mammals in vivo has not been explored. Here, using single-cell Repli-seq5, we generated genome-wide RT maps of mouse embryos from the zygote to the blastocyst stage. Our data show that RT is initially not well defined but becomes defined progressively from the 4-cell stage, coinciding with strengthening of the A and B compartments. We show that transcription contributes to the precision of the RT programme and that the difference in RT between the A and B compartments depends on RNA polymerase II at zygotic genome activation. Our data indicate that the establishment of nuclear organization precedes the acquisition of defined RT features and primes the partitioning of the genome into early- and late-replicating domains. Our work sheds light on the establishment of the epigenome at the beginning of mammalian development and reveals the organizing principles of genome organization.
| S-EPMC10781638 | biostudies-literature
Project description:We generated human induced pluripotent cells from intellectual disability patients carrying the c.2T>C mutation in KDM5C (Called “Mutant”). We generated a paired, isogenic human iPS cell line (called “Corrected”) using CRISPR/Cas9 and PiggyBac gene-editing technologies and conducted neuronal differentiation based on “Yichen Shi et al. Nat. Protoc. 7, 1836–1846 (2012)” to define differences in gene expression between the Mutant and Corrected during neurodevelopment.
2023-10-13 | E-MTAB-7551 | biostudies-arrayexpress
Project description:Multiple myeloma (MM) remains an essentially incurable hematologic malignancy. However, new treatment modalities and novel drugs have been introduced and thus additional tools for therapy monitoring are increasingly needed. Therefore, we evaluated the radiotracers 11C-Methionine (paraprotein-biosynthesis) and 18F-FDG (glucose-utilization) for monitoring response to anti-myeloma-therapy and outcome prediction. Influence of proteasome-inhibition on radiotracer-uptake of different MM cell-lines and patient-derived CD138+ plasma cells was analyzed and related to tumor-biology. Mice xenotransplanted with MM.1S tumors underwent MET- and FDG-?PET. Tumor-to-background ratios before and after 24 h, 8 and 15 days treatment with bortezomib were correlated to survival. Treatment reduced both MET and FDG uptake; changes in tracer-retention correlated with a switch from high to low CD138-expression. In xenotransplanted mice, MET-uptake significantly decreased by 30-79% as early as 24 h after bortezomib injection. No significant differences were detected thus early with FDG. This finding was confirmed in patient-derived MM cells. Importantly, early reduction of MET- but not FDG-uptake correlated with improved survival and reduced tumor burden in mice. Our results suggest that MET is superior to FDG in very early assessment of response to anti-myeloma-therapy. Early changes in MET-uptake have predictive potential regarding response and survival. MET-PET holds promise to individualize therapies in MM in future.
| S-EPMC4480763 | biostudies-literature