Timing of treatment of smoldering myeloma: early treatment.
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ABSTRACT:
SUBMITTER: Mateos M
PROVIDER: S-EPMC6234377 | biostudies-other | 2018 Nov
REPOSITORIES: biostudies-other
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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.
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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.
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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.
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