Multiple myeloma (MM) has been the most intractable hematological disease for many years. Recently, basic and clinical research has advanced remarkably and a new therapeutic strategy has been established. The introduction of high-dose melphalan with autologous stem-cell transplantation and the availability of molecular-targeted novel agents such as immunomodulatory drugs and proteasome inhibitors have dramatically changed the treatment strategies for MM. Achievement of a high response rate resulted in the extension of overall survival, but further research and the development of more multimodality therapeutic approaches is warranted to cure this disease. [J Clin Exp Hematopathol 52(3) : 149-159, 2012].
"p53 deletion which was found to be predominantly monoallelic has a reported incidence rate ranging from 10% to 34% of the cases [6, 8, 12, 13]. In particular, this chromosomal abnormality was identified as one of the few factors that defined high risk and poor prognosis in MM . In line with this, p53 deletion has been reported as an important factor associated with resistance to chemotherapy . "
[Show abstract][Hide abstract] ABSTRACT: p53 abnormalities are regarded as an independent prognostic marker in multiple myeloma. Patients harbouring this genetic anomaly are commonly resistant to standard therapy. Thus, various p53 reactivating agents have been developed in order to restore its tumour suppressive abilities. Small molecular compounds, especially, have gained popularity in its efficacy against myeloma cells. For instance, promising preclinical results have steered both nutlin-3 and PRIMA-1 into phase I/II clinical trials. This review summarizes different modes of p53 inactivation in myeloma and highlights the current p53-based therapies that are being utilized in the clinic. Finally, we discuss the potential and promise that the novel small molecules possess for clinical application in improving the treatment outcome of myeloma.
BioMed Research International 06/2014; 2014:717919. DOI:10.1155/2014/717919 · 2.71 Impact Factor
"In our study, a statistically significant higher level of HGF, b-FGF, IL-6, and sIL-6R was observed in the blood plasma of MM patients as compared to the control group. Many studies have demonstrated that plasma levels of IL-6 and sIL-6R are elevated in patients with MM and correlate with the severity of the cancer 1,18-20. Bataille et al. showed that in patients with stage III MM, based on the Durie and Salmon classification, levels of IL-6 were significantly higher compared to patients with stage I and II disease. "
[Show abstract][Hide abstract] ABSTRACT: Background. In the last few years, it has been widely reported that proinflammatory and angiogenic cytokines are important for the development and progression of multiple myeloma (MM).
Objectives. To further validate and acquire more insight into this view we decided to check whether plasma levels of certain cytokines and their soluble receptors differ between MM patients and healthy subjects.
Patients and Methods. The study was conducted in 76 MM patients aged 22 to 77 years (60±10 years) and 35 healthy controls aged 20 to 63 years (33±10 years). Plasma levels of interleukin-6 (IL-6), b-fibroblast growth factor (b-FGF), hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF) and transforming growth factor-β1 (TGF-β1), as well as soluble receptors for IL-6 (sIL-6R) and VEGF (sVEGF-R2) were measured using enzyme-linked immunosorbent assay (ELISA).
Results. Significantly higher plasma levels of IL-6 (13.65±42.61 vs. 1.04±1.12 pg/ml, p=0.006), HGF (2174±2714 vs. 648±130 pg/ml, p<0.001), b-FGF (7.92±10.78 vs. 2.54±5.38 pg/ml, p<0.001) and sIL-6R (37.1±14.2 vs. 25.3±6.4 ng/ml, p=0.003) were observed in MM patients vs. healthy controls, respectively. Plasma sVEGF-R2 was significantly lower in MM patients than in controls (7518±2119 vs. 8725±1281 pg/ml, respectively; p<0.001). We observed an inverse correlation between length of treatment and the level of sIL-6R, and TGF-β1 in plasma.
Conclusions. Plasma levels of HGF, b-FGF, IL-6 and sIL-6R in MM patients were higher when compared to the control group. Antineoplastic therapy leads to a time-dependent decrease in plasma levels of sIL-6R, and TGF-β1 in MM patients. Blood plasma level of HGF is an optimal measure to differentiate patients in whom disease is progressing versus patients who respond to therapy.
Journal of Cancer 06/2014; 5(7). DOI:10.7150/jca.9266 · 3.27 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Circularly permuted TRAIL (CPT), a recombinant mutant of human Apo2L/TRAIL, is a novel antitumor candidate for multiple myeloma (MM) and other hematologic malignancies. In this phase II study, the safety and efficacy of CPT plus thalidomide was investigated in thalidomide-resistant MM patients. A total of 43 patients were recruited into three CPT plus thalidomide cohorts based on CPT dosage in sequence: 5mg/kg (n=11), 8mg/kg (n=17), and 10mg/kg (n=15). CPT was administered via intravenous infusion on days 1-5, and thalidomide was given orally at 100mg once daily in each 21-day cycle. The overall response rate (ORR) of 41 efficacy-evaluable patients was 22.0% (2 complete response, 3 near complete response and 4 partial response). No significant difference in the ORR was observed among the three dose cohorts, however, the ORR tended to be higher with the higher-dose regimen. Median progression-free survival and median duration of response were 6.6 months and 6.1 months, respectively. The most common treatment-related adverse events (TRAEs) were neutropenia (46.5%), leukopenia (41.9%), fever (37.2%), elevated AST (32.6%) and ALT (20.9%). TRAEs of grade 3-4 were mainly neutropenia (18.6%), anemia (9.3%), elevated AST (7.0%) and leukopenia (4.7%). No significant differences were found in the incidence and severity of TRAEs among the three cohorts. In conclusion, CPT plus thalidomide was well tolerated with no occurrence of dose-limiting toxicities and demonstrated promising antitumor activity in RRMM patients. CPT at 10 mg/kg for 5 days in combination with thalidomide and dexamethason will be studied in the next clinical trial.
American Journal of Hematology 11/2014; 89(11). DOI:10.1002/ajh.23822 · 3.80 Impact Factor
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