A phase II trial of thalidomide in refractory multiple myeloma was initiated using a dose schedule that escalated from 200 mg/d to 800 mg/d. More than two thirds of patients had cytogenetic abnormalities and more than half had received at least two cycles of high-dose therapy. A paraprotein reduction of at least 25% was noted in 37% of patients and 14% had either a complete remission (CR) or a near CR. No treatment-related mortality was observed. With a median follow-up of almost 2 years, the 2-year event-free survival (EFS) and overall survival (OS) estimates were 15% and 60%, respectively. A reduction of paraprotein levels by greater than 50% was associated with a significant reduction in bone marrow plasmacytosis and beta(2)-microglobulin levels (beta2M), and greater recovery of hemoglobin and IgM levels compared to patients whose paraprotein was reduced by a lesser degree. Responses occurred more frequently among patients with a lower plasma cell labeling index (PCLI) and normal cytogenetics. Comparing response and survival by thalidomide dose for low- and high-risk groups revealed a thalidomide dose-response effect in the high-risk group of patients. The virtual absence of myelosuppressive toxicity, except in heavily pretreated patients with compromised bone marrow function, suggests that thalidomide is an ideal agent to be used in combination with cytotoxic agents and dexamethasone. Several trials are currently underway at the Arkansas Myeloma and Transplantation Research Center to determine the clinical benefit of adding thalidomide to post-transplant salvage therapy and in the upfront management of patients.
"In the majority of patients , dose reduction results in improvement of the PN symptoms (Bang et al., 2006; Richardson et al., 2006; Badros et al., 2007). Thalidomide (alpha-[n-phthalimido] glutarimide) is an U.S. Food and Drug Administration-approved drug for the treatment of MM (Barlogie et al., 2001). The mechanism of action of thalidomide is poorly understood but thought to involve both immunomodulation and antiangiogenesis. "
[Show abstract][Hide abstract] ABSTRACT: Dose-limiting peripheral neuropathy (PN) is frequently reported with the use of thalidomide and bortezomib, novel proteasome inhibitors. While these two agents have significant activity in multiple myeloma (MM), the combination and the associated PN have not been fully examined in untreated patients. The objective of this study was to report the baseline prevalence and occurrence of PN in newly diagnosed MM patients treated with bortezomib and thalidomide. Twenty-seven patients (11 men and 16 women) with previously untreated MM were prospectively monitored for PN. Total neuropathy score reduced (TNSr) was calculated at baseline and after every two cycles of bortezomib treatment. The median cumulative dose of bortezomib was 35.6 mg/m(2) (median 8 cycles) and of thalidomide was 16.8 g. Only three subjects showed mild PN at baseline (whole group median TNSr 0). At the end of treatment, PN developed in 26 patients (median TNSr 8). PN was of mild to moderate severity (TNSr grade 1 = 11, grade 2 = 10, grade 3 = 5, and grade 4 = 0). Nerve conduction studies showed axonal physiology in all except three subjects in whom demyelinating physiology was noted. The median TNSr was 17 in the demyelinating group and 9 in the axonal group. There was no significant correlation of TNSr with cumulative bortezomib or thalidomide dose. At follow-up, 80% of patients had become asymptomatic after discontinuation of the chemotherapy. We conclude that bortezomib and thalidomide combination chemotherapy induces a reversible length-dependent sensory>motor, predominantly axonal, large-fiber>small-fiber polyneuropathy. In a subset, a more severe demyelinating polyneuropathy may develop.
Journal of the Peripheral Nervous System 12/2008; 13(4):275-82. DOI:10.1111/j.1529-8027.2008.00193.x · 2.76 Impact Factor
"This finding suggests that FGFR3 might play a role in the pathogenesis of MM associated with the t(4; 14) translocation , and is a potential therapeutic target for the treatment of MM. Thal is a glutamic acid derivative that exerts potent antiangiogenic activity in experimental systems and in advanced MM (Singhal et al 1999; Barlogie et al 2001). Although Thal was initially used to treat MM because of its known antiangiogenic effects (D'Amato et al 1994), the mechanism of its activity appears to be more complex and remains unclear. "
[Show abstract][Hide abstract] ABSTRACT: Thalidomide (Thal), a novel agent in the treatment of multiple myeloma, is presumed to act through a variety of mechanisms. In the present study, we examined the relationship between fibroblast growth factor receptor 3 (FGFR3) expression and the therapeutic effect of Thal. The DNA synthesis of KMS-11 clone, which overexpresses FGFR3, was inhibited by Thal in a dose-dependent manner; whereas U266 cells, which lack FGFR3 expression, failed to respond to Thal inhibition. To further examine the intertwining of Thal's therapeutic effects, wild-type human full-length FGFR3 cDNA was transfected into U266 cells. FGFR3 transfected U266 clones revealed increased FGFR3 expression, but resulted in decreased DNA synthesis and increased apoptosis under Thal treatment. Under Thal treatment, the myeloma proliferation-related protein, vascular endothelial growth factor (VEGF), and interleukin-6 (IL-6) were decreased in U266 FGFR3 transfectant as well. These results suggest that Thal inhibits myeloma cell proliferation and may depend on FGFR3 expression status. To further confirm this observation, we transfected a plasmid constructed anti-FGFR3 ribozyme (Rz52) into KMS-11 cells. In the ribozyme transfectant KMS-11 clone, FGFR3 expression was decreased; whereas the effects of Thal in cell growth inhibition were abrogated in KMS-11 Rz52 clone. Further results suggested that Thal inhibition of DNA synthesis, induction of apoptosis, and down-regulation of VEGF and IL-6 might be dependent on FGFR3-associated signal transduction of the ERK and STAT3 phosphorylation pathway. Thus, FGFR3 may be a predictive/surrogate marker for selection of Thal treatment in myeloma.
[Show abstract][Hide abstract] ABSTRACT: Standardized CT-based criteria used for lymphoma staging and follow-up and the current role of FDG-PET are reviewed. The current CT-based International Workshop Criteria (IWC) still have the main advantage of representing standardized criteria allowing comparability of clinical trials in patients with lymphoma. However, functional imaging with integrated IWC and FDG-PET provide more accurate response assessment, and challenge the current paradigm. Although integration of FDG-PET in IWC requires validation in a prospective trial with a large number of patients, new long-term clinical and therapeutic trials probably need to be designed using these new and hopefully standardized functional criteria. This potentially could allow a more risk-adapted approach to the treatment of aggressive lymphoma: intensive (reinforced) therapies for non-responders vs. less intensive therapies for good responders with the main goal of improved clinical outcome.
Cancer Imaging 02/2005; 5 Spec No A(Spec No A):S102-6. DOI:10.1102/1470-7330.2005.0037 · 2.07 Impact Factor
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