Updated survival analyses after prolonged follow-up of the phase 2, multicenter CREST study of bortezomib in relapsed or refractory multiple myeloma

St Vincent's Comprehensive Cancer Center, New York, NY 10011, USA.
British Journal of Haematology (Impact Factor: 4.71). 10/2008; 143(4):537-40. DOI: 10.1111/j.1365-2141.2008.07359.x
Source: PubMed


The Clinical Response and Efficacy Study of Bortezomib in the Treatment of Relapsing Multiple Myeloma (CREST) demonstrated substantial activity with two dose levels of bortezomib (1.0 and 1.3 mg/m(2)), alone or with dexamethasone, in relapsed or refractory multiple myeloma. We present updated survival analyses after prolonged follow-up (median >5 years). One- and 5-year survival rates were 82% and 32%, respectively, in the 1.0 mg/m(2) group (n = 28), and 81% and 45%, respectively, in the 1.3 mg/m(2) group (n = 26). Notable survival, response, and time-to-progression data suggest that a bortezomib starting dose of 1.3 mg/m(2) is preferred. If bortezomib dose reduction is required, the 1.0 mg/m(2) dose still offers patients a substantial survival benefit.

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    • "However, the incidence of neuropathic pain is significantly greater in pretreated patients (15% vs. 39%), the neuropathy is resolved more slowly than in patients receiving bortezomib as first treatment, and these patients more frequently require reduction or suspension of treatment (73% vs. 36%) (Corso et al., 2010). Unfortunately, the reduction in the dosage also results in a reduction of the response ratio (Jagannath et al., 2005, 2008; Richardson et al., 2009) and of the duration of this response (Jagannath et al., 2004; Freimann et al., 2007; Richardson et al., 2005). Bortezomib in a subcutaneous formulation has recently been tested in a phase III trial, as an alternative to the traditional intravenous route, and the results suggest similar efficacy with a lower incidence of neurotoxicity (Moreau et al., 2011). "
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    ABSTRACT: In the last ten years, the proteasome has become one of the most attractive targets for the treatment of several cancer malignancies. Like other types of antineoplastic agents, proteasome inhibitors cause toxic peripheral neuropathy, which indeed is one of the limiting side effects of these treatments, and which thus curtails its potential effectiveness. Bortezomib was the first proteasome inhibitor approved for clinical use and is currently the first line treatment for multiple myeloma. The incidence of neuropathy induced by bortezomib is around 30 to 60%. Although the neurotoxic mechanisms are not completely understood, experimental studies suggest that aggresome formation, endoplasmic reticulum stress, mitotoxicity, inflammatory response, and DNA damage could contribute to this neurotoxicity. Additionally, the second generation of proteasome inhibitors, headed by carfilzomib, is currently being developed in order to reduce the toxic profile, with promising results. However, more extensive clinical experience and further experimental research are needed in order to determine the potential benefits of the second generation over bortezomib. The present review summarizes the main clinical features and mechanistic events related to the neuropathy induced by proteasome-inhibitors.
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    • "One of the main dose-limiting side effects in BTZ therapy (particularly when the drug is delivered intravenously) is the development of a painful, sensory peripheral neuropathy, associated with symptoms such as numbness and tingling, that occurs in a distal stocking-and-glove pattern [17, 18] and is characterized by a marked dysfunction of all fiber types in sensory nerves [17, 19], also extending into areas of the skin that are not perceived as painful [19]. Severe neuropathic pain frequently develops after the first treatment cycle [17, 20] leading to a long-term decreased quality of life [21] and often to BTZ dose modification or discontinuation [22]. Careful follow-up psychophysical studies showed that pain intensity and impairment in sensory function could persist for more than one year after therapy withdrawal [1, 19]. "
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    ABSTRACT: To investigate neurochemical changes associated with bortezomib-induced painful peripheral neuropathy (PN), we examined the effects of a single-dose intravenous administration of bortezomib and a well-established "chronic" schedule in a rat model of bortezomib-induced PN. The TRPV1 channel and sensory neuropeptides CGRP and substance P (SP) were studied in L4-L5 dorsal root ganglia (DRGs), spinal cord, and sciatic nerve. Behavioral measures, performed at the end of the chronic bortezomib treatment, confirmed a reduction of mechanical nociceptive threshold, whereas no difference occurred in thermal withdrawal latency. Western blot analysis showed a relative increase of TRPV1 in DRG and spinal cord after both acute and chronic bortezomib administration. Reverse transcriptase-polymerase chain reaction revealed a decrease of TRPV1 and CGRP mRNA relative levels after chronic treatment. Immunohistochemistry showed that in the DRGs, TRPV1-, CGRP-, and SP-immunoreactive neurons were mostly small- and medium-sized and the proportion of TRPV1- and CGRP-labeled neurons increased after treatment. A bortezomib-induced increase in density of TRPV1- and CGRP-immunoreactive innervation in the dorsal horn was also observed. Our findings show that bortezomib-treatment selectively affects subsets of DRG neurons likely involved in the processing of nociceptive stimuli and that neurochemical changes may contribute to development and persistence of pain in bortezomib-induced PN.
    Full-text · Article · Apr 2014 · BioMed Research International
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    • "It not only targets the myeloma cell, but also acts in the bone marrow micro-environment , inhibiting the binding of myeloma cells to bone marrow stromal cells [1]. Two open-label Phase II trials (SUMMIT (n = 202) and CREST (n = 54)) established the efficacy of bortezomib in a dosage between 1.0 and 1.3 mg/m 2 administered by intravenous bolus on Days 1, 4, 8 and 11 of a 21-day cycle for a maximum of 8 cycles in heavily pre-treated patients suffering from relapsed/refractory multiple myeloma [3] [4]. The randomized open-label Phase III APEX trial which recruited 669 patients in North America and Europe with relapsed multiple myeloma after up to three previous therapies demonstrated the superiority of a bortezomib 1.3 mg/m 2 regimen over a high-dose dexamethasone regimen [5]. "

    Preview · Article · Jul 2010 · International journal of clinical pharmacology and therapeutics
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