Bortezomib, low-dose intravenous melphalan, and dexamethasone for patients with relapsed multiple myeloma.
ABSTRACT This multicenter phase I/II study investigated the maximum tolerated dose (MTD), safety, and efficacy of low dose intravenous (IV) melphalan in combination with bortezomib for patients with relapsed multiple myeloma (MM). Patients received bortezomib 1.3 mg/m(2) on days 1, 4, 8, and 11 and escalating doses of IV melphalan (2.5-10.0 mg/m(2)) on day 2 of a 28-day cycle for a maximum of eight cycles. Dexamethasone 20 mg was added for progressive or stable disease. Fifty-three patients were enrolled. The MTD was defined at melphalan 7.5 mg/m(2) and bortezomib 1.3 mg/m(2). The overall response rate (ORR) was 68% (23% complete or near-complete responses [CR/nCR]) whilst at the MTD (n = 33) the ORR was 76% (34% CR/nCR). After median follow-up of 17 months, the median progression free survival was 10 months, rising to 12 months at the MTD (P < 0.05 vs. non-MTD regimens). The median overall survival was 28 months, but was not yet reached at the MTD. Grade 3/4 adverse events included thrombocytopenia (62%), neutropenia (57%), infection (21%), and neuropathy (15%). Bortezomib and low-dose IV melphalan combination therapy is a safe and highly effective regimen for patients with relapsed MM. These data suggest further investigation of this combination is warranted.
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ABSTRACT: Multiple myeloma (MM) is a neoplastic disorder. It results from proliferation of clonal plasma cells in bone marrow with production of monoclonal proteins, which are detectable in serum or urine. MM is clinically characterized by destructive bone lesions, anemia, hypercalcemia and renal insufficiency. Its prognosis is severe, with a median survival after diagnosis of approximately 3 years due to frequent relapses. Treatments for patients with relapsed/refractory MM include hematopoietic cell transplantation, a rechallenge using a previous chemotherapy regimen or a trial of a new regimen. The introduction of new drugs such as thalidomide, lenalidomide and bortezomib has markedly improved MM outcomes. When relapse occurs, the clinician's challenge is to select the optimal treatment for each patient while balancing efficacy and toxicity. Patients with indolent relapse can be first treated with a 2-drug or a 3-drug combination. Patients with more aggressive relapse often require therapy with a combination of multiple active agents. Autologous stem cell transplantation should be considered as salvage therapy at first relapse for patients who have cryopreserved stem cells early in the disease course. The aim of this review is to provide an overview on the pharmacological and molecular action of treatments used for patients with relapsed/refractory multiple myeloma.Clinical Medicine Insights: Oncology 01/2013; 7:209-219.
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ABSTRACT: We conducted a systematic review and meta-analysis to clarify the incidence and risk of cardiotoxicity associated with bortezomib in cancer patients. Databases from PubMed, Web of Science and abstracts presented at ASCO meeting up to July 31, 2013 were searched to identify relevant studies. Eligible studies included prospective phase II and III trials evaluating bortezomib in cancer patients with adequate data on cardiotoxicity. Statistical analyses were conducted to calculate the summary incidence, odds ratio (OR) and 95% confidence intervals (CIs) by using either random effects or fixed effect models according to the heterogeneity of included studies. A total of 5718 patients with a variety of malignancies from 25 clinical trials were included in our analysis. The incidence of all-grade and high-grade cardiotoxicity associated with bortezomib was 3.8% (95%CI: 2.6-5.6%) and 2.3% (1.6-3.5%), with a mortality of 3.0% (1.4-6.5%). Patients treated with bortezomib did not significantly increase the risk of all-grade (OR 1.15, 95%CI: 0.82-1.62, p = 0.41) and high-grade (OR 1.13, 95%CI: 0.58-2.24, p = 0.72) cardiotoxicity compared with patients treated with control medication. Sub-group analysis showed that the incidence of cardiotoxicity varied with tumor types, treatment regimens and phases of trials. No evidence of publication bias was observed. The use of bortezomib does not significantly increase the risk of cardiotoxicity compared to control patients. Further studies are recommended to investigate this association and risk differences among different tumor types, treatment regimens and phases of trials.PLoS ONE 01/2014; 9(1):e87671. · 3.53 Impact Factor
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ABSTRACT: Multiple myeloma (MM) is a clonal plasma cell disorder that is still incurable using conventional treatments. Over the last decade, advances in front-line therapy have led to an increase in survival, but there are still some doubts in the case of relapsed/refractory disease. We searched the PubMed database for articles on treatment options for patients with relapsed/refractory MM published between 1996 and 2013. These treatments included hematopoietic cell transplantation (HCT), rechallenges using previous chemotherapy regimens, and trials of new regimens. The introduction of new agents such as the immunomodulatory drugs (IMIDs) thalidomide and lenalidomide, and the first-in-its-class proteasome inhibitor bortezomib, has greatly improved clinical outcomes in patients with relapsed/refractory MM, but not all patients respond and those that do may eventually relapse or become refractory to treatment. The challenge is therefore to select the optimal treatment for each patient by balancing efficacy and toxicity. To do this, it is necessary to consider disease-related factors, such as the quality and duration of responses to previous therapies, and the aggressiveness of the relapse, and patient-related factors such as age, comorbidities, performance status, pre-existing toxicities and cytogenetic patterns. The message from the trials reviewed in this article is that the new agents may be used to re-treat relapsed/refractory disease, and that the sequencing of their administration should be modulated on the basis of the various disease and patient-related factors. Moreover, our understanding of the pharmacology and molecular action of the new drugs will contribute to the possibility of developing tailored treatment.Expert Review of Anti-infective Therapy 12/2013; · 2.07 Impact Factor