Bortezomib, low-dose intravenous melphalan, and dexamethasone for patients with relapsed multiple myeloma

Department of Haematology, St. Bartholomew's Hospital, London, UK.
British Journal of Haematology (Impact Factor: 4.71). 03/2009; 144(6):887-94. DOI: 10.1111/j.1365-2141.2008.07572.x
Source: PubMed


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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Available from: Nicola Foot, Oct 06, 2014
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    • "Recent studies provide evidence that bortezomib at high doses may be of interest in patients with del(17p) mutation.41,42 In conclusion several authors have shown efficacy of bortezomib alone or in combination in relapsed refractory MM.42–49 "
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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.
    Full-text · Article · Aug 2013 · Clinical Medicine Insights: Oncology
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    • "Response occurred rapidly (median time to first response 36 days) and were long-lasting with a median PFS of 19.1 months (95% CI 11.9–22.2) overlapping data reported by other authors using similar three drug combinations 7,9,31–33. Outcome were even better if patients received B-MuD as second line therapy with a median PFS of 21.3 months. Response was significantly associated with outcome (P = 0.024) 16,34, with similar clinical benefit for patients reaching at least a partial response when compared to patients with good responses (median PFS 19.1 vs. 22.2 months in patients with PR and ≥VGPR respectively, P = 0.3). "
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    ABSTRACT: Since multiple myeloma (MM) is still not-curable, the management of relapse remains challenging. Given the known efficacy of alkylating agents in MM, we conducted a phase I/II study to test a new three drug combination in which Fotemustine (Muphoran), an alkylating agent of nitrosurea family, was added to bortezomib + dexamethasone backbone (B-MuD) for the treatment of MM relapsed patients. Fotemustine was administered at two dose levels (80-100 mg/m(2) i.v.) on day 1. The original 21-day schedule was early amended for extra-hematological toxicity and a 35-day schedule was adopted (Bortezomib 1.3 mg/m(2) i.v. on days 1, 8, 15, and 22, Dexamethasone 20 mg i.v. on days 1, 8, 15, and 22) for a total of six courses. Twenty-four patients were enrolled. The maximum tolerated dose of Fotemustine was 100 mg/m(2) . The overall response rate was of 62% (CR 8%, VGPR 33%, and PR 21%). The median OS was 28.5 months, the median progression-free survival (PFS) was 19.1 months. B-MuD resulted effective in patients previous exposed to bortezomib without difference of response (P = 0.25) and PFS (P = 0.87) when compared to bortezomib-naive patients. Thrombocytopenia was the most common AE overall. In conclusion, B-MuD is an effective and well tolerated combination in relapsed MM patients even in advanced disease phase. © Am. J. Hematol., 2012. © 2012 Wiley Periodicals, Inc.
    Full-text · Article · Feb 2013 · American Journal of Hematology
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    • "Bortezomib in combination with melphalan is efficacious for patients with multiple myeloma (MM), both in the untreated (San Miguel et al, 2008) and relapsed (Popat et al, 2009) setting . Responses are high, but as only a minority achieve a complete response and toxicities are observed, there is a need to optimise the combination. "

    Preview · Article · Oct 2012 · British Journal of Haematology
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