Efficacy and Safety of Re-Treatment with Bortezomib (Velcade©) in Patients with Multiple Myeloma: Results from a Prospective International Phase II Trial

Background : Bortezomib has been shown to be effective in the treatment of multiple myeloma (MM). However, the data on response to re-treatment with bortezomib is very limited, mostly coming from small retrospective studies. Response to re-treatment is particularly relevant in patients with relapsing incurable conditions such as MM. The primary objective of this first international prospective phase II trial was to determine the best response to bortezomib re-treatment in patients with MM. Secondary objectives included safety profile, duration of response, time to progression, best M protein response and the evaluation of the best investigator-assessed response compared to the best response reported to the previous bortezomib treatment. Methods : Patients with secretory MM were eligible if they had responded (CR or PR) to a bortezomib-based most recent treatment and had a treatment-free interval of at least 6 months since the last bortezomib dose. They needed to meet the PD criteria as defined by European Group for Blood and Marrow Transplantation (EBMT). Patients received bortezomib starting at the last tolerated dose in the previous bortezomib regimen (1.3 or 1.0 mg/m 2 ). Bortezomib was administered alone or in combination with dexamethasone at investigator discretion. Bortezomib was administered as an intravenous injection on days 1, 4, 8 and 11 of a 21-day cycle up to a maximum of 8 cycles. Response was evaluated every 6 weeks according to EBMT criteria. Adverse events (AEs) were assessed from informed consent until at least 30 days after treatment and were graded by the NCI-CTCAE. This clinical trial closed to recruitment on 30 th June 2008 after reaching the planned sample size of 128 patients, with 57 patients still receiving treatment. The results presented include the efficacy and safety data available for 100 patients who had completed at least 2 treatment cycles at the time of data cut-off (16 July 2008) or who had withdrawn from therapy for any reason. Results : The 100 patients (M: 59, F: 41; median age 66 years) who received at least 1 dose of bortezomib are included in the current safety analysis. The median time from diagnosis of MM was 4.5 years (range 0–14 years) and 59% had received 3 or more lines of prior therapy (including the previous bortezomib therapy). Karnofsky performance status was £ 70% in 16% of patients. Twenty-six percent of patients had achieved a complete response (CR) with the last bortezomib regimen. The median treatment free interval since the previous bortezomib treatment was 14.3 months. Eighty-seven percent of the patients received at least 3 cycles and the median number of completed cycles was 5 cycles. Dexamethasone was added to the bortezomib treatment in 69% of patients. In the 97 patients eligible for the current efficacy analysis, the overall response rate (ORR) by EBMT criteria [CR+PR] was 26.8% (CI=18.3– 36.8), with 3.1% complete responses, whilst ORR + minimal response (MR) was 46.4%. The ORR did not differ in patients treated with bortezomib plus dexamethasone (27.9%, CI=17.7– 40.1) versus those treated with bortezomib alone (24.1%, CI=10.3–43.5). The median time to at least PR was 43 days, with a median time to best response of 64 days. The most commonly reported related grade 3/4 adverse events were thrombocytopenia (24%), neutropenia (5%) and diarrhea (5%). Peripheral neuropathy (PN) was observed in 20% of patients, with grade 3 PN reported in 6% of patients only. Serious TEAE’s were reported in 23% of patients and 10% of patients discontinued bortezomib due to related TEAE’s including 6 cases of PN. TEAE’s leading to death were reported in three patients. Conclusions: Response after re-treatment with bortezomib alone or in combination with dexamethasone in heavily pre-treated multiple myeloma patients was still high, and the adverse event profile was consistent with the already known safety profile. Updated results will be presented at time of the meeting.