No abstract

No abstract

Summary In a phase 2 open‐label study of the novel proteasome inhibitor bortezomib, 54 patients with multiple myeloma who had relapsed after or were refractory to frontline therapy were randomized to receive intravenous 1·0 or 1·3 mg/m2 bortezomib twice weekly for 2 weeks, every 3 weeks for a maximum of eight cycles. Dexamethasone was permitted in patients with progressive or stable disease after two or four cycles respectively. Responses were determined using modified European Group for Blood and Marrow Transplantation criteria. The complete response (CR) + partial response (PR) rate for bortezomib alone was 30% [90% confidence interval (CI), 15·7–47·1] and 38% (90% CI, 22·6–56·4) in the 1·0 mg/m2 (8 of 27 patients) and 1·3 mg/m2 (10 of 26 patients) groups respectively. The CR + PR rate for patients who received bortezomib alone or in combination with dexamethasone was 37% and 50% for the 1·0 and 1·3 mg/m2 cohorts respectively. The most common grade 3 adverse events were thrombocytopenia (24%), neutropenia (17%), lymphopenia (11%) and peripheral neuropathy (9%). Grade 4 events were observed in 9% (five of 54 patients). Bortezomib alone or in combination with dexamethasone demonstrated therapeutic activity in patients with multiple myeloma who relapsed after frontline therapy.

myeloma patients showed significantly longer time to progression, higher response rate, and improved survival with single-agent bortezomib versus high-dose dexamethasone. In this updated analysis (median follow-up: 22 months), survival was assessed in both arms, and efficacy updated for the bortezomib arm. Median survival was 29.8 months for bortezomib versus 23.7 months for dexamethasone, a 6-month benefit, despite substantial crossover from dexamethasone to bortezomib. Overall and complete response rates with bortezomib were 43% and 9%, respectively; among responding patients, 56% improved response with longer therapy beyond initial response, leading to continued improvement in overall quality of response. Higher response quality (100% M-protein reduction) was associated with longer response duration; response duration was not associated with time to response. These data confirm the activity of bortezomib and support extended treatment in relapsed multiple myeloma patients tolerating therapy. This study is regis- IntroductionThe international, randomized, phase 3 Assessment of Proteasome Inhibition for Extending Remissions (APEX) trial led to full approval of bortezomib in 2005 for treatment of multiple myeloma (MM) patients who have received at least one prior therapy. In the initial APEX report, single-agent bortezomib demonstrated superior efficacy to high-dose dexamethasone in terms of significantly longer median time to progression (TTP, 6.2 vs 3.5 months, P Ͻ .001), higher response rates (38% vs 18%, P Ͻ .001), and improved survival (1-year survival rate: 80% vs 66%, P ϭ .003; hazard ratio for overall survival [OS]: 0.57, P ϭ .001). 1 As a result, the high-dose dexamethasone arm was halted at interim analysis following the recommendations of an independent data-monitoring committee. A companion crossover study, which offered single-agent bortezomib initially only to patients with progressive disease (PD) on high-dose dexamethasone, was opened to all patients randomized to high-dose dexamethasone.In this updated analysis, we report whether bortezomib continues to provide improved survival compared with high-dose dexamethasone. Other updated efficacy parameters for the bortezomib arm are reported. The relationship between duration of response (DOR) and quality of response as measured by M-protein reduction was analyzed, as was the relationship between DOR and time to first response (TTR). In addition, we report an exploratory analysis comparing patients who initially received bortezomib on APEX with those who first received high-dose dexamethasone and crossed over to receive bortezomib on the companion study. MethodsApproval was obtained from the institutional review boards of all participating institutions (Document S1, available on the Blood website; see the Supplemental Materials link at the top of the online article). For personal use only. on April 29, 2019. by guest www.bloodjournal.org From for five 4-week cycles. Patients were assessed for disease status and survival every 3 weeks for 39 weeks. Fo...

The aims of this study were to assess the feasibility of prospective pharmacogenomics research in multicenter international clinical trials of bortezomib in multiple myeloma and to develop predictive classifiers of response and survival with bortezomib. Patients with relapsed myeloma enrolled in phase 2 and phase 3 clinical trials of bortezomib and consented to genomic analyses of pretreatment tumor samples. Bone marrow aspirates were subject to a negative-selection procedure to enrich for tumor cells, and these samples were used for gene expression profiling using DNA microarrays. Data quality and correlations with trial outcomes were assessed by multiple groups. Gene expression in this dataset was consistent with data published from a single-center study of newly diagnosed multiple myeloma. Response and survival classifiers were developed and shown to be significantly associated with outcome via testing on independent data. The survival classifier improved on the risk stratification provided by the Interna-