Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial

Abstract

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...

Bortezomib plus intermediate‐dose dexamethasone and thalidomide in elderly untreated patients with multiple myeloma: A Chinese experience

“…The higher response rates observed in this study were similar as previous studies [8,20]. The APEX study showed that patients receiving bortezomib earlier have higher response rates and longer survival [15]. Additionally, this study had a rapid response to bortezomib-based treatment, after a median time of 22 days, namely the first cycle of treatment.…”

“…The activity and safety of bortezomib in MM has been clearly demonstrated in several large multicenter studies [13][14][15]. Based in part on data from the SUMMIT [13] and CREST [14] studies, single-agent bortezomib was approved at 1.3 mg/m 2 twice weekly every 3 weeks for the treatment of MM in patients who have received at least one prior therapy.…”

A phase I safety study of enzastaurin plus bortezomib in the treatment of relapsed or refractory multiple myeloma

“…Although a confirmed partial response or better was observed in only 17.4% of the patients, most of these patients were heavily pretreated and refractory to prior therapies. In addition, the median TTP observed in this study (7.9 months) was slightly longer than that reported in patients treated with bortezomib as a single agent (6.2-7.0 months) [3,15].…”

“…Even after initial response to treatment, nearly all multiple myeloma patients eventually relapse or become refractory to treatment [2]. Median survival of patients with relapsed multiple myeloma treated with bortezomib in the Assessment of Proteasome Inhibition for Extending Remissions (APEX) trial was 29.8 months [3]; however, survival of such patients declines after each subsequent regimen [4]. A significant unmet medical need remains, and new agents are needed for the treatment of patients with multiple myeloma.…”

“…In the APEX trial, single-agent bortezomib therapy resulted in a response rate (RR) of 38%, time to progression of 6.2 months, and a 1-year survival rate of 80% in patients with relapsed multiple myeloma [3]. Proteosome inhibition leads to disruption of cell cycle functions resulting in apoptosis.…”