Robert Z Orlowski1, Arnon Nagler2, Pieter Sonneveld3, Joan Bladé4, Roman Hajek5, Andrew Spencer6, Tadeusz Robak7, Anna Dmoszynska8, Noemi Horvath9, Ivan Spicka10, Heather J Sutherland11, Alexander N Suvorov12, Liang Xiu13, Andrew Cakana13, Trilok Parekh13, Jesús F San-Miguel14. 1. Department of Lymphoma/Myeloma, The University of Texas, MD Anderson Cancer Center, Houston, Texas. 2. Division of Hematology, Chaim Sheba Medical Center, Tel-Hashomer, Israel. 3. Department of Hematology, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands. 4. Department of Clinical Hematology, August Pi I Sunyer Biomedical Research Institute, University of Barcelona, Barcelona, Spain. 5. Department of Hemato-Oncology, University Hospital and Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic. 6. Malignant Hematology and Stem Cell Transplantation Service, The Alfred Hospital, Melbourne, Australia. 7. Department of Hematology, Medical University of Łódź, Łódź, Poland. 8. Hematology and Bone Marrow Transplant Department, Medical University of Lublin, Lublin, Poland. 9. Department of Hematology, Royal Adelaide Hospital, West Australia, Australia. 10. Department of Internal Medicine, Charles University General Faculty Hospital, Prague, Czech Republic. 11. Division of Hematology, University of British Columbia, Vancouver, British Columbia, Canada. 12. Department of Hematology, First Republican Clinical Hospital of the Ministry of Healthcare of the Udmurt Republic, Izhevsk, Russia. 13. Janssen Research & Development, LLC, Raritan, New Jersey. 14. Center for Applied Medical Research, August Pi I Sunyer Biomedical Research Institute, University of Navarra, Pamplona, Spain.
Abstract
BACKGROUND: Previous results from an interim analysis of an open-label, randomized, phase 3 study demonstrated that bortezomib combined with pegylated liposomal doxorubicin (PLD) was superior to bortezomib monotherapy in patients with relapsed/refractory multiple myeloma who had previously received one or more lines of therapy. Protocol-defined final survival data from that study are provided here. METHODS: Patients were randomized (1:1) to receive either bortezomib alone (1.3 mg/m(2) intravenously on days 1, 4, 8, and 11 of every 21-day cycle) or bortezomib-PLD (bortezomib plus PLD 30 mg/m(2) intravenously on day 4). The primary endpoint was the time to progression. Secondary efficacy endpoints included overall survival (OS), progression-free survival, and the overall response rate. RESULTS: In total, 646 patients (bortezomib-PLD, n = 324; bortezomib alone, n = 322) were randomized between December, 2004, and March, 2006. On the clinical cutoff date (May 16, 2014) for the final survival analysis, at a median follow-up of 103 months, 79% of patients had died (bortezomib-PLD group: 253 of 324 patients; 78%; bortezomib alone group: 257 of 322 patients; 80%). The median OS in the bortezomib-PLD group was 33 months (95% confidence interval [CI], 28.9-37.1) versus 30.8 months (95% CI, 25.2-36.5) in the bortezomib alone group (hazard ratio, 1.047; 95% CI, 0.879-1.246; P = .6068). Salvage therapies included conventional and novel drugs, which were well balanced between the two treatment groups. CONCLUSIONS: Despite inducing a superior time to progression, long-term follow-up revealed that PLD-bortezomib did not improve OS compared with bortezomib alone in patients with relapsed/refractory multiple myeloma. The inability to sustain the early observed survival advantage may have been caused by the effects of subsequent lines of therapy, and underscores the need for long-term follow-up of phase 3 trials while recognizing the challenge of having adequate power to detect long-term differences in OS. Cancer 2016;122:2050-6.
RCT Entities:
BACKGROUND: Previous results from an interim analysis of an open-label, randomized, phase 3 study demonstrated that bortezomib combined with pegylated liposomal doxorubicin (PLD) was superior to bortezomib monotherapy in patients with relapsed/refractory multiple myeloma who had previously received one or more lines of therapy. Protocol-defined final survival data from that study are provided here. METHODS:Patients were randomized (1:1) to receive either bortezomib alone (1.3 mg/m(2) intravenously on days 1, 4, 8, and 11 of every 21-day cycle) or bortezomib-PLD (bortezomib plus PLD 30 mg/m(2) intravenously on day 4). The primary endpoint was the time to progression. Secondary efficacy endpoints included overall survival (OS), progression-free survival, and the overall response rate. RESULTS: In total, 646 patients (bortezomib-PLD, n = 324; bortezomib alone, n = 322) were randomized between December, 2004, and March, 2006. On the clinical cutoff date (May 16, 2014) for the final survival analysis, at a median follow-up of 103 months, 79% of patients had died (bortezomib-PLD group: 253 of 324 patients; 78%; bortezomib alone group: 257 of 322 patients; 80%). The median OS in the bortezomib-PLD group was 33 months (95% confidence interval [CI], 28.9-37.1) versus 30.8 months (95% CI, 25.2-36.5) in the bortezomib alone group (hazard ratio, 1.047; 95% CI, 0.879-1.246; P = .6068). Salvage therapies included conventional and novel drugs, which were well balanced between the two treatment groups. CONCLUSIONS: Despite inducing a superior time to progression, long-term follow-up revealed that PLD-bortezomib did not improve OS compared with bortezomib alone in patients with relapsed/refractory multiple myeloma. The inability to sustain the early observed survival advantage may have been caused by the effects of subsequent lines of therapy, and underscores the need for long-term follow-up of phase 3 trials while recognizing the challenge of having adequate power to detect long-term differences in OS. Cancer 2016;122:2050-6.
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