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. © 2016 American Cancer Society.

Center for Applied Medical Research August Pi 1 Sunyer Biomedical Research Institute University of Navarra Pamplona Spain

Department of Clinical Hematology August Pi 1 Sunyer Biomedical Research Institute University of Barcelona Barcelona Spain

Department of Hemato Oncology University Hospital and Faculty of Medicine University of Ostrava Ostrava Czech Republic

Department of Hematology 1st Republican Clinical Hospital of the Ministry of Healthcare of the Udmurt Republic Izhevsk Russia

Department of Hematology Erasmus Medical Center Cancer Institute Rotterdam the Netherlands

Department of Hematology Medical University of Łódź Łódź Poland

Department of Hematology Royal Adelaide Hospital West Australia Australia

Department of Internal Medicine Charles University General Faculty Hospital Prague Czech Republic

Department of Lymphoma Myeloma The University of Texas MD Anderson Cancer Center Houston Texas

Division of Hematology Chaim Sheba Medical Center Tel Hashomer Israel

Division of Hematology University of British Columbia Vancouver British Columbia Canada

Hematology and Bone Marrow Transplant Department Medical University of Lublin Lublin Poland

Janssen Research and Development LLC Raritan New Jersey

Malignant Hematology and Stem Cell Transplantation Service The Alfred Hospital Melbourne Australia

Cancer. 2016 Jul 1;122(13):1971-3. doi: 10.1002/cncr.30024. PubMed

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Munshi NC, Anderson KC. New strategies in the treatment of multiple myeloma. Clin Cancer Res. 2013;19:3337–3344. PubMed PMC

Redic K. Carfilzomib: a novel agent for multiple myeloma. J Pharm Pharmacol. 2013;65:1095–1106. PubMed

Barlogie B, Anaissie E, van Rhee F, et al. Incorporating bortezomib into upfront treatment for multiple myeloma: early results of total therapy 3. Br J Haematol. 2007;138:176–185. PubMed

Jakubowiak AJ, Kendall T, Al-Zoubi A, et al. Phase II trial of combination therapy with bortezomib, pegylated liposomal doxorubicin, and dexamethasone in patients with newly diagnosed myeloma. J Clin Oncol. 2009;27:5015–5022. 2009;27:5015–5022. PubMed

Offidani M, Corvatta L, Piersantelli MN, et al. Thalidomide, dexamethasone, and pegylated liposomal doxorubicin (ThaDD) for patients older than 65 years with newly diagnosed multiple myeloma. Blood. 2006;108:2159–2164. PubMed

San-Miguel JF, Schlag R, Khuageva N, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359:906–917. PubMed

Voorhees PM, Orlowski RZ, Mulkey F, et al. Long-term outcomes for newly-diagnosed multiple myeloma patients treated with pegylated liposomal doxorubicin and bortezomib: final results of CLAGB (Alliance) 10303, a multicenter phase II study. Br J Haematol. 2015;171:373–377. PubMed PMC

Orlowski RZ, Nagler A, Sonneveld P, et al. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol. 2007;25:3892–3901. PubMed

Mitsiades N, Mitsiades CS, Richardson PG, et al. The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications. Blood. 2003;101:2377–2380. PubMed

Orlowski RZ, Voorhees PM, Garcia RA, et al. Phase 1 trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignancies. Blood. 2005;105:3058–3065. PubMed

Sonneveld P, Hajek R, Nagler A, et al. Combined pegylated liposomal doxorubicin and bortezomib is highly effective in patients with recurrent or refractory multiple myeloma who received prior thalidomide/lenalidomide therapy. Cancer. 2008;112:1529–1537. PubMed

Blade J, Sonneveld P, San Miguel JF, et al. Pegylated liposomal doxorubicin plus bortezomib in relapsed or refractory multiple myeloma: efficacy and safety in patients with renal function impairment. Clin Lymphoma Myeloma. 2008;8:352–355. PubMed

Garderet L, Iacobelli S, Moreau P, et al. Superiority of the triple combination of bortezomib-thalidomide-dexamethasone over the dual combination of thalidomide-dexamethasone in patients with multiple myeloma progressing or relapsing after autologous transplantation: the MMVAR/IFM 2005-04 randomized phase III trial from the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. 2012;30:2475–2482. PubMed

Moreau P, Richardson PG, Cavo M, et al. Proteasome inhibitors in multiple myeloma: 10 years later. Blood. 2012;120:947–959. PubMed PMC

Wright JJ. Combination therapy of bortezomib with novel targeted agents: an emerging treatment strategy. Clin Cancer Res. 2010;16:4094–4104. PubMed

Lonial S, Mitsiades CS, Richardson PG. Treatment options for relapsed and refractory multiple myeloma. Clin Cancer Res. 2011;17:1264–1277. PubMed

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