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Clinical Trial
. 2016 Jul 1;122(13):2050-6.
doi: 10.1002/cncr.30026. Epub 2016 May 18.

Final overall survival results of a randomized trial comparing bortezomib plus pegylated liposomal doxorubicin with bortezomib alone in patients with relapsed or refractory multiple myeloma

Robert Z Orlowski  1 , Arnon Nagler  2 , Pieter Sonneveld  3 , Joan Bladé  4 , Roman Hajek  5 , Andrew Spencer  6 , Tadeusz Robak  7 , Anna Dmoszynska  8 , Noemi Horvath  9 , Ivan Spicka  10 , Heather J Sutherland  11 , Alexander N Suvorov  12 , Liang Xiu  13 , Andrew Cakana  13 , Trilok Parekh  13 , Jesús F San-Miguel  14
Affiliations
Clinical Trial

Final overall survival results of a randomized trial comparing bortezomib plus pegylated liposomal doxorubicin with bortezomib alone in patients with relapsed or refractory multiple myeloma

Robert Z Orlowski et al. Cancer. .

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. © 2016 American Cancer Society.

Keywords: bortezomib; doxorubicin; multiple myeloma; pegylated liposomal doxorubicin; survival.

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Conflict of interest statement

CONFLICT OF INTEREST DISCLOSURES

Robert Z. Orlowski reports research funding from Janssen-Cilag and Janssen Research &Development, LLC (Janssen R&D); grants from Amgen, Array BioPharma Inc, Bristol-Myers Squibb, Celgene Corporation, Janssen R&D, Millennium Pharmaceuticals, Onyx Pharmaceuticals, and Spectrum Pharmaceuticals; and personal fees from Abbott Laboratories, Amgen, Array BioPharma Inc, Bio-Theryx, Bristol-Myers Squibb, Celgene Corporation, Cephalon Inc, Forma Therapeutics, Genentech Inc, Incyte, Janssen-Cilag, Janssen R&D, Millennium Pharmaceuticals, and Novartis. Pieter Sonneveld reports grants from Celgene Corporation, Janssen-Cilag, Amgen, Takeda, and Karyopharm Therapeutics, Inc., and personal fees from Celgene Corporation, Janssen-Cilag, and Ortho Biotech. Joan Bladé reports grants from Janssen-Cilag and Celgene Corporation and personal fees from Amgen, Binding Site, Celgene Corporation, Janssen-Cilag, Janssen R&D, and Takeda Pharmaceuticals. Roman Hajek reports research funding and personal fees from Janssen R&D. Andrew Spencer is a consultant for Janssen-Cilag. Tadeusz Robak reports research funding from Janssen R&D. Anna Dmoszynska reports research funding from Janssen R&D. Noemi Horvath reports research funding and personal fees from Janssen R&D. Ivan Spicka reports grants from Celgene Corporation; personal fees from Amgen, Bristol-Myers Squibb, Janssen-Cilag, and Janssen R&D; and nonfinancial support from Celgene Corporation and Janssen-Cilag. Heather J. Sutherland reports research funding from Janssen R&D and personal fees from Orthobiotech. Liang Xiu is an employee of Janssen R&D. Andrew Cakana is a contract worker for Janssen Pharmaceuticals. Jesús F. San-Miguel reports personal fees from Janssen-Cilag. Trilok Parekh is an employee of Johnson & Johnson and owns stock in the company.

Figures

Figure 1
Figure 1
This is a Consolidated System for Reporting Trials (CONSORT) diagram for the intent-to-treat analysis set. PLD indicates pegylated liposomal doxorubicin.
Figure 2
Figure 2
This Kaplan-Meier curve illustrates overall survival in the intent-to-treat analysis set. CI indicates confidence interval; HR, hazard ratio; PLD, pegylated liposomal doxorubicin.
Figure 3
Figure 3
Overall survival analysis is illustrated by subgroup (intent-to-treat analysis set). ECOG indicates Eastern Cooperative Oncology Group; PLD, pegylated liposomal doxorubicin.
See this image and copyright information in PMC

Comment in

References

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