Originally published as JCO Early Release 10.1200/JCO.2006.10.5460 on August 6 2007

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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

Robert Z. Orlowski, Arnon Nagler, Pieter Sonneveld, Joan Bladé, Roman Hajek, Andrew Spencer, Jesús San Miguel, Tadeusz Robak, Anna Dmoszynska, Noemi Horvath, Ivan Spicka, Heather J. Sutherland, Alexander N. Suvorov, Sen H. Zhuang, Trilok Parekh, Liang Xiu, Zhilong Yuan, Wayne Rackoff, Jean-Luc Harousseau

From the University of North Carolina at Chapel Hill, Chapel Hill, NC; Chaim Sheba Medical Center, Tel Hashomer, Israel; Erasmus MC, Rotterdam, the Netherlands; Hospital Clinic I Provincial, Barcelona, Spain; Interní Hematoonkologická klinika Fakultní Brno, Brno; General Faculty Hospital, Prague, Czech Republic; Alfred Hospital, Melbourne; Institute of Medicine and Veterinary Science, Adelaide, Australia; Hospital Universitario de Salamanca, Centro de Investigación del Cáncer- IBMCC (CSIC-USAL), Spain; Medical University of Lodz, Lodz; Medical University of Lublin, Lublin, Poland; University of British Columbia, Vancouver, Canada; First Republican Clinical Hospital of Udmurtia, Izhevsk, Russia; Johnson & Johnson Pharmaceutical Research & Development LLC, Raritan, NJ; and University Hospital Hotel-Dieu, Nantes, France

Address reprint requests to Robert Z. Orlowski, MD, Department of Medicine, Division of Hematology/Oncology, The University of North Carolina at Chapel Hill, Lineberger Comprehensive Cancer Center, Chapel Hill, NC 27599-7295; e-mail: R_Orlowski{at}med.unc.edu

Purpose This phase III international study compared the efficacy and safety of a combination of pegylated liposomal doxorubicin (PLD) plus bortezomib with bortezomib monotherapy in patients with relapsed or refractory multiple myeloma.

Patients and Methods Six hundred forty-six patients were randomly assigned to receive either intravenous bortezomib 1.3 mg/m² on days 1, 4, 8, and 11 of an every 21-days cycle, or the same bortezomib regimen with PLD 30 mg/m² on day 4.

Results Median time to progression was increased from 6.5 months for bortezomib to 9.3 months with the PLD + bortezomib combination (P = .000004; hazard ratio, 1.82 [monotherapy v combination therapy]; 95% CI, 1.41 to 2.35). The 15-month survival rate for PLD + bortezomib was 76% compared with 65% for bortezomib alone (P = .03). The complete plus partial response rate was 41% for bortezomib and 44% for PLD + bortezomib, a difference that was not statistically significant. Median duration of response was increased from 7.0 to 10.2 months (P = .0008) with PLD + bortezomib. Grade 3/4 adverse events were more frequent in the combination group (80% v 64%), with safety profiles consistent with the known toxicities of the two agents. An increased incidence in the combination group was seen of grade 3/4 neutropenia, thrombocytopenia, asthenia, fatigue, diarrhea, and hand-foot syndrome.

Conclusion PLD with bortezomib is superior to bortezomib monotherapy for the treatment of patients with relapsed or refractory multiple myeloma. The combination therapy is associated with a higher incidence of grade 3/4 myelosuppression, constitutional symptoms, and GI and dermatologic toxicities.

published online ahead of print at www.jco.org on August 6, 2007.

Supported by Johnson & Johnson Pharmaceutical Research & Development LLC, and is registered at ClinicalTrials.gov corresponding to NCT00103506 [ClinicalTrials.gov] . Also supported by the Leukemia & Lymphoma Society (Grant No. 6096-07), the Multiple Myeloma Research Foundation, and the National Cancer Institute (RO1 CA102278; all to R.Z.O.).

Presented in part at the 48th Annual Meeting of the American Society of Hematology, Orlando, FL, December 9-12, 2006.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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