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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

2007; Lippincott Williams & Wilkins; Volume: 25; Issue: 25 Linguagem: Inglês

10.1200/jco.2006.10.5460

1527-7755

Robert Z. Orlowski, Arnon Nagler, Pieter Sonneveld, Joan Bladé, Roman Hájek, Andrew Spencer, Jesús F. San Miguel, Tadeusz Robak, Anna Dmoszyńska, Noemi Horvath, Ivan Špıčka, Heather J. Sutherland, А. Н. Суворов, Sen Hong Zhuang, Trilok Parekh, Liang Xiu, Zhilong Yuan, Wayne Rackoff, Jean‐Luc Harousseau,

Protein Degradation and Inhibitors

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/m 2 on days 1, 4, 8, and 11 of an every 21-days cycle, or the same bortezomib regimen with PLD 30 mg/m 2 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.