The Combination of Pegylated Liposomal Doxorubicin and Bortezomib Significantly Improves Time to Progression of Patients with Relapsed/Refractory Multiple Myeloma Compared with Bortezomib Alone: Results from a Planned Interim Analysis of a Randomized Phase III Study.

Introduction: Proteasome inhibition with bortezomib (VELCADE ® ) is a standard of care for patients with relapsed/refractory multiple myeloma (MM) who have received at least one prior therapy. Pre-clinical studies have shown that bortezomib acts synergistically with anthracyclines, and clinical trials have shown encouraging evidence of enhanced anti-myeloma activity for the combination of bortezomib with pegylated liposomal doxorubicin (PLD; DOXIL ® ). We therefore sought to test the hypothesis that the bortezomib/PLD regimen would improve clinical outcome measures in this patient population. Methods: Between December, 2004 and March, 2006, 646 patients with relapsed or refractory MM after at least one prior line of therapy were randomized on the DOXIL-MMY-3001 study conducted at 144 sites in 18 countries. Patients were eligible if they had not previously received bortezomib, progressed on an anthracycline-containing regimen, or received more than 240 mg/m 2 of doxorubicin, or the equivalent amount of another anthracycline. Subjects were randomized in a 1:1 ratio to receive either bortezomib at 1.3 mg/m 2 on days 1, 4, 8, and 11 of every 21-day cycle, or the same dose and schedule of bortezomib but with the addition of PLD at 30 mg/m 2 given on day 4 of each cycle. Treatment was to continue for up to a total of 8 cycles unless a complete response (CR) was attained, or disease progression occurred, or unacceptable treatment-related toxicity was noted. Exceptions included patients achieving CR at any time, who were treated with an additional two cycles, and patients experiencing a continued paraprotein response after 8 cycles, who were allowed to continue for as long as treatment was tolerated, and they continued to respond. Disease assessments were to occur at the start of each cycle, beginning at cycle 2, and were made according to the stringent criteria recommended by the European Group for Blood & Marrow Transplantation. Subjects who did not progress after the initial 42-week period were assessed every 6 weeks until disease progression was documented. Results: During the course of the study, an Independent Data Monitoring Committee (IDMC) reviewed safety data every 3 months, and a planned interim analysis (IA) was performed after at least 230 progression events were collected. Upon review, the IDMC concluded that, based on the IA, there was a significant benefit to patients randomized to the bortezomib/PLD arm of the trial in the primary study endpoint, time to progression, as well as in progression-free survival. No survival advantage had yet been demonstrated to date. While there was an increase in adverse events associated with the combination therapy, this increase was judged to be acceptable in the context of the benefits. In light of these results, the IDMC recommended that study results be communicated. Toxicity, time to progression, and progression free survival data will be available for presentation at the time of the annual meeting. Conclusions: At the IA, PLD plus bortezomib was significantly more effective than bortezomib monotherapy for patients with previously treated multiple myeloma.