Extended follow-up of outcome measures in multiple myeloma patients treated on a phase I study with bortezomib and pegylated liposomal doxorubicin

Abstract

A phase I study of a combination of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin showed significant anti-tumor activity against advanced multiple myeloma, with 36% of patients achieving a complete or near-complete response and 73% having a partial response or better. Given this encouraging efficacy, it was therefore of interest to update the prior experience and define parameters such as time to progression, time to retreatment, and overall survival. Additional follow-up was collected on all evaluable multiple myeloma patients and revealed a median time to progression of 9.3 months versus 3.8 months on whatever had been the patient's prior therapy. Time to retreatment was prolonged from 5.9 months after the patient's prior therapy to 24.2 months after bortezomib with pegylated liposomal doxorubicin. The median overall survival after therapy with bortezomib and pegylated liposomal doxorubicin was 38.3 months. These findings compare favorably with results reported for bortezomib alone and support the possibility that the bortezomib/pegylated liposomal doxorubicin regimen may provide superior efficacy against relapsed/refractory multiple myeloma.

Proteasomal inhibition stabilizes topoisomerase IIα protein and reverses resistance to the topoisomerase II poison ethonafide (AMP-53, 6-ethoxyazonafide)

“…The liposomal formulation of doxorubicin provides a prolonged half-life for the drug, potentially resulting in tumor exposure similar to the sequential dosing presented here. An extended follow-up study of multiple myeloma patients treated on this phase I study confirms that a regimen of bortezomib and PegLD provides not only superior response rates but also prolongs time to progression (26). These results support the hypothesis that bortezomib may enhance sensitivity to topo II poisons and overcome topo II poison resistance in a clinical setting.…”

“…Recently, Orlowski et al conducted a Phase I trial of bortezomib and pegylated liposomal doxorubicin (PegLD) in patients with advanced hematologic malignancies (26). The combination of bortezomib and PegLD showed significant antitumor activity against advanced multiple myeloma, with 36% of heavily pre-treated patients having a complete or nearcomplete response and 73% having a partial response or better.…”

Proteasome Inhibitors in Cancer Therapy: Lessons from the First Decade

“…From these studies, it seems possible to conclude that bortezomib has generally been successfully combined with other agents without significantly increased toxicity, and without the need for large dose adjustments. In several cases, these combinations have shown evidence of enhanced activity, most notably with the bortezomib/pegylated liposomal doxorubicin regimen, in which myeloma patients showed a 73% overall response rate (81) and an excellent response duration and overall survival (85). These findings led to a randomized trial comparing bortezomib Fig.…”

Treatment Options for Relapsed and Refractory Multiple Myeloma

“…Many bortezomib combinations have been evaluated in phase I-II trials, summarized in Table 3; refs. 56,57,[74][75][76][77][78][79][80][81][82][83]. These combinations generally produce high ORRs, in the range of 50 to 80% with CR and/or near CR (nCR) rates of 15 to 30%, with encouraging duration of response and OS.…”