In a 2007 interim analysis of a phase III randomized trial, the combination of bortezomib and pegylated liposomal doxorubicin (PLD), compared with bortezomib monotherapy, reduced disease progression and prolonged overall survival (OS) in patients with relapsed/refractory multiple myeloma (MM). However, according to follow-up data published in Cancer, the OS benefits of the bortezomib-PLD combination therapy did not persist.
"Despite the superiority in time-to-progression and an early trend in OS favoring the combination therapy in the interim analysis, the long-term follow-up results revealed similar OS for bortezomib-PLD combination therapy and bortezomib monotherapy," the authors, led by Robert Z. Orlowski, MD, PhD, from the University of Texas MD Anderson Cancer Center, in Houston, Texas, wrote. "[The results] underscore the need for long-term follow-up of phase III trials."
The phase III, open-label, randomized, active-controlled, multicenter study included 646 patients with confirmed relapsed/refractory MM who had received at least one prior line of therapy or were refractory to initial treatment. All patients were bortezomib-naÃ¯ve and had not received prior doxorubicin or other anthracycline exposure >240 mg/m2.
Patients were randomized 1:1 to receive:
- Bortezomib 1.3 mg/m2 intravenously on days 1, 4, 8, and 11 of every 21-day cycle (n=322)
- Bortezomib 1.3 mg/m2 intravenously on days 1, 4, 8, and 11 of every 21-day cycle, plus PLD 30 mg/m2 as a 1-hour intravenous infusion on day 4 of each 21-day cycle (n=324)
Treatment was continued until disease progression, unacceptable toxicity, or for up to eight treatment cycles; patients who still responded after eight cycles and had acceptable tolerability could continue treatment. Crossover from monotherapy to combination therapy was not allowed during the study.
At the clinical cut-off date (May 16, 2014) for the final survival analysis, 79 percent of patients had died: 253 (78%) in the bortezomib-PLD cohort and 257 (80%) in the bortezomib monotherapy cohort. Six percent of patients withdrew consent, four percent were lost to follow-up, and 11 percent were still alive: 37 patients (11%) in the combination cohort and 34 (11%) in the monotherapy group.
After a median follow-up of 8.6 years, OS in the bortezomib-PLD cohort was 33 months (95% CI 28.9-37.1) compared with 30.8 months (95% CI 25.2-36.5) in the bortezomib monotherapy group. The two-month difference in OS was not statistically significant (hazard ratio [HR] = 1.047; 95% CI 0.879-1.246; p=0.6068). In the interim analysis, Dr. Orlowski and co-authors noted, the early OS benefit for bortezomib-PLD therapy over bortezomib monotherapy was significantly higher (HR=1.41; 95% CI 1.002-1.97; p=0.047).
Results from subgroup analyses were similar and generally consistent, though there was a small, non-significant trend in favor of the combination therapy among women, patients â‰¥65 years, and those who had an ECOG status of 0 or cytogenetic abnormalities.
The majority of patients in both the bortezomib-PLD group and the bortezomib monotherapy group received salvage therapy (78% and 80%, respectively). The most frequently used (>10% of patients) salvage therapies in the combination and monotherapy cohorts included dexamethasone (47% vs. 51%), thalidomide (31% vs. 31%), cyclophosphamide (26% vs. 31%), melphalan (24% vs. 22%), lenalidomide (23% vs. 21%), bortezomib (23% vs. 18%), and doxorubicin (6% vs. 11%).
"The inability to sustain the observed early survival advantage may have been caused by the effects of subsequent lines of therapy," Dr. Orlowski and colleagues wrote, also noting that the study results were limited by the initial study design, which set a median survival of just 20 months in the bortezomib monotherapy group. "[That number] was exceeded by 50 percent, suggesting the benefits of novel agents."
The number of effective salvage therapy options now available to MM patients, the authors added, "presents a practical challenge of having adequate power for long-term survival as a primary endpoint."
Orlowski RZ, Nagler A, Sonneveld P, et al. 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. Cancer. 2016 May 18. [Epub ahead of print]