The proteasome inhibitor bortezomib (B) is an effective therapy for patients with relapsed multiple myeloma (MM), improving survival and time to progression as compared with single-agent, high-dose dexamethasone.1 B also showed a high response rate and acceptable safety profile in combination with pegylated liposomal doxorubicin (PLD) in a phase I study.2 In order to further assess the safety and efficacy of this combination, Orlowski and colleagues conducted a phase III clinical trial of B versus B+PLD for myeloma patients progressing after prior therapy and for those with primary refractory disease. This international, open-label trial enrolled 646 patients at 123 centers. Two-thirds of patients in each group had received prior anthracycline-containing regimens and over half had prior stem cell transplantation; none had received prior B treatment. Patients were randomized to receive either B 1.3 mg/m2 on days 1, 4, 8, and 11 of each 21-day cycle, or B in the same dose and schedule in combination with PLD 30 mg/m2 on day 4 following infusion of B. Eight cycles of treatment were planned, although responding patients could continue the assigned treatment if tolerated. There was no crossover from B→B+PLD, but patients in the latter arm could continue protocol therapy with B alone if PLD was discontinued due to toxicity. Overall response rates did not differ between the two arms: B 41 percent and B+PLD 44 percent. Assessment at a planned interim analysis of intent-to-treat patients revealed a significant benefit in time to progression (TTP, the primary study endpoint) for B+PLD versus B (9.3 months versus 6.5 months, p=0.000004). Responses were observed in patients with prior anthracycline, stem cell transplantation, and immunomodulatory therapies. An updated survival analysis also showed a significant benefit for survival at 15 months of 76 percent for the combination versus 65 percent for B alone (p=0.03). Toxicity was increased in the combination arm, primarily myelosuppression, nausea, vomiting, or diarrhea, but with no increase in peripheral neuropathy. Hand-foot syndrome occurred in 16 percent of patients treated with PLD; 5 percent were grade 3 and PLD was discontinued in these patients. Only three patients in each group had a thromboembolic event; 7 percent of B and 9 percent of B+PLD patients had a decrease in left ventricular ejection fraction, although only three in each group developed congestive heart failure. Treatment-related death was recorded for three B-treated and four B+PLD-treated patients.
In Brief
With the availability and efficacy of newer agents for MM treatment, including the immunomodulatory drugs and bortezomib, the use of traditional alkylator and anthracycline-containing cytotoxic regimens has markedly decreased. This clinical trial reintroduces doxorubicin in a potentially less toxic formulation and demonstrates an improved TTP as well as improved 15-month survival when given in combination with B for patients with relapsed and refractory MM, despite the absence of an increase in overall response rate versus B alone. Given the modest prolongation in TTP, it will be necessary for clinicians and patients to carefully consider the additional toxicities and cost of this combination regimen. As noted by the authors, the combination does provide an important option for patients intolerant or resistant to corticosteroid therapy and for those at high risk for thromboembolic disease. Further clinical research will be necessary to assess response rates in less heavily pretreated patients and with the addition of agents such as dexamethasone to B+PLD. The incorporation of correlative biomarker analyses in such trials will be an important means to identify molecular or phenotypic subsets of patients with MM most likely to benefit.
References
Competing Interests
Dr. Williams indicated no relevant conflicts of interest.
