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

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.