A Phase I/II Study of Bortezomib in Combination with Doxorubicin and Intermediate-Dose Dexamethasone (iPAD therapy) for Relapsed or Refractory Multiple Myeloma

Bortezomib and doxorubicin have synergistic activity against myeloma cells. However, the combination of bortezomib and cytotoxic agents has not long been permitted in Japan because the safety of the combination therapy has not been determined in Japanese patients. We, therefore, decided to undergo a phase I/II study of bortezomib, doxorubicin and intermediate-dose dexamethasone (iPAD) combination therapy in Japanese patients with relapsed or refractory myeloma.

In a phase I study, the maximally tolerated dose of bortezomib was determined when given in combination with a fixed dose of doxorubicin and dexamethasone. Bortezomib was administered iv on days 1, 4, 8 and 11 at a dose of 1.0 mg/m² in cohort 1 and 1.3 mg/m² in cohort 2. Doxorubicin 9 mg/m² was given iv on days 1–4, and dexamethasone 20 mg po on days 1–2, 4–5, 8–9 and 11–12. After a recommended dose of bortezomib was determined, a phase II study was undertaken to examine overall response rate, survival time and toxicity profiles.

The dose-limiting toxicity (DLT), defined as grade 4 hematological toxicity lasting more than 5 days and/or grade 3 or higher non-hematological toxicity, was observed in 2 of 6 patients in cohort 1, indicating this dose was considered tolerable. In cohort 2, 3 of 5 patients developed DLTs including grade 4 thrombocytopenia lasting more than 5 days, grade 3 elevated hepatic transaminase levels and grade 3 ileus in one of each patient, indicating this dose was intolerable. Thus, 1.0 mg/m² of bortezomib is a recommended dose in iPAD therapy. In a phase II study, 27 patients, aged 40 to 78 (median 63), were enrolled to receive iPAD therapy by using 1.0 mg/m² dose of bortezomib. Overall response (CR+PR) was achieved in 89% (95% CI, 76–100%), and complete response (CR+nCR) in 30% (95% CI, 11–48%). The median overall survival time was not reached and progression-free survival time was 12.3 months (95% CI, 6.1–18.5 months). One patient died of pneumonia. Grade 3/4 thrombocytopenia, neutropenia and anemia developed in 67%, 41% and 19%, respectively, and febrile neutropenia in 11%. Sensory neuropathy was observed in 78% with grade 3/4 in 22% of the patients. Grade 3/4 hypokalemia developed in 15%, hyponatremia in 11%, and fatigue, nausea and diarrhea in 4%.

The iPAD therapy is feasible and effective to treat relapsed or refractory myeloma in Japanese population.

(This clinical study was registered in University hospital Medical Information Network (UMIN) (registration number; UMIN000001210))

No relevant conflicts of interest to declare.