The Combination of Bortezomib, Doxorubicin, and Dexamethasone (PAD) Is an Effective Regimen for High Risk, Newly Diagnosed, Patients with Multiple Myeloma, Reduces Bone Resorption and Normalizes Angiopoietin-1 to Angiopoietin-2 Ratio.

Bortezomib has significant activity in multiple myeloma (MM). Its efficacy is increased with the addition of dexamethasone and doxorubicin in vitro , thus providing the rationale for combination regimens with these agents. The aim of this study was to evaluate the efficacy and safety of PAD regimen (bortezomib, doxorubicin, dexamethasone) in high-risk, newly diagnosed, MM patients and evaluate its effect on bone remodeling and angiogenesis. The inclusion criteria included newly diagnosed MM, ISS 2/3 disease or del13q detected by FISH. Patients received four 21-day cycles of PAD: bortezomib 1.3 mg/m 2 on days 1, 4, 8 and 11; dexamethasone 40 mg on days 1–4 and 8–11; bolus doxorubicin 9 mg/m 2 on days 1–4. All patients received monthly zoledronic acid and prophylactic dose of co-trimoxazole and acyclovir. Following peripheral blood stem cell (PBSC) collection, eligible patients received high-dose melphalan with PBSC transplantation. Effect of PAD on angiogenesis was evaluated by measuring serum levels of VEGF, VEGF-A, angiogenin, angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), and basic fibroblast growth factor at baseline and on day 21 of cycle 4. Bone remodeling was studied by the measurement of serum indices: osteoclast stimulators [soluble RANKL, and osteoprotegerin (OPG)], bone resorption markers [C-telopeptide of collagen type-I (CTX), and tartrate resistant acid phosphatase-5b (TRACP-5b)], and bone formation markers [bone alkaline phosphatase (bALP), and osteocalcin] at baseline and on day 21 of cycle 4. All above molecules were also measured in 22 healthy controls of similar age and gender. To-date, 23 patients (14M/9F, median age 60 years) completed 4 cycles of therapy: 12 (52%) had ISS stage 2 and 11 (47%) stage 3 disease. Del13q was detected in 12 patients. The majority of patients (n=12) had more than 3 lytic lesions and/or a pathological fracture in the plain radiography of the skeleton. The objective response rate was 95% (22/23 patients): CR 26%, vgPR 13% and PR 56%. Median time to response was 35 days. Grade 3/4 adverse events included infections (7 patients-30%; one died due to septicemia), lymphopenia (6-26%), thrombocytopenia (6–26%), neutropenia (4–17%), peripheral neuropathy (3–13%), fatigue (2–8%), and hyponatremia (2–8%). At baseline, MM patients had increased serum levels of CTX, TRACP-5b, OPG, angiogenin, and Ang-2 compared with controls (p 6 /kg (range: 2.3-13x10 6 cells/kg). In conclusion, PAD has significant activity in high-risk, newly diagnosed patients with MM, overriding del13q. This regimen reduces bone resorption and normalizes Ang-1/Ang-2 balance which is crucial for the process of angiogenesis in MM.