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/m² on days 1, 4, 8 and 11; dexamethasone 40 mg on days 1–4 and 8–11; bolus doxorubicin 9 mg/m² 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<0.01), while the ratio of Ang-1/Ang-2 was reduced. The administration of PAD resulted in a dramatic reduction of bone resorption markers (p<0.01) and a borderline increase in bALP (p=0.09). PAD also produced a significant increase of Ang-1/Ang-2 ratio (p=0.006), which was normalized. No patient developed a skeletal related event during 4 cycles of therapy. Eight patients (34%) had a PBSC collection; the median number of CD34+ cells was 6.45x10⁶/kg (range: 2.3-13x10⁶cells/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.