The Combination of Bortezomib, Melphalan, Dexamethasone and Intermittent Thalidomide (VMDT) Is an Effective Treatment for Relapsed/Refractory Myeloma: Results of a Phase II Clinical Trial.

Abstract Interactions between myeloma (MM) cells and marrow microenvironment are crucial for myeloma growth and resistance to anti-myeloma therapy. Bortezomib (VELCADE®; V) and thalidomide (T) have proven anti-MM effect and exert their action partly through perturbation of the MM microenvironment. Furthermore, bortezomib enhances the cytotoxic potential of other agents, such as melphalan (M), and dexamethasone (D) in resistant cell lines. We hypothesize that combining VT (to target both MM cells and microenvironment) with M and D may help overcome resistance and increase clinical efficacy of these agents in relapsed/refractory disease. The aim of this phase II study was to determine the efficacy and safety of the VMDT regimen and its effect on angiogenesis and bone remodeling in relapsed/refractory MM. Bortezomib (1.0 mg/m2) was given iv, on days 1, 4, 8, and 11; oral melphalan (0.15 mg/kg) was administered on days 1–4, while thalidomide (100 mg/day) and dexamethasone (12 mg/m2) were given on days 1–4 and 17–20 of a 28-day cycle, for 4 cycles. Responders and patients with SD continued for up to 8 cycles. Effect of VMDT on angiogenesis was evaluated by measuring the serum levels of angiogenic cytokines, such as VEGF, angiogenin, angiopoietin-2, and bFGF at baseline and after cycles 4 and 8. Bone remodeling was studied by the measurement of a series of serum indices: i) osteoclast stimulating factors [sRANKL, osteoprotegerin (OPG), osteopontin, MIP-1α ], ii) bone resorption markers (CTX, TRACP-5b), and iii) bone formation markers [bALP, osteocalcin (OC), and CICP]. Thirty-one pretreated pts (median age: 66 y; range: 45–83 y) have been enrolled in this study, including 20 pts treated during refractory relapse. Median time from 1st treatment to VMDT was 40 months. Many pts had features of advanced disease including ISS stage 3 (32%), high LDH (23%), and creatinine >2mg% (10%). The median number of previous treatments was 2 (range: 1–6), including M (48% of pts), T (65%), D (100%), V (3%) and ASCT (39%). Among 25 pts evaluable for response so far, 14 (56%) achieved an objective response (CR 8% and PR 48%). Furthermore, 2 pts (8%) achieved a MR and 5 (20%) SD. Median time to response was 30 days. Adverse events included fatigue (56%), thrombocytopenia (12% grade 3/4), neutropenia (8% grade 3/4), anemia (8% grade 3), neuropathy (48% grade 1/2, no grade 3/4 observed), infections (36%, including 2 HZ cases), and hyponatremia (12%). No pt experienced DVT, while 2 pts died due to sepsis. At baseline, MM pts had increased serum levels of sRANKL, sRANKL/OPG ratio, MIP-1α , VEGF, angiogenin, angiopoietin-2, and bFGF (p<0.01) compared with controls, while serum levels of CTX, TRACP-5b, bALP, OC were decreased (p<0.03) since all pts have been on zoledronic acid treatment. Our preliminary analysis showed that sRANKL and MIP-1α levels reduced after 4 cycles of VMDT. In conclusion the VMDT combination with intermittent T is associated with significant activity in pts with heavily pretreated MM. The toxicities are manageable; due to intermittent T administration there was no severe neurotoxicity and no DVT. Our study will also provide further data regarding post-treatment changes of cytokines involved in interactions between MM and stromal cells.