The Combination of Bortezomib, Melphalan, Dexamethasone and Intermittent Thalidomide (VMDT) Is an Effective Regimen for Relapsed/Refractory Myeloma and Reduces Serum Levels of Dickkopf-1, RANKL, MIP-1α and Angiogenic Cytokines.
Authors: Terpos Evangelos , Anagnostopoulos Athanasios , Heath Deborah , Kastritis Efstathios , Christoulas Dimitrios , Anagnostopoulos Nikolaos , Roussou Maria , Tsionos Konstantinos , Croucher Peter , Dimopoulos Meletios A. 
Published: October 2019

Abstract
Bortezomib (V) and thalidomide (T) exert their anti-myeloma (MM) action partly through perturbation of the MM microenvironment. The aim of this phase II study was to determine the efficacy and safety of the combination of VT with melphalan (M) and dexamethasone (D) 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 14, 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. Patients without progression continued for up to 8 cycles. Effect of VMDT on angiogenesis was evaluated by measuring serum levels of VEGF, angiogenin (ANG), angiopoietin-2 (ANGP-2), and basic fibroblast growth factor (bFGF) at baseline and after 4th and 8th cycle. Bone remodeling was studied by the measurement of serum indices:osteoclast stimulators [sRANKL, osteoprotegerin (OPG), osteopontin, MIP-1α],osteoblast inhibitor, dickkopf-1 (DKK-1),bone resorption markers [C-telopeptide of collagen type-I (CTX), tartrate resistant acid phosphatase-5b (TRACP-5b)], andbone formation markers [bone alkaline phosphatase (bALP), osteocalcin (OC), and CICP].Among 60 pts registered in this study, 53 have completed 4 courses of therapy as of June 2006 and form the basis for the current analysis. Median time from 1st treatment to VMDT was 36 months. The median number of previous treatments was 2 (range: 1–7). Prior agents included V (11%), M (43%), D (100%), T (56%), and ASCT (30%). The objective response rate was 60%(32/53 pts): CR 11%, vgPR 26% and PR 22%. Furthermore, 6 pts (11%) achieved a MR and 8 SD. Median time to response was 35 days. Median PFS was 9.5 months with a median follow-up period of 12 months. Adverse events included fatigue (58%), thrombocytopenia (20% grade 3/4), neutropenia (8% grade 3/4), anemia (5% grade 3), neuropathy (50% grade 1/2, and 7% grade 3), infections (45%, including 5 HZV cases), and hyponatremia (15%). No patient experienced DVT, while 2 pts died due to sepsis and one due to necrotizing fasciitis. At baseline, MM patients had increased serum levels of DKK-1, sRANKL, sRANKL/OPG ratio, MIP-1α, CTX, VEGF, ANG, ANGP-2, and bFGF (p<0.01) compared with controls (n=36), while serum levels of bALP, and OC were reduced (p<0.0001). DKK-1, sRANKL, sRANKL/OPG ratio, MIP-1α, CTX and all angiogenic cytokines were reduced significantly after 4 and 8 cycles of VMDT. Reduction (%) of RANKL correlated with reduction (%) of VEGF (p=0.003) and MIP-1α(p=0.04), while reduction (%) of VEGF also correlated with (%) changes of DKK-1 (p=0.01), ANG (p=0.005), and ANGP-2 (p=0.04). Only CTX reduction was greater in responders, while all other alterations of studied biochemical indices were observed irrespective of treatment response. In conclusion, VMDT has significant activity in relapsed/refractory MM, with manageable toxicities. Furthermore, this regimen reduces serum cytokines that are involved in the interaction between myeloma and stromal cells.