Fewer bone disease events, improvement in bone remodeling, and evidence of bone healing with bortezomib plus melphalan–prednisone vs. melphalan–prednisone in the phase III VISTA trial in multiple myeloma Michel Delforge 1 , Evangelos Terpos 2 , Paul G. Richardson 3 , Ofer Shpilberg 4 , Nuriet K. Khuageva 5 , Rudolf Schlag 6 , Meletios A. Dimopoulos 2 , Martin Kropff 7 , Ivan Spicka 8 , Maria T. Petrucci 9 , Olga S. Samoilova 10 , Maria-Victoria Mateos 11 , Hila Magen-Nativ 4 , Hartmut Goldschmidt 12 , Dixie-Lee Esseltine 13 , Deborah S. Ricci 14 , Kevin Liu 14 , William Deraedt 15 , Andrew Cakana 16 , Helgi van de Velde 15 , Jesu ´ s F. San Miguel 11 1 Myeloma Study Group, Belgian Hematological Society, Belgium; 2 School of Medicine, University of Athens, Athens, Greece; 3 Dana-Farber Cancer Institute, Boston, MA, USA; 4 Rabin Medical Center, Petah-Tiqva, Israel; 5 SP Botkin Moscow City Clinical Hospital, Moscow, Russian; 6 Praxisklinik Dr. Schlag, Wu ¨ rzburg, Germany; 7 University of Mu ¨ nster, Mu ¨ nster, Germany; 8 University Hospital, Prague, Czech Republic; 9 University La Sapienza, Rome, Italy; 10 Nizhnii Novgorod Region Clinical Hospital, Nizhnii Novgorod, Russia; 11 Hospital Universitario Salamanca, CIC, IBMCC (USAL-CSIC), Salamanca, Spain; 12 Hematology and Oncology, University of Heidelberg and National Center for Tumour Diseases, Heidelberg, Germany; 13 Millennium Pharmaceuticals, Inc., Cambridge, MA, USA; 14 Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Raritan, NJ, USA; 15 Johnson & Johnson Pharmaceutical Research & Development, Beerse, Belgium; 16 Johnson & Johnson Pharmaceutical Research & Development, High Wycombe, UK Abstract Objectives: Bone disease is a key presenting feature of myeloma. This post hoc analysis of the phase III VISTA trial of bortezomib plus melphalan–prednisone (VMP) vs. MP in previously untreated myeloma patients assessed clinical bone disease events and changes in alkaline phosphatase (ALP), a marker for osteoblast activation, and serum Dickkopf-1 (DKK-1), an inhibitor of osteoblast differentiation, during treat- ment. Methods: Patients received nine 6-wk cycles of VMP (bortezomib 1.3 mg ⁄ m 2 , days 1, 4, 8, 11, 22, 25, 29, 32, cycles 1–4, days 1, 8, 22, 29, cycles 5–9, plus melphalan 9 mg ⁄ m 2 and prednisone 60 mg ⁄ m 2 , days 1–4, cycles 1–9; N = 344) or MP alone (N = 338). Results: Rates of bisphosphonates use during treatment (73% vs. 82%), progression because of worsening bone disease (3% vs. 11%), and require- ment for subsequent radiotherapy (3% vs. 8%) were lower with VMP vs. MP. Median maximum ALP increase was significantly higher with VMP vs. MP overall (49.7% vs. 30.3%, P = 0.029), and higher by response group (complete response [CR]: 68.7% vs. 43.9%; partial response [PR]: 41.5% vs. 31.2%). Greater maximum ALP increase was strongly associated with achievement of CR (P £ 0.0001) and CR ⁄ PR (P £ 0.01). Median DKK-1 decreased with VMP by 694.4 pg ⁄ mL and increased with MP by 1273.3 pg ⁄ mL from baseline to day 4 (P = 0.0069). Available radiologic data revealed evidence of bone healing in 6 ⁄ 11 VMP-treated patients, who achieved best responses of three CR, one PR, and two stable disease. Conclu- sions: These results suggest a positive effect of bortezomib on bone metabolism and potentially bone healing in myeloma. Key words VISTA; bone; myeloma; bortezomib; melphalan–prednisone Correspondence Professor Michel Delforge, Department of Hematology, University Hospital Leuven, Herestraat 49, B–3000 Leuven, Belgium. Tel: +32 16 34 68 88; Fax: +32 16 34 68 81; e-mail: michel.delforge@uzleuven.be Accepted for publication 28 February 2011 doi:10.1111/j.1600-0609.2011.01599.x ORIGINAL ARTICLE European Journal of Haematology 86 (372–384) 372 ª 2011 John Wiley & Sons A/S