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

Eur J Haematol. 2011 May;86(5):372-84. doi: 10.1111/j.1600-0609.2011.01599.x. Epub 2011 Mar 30.

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 treatment.

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 9mg/m(2) and prednisone 60mg/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 requirement 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 694.4pg/mL and increased with MP by 1273.3pg/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.

Conclusions: These results suggest a positive effect of bortezomib on bone metabolism and potentially bone healing in myeloma.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alkaline Phosphatase / blood
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Biomarkers / blood
  • Bone Diseases / etiology
  • Bone Diseases / pathology
  • Bone Diseases / physiopathology
  • Bone Diseases / prevention & control*
  • Bone Remodeling / drug effects*
  • Boronic Acids / administration & dosage
  • Bortezomib
  • Cell Differentiation / drug effects
  • Female
  • Humans
  • Intercellular Signaling Peptides and Proteins / blood
  • Male
  • Melphalan / administration & dosage
  • Middle Aged
  • Multiple Myeloma / complications
  • Multiple Myeloma / drug therapy*
  • Multiple Myeloma / pathology
  • Multiple Myeloma / physiopathology
  • Osteoblasts / drug effects
  • Osteoblasts / metabolism
  • Osteoblasts / pathology
  • Prednisone / administration & dosage
  • Pyrazines / administration & dosage
  • Radiotherapy, Adjuvant

Substances

  • Biomarkers
  • Boronic Acids
  • DKK1 protein, human
  • Intercellular Signaling Peptides and Proteins
  • Pyrazines
  • Bortezomib
  • Alkaline Phosphatase
  • Melphalan
  • Prednisone