title: Salvage therapy with thalidomide in patients with advanced relapsed/refractory multiple myeloma.
abstract: OBJECTIVE
  Few therapeutic options are presently available for patients with multiple myeloma (MM) who relapse after autologous or allogeneic stem cell transplantation, or for patients who are refractory to conventional chemotherapy and not eligible for salvage high-dose therapy. Thalidomide, a glutamic acid derivative with anti-angiogenic properties, has been recently proposed as an effective therapy for patients with advanced refractory disease. The aim of this study was to evaluate the activity of thalidomide in a large series of MM patients.
  
  
  METHODS
  From October 1999 to January 2001, 65 patients (46 males/19 females) from 8 Italian institutions were treated with thalidomide. Twenty-six patients had relapsed after autologous stem cell transplantation, either single (n = 12) or double (n= 12); 38 patients had shown disease progression after >= 2 lines of conventional chemotherapy, 2 patients had relapsed after allotransplant, one single patient had not received previous treatment. Sixty-one (93.8%) patients were in stage III, median b2 microglobulin was 2.9 mg/L, and median bone marrow plasma cell infiltration was 50%. Thalidomide was initially administered at a dose of 100 mg/day; if well tolerated, the dose was to be increased serially by 200mg every other week to a maximum of 800 mg/day.
  
  
  RESULTS
  The median administered dose of thalidomide was 400 mg/day. WHO grade > II toxic effects were constipation (52%), lethargy (34%), skin rash (11%), peripheral neuropathy (14%) and leukopenia (3%). Sixty patients are presently evaluable for response; of these, 17 (28.3%) showed > or = 50% reduction in serum or urinary M protein concentration and 11 (18.3%) showed > or = 25% tumor reduction, for a total response rate averaging 46.6%. After a median of 8 months' follow-up, 15/28 patients are alive and progression-free (at 2 to 16 months), 12 patients have relapsed, and 1 patient died of pulmonary edema while still in partial remission. Among pre-treatment variables that were analyzed for their potential relationship with tumor response, only the concentration of vascular endothelial growth factor (VEGF) in the conditioned media obtained upon culture of bone marrow plasma cells was statistically significant. Plasma cells from patients who responded favorably to thalidomide secreted a significantly lower amount of VEGF than plasma cells from resistant patients (126.45 165 pg/mL vs 227.11 70 pg/mL, p=0.04).
  
  
  CONCLUSIONS
  These data confirm that thalidomide is active in patients with advanced relapsed/refractory MM and represent the basis for ongoing clinical trials aimed at testing the role of this drug as front line therapy for newly diagnosed disease.
authors.affiliation: Istituto di Ematologia e Oncologia Medica "L. e A. Seràgnoli", Policlinico S. Orsola, via Massarenti 9, 40138 Bologna, Italy. ptosi@med.unibo.it
authors.forename: Patrizia
authors.initials: P
authors.lastname: Tosi
authors.forename: Elena
authors.initials: E
authors.lastname: Zamagni
authors.forename: Claudia
authors.initials: C
authors.lastname: Cellini
authors.forename: Sonia
authors.initials: S
authors.lastname: Ronconi
authors.forename: Francesca
authors.initials: F
authors.lastname: Patriarca
authors.forename: Filippo
authors.initials: F
authors.lastname: Ballerini
authors.forename: Pellegrino
authors.initials: P
authors.lastname: Musto
authors.forename: Francesco
authors.initials: F
authors.lastname: Di Raimondo
authors.forename: Antonio
authors.initials: A
authors.lastname: Ledda
authors.forename: Francesco
authors.initials: F
authors.lastname: Lauria
authors.forename: Luciano
authors.initials: L
authors.lastname: Masini
authors.forename: Marco
authors.initials: M
authors.lastname: Gobbi
authors.forename: Angelo
authors.initials: A
authors.lastname: Vacca
authors.forename: Roberto
authors.initials: R
authors.lastname: Ria
authors.forename: Delia
authors.initials: D
authors.lastname: Cangini
authors.forename: Sante
authors.initials: S
authors.lastname: Tura
authors.forename: Michele
authors.initials: M
authors.lastname: Baccarani
authors.forename: Michele
authors.initials: M
authors.lastname: Cavo
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000032:analysis; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D018929:Cell Culture Techniques; D016228:Endothelial Growth Factors / Q000032:analysis / Q000378:metabolism; D005260:Female; D006801:Humans; D008222:Lymphokines / Q000032:analysis / Q000378:metabolism; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009101:Multiple Myeloma / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D011379:Prognosis; D016879:Salvage Therapy; D013792:Thalidomide / Q000008:administration & dosage* / Q000633:toxicity; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D015415:Biomarkers; D016228:Endothelial Growth Factors; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D013792:Thalidomide