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KOS 2007: Final Results of a Phase II PETHEMA Trial of Alternating Bortezomib and Dexamethasone as Induction Regimen Prior Autologous Stem Cell Transplantation (ASCT) in YOunger Patients with Multiple Myeloma (MM): Efficacy and Clinical Implications of Tumor Response Kinetics
Laura Rosiñol, MD
Hospital Clinic
Barcelona, Spain
06.27.07

AUTHORS: L. Rosiñol,1 A. Oriol,2 M.V. Mateos,3 A. Sureda,4 P. Garcia-Sanchez,5J. de la Rubia,6 J.J. Lahuerta,7 A. Alegre,8 C. Herrero,9 Xiangyang Liu,10H. Van de Velde,11 J. San Miguel,3 J. Blade1
1Hospital Clinic Barcelona, Spain; 2Hospital Germans Trias i Pujol Badalona,Spain; 3Hospital Clinico Salamanca, Spain; 4Hospital Sant Pau Barcelona,Spain; 5Hospital Clinico Madrid, Spain; 6Hospital La Fe Valencia; 7Hospital 12de Octubre Madrid, Spain; 8Hospital La Princesa Madrid; 9Janssen Cilag Spain;10Johnson&Johnson Pharmaceutical R&D, Raritan, USA; 11Johnson&JohnsonPharmaceutical R&D, Beerse, Belgium

Background. Dexamethasone-based combinations are the standardinduction regimens for younger patients with MM prior ASCT. This isthe first study in which bortezomib and dexamethasone were administeredon an alternating basis. Aims. efficacy and kinetics of response.Patiens and Methods. patients with newly diagnosed MM under the ageof 66 years were treated with bortezomib at 1.3 mg/m2 on days 1, 4, 8and 11 (cycles 1, 3, 5) and dexamethasone 40 mg p.o. on days 1-4, 9-12and 17-20 (cycles 2, 4 and 6), followed by ASCT with melphalan-200.Responses were evaluated by the EBMT criteria but a VGPR was included.Random effects models were utilized to analyze the tumor responsekinetics to bortezomib and dexamethasone with the absolute value ofM-protein overtime and decrease by cycle. Because the nonlinearity inthe change of M-protein overtime, a piecewise linear model wasemployed. Results. between August, 2005 and March, 2006, 40 patients(18 M, 22F, median age 57) were enrolled. The overall response rate was82% (12% CR, 10% VGPR). The response was quick with 82% M-proteinreduction achieved with the first 2 cycles. There was no furtherdecrease of the mean M-protein in cycles 5 and 6. The M-proteindecrease was not significantly different with dexamethasone and withbortezomib (p=0.48). Chromosome 13 deletion, t(4;14) and t(14;16) didnot had a negative impact on response. Toxicity was low: ten (25%)patients developed mild peripheral neuropathy (grade 1:9 cases, grade2:1 case) and 11 grade 1 thrombocytopenia. Grade 3 toxicity wasobserved in 7 patients (neutropenia 6, skin/liver 1 case). No patient developedgrade 4 toxicity. In all patients stem cells could be adequately collected(median of CD34+ 5×106/Kg). The overall response rate afterASCT was 90% with 40% CR plus 20% VGPR. Conclusions. Bortezomibalternating with dexamethasone is highly effective as up-front therapyin patients with MM, and is associated with a low toxicity. The resultsof the tumor response kinetics analysis support a short program of alternatingbortezomib and dexamethasone (i.e., maximum of 4 cycles) as aneffective and safe therapy for younger myeloma patients prior ASCT.


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