Alternating Bortezomib and Dexamethasone as Induction Regimen Prior to Autologous Stem-Cell Transplantation in Newly Diagnosed Younger Patients with Multiple Myeloma: Results of a PETHEMA Phase II Trial.

Dexamethasone-based combinations have been the standard induction regimens in younger patients with multiple myeloma (MM) prior to stem cell transplantation. Bortezomib alone or in association with dexamethasone has shown significant activity in patients with both refractory/relapsed and newly diagnosed MM. We investigated the efficacy of bortezomib and dexamethasone administered on an alternating basis, the end-points of the study being response rate, kinetics of response, safety, stem cell mobilization and response postransplant. Patients with newly diagnosed MM under the age of 66 years and with adequate organ and function status were eligible. Patients were treated with bortezomib 1.3 mg/m² on days 1, 4, 8 and 11 (cycles 1, 3, 5) and dexamethasone 40 mg p.o. on days 1–4, 9–12 and 17–20 (cycles 2, 4 and 6), followed by high dose-therapy intensification (HDT) with melphalan -200. Responses were evaluated by the EBMT criteria but a near-CR (n-CR) response category was included. Stem cell mobilization was performed after G-CSF priming. Between August, 2005 and March, 2006, 40 patients (18 M, 22F, median age 57 yrs) were enrolled. The M-protein type was IgG in 26 patients, IgA in 11 and light chain in 3. Six patients had extramedullary plasmacytomas. At the time of this analysis response data after the 6 cycles were available for 26 of the 40 patients. The overall response rate was 76% and the CR rate 15% (4 CR, 5 n-CR, 7 PR, 4 MR, 2 stable disease, 3 progressive disease, 1 non-evaluable because of treatment discontinuation due to toxicity after cycle 1). In patients who achieved at least PR the mean M-protein decrease was 84% (48% associated with bortezomib cycles and 36% with dexamethasone). Two responding patients showed disease progression immediately before HDT. In all thirteen patients mobilized to date stem cells could be adequately collected (median CD34+ cells: 4.85 x10⁶/Kg; range 2–10.6) with only one apheresis. Toxicity was low and mainly consisted of grade 1 and 2 neutropenia, fever, GI symptoms, fatigue, peripheral neuropathy and thrombocytopenia. Ten (25%) patients developed mild peripheral neuropathy (grade 1=9 cases; grade 2=1 case) and 11 patients grade 1 thrombocytopenia. Grade 3 toxicity was only observed in 7 patients (neutropenia 6, skin/liver 1 case) and no patient developed grade 4 toxicity. Updated results on all patients along with cytogenetic data will be presented at the meeting. In conclusion, bortezomib alternating with dexamethasone is highly effective as up-front therapy in patients with MM, is associated with an extremely low toxicity and results in an excellent stem cell harvesting. The results of this trial support a short program of alternating bortezomib and dexamethasone as an effective and safe induction regimen for newly diagnosed younger myeloma patients.