Bortezomib and high-dose melphalan conditioning regimen in frontline multiple myeloma: an IFM randomized phase 3 study
Murielle Roussel, Valérie Lauwers‐Cancès, Margaret Macro, Xavier Leleu, Bruno Royer, Cyrille Hulin, Lionel Karlin, Aurore Perrot, Cyrille Touzeau, Marie‐Lorraine Chrétien, Sophie Rigaudeau, Mamoun Dib, Emmanuelle Nicolas‐Virelizier, Martine Escoffre‐Barbe, Karim Belhadj, Clara Mariette, Anne‐Marie Stoppa, Carla Araujo, Chantal Doyen, Jean Fontan, Brigitte Kolb, Laurent Garderet, Sabine Bréchignac, Jean‐Valère Malfuson, Arnaud Jaccard, Pascal Lenain, Cécile Borel, Benjamin Hébraud, Omar Benbrahim, Véronique Dorvaux, Salomon Manier, Karine Augeul-Meunier, Marie‐Christiane Vekemans, Edouard Randriamalala, Driss Chaoui, Jo Caers, Carine Chaleteix, Lofti Benboubker, Laure Vincent, Sylvie Glaisner, Patricia Zunic, Borhane Slama, Jean‐Richard Eveillard, Catherine Humbrecht-Kraut, Véronique Morel, Philippe Mineur, Jean‐Claude Eisenmann, Hélène Demarquette, Valentine Richez, Marguerite Vignon, Denis Caillot, Thierry Façon, Philippe Moreau, Anne‐Laurène Colin, Pascale Olivier, Soraya Wuillème, Hervé Avet‐Loiseau, Jill Corre, Michel Attal
Abstract
High-dose melphalan (HDM) and transplantation are recommended for eligible patients with multiple myeloma. No other conditioning regimen has proven to be more effective and/or safer. We previously reported in a phase 2 study that bortezomib can safely and effectively be combined with HDM (Bor-HDM), with a 32% complete response (CR) rate after transplantation. These data supported a randomized phase 3 trial. Randomization was stratified according to risk and response to induction: 300 patients were enrolled, and 154 were allocated to the experimental arm (ie, arm A) with bortezomib (1 mg/m2 intravenously [IV]) on days -6, -3, +1, and +4 and melphalan (200 mg/m2 IV) on day -2. The control arm (ie, arm B) consisted of HDM alone (200 mg/m2 IV). There were no differences in stringent CR + CR rates at day 60 posttransplant (primary end point): 22.1% in arm A vs 20.5% in arm B (P = .844). There were also no differences in undetectable minimum residual disease rates: 41.3% vs 39.4% (P = .864). Median progression-free survival was 34.0 months for arm A vs 29.6 months for arm B (adjusted HR, 0.82; 95% CI, 0.61-1.13; P = .244). The estimated 3-year overall survival was 89.5% in both arms (hazard ratio, 1.28; 95% CI, 0.62-2.64; P = .374). Sixty-nine serious adverse events occurred in 18.7% of Bor-HDM-treated patients (vs 13.1% in HDM-treated patients). The proportion of grade 3/4 AEs was similar within the 2 groups (72.0% vs 73.1%), mainly (as expected) blood and gastrointestinal disorders; 4% of patients reported grade 3/4 or painful peripheral neuropathy in arm A (vs 1.5% in arm B). In this randomized phase 3 study, a conditioning regimen with Bor-HDM did not improve efficacy end points or outcomes compared with HDM alone. The original trial was registered at www.clinicaltrials.gov as #NCT02197221.