Kategorie: Mnohočetný myelom
Téma: Myeloma - Clinical 1
Číslo abstraktu: 0281
Autoři: Meletios Athanasios Dimopoulos, MD; Sundar Jagannath; MD Sung-Soo Yoon, PhD; MD David Samuel diCapua Siegel, PhD; Prof. MD Sagar Lonial; J. Qi; prof. MUDr. Roman Hájek, CSc.; MD Thierry Facon; MD Laura Rosiñol, PhD; Catherine D. Williams, MBBS, MRCP, FRCPath; MD Hilary Anne Blacklock; Prof. Dr. med. Hartmut Goldschmidt; Vânia Tietsche de Moraes Hungria; MD Andrew Spencer; MD Antonio P. Palumbo; MD Donna E. Reece, FRCPC; MD Thorsten Graef, PhD; Jeniffer Houp; Linda Sun, PhD; MD Joseph E. Eid; MD Kenneth C. Anderson
Background. The synergistic effects of vorinostat (VOR), an oral multi-histone deacetylase inhibitor, and bortezomib (BTZ) were shown in preclinical studies and confirmed in independent phase 1 trials in patients with relapsed/refractory multiple myeloma (MM). Aims. We conducted a global, randomized, placebo- controlled, phase 3 trial to investigate the benefits of VOR in combination with BTZ for the treatment of relapsed/refractory MM patients. Methods. Eligible patients (≥18 years, measurable MM, 1-3 prior regimens, ECOG ≤2) were randomized 1:1 to receive 21-day cycles of BTZ (1.3 mg/m2 intravenously; days 1, 4, 8, 11) in combination with oral VOR (400 mg/d) or matching placebo, on days 1 to 14. Patients with prior resistance to BTZ were excluded, and additional use of corticosteroids for the treatment of MM was not allowed during the trial. All randomized patients were treated until disease progression, unacceptable toxicities, or withdrawal of consent. The primary end point was progression-free survival (PFS; after the occurrence of ~412 PFS events); all responses and progressions were determined according to the European Bone and Marrow Transplantation Group criteria and confirmed by an independent adjudication committee. Results. The trial enrolled 637 patients in 174 centers from 33 countries, making this trial one of the largest studies conducted in relapsed/refractory MM. The median age was 61 years (range 30-85 years), and patients had received a median of 2 prior regimens (range 1-3). Patients treated with VOR + BTZ compared with BTZ alone had a significant improvement in objective response rate (56% vs 41%; P<0.0001) and clinical benefit rate (71% vs 54%; P<0.0001). The durations of the induced responses were similar in both arms (8.5 vs 8.4 months); PFS and time to progression were signif icantly improved with VOR + BTZ compared with BTZ alone, with hazard ratio (HR) reductions of 23% (P=0.01) and 21% (P=0.02), respectively. With only 151 deaths, a favorable, nonsignificant trend in overall survival for VOR + BTZ was observed compared with BTZ alone (14% HR reduction; P=0.35). As expected, the most common treatment-emergent adverse events in both arms were predominantly hematologic and gastrointestinal disorders, with a significant increase for grade ≥3 thrombocytopenia (45% vs 24%; P<0.001) and grade ≥3 diarrhea (17% vs 9%; P=0.003) in the VOR + BTZ arm compared with BTZ alone. Mean exposure to study treatment was higher in the VOR + BTZ versus BTZ alone arm (7 vs 6 cycles); no differences in discontinuation rates were observed between the study arms (21% vs 22%, respectively). The combination was generally well-tolerated, and side effects were clinically manageable. Despite the increased incidence of grade ≥3 thrombocytopenia, no clinically relevant bleeding events have been reported. Summary and Conclusions. As the combination of VOR + BTZ induces significantly higher response rates and prolongs PFS in comparison with BTZ alone, VOR + BTZ may provide a new treatment option for relapsed/refractory MM patients. Subgroup analyses of high-risk patients will be presented at the meeting.
Haematologica, 2012; 97(s1): 113
Datum přednesení příspěvku: 14. 6. 2012