In the phase III SWOG S0777 trial reported in The Lancet, Durie et al found that adding bortezomib (Velcade) to lenalidomide (Revlimid)/dexamethasone improved progression-free and overall survival in patients with newly diagnosed myeloma who were not planned for immediate autologous stem cell transplantation.
In this open-label trial, 471 eligible patients from 139 Southwest Oncology Group (SWOG) and National Clinical Trial Network (NCTN) institutional sites were randomized between April 2008 and February 2012 to receive bortezomib plus lenalidomide/dexamethasone (VRd, n = 242) or lenalidomide/dexamethasone (Rd, n = 229). Patients had to have CRAB (C = calcium elevation; R = renal impairment; A = anemia; B =bone involvement) criteria with measurable disease, Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 3, hemoglobin ≥ 9 g/dL, absolute neutrophil count ≥ 1 x 10³ cells/µL, and platelet count ≥ 80,000/µL. Randomization was stratified by International Staging System (ISS) stage and intent to transplant.
VRd was given as eight 21-day cycles, with bortezomib given at 1.3 mg/m² on days 1, 4, 8, and 11, combined with lenalidomide at 5 mg daily on days 1 to 14 and oral dexamethasone at 20 mg/d on days 1, 2, 4, 5, 8, 9, 11, and 12. Rd was given as six 28-day cycles, with the standard regimen consisting of lenalidomide at 25 mg/d for days 1 to 21 plus oral dexamethasone at 40 mg/d on days 1, 8, 15, and 22.
The primary endpoint was progression-free survival, with a prespecified one-sided stratified log rank test with a significance level of .02. Analyses were performed in the intent-to-treat (eligible) population.
For the VRd vs Rd groups, 12% vs 16% had an ECOG performance status > 1, 32% vs 34% had ISS stage III disease, 38% vs 48% were aged ≥ 65 years, 37% vs 47% were women, and there was an intent to transplant for 69% and 68%.
Median follow-up was 55 months. At the time of the report, ≥ 10% of patients had proceeded to stem cell harvest and planned transplantation after leaving the study. Median progression-free survival was 43 months in the VRd group vs 30 months in the Rd group (stratified hazard ratio [HR] = 0.712, one-sided P = .0018; two-sided P = .0037).
Median overall survival was 75 vs 64 months (HR = 0.709, P = .025). Hazard ratios remained significant for progression-free survival (0.73, P = .007) and overall survival (0.74, P = .048) in age-adjusted multivariate analysis accounting for effect of age ≥ 65 years. Overall response rates were 82% vs 72%, with complete response or better in 16% vs 8%. Median duration of response was 52 vs 38 months.
Adverse events of grade ≥ 3 were reported in 82% of patients in the VRd group and 75% of patients in the Rd group. Overall, adverse events were generally well balanced between the groups. The most common adverse events ≥ grade 3 and at least possibly related to treatment were anemia, lymphopenia, neutropenia, and thrombocytopenia among hematologic adverse events and fatigue, sensory neuropathy, hyperglycemia, thrombosis/embolism, hypokalemia, muscle weakness, diarrhea, and dehydration among nonhematologic adverse events. Grade ≥ 3 neurologic toxicity was more common in the VRd group (33% vs11%, P < .0001). Second primary cancers occurred in 4% of patients in each group.
Treatment was discontinued due to adverse events in 23% vs 10% of patients. Two treatment-related deaths occurred in the VRd group.
The investigators concluded: “In patients with newly diagnosed myeloma, the addition of bortezomib to lenalidomide and dexamethasone resulted in significantly improved progression-free and overall survival and had an acceptable risk-benefit profile.”
The study was funded by the National Cancer Institute (NCI), the NCI National Clinical Trials Network, Millennium Pharmaceuticals, Takeda Oncology Company, and Celgene Corporation.
Brian G. M. Durie, MD, of Cedars-Sinai Samuel Oschin Cancer Center, is the corresponding author of The Lancet article.
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