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.

— Brian G.M. Durie, MD, and colleagues

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In the phase III SWOG S0777 trial reported in The Lancet, Brian G.M. Durie, MD, of Cedars-Sinai Samuel Oschin Cancer Center, and colleagues found that adding bor­tezomib ­(Velcade) to lenalidomide (Revlimid)/dexamethasone improved progression-free and overall survival in patients with newly diagnosed multiple myeloma who were not planned for immediate autologous stem cell transplantation.¹

Study Details

In this open-label trial, 471 eligible patients from 139 SWOG and National Clinical Trial Network (NCTN) institutional sites were randomly assigned between April 2008 and February 2012 to receive bortezomib plus lenalidomide/dexamethasone (VRd, n = 242) or lenalidomide/dexamethasone alone (Rd, n = 229). Patients had to have CRAB criteria (calcium elevation, renal impairment, anemia, bone involvement) with measurable disease, Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 3, hemoglobin ≥ 9 g/dL, absolute neutrophil count ≥ 1 10³ cells/µL, and platelet count of ≥ 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 25 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%.

Efficacy Outcomes

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 months 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 the 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

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% vs 11%, 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.” ■

Disclosure: The study was funded by the National Cancer Institute (NCI), the NCI National Clinical Trials Network, Millennium Pharmaceuticals, Takeda Oncology, and Celgene. For full disclosures of the study authors, visit www.thelancet.com.

Reference

1. Durie BG, Hoering A, Abidi MH, et al: Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): A randomised, open-label, phase 3 trial. Lancet 389:519-527, 2016.