SWOG 0777: Earlier Treatment With Bortezomib Improved Survival in Untreated Multiple Myeloma

di Mary Mosley

Induction therapy that added the second-line drug bortezomib to the standard first-line combination of lenalidomide and dexamethasone, compared with that combination alone, significantly improved progression-free survival (PFS) and overall survival (OS) in patients with newly-diagnosed, untreated, multiple myeloma, according to results of the phase 3 SWOG 0777 trial presented at the 2015 Annual Meeting of the American Society of Hematology. The overall study results suggest the three-drug regimen should be a new standard of care, stated the principal investigator Brian Drurie, MD, Cedars-Sinai Comprehensive Cancer Center, Los Angeles, CA, USA, noting these patients lived 1 year longer.

A total of 473 patients with light-chain multiple myeloma were randomized between 2008 and 2012 at 139 hospitals in the United States to the three-drug regimen of bortezomib, a proteasome inhibitor, lenalidomide, an immunodulator, and dexamethasone (VRd arm, n = 243) or the two-drug regimen of lenalidomide and dexamethasone (Rd arm, n = 230). The trial stratified patients by International Staging System (ISS) and excluded patients who intended to undergo immediate autologous stem cell transplant for disease progression.

The median age of the patients was 63 years (range, 28-57), and the study is notable for including patients younger and older than 65 years. Overall, the patients were well matched, although in the VRd arm versus the Rd arm there were fewer women (37% vs. 47%; p = 0.033) and fewer patients ≥65 years (38% vs. 48%; p = 0.042). One-third of patients were ISS stage III.

During the 6-month induction period, patients in the VRd arm received eight 21-day cycles while those in the Rd arm received the standard six 28-day cycle. The VRd regimen comprised lenalidomide 25 mg/day administered on days 1 to 14, dexamethasone 20 mg/day on days 1, 2, 4, 5, 8, 9, 11, and 12, plus bortezomib 1.3 mg/m2 intravenously on days 1, 4, 8, and 11. In the Rd arm, lenalidomide 25 mg/day was administered on days 1 to 21 and dexamethasone 40 mg/day on days 1, 8, 15, and 22. All patients received aspirin 325 mg/day and VRd patients received prophylaxis for the herpes simplex virus.

The median duration of maintenance therapy with lenalidomide and dexamethasone was 385 days, with a similar number of patients completing maintenance therapy in each arm (135 and 143 in the VRd and Rd arms, respectively). However, more patients in the Rd arm versus the VRd arm stopped maintenance therapy secondary to disease progression or relapse, revealing an early difference between the treatment arms, while more patients in the VRd arm stopped therapy because of adverse events or side effects. A total of 97 of 212 (46%) patients did not have disease progression after stopping MT. At end of the study, 66 patients (14% of those eligible) remained on maintenance therapy.

The primary endpoint of PFS was significantly longer at a median of 43 months in the VRd arm versus 30 months in the Rd arm (HR, 0.712; 96% Wald CI, 0.560-0.906; one-sided p = 0.0018). There were 137 deaths in the VRd arm and 166 in the Rd arm. The secondary endpoint of OS was also significantly longer with the addition of bortezomib, at a median of 75 months versus 64 months in the VRd and Rd arms, respectively (HR, 0.709; two-sided p = 0.0250).

The patients in the VRd arm had a deeper response to treatment, compared with those in the Rd arm, stated Dr. Drurie, reflected by the greater complete response and very good partial response (Table 1). The overall response rate was higher in the VRd arm at 81.5%, compared with 71.5% in the Rd arm. During the 6-month induction period, disease progression or death was lower in the patients in the VRd arm versus those in the Rd arm (2.8% vs 4.2%).
The multivariate age-adjusted analysis showed there was a consistent benefit with the addition of bortezomib regardless of age or ISS stage (Table 2).

Both arms had a similar rate (4%) of secondary primary malignancies, primarily skin cancer. Despite the clinically-meaningful improvements in the VRd-treated patients, there was more neuropathy ≥ grade 3, compared with the Rd-treated patients (24% vs. 5%; p <0.0001). Overall, the safety profile was similar in both treatment groups and bortezomib was well tolerated.

The longer survival of 1 year, striking reduction in deaths, and longer disease remission gained by the addition of bortezomib to induction therapy for multiple myeloma reported from the SWOG S0777 trial may represent a new standard of care for these patients.

Source: ASH 2015,
abs 25

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