Longer Term Follow up of the  Randomized Phase III Trial SWOG S0777: Bortezomib, Lenalidomide and Dexamethasone Vs. Lenalidomide and Dexamethasone in Patients (Pts) with Previously Untreated Multiple Myeloma without an Intent for Immediate Autologous Stem Cell Transplant (ASCT)

Background: SWOG S0777, a randomized phase III trial, compared bortezomib, lenalidomide and dexamethasone (VRd) with lenalidomide and dexamethasone (Rd). The primary end point was progression-free survival (PFS) using a pre-specified one-sided stratified log rank test at a significance level of 0.02. The stratification factors were International Staging System (ISS) stage (I, II or III) and intent to transplant (yes or no), among a total of 6 strata. Overall response rate (ORR), overall survival (OS) and safety were secondary end points. Results of the primary analysis of this trial were published in Lancet (2016, Volume 389, Issue 10068, 519 - 527).

Methods: This updated analysis includes 460 patients evaluable for survival endpoints: 225 eligible and analyzable patients were randomized to Rd and 235 patients to VRd. Rd patients received lenalidomide 25 mg/day on days 1-21 and dexamethasone 40 mg/day on days 1, 8, 15 and 22 of a 28-day cycle. VRd patients received lenalidomide 25 mg/day on days 1-14 and dexamethasone 20/mg/day on days 1, 2, 4, 5, 8, 9, 11 and 12 plus bortezomib 1.3 mg/m² IV push on days 1, 4, 8 and 11 of a 21-day cycle. All patients received aspirin 325 mg/day and VRd patients received VZV prophylaxis per institutional standard. The 6-month induction was six 28-day cycles of Rd and eight 21-day cycles of VRd followed by Rd maintenance for all patients until progression, unacceptable toxicity or withdrawal of consent.

Results: Between 2008 and 2012, 525 patients from 48 institutions were randomized. Patient data have been rigorously updated for this analysis based upon a May 15, 2018 datalock. The median follow up is now 84 months (7 years). The median PFS is 41 months for VRd and 29 months for Rd: stratified hazard ratio (96% Wald Confidence Interval) was 0.742 (0.594, 0.928) and one-sided stratified log-rank P-value 0.003 (see Figure 1). The median OS for VRd is still not reached with median OS for Rd being 69 months: stratified hazard ratio (96% Wald Confidence Interval) was 0.709 (0.543, 0.926) and stratified two-sided P-value was 0.0114 (see Figure 2). The impact of age was assessed in several ways including using 3 cutoffs (<65 years; 65-75 years; >75 years) and multivariate cox proportional hazards regression analyses adjusted for age. As in prior analyses, both PFS and OS were improved with VRd versus Rd adjusting for age (P-values: 0.013 [PFS]; 0.033 [OS])). Depth of response was assessed incorporating new serial data and additional bone marrow results. The CR plus VGPR was 74.9% for VRd versus CR plus VGPR of 53.7% for Rd (P-value 0.006 for response differences using a stratified Cochran-Mantel- Haenszel analysis). The median duration of lenalidomide plus dexamethasone maintenance was 17.4 months. The number of second cancers was 19/235 (8%) with VRd and 16/225 (7%) with Rd.

Conclusion: The addition of bortezomib to lenalidomide dexamethasone for induction therapy in previously untreated myeloma results in a statistically significant and clinically meaningful improvement in PFS as well as better OS with follow up of 7 years. VRd had an acceptable safety and tolerability profile and continues to represent an appropriate standard of care irrespective of age.

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