Comparison of Autologous Hematopoietic Cell Transplant (autoHCT), Bortezomib, Lenalidomide (Len) and Dexamethasone (RVD) Consolidation with Len Maintenance (ACM), Tandem Autohct with Len Maintenance (TAM) and Autohct with Len Maintenance (AM) for up-Front Treatment of Patients with Multiple Myeloma (MM): Primary Results from the Randomized Phase III Trial of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0702 - StaMINA Trial)

Background: Len maintenance after autoHCT has improved progression-free (PFS) and overall survival (OS). However, the role of additional interventions after autoHCT such as tandem autoHCT or triple therapy consolidation remains to be determined.

Methods: This is a phase III clinical trial (NCT#01109004) of transplant-eligible patients (pts) with symptomatic MM <71 years of age within 12 months of initiating therapy and without prior progression who were randomly assigned 1:1:1 to receive melphalan 200mg/m2 autoHCT and 4 cycles of RVD consolidation (lenalidomide 15mg daily days 1-14, dexamethasone 40mg day 1,8 and 15, and bortezomib 1.3mg/m2 days 1,4,8 and 11 every 21 days) (ACM), versus tandem melphalan 200mg/m2 autoHCT (TAM) or versus a single autoHCT (AM). Randomization was stratified by disease risk (cytogenetic abnormalities - del13q by karyotype, del17q, t(4;14), t(14;16), t(14;20) and hypodyploid; or high beta-2 microglobulin) and center. All arms included Len maintenance (at maximum tolerated dose of 5 to 15 mg orally daily until progression) with dose modifications for toxicities. All patients were reviewed centrally for eligibility, response and progression. The primary objective was to compare 38-month PFS of the three arms. The events for PFS included progression, non-protocol anti-myeloma therapy, or death. Comparisons between treatment groups were based on pairwise log-rank tests stratified on disease risk, with significance levels adjusted for the 3 pairwise comparisons and for interim analyses. In calculating the cumulative incidence of progression, the events were progression or non-protocol anti-myeloma therapy, and death was a competing risk.

Results: From June 2010 to November 2013, 758 pts (ACM, N=254; TAM, N=247; AM, N=257) aged 20-70 years (median 57y) were enrolled. Of those enrolled, 24% were classified as high risk. Non-compliance rates following the first autoHCT were 12%, 32% and 5% for ACM, TAM and AM, respectively. Median available follow up from randomization was 38 months. Follow-up is continuing through January 2017. 38-month estimated probabilities for PFS were 57% (95% CI: 50-63%), 56% (95% CI: 49-63%) and 52% (95% CI: 45-59%) for ACM, TAM and AM, respectively (ACM vs TAM p=0.75, ACM vs AM p=0.21, TAM vs AM p=0.37). Corresponding probabilities of OS were 86% (95% CI: 80-90%), 82% (95%CI: 76-87%) and 83% (95% CI: 78-88%). Median OS has not been reached. Cumulative incidences of disease progression at 38 months were 42% (95% CI: 36-48%), 42% (95% CI: 35-48%) and 47% (95% CI: 40-54%) for the ACM, TAM and AM arms, respectively. There were 39 cases of second primary malignancy (SPM) reported in 36 participants and the cumulative incidences for first SPM were 6.0% (95% CI: 3.4-9.6%), 5.9% (95% CI: 3.3-9.6%) and 4.0% (95% CI: 1.9-7.2%) for the ACM, TAM, and AM, respectively.

Conclusions: The primary results of the largest randomized US transplant trial in MM demonstrated comparable PFS and OS. The addition of RVD consolidation or a second auto-HCT was not superior to a single auto HCT followed by Len maintenance in the upfront treatment of MM. A long term follow-up trial to track outcomes in these patients is ongoing.