Triplet therapy plus early ASCT improves PFS in newly diagnosed multiple myeloma versus triplet therapy alone

In the phase 3 DETERMINATION trial, the addition of early ASCT to triplet therapy of lenalidomide, bortezomib, and dexamethasone followed by lenalidomide maintenance therapy until disease progression significantly improved progression-free survival (PFS) in patients with newly diagnosed multiple myeloma (MM). However, overall survival (OS) did not improve.

The optimal use of induction therapy, allogeneic stem cell transplantation (ASCT), and maintenance therapy in transplant-eligible, newly diagnosed MM patients continues to evolve. Based on the knowledge at that time, the phase 3 DETERMINATION trial (NCT01208662) was developed in 2010 to evaluate the efficacy addition of early (first-line) ASCT to triplet therapy (lenalidomide, bortezomib, and dexamethasone [RVd]) followed by lenalidomide maintenance therapy until disease progression in patients with newly diagnosed MM.

A total of 722 patients were randomised 1:1 to RVd alone (8 cycles) followed by lenalidomide maintenance, or RVd (5 cycles) plus ASCT followed by lenalidomide maintenance. The primary endpoint of the study was PFS, secondary endpoints were OS, response rate, duration of response, quality-of-life, and safety. Dr Paul Richardson (Dana-Farber Cancer Institute, MA, USA) presented the results of the study, which had been published days previously in the New England Journal of Medicine  [1,2].

After a median follow-up of 76.0 months, the primary endpoint was met: median PFS in the RVd alone arm was 46.2 months versus 67.5 months in the RVd plus ASCT arm (HR 1.53; P<0.0001). However, a post-hoc sensitivity analysis showed that for median event-free survival, the difference narrowed (32.0 months vs 47.3 months; HR 1.23). OS was comparable in both treatment arms: 5-year OS was 80.7% and 79.2% in RVd plus ASCT and RVd alone, respectively. “This could be related to subsequent therapies in patients off protocol therapy,” Dr Richardson said. Best response rates did not significantly differ between the treatment arms. Best response ≥PR was reached in 97.5% and 95% in RVd plus ASCT and RVd alone, respectively; best response ≥VGPR in 82.7% and 79.6%; and best response ≥CR in 46.8% and 42% of patients. However, duration of response favoured RVd plus ASCT (median 56.4 vs 38.9 months; HR 1.45; P=0.003) for response ≥PR. Quality-of-life in the RVd plus ASCT showed a significant but transient decrease at the time of ASCT.

Dr Richardson summarised that “among adults with MM, RVd plus ASCT was associated with longer PFS than RVd alone. However, no overall survival benefit was observed.”

1. Richardson PG, et al. The phase 3 DETERMINATION trial in newly diagnosed multiple myeloma: lenalidomide, bortezomib, and dexamethasone (RVd) with or without autologous stem cell transplantation (ASCT) and lenalidomide maintenance to progression. Abstract LB2366. EHA2022 Hybrid Congress, 09–12 June.
2. Richardson PG, et al. N Engl J Med 2022; June 5. DOI: 10.1056/NEJMoa2204925.

 

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Posted on 1 July 2022