Treatment of Newly Diagnosed Myeloma (excluding t-cell redirection therapy)
Andrzej Jakubowiak, MD, PhD
Professor of Medicine
The University of Chicago
Maintenance treatment after autologous stem cell transplantation (ASCT) prolongs remission and may prolong survival. Post-ASCT maintenance with lenalidomide (R) monotherapy is established as the current standard of care. The role of multi-agent maintenance is currently intensively evaluated. Here we report final results from the primary analysis of the phase 3 ATLAS trial, which compared post-ASCT KRd vs R, with post-hoc analysis of subset of patients with high-risk cytogenetics.
Methods:
This international, open-label phase 3 study randomly assigned patients who completed induction and had stable disease or better after ASCT to KRd or R alone (1:1 ratio) as maintenance therapy. Randomization was stratified by post-ASCT very good partial response or better, presence of at least one high-risk cytogenetic abnormality [del(13) (q14), t(4;14)(p16;q32), t(14;16)(q32;q23), del(17)(p13.1), or hypodiploidy)], and by treatment country. For the KRd group, patients with standard-risk cytogenetics and measurable residual disease (MRD) negativity at 10-5 after cycle 6 were switched to R maintenance after cycle 8; remaining patients continued KRd up to 36 cycles and then switched to R. The primary endpoint was PFS from randomization. Secondary endpoints included OS and MRD negativity.
Results:
One hundred and eighty patients were randomized (92 to KRd and 88 to R alone). At the data cutoff (21 Oct 2024), median follow-up was 5.7 years. After cycle 8, 40 of 81 patients on KRd switched to R. For all randomized patients, PFS was superior for KRd vs R, with 4-year PFS of 67.5% vs 38.0% (median, 72.8 vs 37.3 months; hazard ratio [HR] 0.46 [95% CI: 0.30, 0.70]; p=0.0002). In post-hoc analysis, the PFS benefit was consistent across most of the categories, including 40 patients (22 in KRd and 18 in R) with high-risk cytogenetics (HR 0.52 [95% CI: 0.24, 1.1]). Across all subsets, deeper and more sustained responses were achieved with KRd vs R: rate of MRD < 10- 5 and at least a complete response improved over time and as best response was 73% vs 51% (odds ratio [OR] 2.56 [95% CI: 1.37, 4.77]; p=0.003). Among the high-risk patients, MRD-negativity rates improved from screening to cycle 6 in those treated with KRd (8 converted to MRD-negative and none lost it; p = 0.013), while no change was observed in the R arm (1 gained and 1 lost MRD negativity), suggesting that KRd may be more effective in deepening responses also in this subset of patients. In all randomized patients, OS was longer with KRd compared to R, demonstrating 4-year OS of 84.3% vs 79.2% (median, not reached vs 82.2 months; HR 0.49 [95% CI: 0.26, 0.90]; p=0.023. However, this OS was not statistically significant in a high-risk subset of patients. No new safety signals were observed.
Conclusions:
In addition to a superior PFS and OS from the primary analysis of all randomized patients in phase 3 ATLAS trial of post-transplant KRd vs R, this post-hoc analysis shows PFS benefit also in a subset of high-risk patients.