Superior PFS with extended KRd versus standard lenalidomide maintenance after stem cell transplant for multiple myeloma
To date, treatment following autologous stem cell transplantation for multiple myeloma (MM) remains an area of active investigation. The ATLAS study is the first randomised phase III trial demonstrating superior progression-free survival with extended post-transplant carfilzomib-lenalidomide-dexamethasone (KRd) therapy compared to lenalidomide maintenance in patients with newly diagnosed MM.
Lenalidomide (R) maintenance post autologous stem cell transplant (ASCT) for multiple myeloma (MM) has been established as a standard of care. Post-ASCT treatment for MM remains an area of active investigation. Extended post-ASCT carfilzomib-lenalidomide-dexamethasone (KRd) after KRd induction further improves the depth of response associated with long PFS, suggestive of a benefit of extended post-ASCT KRd therapy. In the ongoing phase III ATLAS study, researchers directly compared post-ASCT KRd to standard lenalidomide maintenance in patients with newly diagnosed MM.
Study design
Newly-diagnosed MM patients who received any induction therapy for up to 12 months followed by single ASCT and who achieved at least stable disease within 100 days afterwards were randomised to receive either KRd or R, stratified by post-transplant response and standard vs. high-risk cytogenetics. In the KRd arm, patients received carfilzomib (36 mg/m2) on days 1,2,8,9,15,16 for cycles 1-4, then on days 1,2,15,16 for cycles 5-8; lenalidomide (25 mg) on days 1-21 for cycles 1-8 and dexamethasone (20 mg) on days 1,8,15,22 for cycles 1-8 in 28-day cycles. KRd patients with standard risk who reached IMWG-defined MRD-negativity after cycle 6 de-escalated therapy to R alone (15 mg) after cycle 8. All other patients continued KRd through cycle 36, followed by R alone until progression. Patients randomised to R received lenalidomide 10 mg for cycles 1-3 and then 15 mg daily (if tolerated). The primary endpoint was progression-free survival (PFS).
Results
Of the 180 patients enrolled, 87 were allocated to lenalidomide alone and 93 were randomised to KRd. One patient in each arm withdrew before treatment. In total, 34 KRd patients eligible for de-escalation converted to R alone after C8 and were analysed on the KRd arm per intention-to-treat. Baseline patient characteristics in the KRd and R arms were generally well balanced; median age (57 vs. 59 years), ≥VGPR at study entry (88% vs. 92%), and high-risk cytogenetics (23% vs. 21%). The majority of patients were treated with VTD or VCD as an induction regimen.
After a median follow-up of 33.8 months, there were 61 PFS events; 23 in the KRd arm and 38 in the R arm. Median PFS was 59.0 months in the KRd arm vs. 41.1 months in the R arm (HR[95%CI]: 0.56[0.34-0.93], p= 0.026). Subgroup analysis suggest a benefit for KRd in the majority of analysed subgroups, although the number of events remains low in some subsets of patients. After 6 cycles, 44% of patients in the KRd arm and 27% in the R arm achieved MRD-negativity as per IMWG definition (p= 0.027). In the standard-risk population, the IMWG-defined MRD-negativity rate was 44% vs. 26% for KRd and R arms, respectively. PFS for patients treated with KRd was much longer than for those treated with R (HR[95%CI]: 0.44[0.24-0.81], p= 0.01). For those who are standard-risk and achieved MRD negativity at cycle 6, a 77% reduction in the risk of disease progression or death was reported upon treatment with KRd (HR[95%CI]: 0.23[0.06-0.86], p= 0.01).
At the data cut-off, 20 (11.2%) of the patients had died, 9 in the KRd arm and 11 in the R arm. The median OS was not reached in the KRd arm, as compared to 81.8 months in the R arm (HR[95%CI[: 0.92[0.37-2.26], p= 0.86). All-grade toxicities were generally comparable between arms. The most common grade ≥ 3 AEs and those of special interest were neutropenia (48% vs. 59% for KRd and R respectively), thrombocytopenia (13% vs. 7%), infections (15% vs. 6%), cardiovascular toxicities (4% vs. 6%), and secondary malignancies (2% vs. 2%).
Conclusion
The ATLAS study is the first randomised phase III trial which could demonstrate superior PFS with extended post-transplant KRd therapy compared to lenalidomide maintenance. MRD-directed, risk-adapted KRd maintenance is potentially a more effective alternative to lenalidomide maintenance. As such, MRD-directed, risk-adapted KRd maintenance may represent a new standard of care.
Reference
Dytfeld D, et al. ATLAS: a phase 3 randomized trial of carfilzomib, lenalidomide, and dexamethasone versus lenalidomide alone after stem-cell transplant for multiple myeloma. Presented at EHA 2022; Abstract S175.
