ATLAS: A phase 3 randomized trial of carfilzomib, lenalidomide, and dexamethasone versus lenalidomide alone after stem-cell transplant for multiple myeloma.
Authors: Dytfeld Dominik , Wrobel Tomasz , Jamroziak Krzysztof , Kubicki Tadeusz , Robak Pawel , Czyz Jaroslaw , Tyczyńska Agata , Druzd-Sitek Agnieszka , Giannopoulos Krzysztof , Nowicki Adam , Łojko-Dankowska Anna , Matuszak Magdalena , Gil Lidia , Puła Bartosz , Rybka Justyna , Usnarska-Zubkiewicz Lidia , Czabak Olga , Stefka Andrew T. , Derman Benjamin Avi , Jakubowiak Andrzej J. ,   Polish Myeloma Consortium and University of Chicago Multisite Consortium
Published: June 2022

8001

Background: Treatment following autologous stem cell transplantation (ASCT) for multiple myeloma (MM) remains an area of active investigation. We have shown that extended post-ASCT treatment with carfilzomib, lenalidomide, and dexamethasone (KRd) after KRd induction improved the depth and duration of response (Jasielec et al, Blood 2020), suggesting a benefit of post-ASCT KRd therapy. Here we directly compare that strategy to standard lenalidomide (R) maintenance. Methods: This international open-label phase 3 randomized trial recruited newly-diagnosed MM patients (pts) who received any induction therapy for up to 12 months (mo) followed by single ASCT and achievement of at least stable disease within 100 days afterward. Pts were randomized to receive either KRd or R, stratified by post-transplant response (≥VGPR vs < VGPR) and cytogenetic risk [standard risk (SR) vs high [HR: presence of t(4;14), t(14;16), or del(17p)]. Pts randomized to KRd received carfilzomib 36 mg/m2 on days (D) 1,2,8,9,15,16 for 4 cycles (C) then D1,2,15,16 starting C5; R 25 mg D1-21, and dexamethasone 20 mg D1,8,15,22 in 28-day cycles. KRd pts with SR who reached IMWG-defined MRD-negativity after C6 de-escalated therapy to R alone after C8 (KRd- > R); the rest continued KRd through C36 followed by R alone until progression. Pts randomized to R received lenalidomide 10 mg C1-3 and then 15 mg daily. The primary objective was to compare progression free survival (PFS) rate between the two arms. Based on historical PFS rates, a sample size of 180 Pts was calculated to provide 85% power with 2-sided alpha 0.05. Results: 180 pts were enrolled (R n = 87; KRd n = 93) through 10/21/20; data cutoff was 12/31/21. Pt characteristics in the KRd and R arms were balanced for median age (58 vs 59 yrs), >VGPR (88% vs 92%), and HR (23% vs 21%). After 6 cycles, 47% pts in the KRd arm and 29% in the R arm achieved MRD-negativity (p = 0.017). 34 KRd pts eligible for de-escalation converted to R alone after C8 and were analyzed on the KRd arm per intention-to-treat. At median follow-up of 33.8 mo, 23 pts (25%) on the KRd arm and 38 pts (44%) on the R arm progressed; estimated median PFS was 59.0 mo for KRd vs 41.4 mo for R (Hazard Ratio 0.56, logrank p = 0.026). At cutoff, 90% of KRd and 87% of R pts were alive; no deaths were treatment-related. All-grade toxicities were generally comparable between arms. The most common grade 3+ AEs and those of special interest were neutropenia (KRd 47%; R 59%), thrombocytopenia (KRd 13%; R 7%), infections (KRd 15%; R 6%), cardiovascular toxicities (KRd 4%, R 5%), and secondary malignancies (KRd 2, R 2). Conclusions: This is the first randomized phase 3 trial demonstrating superior PFS with extended post-transplant KRd therapy compared to R maintenance. Therefore, MRD/risk-adapted post-ASCT extended KRd treatment may represent a new standard of care. Clinical trial information: NCT02659293.