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4715 Longitudinal Assessment of Minimal Residual Disease (MRD) in the ATLAS Randomized Phase 3 Trial of Post-Transplant Treatment with Carfilzomib, Lenalidomide, and Dexamethasone (KRd) Versus Lenalidomide (R) Alone in Patients with Newly Diagnosed Multiple Myeloma (NDMM)

Program: Oral and Poster Abstracts
Session: 652. Multiple Myeloma: Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
Minimal Residual Disease
Monday, December 11, 2023, 6:00 PM-8:00 PM

Tadeusz Kubicki1,2*, Dominik Dytfeld2*, Tomasz Wrobel, MD, PhD3*, Krzysztof Jamroziak4*, Pawel Robak5*, Jaroslaw Czyz6*, Agata Tyczynska7*, Agnieszka Druzd-Sitek8*, Krzysztof Giannopoulos9*, Adam Nowicki2*, Tomasz Szczepaniak2*, Anna Lojko-Dankowska2*, Magdalena Matuszak2*, Lidia Gil2, Bartosz Michal Pula4*, Justyna Rybka3*, Maciej Majcherek3*, Lidia Usnarska-Zubkiewicz3*, Lukasz Szukalski6*, Agnieszka Konska4*, Jan M. Zaucha7*, Jan Walewski8, Damian Mikulski5*, Olga Czabak10*, Tadeusz Robak5*, Dorota Kruk-Kwapisz11*, Oscar Boutros Lahoud12, Jeffrey A. Zonder, MD13, Kent Griffith14*, Andrew T Stefka1*, Ken Jiang1*, Jennifer H Cooperrider1, Ben A Derman, MD15 and Andrzej J Jakubowiak, MD, PhD1

1University of Chicago, Chicago, IL
2Poznan University of Medical Sciences, Poznan, Poland
3Wroclaw Medical University, Wroclaw, Poland
4Institute of Hematology and Blood Transfusion, Warsaw, Poland
5Medical University of Lodz, Lodz, Poland
6Nicolaus Copernicus University in Torun Ludwik Rydygier, Collegium Medicum in Bydgoszcz, Bydgoszcz, Poland
7Medical University of Gdansk, Gdansk, Poland
8Maria Sklodowska-Curie National Research Institute of Oncology, Warszawa, Poland
9Department of Experimental Hematooncology, Medical University of Lublin, Lublin, Poland
10Medical University of Lublin, Lublin, Poland
11Clinscience, Warsaw, Poland
12Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
13Karmanos Cancer Institute, Detroit, MI
14University of Michigan Health System, Ann Arbor, MI
15University of Chicago, CHICAGO, IL


The interim results of the ATLAS trial (Dytfeld, Lancet Oncology 2023) suggest a progression-free survival (PFS) benefit for NDMM patients after autologous hematopoietic stem cell transplantation (ASCT) treated with MRD-directed and risk-adapted maintenance using KRd compared to single-agent R. In order to gain a better understanding of the differences in response dynamics and depth achieved by the two regimens, we conducted a detailed analysis of MRD results assessed at multiple timepoints.


ATLAS is an ongoing phase 3 trial that randomized 180 patients with NDMM after ASCT to receive maintenance therapy with KRd or R. In the KRd arm, patients with standard-risk cytogenetics who achieved MRD-negativity after cycle 6 de-escalated therapy to receive R alone, starting from cycle 9. MRD assessments were performed using multicolor flow cytometry (MFC) with a limit of detection (LoD) of 10-5 and next-generation sequencing (NGS) with LoD 10-6 at screening, cycle 6 (C6), C12, C18, C24, and C36. Patients with MRD>10-5 were considered MRD positive. When both MFC and NGS results were available, at least one positive result qualified a patient as MRD-positive. In line with the MRD reporting harmonization guidelines (Costa, Leukemia 2021), patients who have not reached a landmark timepoint for analysis were excluded from the denominator. MRD rates between the treatment arms were compared using the chi-square test. PFS and MRD-free survival (death, progression or MRD resurgence counted as an event) were analyzed using the Kaplan-Meier method to calculate survival rates, and the log-rank test was performed to compare the groups.


We previously reported MRD rates at the end of 6 cycles (Dytfeld, Lancet Oncology 2023). In this analysis, MRD results were evaluable for the following number of subjects at the respective timepoints: 180 at screening, 180 at C6, 180 at C12, 179 at C18, 175 at C24, and 160 at C36. All the reported data, including MRD results, response rates, and time to event, were obtained at the cut-off date 31-DEC-2021, as in the Lancet Oncology manuscript. In the landmark analysis, MRD-negativity after C6 was associated with improved PFS for the entire study patient population [HR=0.49 (95% CI: 0.27-0.90), p=0.01]. Although the proportion of MRD-negative patients at screening was higher in the R arm (46/87, 53%) compared to the KRd arm (36/93, 39%, p=0.06), MRD-negative rates were higher in the KRd arm in the subsequent landmark evaluations. The MRD-negativity rates for KRd and R were: 61/93 (66%) vs 41/87 (47%, p=0.01) at C6; 49/93 (53%) vs 41/87 (47%, p=0.46) at C12; 48/93 (52%) vs 35/86 (41%, p=0.14) at C18; 43/90 (48%) vs 26/85 (31%, p=0.02) at C24; 34/82 (41%) vs 16/78 (21%, p= 0.004) at C36. These findings were consistent with a higher number of patients in the KRd arm who converted from MRD-positivity at screening to MRD-negativity at any timepoint (Figure 1). Of the 50 patients with detectable MRD at screening in the KRd arm, 33 (66%) achieved MRD-negativity as their best response. Among them, 24 achieved MRD-negativity at the end of C6, with 2 patients converting as late as C24. The numbers were significantly lower for the R arm, with 14 out of 32 (44%) MRD-positive patients at screening achieving MRD-negativity (p=0.047). Sustained MRD-negativity for at least 12 months was reached in 51 out of 93 patients (55%) in the KRd arm and in 36 out of 87 (41%) in the R arm (p=0.06). Those who achieved sustained MRD-negativity have had significantly longer PFS (HR=0.35 (0.20-0.59), p<0.0001). Among patients with sustained MRD-negativity, patients in the KRd arm had superior PFS [HR=0.30 (0.12-0.79), p=0.01], and MRD-free survival [HR=0.42 (0.20-0.89), p=0.02, Figure 2]. In the KRd arm, sustained MRD-negativity was confirmed in 32 out of 41 (78%) patients who had de-escalated therapy from KRd to R. In this group there were 8 events (25%) of progressive disease or MRD resurgence, which compared favorably to 17/36 (47%, p=0.057) events observed in the R arm.


The improved PFS in patients with NDMM receiving post-ASCT KRd maintenance may be attributed to higher rates of MRD conversion and longer duration of MRD-negativity. Importantly, this benefit, compared to R alone, appears to be sustained even in the subset of patients who received only 8 cycles of MRD-directed, risk-adapted KRd and subsequently de-escalated to R alone.

Disclosures: Dytfeld: BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wrobel: Roche: Research Funding; Roche, Novartis, Takeda,Celgene, BMS, Janssen-Cilag, Beigene, Pfizer, Gilead, Sanofi, GSK: Consultancy; Roche, Takdea, Novartis, BMS, Celgene, Janssen-Cilag, Beigene, Gilead, Sanofi: Honoraria; Roche, Novartis, Takeda, Celgene, BMS, Janssen-Cilag, Beigene, Sanofi: Speakers Bureau; Gilead, Roche, Takeda: Other: Travel, Accomodations, Expenses. Gil: Janssen: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Abbvie: Honoraria; Astellas: Honoraria; Celgene/BMS: Honoraria; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rybka: Abbvie: Honoraria; Celgen/BMS: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Zaucha: BMS: Research Funding; Medical University of Gdańsk: Current Employment; Pierre Fabre, Takeda, BMS, Gilead, Novartis, Pfizer, Amgen, F. Hoffmann-La Roche Ltd, Astra Zeneca, Abbvie: Honoraria; MSD: Research Funding. Walewski: GSK/Novartis: Research Funding; Takeda: Consultancy, Honoraria; Servier: Honoraria; Roche: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Amgen: Honoraria; Abbvie: Consultancy, Honoraria. Robak: Regeneron: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; BeiGene: Honoraria, Research Funding; OctoPharma: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Abbvie: Honoraria; GSK: Honoraria, Research Funding. Kruk-Kwapisz: Clinscience: Current Employment. Lahoud: MorphoSys Inc, Kite: Consultancy. Zonder: Takeda, Telios: Other: Consultancy which has ended within the past 24 months; Janssen, Prothena, Regeneron: Consultancy; Bristol-Myers Squibb/Celgene: Research Funding. Derman: COTA Healthcare: Consultancy; Janssen: Consultancy, Honoraria. Jakubowiak: GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

OffLabel Disclosure: Carfilzomib, Lenalidomide, Dexamethasone as maintenance after autologous stem cell transplantation in multiple myeloma

*signifies non-member of ASH