AUTHORS
Pieter Sonneveld, MD, PhD, Mario Boccadoro, MD2, Meletios-Athanasios (Thanos) C. Dimopoulos, MD3, Hermann Einsele, MD, PhD4, Hang Quach, MBBS MD FRACP FRCPA5, P. Joy Ho, MBBS, DPhil, FRACP, FRCPA6, Meral Beksac, MD7, Cyrille Hulin, MD8, Elisabetta Antonioli, MD9, Xavier Leleu Sr, MD, PhD10, Silvia Mangiacavalli, MD11, Aurore Perrot Sr, MD12, Michele Cavo13, Angelo Belotti, MD14, Francesca Gay, MD, PhD15, Robert Mina16, Inger Nijhof17, Niels van de Donk, MD, PhD18, Eirini Katodritou, MD, PhD19, Fredrik Schjesvold, MD,PhD20, Anna Maria Sureda Balari, MD,PhD21, Laura Rosiñol Dachs Sr, MD, PhD22, Michel Delforge, MD23, Wilfried Roeloffzen, MD, PhD24, Tobias Silzle, MD25, Annette Vangsted, MD26, Andrew Spencer, MBBS FRACP FRCPA DM27, Roman Hajek, MD, PhD28, Artur Jurczyszyn, MD29, Yangfang Liu, MD30, Diego Vieyra, PhD31, Alba Tuozzo, BS32, Carla De Boer, PhD33, Fredrik Borgsten, MD34, Anna Sitthi-Amorn, MD35, Melissa Rowe, MD36, Robin Carson, MD37, Paula Rodriguez Otero, MD, PhD38, Joan Batista Blade Creixenti Sr, MD39, Philippe Moreau Sr, MD, PhD40
AFFILIATIONS
1 Department of Hematology, Erasmus MC Cancer Institute; European Myeloma Network, Rotterdam, Netherlands
2 European Myeloma Network, EMN, Torino, Italy
3 Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens; Department of Medicine, Korea University, Athens, Greece
4 Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany
5 University of Melbourne, St Vincent’s Hospital, Melbourne, Australia
6 Institute of Haematology, Royal Prince Alfred Hospital & University of Sydney, Sydney, Australia
7 Department of Hematology, Ankara Liv Hospital, Istinye University, Ankara, Turkey
8 Hôpital Haut Lévêque, University Hospital, Pessac, France
9 Department of Hematology, Careggi Hospital and University of Florence, Florence, Italy
10 University of Poitiers, CHU and Inserm 1313, Poitiers, France
11 Hematology Division, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy
12 Université de Toulouse, CHU de Toulouse Hématologie, IUCT-Oncopole, Toulouse, France
13 IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia “Seràgnoli”, Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, Bologna, Italy
14 Department of Hematology, ASST Spedali Civili di Brescia, Brescia, Italy
15 Division of Hematology, AOU Città della Salute e della Scienza di Torino, University of Torino; Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
16 Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia, United States
17 Department of Hematology, Amsterdam University Medical Center, Vrije Universiteit Amsterdam; Department of Hematology, St Antonius Hospital, Amsterdam, Netherlands
18 Department of Hematology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
19 Department of Hematology, Theagenion Cancer Hospital, Thessaloniki, Greece
20 Department of Hematology, Oslo University Hospital, Oslo, Norway
21 Clinical Hematology Department, Institut Català d’Oncologia (ICO) – Hospitalet / Hospital Duran i Reynals, Barcelona, Spain
22 Myeloma & Amyloidosis Unit, Hospital Clínic de Barcelona, Barcelona, Spain
23 Department of Hematology, UZ Leuven / KU Leuven, Leuven, Belgium
24 Hematology, University Medical Center Groningen (UMCG), Groningen, Netherlands
25 Medical Oncology & Hematology, Cantonal Hospital St. Gallen (KSSG), St. Gallen, Switzerland
26 Department of Hematology, Rigshospitalet, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark
27 Malignant Haematology and Stem Cell Transplantation Service, Alfred Health-Monash University, Melbourne, Australia
28 Department of Hematooncology, University Hospital Ostrava; Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
29 Plasma Cell Dyscrasias Center, Department of Hematology, Jagiellonian University Medical College, Kraków, Poland
30 Johnson & Johnson, Beijing, China
31 Johnson & Johnson, Spring House, Pennsylvania, United States
32 Johnson & Johnson, Spring House, Pennsylvania, United States
33 Johnson & Johnson, Leiden, Netherlands
34 Johnson & Johnson, Raritan, New Jersey, United States
35 Johnson & Johnson, Spring House, Pennsylvania, United States
36 Johnson & Johnson, High Wycombe, United Kingdom
37 Johnson & Johnson, Spring House, Pennsylvania, United States
38 Departamento de Hematología, Clinica Universidad de Navarra, Pamplona, Spain
39 Amyloidosis and Multiple Myeloma Unit, Hematology, Hospital Clinic of Barcelona, Barcelona, Spain
40 Hematology Department, University Hospital of Nantes, Nantes, France
ABSTRACT
Introduction: In phase 3 PERSEUS, daratumumab, bortezomib, lenalidomide, and dexamethasone induction/consolidation plus DR maintenance (DVRd-DR) showed superior efficacy vs VRd-R in patients (pts) with TE-NDMM. In an updated analysis of the intent-to-treat (ITT) population (median follow-up [mFU] 81.3 months [mo]), progression-free survival (PFS) continued to favor DVRd-DR vs VRd-R (hazard ratio [HR] 0.35; 95% CI, 0.26–0.46; P<0.0001). Median PFS was not reached (NR; DVRd-DR) vs 81.5mo (95% CI, 73.8–NE; VRd-R). The estimated 6y PFS rate was 81.1% (DVRd-DR) vs 56.1% (VRd-R). Overall survival favored DVRd-DR vs VRd-R (14.4% vs 23.7% [HR 0.57; P=0.0014]). Overall MRDneg favored DVRd-DR vs VRd-R at 10-5 (77.2% vs 50.3%, [odds ratio (OR) 3.41; P<0.0001]) and 10-6 (68.7% vs 36.7% [OR, 3.88; P<0.0001]). We further examined sustained MRDneg and maintenance outcomes following per-protocol MRD-guided daratumumab (Dara) discontinuation at a longer mFU of 81.3mo (6.8y).
Methods: MRDneg (ITT population) was defined as achievement of both ≥CR and MRDneg by next-generation sequencing (NGS [clonoSEQ]). Sustained MRDneg (without MRD positivity in between) rates were analyzed in ITT and MRD-evaluable populations (pts with ≥CR, successful baseline NGS calibration, and a positive or negative MRD result at the specified time point) using NGS (10-5 and 10-6). Nominal two-sided P-values are reported (not adjusted for multiplicity).
Results: In PERSEUS, 709 TE pts were randomized 1:1 (DVRd-DR, n=355; VRd-R, n=354). With an additional 33.8mo (~2.8y) of FU since the primary analysis, and a mFU of 81.3mo (0.03–88.3), long-term sustained MRDneg rates in the ITT population were higher with DVRd-DR vs VRd-R at 48mo (10-5: 53.5% vs 22.9% [OR 4.07; P<0.0001]; 10-6: 40.0% vs 13.0% [OR 4.61; P<0.0001]). Long-term sustained MRDneg for ≥60mo in the ITT population (10-5: DVRd-DR 43.4% vs VRd-R 19.5% [OR 3.29; P<0.0001]) demonstrated deep and durable responses with per-protocol Dara treatment modifications.
Sustained MRDneg rates in the MRD-evaluable population were consistently higher with DVRd-DR vs VRd-R at 10-5 (24mo: 94.7% vs 76.6% [OR 5.51; P<0.0001]; 36mo: 93.4% vs 73.6% [OR 5.08; P<0.0001]; 48mo: 90.5% vs 73.0% [OR 3.52; P<0.0001]) and 10-6 (24mo: 90.8% vs 73.8% [OR 3.50; P=0.0001]; 36mo: 86.7% vs 67.8% [OR 3.09; P=0.0003]; 48mo: 83.0% vs 63.0% [OR 2.87; P=0.0014]).
In pts achieving MRDneg, PFS favored DVRd-DR vs VRd-R (10-5: HR 0.41, 95% CI 0.27–0.63, P<0.0001; and 10-6: HR 0.55, 95% CI 0.33–0.89, P=0.0139). Similarly, PFS favored DVRd-DR vs VRd-R among MRD-positive pts (10-5: HR 0.60, 95% CI 0.40–0.90, P=0.0114; and 10-6: HR 0.50, 95% CI 0.34–0.72, P=0.0002).
At 81.3mo, 236 (73.3%) of 322 DVRd-DR pts who started maintenance stopped Dara per protocol: after receiving ≥24mo of maintenance therapy and attaining ≥CR and sustained MRDneg status for ≥12mo. Median Dara maintenance treatment duration was 26.8mo (24.5–68.5). After Dara discontinuation, 10 (4.2%) pts had progressive disease (median time to progressive disease 32.6mo [12.4–44.9]). Twenty-nine (12.3%) pts restarted Dara due to loss of CR (n=23) or MRDneg (n=6) after a median 17.8mo (4.6–37.4) following discontinuation, of which 19 remain on Dara.
In a landmark PFS analysis in pts who stopped Dara treatment per protocol vs VRd-R pts who had also received ≥24mo of maintenance therapy and attained sustained MRDneg ≥CR status for ≥12mo, PFS favored DVRd-DR vs VRd-R, with median PFS NR in either arm (HR 0.36; 95% CI 0.19–0.71; P=0.0022); the 48mo PFS rate after ≥24mo maintenance and ≥12mo MRDneg ≥CR status was 91.4% (DVRd-DR) vs 75.3% (VRd-R).
In a subset of pts (DVRd-DR and VRd-R) who discontinued all treatment without PFS events within 3mo after last exposure (n=211), treatment-free survival favored DVRd-DR vs VRd-R (HR 0.27; 95% CI 0.14–0.54).
Overall safety findings were consistent with the primary analysis, with no new signals after ~2.8y of additional FU in the DVRd-DR arm.
Conclusions:
Long-term FU (6.8y) confirms that DVRd induction/consolidation and DR maintenance delivers deeper and more durable MRD responses and improved clinical outcomes vs VRd-R in TE-NDMM. In DVRd-DR pts who discontinued Dara maintenance, outcomes including PFS and sustained MRDneg remain superior to VRd-R. Low rates of progression combined with sustained MRDneg and a very low proportion of pts required to restart Dara reinforce the feasibility of sustained MRD-guided Dara discontinuation during maintenance.
DISCLOSURES
Pieter Sonneveld, MD, PhD: Celgene - Research Funding; Karyopharm - Research Funding; Janssen - Research Funding; Amgen - Research Funding; Bristol Myers Squibb - Research Funding; Karyopharm - Consultancy (Includes expert testimony); Pfizer - Consultancy (Includes expert testimony); Amgen - Consultancy (Includes expert testimony); Celgene - Consultancy (Includes expert testimony); Janssen - Consultancy (Includes expert testimony); Bristol Myers Squibb - Consultancy (Includes expert testimony)