DARATUMUMAB MAINTENANCE VS OBSERVATION IN PATIENTS WITH NEWLY DIAGNOSED MULTIPLE MYELOMA TREATED WITH BORTEZOMIB, THALIDOMIDE, AND DEXAMETHASONE ± DARATUMUMAB AND ASCT: CASSIOPEIA PART 2 RESULTS
Author(s): ,
Philippe Moreau
Affiliations:
University Hospital Hôtel-Dieu,Nantes,France
,
Cyrille Hulin
Affiliations:
Bordeaux University Hospital Center,Bordeaux,France
,
Aurore Perrot
Affiliations:
Institut Universitaire du Cancer de Toulouse-Oncopole,Toulouse,France
,
Bertrand Arnulf
Affiliations:
Hôpital Saint Louis, APHP,Paris,France
,
Karim Belhadj
Affiliations:
Hôpital Henri Mondor,Creteil,France
,
Lotfi Benboubker
Affiliations:
Tours University Hospital, Hôpital de Bretonneau,Tours,France
,
Marie Béné
Affiliations:
Nantes University Hospital,Nantes,France
,
Sonja Zweegman
Affiliations:
Vrije Universiteit Amsterdam,Amsterdam,Netherlands
,
Hélène Caillon
Affiliations:
University Hospital,Nantes,France
,
Denis Caillot
Affiliations:
Dijon University Hospital, Hôpital du Bocage,Dijon,France
,
Jill Corre
Affiliations:
Unité de Genomique du Myélome, IUC-T Oncopole,Toulouse,France
,
Michel Delforge
Affiliations:
University Hospital Leuven,Leuven,Belgium
,
Thomas Dejoie
Affiliations:
University Hospital,Nantes,France
,
Chantal Doyen
Affiliations:
Université Catholique de Louvain, CHU UCL Namur,Yvoir,Belgium
,
Thierry Facon
Affiliations:
Hôpital Claude Huriez,Lille,France
,
Cécile Sonntag
Affiliations:
University Hospital, Hôpital Hautepierre,Strasbourg,France
,
Jean Fontan
Affiliations:
University Hospital Jean Minjoz,Besancon,France
,
Laurent Garderet
Affiliations:
Sorbonne Université,Paris,France
,
Kon-Siong Jie
Affiliations:
Zuyderland MC,Sittard,Netherlands
,
Lionel Karlin
Affiliations:
Lyon University Hospital,Pierre – Benite,France
,
Frédérique Kuhnowski
Affiliations:
Institut Curie Paris,Paris,France
,
Jérôme Lambert
Affiliations:
Hôpital Saint-Louis,Paris,France
,
Xavier Leleu
Affiliations:
Poitiers University Hospital, CHU la Milétrie,Poitiers,France
,
Margaret Macro
Affiliations:
Caen University Hospital,Caen,France
,
Frédérique Orsini-Piocelle
Affiliations:
Centre Hospitalier Annecy Genevois,Pringy,France
,
Murielle Roussel
Affiliations:
Institut Universitaire du Cancer de Toulouse-Oncopole,Toulouse,France
,
Anne-Marie Stoppa
Affiliations:
Institut Paoli Calmettes,Marseille,France
,
Niels W C J van de Donk
Affiliations:
Vrije Universiteit Amsterdam,Amsterdam,Netherlands
,
Soraya Wuillème
Affiliations:
Nantes University Hospital,Nantes,France
,
Annemiek Broijl
Affiliations:
Erasmus MC Cancer Institute,Rotterdam,Netherlands
,
Cyrille Touzeau
Affiliations:
University Hospital Hôtel-Dieu,Nantes,France
,
Mourad Tiab
Affiliations:
Centre Hospitalier Départemental Vendée,La Roche sur Yon,France
,
Jean-Pierre Marolleau
Affiliations:
Amiens University Hospital,Amiens,France
,
Nathalie Meuleman
Affiliations:
Institut Jules Bordet, Université Libre de Bruxelles,Brussels,Belgium
,
Marie-Christiane Vekemans
Affiliations:
Université Catholique de Louvain, Cliniques Universitaires Saint-Luc,Brussels,Belgium
,
Matthijs Westerman
Affiliations:
Northwest Clinics,Alkmaar,Netherlands
,
Saskia Klein
Affiliations:
Meander Medical Centre,Amersfoort,Netherlands
,
Mark-David Levin
Affiliations:
Albert Schweitzer Ziekenhuis,Dordrecht,Netherlands
,
Fritz Offner
Affiliations:
University Hospital Ghent,Ghent,Belgium
,
Martine Escoffre-Barbe
Affiliations:
Rennes University Hospital, Hôpital de Pontchaillou,Rennes,France
,
Jean-Richard Eveillard
Affiliations:
Brest University Hospital, Hôpital A. Morvan,Brest,France
,
Reda Garidi
Affiliations:
Saint-Quentin Hospital Center,Saint Quentin,France
,
Tahamtan Ahmadi
Affiliations:
Genmab US, Inc,Princeton,United States
,
Maria Krevvata
Affiliations:
Janssen Research & Development,Spring House,United States
,
Ke Zhang
Affiliations:
Janssen Research & Development, LLC,La Jolla,United States
,
Carla de Boer
Affiliations:
Janssen Research & Development, LLC,Leiden,Netherlands
,
Sanjay Vara
Affiliations:
Janssen Research & Development, LLC,High Wycombe,United Kingdom
,
Tobias Kampfenkel
Affiliations:
Janssen Research & Development, LLC,Leiden,Netherlands
,
Veronique Vanquickelberghe
Affiliations:
Janssen Research & Development,Beerse,Belgium
,
Jessica Vermeulen
Affiliations:
Janssen Research & Development, LLC,Leiden,Netherlands
,
Hervé Avet-Loiseau
Affiliations:
Unité de Genomique du Myélome, IUC-T Oncopole,Toulouse,France
Pieter Sonneveld
Affiliations:
Erasmus MC Cancer Institute,Rotterdam,Netherlands
EHA Library. Moreau P. 06/09/21; 324588; S180
Prof. Philippe Moreau
Prof. Philippe Moreau
Contributions
Abstract
Presentation during EHA2021: All Oral presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

This abstract is embargoed until Saturday, June 12, 09:00 CEST

Abstract: S180

Type: Oral Presentation

Session title: New treatment strategies for newly diagnosed multiple myeloma

Background
Daratumumab in conjunction with bortezomib, thalidomide, and dexamethasone (D-VTd) and autologous stem cell transplantation (ASCT) is approved for the treatment of transplant-eligible patients with newly diagnosed multiple myeloma (NDMM) based on results from CASSIOPEIA part 1.

Aims
To assess daratumumab maintenance vs observation (OBS) in patients with partial response or better (≥PR) in part 1, regardless of induction/consolidation treatment (CASSIOPEIA part 2 prespecified interim analysis). 

Methods
CASSIOPEIA is a 2-part, open-label, randomized, phase 3 study in transplant-eligible patients with NDMM. Written informed consent was obtained from all patients. In part 1, patients received 4 cycles of induction and 2 cycles of consolidation with D-VTd or VTd alone. All responders in part 1 (≥PR; n=886) were rerandomized in part 2 to receive maintenance (intravenous daratumumab 16 mg/kg every 8 weeks for ≤2 years [n=442]) or OBS (n=444) until disease progression (IMWG criteria). Patients were stratified by induction (D-VTd vs VTd) and depth of response (minimum residual disease [MRD] status and ≥PR post consolidation). Progression-free survival (PFS) after rerandomization was the primary endpoint. The efficacy and safety were assessed after 281 PFS events. Key secondary endpoints (preplanned hierarchical order) were time to progression, complete response or better (≥CR), MRD negativity rates by next-generation sequencing, and overall survival (OS).

Results
Median PFS was not reached with daratumumab vs 46.7 months for OBS (median follow up, 35.4 months; hazard ratio [HR] 0.53 [95% CI 0.42–0.68]; P<0.0001). Daratumumab showed consistent PFS advantage across most subgroups, except for a significant interaction with induction/consolidation treatment arm (P<0.0001; prespecified analysis). The daratumumab vs OBS PFS HR was 0.32 (95% CI 0.23–0.46) in the VTd arm and 1.02 (0.71–1.47) in the D-VTd arm. The median time to progression was not reached for daratumumab vs 46.7 months for OBS (HR 0.49 [0.38–0.62]; P<0.0001). Compared with OBS, more patients with daratumumab maintenance achieved ≥CR (60.8% vs 72.9%; odds ratio [OR] 2.17 [1.54–3.07]; P<0.0001). In patients with ≥CR at 10−5, the MRD negativity rate was 58.6% with daratumumab maintenance vs 47.1% with OBS (OR 1.80 [1.33–2.43]; P=0.0001). Median OS was not reached in either arm. Most common (≥2.5%) grade 3/4 adverse events (AEs) reported with daratumumab maintenance vs OBS were lymphopenia (3.6% vs 1.8%), hypertension (3.0% vs 1.6%), and pneumonia (2.5% vs 1.4%). Serious AEs were reported in 22.7% of patients with daratumumab maintenance vs 18.9% with OBS; the most common (≥2.5%) being pneumonia (2.5% vs 1.6%). Thirteen patients (3.0%) discontinued daratumumab due to an AE. The rate of infusion-related reactions (90% were grade 1/2) was 54.5% in daratumumab-naive patients and 2.2% in daratumumab-pretreated patients. Second primary malignancies occurred in 5.5% of patients with daratumumab maintenance vs 2.7% with OBS.

Conclusion
CASSIOPEIA part 2 interim analysis showed a significantly longer PFS with daratumumab maintenance vs OBS in transplant-eligible patients with NDMM. The maintenance PFS benefit appeared only in patients treated with VTd as induction/consolidation. Patients who received D-VTd induction/consolidation ± daratumumab maintenance achieved similar PFS; longer follow up is needed for OS and PFS2. Compared with OBS, daratumumab maintenance significantly increased deeper response and MRD negativity rates, and it was well tolerated with no new safety signals.

Keyword(s): Multiple myeloma

Presentation during EHA2021: All Oral presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

This abstract is embargoed until Saturday, June 12, 09:00 CEST

Abstract: S180

Type: Oral Presentation

Session title: New treatment strategies for newly diagnosed multiple myeloma

Background
Daratumumab in conjunction with bortezomib, thalidomide, and dexamethasone (D-VTd) and autologous stem cell transplantation (ASCT) is approved for the treatment of transplant-eligible patients with newly diagnosed multiple myeloma (NDMM) based on results from CASSIOPEIA part 1.

Aims
To assess daratumumab maintenance vs observation (OBS) in patients with partial response or better (≥PR) in part 1, regardless of induction/consolidation treatment (CASSIOPEIA part 2 prespecified interim analysis). 

Methods
CASSIOPEIA is a 2-part, open-label, randomized, phase 3 study in transplant-eligible patients with NDMM. Written informed consent was obtained from all patients. In part 1, patients received 4 cycles of induction and 2 cycles of consolidation with D-VTd or VTd alone. All responders in part 1 (≥PR; n=886) were rerandomized in part 2 to receive maintenance (intravenous daratumumab 16 mg/kg every 8 weeks for ≤2 years [n=442]) or OBS (n=444) until disease progression (IMWG criteria). Patients were stratified by induction (D-VTd vs VTd) and depth of response (minimum residual disease [MRD] status and ≥PR post consolidation). Progression-free survival (PFS) after rerandomization was the primary endpoint. The efficacy and safety were assessed after 281 PFS events. Key secondary endpoints (preplanned hierarchical order) were time to progression, complete response or better (≥CR), MRD negativity rates by next-generation sequencing, and overall survival (OS).

Results
Median PFS was not reached with daratumumab vs 46.7 months for OBS (median follow up, 35.4 months; hazard ratio [HR] 0.53 [95% CI 0.42–0.68]; P<0.0001). Daratumumab showed consistent PFS advantage across most subgroups, except for a significant interaction with induction/consolidation treatment arm (P<0.0001; prespecified analysis). The daratumumab vs OBS PFS HR was 0.32 (95% CI 0.23–0.46) in the VTd arm and 1.02 (0.71–1.47) in the D-VTd arm. The median time to progression was not reached for daratumumab vs 46.7 months for OBS (HR 0.49 [0.38–0.62]; P<0.0001). Compared with OBS, more patients with daratumumab maintenance achieved ≥CR (60.8% vs 72.9%; odds ratio [OR] 2.17 [1.54–3.07]; P<0.0001). In patients with ≥CR at 10−5, the MRD negativity rate was 58.6% with daratumumab maintenance vs 47.1% with OBS (OR 1.80 [1.33–2.43]; P=0.0001). Median OS was not reached in either arm. Most common (≥2.5%) grade 3/4 adverse events (AEs) reported with daratumumab maintenance vs OBS were lymphopenia (3.6% vs 1.8%), hypertension (3.0% vs 1.6%), and pneumonia (2.5% vs 1.4%). Serious AEs were reported in 22.7% of patients with daratumumab maintenance vs 18.9% with OBS; the most common (≥2.5%) being pneumonia (2.5% vs 1.6%). Thirteen patients (3.0%) discontinued daratumumab due to an AE. The rate of infusion-related reactions (90% were grade 1/2) was 54.5% in daratumumab-naive patients and 2.2% in daratumumab-pretreated patients. Second primary malignancies occurred in 5.5% of patients with daratumumab maintenance vs 2.7% with OBS.

Conclusion
CASSIOPEIA part 2 interim analysis showed a significantly longer PFS with daratumumab maintenance vs OBS in transplant-eligible patients with NDMM. The maintenance PFS benefit appeared only in patients treated with VTd as induction/consolidation. Patients who received D-VTd induction/consolidation ± daratumumab maintenance achieved similar PFS; longer follow up is needed for OS and PFS2. Compared with OBS, daratumumab maintenance significantly increased deeper response and MRD negativity rates, and it was well tolerated with no new safety signals.

Keyword(s): Multiple myeloma

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