Sustained minimal residual disease (sMRD) negativity in transplant ineligible newly diagnosed multiple myeloma treated with isatuximab plus lenalidomide and dexamethasone with bortezomib (Isa-VRd) versus isa-rd: 12-24-month data from the phase 3 bene

Abstract Introduction. Sustained minimal residual disease (sMRD) negativity has shown a stronger correlation with survival outcomes than MRD negativity at a single time point or at best response. We evaluated MRD negativity between 12 and 24 months in newly diagnosed multiple myeloma (NDMM) transplant-ineligible (TI) patients enrolled in the BENEFIT study. Methods. BENEFIT is a multicenter, phase 3 randomized trial comparing isatuximab-lenalidomide-dexamethasone with or without bortezomib (Isa-Rd ± V) in NDMM TI patients. In the Isa-VRd arm, bortezomib (V) was administered weekly for up to 18 months, dexamethasone was permanently discontinued after 12 months, and isatuximab-lenalidomide (Isa-R) was continued until progression. Data are presented in the intention-to-treat (ITT) population. Results.With a median follow-up of 33.4 months (95% CI, 33.0–34.0), 78 patients (29%) discontinued treatment, primarily due to progressive disease. At 24 months, the MRD negativity rate at 10⁻⁵ was significantly higher in the Isa-VRd arm (odds ratio [OR] 2.26; 95% CI, 1.35–3.79; p=0.002). Sustained MRD negativity at 10⁻⁵ was also more frequent in the Isa-VRd arm (OR 2.73; 95% CI, 1.50–4.80; p=0.0007). Similar results were observed for sMRD at the 10⁻⁶ threshold. Importantly, MRD negativity at both 10⁻⁵ and 10⁻⁶ was evaluated in the t(11;14) NDMM TI subgroup. In this subgroup, MRD negativity rates were consistently lower at all time points up to 24 months, consistent with recent observations from the MIDAS study. Due to the small number of patients per group, no subgroup-specific analysis was feasible. Larger cohorts are required to determine whether t(11;14) MM in TI patients achieves delayed or less frequent MRD negativity, potentially reflecting a MGUS-like phenotype. No new safety signals were observed in either treatment arm, including in high-risk multiple myeloma (HRMM) patients. Conclusion. The BENEFIT study continues to support the efficacy of the quadruplet Isa-VRd regimen in NDMM TI patients, notably through improved sustained MRD negativity rates. These data support Isa-VRd as a new standard of care (SOC) for NDMM TI patients aged 65–79 years, including those with HRMM. ClinicalTrials.gov Identifier: NCT04751877

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Journal
Blood
Published
2025-11-03
DOI
https://doi.org/10.1182/blood-2025-368
Primary Topic
Multiple Myeloma Research and Treatments
Type
article
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article

Sustained minimal residual disease (sMRD) negativity in transplant ineligible newly diagnosed multiple myeloma treated with isatuximab plus lenalidomide and dexamethasone with bortezomib (Isa-VRd) versus isa-rd: 12-24-month data from the phase 3 bene

Karim Belhadj Merzoug, Anaïs Schavgoulidze, Stéphanie Harel, Kamel Laribi et al.
Blood
Multiple Myeloma Research and Treatments
article

Sustained minimal residual disease (sMRD) negativity in transplant ineligible newly diagnosed multiple myeloma treated with isatuximab plus lenalidomide and dexamethasone with bortezomib (Isa-VRd) versus isa-rd: 12-24-month data from the phase 3 bene

Karim Belhadj Merzoug, Anaïs Schavgoulidze, Stéphanie Harel, Kamel Laribi, Bertrand Arnulf, Ronan Le Calloch, Mohamad Mohty, Thierry T.F. Facon, Lionel Karlin, Jill Corre, Murielle Roussel, Salomon Manier, C. Dingremont, M. Macro, Claire Calmettes, Jérôme Lambert, Philippe Moreau, Xavier P Leleu, Clara Mariette, Cyrille Touzeau, Valentine Richez, Arthur Bobin, Pascal Godmer, Laure Vincent, Bruno Royer, Aurore Perrot, Sophie Rigaudeau, Hélène Gardeney, Christophe Roul, Cyrille Hulin, Émilie Chalayer, Laurent Frenzel, Jacques Delaunay, Noémie Bigot, Jean Pierre Marolleau, Olivier Decaux, Mamoun Dib, Mourad Tiab
article en

Abstract

Abstract Introduction. Sustained minimal residual disease (sMRD) negativity has shown a stronger correlation with survival outcomes than MRD negativity at a single time point or at best response. We evaluated MRD negativity between 12 and 24 months in newly diagnosed multiple myeloma (NDMM) transplant-ineligible (TI) patients enrolled in the BENEFIT study. Methods. BENEFIT is a multicenter, phase 3 randomized trial comparing isatuximab-lenalidomide-dexamethasone with or without bortezomib (Isa-Rd ± V) in NDMM TI patients. In the Isa-VRd arm, bortezomib (V) was administered weekly for up to 18 months, dexamethasone was permanently discontinued after 12 months, and isatuximab-lenalidomide (Isa-R) was continued until progression. Data are presented in the intention-to-treat (ITT) population. Results.With a median follow-up of 33.4 months (95% CI, 33.0–34.0), 78 patients (29%) discontinued treatment, primarily due to progressive disease. At 24 months, the MRD negativity rate at 10⁻⁵ was significantly higher in the Isa-VRd arm (odds ratio [OR] 2.26; 95% CI, 1.35–3.79; p=0.002). Sustained MRD negativity at 10⁻⁵ was also more frequent in the Isa-VRd arm (OR 2.73; 95% CI, 1.50–4.80; p=0.0007). Similar results were observed for sMRD at the 10⁻⁶ threshold. Importantly, MRD negativity at both 10⁻⁵ and 10⁻⁶ was evaluated in the t(11;14) NDMM TI subgroup. In this subgroup, MRD negativity rates were consistently lower at all time points up to 24 months, consistent with recent observations from the MIDAS study. Due to the small number of patients per group, no subgroup-specific analysis was feasible. Larger cohorts are required to determine whether t(11;14) MM in TI patients achieves delayed or less frequent MRD negativity, potentially reflecting a MGUS-like phenotype. No new safety signals were observed in either treatment arm, including in high-risk multiple myeloma (HRMM) patients. Conclusion. The BENEFIT study continues to support the efficacy of the quadruplet Isa-VRd regimen in NDMM TI patients, notably through improved sustained MRD negativity rates. These data support Isa-VRd as a new standard of care (SOC) for NDMM TI patients aged 65–79 years, including those with HRMM. ClinicalTrials.gov Identifier: NCT04751877

BloodVol. 146(Supplement 1)
École Nationale d'Ingénieurs de Tarbes (FR), Sciences Po Bordeaux (FR), Université de Bordeaux (FR), Université de Montpellier (FR), Université Côte d'Azur (FR), Université de Lille (FR), Agricultural University of Havana (CU), Centre Hospitalier Universitaire de Lille (FR), Université Rennes 2 (FR), Université de Poitiers (FR), Communauté urbaine de Lyon (FR), Centre Hospitalier Universitaire Amiens-Picardie (FR), Institut universitaire du cancer de Toulouse Oncopole (FR), Laboratoire de Physique Corpusculaire de Caen (FR), Centre hospitalier Bretagne Atlantique (FR), Centre Hospitalier Universitaire de Poitiers (FR), Centre Hospitalier Universitaire de Caen Normandie (FR), Centre Hospitalier de Cornouaille (FR), École Nationale Supérieure d'Architecture de Versailles (FR), Centre Hospitalier du Mans (FR), Centre Pour La Recherche Economique et ses Applications (FR), Académie de Versailles (FR), Centre d'Investigation Clinique de Nantes (FR), Montpellier Business School (FR), Hôpital privé du Confluent (FR), Centre Hospitalier de La Rochelle (FR), Excelia Business School (FR), Hôpital Saint Roch (FR), Centre Hospitalier Départemental Vendée (FR), Services déconcentrés d'appui à la recherche Occitanie-Montpellier (FR), Centre Hospitalier Universitaire de Saint-Étienne (FR), Institut Lavoisier de Versailles (FR), Université d'Angers (FR), Université de Rennes (FR), Université de Limoges (FR), La Rochelle Université (FR), Université de Caen Normandie (FR)
Openalex Percentile: Top 46%
Multiple Myeloma Research and Treatments
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