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1976 Isatuximab, Bortezomib, Lenalidomide, and Dexamethasone (Isa-VRd) in Patients with Newly Diagnosed Multiple Myeloma (NDMM) Not Eligible or with No Immediate Intent for Transplant: Long-Term Efficacy and Safety in a Phase 1b Study

Program: Oral and Poster Abstracts
Session: 654. Multiple Myeloma: Pharmacologic Therapies: Poster I
Hematology Disease Topics & Pathways:
Research, Clinical trials, Combination therapy, Drug development, Clinical Research, Treatment Considerations, Biological therapies, Immunotherapy, Monoclonal Antibody Therapy
Saturday, December 7, 2024, 5:30 PM-7:30 PM

Enrique M Ocio, MD, PhD1*, Aurore Perrot, MD, PhD2, Pierre Bories, MD3*, Jesús F. San-Miguel, MD, PhD4, Lionel Karlin5*, Joaquin Martinez-Lopez, MD, PhD6*, Song-Yau Wang, MD7*, Sara Bringhen, MD, PhD8, Maria-Victoria Mateos, MD, PhD9, Paula Rodríguez-Otero, MD, PhD10*, Stefania Oliva, MD, PhD11*, Axel Nogai, MD12*, Bruno Paiva, PhD4*, Yi Li, PhD13*, Eric Le Bras, PhD14*, Sandrine Macé, PhD14*, Ercem Kodas, PhD14*, Helgi Van de Velde, MD, PhD15 and Philippe Moreau, MD, PhD16*

1Hospital Universitario Marqués de Valdecilla (IDIVAL), Universidad de Cantabria, Santander, Spain
2CHU de Toulouse, IUCT-O, Université de Toulouse, UPS, Service d’Hématologie, Toulouse, France
3Early Phase Unit, University Cancer Institute Toulouse Oncopole, Toulouse, France
4Clinica Universidad de Navarra (CCUN), Center for Applied Medical Research (CIMA), IDISNA, CIBER-ONC, Pamplona, Spain
5Hôpital Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite, France
6Department of Hematology, Hospital Universitario 12 de Octubre, CNIO, Universidad Complutense de Madrid, Madrid, Spain
7Department of Hematology and Oncology, University of Leipzig, Leipzig, Germany
8SSD Clinical Trials, Onco-Ematologia e Myeloma Multiplo, AOU Città della Salute e della Scienza di Torino, Torino, Italy
9University Hospital of Salamanca/IBSAL/Cancer Research Center-IBMCC (USAL-CSIC), Salamanca, Spain
10Department of Hematology, Centre for Applied Medical Research, Cancer Center Clinica Universidad de Navarra, University of Navarra, IdiSNA, CIBERONC, Pamplona, Spain
11Division of Hematology, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, University of Torino, Torino, Italy
12Charité Medical University, Berlin, Germany
13Sanofi, Bejing, China
14Sanofi, R&D, Vitry-sur-Seine, France
15Sanofi R&D, North America, Cambridge, MA
16Department of Hematology, Nantes University Hospital, Nantes, France

Introduction

The anti-CD38 antibody isatuximab (Isa) mediates anti-myeloma activity through multiple mechanisms of action and it is approved with carfilzomib-dexamethasone or pomalidomide-dexamethasone for the treatment of patients (pts) with relapsed and/or refractory MM. A multi-center Ph. 1b study (TCD13983; NCT02513186) showed preliminary efficacy of Isa in quadruplet combination with VRd followed by Isa-Rd maintenance therapy in pts with NDMM not eligible or with no immediate intent for autologous stem cell transplantation (ASCT), with a manageable safety profile (Ocio et al. Leukemia 2023;37:1521–29). In a prespecified interim analysis of the randomized, global Ph. 3 IMROZ study (NCT03319667), treatment with Isa-VRd followed by Isa-Rd demonstrated a significant progression-free survival (PFS) benefit (HR, 0.60; 98.5% CI, 0.41–0.88; p<0.001) and deep responses in transplant-ineligible NDMM pts compared with VRd followed by Rd (Facon et al. N Engl J Med 2024;June 3).

In this analysis, we evaluated long-term efficacy and safety of treatment with Isa-VRd followed by Isa-Rd in the overall Ph. 1b pt population and in the subgroups of pts ≥75 yrs of age or with no immediate intent for ASCT (noIInt-ASCT pts included in Part B of the study).

Methods

NDMM pts without age restriction received four 6-week cycles of Isa-VRd (Isa 10 mg/kg IV, bortezomib 1.3 mg/m2 SC, lenalidomide 25 mg PO, dexamethasone 20 mg IV/PO) followed by Isa-Rd maintenance in 4-week cycles. Primary study endpoint was complete response (CR).

The efficacy population included pts who had completed cycle 1 and received >2 weekly Isa administrations, with investigator-assessed response. MRD negativity was evaluated by central-laboratory next-generation sequencing (NGS) at 10-5 sensitivity in pts with ≥VGPR as best response at any point on study. PFS was analyzed with the Kaplan-Meier method. Adverse events (AEs) were graded by NCI-CTCAE v4.03.

Results

73 NDMM pts received Isa-VRd followed by Isa-Rd. Median age was 71.0 (range, 49–87) yrs, including 15 (20.5%) pts ≥75 yrs and 4 (5.5%) >80 yrs of age. Nine (12.3%) pts had a creatinine clearance ≥30 to <60 mL/min/1.73 m2. Thirteen (17.8%) noIInt-ASCT pts did not receive an ASCT in frontline (4/13 received an ASCT in 2nd line).

The overall response rate was 98.6% in all efficacy-evaluable pts (n=71), 100% in pts ≥75 yrs (n=14), and 100% in noIInt-ASCT pts (n=13), with ≥CR in 63.4%, 64.3%, and 53.8% of pts, respectively. Median PFS was not reached in the overall population nor in the noIInt-ASCT pt subgroup (data cutoff 3May23; median follow-up, 44.3 mo and 30.7 mo, respectively), and it was 51.9 mo in pts ≥75 yrs (median follow-up, 46.3 mo). Rates of PFS in all efficacy-evaluable pts (n=71) were 77.5% at 3 yrs and 71.9% at 5 yrs, 64.3% at 3 yrs and 48.2% at 5 yrs in pts ≥75 yrs (n=14), and 90.0% at 3 yrs in noIInt-ASCT pts (n=13), consistent with IMROZ Isa-VRd observations of 76.1% at 3 yrs and 63.2% at 5 yrs. MRD negativity by NGS (at 10-5 in pts with ≥VGPR) was achieved by 56.3% of pts overall (n=71), 57.1% of pts ≥75 yrs (n=14), and 30.8% of noIInt-ASCT pts (n=13).

34.2% of all pts, 33.3% of pts ≥75 yrs, and 30.7% of noll-ASCT pts were still on treatment, with a median duration of exposure of 41.5 mo (43.3 mo in pts ≥75 yrs; 16.5 mo in noIInt-ASCT pts). Grade ≥3 treatment-emergent AEs (TEAEs) were reported in 80.8% of all treated pts (n=73), 100% of pts ≥75 yrs (n=15), and 61.5% of noIInt-ASCT pts (n=13); serious TEAEs occurred in 58.9%, 80.0%, and 61.5% of pts, respectively. Grade ≥3 infections were observed in 26.0% of all treated pts, 40.0% of pts ≥75 yrs, and 23.1% of noIInt-ASCT pts (44.9% in IMROZ Isa-VRd, 38.1% in VRd pts). Treatment was well tolerated with definitive treatment discontinuations due to AE in 21.9% of all treated pts, 33% of pts ≥75 yrs, and 15.4% of noIInt-ASCT pts.

Conclusions

Our findings demonstrate long-term efficacy and safety of treatment with Isa-VRd followed by Isa-Rd maintenance in the overall population of NDMM pts without age restriction and in the subgroups of pts ≥75 yrs old or with no immediate intent for ASCT. The PFS results observed in this study are consistent with those reported in transplant-ineligible pts in the IMROZ trial, suggesting that the longer-term benefit with Isa-VRd extends to this broader population of pts with NDMM.

Clinical trial registration: NCT02513186. Funding: Sanofi.

Disclosures: Ocio: Menarini: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Johnson & Johnson - Janssen: Consultancy, Honoraria, Speakers Bureau; Regeneron: Honoraria; GSK: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria. Perrot: Sanofi: Honoraria, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Research Funding; Amgen: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Menarini Stemline: Honoraria. Bories: Kite/Gilead, Novartis: Other: Travel/accommodation expenses ; BMS Foundation, Janssen: Research Funding; AbbVie, BMS/Celgene, Kite/Gilead, Novartis, Servier: Honoraria. San-Miguel: Amgen: Consultancy, Other: Advisory Board ; Bristol Myers Squibb: Other: Advisory board; Celgene: Other: Advisory board; MSD: Other: Advisory board; GlaxoSmithKline: Other: Advisory board; Haemalogix: Other: Advisory board; Karyopharm: Other: Advisory board; Janssen-Cilag: Other: Advisory board; Regeneron: Other: Advisory board; Novartis: Other; Takeda: Other: Advisory board; Abbvie: Consultancy, Other: Advisory Board; Roche: Other: Advisory board; Sanofi: Other: Advisory board; SecuraBio: Other: Advisory board. Karlin: AbbVie, Amgen, Celgene, Janssen, Sanofi, Takeda: Honoraria; Amgen, Celgene, GSK, Janssen, and Takeda: Other: Advisory role. Martinez-Lopez: BMS/Celgene, Incyte, Janssen, Novartis, Roche, Sanofi: Consultancy, Honoraria; BMS, Janssen, Novartis, Roche, Sanofi: Other: Travel and accommodation support . Bringhen: Bristol Myers Squibb, Janssen, Oncopeptides, Pfizer, Stemline Therapeutics, and Takeda: Other: Participation in advisory boards; Sanofi: Consultancy, Honoraria; AbbVie, Amgen, Bristol Myers Squibb, GlaxoSmithKline, Janssen, and Sanofi: Speakers Bureau. Mateos: AbbVie, Amgen, Bluebird bio, Celgene, GlaxoSmithKline, Janssen, Kite, Oncopeptides, Pfizer, Regeneron, Roche, Sanofi, Stemline, and Takeda: Honoraria. Rodríguez-Otero: Johnson & Johnson - Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Amgen: Other: Honoraria for lectures; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Regeneron: Other: Honoraria for lectures; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures. Oliva: Amgen, Celgene/Bristol Myers Squibb, Janssen, Sanofi: Honoraria; Adaptive Biotechnologies, Amgen, Janssen, Pfizer, Sanofi, Takeda: Other: Participation in advisory boards. Nogai: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; Jannsen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Keiner: Current holder of stock options in a privately-held company; Amgen: Other: travel grants; Beigene: Other: travel grants. Paiva: Adaptive, Amgen, Becton Dickinson, Bristol Myers Squibb/Celgene, Janssen, Merck, Novartis, Roche, Sanofi and Takeda: Honoraria; Aztra Zeneca, Bristol Myers Squibb/Celgene, EngMab, Roche, Sanofi, and Takeda: Research Funding; Bristol Myers Squibb/Celgene, Janssen, Sanofi, and Takeda: Consultancy. Li: Sanofi: Current Employment, Current equity holder in publicly-traded company. Le Bras: Sanofi: Current Employment, Current equity holder in publicly-traded company. Macé: Sanofi: Current Employment, Current equity holder in publicly-traded company. Kodas: Sanofi: Current Employment. Van de Velde: Sanofi: Current Employment. Moreau: AbbVie, Amgen, Celgene, Janssen, Oncopeptides, Roche, Sanofi: Consultancy, Honoraria.

OffLabel Disclosure: Investigational use of the anti-CD38 monoclonal antibody isatuximab in combination with bortezomib, lenalidomide, and dexamethasone for the treatment of patients with newly diagnosed multiple myeloma

*signifies non-member of ASH