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.

Off Label 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

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2024
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