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1411 Isatuximab Plus Pomalidomide and Dexamethasone in Frail Patients with Relapsed/Refractory Multiple Myeloma: Icaria-MM Subgroup Analysis

Program: Oral and Poster Abstracts
Session: 653. Myeloma/Amyloidosis: Therapy, excluding Transplantation: Poster I
Hematology Disease Topics & Pathways:
Adult, Biological, antibodies, Diseases, Elderly, Therapies, Combinations, Study Population, Myeloid Malignancies
Saturday, December 5, 2020, 7:00 AM-3:30 PM

Fredrik Schjesvold, MD, PhD1, Sara Bringhen, MD2, Paul G. Richardson, MD3, Aurore Perrot, MD, PhD4*, Xavier Leleu, MD5, Philippe Moreau6*, Meletios A. Dimopoulos, MD7, Cyrille Hulin, MD8*, Christina Tekle9*, Meredith Foster10*, Elizabeth M Poole11*, Helgi van de Velde, MD, PhD10 and Thierry Facon, MD12*

1Oslo Myeloma Center, Oslo University Hospital and KG Jebsen Center for B Cell Malignancies, University of Oslo, Oslo, Norway
2Myeloma Unit, Division of Hematology, University of Torino, Azienda-Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Torino, Italy
3Dana-Farber Cancer Institute, Boston, MA
4CHU de Toulouse, IUCT-O, Université de Toulouse, UPS, Service d’Hématologie, Toulouse, France
5CHU and CIC Inserm 1402, Service D'Hématologie Et Thérapie Cellulaire, Poitiers Cedex, France
6University of Nantes, Nantes, France
7Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
8Bordeaux University Hospital, Bordeaux, France
9Sanofi Oncology, Cambridge, MA
10Sanofi, Cambridge, MA
11Sanofi Genzyme, Global Medical Affairs, Cambridge, MA
12Bordeaux Hospital University Center (CHU), Lille, France

Introduction: Multiple myeloma (MM) is a neoplastic disease that typically affects elderly patients (pts), with a median age at diagnosis of 69 years. Elderly pts are a heterogeneous group with fitness ranging from very frail to remarkably fit. Frailty is a state of cumulative decline in many physiological systems, leading to a diminished resistance to stressors, such as cancer and its treatment. Isatuximab (Isa), a monoclonal CD38 antibody, is approved in combination with pomalidomide and dexamethasone (Pd) in the United States, the European Union, Canada, Australia, Switzerland, and Japan for the treatment of adult pts with relapsed/refractory MM (RRMM) who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor (PI). The Phase 3 ICARIA-MM study (NCT02990338) demonstrated the efficacy and safety of Isa-Pd in pts with RRMM. Progression-free survival (PFS) was significantly improved with Isa-Pd vs Pd, and in elderly pts ≥75 years it was 11.4 vs 4.5 months (HR 0.48; 95% CI 0.24–0.95). This post hoc analysis used a frailty score derived from pt baseline characteristics to investigate the impact of frailty on clinical outcomes and toxicity in pts receiving Isa-Pd vs those receiving Pd.

Methods: A total of 307 pts (154 Isa-Pd, 153 Pd), who had received ≥2 prior lines, including lenalidomide and a PI, were randomized. The Isa-Pd arm received Isa 10 mg/kg intravenously weekly for the first 4 weeks, then every 2 weeks thereafter. Both arms received recommended doses of Pd. Treatment continued until disease progression or unacceptable adverse events (AEs). Frailty scores at baseline were calculated based on age, modified Charlson Comorbidity Index ([CCI], calculated using the medical history recorded on physical examination at baseline), and Eastern Cooperative Oncology Group (ECOG) performance status. Pts with no medical history available were excluded from the analysis. Pts with frailty score sums of 0, 1, or ≥2 were classified as fit, intermediate, or frail, respectively.

Results: The overall ICARIA-MM population consisted of 28.0% frail (31.2% Isa-Pd vs 24.9% Pd) and 69.4% fit/intermediate pts (2.6% missing). At baseline, median (range) age in years in frail and fit/intermediate pts was 76 (56–83) vs 75 (55–86) and 65 (36–80) vs 64 (41–80) in Isa-Pd vs Pd, respectively. In frail and fit/intermediate pts, median PFS was 9.0 vs 4.5 months (HR 0.81; 95% CI 0.45–1.48; p=0.4928) and 12.7 vs 7.4 months (HR 0.49; 95% CI 0.33–0.73; p=0.0004) in Isa-Pd vs Pd, respectively (Figure A). Median overall survival (OS) was not reached (Figure B); the probability of OS at 12 months in frail and fit/intermediate pts was 66.9% (95% CI 0.51–0.79) vs 58.8% (95% CI 0.41–0.73) and 75.0% (95% CI 0.65–0.83) vs 64.5% (95% CI 0.54–0.73) in Isa-Pd vs Pd, respectively. The overall response rate in frail and fit/intermediate pts was 52.1% vs 34.2% (p=0.0476) and 66.3% vs 35.7% (p<0.0001) in Isa-Pd vs Pd, respectively. The ≥very good partial response rate in frail and fit/intermediate pts was 29.2% vs 2.6% (p=0.0013) and 34.7% vs 10.7% (p<0.0001) in Isa-Pd vs Pd, respectively. A longer treatment duration was observed for frail and fit/intermediate pts treated with Isa-Pd vs Pd, with a median (range) number of cycles started of 9.5 (1–18) vs 5.5 (1–17) and 10.0 (1–19) vs 6.0 (1–18) cycles, respectively. The median (range) duration of exposure for frail and fit/intermediate pts was 40.8 (1.3–75.1) vs 22.1 (1.6–69.0) and 41.6 (4.0–76.7) vs 24.0 (1.0–73.7) weeks, respectively. Among frail pts, Grade ≥3 and any Grade 5 treatment-emergent AEs (TEAEs) occurred in 91.7% and 10.4% pts, respectively, with Isa-Pd vs 80.6% and 11.1%, respectively, with Pd. Among frail pts treated with Isa-Pd, 8.3% and 41.7% discontinued treatment due to AEs and progressive disease, respectively, compared with 16.7% and 58.3% of patients treated with Pd. The most common TEAEs in frail patients treated with Isa-Pd and Pd, respectively, were neutropenia (50.0% vs 38.9%), diarrhea (33.3% vs 27.8%), infusion reactions (31.3 % vs 0%), upper respiratory tract infection (25.0% vs 8.3%), and bronchitis (27.1% vs 11.1%).

Conclusion: The tumor response, long-term treatment benefit and safety profile of frail pts treated with Isa-Pd are consistent with the overall ICARIA-MM study population and the elderly subgroup analysis. Fewer frail patients discontinued on Isa-Pd vs Pd, further supporting that frail pts with RRMM benefit from Isa-Pd therapy.

Disclosures: Schjesvold: Amgen, Celgene, Janssen, MSD, Novartis, Oncopeptides, Sanofi, Takeda: Consultancy; Celgene, Amgen, Janssen, Oncopeptides: Research Funding; Amgen, Celgene, Janssen, MSD, Novartis, Oncopeptides, Sanofi, SkyliteDX, Takeda: Honoraria. Bringhen: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria; Takeda: Consultancy. Richardson: Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. Perrot: Amgen, BMS/Celgene, Janssen, Sanofi, Takeda: Consultancy, Honoraria, Research Funding. Leleu: Janssen: Honoraria. Moreau: Abbvie: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Novartis: Honoraria; Takeda: Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Dimopoulos: Takeda: Honoraria; Amgen: Honoraria; Beigene: Honoraria; Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Hulin: AbbVie: Honoraria; Amgen: Honoraria; Celgene/Bristol-Myers Squibb, Janssen, GlaxoSmithKline, and Takeda: Consultancy, Honoraria; Janssen: Honoraria. Tekle: Sanofi: Current Employment. Foster: Sanofi Genzyme: Current Employment. Poole: Sanofi Genzyme: Current Employment. van de Velde: Sanofi: Current Employment, Current equity holder in publicly-traded company. Facon: Janssen, Takeda, Amgen, Roche, Karyopharm, Oncopeptides, BMS, Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

*signifies non-member of ASH