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

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.