Fredrik Schjesvold, MD, Ph.D. from Oslo Myeloma Center, Oslo University Hospital and KG Jebsen Center for B Cell Malignancies, University of Oslo, Oslo, Norway speaks about the ASH 2020 abstract - 1411 Isatuximab Plus Pomalidomide and Dexamethasone in Frail Patients with Relapsed/Refractory Multiple Myeloma: Icaria-MM Subgroup Analysis.
Multiple myeloma (MM) is a neoplastic disorder with a median age at diagnosis of 69 years that usually affects elderly patients (pts). Elderly pts are a heterogeneous group ranging from very delicate to exceptionally balanced with fitness. In many physiological processes, frailty is a condition of gradual deterioration, leading to reduced resistance to stressors, such as cancer and its treatment. Isatuximab (Isa), a monoclonal CD38 antibody, is approved in conjunction with pomalidomide and dexamethasone (Pd) for the treatment of adult relapsed/refractory MM pts (RRMM) who have undergone at least two prior therapies, including lenalidomide and a proteasome inhibitor, in the United States, the European Union, Canada, Australia, Switzerland, and Japan (PI). The ICARIA-MM Phase 3 (NCT02990338) analysis demonstrated the efficacy and protection of Isa-Pd in RRMM pts. With Isa-Pd vs Pd, progression-free survival (PFS) was greatly enhanced, and it was 11.4 vs 4.5 months (HR 0.48; 95 percent CI 0.24–0.95) in older pts ⁇ 75 years. To examine the influence of frailty on clinical outcomes and toxicity in pts receiving Isa-Pd vs. those receiving Pd, this post hoc study used a frailty score derived from pt baseline characteristics.
A total of 307 pts (154 Isa-Pd, 153 Pd) were randomized, receiving ~2 prior lines, including lenalidomide and a PI. For the first 4 weeks and then every 2 weeks thereafter the Isa-Pd arm received Isa 10 mg/kg intravenously regularly. Recommended doses of Pd were received by both arms. Therapy continued until the worsening of the disease or undesirable adverse events (AEs). Baseline frailty scores were calculated on the basis of age, updated Charlson Comorbidity Index ([CCI], calculated using the medical history reported on baseline physical examination), and performance status of the Eastern Cooperative Oncology Group (ECOG). Pts were omitted from the study with no available medical history. Pts were graded as fit, intermediate or weak, respectively, with frailty score sums of 0, 1, or ⁇ 2.
28.0 percent fragile (31.2 percent Isa-Pd vs 24.9 percent Pd) and 69.4 percent fit/intermediate pts were the total ICARIA-MM population (2.6 percent missing). At baseline, in Isa-Pd vs Pd, the 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). Median PFS was 9.0 vs 4.5 months (HR 0.81; 95 percent CI 0.45–1.48; p=0.4928) and 12.7 vs 7.4 months (HR 0.49; 95 percent CI 0.33–0.73; p=0.0004) in Isa-Pd vs Pd, respectively, in fragile and fit/intermediate pts (Figure A). Median overall survival (OS) was not achieved (Figure B); in weak and fit/intermediate pts, the likelihood of OS at 12 months was 66.9 percent (95 percent CI 0.51–0.79) vs 58.8 percent (95 percent CI 0.41–0.73) and 75.0 percent (95 percent CI 0.65–0.83) vs 64.5 percent (95 percent CI 0.54–0.73) in Isa-Pd vs Pd, respectively. In weak and fit/intermediate pts, the overall response rate was 52.1 percent vs 34.2 percent (p=0.0476) and 66.3 percent vs 35.7 percent (p<0.0001) in Isa-Pd vs Pd. In weak and fit/intermediate pts, the very strong partial answer rate was 29.2 percent vs 2.6 percent (p=0.0013) and 34.7 percent vs 10.7 percent (p<0.0001) in Isa-Pd vs Pd. For weak and fit/intermediate pts treated with Isa-Pd vs Pd, a longer treatment period was observed, with a median (range) a number of cycles beginning from 9.5 (1-18) vs 5.5 (1-17) and 10.0 (1-19) vs 6.0 (1-18) cycles, respectively. For fragile and fit/intermediate pts, the median (range) exposure period 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. Grade 3 and any Grade 5 treatment-emergent AEs (TEAEs) among frail pts occurred in 91.7 percent and 10.4 percent pts, with Isa-Pd vs 80.6 percent and 11.1 percent, with Pd, respectively. 8.3 percent and 41.7 percent discontinued care due to AEs and progressive disease among fragile pts treated with Isa-Pd, respectively compared with 16.7 percent and 58.3 percent of patients treated with Pd. Neutropenia (50.0 percent vs 38.9 percent), diarrhea (33.3 percent vs 27.8 percent), infusion reactions (31.3 percent vs 0 percent), upper respiratory tract infection (25.0 percent vs 8.3 percent), and bronchitis were the most common TEAEs in fragile Isa-Pd and Pd treated patients, respectively (27.1 percent vs 11.1 percent ).
The tumor response, long-term gain, and safety profile of fragile pts treated with Isa-Pd are consistent with the general population of the ICARIA-MM study and the elderly subgroup review. Fewer vulnerable patients have discontinued Isa-Pd versus Pd, further endorsing the value of Isa-Pd therapy for frail pts with RRMM.