Real-World Experience with Isatuximab in Patients with Relapsed and/or Refractory Multiple Myeloma (RRMM): Iona-MM Second Interim Analysis
Authors: Gaballa Mahmoud R. , Martin Thomas G , Tsukada Nobuhiro , Suzuki Kazuhito , Iriuchishima Hirono , Chalayer Emilie , Camus Vincent , Alcala Peña Maria Magdalena , Furlan Anna , Hubmann Max Christian Georg , Knauf Wolfgang Ulrich , Tekle Christina , Minasyan Ani , Qiu Chunfu , Beksac Meral 
Published: December 2024

Introduction
Isatuximab (Isa) is an anti-CD38 monoclonal antibody targeting a specific CD38 epitope and induces myeloma cell death via multiple mechanisms. Isa was approved in combination with pomalidomide and dexamethasone (Pd) and in combination with carfilzomib and dexamethasone (Kd) for relapsed/refractory multiple myeloma (RRMM) patients (pts), based on the Phase 3 ICARIA-MM and IKEMA trials, respectively. There is limited real-world evidence reported for the safety and efficacy of Isa-Pd and Isa-Kd. Here we present updated results from the second interim analysis of the multinational IONA-MM registry study of Isa treatment (tx) in the real-world setting.
Methods
IONA-MM is an ongoing, non-interventional, multinational, observational study of RRMM pts treated with Isa in a real-world setting. Pts with RRMM aged ≥18 years who received ≥1 prior tx line were prospectively and retrospectively enrolled (if exposed to Isa ≤3 months (mo) prior to study enrollment). Treating physicians determined Isa tx before and independent of enrollment. The Isa tx observation period began at Isa initiation; routine clinical assessments were collected 4 weeks after tx initiation and every 3 mo up to 30 days after tx discontinuation. Upon discontinuation, pts were followed up for a maximum of 6 mo. Primary outcome measures included overall response rate (ORR), very good partial response or better rate (≥VGPR), complete response or better rate (≥CR), duration of response (DOR), time to first response, progression-free survival (PFS), PFS rate, time to subsequent anti-MM therapy, quality of life, and adverse events (AEs). AEs and laboratory abnormalities were graded according to CTCAE v5.0.
Results
As of 31 December 2023 (patient inclusion cut-off), 408 pts were enrolled, received ≥1 dose of Isa in combination with Pd (n=230), Kd (n=156), or other Isa regimens (n=22), and had ≥1 post-baseline assessment. In this analysis, enrolled pts had a data cut-off of 31 March 2024. 35.2%/19.9% of Isa-Pd/Isa-Kd pts were aged ≥75 years, 15.9%/25.0% had high-risk cytogenetics [presence of del(17p), t(4;14) or t(14;16)], and 60.4%/51.9% were lenalidomide (len)-refractory. Pts in both Isa-Pd and Isa-Kd arms had a median of 2 prior lines of therapy, while those who received other Isa regimens had a median 4 prior lines of therapy. The median relative dose intensity of Isa in this real-world cohort was 78.3% and 76.1% in the Isa-Pd and Isa-Kd arms, respectively, and median time in study was 11.2 and 9.6 mo respectively at time of analysis. The ORR was 64.5% (111/172) in the Isa-Pd arm and 75.7% (84/111) in Isa-Kd arm, of which 39.0% and 47.7% had ≥VGPR. 15.1% and 18.9% of Isa-Pd and Isa-Kd pts had ≥CR. Pts who were len-refractory had an ORR of 61.7% and 72.1% in the Isa-Pd and Isa-Kd arms, respectively; of which ≥VGPR was 34.6% and 49.2% and ≥CR was 14.0% and 23.0%, respectively. The median DOR was 30.8 mo in Isa-Pd arm and had not been reached [not estimable (NE)] in the Isa-Kd arm. The median PFS was 20.4 (95% CI: 15.6-NE) mo with Isa-Pd and had not been reached [(95% CI: 15.7-NE) mo] with Isa-Kd. At month 30, 45.8% and 57.8% of pts in Isa-Pd and Isa-Kd arm, respectively, remained free of disease progression. In the safety population (N=429, of enrolled pts who received ≥1 dose of Isa), all-grade treatment-emergent AEs (TEAEs) occurred in 167/239 (69.9%) and 129/167 (77.2%) of Isa-Pd and Isa-Kd pts, respectively. Grade ≥3 TEAEs occurred in 119 (49.8%) and 71 (42.5%) pts. Infections and infestations of any grade occurred in 35.1% of Isa-Pd pts and 34.1% of Isa-Kd pts, of which 12.1% and 9.0% respectively were COVID-19, and 10.9% and 6.6% were pneumonia. All grade neutropenia occurred in 34.3% of Isa-Pd and 11.4% of Isa-Kd pts, while all grade infusion associated reactions occurred in 10.9% and 19.8% of pts respectively. TEAEs leading to definitive Isa discontinuation occurred in 12.1% (Isa-Pd) and 10.2% (Isa-Kd).
Conclusions
These results of the second interim analysis of the observational IONA-MM study indicate Isa-Kd has similar efficacy and safety in the real world to that observed in the IKEMA trial; median PFS of Isa-Pd was longer in IONA-MM vs the ICARIA-MM trial. The safety profile of Isa-Pd and Isa-Kd was manageable, in line with pivotal studies. These data support the use of Isa in combination with Pd and Kd in RRMM outside clinical trials and in wider populations including elderly and len-refractory pts.
Clinical trial registration: NCT04458831. Funding: Sanofi