Citations

Abstract Introduction: IRAKLIA is an international, open-label, non-inferiority (NI) trial (NCT05405166) investigating isatuximab (Isa) subcutaneous (SC) vs intravenous (IV) administration, plus pomalidomide-dexamethasone (Pd) and the first Phase 3 multiple myeloma (MM) trial using an on-body injector (OBI). IRAKLIA demonstrated NI in its co-primary endpoints: overall response rate (ORR) and steady state trough concentration (Ctrough; Cycle(C) 6 Day(D) 1 predose). IsaOBI offers hands-free administration of flat-dose Isa, a small, hidden, retractable needle to prevent sharps injury and low-pressure delivery. Here, we examine the effect of body weight (BW) on pharmacokinetics (PK) as well as efficacy and safety outcomes with flat-dose IsaOBI vs IV + Pd in IRAKLIA. Methods: Patients (pts) with relapsed/refractory MM ≥18 years (yr) with ≥1 prior line of therapy (LOT) were randomized 1:1 to IsaOBI (1400mg; n=263) or IV (10mg/kg; n=264 weekly in C1, then every 2 weeks + P (4mg/day, D1–21) + d (40mg [20mg if ≥75yr] weekly) in 4-week cycles. This analysis is run by BW (≤65kg, >65–≤85kg, >85kg) which was a stratification factor, and extreme BW (≤50kg, >50–≤100kg, >100kg). Results: Number of pts per BW group were: ≤50kg [OBI n=16, IV n=14], ≤65kg [OBI n=84, IV n=85], >65–≤85kg [OBI n=117, IV n=118], >85kg [OBI n=62, IV n=65], and >100kg [OBI n=22, IV n=22]. Baseline (BL) demographic and disease characteristics were generally balanced across BW groups for IsaOBI vs IV, including age (median 66yr) and prior LOT (median 2). However, in the >100kg group, more IsaOBI vs IV pts exhibited poor prognostic characteristics including plasmacytoma, International Staging System Stage II/III disease, beta 2-microglobulin level ≥5.5mg/L, estimated glomerular filtration rate <60mL/min/1.73m2 and a lower very good partial response (VGPR) rate as best overall response at last regimen. Flat-dose IsaOBI showed adequate exposure (C2D1 Ctrough) for all BW groups, with geometric mean ratios (90% CI) vs IV >1: ≤65kg (1.628 [1.294–2.048]), >65–≤85kg (1.303 [1.089–1.560]) and >85kg (1.006 [0.817–1.239]). IsaOBI ORRs were comparable to IV across BW: ≤65kg, 66% vs 71% (relative risk [RR]: 0.928), >65–≤85kg, 70% vs 70% (RR: 1.009), and >85kg, 81% vs 72% (RR: 1.115). For extreme BW groups, ORRs (95% CI) were similar between IsaOBI and IV for ≤50kg group [56% vs 60%] and for >50–≤100kg [72(66–78)% vs 70(63–76)%] but lower [68% vs 86%] in >100kg group. An exposure-response (E-R) analysis showed the impact of BW on response: IsaOBI pts ≤50kg tended to respond less vs IsaOBI pts >50kg despite correct exposure because they were confounded by BL disease characteristicsincluding a higher proportion of high-risk cytogenetics and plasma cells in the bone marrow vs other BW group pts. For IsaOBI and IV, Grade (Gr)≥3 treatment-emergent adverse events (TEAEs) and Gr≥3 treatment-related TEAEs decreased with increasing BW. They were similar between arms in ≤65kg group (OBI vs IV, Gr≥3 TEAEs: 87% vs 88%; Gr≥3 treatment-related TEAEs: 73% vs 77%). A similar trend was observed in extreme BW groups along with similar incidences between arms in ≤50kg group. While TE serious AEs (TESAEs) and treatment-related TESAEs decreased with increasing BW for IsaIV, incidence was stable in the IsaOBI arm. OBI arm OBI Gr5 TEAEs were similar between groups and arms, except for higher incidence in ≤65kg group (12% vs 5%) with OBI vs IV that was not reflected in ≤50 or >50–≤100kg groups. Treatment discontinuation rates for all drugs with IsaOBI vs IV were 14% vs 6% (≤65kg), 8% vs 10% (>65–≤85kg), and 2% vs 10% (>85kg). Similar incidence of Gr≥3 laboratory (lab) neutropenia was observed across BW in IsaOBI: 86.9% (≤65kg), 83.5% (>65–≤85kg) and 83.9% (>85kg). Higher rates of Gr≥3 lab neutropenia were observed in ≤50kg group (93.8%, IsaOBI vs 71.4%, IsaIV), which did not translate into higher rates of neutropenic complications (18.8% vs 14.3%). The E-R analysis revealed no relationship between Isa PK exposure and safety for OBI and IV arms. Conclusions: No notable impact from IsaOBI flat dosing was observed across BW groups. Flat-dose Isa OBI showed consistent safety and efficacy across different BW groups, with differences likely linked to BL disease characteristics according to the E-R analysis. The IsaOBI C2D1 Ctrough, a time-independent predictor of efficacy, was similar to, or higher vs IsaIV in each BW group, supportive of a flat dose providing adequate exposure without need for adjustment.

Abstract Introduction: IRAKLIA (NCT05405166) is an ongoing, global, non-inferiority trial of isatuximab (Isa) subcutaneous (SC) administration plus pomalidomide-dexamethasone (Pd), and the first Phase 3 multiple myeloma (MM) trial using an on-body injector (OBI) for SC administration. In IRAKLIA, Isa SC OBI demonstrated non-inferiority in the 2 co-primary endpoints of efficacy and pharmacokinetics compared with Isa intravenous (IV). Significantly more patients expressed higher satisfaction with Isa SC OBI vs Isa IV in IRAKLIA, and more patients and health care providers (HCPs) preferred Isa SC OBI over Isa SC manual push in the Phase 2 IZALCO trial (NCT05704049). The Isa OBI is a wearable, automated injector that adheres to the skin of the abdomen and administers Isa SC with the push of a button without any batteries or electronics. The Isa SC OBI offers hands-free administration; a small, hidden, retractable needle to prevent sharps injury and reduce patient anxiety; low-pressure delivery; a simplified user interface; and flexible administration in either outpatient or home settings. Here, we examine the safety of Isa SC OBI administered by trained nursing professionals during at-home patient visits in IRAKLIA. Methods In IRAKLIA, patients with relapsed/refractory MM (RRMM) aged ≥18 years with ≥1 prior line of therapy (LOT) were randomized 1:1 to Isa SC OBI (1400 mg; n=263) or IV (10 mg/kg; n=264) weekly in Cycle (C)1, then every 2 weeks + P (4 mg/day, Day [D]1–21) + d (40 mg [20 mg if age ≥75 years] weekly) in 4-week cycles. Home administration by a HCP was proposed as an option after 5 cycles for Isa OBI arm patients on D15 from C6 onward, and D1 visits from C6 remained clinic based. Eligibility for home-administration depended on an absence of infusion reactions (IRs) at C4 and C5, hematology test results at D1 of each cycle, investigator judgement, and patient willingness. During at-home visits, providers prepared and applied Isa SC OBI and safely disposed of the device upon completion. Following at-home administration, providers evaluated the injection site for reactions, took vitals, and completed documentation. No specific monitoring was planned after the end of injections. At-home administration was not allowed in some countries due to local regulations. Results In the ongoing IRAKLIA trial, 202 patients were treated with Isa SC OBI within countries where at-home administration was permissible. 11 (5.4%) of these patients from 5 different countries [Australia (n=6), Hungary (n=2), Italy (n=1), Norway (n=1), and Spain (n=1)] have participated in home administration as of the cutoff date (06-Nov-2024), with additional sites and countries initiated after the cutoff date. First at home administrations started at Cycle 6 for the majority of patients (n =7) and at Cycle 7 (n =1), Cycle 8 (n =2), and Cycle 10 (n =1) for the remaining patients. Among the 11 patients participating in at-home visits, more than half switched to at-home administration and have not returned to the hospital for their next Day 15 cycle visit. 55 injections were performed at home. The median injection duration was the same between clinic and at-home administration (13 minutes). Similar to Isa SC OBI use in the clinic, home administration was well tolerated with no new safety signals and a 100% completed injection rate. No at-home Isa OBI administration was omitted or interrupted during the injection. At-home administration had a very low rate of injection-site reactions (ISR; n=1). The single ISR was a Grade 1 episode consisting of injection swelling, which resolved within the same day, and most subsequent Day 15 administrations were performed at home for this patient. No other adverse events (AEs), including no IRs, were linked to at-home visits. No device event linked to at-home visits was reported. Conclusions Initial data from the ongoing IRAKLIA trial support the safety of at-home administration of Isa SC OBI for the treatment of patients with MM. Home administration was well tolerated, with no safety concerns and a median injection time of 13 minutes consistent with in-clinic use of Isa SC OBI. The option of either home or outpatient administration of Isa SC OBI for patients with MM allows for greater flexibility and accessibility of treatment, with the potential to improve patient care and reduce common barriers to patient retention and therapy compliance.

PURPOSE To report the results of the multicenter, open-label IRAKLIA trial (ClinicalTrials.gov identifier: NCT05405166 ) of isatuximab subcutaneous (SC) versus intravenous (IV), plus pomalidomide and dexamethasone, in relapsed/refractory multiple myeloma (MM), to our knowledge, the first phase III MM trial using an on-body injector (OBI). METHODS Patients with ≥1 prior line of therapy were randomly assigned 1:1 to Isa OBI (1,400 mg) or IV (10 mg/kg) once weekly in cycle (C)1 and then every 2 weeks, plus pomalidomide (4 mg once daily, day [D]1-21) and dexamethasone (40 mg once weekly [age ≥75: 20 mg]) and treated until progression, unacceptable toxicity, or patient request. Coprimary end points were overall response rate (ORR; noninferiority margin, 0.839) and Isa C trough (C6D1 predose; noninferiority margin, 0.8). Noninferiority of OBI versus IV was demonstrated if both coprimary end points achieved noninferiority. RESULTS IRAKLIA randomly assigned 531 patients (OBI, n=263; IV, n=268). After 12-month median follow-up, the ORR was 71.1% (OBI) and 70.5% (IV; relative risk, 1.008 [95% CI, 0.903 to 1.126]; lower CI exceeded noninferiority margin). The mean (standard deviation) C6D1 C trough was 499 (259) μg/mL (OBI) and 340 (169) μg/mL (IV). The C trough geometric mean ratio (90% CI) was 1.532 (1.316 to 1.784); lower CI exceeded noninferiority margin. Grade ≥3 treatment-emergent adverse event incidences were 81.7% (OBI) and 76.1% (IV); infusion reaction incidences were 1.5% and 25.0%. Injection site reactions occurred in 0.4% of OBI injections (all grade 1-2); 99.9% of injections completed without interruption. CONCLUSION IRAKLIA demonstrated efficacy and pharmacokinetic noninferiority between Isa OBI and IV. No unexpected safety signal was observed, with excellent local tolerability of Isa OBI. Efficacy and safety were comparable with Isa IV in ICARIA-MM, except the lower OBI infusion reaction rate. These results support potential use of the OBI, designed to improve practice efficiency.

7506 Background: IV Isa-Pd is approved to treat RRMM patients (pts) based on the ICARIA-MM study. A Phase 1b study showed safety and efficacy of Isa SC via an OBDS, an investigational wearable bolus injector, plus Pd, in RRMM pts. Isa SC offers shorter duration, fixed dose and smaller administration volume. Here, we report results of the IRAKLIA trial (NCT05405166); Isa SC vs IV + Pd in RRMM pts, the first Phase 3 myeloma trial reporting the use of an OBDS. Methods: This multicenter, open-label study enrolled pts aged ≥18 years with ≥1 prior line of therapy (LOT). Pts were randomized 1:1 to Isa SC (1400 mg) or Isa IV (10 mg/kg) weekly in Cycle (C)1, then every 2 weeks + P (4 mg/day, Day [D]1–21) + d (40 mg [20 mg if age ≥75 years] weekly). Pts had 4-week cycles until progression, unacceptable toxicity or patient request. Co-primary endpoints were overall response rate (ORR; non-inferiority [NI] margin of 0.839) and Isa trough level (C trough ) at steady state (predose at C6D1; NI if lower limit of 90% CI of geometric mean ratio ≥0.8). Results: 531 pts (SC n=263; IV n=268 [4 not treated]) were randomized. Baseline characteristics were balanced (median age 66 years; median 2 prior LOT). After median 12 months follow-up, ORR was 71% (SC arm) and 71% (IV arm; relative risk [95% CI] = 1.008 [0.903–1.126]; lower CI > NI margin). Mean (SD) C trough at C6D1 was 499 (259) μg/mL for SC and 340 (169) μg/mL for IV. C trough geometric mean ratio (90% CI) was 1.532 (1.316–1.784); lower CI > NI margin. Co-primary and all 4 key secondary endpoints including pt experience are in the Table. Grade ≥3 treatment-emergent adverse events occurred in 82% (SC) and 76% (IV) of pts; with treatment discontinuation rates of 8% and 9%. Injection site reactions (ISRs) occurred in 4% (11/263) of the SC arm and in 19 (0.4%) of 5145 SC injections (all Grade 1–2). 99.9% of OBDS injections were completed without interruption. Conclusions: IRAKLIA met its co-primary endpoints, showing efficacy and pharmacokinetic NI between Isa SC vs IV + Pd. No new safety signal besides a low ISR incidence was observed, showing excellent Isa SC tolerability. Far fewer infusion reactions and higher pt satisfaction were also noted for SC vs IV. Efficacy and safety are comparable to Isa IV in ICARIA-MM. These results support potential use of Isa SC delivered via the OBDS, designed to improve pt experience and practice efficiency. Clinical trial information: NCT05405166 . Isa SC + Pd Isa IV + Pd Efficacy, % N=263 N=268 ORR 71 71 ≥VGPR 46 46 PK*, µg/mL N=131/121 N=126/121 Geometric mean Isa C trough at C2D1 / C6D1 360/426 277/278 Safety, % N=263 N=264 All grade IR 2 25 Pt satisfaction with injection method at C5D15, % 70 53 *PK was analyzed at C6D1 with PP PK population and at C2D1 with PP CT4W population. CT4W, C trough at 4 weeks; IR, infusion reaction; PK, pharmacokinetics; PP, per protocol; VGPR, very good partial response.