Hus, Marek

7516 Background: With the growing use of anti-CD38 therapies in early multiple myeloma (MM) management, there is a need for data in patients previously exposed to anti-CD38 therapy to guide decision making. In the Phase 3 IRAKLIA trial (NCT05405166), patients with relapsed/refractory MM (RRMM) received the anti-CD38 monoclonal antibody isatuximab (Isa) subcutaneously (SC) delivered via an innovative on-body injector (OBI) or intravenously (IV), with pomalidomide and dexamethasone (Pd). In this post hoc analysis, we examined outcomes in IRAKLIA patients with vs without prior anti-CD38 exposure. Methods: RRMM patients ≥18 years with ≥1 prior line of therapy including lenalidomide and a proteasome inhibitor were randomized to receive Isa SC (n=263) or IV (n=268) weekly in Cycle 1, then every 2 weeks, with Pd. Patients with prior anti-CD38 exposure <9 months (mos) before randomization or intolerance to anti-CD38 were excluded. Refractory patients were defined as those who failed to achieve minimal response on treatment or had progression within 60 days after last dose. Patients receiving Isa SC or IV were pooled. Results: Overall, 67 patients (12.6%) had prior anti-CD38 exposure with a median washout period of 20.2 mos, of which 26 (38.8%) were anti-CD38 refractory. Baseline characteristics were largely consistent between patients with or without prior anti-CD38 exposure; the median follow-up for the overall population was 12 mos. Patients with prior anti-CD38 exposure had an overall response rate (ORR) of 52.2%, 12-mo progression-free survival (PFS) rate of 40.6%, and median PFS of 8.5 mos. In patients without prior exposure, an ORR of 73.5%, 12-mo PFS of 68.8%, and non-estimable (NE) median PFS were reported. Anti-CD38 non-refractory vs refractory patients had an ORR of 48.8% vs 57.7%, 12-mo PFS of 38.9% vs 42.2%, and median PFS of 9.0 vs 7.5 mos. Patients with a longer washout period (>median of 20.2 mos) had an ORR of 63.6%, 12-mo PFS of 61.8% and NE median PFS, whereas patients whose prior anti-CD38 therapy ended more recently (≤median of 20.2 mos) had an ORR of 41.2%, 12-mo PFS of 19.2%, and median PFS of 6.7 mos. The safety profile of Isa + Pd was similar in patients with vs without prior anti-CD38 exposure. Conclusions: Isa + Pd demonstrated clinical benefit across anti-CD38–naïve, anti-CD38–exposed, and anti-CD38–refractory patients. A washout period >median of 20.2 mos resulted in outcomes comparable to those in anti-CD38–naïve patients, and outcomes were consistent between anti-CD38–exposed and anti-CD38–refractory patients after a >9-mo washout period. Efficacy of Isa + Pd in patients with prior anti-CD38 exposure from the IRAKLIA trial presents an opportunity to address an unmet need in a difficult-to-treat patient population. Clinical trial information: NCT05405166 .

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, &gt;65–≤85kg, &gt;85kg) which was a stratification factor, and extreme BW (≤50kg, &gt;50–≤100kg, &gt;100kg). Results: Number of pts per BW group were: ≤50kg [OBI n=16, IV n=14], ≤65kg [OBI n=84, IV n=85], &gt;65–≤85kg [OBI n=117, IV n=118], &gt;85kg [OBI n=62, IV n=65], and &gt;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 &gt;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 &lt;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 &gt;1: ≤65kg (1.628 [1.294–2.048]), &gt;65–≤85kg (1.303 [1.089–1.560]) and &gt;85kg (1.006 [0.817–1.239]). IsaOBI ORRs were comparable to IV across BW: ≤65kg, 66% vs 71% (relative risk [RR]: 0.928), &gt;65–≤85kg, 70% vs 70% (RR: 1.009), and &gt;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 &gt;50–≤100kg [72(66–78)% vs 70(63–76)%] but lower [68% vs 86%] in &gt;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 &gt;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 &gt;50–≤100kg groups. Treatment discontinuation rates for all drugs with IsaOBI vs IV were 14% vs 6% (≤65kg), 8% vs 10% (&gt;65–≤85kg), and 2% vs 10% (&gt;85kg). Similar incidence of Gr≥3 laboratory (lab) neutropenia was observed across BW in IsaOBI: 86.9% (≤65kg), 83.5% (&gt;65–≤85kg) and 83.9% (&gt;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 Background: Systemic mastocytosis (SM) comprises a spectrum of subtypes characterized by neoplastic mast cell (MC) infiltration of tissues and release of MC mediators. Non-advanced SM (NonAdvSM), including indolent SM (ISM), smoldering SM (SSM), and bone marrow mastocytosis (BMM) subtypes, is the most prevalent form of SM. NonAdvSM can be associated with debilitating symptomology which can significantly impair quality of life. The gain-of-function somatic KIT c.2447 C&gt;T (p.D816V) mutation is found in up to 95% of patients with SM. Bezuclastinib (CGT9486) is an oral, potent, and selective type 1 tyrosine kinase inhibitor with activity against KIT D816V. Results from Summit (NCT05186753) Part 1 informed the recommended phase 2 dose (100 mg QD bezuclastinib) for Part 2. We report topline results from the 24-week assessment of Summit Part 2. Methods: Summit is a multi-center, randomized, double-blind, placebo (PBO)-controlled Phase 2 trial of bezuclastinib in patients with NonAdvSM who had inadequate symptom control despite best supportive care (BSC) medications. The primary endpoint was 24-week mean change from baseline in Mastocytosis Symptom Severity Daily Diary (MS2D2) total symptom score (TSS) (range 0–110), which is a fit-for-purpose patient-reported outcome measure of NonAdvSM symptom severity. Key secondary endpoints included the proportion of patients with ≥50% reduction in serum tryptase, KIT p.D816V variant allele frequency (VAF), bone marrow (BM) MC burden, and MS2D2 TSS, ≥30% TSS reduction. Patients were randomized 2:1 to receive 100mg QD bezuclastinib + BSC or PBO + BSC. Results: As of May 22, 2025, 179 patients were enrolled in Part 2: 119 were randomized to receive bezuclastinib and 60 to placebo. Patients enrolled were representative of the NonAdvSM population with moderate to severe symptoms. Median age (range) was 51 (23-78) years; 65.9% female; mean (SD) baseline MS2D2 TSS 55.6 (19.8); 82% of patients had ISM, 11% had BMM, and 7% had smoldering SSM. At baseline, median (range) KIT p.D816V VAF in whole blood, BM MC burden, and serum tryptase was 0.25% (0-34%), 10% (1-75%), and 40 (6-692) ng/mL, respectively. Bezuclastinib demonstrated statistically significant superiority to placebo on all primary and key secondary endpoints. At Week 24, bezuclastinib led to significantly greater symptom improvement vs placebo (LS mean [95% CI] MS2D2 TSS change: –24.3 [–27.6 to –21.1] vs –15.4 [–19.6 to –11.2]; placebo-adjusted difference: –8.9 points; P=0.0002). A ≥50% reduction in serum tryptase was achieved in 87.4% of bezuclastinib-treated patients vs 0% on placebo (P&lt;0.0001). Significantly more patients receiving bezuclastinib achieved ≥50% reductions in KIT D816V VAF, serum tryptase, BM MCs (P&lt;0.0001), MS2D2 TSS (P=0.01), and ≥30% reduction in MS2D2 TSS (P=0.0004). Most treatment-emergent adverse events (TEAEs) were low grade (gr; 70% Gr 1) and reversible. The most common TEAEs (≥10%) in any treatment group and occurring in greater frequency in the bezuclastinib arm were hair color changes (69.5% vs 5.0%), altered taste (23.7% vs 0%), nausea (22.0% vs 13.3%), increased ALT/AST (22.0% vs 6.6%), headache (17.8% vs 11.7%), alopecia (11.9% vs 3.3%), and increased ALP (10.2% vs 3.3%). TEAEs (≥10%) that occurred more often in the placebo group were diarrhea (13% vs 18%), dizziness (10% vs 12%), fatigue (7% vs 12%), and arthralgia (6% vs 15%). ALT/AST elevations ≥Gr 3 were experienced by 5.9% of patients. The only hepatic adverse events (AEs) reported were transient lab abnormalities; none required hospitalization. Treatment-related AEs requiring dose reductions occurred in 11% of patients receiving bezuclastinib. All discontinuations (5.9%) due to treatment-related AEs were due to transaminase elevations; all fully resolved. Conclusions: At 24-weeks, bezuclastinib 100 mg QD demonstrated statistically and clinically significant improvements in symptom burden and biomarkers of disease vs placebo in patients with NonAdvSM. The treatment was generally well-tolerated and effective across a population that is representative of the real-world NonAdvSM population, including SSM. These results support the use of bezuclastinib to reduce SM burden and symptoms in pts with NonAdvSM, and a potentially disease-modifying impact.

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.

7046 Background: Momelotinib (MMB) is a potent JAK1, JAK2 and ACVR1 inhibitor with clinical activity against the hallmark features of myelofibrosis (MF), namely anemia, constitutional symptoms and splenomegaly, across the continuum of JAKi naïve or previously JAKi treated intermediate/high risk MF patients as demonstrated in the previously conducted Phase 3 SIMPLIFY-1 & -2 clinical trials (S1, S2). S1 enrolled JAKi-naïve patients with MF (n = 432) double-blind randomized 1:1 to MMB or ruxolitinib (RUX). S2 enrolled patients with MF with hematological toxicity during prior RUX therapy (n = 156) randomized 2:1 to open-label MMB or best available therapy (BAT; consisting of RUX in 88% of patients). In both trials, following the 24-week randomized treatment (RT) period, patients could continue MMB (MMB→MMB) and those randomized to RUX/BAT could cross-over to MMB (RUX/BAT→MMB) for extended treatment (ET). Previously published data from the SIMPLIFY studies demonstrate robust overall survival (OS) for MMB-treated patients in S1 and S2 (median not reached and 34.3 months, respectively) with a maximum follow up of approximately 5 years and median of 2.9 years in S1 and 2.3 years in S2. Methods: OS data for patients receiving MMB in S1 and S2 are reported here for subgroups defined by Week 24 (W24) transfusion independence (TI) responders vs non-responders, and also other efficacy endpoints. Survival was estimated using KM analysis with descriptive log-rank tests for comparison applied (all p-values are descriptive). Results: As previously reported, W24 TI rates were higher in the MMB arms of S1 (67% vs 49%) and S2 (43% vs 21%). In S1, W24 TI responders in the MMB group show an OS advantage, with median OS not reached and 3-year survival of 80% (HR = 0.30; p = 0.0001) compared to MMB TI non-responders. Similarly in S2, W24 TI responders in the MMB group show a trend toward better OS compared to TI non-responders (HR = 0.57; p = 0.0652). The HRs in S1 for MMB responders vs non-responders for W24 SRR and TSS were 0.59 (p = 0.0904) and 0.65 (p = 0.1657), respectively. Alternative analyses using OS defined from W24 demonstrated consistent results. Conclusions: These new analyses suggest JAKi naïve patients receiving MMB who maintain or achieve TI at W24 have favorable OS compared to MMB TI non-responders, with a similar trend observed in S2. These findings are consistent with anemia and transfusion dependency being key predictors of shortened OS in MF and suggest that TI response at W24 may become a surrogate for clinical benefit, supporting the clinical relevance of MMB’s differentiated pro-erythropoietic ACVR1 inhibition. Clinical trial information: NCT01969838.