Citations

7563 Background: Subcutaneous (SC) drug delivery options have become more widely available in multiple myeloma (MM). SC delivery of isatuximab (Isa), an anti-CD38 monoclonal antibody, has been investigated across clinical trials via a novel hands-free on-body injector (OBI). Isa SC OBI features a small, retractable needle, establishing the first device-enabled delivery of an oncologic treatment. The Phase 3 IRAKLIA, Phase 2 IZALCO, and Phase 1b (TCD15484) trials consistently demonstrated similar efficacy and safety of Isa SC OBI vs Isa IV in relapsed/refractory MM (RRMM) patients (pts). Here, we present a cross-trial analysis exploring safety and reliability of Isa SC OBI in RRMM pts. Methods: Pts with RRMM in IRAKLIA (N=263) and the Phase 1b expansion cohort (N=22) received 1400 mg Isa SC OBI plus pomalidomide and dexamethasone (d). In IZALCO, RRMM pts (N=64) received 1400 mg Isa SC OBI + carfilzomib (K)-d. Pts were monitored for 4 hrs (IRAKLIA) or 1-2 hrs (IZALCO) following first administration and for 1 hr for the following cycle (C) 1 administrations to assess local tolerability. Pre-infusion medications included montelukast (C1), steroids, acetaminophen and H1 antihistamines. Pts without systemic infusion-related reactions (IRRs) after 4 consecutive administrations of Isa SC OBI had subsequent pre-medication reassessed at investigator’s discretion. Safety and device performance explored in this cross-trial analysis of company sponsored studies were assessed in the Isa SC OBI cohorts by the duration of injection, IRRs, local injection-site reactions (ISRs), and injection/device success, which were defined similarly across all trials. Results: The median duration of Isa SC OBI injection was 13 mins in IRAKLIA, 12 mins in IZALCO, and 10 mins in the Phase 1b trial (6426 total injections, N=349 pts). IRRs across trials occurred in 6/6426 (0.09%) injections and 4/349 (1.15%) pts. IRRs were mostly grade 1 (G; 3/6426, 0.05%) with 1 G3 (0.02%); none leading to discontinuation. In IRAKLIA, 80/263 (30.4%) pts did not require premedication (931/5145 injections, 18.1%); no IRRs occurred in this group. Across trials, ISRs occurred in 21/349 (6.02%) pts resulting in 35 (0.54%) ISR events. Most ISRs were G1 (33, 0.51%), the remaining were G2 (2, 0.03%) and generally occurred on the day of injection. 99.9% (6421/6426) of injections in 98.6% (344/349) pts were successful (completed without interruption) across all trials. Conclusions: These findings support overall low, self-limiting rates of IRRs and ISRs across trials, with >6000 (99.9%) Isa SC OBI injections successfully delivered. Isa SC OBI shows reproducible safety and reliability in IRAKLIA, IZALCO and Phase 1b trials, supporting it as a novel administration option for MM pts and its potential for future exploration in at-home administration. Clinical trial information: NCT04045795 , NCT05405166 , and NCT05704049 .

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 : Current standard of care for smoldering multiple myeloma (SMM), an asymptomatic precursor of multiple myeloma (MM), is observation until progression to active MM. Increasing evidence suggests that patients (pts) with SMM at high risk for progression to active MM may benefit from early treatment (tx). In AQUILA, a phase 3 study in pts with high-risk SMM (NCT03301220), daratumumab (Dara) monotherapy significantly reduced risk of progression to active MM or death with a trend of extending overall survival (OS) vs active monitoring (ActMon), with no new safety concerns. Given the evolution in SMM risk stratification, a post hoc analysis was performed to assess outcomes using the IMWG 2020 and IMWG 2020 plus cytogenetic risk models to assess which AQUILA pts benefited most from Dara monotherapy. Safety and efficacy analysis by age and stem cell collection outcomes were also assessed. Methods: Eligible pts with a confirmed diagnosis (≤5 y) of high-risk SMM per IMWG 2014 criteria, defined as clonal bone marrow plasma cells (BMPC) ≥10% and ≥1 risk factor (IgA SMM, serum protein ≥30 g/dL, serum involved:uninvolved free light chain [I/U FLC] ratio ≥8 and &lt;100, immunoparesis with reduction of 2 uninvolved Ig isotypes, and/or clonal BMPC &gt;50% to &lt;60%) at study entry, were randomized 1:1 to receive subcutaneous Dara or ActMon for 39 cycles, 36 months, or until confirmed disease progression (PD), whichever came first. Primary endpoint was progression-free survival (PFS) assessed by independent review committee, defined as progression to active MM (based on IMWG SLiM-CRAB diagnostic criteria) or death. Secondary endpoints included time to first-line (1L) MM tx and OS. For this post hoc analysis, we assessed outcomes by age, IMWG 2020 high-risk SMM criteria (BMPC &gt;20%, monoclonal spike &gt;2 g/dL, serum FLC ratio &gt;20; ≥2 factors=high risk; also known as the Mayo 2018 or the 20-2-20 criteria), and the IMWG 2020 plus cytogenetic criteria (IMWG 2020 criteria + presence of ≥1 high-risk cytogenetic abnormalities [t(4;14), t(14;16), +1q and/or del13q]; ≥3 factors=high risk). Results : Dara tx showed a PFS benefit across all IMWG 2020 risk subgroups (low: hazard ratio [HR], 0.59; intermediate: HR, 0.70), with the largest benefit in the high-risk subgroup, where the PD/death rate in the ActMon arm was ~1.6-fold that in the Dara arm (62.8% vs 37.5%; HR, 0.36). This benefit of Dara vs ActMon was preserved over time, with 5-year PFS rates of 78.2% vs 71.6%, 56.2% vs 42.9%, and 60.4% vs 23.6% in IMWG 2020 low-, intermediate-, and high-risk groups, respectively. There was a positive trend favoring Dara for time to 1L MM treatment across all IMWG 2020 risk groups (low-risk HR, 0.63; 95% CI, 0.22–1.80; intermediate-risk HR, 0.57; 95% CI, 0.35–0.92; high-risk HR, 0.39; 95% CI, 0.25–0.62). IMWG 2020 plus cytogenetic risk classification results will be available at the time of presentation. When comparing the younger (&lt;65y HR, 0.51; 95% CI, 0.32–0.79) vs the older (≥65y, HR, 0.50; 95% CI, 0.32–0.77) pt population, a PFS benefit was observed regardless of age. Similarity was also observed in TEAE incidence rate when looking into &lt;65, 65 to &lt;75, and ≥75 y subgroups (82.7%, 81.1%, and 87.5% with ActMon; 96.2%, 98.5%, and 95.2% with Dara); however, serious TEAEs were more frequently observed in older ActMon pts (12.2%, 18.9%, and 50.0% with ActMon; 24.8%, 35.8%, and 28.6% with Dara). Across all pts treated/monitored in AQUILA, 23 (11.9%) and 41 (20.9%) pts in the Dara and ActMon arms, respectively, received autologous stem cell transplant as part of their first tx after progressing to active MM, with very limited plerixafor use (Dara, 3 [1.6%] vs ActMon, 9 [4.6%]). Median (range) CD34+ cell yield was 5.0 (2–20)×106 cells/kg body weight among 22 pts in the Dara arm and 5.1 (2–21)×106 cells/kg body weight among 39 pts in the ActMon arm. Conclusions : In this analysis, pts with high-risk SMM from the phase 3 AQUILA study treated with Dara monotherapy experienced long-term PFS benefit across IMWG 2020 subgroups, with the most pronounced benefit in the high-risk subgroup. No notable differences in PFS or safety were observed across age subgroups. Early Dara tx for high-risk SMM did not have a detrimental impact on stem cell yield. Although mature OS analyses are forthcoming, overall, these results further support early intervention with Dara monotherapy vs ActMon among pts with high-risk SMM, regardless of risk stratification criteria used.

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 Introduction: The CARTITUDE-4 study (NCT04181827), which enrolled patients with lenalidomide-refractory multiple myeloma (MM) after 1–3 prior lines of therapy (pLOT), demonstrated a significant benefit of ciltacabtagene autoleucel (cilta-cel) over established triplet regimens. However, the benefit of cilta-cel for patients with standard-risk cytogenetics remains less defined. Here, we report outcomes in patients with standard-risk cytogenetics from the intent-to-treat and as-treated populations in CARTITUDE-4. Methods: InCARTITUDE-4, patients randomized to the cilta-cel arm underwent apheresis and bridging treatment with either pomalidomide, bortezomib, and dexamethasone (PVd) or daratumumab, pomalidomide, and dexamethasone (DPd), followed by lymphodepletion therapy with cyclophosphamide and fludarabine, and then a single cilta-cel infusion. Progression-free survival (PFS) was assessed using a validated computerized algorithm. The intent-to-treat population included 208 patients; 32 patients progressed or died on bridging therapy, resulting in an as-treated population of 176 patients. Patients with high-risk cytogenetics, defined as del(17p), t(14;16), t(4;14), gain/amp(1q) (n=105), or with unknown cytogenetics (n=12), were excluded from the as-treated analysis. The 12-month minimal residual disease (MRD)-negative complete response (CR) was defined per the International Myeloma Working Group criteria as the proportion of participants with CR or better prior to and at 12 months (±3 months), achieving MRD-negative status at 12 months (+3 months) after cilta-cel infusion, as determined by next-generation sequencing (10-5), prior to progressive disease or subsequent anti-myeloma therapy. For the as-treated population, PFS rates were measured from the time of cilta-cel infusion. Results: In CARTITUDE-4, in the intent-to-treat population, at a median follow-up of 33.6 months, patients with standard-risk cytogenetics had a 30-month PFS rate (95% CI) of 71.0% (58.8–80.2) in the cilta-cel arm (N=69) vs 43.2% (31.3–54.5) in the standard-of-care (SOC) arm (N=70). Patients with standard-risk cytogenetics in the as-treated population (n=59) had a 30-month PFS rate of 80.5% (95% CI, 67.2–88.8). In CARTITUDE-1 (NCT03548207), which evaluated cilta-cel in patients with heavily pretreated relapsed/refractory MM (RRMM; ≥3 pLOT), the 30-month PFS rate among patients with standard-risk cytogenetics (negative for del(17p), t(14;16), or t(4;14); n=68) was 59.9% (95% CI, 47.2–70.5). In the CARTITUDE-4 as-treated population with standard-risk cytogenetics, 8 PFS events occurred within 1 year and 4 PFS events beyond 1 year of cilta-cel infusion. Twenty-six patients achieved MRD-negative CR at 12 months after cilta-cel; 100.0% of these patients were progression free at 30 months. Fourteen patients were not evaluable for MRD due to: calibration failure (n=12), no sample availability for testing (n=1), or indeterminate results post baseline (n=1). Conclusions: The PFS rate at 2.5 years for patients with standard-risk RRMM was higher in CARTITUDE-4 compared with CARTITUDE-1, supporting the use of cilta-cel as early as second line in the treatment course. In CARTITUDE-4 (as-treated population), 80.0% of patients with standard-risk cytogenetics were progression free and off treatment at 2.5 years. In patients with standard-risk disease who achieved MRD-negative CR at 1 year, this rate increased to 100.0%. The low rate of progression events in cilta-cel-treated patients with standard-risk cytogenetics shows the profound benefit of a single cilta-cel infusion in this population.

Abstract Introduction LINVO, a human B-cell maturation antigen (BCMA)xCD3 bispecific antibody, was recently approved for triple-class exposed (TCE) RRMM after ≥3 prior therapies (EU) or ≥4 prior lines of therapy (US), demonstrating high efficacy and a generally manageable safety profile. Combining LINVO with an anti-CD38 mAb, such as DARA or ISA, may provide additional benefit to pts with RRMM. Here we report pooled safety and efficacy results from the LINVO + DARA and LINVO + ISA cohorts during the dose-finding portion of the Phase 1b LINKER-MM2 trial (NCT05137054). Methods Eligible pts were aged ≥18 years with RRMM that progressed after ≥3 lines of therapy (LoTs), or ≥2 LoTs if TCE or double-class refractory (immunomodulatory drug [IMiD] + proteasome inhibitor [PI]). Prior treatment (tx) with DARA or ISA was allowed if previously tolerated and ≥6 months (mos) or ≥3 mos washout, respectively, had elapsed since last exposure. Tx began with LINVO monotherapy (Cycle [C]0; 28-day cycle) consisting of 2 step-up doses (5 mg, 25 mg) and 2 full doses (dose level [DL]1 100 mg; DL1b 150 mg; DL2 200 mg) before standard dosing of DARA or ISA was added at C1. LINVO was given once weekly in C1–3 and once every 2 weeks in C4+. At the end of 2024, dosing once every 4 weeks was implemented after C6 if a very good partial response or better (≥VGPR) was achieved. Dexamethasone premedication was required during the first 2 cycles and then given per label for DARA or ISA. Primary endpoints: dose-limiting toxicities (DLTs) and tx-emergent adverse events (TEAEs). Key secondary endpoints: overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and rate of minimal residual disease (MRD) negativity. The analyses reported here combine the LINVO + DARA and LINVO + ISA cohorts. Results As of May 7, 2025, 42 pts were enrolled. All pts were included in the safety analysis set: DL1 (DARA, n=12; ISA, n=6), DL1b (n=6; n=10), or DL2 (n=8; n=0); 37 were included in the efficacy analysis set: DL1 (DARA, n=11; ISA, n=5), DL1b (n=5; n=9), or DL2 (n=7; n=0). At baseline, all pts had received ≥1 PI (refractory to ≥1 PI: 76%) or ≥1 IMiD (refractory to ≥1 IMiD: 86%), and 21 pts (50%) had received prior DARA or ISA (refractory to DARA or ISA: 33% [DARA, n=4; ISA, n=10]). Median number of prior LoTs was 3 (range 2–8), including 50% of pts with TCE and 21% with triple-class refractory disease. Median age was 68 years (range 42–86); male, 57%; ISS stage III at study entry, 12%; high-risk cytogenetics, 31%; bone marrow plasma cells ≥50%, 31%; and soft tissue plasmacytomas, 33% (extramedullary, 12%). Median follow-up duration was 14.8 mos for DL1 (DARA 21.3; ISA 11.3), 7.6 mos for DL1b (DARA 13.5; ISA 5.2), and 5.9 mos for DL2 (all DARA), with 44%, 50%, and 63% of pts still receiving tx, respectively. The most common TEAEs were anemia (any grade [Gr] 48%; Gr 3/4 26%), neutropenia (41%; 41%), diarrhea (38%; 2%), and thrombocytopenia (38%; 17%). Cytokine release syndrome was reported in 33% of pts (all Gr 1/2 events except 1 Gr 3 event during the step-up period that fully resolved). No pts experienced immune effector cell-associated neurotoxicity syndrome (ICANS). Infections were reported in 32 pts (any Gr 76%; Gr ≥3 40%), and 3 resulted in death (1 tx related: cytomegalovirus [CMV] pneumonia; 2 tx unrelated: C. diff colitis and lower respiratory infection). One DLT was observed at DL1b in the ISA cohort (Gr 3 Epstein–Barr virus pharyngitis) and 1 was observed at DL2 in the DARA cohort (Gr 5 CMV pneumonia). Among efficacy evaluable pts, ORR was 75% at DL1 (12/16; ≥VGPR rate 75%), 93% at DL1b (13/14; ≥VGPR rate 57%), and 86% at DL2 (6/7; ≥VGPR rate 86%). Of 10 MRD-evaluable pts, all were MRD negative (&lt;10−5by clonoSEQ or EuroFlow). The 12-mo DOR rate was 79% (95% confidence interval [CI] 52–92; median DOR not reached) and 12-mo PFS rate was 73% (95% CI 53–86; median PFS not reached). Pharmacokinetic analyses showed LINVO concentrations were not affected by the addition of DARA or ISA. ConclusionsIn pts with heavily pretreated RRMM, half of whom had prior anti-CD38 mAb exposure, the combination of LINVO and DARA or ISA was feasible, inducing a high rate of deep and durable responses, and exhibiting a safety profile similar to that reported for each individual drug. These preliminary data support continued development of LINVO plus an anti-CD38 mAb for the tx of pts with MM.

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.

Introduction: High-risk smoldering multiple myeloma (SMM) is an asymptomatic precursor disorder to active multiple myeloma (MM) without approved treatment options. However, recent evidence suggests patients at high risk of progression to MM may benefit from early treatment. Daratumumab (DARA) is a human IgGκ monoclonal antibody targeting CD38 with direct on-tumor and immunomodulatory mechanisms of action. DARA is approved as monotherapy for relapsed/refractory MM (RRMM) and in combination with standard-of-care regimens for RRMM and newly diagnosed MM. Based on the encouraging activity and tolerability observed with DARA monotherapy in patients with intermediate- or high-risk SMM in the phase 2 CENTAURUS study, the phase 3 AQUILA study sought to determine if DARA could delay progression to MM versus active monitoring. Here we report the primary analysis from the AQUILA study. Methods: Eligible patients had a confirmed diagnosis of high-risk SMM for ≤5 years, defined as clonal bone marrow plasma cells (BMPCs) ≥10% and ≥1 risk factor (serum M protein ≥30 g/L, IgA SMM, immunoparesis with reduction of 2 uninvolved Ig isotypes, serum involved:uninvolved free light chain ratio ≥8 and &lt;100, and/or clonal BMPCs &gt;50% to &lt;60%). Focal and lytic lesion assessment was performed in screening by CT and MRI and centrally reviewed prior to study enrollment. Patients were randomized 1:1 to receive DARA SC versus active monitoring. DARA (QW in Cycles 1 and 2, Q2W in Cycles 3-6, and Q4W thereafter) was given in 28-day cycles until cycle 39, 36 months, or disease progression, whichever came first. The primary endpoint was progression-free survival (PFS), defined as progression to active MM as assessed by an independent review committee and according to IMWG diagnostic criteria for MM (SLiM-CRAB) or death. Major secondary endpoints included overall response rate (ORR), PFS on first-line MM treatment (PFS2), and overall survival (OS). Results: A total of 390 patients (DARA, n = 194; active monitoring, n = 196) were randomized. Median (range) age (64 [31-86] years) and time from initial SMM diagnosis to randomization (0.72 [0-5.0] years) were balanced between treatment groups. Median treatment duration in the DARA group was 38 cycles (35.0 months). At a median (range) follow-up of 65.2 (0-76.6) months, PFS was significantly improved with DARA versus active monitoring (HR, 0.49; 95% CI, 0.36-0.67; P &lt;0.0001). Median PFS was not reached in the DARA group versus 41.5 months for active monitoring; estimated 60-month PFS rates were 63.1% versus 40.8%, respectively. Prespecified analyses showed generally consistent PFS improvement with DARA versus active monitoring across subgroups. ORR was 63.4% with DARA versus 2.0% with active monitoring (P &lt;0.0001). As of the clinical cutoff, 64 (33.0%) patients in the DARA group and 102 (52.0%) patients in the active monitoring group had started first-line MM treatment. Median time from randomization to the date of first-line MM treatment was not reached with DARA versus 50.2 months with active monitoring (HR, 0.46; 95% CI, 0.33-0.62; nominal P &lt;0.0001). There was a positive trend in favor of DARA for PFS2 (HR, 0.58; 95% CI, 0.35-0.96) and OS (60-month OS rates: DARA, 93.0%; active monitoring, 86.9%; HR, 0.52; 95% CI, 0.27-0.98). A total of 41 deaths were observed, 15 for the DARA group and 26 for the active monitoring group. Grade 3/4 treatment-emergent adverse events (TEAEs) occurred in 40.4% and 30.1% of patients in the DARA and active monitoring groups, respectively. The most common (≥5% in either group) grade 3/4 TEAE was hypertension (DARA, 5.7%; active monitoring, 4.6%). The frequency of TEAEs leading to DARA discontinuation was low (5.7%), as was the incidence of fatal TEAEs in both groups (DARA, 1.0%; active monitoring, 2.0%). Conclusions: DARA monotherapy was well tolerated and demonstrated a clinically meaningful and significant benefit in preventing or delaying progression to active MM compared with active monitoring in patients with high-risk SMM. ORR was significantly higher and time to first-line MM treatment was prolonged with DARA compared with active monitoring. This was accompanied by positive trends for PFS2 and OS in favor of DARA. These results strongly support the benefit of early intervention with DARA monotherapy versus active monitoring, the current standard of care, in patients with high-risk SMM.