A subgroup analysis of efficacy, safety and QOL in patients who received selinexor in combination with bortezomib and dexamethasone (SVd) with and without selinexor dose reduction and who had lenalidomide-refractory disease in the phase 3 BOSTON trial showed improvements in efficacy, quality of life (QOL) and safety outcomes with selinexor dose reduction in this difficult-to-treat population. These findings demonstrate the benefit of selinexor dose reductions in optimizing the treatment of patients with lenalidomide-refractory multiple myeloma (MM) receiving SVd.

IntroductionMultiple myeloma is a haematological malignancy based on pathological monoclonal proliferation of plasma cells, which usually occurs in the bone marrow. Known aspects of its symptomatology include anaemia, renal failure, hypercalcaemia, osteolytic bone lesions and potentially consequences of AL amyloidosis. Diagnostics is multimodal and relies on laboratory and imaging methods of conventional radiology and nuclear medicine. Treatment is then the domain of the haematologist-oncologist. One form of this disease is extramedullary plasmacytoma, i.e., a solitary or multiple focus of multiple myeloma, which is not anatomically associated with bone marrow. This case report focuses on a patient with an advanced form of extramedullary plasmacytoma, who underwent partial cytoreductive surgery as a therapeutic attempt after exhausting all lines of conventional treatment.Case presentationA 67-year-old male patient with an advanced form of extramedullary plasmacytoma was referred by his attending haematologist to the 1st Department of Surgery of General University Hospital in Prague of his attending haematologist to assess the possibility of extirpation of EMP lesions, due to the exhaustion of systemic therapy options. The aim of considered intervention was one of the macroscopically manifested soft tissue lesions of extramedullary plasmacytoma, which appeared suitable for surgical removal. After comprehensive preoperative assessment the elective surgical cytoreduction of the large lesion of extramedullary plasmacytoma above the right scapula was successfully performed. From the surgeon's perspective, the postoperative course was quite favourable without periprocedural complications, which ultimately led to the complete healing of the surgical wound. Despite achieving the primary surgical goal and the ongoing systemic treatment, the underlying disease developed to the stage beyond all possible therapeutic options, which ultimately led to the death of the patient.DiscussionIn conclusion, despite the overall result of this case, it can be said about this therapeutic attempt that, assuming careful consideration of indications within the framework of interdisciplinary cooperation, considering all eventualities, this may be a relatively undemanding and safe procedure that does not exceed the capabilities of a standard surgical facility, is reproducible and potentially available as an addition to conventional treatment of extramedullary plasmacytoma in highly specific cases.

ABSTRACT:Quadruplet therapy with Isa-VRd (isatuximab, Velcade [bortezomib], Revlimid [lenalidomide], and dexamethasone) followed by Isa-Rd in the randomized phase 3 IMROZ study provided a significant progression-free survival benefit to transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). In the primary analysis, more Isa-VRd/Isa-Rd-treated patients achieved minimal residual disease (MRD) negativity and MRD-negative complete response (CR) at any time point than patients receiving VRd followed by Rd. Here, we report landmark analysis results of MRD negativity over time and its impact on clinical outcomes in IMROZ. Treatment with Isa-VRd/Isa-Rd led to deeper responses, with higher rates of MRD negativity and MRD-negative CR at the end of induction and during maintenance vs VRd/Rd, up to 60 months of follow-up. Benefit with Isa-VRd/Isa-Rd was observed across key patient subgroups, including older (>70 years) and frail patients. Time to progression (TTP) was significantly prolonged with Isa-VRd/Isa-Rd vs VRd/Rd in patients who converted from MRD negative to MRD positive at any time point. In a landmark analysis of the time of conversion to MRD positivity, TTP in patients who converted from MRD negative at the end of induction to MRD positive also favored Isa-VRd/Isa-Rd. Evaluating MRD status of patients at >1 time point may therefore be useful to support decisions on treatment selection and treatment continuation/discontinuation. Our findings on the degree of MRD negativity and MRD-negative CR benefit achieved during induction and maintenance by patients receiving Isa-VRd/Isa-Rd vs VRd/Rd extend the IMROZ primary analyses and further support Isa-VRd as standard of care for frontline treatment of transplant-ineligible patients with NDMM. This trial was registered at www.clinicaltrials.gov as #NCT03319667.

7564 Background: In combination with conventional doublet and triplet therapy, isatuximab (Isa) provides significant benefit to patients (pts) across the multiple myeloma (MM) spectrum. Subcutaneous (SC) administration of Isa could be a more convenient option for pts and caregivers. The Phase (Ph)3 IRAKLIA trial in relapsed/refractory MM (RRMM) pts demonstrated non-inferiority in efficacy and pharmacokinetics of Isa SC delivered via a wearable on-body injector (OBI) in combination with pomalidomide and dexamethasone (Pd) vs Isa IV Pd. The Ph2 IZALCO study (NCT05704049) also showed efficacy and safety of Isa SC plus carfilzomib and dexamethasone (Kd), either by manual or OBI injections, in RRMM pts. Following exposure to both methods, pts showed higher preference for OBI vs manual SC injection. Here we present updated efficacy and safety results from IZALCO. Methods: Isa SC 1400 mg was given weekly in Cycle (C)1 then biweekly. In Part 1, pts received Isa injected SC manually. In Part 2, pts were randomized to Isa administered SC via OBI (Isa SC OBI; C1-C3) followed by manual SC injection (C4-C6), or to manual SC injection (C1-C3) followed by Isa SC OBI (C4-C6). Starting at C7, pts could choose either treatment method. All pts were treated with carfilzomib (20 mg/m 2 on Day [D]1-2 then 56 mg/m 2 on D8-9, 15-16 at C1, then D1-2, 8-9, and 15-16) and dexamethasone (20 mg on D1-2, 8-9, 15-16, and 22-23). Results: A total of 74 RRMM pts were enrolled (8 in Part 1; 66 in the randomized cohort, Part 2). At the data cut-off of November 10, 2025, 59 pts remained on study. At study entry, pts had median age of 65 (44-85) years, median weight of 75.9 (40.0-129.0) kg, and median of 1 prior line of therapy (1-5), and 56.8% had ISS stage I. The median duration of Isa SC OBI administration was 12 mins and manual SC injection was 6 mins. None of the Isa SC injections, manual or OBI, were interrupted. Median time to best response was 5.3 months (mos) (95% CI: 3.25-6.24). At median follow-up of 21.9 mos, median PFS was not reached (NR) (95% CI: 16.23-NR). PFS at 18 mos was 61.5% (95% CI: 48.7–72.0). OS at 18 mos was 80.8% (95% CI: 69.8-88.2); median OS was not reached (95% CI: NR-NR). Overall, grade (G) ≥3 TEAEs occurred in 66.2%, and serious TEAEs in 51.4% pts. Infusion reaction (IR) on C1D1 occurred in 2 pts (2.7%) with manual SC injections; no IRs occurred with OBI. Six (8.1%) pts had 13 injection-site reactions (ISR), all G1, in 2425 (0.54%) manual or OBI injections. Only 1 ISR was deemed related to OBI. Pt satisfaction with injection method remained consistently high with Isa SC OBI up to C25D15. Conclusions: Updated results of the IZALCO study continue to show the efficacy and safety of Isa SC plus Kd delivered either by manual injection or Isa SC OBI, while demonstrating high pt satisfaction and preference for Isa SC OBI. These findings are consistent with those reported in the Ph3 IKEMA study (Isa IV plus Kd). Clinical trial information: NCT05704049 .

7566 Background: B-cell maturation antigen (BCMA)–directed therapies have transformed the treatment landscape in RRMM. Belamaf, a BCMA-targeting antibody-drug conjugate, in combination with Pd significantly improved progression-free survival (PFS) vs PVd (hazard ratio [HR], 0.52; 95% CI, 0.37-0.73; P <0.001) in pts with RRMM in DREAMM-8 (median follow-up, 22 mo). This PFS benefit was maintained with extended follow-up (HR, 0.49; 95% CI, 0.36-0.67; median follow-up 36 mo); median PFS2 also favored BPd vs PVd (47.1 vs 21.7 mo, respectively; HR, 0.52; 95% CI, 0.38-0.70), indicating sustained clinical benefit over time. We report PFS2 outcomes from DREAMM-8 in subgroups based on prior therapy to further understand the long-term impact of BPd and inform treatment sequencing. Methods: DREAMM-8 (NCT04484623) is a phase 3, randomized, open-label study evaluating BPd vs PVd in pts with RRMM with ≥1 prior line of therapy including lenalidomide (LEN). Pts could not have received prior BMCA-targeted therapy. PFS2 was defined as time from randomization to disease progression after initiation of subsequent antimyeloma therapy or death. PFS2 was assessed based on prior-treatment subgroups. Results: In the BPd arm (DCO: Jul 7, 2025; median follow-up, 36 mo), PFS2 benefit was maintained in all subgroups, including pts who were LEN refractory and anti-CD38 exposed/refractory. In LEN-refractory pts, BPd treatment led to almost a 3-fold median PFS2 improvement vs PVd (41.7 vs 15.0 mo). A total of 56/155 pts (36%) in the BPd arm and 93/147 (63%) in the PVd arm received any first subsequent therapy (FST) at data cutoff. Across both arms, 36% of pts received steroids, 28% received anti-CD38 therapies (>50% of pts with any subsequent therapy in each arm), and 23% received proteasome inhibitors as FST. A total of 21 pts (7%) received novel therapies (BPd, n=6 [4%]; PVd, n=15 [10%]) as FST, including BCMA-targeted bispecific antibodies (bsAbs), non-BCMA bsAbs, CELMoDs, venetoclax, and belamaf. Improved median PFS2 was observed in patients who had novel therapies as FST (n=21) vs non-novel agents (n=128) (26.0 vs 20.1 mo; HR, 0.61; 95% CI, 0.34-1.09). Conclusions: BCMA-directed therapy, BPd, resulted in improved PFS2 outcomes vs PVd, demonstrating sustained clinical benefit beyond initial belamaf therapy. This benefit was seen regardless of prior treatment, with LEN-refractory pts experiencing almost a 3-fold PFS2 benefit, and despite a higher proportion of pts receiving novel therapies as FST in the PVd arm. PFS2 benefit with high use of subsequent anti-CD38 agents supports sequencing of belamaf combinations early in the treatment paradigm prior to anti-CD38 agents.

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 .

7565 Background: BCMA–directed therapies have changed the RRMM treatment landscape. In the phase 3, open-label, randomized DREAMM-8 trial (NCT04484623), BPd demonstrated significant progression-free survival (PFS) benefit compared with pomalidomide, bortezomib, and dexamethasone (PVd) in patients (pts) with RRMM who received ≥1 prior line of therapy (LOT). This post hoc analysis examined the characteristics of and outcomes in pts achieving sustained clinical benefit with BPd. Methods: DREAMM-8 is an ongoing, phase 3, open label study evaluating BPd and PVd in pts with RRMM with ≥1 prior LOT, including lenalidomide. Pts were randomized 1:1 and treatment continued until disease progression, unacceptable toxicity, withdrawal of consent, or death, whichever occurred first. The primary endpoint was PFS; secondary endpoints included minimal residual disease (MRD) negativity (10 -5 ), PFS2, response rates, and safety. LTRs were pts with PFS ≥30 months (data cutoff: July 7, 2025; median follow up 36 months in both arms). Results: Of the 302 pts in DREAMM-8 (BPd, n=155; PVd, n=147), 81 were LTRs. The BPd arm had more than twice the proportion of LTRs (n=59 [38%]) as the PVd arm (n=22 [15%]). Baseline characteristics between treatment arms were generally well balanced. In LTRs, median PFS potentially favored BPd (not reached [NR]; 95% CI, NR-NR) vs PVd (NR; 95% CI, 42.7 months-NR), with a hazard ratio (HR) of 0.72 (95% CI, 0.20-2.53). BPd LTRs continued to demonstrate potential benefits after the first subsequent therapy, with median PFS2 (95% CI) of NR (NR-NR) in the BPd LTR arm and NR (44.2 months-NR) in the PVd LTR arm (HR, 0.33; 95% CI, 0.07-1.69). LTRs treated with BPd vs PVd had deeper responses: 76% vs 59% had complete response or better (≥ CR), 56% vs 32% had MRD negativity plus ≥ CR overall (73% vs 54% of pts with ≥ CR), and 39% vs 18% had sustained MRD negativity for ≥12 months, respectively. A higher proportion of pts with high-risk cytogenetics (ie, ≥1 of t[4;14], t[14;16], or del[17p13]) treated with BPd vs PVd achieved long-term response (27% vs 11%). The safety profile in LTRs was generally consistent with that previously reported. Conclusions: More than one-third of pts treated with BPd achieved LTR status, representing a 2.5-fold higher rate than with PVd, with similar rates in pts with high-risk cytogenetics; median PFS with BPd remains unreached. These findings suggest that this broadly accessible BCMA-targeted regimen delivers potential durable clinical benefit, characterized by deep and sustained disease-free survival. Clinical trial information: NCT04484623 .

We explored single or consecutive chimeric antigen receptor (CAR) T and bispecific antibody (BsAb) treatment modalities as correlates of clinical outcomes, by complementary bias-correction analysis of a retrospective multicenter study of 640 patients with relapsed/refractory multiple myeloma. The sequential use of both modalities seemed to yield the most favorable survival trajectories. Initiating treatment with CAR T [idecabtagene vicleucel (ide-cel), ciltacabtagene autoleucel (cilta-cel), cesnicabtagene autoleucel (cesni-cel)] was associated with longer remission. However, mortality from early progression was similar regardless of initial modality, suggesting that resistance may negate initial efficacy difference. On the product level, the benefit of CAR T seemed to be driven by cilta-cel and cesni-cel, whereas BsAbs showed at least comparable outcomes with ide-cel. These exploratory findings highlight the critical importance of treatment sequencing in optimizing long-term outcomes and underscore the need for equitable and timely access to both modalities across healthcare systems. SIGNIFICANCE:In this real-world cohort, initiating treatment with CAR T was associated with longer remission, and sequential immunotherapy incorporating both modalities yielded the most favorable outcomes. However, early treatment failure negated initial efficacy differences between modalities. These findings provide a rationale for prospective sequencing trials and equitable access to both treatments. See related commentary by Banerjee, p. 650.

BACKGROUND:Information about safety and pharmacokinetics (PK) of melflufen (melphalan flufenamide) is limited in renal impairment (RI) patients. The BRIDGE study evaluated the impact of renal function on PK of the main alkylating agent of melflufen, melphalan, and assessed the safety of melflufen plus dexamethasone in relapsed/refractory multiple myeloma (RRMM) patients. METHODS:BRIDGE was a Phase 2, open-label study in RRMM patients with moderate (estimated glomerular filtration rate [eGFR] ≥30 to <45 mL/min/1.73 m²) or severe (eGFR ≥15 to <30 mL/min/1.73 m2) RI. Patients received melflufen 20 to 40 mg intravenously every 28 days, plus weekly dexamethasone 40 mg. Three post-infusion blood samples were collected in Cycles 1 and 2. Primary endpoints were safety and melphalan PK. RESULTS:Thirty-five RRMM patients were enrolled; Cohort 1a (n=21; moderate RI, melflufen 40 mg), Cohort 1b (n=10; moderate RI, melflufen 30 mg), and Cohort 2a (n=4; severe RI, melflufen 20 mg). In Cycle 1, mean Cmax and AUCinf were lower in Cohort 1b (472.2 ng/mL and 1286.2 h·ng/mL, respectively) and Cohort 2a (181.2 ng/mL and 528.5 h·ng/mL, respectively) compared to Cohort 1a (550.2 ng/mL and 1418.7 h·ng/mL, respectively). Mean elimination half-life increased slightly with declining renal function (Cohort 1a to 2a: 89.1-109.6 min). Treatment-emergent adverse events occurred in 34 patients and 6 patients died due to a treatment-emergent adverse events. CONCLUSIONS:PK results from the BRIDGE study support the recommended dose of melflufen 30 mg for moderate RI patients. No new safety signals were reported in RRMM patients with moderate-to-severe RI.

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 <100, immunoparesis with reduction of 2 uninvolved Ig isotypes, and/or clonal BMPC >50% to <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 >20%, monoclonal spike >2 g/dL, serum FLC ratio >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 (<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 <65, 65 to <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.

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 .

7515 Background: B-cell maturation antigen (BCMA)–directed therapies have changed the RRMM treatment landscape. In the phase 3 DREAMM-8 trial (NCT04484623), BCMA-directed antibody-drug conjugate (ADC) belantamab mafodotin + pomalidomide and dexamethasone (BPd) demonstrated significant progression-free survival (PFS) benefit and higher rates of complete response (CR)–based MRD negativity vs triplet pomalidomide, bortezomib, dexamethasone (PVd) in pts with RRMM and ≥1 prior line of therapy (LOT). As MRD negativity predicts improved survival in MM, this long-term, postbaseline update describes clinical outcomes and characteristics of pts with sustained MRD negativity. Methods: Pts with ≥1 prior LOT including lenalidomide were randomized 1:1 to BPd or PVd. The primary endpoint was PFS (independent review committee assessed); PFS2 was investigator assessed. CR-based sustained MRD negativity (≥12 mo) was an exploratory endpoint. Pts with ≥ CR were tested for MRD negativity by next-generation sequencing (10 −5 sensitivity). Results: At data cutoff (7/7/2025), with median follow-up of 35.8 mo overall, the intention-to-treat population of BPd (n=155) vs PVd (n=147) was >4× more likely to achieve ≥ CR + MRD negativity (27.7% vs 6.1%) and sustained MRD negativity (15.5% vs 2.7%). In pts with ≥ CR (BPd, n = 67; PVd, n = 25), rates of MRD negativity were also higher with BPd vs PVd (64.2% vs 36.0%), as were rates of sustained MRD negativity (55.8% vs 44.4%) among all ≥ CR + MRD negative pts. Pts with sustained MRD negativity had durable PFS in both arms; 1 of 24 and 0 of 4 pts experienced PFS events with BPd and PVd, respectively. In pts without sustained MRD negativity, median PFS was 21.1 mo with BPd (HR vs sustained MRD negative, 0.04; 95% CI, 0.01-0.32) and 10.2 mo with PVd (HR vs sustained MRD negative, not estimable [NE]). Sustained MRD negativity was also associated with durable PFS2 in both arms; 2 of 25 and 0 of 4 pts experienced PFS2 events with BPd and PVd, respectively. In pts without sustained MRD negativity, median PFS2 was 20.2 mo with BPd (HR vs sustained MRD negative, 0.08; 95% CI, 0.02-0.33) and 9.3 mo with PVd (HR vs sustained MRD negative, NE). Findings were similar in pts with vs without ≥ CR + MRD negativity. Of BPd-treated pts, those with MRD negativity (n=43) received 1-3 prior LOT, of which most (74.4%) had 1. MRD-positive pts (n=112) received up to 6 prior LOT, of which 44.6% received 1 and 17.0% received >3. Almost 40% of pts with CR-based MRD negativity had high-risk cytogenetics. Conclusions: Pts receiving BPd vs PVd were >4× more likely to achieve sustained MRD negativity, which was associated with improved PFS and PFS2. MRD negative vs positive pts in the BPd arm more often had 1 prior LOT. These findings further support BPd, a BCMA-directed ADC regimen, in earlier LOTs for RRMM, including in pts with high-risk cytogenetics. Clinical trial information: NCT04484623 .