Citations

7514 Background: Iberdomide (Iber) is a CELMoD that binds with greater specificity & affinity to the cereblon protein of the E3 ligase complex than a traditional IMiD. Both transplant-eligible (TE) & ineligible (TIE) patients (pts) with newly diagnosed multiple myeloma (NDMM) are currently treated with quadruplet induction, consisting of an anti-CD38 monoclonal antibody, a proteasome inhibitor, an IMiD & dexamethasone (dex). We conducted a clinical trial (NCT05392946, IDEAL) to examine the efficacy of a novel finite-duration approach, using Iber, daratumumab, bortezomib & dex (Iber-DVd) quadruplet induction followed by Iber monotherapy maintenance. Methods: Both TE and TIE pts with NDMM were enrolled in this Phase 1 (3+3 design)/Phase 2 (single stage) trial. The primary goal was to assess the ≥complete response (CR) rate — utilizing the more sensitive serum MASS-FIX assay in lieu of serum immunofixation — during induction. Treatment involved twelve 28-day cycles of induction with Iber, given PO at the recommended phase 2 dose (RP2D), days 1-21, daratumumab 1800mg SQ, weekly for 2 cycles, every other week during Cycles 3-6, & every 4 weeks thereafter, bortezomib 1.3 mg/m 2 SQ, weekly & dex 40 mg, weekly, followed by Iber monotherapy (24 cycles). Growth factor was not allowed during the dose-limiting toxicity (DLT) assessment period (Cycle 1). Results: Among 47 pts enrolled, 9 pts were in Phase 1 portion which assessed the maximum tolerated dose (MTD), with Iber starting at 1 mg/day dose, days 1-21 [Dose Level (DL) 1]. DLT (all grade 4 neutropenia) was noted in 3 pts, 2 at DL 1 & 1 at DL -1. This analysis includes 44 pts who received Iber at the RP2D (0.75 mg/day, days 1-21), including 6 pts from the Dose Confirmation Cohort (Phase 1, DL -1), dosed at MTD, & 38 pts in the Dose Expansion Cohort. The median age at registration was 65 years (range 36-86 years), & 23 pts (52.3%) were deemed high-risk. At data cut-off, pts had received a median of 15 cycles (range 3-36) of therapy. Overall response rate was 100%; ≥CR rate, 36.4% (95% CI: 22.4, 52.2) during induction & 52.3% (95% CI: 36.7, 67.5), overall, including the maintenance phase. The marrow flow-based (10 -5 ) MRD negative rate was 29.5% during induction & 47.7% overall. At a median follow-up (FU) 18.3 mos, 2 pts have died (one during FU due to progressive disease & the other on-treatment due to COVID-19). 12- (& 18-) month progression-free survival & overall survival rates were 91% (88%) & 97% (94%), respectively. Most common toxicities at RP2D were lymphopenia, neutropenia (leading 27% of pts to require pegfilgrastim support), rash, peripheral neuropathy, diarrhea, & infections. Cases of high-grade fatigue were low (<5%). Updated data will be presented at the meeting. Conclusions: Iber-DVd is an active and safe regimen for both TE and TIE pts with NDMM, leading to high response rates which improved over time, with nearly one-half of the pts achieving MRD negative state. Clinical trial information: NCT05392946 .

7532 Background: BsAbs are highly effective, off-the-shelf T-cell engagers recently approved for relapsed/refractory multiple myeloma (MM) but remain underutilized in real-world settings. In partnership with the Florida Society of Clinical Oncology (FLASCO), a statewide initiative was launched to expand BsAb access through peer-led regional discussions focused on operational barriers, care transitions, and therapy management strategies. This study assessed the real-world impact of these interventions on BsAb utilization in FL. Methods: Multidisciplinary discussion forums were held in 4 FL metropolitan areas (Jan-Apr 2024). We conducted single and controlled interrupted time series (ITS) analyses using IQVIA eLAAD claims data (Apr 2023 - Sep 2025) including adult patients with a diagnosis of MM, evidence of claim activity, and provider state information. Fifth line or later (5L+) status was estimated as 3.3% of MM prevalence (Nikolaou et al.) BsAb utilization (% of MM 5L+ patients receiving a BsAb) was evaluated using segmented regression to estimate pre- and post-intervention trends, excluding the intervention period. We reported BsAb utilization by comparing FL with all other states, between community versus academic settings, and assessing the number of sites administering BsAb. Results: Before the intervention, BsAb utilization among MM 5L+ patients in FL rose from 8.2% (Apr 2023) to 11.2% (Dec 2023) (0.3 pp/mo; p=0.23), compared with a rise from 6.7% to 16.3% (1.3 pp/mo; p<0.0001) across all other states over the same time period. Post-intervention, BsAb utilization in FL increased from 22.8% (May 2024) to 35.9% (Sep 2025), reflecting a 7.0% immediate increase and 0.8 pp/mo sustained growth, exceeding the post-intervention trend observed across all other states (23.5% to 30.3%; 0.5 pp/mo). Overall, although pre-intervention BsAb utilization in FL was lower than all other states, FL demonstrated a 1.2 pp/month higher post-intervention utilization trend (p<0.001; Table). Post-intervention, FL community sites showed a 0.13 pp/mo higher BsAb utilization trend than academic sites, and the number of community sites administrating BsAb increased from 5 to 9, with no change among academic sites. Conclusions: This study suggests that the FLASCO-led, collaborative model increased BsAb utilization in FL community oncology sites and offers a framework for broader community adoption across other states. Parameter estimates from ITS model(s). FL (%) p-value Other US States (%) p-value Difference CITS:FL - Other US States (%) p-value Intercept (Apr 2023) 8.6 <.0001 7.7 <.0001 0.9 0.52 Monthly change pre-intervention 0.3 0.23 1.3 <.0001 -0.9 0.002 (Apr - Dec 2023) Immediate change post-intervention 7 0.01 0.2 0.87 6.8 0.01 (May 2024) Monthly change post-intervention 0.8 <.0001 0.5 <.0001 1.2 0.0003 (May 2024 – Sep 2025)

7508 Background: Data on response to BCMA-targeted therapies among BCMA-exposed pts with RRMM are limited. Outcomes after sequential/subsequent anti-BCMA bispecific T-cell engagers (Bs-TCE) are vital to evaluate. Etentamig is a next-generation differentiated BCMA x CD3 Bs-TCE composed of a bivalent BCMA-binding domain with a high-avidity, low-affinity CD3-binding domain potentially reducing cytokine release syndrome (CRS), and a silenced Fc tail for extended half-life and convenient monthly (Q4W) dosing. Phase 1 results of etentamig in RRMM showed robust efficacy and potential best-in-class safety. Methods: Arm B of the open-label, Phase 1b MOVISO study (NCT05650632) evaluated etentamig in pts with RRMM with ≥2 prior lines of therapy (PLT), including triple-class and prior BCMA exposure (antibody-drug conjugate [ADC] >30 days or CAR-T >6 months [mo] after last exposure). Primary safety endpoints were CRS and immune effector cell-associated neurotoxicity syndrome (ICANS); efficacy endpoints included objective response rate (ORR; IMWG 2016), duration of response (DoR), and progression-free survival (PFS). Pts received etentamig (60 mg IV; no step-up dosing [SUD]) on Cycle 1 Day 1 and Q4W thereafter. Results: At cutoff (June 11, 2025), 41 prior BCMA-exposed pts (CAR-T, n=24; ADC, n=17) had been treated; 24 (57%) were male, 38 (93%) were White, median (mdn) (range) age was 68 (43–89) years, 37 (88%) had ECOG PS ≤1, and 34 (81%) were triple-class refractory. Mdn (range) PLT was 6 (3–15). For 21 (51%) pts, the last PLT was BCMA directed; 23 (56%) had previously responded to anti-BCMA therapy (17/24 [71%] for CAR-T and 6/17 [35%] for ADC). Mdn (range) time from last prior CAR-T or ADC to first dose of etentamig was 15 (1–30) and 4 (1–45) mo, respectively. Mdn (range) follow-up was 5.5 (0.2–17.1) mo. Despite no SUD, CRS and ICANS were reported in 24 (57%) and 3 (7%) pts, respectively; all G1/2 events, except 1 G3 ICANS. G3/4 neutropenia and infections were reported in 15 (36%) and 17 (41%) pts, respectively. Efficacy outcomes are detailed in the Table (NE, not estimable). For pts whose last PLT was BCMA directed, MRD negativity (clonoSEQ, 10 –5 ) was seen in 2/3 (67%) evaluable pts, along with robust peak activation and proliferation of CD8+ T cells. Conclusions: Pts treated with etentamig achieved durable responses; rates were higher in pts who received CAR-T as last line. No new safety signals were observed; only low-grade CRS was seen despite no SUD. Clinical trial information: NCT05650632 . All prior BCMA (N=41) Prior BCMA CAR-T (N=24) ORR, n/n (%) [95% CI] Overall 17/36 (47) [30–65] 11/22 (50) [28–72] BCMA-directed last PLT 11/19 (58) [34–80] 7/11 (64) [31–89] Mdn DoR, mo [95% CI], No. of pts Overall 13 [7–NE], N=17 13 [7–NE], N=11 BCMA-directed last PLT 13 [7–NE], N=11 13 [7–NE], N=7 Mdn PFS, mo [95% CI], No. of pts Overall 3.4 [3–11], N=41 8.3 [2–NE], N=24 BCMA-directed last PLT 9.4 [2–NE], N=21 9.4 [2–NE], N=12

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 .

7548 Background: Glucagon-like peptide-1 (GLP-1) receptor agonists are widely used for the treatment of type 2 diabetes and obesity, and emerging evidence suggests their benefits beyond glycemic control, including cardiovascular effects and potential anti-inflammatory and anti-proliferative properties. Therapeutic advances in multiple myeloma (MM) have improved the overall life-expectancy in our patients. However, metabolic comorbidities remain common, likely driven by disease burden, functional decline, ongoing inflammation, and treatment related effects. Our study evaluates the impact of GLP-1 receptor agonists on outcomes in patients with MM, exploring potential interactions between metabolic modulation and disease outcomes. Methods: We conducted a real-world retrospective cohort study using the TriNetX Global Collaborative Network, covering January 2000 to December 2025, encompassing data from 168 global healthcare organizations. Patients aged 18 and above with multiple myeloma were identified and then stratified into two groups based on treatment with GLP-1 agonists or not. The two groups were then propensity-matched based on age, sex, race, and various comorbidities. We assessed outcomes including overall mortality, myocardial infarction (MI), ischemic stroke, sepsis, anemia, pancreatitis, venous thromboembolism (VTE), and ED visits. Time-to-event analyses were performed using Kaplan-Meier methods and Cox proportional hazards models. Results: We identified 1716 patients with MM and obesity who received GLP-1 receptor agonists, and 13,491 patients with MM and obesity who did not receive GLP-1 therapy. After propensity matching, each cohort consisted of 1712 patients with well-balanced baseline characteristics. We followed these patients for 5 years from treatment initiation. Patients with MM who received GLP-1 had a significantly lower risk of overall mortality (Hazard Ratio [HR]: 0.423, 95% CI: 0.351-0.509, p-value <0.001), MI (Risk Difference [RD]: -3.6 %, 95% CI: -5.4 % to -1.7 %, p-value <0.001), ischemic stroke (RD: -1.7 %, 95% CI: -3.3 % to -0.1 %, p-value = 0.04), sepsis with and without shock (RD: -3.0 %, 95% CI: -4.9 % to -1.1 %, p-value = 0.002), and anemia (RD: -9.6 %, 95% CI: -12.9 % to -6.4 %, p-value <0.001). There was no statistically significant difference in the rates of VTE, ED visits, and pancreatitis between the two cohorts. Conclusions: Our study revealed that patients with MM with obesity who received GLP-1 therapy had significantly lower rates of overall mortality, MI, ischemic stroke, sepsis with and without shock, and anemia. Additional longitudinal cohort studies are required to explore the associations between these agents and inform clinical practice guidelines in these patients.

7528 Background: Lenalidomide (Len) maintenance after ASCT has been a standard of care for patients (pts) with MM. Historically, ~30% of pts discontinue Len within 1 year (yr) due to toxicity and there is a need for more effective and better tolerated maintenance strategies. Iber is a potent, oral cereblon E3 ligase modulator under evaluation in the relapsed/refractory and newly diagnosed settings. We report the results of the primary analysis of a Phase II trial of Iber maintenance following upfront ASCT. Methods: Pts ≥ 19 yrs of age with MM, within 1-yr of initiation of induction therapy and in a ≥ partial response (PR) at day 80-110 post-ASCT, were accrued. Iber was administered 1.0 mg orally days 1-21 of a 28-day cycle, continued until progressive disease (PD) or toxicity. Up to 2 dose reductions (0.75 mg/day then 0.6 mg/day) were allowed. Growth factor support was not permitted. Minimal residual disease (MRD) assessment by flow cytometry (10 -5 ) was performed at registration, post-cycle 12 and post-cycle 24. An optimal Simon two-stage design with type I and II errors of 0.1 was chosen to test whether the proportion of pts who are progression-free and on treatment at 1 yr is <60% against the alternative of ≥ 80%. If ≥ 27 out of 38 pts were progression-free (by 2016 IMWG criteria) and on treatment at 1 yr, Iber would be considered to have promising activity. Results: 38 pts (55% males, median age 61 yrs (range: 41-77)) received Iber. R-ISS at diagnosis was stage I (34%), II (39%), III (8%) and unknown (18%), with 34% having high-risk disease per 2025 IMS/IMWG criteria. All pts received triplet or quadruplet induction therapy, with 97% receiving Len and 84% receiving daratumumab. At day 80-110 post-ASCT, all pts had ≥ very good PR, with 22 (58%) ≥ complete response (CR) and 33 (87%) MRD-negative (neg). The median number of administered treatment cycles is 18 (range: 1-45), with 18 (47%) pts having ≥ 1 dose reduction, most commonly due to neutropenia (n=12). The most common grade (gr) 3/4 adverse event was neutropenia (gr 3 (n=19), gr 4 (n=5)). Within yr 1, 29% (11/38) discontinued Iber due to neutropenia (n=5), rash (n=1), infection (n=1), pt choice (n=1), or PD (n=3). After 1 yr, 6 pts discontinued due to neutropenia (n=4) and PD (n=2). While on Iber, 19 pts had deepening of response to stringent CR and 3 pts converted from MRD-positive to MRD-neg. The post-cycle 12 and 24 MRD-neg rates are 85% (23/27) and 100% (14/14), respectively. Conclusions: Iber demonstrated promising activity with dose reductions/discontinuations mainly due to neutropenia. Strategies including lower starting dose, growth factor support and more flexible management of neutropenia may enable more pts to remain on treatment. Longer follow-up will permit evaluation of sustained MRD-negativity and PFS, but overall, these results provide rationale for further exploration of Iber-based post-ASCT maintenance strategies. Clinical trial information: NCT05177536 .

7094 Background: Waldenström Macroglobulinemia (WM) remains incurable with current available therapeutic options. Treatment options for relapsed/refractory pts are limited and often continuous, underscoring the need for new agents with novel mechanisms of action and pt-centered, fixed duration therapy. Iopofosine I 131 is a novel radiopharmaceutical compound composed of a lipid raft-targeting phospholipid ether covalently bound to 131 I, a beta emitting radioisotope. Here, we report preliminary sub-group results of the CLOVER-WaM study [NCT02952508] in WM pts treated with a Bruton’s Tyrosine Kinase inhibitor (BTKi) immediately prior to iopofosine. Methods: Eligible WM pts had received >2 prior therapies and had symptomatic disease requiring therapy according to consensus recommendations for WM. Treatment consisted of 2 cycles of iopofosine I 131 administered at 15 mCi/m 2 on days 1 and 15 of each 57-day cycle. The primary efficacy endpoint was major response rate (MRR; partial response or better, as determined by the modified IWWM-VI). Secondary and exploratory endpoints included overall response rate (ORR), treatment-free survival (TFS), progression free survival (PFS), duration of response (DOR), and clinical benefit rate (CBR; stable disease or better). Herein, efficacy endpoints were assessed in the modified intent-to-treat (mITT) population (all pts who received ≥60 mCi total administered dose of iopofosine I 131), and whose treatment regimen prior to iopofosine included a BTKi. Safety was evaluated using CTCAE v4.03 in pts who received ≥1 dose of iopofosine. Data cut off for this analysis was Jan. 16, 2026. Results: As previously reported, 65 pts were dosed and 55 are included in the mITT population. Of those, 22 (40%) had received a BTKi containing regimen immediately prior to iopofosine; and 11 who previously received at least 2 regimens utilizing BTKis and 12 who were refractory to rituximab. In this subgroup, median age was 70.5 (range 55-88), 17 (77%) were male, and 5 (23%) were female. The median number of prior therapies was 3 (range 2-7), 15/22 (68%) were MYD88 mutated and 18/22 (82%) were TP53 wildtype. The MRR was 15/22 (68.2%), ORR was 19/22 (86.4%) and CBR was 100%, median PFS was 12 months (range 1.6 to 28.0) and median TFS was 19.1 months (range 2.5-34.4). Grade ≥ 3, related treatment emergent adverse events (TEAE) occurring in > 10% of pts included anemia (41%), leukopenia (41%), neutropenia (58%), and thrombocytopenia (86%). Conclusions: Iopofosine I 131 demonstrated significant efficacy; 100% CBR, 86.4% ORR and 68.2% MRR with a median PFS of 12 months (range: 1.6 – 28.0 months) in a pt population with no current standard of care therapy. The treatment was well-tolerated with a manageable toxicity profile with cytopenias as the only Grade 3 or greater TEAE. Based on the results of this pivotal trial, iopofosine I 131 could be a promising novel treatment for WM pts after BTKi therapy. Clinical trial information: NCT02952508 .

7530 Background: B-cell maturation antigen (BCMA)-directed CAR-T therapy is a highly effective treatment with potential for long-term remission of RRMM with improved outcomes vs daratumumab-based regimens. CAR-T suitability may be limited by delays/manufacturing failure and changes in pt condition, financial situation, or access to specialized treatment centers. We characterized pts with RRMM who underwent leukapheresis to prepare for CAR-T and pt treatment waiting time, to understand the delays incurred prior to CAR-T infusion. Methods: A real-world study in the US using the PharMetrics Plus claims database (July 2020–September 2024) was performed. Eligible pts were aged ≥18 years with RRMM, had their first leukapheresis claim (index date) during the index period (March 2021–August 2024), were continuously enrolled in medical/pharmacy benefits for ≥180 days prior to and ≥30 days after index date, and were not clinical trial participants. Pt characteristics, rate of CAR-T receipt, and time to CAR-T receipt were assessed during the variable follow-up. Results: Overall, 337 pts who received leukapheresis were identified. Median (interquartile range) age was 62 (55–67) years, and 59.1% of pts were male. Mean National Cancer Institute (NCI) comorbidity index was 0.52. Most pts received care in the Midwest (31.8%) or Northeast (24.6%) regions. Most pts (95.9%) received leukapheresis in an outpatient setting. Median available follow-up time was 255 days (mean 337 days). During follow-up, 183 pts (54.3%) did not receive CAR-T after leukapheresis. Among pts who had ≥12 months of follow-up (n=143), the proportion of pts who did not receive CAR-T was similar at 53.1% (n=76). Among pts who received CAR-T during the follow-up (n=154; 45.7%), the median waiting time was 54.0 days (mean 56.7 days). The cohort of pts who did not receive CAR-T had a higher proportion of females (48.6%/31.8%), were more likely to have Medicaid (29.5%/7.8%), had higher NCI comorbidity index (scores 0.55/0.47), and most commonly received care in the Northeast (35.5%/11.7%) while pts who received CAR-T most commonly received care in the Midwest (23.0%/42.2%). The most common first classes of multiple myeloma medications after leukapheresis but prior to CAR-T infusion in pts who did/did not receive CAR-T were an alkylating agent (65.6%/36.1%), proteasome inhibitor (40.3%/30.6%), steroid (38.3%/39.3%), immunomodulatory drug (22.7%/27.3%), anti-CD38 (20.8%/20.8%), and stem cell transplant (0%/17.5%). Conclusions: Over half of pts receiving leukapheresis did not receive CAR-T infusion, highlighting a persistent gap between eligibility and treatment delivery. These data emphasize an urgent need for broadly accessible BCMA-targeted therapies that provide deep and durable responses.

7546 Background: MRD assessment informs relapse risk in MM but is typically bone marrow-based and invasive. We therefore compared two minimally invasive MRD assays: BM-informed cfDNA whole-genome sequencing (cfWGS) and plasma proteomic MRD (EasyM). Methods: 71 longitudinal plasma samples (22 diagnosis, 49 follow-up) from 22 newly diagnosed MM patients across 8 Canadian sites (TFRIM4) had paired cfWGS and EasyM (Rapid Novor Inc). cfWGS MRD used patient-specific mutation lists from diagnostic BM WGS (Abelman et al., medRxiv 2025). EasyM used mass spectrometry to quantify residual M-protein from baseline. The primary endpoint was progression-free survival (PFS). Results: Among 22 MM patients (8 male, 14 female; median age at diagnosis 62 years), 8 progressed at a median follow-up of 52.6 months (range: 10-79 months). At 1-year maintenance (n = 18 available), cfWGS MRD+ (6/18) predicted inferior PFS (HR 20.12, 95% CI 2.23-181.60, p = 0.007). EasyM any-detect positivity was frequent (16/18, reflecting delayed clearance) and not prognostic (p = 0.99), with poor agreement vs cfWGS (44.4%, κ = 0.118). An exploratory EasyM clearance threshold of 0.93% (hypothesis-generating) classified 5/18 patients as MRD+ and stratified PFS (HR 8.78, 95% CI 1.55-49.82, p = 0.004), improving agreement with cfWGS (17/18, 94.4%, κ = 0.870). Progression clustered in cfWGS+/EasyM-high patients (EasyM >0.93%; 4/5; median 11.9 months post-collection [1.9–22.8]) and occurred once in cfWGS−/EasyM-low patients (1/12, 27.6 months). The only discordant case (cfWGS+/EasyM−) progressed 8.7 months after collection. Higher quantitative MRD burden was associated with inferior PFS (cfWGS: HR 2.92 per 1 SD, 95% CI 1.29-6.59, p = 0.01; EasyM: HR 5.48 per 1 SD, 95% CI 0.79-37.90, p = 0.085). At ~100 days post-autologous stem cell transplantation (ASCT; n = 16 available), EasyM was uniformly MRD+ (16/16) while cfWGS was MRD+ in 7/16 patients. Applying an EasyM clearance threshold (2.13%; 9 cleared vs 7 residual) improved agreement with cfWGS (14/16; 87.5%; κ = 0.746). Of two discordant cases, one cfWGS+/EasyM-cleared patient relapsed 38.6 months post-collection and one cfWGS−/EasyM-residual patient remained progression-free at last follow-up. At post-ASCT, both assays showed consistent but underpowered associations with PFS (cfWGS HR 6.32, 95% CI 0.70–56.76, p = 0.100; EasyM-clearance HR 2.36, 95% CI 0.39–14.18, p = 0.335). Across all post-treatment samples (n = 49), continuous cfWGS burden correlated with EasyM residual M-protein (rho = 0.535, p < 0.001). Conclusions: BM-informed cfWGS MRD strongly stratified PFS, whereas EasyM required a clearance definition due to near-universal early positivity. Concordant plasma burdens support complementary MRD information. Future work will validate these findings in larger cohorts and quantify the incremental value of combined cfWGS and proteomic MRD for early relapse prediction.

7533 Background: Ciltacabtagene autoleucel (cilta-cel) shows benefit for patients (pts) with relapsed/refractory multiple myeloma (RRMM). A recently recognized uncommon adverse reaction, IEC-EC is characterized by severe/persistent diarrhea typically 1–3 months post CAR-T cell infusion. Here we summarize incidence and features of IEC-EC in clinical trials of cilta-cel for RRMM. Methods: 483 pts across RRMM studies (CARTITUDE-1, -2, -4, and CARTIFAN-1) were evaluated for evidence of IEC-EC. The clinical picture and nomenclature for IEC-EC were described in the real-world setting after infusion of most pts. As such, retrospective analysis was performed to identify cases consistent with IEC-EC, defined as prolonged (≥3 weeks) and severe (≥grade 3) diarrhea after cilta-cel infusion, without clear infectious etiology. Correlative biomarker analyses included peripheral CAR-T cell expansion/persistence, immune cell composition, and cytokines/inflammatory markers. Centralized pathomorphological review and immunohistochemical analysis of available biopsies was conducted. Results: Across RRMM studies, 6/483 (1.2%) pts demonstrated the clinical picture of IEC-EC, presenting 12–214 days after receiving cilta-cel (median onset 67 days post infusion). Best response was CR/sCR for all subjects. Pts received therapies including steroids (4/6). Four pts experienced symptom resolution within 123–227 days; 2 had persistent symptoms until death (causes: multiorgan failure and COVID19). Pts with IEC-EC had lower levels of B cells and higher levels of CAR+ T cells and inflammatory cytokines (eg, IL-6) at onset compared to a GI symptom-free control group at comparable time; while all cilta-cel–treated pts experienced B cell depletion, pts with IEC-EC had more prolonged deficiency. Histological analyses of GI biopsies from 5 pts with IEC-EC revealed plasma cells, normally present in the GI tract, were absent. CAR-T cells were detected and localized to the lamina propria and were not observed juxtaposed with epithelia, making it unlikely direct damage to epithelia was caused by CAR-T cells. Histologic damage was greater in the small intestine (predominantly duodenum) than the colon. Conclusions: Retrospective analysis of cilta-cel trials identified a low IEC-EC incidence (1.2%). Findings support a reactive mechanism involving plasma cell depletion and immune dysregulation rather than direct CAR-T cell cytotoxicity and highlight the importance of upper endoscopy to identify injury patterns in the small intestine that may be less pronounced in the colon. Although the pathophysiology is not fully defined, increased awareness and earlier diagnosis may improve understanding of management and enhance likelihood of IEC-EC reversibility.