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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 (<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.

ABSTRACT Acute renal failure due to cast nephropathy (CAN) is a severe complication of multiple myeloma (MM). Here, we aimed to identify parameters associated with renal outcomes and survival in newly diagnosed MM patients with CAN‐related acute renal failure and to validate the IMWG criteria for renal response. CAN diagnosis was based on biopsy or clinical assessment. Of 787 registered patients, 354 met the inclusion criteria, requiring at least two therapy cycles with documented chemotherapy response, renal response, and eGFR. Baseline free light chain (FLC) levels (median 6825.65 mg/L) decreased below 500 mg/L in 67.8% of patients. According to IMWG classification, renal complete response, partial response, and minimal response were achieved in 33.9%, 19.5%, and 28.0% of patients, respectively. The best eGFR values > 60 mL/min/1.73 m 2 were observed in 33.9% of patients, while 33.3%, 22.3%, and 10.5% had best eGFR values of 30–59, 15–29, and < 15 mL/min/1.73 m 2 , respectively. Renal response correlated with baseline FLC levels, IgG kappa, eGFR, and ECOG status in multivariate analysis, as well as with myeloma response and FLC reduction in univariate analysis. Median overall survival was 77.6 months. Survival correlated with age, myeloma response, ECOG status, FLC kappa type, baseline eGFR, standard‐risk cytogenetics, and calcium levels, among other factors. A comparison of IMWG renal response criteria with classification based solely on best eGFR showed similar utility. Of 136 patients requiring dialysis, 80 (58.8%) were able to discontinue dialysis during therapy. Bortezomib containing myeloma therapy, along with significant FLC reduction, was associated with favorable outcome.

Abstract Accurate prediction of risk of progression from smoldering (SMM) to active multiple myeloma (MM) is paramount to individualized early therapeutic strategies with minimum risk of overtreatment. Current risk stratification models do not account for evolving biomarker trajectories. We assembled the largest cohort to date of 2,270 SMM patients from six international centers with longitudinal clinical and biological data to train and validate the PANGEA 2.0 risk models. Four evolving biomarkers were significantly associated with shorter time-to-progression: M-protein increase ≥0.2g/dL, involved:uninvolved serum free light chain ratio increase ≥20, creatinine increase >25%, and hemoglobin decrease ≥1.5g/dL. PANGEA 2.0 outperforms established models including the 20/2/20 and IMWG models by more accurately predicting progression (C-statistics=0.69–0.84), even without biomarker history (C-statistics=0.69–0.83) or recent bone marrow biopsy. PANGEA 2.0 is an easy-to-use, open-access tool (https://ghobrial.shinyapps.io/pangea_2_calculator) to improve and individualize SMM risk stratification. Validation tools are available to compare PANGEA 2.0 to established models (https://ghobrial.shinyapps.io/pangea_validation).

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.

PURPOSE The combination of the Bruton tyrosine kinase inhibitor ibrutinib with bendamustine-rituximab for first-line treatment of mantle cell lymphoma (MCL) prolonged progression-free survival (PFS), but without improvement in overall survival (OS), likely because of toxicity. Acalabrutinib was shown to be efficacious and less toxic than ibrutinib in a head-to-head trial in chronic lymphocytic leukemia and therefore might lead to better outcomes in MCL. METHODS Patients 65 years and older with previously untreated MCL received acalabrutinib (100 mg twice daily) or placebo (until disease progression or unacceptable toxicity), plus six cycles of bendamustine (90 mg/m 2 once daily; days 1 and 2) and rituximab (375 mg/m 2 as a single dose; day 1) followed by rituximab maintenance in responding patients for 2 years. Crossover to acalabrutinib at disease progression was permitted. The primary end point was PFS per the independent review committee; overall response rate and OS were secondary end points. RESULTS In total, 598 patients were randomly assigned, with 299 in each arm. At a median follow-up of 49.8 months using the reverse Kaplan-Meier method, the median PFS was 66.4 months in the acalabrutinib arm and 49.6 months in the placebo arm (hazard ratio [HR], 0.73 [95% CI, 0.57 to 0.94]; P = .0160). Benefit was seen across all subgroups, including those with high-risk features. Overall response/complete response rates were 91.0%/66.6% and 88.0%/53.5% in the acalabrutinib and placebo arms, respectively. OS was not significantly different (HR, 0.86 [95% CI, 0.65 to 1.13]; P = .27). Grade 3 or greater adverse events were reported in 88.9% and 88.2% in the acalabrutinib and placebo arms, respectively. CONCLUSION The combination of acalabrutinib with bendamustine-rituximab significantly improved PFS. Clinical benefit of acalabrutinib with bendamustine-rituximab was achieved with manageable toxicity.

Introduction: Teclistamab (Tec) is the first approved BCMA x CD3 bispecific antibody for the treatment of triple-class-exposed patients with relapsed/refractory multiple myeloma (RRMM) based on the pivotal MajesTEC-1 study. Tec was associated with high overall response rate (ORR) of 63% in heavily pretreated patients. After a longer follow-up of 30.4 months, CR rate was 46.1%, median duration of response (DOR) was 24 months (95% CI, 17.0 - not estimable), and median progression-free survival (PFS) was 11.4 months (95% CI, 8.8 - 16.4). Herein, we present updated analysis of real-world outcomes and safety with tec in RRMM with extended follow-up of more than 12 months. Methods: This is an international multicenter retrospective study of patients with RRMM treated with tec on-label at 9 academic centers from 5 countries (United States, United Kingdom, Greece, Spain, and Canada) through the International Myeloma Working Group (IMWG) Immunotherapy Committee. Patients with RRMM treated with commercial tec at the respective institutions between May 24, 2022 to January 4, 2024 were included. Median follow-up was 14 months with data collected until July 15, 2024. High-risk cytogenetic abnormalities (HRCA) was defined as 1q+, t(4;14), t(14;16), t(14;20), and/or del(17p). Response was assessed using the IMWG consensus criteria. Patient characteristics were summarized by frequency (percentage) or median (interquartile range [IQR] or range). PFS, overall survival (OS), DOR were evaluated using the Kaplan-Meier method. Results: There were 223 patients included in this analysis with the following characteristics: median age of 67 (range 33-91) with 24% ≥75 years; 45% female; 74% White, 10% Black, 9% Asian, and 7% other/unknown; 86 of 176 (49%) with high risk cytogenetics, including del(17p), t(4;14), t(14;16), t(14;20), and gain/amp 1q; 29.4% (37/126) with known extramedullary disease; 14% with creatinine clearance ≤30 ml/min. Patients received a median of 6 (IQR, 4-8) prior lines of therapy with 52% (107/206) being penta-drug refractory. Among 212 patients with available data, 161 (75.9%) patients would have been ineligible for MajesTEC-1. There were 94 (42%) patients who received prior BCMA-directed therapy (29.8% antibody-drug conjugate [ADC] alone; 45.7% CART alone; 6.3% bispecific antibody alone; 17.0% ADC and CART). Median time from diagnosis to tec initiation was 6.1 (range 0.6-29.2) years. For the 206 response-evaluable patients, ORR was 66%, including 25.2% ≥CR, 33.5% VGPR, and 7.3% PR. ORR for the 90 response-evaluable patients with prior BCMA-directed therapy was 54.5% (21.1% ≥CR, 26.7% VGPR, 6.7% PR). After a median follow-up of 14 (95%CI, 13-14) months, median PFS and OS were 8.8 (95% CI, 5.5-14) and 20 (95% CI, 18-not reached [NR]) months, respectively. 12-month PFS estimate was 46% (95% CI, 40%-54%), and 12-month OS rate was 65% (95% CI, 59%-72%). Median DOR was 17 (95% CI, 17-NR) months with 12-month estimate of 68% (95% CI, 60%-77%). Tec step-up dosing occurred in the outpatient setting for 57 (25.6%) patients. CRS occurred in 119 out of 222 (53.6%) patients with almost all being grade 1-2, except for 1 grade 4 event. ICANS occurred in 18 out of 216 (8.3%) patients (grade 1-2: 5.1%; grade 3-4: 2.8%). Any grade infection occurred in 130 (58.3%) patients; 25.1% of patients had grade ≥3 infection, including 10 patients with grade 5 infection. While receiving teclistamab, 79 (35.4%) patients had ≥2 infections. IVIG was given in 114 out of 164 (69.5%) patients. Conclusion: In this multicenter international real-world analysis of outcomes and safety associated with tec, ORR was high at 66% with 25.2% of patients achieving ≥CR. CR rates may be underestimated due to infrequent bone marrow confirmation in the real-world datasets. Encouragingly, ORR was 54.5% in BCMA exposed RRMM patients, including 21.1% with ≥CR. After a median follow-up of 14 months, heavily pretreated patients including patients with prior BCMA therapy had durable responses with median PFS of 8.8 months and median DOR of 17 months. There were no new safety signals noted in this real-world study. This is the largest real-world study to date of teclistamab with long-term follow-up of more than 12 months. Additional data including more patients, longer follow-up and results from difficult to treat subgroups will be presented at the meeting.

Introduction: Acute kidney injury (AKI) due to cast nephropathy is a medical emergency that leads to a diagnosis of myeloma in less than 3% of cases, but up to 30% of patients develop kidney impairment during the course of their disease. Currently, studies aiming to identify parameters that correlate with kidney function recovery and response to myeloma are limited due to small sample size or single center reports. We have therefore initiated an international collaboration and collected a large number patients (pts) from 16 participating centers. Objectives: To assess the impact of pts and disease characteristics and treatment-specific factors on renal outcome and overall survival and to validate the IMWG criteria for renal response in pts with cast nephropathy and newly diagnosed MM. Patients and Methods: Three-hundred forty-three pts (median age: 65.5 range 35-93 yrs) with newly diagnosed MM and an eGFR &lt;40ml/min/1.73m2 have been selected from 704 pts that had been enrolled in the database hosted by RedCap. Eligibility criteria were a diagnosis of AKI due to cast nephropathy diagnosed either by kidney biopsy (n=119) or on clinical criteria (AKI in the setting of involved free light chain concentration of ≥500 mg/L), newly diagnosed multiple myeloma, &gt;2 cycles of therapy, time and type of therapy, best eGFR and best myeloma response available. Results: Median follow up was 36.9 months. Myeloma therapy resulted in renal CR, and PR as defined by the IMWG criteria in 131 (38.2%) and 57 (16.6%) pts, respectively, 54 (15.7%) and 82 (23.9%) pts had minor response or no response, respectively. Nineteen (5.5%) pts were not classifiable by the IMWG response criteria (pts with eGFR 15-&lt;30, with increase to eGFR to ≥30-&lt;40). An eGFR of &gt;60, ≥30-&lt;60, ≥15-&lt;30, and &lt;15ml/min was achieved by 131 (38.2%), 112 (32.7%), 67 (19.5%), and 33 (9.6%) pts respectively. Myeloma response (≥VGPR) correlated significantly with renal response (≥PRrenal) (OR 1.64, CI 1.05-2.56, p=0.03) and with OS compared to no myeloma response (median 89.7 vs. 39.7 months, HR 2.12, CI 1.55-2.89, p&lt;0.0001). A &gt;50% reduction in FLCs from baseline to treatment cycle 2 (OR 5.92, CI 2.15-19.23, p=0.001) and cycle 3 (OR 5.25, CI 2.15-19.25, p=0.006) were strongly associated with renal response Median OS was 69.6 months (CI 55.4-89.7). Forty-three pts died within the first 12 months of treatment and additional 146 during further FU. Pts with a best GFR of &gt;15ml/min had a significantly longer OS compared to those with GFR &lt;15ml/min (median: 77.9 vs 31.9 months, HR 1.85, CI 1.16-2.94, p=0.01). The comparison of survival of pts with different renal response groups and with the best eGFR showed no statistically significant difference (log rank p=0.1, long rank p=0.057, respectively). Other factors that correlated with longer OS were bortezomib-based therapy (77.9 vs. 44.0 months, HR 1.59, CI 1.05-2.38, p=0.03), M-protein isotype with κ as compared to l light chain type (84.9 vs. 51.4 months, HR 1.47, CI 1.09-2.00, p=0.013), and higher hemoglobin (HR 1.16, CI 1.06-1.26, p=0.001). In contrast, hypercalcemia which was noted in 101 (29.4%) pts (HR 1.10, CI 1.03-1.18, p=0.005), ISS stage III vs. I-II (57.8 vs. 126.2 months, HR 2.26, CI 1.22-4.17, p=0.009), and ECOG status 3+4 vs. 2 vs. 0+1 (24.4 vs. 44.6 vs. 103 months, HR 2.83, CI 2.15-3.74, p&lt;0.0001) were associated with shorter OS. Hypercalcemia, correlated with renal response (OR 1.27, CI 1.12-1.44, p=0.0002), and best eGFR ≥46.4 ml/min (median dichotomized) (OR 1.28, CI 1.14-1.46, p&lt;0.0001). 119 (34.7%) pts required initial dialysis, OS was significantly longer in those who achieved best eGFR levels of &gt;15ml/min. (77.6 vs 31.9 months, HR 0.54, CI 0.34-0.86, p=0.01); 64 (53%) pts discontinued dialysis. Conclusion: Myeloma response correlated with renal response as defined by IMWG criteria. A &gt;50% reduction in FLCs from baseline to treatment cycle ≥2 was strongly associated with renal response. OS was longer in pts with renal response, in pts receiving bortezomib-based therapy, and in pts with kappa light chain M-proteins. Hypercalcemia was frequent (29.4%), and associated with higher renal response rate and best eGFR, but shorter OS. Pts on dialysis who achieved eGFR &gt;15ml/min had better survival. Fast diagnostic work up, rapid treatment initiation and achieving significant myeloma response (≥VGPR) is essential to prevent irreversible kidney damage. Including novel immunotherapies may further improve outcome.