Nagarajan, Chandramouli

Abstract Introduction: Elranatamab (Elra) is a bispecific antibody (BsAb) targeting BCMA that is approved for patients with triple class exposed relapsed refractory myeloma (RRMM) on the basis of the MagnetisMM-3 phase 2 trial. For BCMA naïve patients, an overall response rate (ORR) of 61.0% and median progression free survival (PFS) of 17.2m was observed with a median overall survival (OS) of 24.6m. However, efficacy and safety information in the real world is lacking. Methods: This was an international retrospective study of patients with RRMM treated with Elra monotherapy outside of clinical trials. Data was collected through the International Myeloma Foundation Immunotherapy Database from 7 countries (UK, USA, Canada, Greece, Spain, Czech Republic and Singapore). High-risk cytogenetic abnormalities (HRCA) were defined as 1q+, t(4;14), t(14;16), t(14;20), and/or del(17p). Response was assessed using IMWG consensus criteria. Patient characteristics were summarized by frequency (percentage) or median (range). PFS, OS were evaluated using the Kaplan-Meier method and reported with 95% confidence intervals. Results: 79 patients were included. Median age was 67 years (range: 41-95y) with 20% ≥75 years. Racial distribution was: 75% White, 16% Black/African American, 8% Asian/Pacific. 55% were ECOG performance status (PS) 1-2. Patients received a median of 5 prior lines (range 1-11), and 35% were BCMA exposed (9% CAR-T, 5% ADC, 7% BsAb, 8% BsAb plus CAR-T, 4% ADC plus BsAb). Of those with available data, 45% had HRCA,13% had extramedullary disease (EMD) and 32% had penta-drug refractory RRMM. Overall, 48% would not have been eligible for the MagnetisMM-3 trial. Median follow-up was 6.3m (range 0.5-35.0). ORR was 53% (PR 11%, VGPR 33%, CR 8%, sCR 1%) and 67% for BCMA naïve patients. Responses were significantly lower for BCMA exposed patients (ORR 31%) but did not differ by age (51% <75yrs vs 60% ≥75yrs). On univariate analysis, prior BCMA exposure, platelets <50, presence of HRCA and penta-refractoriness were significantly associated with a lower response rate. PFS for the whole cohort at 6 and 12m was 64% (95%CI, 54-77%) and 52% (40-67%); for BCMA naïve patients, it was 77% (65-90%) and 67% (54-84%), respectively. Within the whole cohort, PFS was shorter for: BCMA exposed (median 4.0m vs not reached (NR)), platelets <50 (2.0 vs 21.7m), HRCA (7.2m vs NR), penta-refractory (4.3m vs NR). PFS did not differ significantly by EMD, PS, age, or creatinine clearance. OS for the whole cohort at 6 and12m was 74% (64-85%) and 58% (45-74%); for BCMA-naïve patients, it was 80% (43-85%) and 70% (57-87%), respectively. Within the whole cohort, OS was shorter for: BCMA exposed (median 10.3m vs NR), platelets <50 (4.3m vs NR), HRCA (10.7m vs NR) and penta-refractory (10.3m vs NR). Univariate regression analysis demonstrated that prior BCMA exposure, platelets <50 and penta-refractoriness were significantly associated with a worse PFS and OS, and HRCA predicted poorer survival CRS was observed in 41% of patients (grade(G)1: 35%, G2: 5%, ≥G3: 0%) with most occurring with the first step up dose (SUD): SUD1: 29%, SUD2: 15%, full dose: 4%. Tocilizumab was used in 20% and steroids in 3%. ICANS was observed in 4 cases (5%): G1: 2, G2: 1, G4: 1. Treatment was with steroids (n=3) and tocilizumab (n=2). G3-4 thrombocytopenia was observed in 19% and 14% required platelet transfusions. G3-4 neutropenia occurred in 25% with overall 31% requiring GCSF. Infections were reported in 33 (42%) patients with median time to infection of 41 days. A total of 94 infection episodes were observed over 581 personal months. There were 2 infection-related deaths reported (1 had IVIG, 1 did not). 64% had hypogammaglobulinemia (IgG < 400mg/dl) and IVIG was given in 65% of patients. Conclusions: In this first international real world analysis, Elranatamab achieved a response rate of 67% and a 12m PFS of 67% in BCMA naïve patients, similar to the MagnetisMM-3 trial despite almost half not meeting trial eligibility. However, prior BCMA exposure, platelets <50, high risk cytogenetics and penta refractory status were predictors of poorer outcomes. Acknowledgements: The International Myeloma Foundation, International Myeloma Working Group (IMWG)

Abstract Background: BCMA- and GPRC5D-targeting immunotherapies including CART cell therapy and Bispecific antibodies are currently approved for the treatment of multiple myeloma. However, clinical outcomes after dual antigenic exposure remain undefined. Herein we report the first report of BCMA-GPRC5D dual targeted multiple myeloma (DEMM). Methods: We conducted a retrospective multi-center study of RRMM patients treated with both BCMA- and GPRC5D-targeted treatments (TT) (CAR T, bispecific antibodies, ADCs) between November 1, 2022, and July 1, 2025. Outcomes included PFS1 (post-dual exposure), and overall survival (OS). Kaplan-Meier estimates and event-free probabilities were calculated. Results: One hundred and fifty patients who underwent TCE treatments were included and 49 patients met the criteria for inclusion. Median age was 65 years, 22.4% had creatinine clearance <=30 and ECOG 2 or greater was present in 22.2%; 57% had high-risk cytogenetics (IMWG 2016), and 60.5% were penta-refractory. Patients received a median of 6 prior lines of therapy (LOT) before 1st TCE and 9 prior LOT before DEMM. 65.3% received 1 TCE, 30.6% received 2 TCE and 4.1% received 3 TCE before DEMM. Similarly, 67.3% received 1 BCMA, 24.5% received 2 BCMA TT and 4.1% received 3 BCMA TT before DEMM. Prior TT included- BCMA CART (57.1%), BCMA Bispecific (57.1%), BCMA ADC (18.4%), other TCE (10.2%). The last dual exposure was GPRC5D Bispecific in 91.8%, BCMA Bispecific in 6.1% and BCMA CART in 2%. The median followup post relapse was 3.4 months (range 0.0-16 mos). The median PFS during the last dual exposure TT was 3.98 months (95% CI: 2.96–6.70). 32.7% did not receive any subsequent LOT and died due to progressive disease. 67.3% of patients had progressive MM and received next LOT. Median PFS1 was 1.77 months (95% CI: 1.28–6.21) with 3-, 6-, and 12-month event-free probabilities of 44%%, 19% and 0% respectively. Median OS was 5.7 months (95% CI: 2.53-12.16) for DEMM from the time of refractoriness to dual antigenic targets. Conclusions: Patients dual-exposed to BCMA- and GPRC5D-directed therapies have a poor prognosis, 32.7% had not received further treatment and in those who received treatment the PFS1 was less than 2 months and an OS of 5.7 months from progression. This reflects an area of high unmet need for the patients that are dual-exposed to BCMA- and GPRC5D-directed therapies. Further data on the cohort will be updated at the meeting. Acknowledgements include, the International Myeloma Foundation, IMWG.

7510 Background: The randomized Phase 3 CANOVA study’s (NCT03539744) primary analysis showed multiple numerically improved efficacy endpoints with VenDex v PomDex, but the primary endpoint of mPFS by IRC was not statistically significant. Here, we report correlative biomarker analyses from CANOVA. Methods: CANOVA is a randomized, global, open-label Phase 3 study of VenDex v PomDex in pts with t(11;14)+ RRMM and ≥2 prior lines of therapy (LOTs). The primary endpoint was mPFS by IRC. Key secondary endpoints included ORR, ≥VGPR, mOS, and MRD negativity (<10-5). In post hoc mPFS sensitivity analysis, disease progression, death, and start of next LOT were defined as events. BCL2 gene expression by RNAseq (3.7 log2 FPKM prespecified median cutoff for BCL2high v BCL2low) and chr1q abnormalities by whole-exome sequencing (normal, gain, or amp) were assessed centrally from pretreatment, CD138-enriched BM aspirates. Results: mPFS, post hoc mPFS, and mOS in the VenDex arm were similar by BCL2 status, with numerically higher ORR, ≥VGPR, and MRD negativity rates in the BCL2highsubgroup. In contrast, mPFS and mOS within the PomDex arm were numerically longer in the BCL2lowsubgroup, despite equal ORR in both subgroups (Table). Presence of 1q abnormalities was evenly distributed across BCL2high v BCL2low subgroups in the VenDex arm (51% v 45%) but not in the PomDex arm (59% v 31%). Normal 1q and gain(1q) subgroups had numerically improved mPFS, mOS, ORR, ≥VGPR, and MRD negativity with VenDex; pts with amp(1q) had poor outcomes regardless of treatment, albeit the sample size was small. Conclusions: Pts with BCL2high or gain(1q) had numerically improved clinical efficacy with VenDex v PomDex. Clinical benefit was consistent across BCL2 subgroups ( BCL2high or BCL2low) with VenDex but not PomDex. Pts with amp(1q) fared poorly irrespective of treatment arm. Clinical trial information: NCT03539744 . [Table: see text]