Berdeja, Jesús G.

Background: Anti-BCMA CAR T cells are a new standard of care for the treatment of RRMM patients. Hence, it is paramount to identify determinants of response and resistance for individualized approaches. There is emerging data about the importance of depth of response in prolonged progression-free survival (PFS) and of genetic antigen escape in treatment resistance. By contrast, there is limited understanding of how patient' outcomes are shaped by immune fitness prior aphaeresis, and virtually no data about CAR T and endogenous profiles post infusion. Aim: Characterize immune dynamics and investigate its prognostic value in RRMM patients treated with CAR T cells. Methods: Immune profiling was performed using multidimensional and computational flow cytometry in 285 bone marrow aspirates from 120 RRMM patients enrolled in the KarMMa phase 2 trial. In total, 170 immune clusters were identified and systematically quantified in a pileup analysis of samples collected before and at months 1, 3, 6 and 12 after CAR T infusion. Immune scores were developed using cox regression with 10-fold cross-validation. Results: At baseline (n = 63), there were significant associations between the bone marrow immune composition and the number of prior lines of treatment, prior autologous transplant and staging. Namely, there were higher proportions of ICOS, PD1, TIGIT and TIM3 positive cells within the CD4+ and CD8+ T cell compartments from heavily pretreated patients and those with R-ISS 3. A baseline immune score defined by the percentages of GrzmB+HLADR+ cytotoxic NK cells, TIGIT+ Tregs, CD4+CD127+ICOS+ and CD4+CD25+CD127+TIGIT+, CD8+TIGIT+, CD8+GrzmB+HLADR+ and CD8+CD27+CD95+CD45RAloCD197lo T cells was associated with PFS. Patients with low vs high risk immune score at baseline had median PFS of 25 vs 6 months, respectively (p < .001). Interestingly, there were no significant associations between the baseline risk score and treatment or staging, suggesting potential complementarity of immune profiling with other prognostic factors. At month 1 after infusion (n = 55), the presence of >1% vs <1% CAR T cells was associated with longer PFS (medians of 20 vs 8 months, p = .002). In addition to the magnitude of CAR T persistence, it was interesting to observe increased percentages of CD8+ CAR T cells in patients with <5 prior lines of therapy, of CD4+HLADR+ and CD8+TEMRA CAR T cells in patients with R-ISS 1/2, as well as of PD1+TIM3+ CD4+ and CD8+ CAR T cells in patients with R-ISS 3. Moreover, the phenotype of CAR T cells was associated with PFS. Patients with low vs high risk immune score (ie, based on the percentages of CD4+CD57+, CD8+CD27-EM, CD8+PD1+TIM3+ and CD4+CD8+ CAR T cells) had median PFS not reached vs 11 months, respectively (p < .0001). Similarly to the above, there were no significant associations between the CAR T immune risk score and treatment or staging, suggesting potential complementarity of CAR T quantification and phenotyping post-infusion with other patient' characteristics. Next, we investigated endogenous T cell dynamics in 51 RRMM patients with paired samples prior and after CAR T infusion. There were significant differences in the frequencies of 30 immune clusters, including CD27+ naïve and EM CD4+ and CD8+ T cells, ICOS+ and TIGIT+ Tregs, CD4+ and CD8+ T cells, as well as of CD25+CD127+ CD4+ and CD8+ T cells. Furthermore, an immune risk score defined at the latest available time point (n = 95) was associated with PFS (p < .0001). Patients with lower levels of GrzmB+ cytotoxic NK cells and of immunoregulatory HLADR- NK cells, as well as of CD4+CD27+CD95+CM, CD4+HLADR+, CD8+PD1+ and CD8+CD27-CD95+EM T cells showed a high risk score and a median PFS of 6 vs 20 months in patients with low risk immune score. Conclusions: This is one of the largest dynamic studies of immune profiling in a clinical trial investigating anti-BCMA CAR T cells in RRMM. Our results uncovered that patient' immune status is shaped by prior treatment and staging, and that the distribution of different NK, Treg, CD4+ and CD8+ T cells prior aphaeresis is associated with PFS. Furthermore, the phenotype of CAR T cells at month 1 after infusion may be as prognostic as its percentage. We also showed how treatment with CAR T cells modulates the bone marrow immune composition and how it may contribute to immune escape vs surveillance. Altogether, this study supports immune profiling for improved understanding of response and resistance to CAR T cells in RRMM.

Background: Proven salvage therapies for pts with triple-class refractory MM who progress on BCMA-targeted therapies are lacking.Fc receptor-homolog 5 (FcRH5) is a type I membrane protein that is expressed exclusively in the B-cell lineage. Cevostamab is a FcRH5xCD3 BsAb that facilitates T cell-mediated killing of MM cells. In an initial Phase I study (GO39775), cevostamab monotherapy was clinically active and had manageable toxicity in pts with heavily pretreated relapsed/refractory MM (Trudel et al. ASH 2021). In Cohort A1 of the subsequent Phase I/II CAMMA 2 study (CO43476; NCT05535244), cevostamab was highly active and had manageable safety at the 160mg target-dose (TD) level in pts with triple-class refractory MM who had received a prior BCMA-targeted antibody-drug conjugate (ADC; overall response rate [ORR]: 60%, 6/10 pts) or chimeric antigen receptor T-cell (CAR-T) therapy (ORR: 73%, 8/11 pts) but had not received a prior BCMA-targeted BsAb (Kumar et al. EHA 2024). We present initial results from Cohort A2, which enrolled pts with triple-class refractory MM who had received prior BCMA-targeted therapies, including ≥1 BCMA-targeted BsAb. An exploratory analysis of baseline patient and tumor-related factors is also presented. Methods: Cevostamab was initiated with step dosing (Cycle [C] 1 Day [D] 1: 0.3mg; C1D2, D3, or D4 depending on the emergence of cytokine release syndrome [CRS] after the initial administration: 3.3mg) and continued at the 160mg TD on C1D8 and on D1 of each subsequent 21-day cycle until disease progression (PD) or unacceptable toxicity. Cytokine, tumor antigen, T-cell function/activation, and inhibitory immune checkpoint expression were assessed in blood and tumor samples collected at baseline and during treatment. Results: As of February 23, 2024, 21 pts (median age: 64 years, range: 46-84) had been enrolled into Cohort A2. Seven pts (33%) had extramedullary disease and 5/12 pts (42%) with a conclusive assay result had high-risk cytogenetics (t(4;14), t(14;16), or del(17p)). All pts were heavily pretreated (median prior lines of therapy: 8, range: 5-14); 62% had received ≥2 prior BCMA-targeted therapies (median time since last: 122 days, range: 68-558) and 33% had received ≥2 prior BsAbs (median time since last: 139 days, range: 68-782). Most pts (86%) were refractory to their last line of therapy; 62% were penta-drug refractory. Median follow-up was 173 days (range: 20-360). Grade (Gr) 3-4 adverse events (AEs) occurred in 71% of pts (15/21). Gr 3-4 AEs in >3 pts were neutropenia, anemia, thrombocytopenia (38% each), and infections (29%). CRS occurred in 76% of pts (16/21) and was mainly Gr 1 (43%) or Gr 2 (29%); 1 patient had Gr 3 CRS. One treatment-related Gr 5 (fatal) AE of pneumonia was reported in the context of PD. No treatment-related AEs leading to cevostamab discontinuation occurred. Objective responses (partial response [PR] or better) were observed in 2/21 pts (ORR: 10%). Both pts achieved a very good PR and had ongoing responses at cut-off. Stable disease was observed in 10 pts (48%). Pts in the prior BsAb group had received more prior lines of therapy than those in the prior ADC and CAR-T groups (median 8 vs 5 and 6, respectively) and more prior BCMA-targeted therapies (median 2 vs 1 and 1). The percentage of pts with low levels (<4.5 ng/mL) of soluble BCMA in plasma was also higher in the prior BsAb group (47% vs 0% and 18%). At baseline, inhibitory immune checkpoint expression across T-cell subsets was more common in the prior BsAb group. Notably, the median frequency of PD1+CD8+Tnaive and TIGIT+CD8+Tnaive cells in blood was higher in the prior BsAb group (21% and 29%, respectively) than in the prior ADC (3% and 6%) and CAR-T groups (4% each). Peak median IL-6 and IFN-γ levels were delayed until the first TD in the prior BsAb group, suggesting a different pharmacodynamic profile. Conclusions: Cevostamab has manageable safety in pts with triple-class refractory MM who have received prior BCMA-targeted therapies, including ≥1 BCMA-targeted BsAb. Clinical responses were less frequent in the prior BsAb group than in the prior ADC and CAR-T groups, which could be explained by the higher number of prior lines of therapy and T-cell exhaustion due to multiple prior exposures to BsAbs. Notably, the high frequency of CD8+ T-cell subsets expressing inhibitory immune checkpoints in the prior BsAb group suggests a level of T-cell dysfunction that could prevent effective T-cell activation.

Abstract Outcomes are poor in triple-class–exposed (TCE) relapsed and refractory multiple myeloma (R/RMM). In the phase 3 KarMMa-3 trial, patients with TCE R/RMM and 2 to 4 prior regimens were randomized 2:1 to idecabtagene vicleucel (ide-cel) or standard regimens (SRs). An interim analysis (IA) demonstrated significantly longer median progression-free survival (PFS; primary end point; 13.3 vs 4.4 months; P < .0001) and higher overall response rate (ORR) with ide-cel vs SRs. At final PFS analysis (median follow-up, 30.9 months), ide-cel further improved median PFS vs SRs (13.8 vs 4.4 months; hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.38-0.63). PFS benefit with ide-cel vs SRs was observed regardless of number of prior lines of therapy, with greatest benefit after 2 prior lines (16.2 vs 4.8 months, respectively). ORR benefit was maintained with ide-cel vs SRs (71% vs 42%; complete response, 44% vs 5%). Patient-centric design allowed crossover from SRs (56%) to ide-cel upon progressive disease, confounding overall survival (OS) interpretation. At IA of OS, median was 41.4 (95% CI, 30.9 to not reached [NR]) vs 37.9 (95% CI, 23.4 to NR) months with ide-cel and SRs, respectively (HR, 1.01; 95% CI, 0.73-1.40); median OS in both arms was longer than historical data (9-22 months). Two prespecified analyses adjusting for crossover showed OS favoring ide-cel. This trial highlighted the importance of individualized bridging therapy to ensure adequate disease control during ide-cel manufacturing. Ide-cel improved patient-reported outcomes vs SRs. No new safety signals were reported. These results demonstrate the continued favorable benefit-risk profile of ide-cel in early-line and TCE R/RMM. This trial was registered at www.ClinicalTrials.gov as #NCT03651128.

Multi-agent regimens incorporating immunomodulatory (IMiD®) agents such as thalidomide, lenalidomide, and pomalidomide have become the preferred standard of care for the treatment of patients with multiple myeloma (MM), resulting in improved survival outcomes. Currently, there are three IMiD agents approved for the treatment of MM: thalidomide, lenalidomide, and pomalidomide. Lenalidomide is commonly used to treat patients with newly diagnosed MM and as maintenance therapy following stem cell transplant or after disease relapse. Pomalidomide, the focus of this review, is approved in patients with relapsed/refractory MM (RRMM). Despite survival benefits, IMiD agents each have different safety profiles requiring consideration both prior to starting therapy and during treatment. Adverse event (AE) management is essential, not only to ensure treatment adherence and thus ensure optimal efficacy but also to maintain patient quality of life. Here, we discuss AEs associated with pomalidomide and present five clinically relevant hypothetical case studies in patients with RRMM to provide scenario-driven guidance regarding treatment selection and AE prevention and management in the clinical setting. Lastly, as new treatment approaches continue to be explored in MM, we also discuss novel cereblon E3 ligase modulator (CELMoD™) agents including iberdomide (CC-220) and mezigdomide (CC-92480).

Background: Despite the development and approval of effective therapies for multiple myeloma (MM), MM remains an incurable disease. Moreover, patients with high-risk cytogenetics, like translocation t(4;14), continue to have a poor prognosis compared to standard-risk patients. No novel agents have been approved specifically for this population. There remains an unmet need for precision therapies for MM that can target specific drivers of high-risk MM like t(4;14). Multiple myeloma SET domain-containing protein (MMSET) overexpression observed in 100% of patients with t(4;14) acts through the MMSET-H3K36me2 axis, which promotes malignant transformation through regulation of multiple oncogenic programs. KTX-1001, a methyl transferase inhibitor, is a novel, first-in-class, potent, oral, small molecule that inhibits MMSET and the methylation of lysine K36. KTX-1001 had favorable drug-like properties, demonstrated in vivo activity, and was well tolerated in non-clinical studies. Based on these data, KTX-1001 is now being studied in a Phase 1 dose escalation and expansion study in relapsed and refractory multiple myeloma (RRMM). Study Design and Methods: This multi-country, Phase 1, open-label study (NCT05651932) is designed to assess the safety, tolerability, and initial clinical activity of KTX-1001. The study will also examine the recommended phase 2 dose (RP2D), pharmacokinetics (PK) and pharmacodynamics (PD). Part A of this trial includes an accelerated titration, followed by 3+3 dose escalation with backfill of cohorts for dose optimization prior to moving to Part B, which is an expansion phase at the RP2D (please see Figure 1 for study design schematic). The expansion phase will only include patients with t(4;14). KTX-1001 will be administered orally daily and given until disease progression, unacceptable toxicity, or withdrawal from the study. Estimated enrollment for Parts A and B will be approximately 60 patients. The study will enroll patients with RRMM who have received ≥3 prior lines of therapy, including a proteasome inhibitor (PI), immunomodulatory drug (IMiD), and anti-CD38 antibody. Patients must have measurable disease, be ≥18 years of age, have an Eastern Cooperative Oncology Group score of ≤2, and adequate bone marrow, liver, and kidney function. Key exclusion criteria include history of or current plasma cell leukemia, active central nervous system (CNS) disease, or active unstable cardiovascular function. The primary endpoints of safety and tolerability include incidence of dose-limiting toxicity (DLTs), treatment-emergent adverse events (AEs), and treatment-related AEs. Secondary endpoints include plasma concentrations of KTX-1001 and efficacy outcomes such as objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Exploratory biomarker and pharmacodynamic assessments will also be performed. The sample size was not determined by formal statistical methods but will be sufficient to provide preliminary information on safety, PK, PD, and efficacy. Statistical analyses will be primarily descriptive. Conclusion: This Phase 1 study will evaluate a potential treatment for RRMM utilizing KTX-1001, which is a novel, first-in-class, potent, oral small-molecule MMSET inhibitor. The study is open and actively enrolling patients at centers in the United States, Spain, France, and Canada.

Introduction Patients (pts) with multiple myeloma (MM) have a higher risk of progression/death following an inadequate response to frontline ASCT (van de Velde Eur J Haematol 2017). Therapies (Tx) with novel mechanisms of action may further improve response outcomes. Ide-cel previously demonstrated frequent, deep, and durable responses in KarMMa (Munshi N Engl J Med 2021) and significantly improved median progression-free survival (PFS) and overall response rate (ORR) versus standard regimens in KarMMa-3 (Rodríguez-Otero N Engl J Med 2023) in pts with triple-class-exposed relapsed and refractory MM. KarMMa-2 (NCT03601078) is a multicohort, phase 2, multicenter trial evaluating the efficacy and safety of ide-cel in pts with MM; cohort 2c included pts with NDMM who had an inadequate response to frontline Tx with ASCT. In cohort 2c, with a median follow-up of 27.9 months, ide-cel demonstrated deep and durable responses; complete response (CR) rate was 74.2% (ORR, 87.1%), with a 24-month PFS rate of 83.1% (Dhodapkar Blood 2022). Here, we report results with an additional 11.5 months of median follow-up for updated efficacy and safety data, and health-related quality of life (HRQoL) outcomes in cohort 2c. Methods Eligible pts had NDMM, received ≥ 3 cycles of induction Tx (including a proteasome inhibitor, an immunomodulatory agent, and dexamethasone), had < very good partial response (VGPR) 70-110 days after ASCT (single/tandem), and had Eastern Cooperative Oncology Group performance status ≤ 1. Pts received a single infusion of ide-cel (dose range: 150-450 × 10 6 CAR+ T cells) after lymphodepletion and could receive maintenance Tx post-infusion at investigator's discretion. The primary endpoint CR rate and secondary endpoints ORR, duration of response (DOR), PFS, overall survival (OS), safety, and patient-reported outcomes on HRQoL, assessed via European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core 30 Questionnaire (QLQ-C30) and EORTC Quality of Life Multiple Myeloma Module 20 Questionnaire (QLQ-MY20), are reported. The exploratory endpoint of minimal residual disease (MRD) negativity (sensitivity, 10 -5) is also reported. Results At data cutoff (May 3, 2023), with a median follow-up of 39.4 (range, 31.6-44.7) months, all 31 pts who were infused with ide-cel were alive; 28 (90.3%) remained in follow-up, with 3 (9.7%) having discontinued due to disease progression. The ORR and CR rates were 87.1% and 77.4%, respectively ( Table); best overall response in 1 pt improved from VGPR to stringent CR. The median DOR was not reached (NR; 95% CI, NR-NR), neither was median PFS (95% CI, 38.0-NR) or median OS (95% CI, NR-NR); the 36-month event-free rates were 80.9%, 76.8%, and 100.0%, respectively. In pts who did not receive lenalidomide (LEN) maintenance, 9 (29.0%) had disease progression; of the 8 pts who received LEN maintenance post ide-cel infusion, none experienced disease progression. At 36 months, MRD negativity was confirmed in 9/14 (64.3%) evaluable pts; all 9 achieved ≥ CR. In this extended follow-up, safety results were generally consistent with the previous data cutoff. All pts experienced ≥ 1 any-grade adverse event (AE), most commonly hematologic, including neutropenia (80.6%), anemia (38.7%), leukopenia (32.3%), and thrombocytopenia (29.0%); infection and infestation AEs occurred in 74.2% of pts. No grade 5 AEs were reported. Incidence of any-grade cytokine release syndrome (58.1%; no grade ≥ 3) was unchanged and there were no additional reports of parkinsonism since the previous report. Overall, HRQoL improved ( Figure) and MM disease symptoms were stable over time based on the EORTC QLQ-C30 and QLQ-MY20, respectively, following ide-cel treatment; by month 3, > 75% of pts had improved or stable global health status/QoL. Conclusions Ide-cel continued to demonstrate deep, durable responses in pts with an inadequate response to frontline ASCT, no new safety signals were observed with extended follow-up, and no deaths were reported. No pts who received LEN maintenance post ide-cel experienced disease progression. Ide-cel treatment resulted in stable or improved HRQoL. Overall, ide-cel continued to demonstrate a favorable clinical benefit-risk profile in NDMM after ASCT. Study support 2seventy bio and Celgene, a Bristol-Myers Squibb Company.

Introduction: BCMA-directed CAR-T and Bispecific T-cell engager (BiTE) therapies have shown remarkable overall response rates in heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM). This has led to the approval of idecabtagene vicleucel, ciltacabtagene autoleucel and teclistamab by the FDA, EMA and other regulatory agencies. We performed a global survey on accessibility, practice patterns, and toxicity management of commercially available CAR-T and BiTE therapies. Methods: An online survey was completed by clinicians attending the International Myeloma Society's Immune Effector Cell Therapies in Multiple Myeloma Workshop, in-person or virtually, made available for 30 days after the meeting held in March 2023, Boston, MA. Results: 87 clinicians from 16 countries completed the survey, most practicing in an academic practice (86%) and in an urban environment (89%). Sixty-four percent of the respondents practice in North America followed by Europe (25.3%) including Germany, United Kingdom, Ireland, Italy, Netherlands, Spain, France, Greece, and Cyprus, and 6.9% from Asia and 3.4% from Australia. Seventy-seven percent reported CAR-T cell therapy was approved in their country with 44.8% treating 1-5 patients and 14.9% treating >5 patients per month; 67% reported BiTE therapy was approved in their country with 14.9% treating >5 patients per month. Of evaluable responses (n = 40), 62% administered CAR-T therapy inpatient and 15% administered CAR-T therapy outpatient ≥ 50% of the time. Length of time between decision to treat with CAR-T therapy to infusion was 6-12 weeks for 42% of responders and <6 weeks for only 20%. Most (75%) reported inpatient administration of BiTE therapy step-up dosing; 17.5% reported outpatient step-up dosing administered ≥ 50% of the time. Use of institutional or practice SOPs for CAR-T and BiTE therapy patient selection was reported by 85% and 58%, respectively, with the factors influencing SOP outlined in Table 1. Of available CAR-T therapies, 53% prefer cilta-cel and 23% reported CAR-T therapy preference depended most on patients' co-morbidities/frailty (89%), timing of next available apheresis (67%), age (56%), CNS disease (44%) and other factors. Maintenance therapy after CAR-T therapy was reportedly used by 25% and 5% of respondents in 1-10% and 11-50% of their patients, respectively, to “maintain level of response achieved” (50%) or “achieve a deeper level of response” (25%). About half (43%) of the respondents reported using an SOP or particular criteria for secondary Hemophagocytic Lympho-Histiocytosis/Macrophage Activation Syndrome/CAR-related-HLH (sHLH/MAS/CarHLH) management that varied between the use of ASTCT Working Group IEC associated HLH-like syndrome Criteria (47%) (Hines 2023), CARTOX HLH Criteria (24%) (Neelapu 2017) and HLH-2004 criteria (6%). Tocilizumab was used as cytokine release syndrome (CRS) prophylaxis only by one responder. Keppra neurologic prophylaxis was used by 47.5% and 15% of responders for CAR-T and BiTE therapy, respectively. Delayed neurotoxicity with CAR-T was reported in 1-5% of patients by 57.5% of responders and 6-10% of patients by 15% of responders; most common manifestations were other movement/neuromuscular disorder (62%), nerve palsy (55%), and Parkinsonism (45%). Infectious prophylaxis was used to protect against HSV (92.5%), PJP (90%), bacterial pathogens (55%), fungal pathogens (60%), and IVIG (77.5%). However, criteria for infectious prophylaxis use varies widely incorporating IgG levels, infectious history, CD4+ count, B-cell aplasia and cytopenias (48.1 - 88.9%). Most respondents (46.3 - 86.5%) reported completing an infectious work-up including CMV, EBV, Hep B/C, and HIV ( Table 2). Conclusions: Trends of CAR-T and BiTE therapy use and patterns of concurrent prophylactic and supportive care in MM vary widely among academic centers across the globe, demonstrating a need for further understanding of toxicity pathogenesis, toxicity management and consistent guidelines. This survey also demonstrates the great unmet need for access beyond urban centers among the international myeloma community. Prospective studies and claims data analysis should be utilized to evaluate the longitudinal cost of care, quality of life, duration of response and management of infectious disease, neurological or related complications of CAR-T and bispecific TCE therapies.

Introduction: ISB 1342 is a humanized CD38xCD3 bispecific T-cell engager using Ichnos proprietary Bispecific Engagement by Antibodies based on the T cell receptor (BEAT ®) platform, designed to simultaneously bind CD38 on multiple myeloma (MM) cells and CD3ε on T cells, to induce tumor killing. This mechanism of action is different from existing monospecific CD38 targeting therapies and was designed to overcome resistance to daratumumab in MM. ISB 1342 exhibits potent killing of the primary MM cells and MM cell lines with low sensitivity to daratumumab ( Pouleau B. et al. Blood 2023; 142 (3): 260-273). We report here, the updated findings from the weekly dose-escalations of intravenous (IV) and subcutaneous (SC) injections of an ongoing, single-agent phase 1 study (NCT03309111) of ISB 1342 in patients with RRMM. Methods: Adult patients with RRMM that relapsed after or were refractory to prior therapies, including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody; received ISB 1342 on a weekly (QW) schedule by IV or SC injection with a priming dose on the first day in 2 parallel dose-escalation schemas. Patients had measurable disease per the International Myeloma Working Group (IMWG) criteria (2016). Dose escalation in the QW schedule began at 0.2/0.3 mg/kg priming/treatment dose and followed a “3 + 3” design. The primary study objectives are to determine the maximum tolerated dose (MTD) and select a recommended phase 2 dose (RP2D) of ISB 1342. Secondary objectives includ evaluation of anti-myeloma activity, pharmacokinetics (PK), pharmacodynamics, and immunogenicity of ISB 1342. Results: As of July 18, 2023, based on ongoing clinical database, 39 subjects had received weekly IV infusions of ISB 1342 in 8 dose-escalation groups from 0.2/0.3 mg/kg to 4.0/16.0 mg/kg as priming/treatment dose; and 7 additional subjects had received weekly SC injections at 2.0/8.0 mg/kg. Two different formulations have been tested in SC group. Median number of cycles administered was 2. The majority were male (57%) and white (74%); 13% were Black or African American. The median age was 69 years (range, 54-76) and the median time since diagnosis was 6.6 years (range, 2.8-22.2). The median number of prior anti-myeloma lines of therapy was 6 (range 1-12). Twenty-one (67%) subjects were considered to be triple-class refractory and 18 (48%) penta-drug refractory. Forty-one (89%) subjects experienced treatment-related adverse events (TRAEs) of any grade. Most TRAEs were grade 1-2, including infusion related reactions (37%), cytokine release syndrome (CRS, 34%, all grade 1or 2), anemia (24%), neutropenia (24%), and thrombocytopenia (17%). Five subjects in SC group (71% of SC) had injection site reaction, all grade 1 or 2. Grade 3 or higher TRAEs occurring in more than 5% of subjects were infusion related reaction (no grade 4), anemia (no grade 4), neutropenia, leukopenia. No Grade 5 TRAE was observed. After QW IV infusion, ISB 1342 serum concentration peaked at the end of infusion and then showed bi-exponential decline. ISB 1342 serum exposures increased in a dose linear fashion across the tested IV infusion dose range. The limited PK data after SC injection suggest slow presentation of ISB 1342 into the systemic circulation leading to lower C max and delayed T max relative to IV. Transient increases in serum cytokines were observed within 24 hours after ISB 1342 dosing, including IFNg, TNFa, IL-2, IL-6 and IL-10. Transient increases in T-cell activation were observed by flow cytometry at 24-48 hours after ISB 1342 dosing at 1.0 / 4.0 μg/kg and above, based on increased expression of CD69 on peripheral blood CD4+ and CD8+ T-cell populations (Figure 1). Comparison of the available data from subjects treated at 2 / 8 μg/kg (Cohort 109) indicated reduced T-cell activation following SC compared to IV administration of ISB 1342. The efficacy signals observed in Cohorts 108 and 109 are consistent with the estimates of the lower boundary of the predicted efficacious dose range using a quantitative systems pharmacology (QSP) model based on preclinical data. Updated clinical data, including response rates and safety data, will be present at the meeting. Conclusions: Treatment with ISB 1342 was well tolerated at higher dose levels evaluated. Observed CRS events were moderate. No increased risk of infection has been observed . Updated safety, efficacy, biomarker and PK data will be presented.

Introduction A single ide-cel infusion showed significantly longer median progression-free survival (PFS) vs std regimens (13.3 vs 4.4 months [mo], HR 0.49, 95% CI 0.38-0.65, P < 0.001) with deep, durable responses in heavily pretreated TCE RRMM at an interim analysis (IA) of KarMMa-3 (NCT03651128); safety data were consistent with prior studies (Rodríguez-Otero et al. NEJM 2023). Ide-cel benefits were consistent across pts in high-risk subgroups and across 2-4 prior lines of therapy (Tx). Results of the preplanned final PFS analysis of KarMMa-3 with 12.3 mo additional follow-up are reported. Methods In the phase 3 KarMMa-3 trial, pts with RRMM who received 2-4 prior regimens, including an immunomodulatory agent, proteasome inhibitor, and daratumumab, and were refractory to last regimen were randomized 2:1 to ide-cel or a std regimen (DPd, DVd, IRd, Kd, or EPd). In the ide-cel arm, pts could receive ≤ 1 cycle of optional bridging Tx for disease control. Pts in the std regimens arm could receive ide-cel after confirmed disease progression (PD). The primary endpoint was IRC-assessed PFS in the ITT population; final PFS was planned to be analyzed with ~289 events. Key secondary endpoints were IRC-assessed overall response rate (ORR) and overall survival (OS); other secondary endpoints included complete response rate (CRR), duration of response (DOR), minimal residual disease (MRD) status, time to next anti-myeloma Tx (TTNT; time from randomization to next anti-myeloma Tx [MTx]), event-free survival (EFS; time from randomization to first PD, next MTx or any-cause death, whichever is first), PFS2 (time from randomization to second objective PD or any-cause death, whichever is first), safety, and health-related quality of life (QOL). Results Of 386 randomized pts (ide-cel, n = 254; std regimens, n = 132), 225 received ide-cel and 126 received a std regimen. Baseline characteristics were generally balanced. Median follow-up from randomization to data cutoff (April 28, 2023) was 30.9 mo (range 12.7-47.8). Ide-cel significantly improved median PFS (95% CI) vs std regimens (13.8 [11.8-16.1] vs 4.4 [3.4-5.8] mo), representing a 51% reduced risk of PD or death (HR 0.49, 95% CI 0.38-0.63; Figure); 18 mo PFS rates were 41% vs 19%, respectively. Ide-cel significantly improved ORR vs std regimens (71% vs 42%) with deeper (CRR 44% vs 5%; ≥CR and MRD negative status [sensitivity level 10 -5], 22% vs 1%), more durable responses (median DOR 16.6 vs 9.7 mo; Table). PFS and ORR benefits of ide-cel vs std regimens were consistent with the IA. Interim OS will be included in the presentation. In pts who received ide-cel (n = 225) or a std regimen (n = 126), median PFS (95% CI) was 15.7 (12.5-18.9) vs 4.4 (3.4-5.8) mo, respectively. In the ITT population, median TTNT, EFS, and PFS2 were numerically longer with ide-cel vs std regimens. Median (range) TTNT was 20.9 (16.6-24.2) vs 7.0 (5.3-8.5) mo. Median (95% CI) EFS was 13.3 (11.3-15.7) vs 3.9 (3.0-5.3) mo. Median PFS2 (95% CI) was 23.5 (18.4-27.9) vs 16.7 (12.2-20.3) mo; ide-cel was next MTx in 70 (53%) pts in the std regimens arm. In the treated population, grade (gr) 3/4 infections occurred in 66/249 (27%) pts in the ide-cel arm vs 25/126 (20%) in the std regimens arm. In the ide-cel safety population, any gr cytokine release syndrome occurred in 197/225 (88%) pts, gr ≥ 3 in 11 (5%); median time to first onset was 1 d (1-14), median duration was 4 d (1-51). Any gr investigator-identified neurotoxicity occurred in 34/225 (15%) pts, gr ≥ 3 in 7 (3%); median time to onset was 3 d (range 1-317); median duration was 2.5 d (range 1-252). Ide-cel continued to demonstrate durable, clinically meaningful improvements in pt-reported outcomes, including symptoms, functioning, and QOL vs std regimens. Conclusions In this final PFS analysis of KarMMa-3, significantly longer PFS was maintained with ide-cel; PD or death risk reduced by 51%; responses were deeper and more durable vs std regimens. CRR with ide-cel increased since the IA, indicating a deepening response, but were unchanged with std regimens. A single ide-cel infusion vs continuous treatment with std regimens resulted in longer median TTNT and PFS2, indicating improved long-term disease control. The ide-cel safety profile was consistent with previous reports, with no parkinsonism or Guillain-Barré syndrome reported. These data continue to support use of ide-cel in pts with TCE RRMM. Study support 2seventy bio and Celgene, a Bristol-Myers Squibb Company.