Raje, Noopur

Despite significant improvements in survival of patients with multiple myeloma (MM), outcomes remain heterogeneous, and a significant proportion of patients experience suboptimal outcomes. Importantly, traditional prognostic factors based on data from patients treated with older therapies no longer capture prognosis accurately in the contemporary era of novel triplet or quadruplet therapies. Therefore, risk stratification requires refinement in the context of available and investigational treatment options in routine practice and clinical trials, respectively. The current identification of high-risk MM (HRMM) in routine practice is based on the Revised International Staging System, which stratifies patients using a combination of widely available serum biomarkers and chromosomal abnormalities assessed via fluorescence in situ hybridization. In recent years, a substantial body of evidence concerning additional clinical, biological, and molecular/genomic prognostic factors has accumulated, along with new MM risk stratification tools and consensus reports. The International Myeloma Society, along with the International Myeloma Working Group, convened an Expert Panel with the primary aim of revisiting the definition of HRMM and formulating a practical and data-driven consensus definition, based on new evidence from molecular/genomic assays, updated clinical data, and contemporary risk stratification concepts. The Panel proposes the following Consensus Genomic Staging (CGS) of HRMM which relies upon the presence of at least one of these abnormalities: (1) del(17p), with a cutoff of >20% clonal fraction, and/or TP53 mutation; (2) an IgH translocation including t(4;14), t(14;16), or t(14;20) along with 1q+ and/or del(1p32); (3) monoallelic del(1p32) along with 1q+ or biallelic del(1p32); or (4) β2 microglobulin ≥5.5 mg/L with normal creatinine (<1.2 mg/dL).

CARTITUDE-1 evaluated ciltacabtagene autoleucel (cilta-cel) in patients with heavily pretreated relapsed/refractory multiple myeloma (RRMM). We describe overall survival (OS), ≥5-year progression-free outcomes, associated biomarkers, and safety, with a median study follow-up of 61.3 months. For the 97 treated patients, median OS was 60.7 months (95% CI, 41.9 to not estimable). One third (32/97) of patients remain alive and progression-free for ≥5 years after a single cilta-cel infusion, without maintenance treatment. Twelve of these patients treated at a single center underwent serial minimal residual disease (MRD) and positron emission tomography-computed tomography assessments, and all (100%) were MRD-negative (at least 10 −5 threshold) and imaging-negative at year 5 or later after cilta-cel. Baseline characteristics, including the presence of high-risk cytogenetics and extramedullary disease, were generally comparable for the 32 patients who were progression-free for ≥5 years versus patients who had progressive disease by year 5. A trend of lower baseline tumor burden, higher fraction of naïve T-cells in the cilta-cel drug product, higher T cell-to-neutrophil ratio, higher hemoglobin and platelets at baseline, and higher effector-to-target ratio were associated with ≥5-year progression-free status. The safety profile of cilta-cel remained consistent with previous reports. To our knowledge, our data provide the first evidence that cilta-cel is potentially curative in patients with RRMM.

7507 Background: CARTITUDE-1 evaluated cilta-cel in pts with heavily pretreated RRMM who historically have an expected median progression-free survival (PFS) of <6 months (mo) and median overall survival (OS) of ~1 year (y). At 33.4 mo median follow-up, median PFS was 34.9 mo, and median OS was not reached (36-mo OS rate, 62.9%; Lin et al, ASCO 2023). We report OS, ≥5 y progression-free outcomes, and safety with a median study follow-up of 60.3 mo. Methods: Pts in CARTITUDE-1 received a single cilta-cel infusion. Correlative analyses were performed utilizing drug product, baseline, and postinfusion samples. Pts are followed for progression, survival, and safety in a 15-y follow-up study, CARTinue (NCT05201781), with pt evaluations per local standard of care (reported annually at a minimum). Results: Of 97 pts treated, 32 (33.0%) remain alive and progression free for ≥5 y after cilta-cel, without further MM treatment. For these 32 pts, prior to enrollment in CARTITUDE-1, median time from start of last line of therapy (LOT) to progression was 4.0 mo (range, 0.7–48.6). Among the 32, median age was 60 y (range, 43–78), median number of prior LOT was 6.5 (range, 3–14), 23.3% had high risk cytogenetics, 12.5% had extramedullary disease (EMD), 90.6% were triple-class refractory, and 46.9% were penta-drug refractory. Baseline characteristics of pts who were progression free for ≥5 y, including those with high-risk cytogenetics and EMD, were comparable to pts with progressive disease (PD) within 5 y. Compared with pts who had PD within 5 y, biomarkers significantly associated with ≥5 y progression free status included a higher fraction of naïve T cells in the drug product, lower neutrophil to T cell ratio, higher hemoglobin and platelets at baseline, and higher effector-to-target ratio (Cmax to sBCMA at baseline). At Cmax, these pts also had significantly higher CD4 central memory CAR+ T cell subsets and CAR+ T cells that were positive for the activation markers CD38, CD25, and PD-1. Data were collected on a subset of pts from a single center where local serial MRD assessments were performed. All 12 pts at this center who were progression free for ≥5 y were MRD negative at 10 –6 and imaging negative by PET/CT yearly for 5 y. Overall, at 60.3 mo median follow-up in CARTITUDE-1 (N=97), median OS was 60.6 mo (95% CI, 41.9–NE). With continued follow-up, 3 additional pts reported a second primary malignancy (1 of which was acute myeloid leukemia; onset, 2.8 y after infusion). No new cases of movement and neurocognitive disorders were reported. Conclusions: The median OS for pts enrolled in CARTITUDE-1 was 5 y, and 33% of pts remain progression free for ≥5 y following a single cilta-cel infusion. These data provide the first evidence that cilta-cel is potentially curative in pts with RRMM. Clinical trial information: NCT03548207 , NCT05201781 .

Introduction: Progression-free survival (PFS), a common endpoint used in multiple myeloma (MM) trials, is defined as the time to the earliest occurrence of disease progression or death. Disease progression in MM is determined by the International Myeloma Working Group (IMWG) Uniform Response Criteria based on imaging and biomarkers from blood, urine, and bone marrow biopsy testing. In clinical trials, IMWG-recommended assessments are protocol-based. However, in routine care, they are often performed and recorded differently based on a multitude of factors. Algorithms to ascertain progression events using routinely collected biomarker data are important to classify disease progression and align with trial-defined endpoints. The aim of this study was to construct and evaluate an optimized real-world Progression (rwP) algorithm using real-world data (RWD) and demonstrate how biomarker data are captured and used to derive endpoints in routine practice. Method: A cohort of 270 transplant ineligible newly diagnosed MM (NDMM) patients starting on lenalidomide and dexamethasone (Rd) and meeting select MAIA (NCT02252172) trial eligibility criteria were included from the nationwide Flatiron Health electronic health record-derived deidentified database from 2015 to 2023. A rwP algorithm was developed using key IMWG-recommended biomarkers, including serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP), and serum free light chains (FLCs). The initial baseline value for each biomarker was identified, if available, during either the pre-treatment period (45 days prior through 7 days after first line treatment (1L) start) or the on-treatment period (8 days after 1L start through 1L end). Available biomarkers were followed for disease assessment. If any subsequent lab value during 1L treatment was less than the initial baseline value, the subsequent “on-treatment baseline” value was adopted as the new lowest value; otherwise, the initial value was used as the “on-treatment baseline” value for assessing progression events. Three hierarchies, which describe the order of utilizing key IMWG-recommended biomarkers to define rwP events, were explored, including: i) strict hierarchy (SH) [SPEP &gt; UPEP &gt; FLCs], ii) partial hierarchy (PH) [SPEP = UPEP &gt; FLCs], and iii) no hierarchy (NH) [SPEP = UPEP = FLCs]. The PH option closely resembles the IMWG criteria, with FLCs only used for rwP assessments when no measurable SPEP/UPEP are identified. The NH approach considers all available biomarkers equally and resembles how they are utilized in real-world clinical practice. The feasibility of requiring confirmatory events following the first suggestion of progression was also explored. Assays following the progression event up to the end of 1L were considered as confirmatory progression events if they met IMWG criteria. Results: We applied the rwP algorithm with each hierarchy to all eligible NDMM patients (N = 270). The SH, PH, and NH approaches respectively identified 106 (39.3%), 106 (39.3%), and 123 (45.6%) patients with progression events. Results from the SH and PH approach are consistent likely due to the rarity of UPEP usage in clinical practice. The NH approach captured more progression events because FLCs are used in the presence of measurable SPEP or UPEP, resulting in 73 progression events captured by FLCs in comparison to 32 from other approaches, potentially increasing false-positive capture due to the volatility of FLC results. Among the 106 PH-identified patients who progressed, 84 (79.2%) had IMWG-recommended tests following their progression event, and 74 (69.8%) had their progression confirmed before the end of 1L, with 35 (33.0%) receiving their confirmatory reading within 2 months after progression. These results suggest that requiring confirmatory testing as part of the rwP is feasible, though it may introduce false negatives for patients receiving clinical progression confirmation instead of getting confirmatory labs in routine clinical practice. Conclusion: We present a comprehensive assessment of important design choices for an rwP algorithm for NDMM, including a hierarchy of key assays and the inclusion of confirmatory testing. Further validation of the algorithm with health care provider assessments and the inclusion of bone marrow biopsy and imaging data is important for evaluating the performance of the algorithm in RWD.

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 &lt; .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 &gt;1% vs &lt;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 &lt;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 &lt; .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 &lt; .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: SAR442257 (SAR'257) is a trispecific antibody that targets CD38, CD3 and CD28. Simultaneous CD3 and CD28 binding triggers T cell co-signaling, and additional CD38 recognition directs the T cells to CD38+ cancer cells such as multiple myeloma (MM) and non-Hodgkin lymphoma (NHL). This is a first-in-human phase 1 study investigating the safety, efficacy, pharmacokinetic (PK) and pharmacodynamic (PD) profile of SAR'257 in patients (pts) with refractory and relapsed (rr) MM and rrNHL. Methods: This is a multicenter, international, open-label, dose-escalation study (NCT04401020) of SAR'257 in pts with rrMM refractory to standard-of-care (SOC) options, including anti-CD38 monoclonal antibodies, and in pts rrNHL without any SOC options. SAR'257 was administered intravenously with lead-in doses (Day 1−5) in the first week, followed by twice weekly (BIW) or once weekly (QW) dosing; 11 target dose levels (TDLs) in pts with rrMM (9 TDLs: 0.06-11 µg/kg BIW; 2 TDLs: 18-27 µg/kg QW), and 2 TDLs in pts with rrNHL (2 µg/kg BIW and 4 µg/kg QW). Results: As of February 19, 2024, 47 pts (rrMM, n=40; rrNHL, n=7) received SAR'257. The median ages (years) were 64 (rrMM; range: 40−84) and 70 (rrNHL; range: 18−75). The median number of prior lines was 5 (range: 3−12) for rrMM and 5 (range: 2−7) for rrNHL cohort. In rrMM cohort, all (100%) pts had prior exposure to an anti-CD38 monoclonal antibody (MAb) and were refractory to anti-CD38 and in rrNHL cohort all were anti-CD38 naïve. The median time from last anti-CD38 dose was 2.7 (range: 1−65) months for rrMM cohort. Safety analysis revealed that 68% (n=32) pts had treatment-emergent adverse events (TEAEs; 26 pts in rrMM and 6 pts in rrNHL); 21.3% pts (n=10) Grade (G) ≥3 TEAEs (7 in rrMM and 3 in rrNHL). Cytokine release syndrome (CRS) was the most common TEAE, occurring in 52.5% of rrMM pts across all TDLs (n=21; G≥3 in 1 pt from 11 µg/kg BIW TDL) and in 57.1% of rrNHL pts (n=4; no G≥3) at the two TDLs tested. Repetitive CRS episodes (&gt;1 episode) were more frequent at higher TDLs. Infusion-related reactions (IRRs; any G) were observed in 22.5% pts with rrMM (n=9; no G≥3) and in 28.5% pts with rrNHL (n=2; G≥3 in 1 pt). Epstein-Barr virus (EBV) infection/reactivation was reported in 17.5% (n=7; G≥3 in 4 pts) and 28.6% (n=2; no G≥3) pts with rrMM and rrNHL respectively. Further, 15% (n=6, G≥3 in 2 pts) from rrMM and 14.3% (n=1; G2 CMV reactivation) pts from rrNHL cohort reported cytomegalovirus (CMV) infection/reactivation. One case of immune effector cell-associated neurotoxicity syndrome (ICANS) was reported (G4) in the rrNHL cohort. Four dose-limiting toxicities (DLTs) were observed in the rrMM cohort [1 at 4 µg/kg BIW (G3 hepatotoxicity); 1 at 11 µg/kg BIW (G5 CRS−EBV reactivation; and 2 at 27 µg/kg QW (G3 CMV infection reactivation and G3 febrile neutropenia in same pt)]. Three DLTs were observed in the rrNHL cohort (2 at 2 µg/kg BIW [G4 neutropenia and G4 thrombocytopenia; same pt] and 1 at 4 µg/kg QW [ICANS G4]). For pts with rrMM, the maximum plasma concentration of SAR'257 reached within or above the theoretical efficacious range (0.1−1nM; extrapolated from ex vivo models), starting at 8 µg/kg BIW and 18 µg/kg QW in the first treatment cycle. As of July 08, 2024, the overall response rate (ORR), defined as partial response (PR) or better, was 5% (n=2) in the rrMM cohort: 1 pt exhibited stringent complete response (duration of response [DOR]=8.1 months, on-going) and 1 showed a complete response (CR) at 27 µg/kg QW TDL. In rrNHL cohort, the ORR was 14.3%, 1 pt achieved PR (DOR=7.1 months) at 2 µg/kg BIW TDL. The disease control rate (stable disease or better for &gt;8 weeks) was 60% (n=24) and 28.6% (n=2) in the rrMM and rrNHL cohorts respectively. For both cohorts exploratory biomarker analysis revealed that: (1) SAR'257 treatment activated peripheral blood T cells and reduced regulatory T cell numbers and CD4/CD8 ratio; (2) CD38 expression on plasma cells positively corelated with time since the last anti-CD38 MAb dose; (3) Among the pts experiencing CRS, the peak values of cytokines (Interleukin (IL)-6, IL-8, and C-reactive protein) were significantly higher during the first cycle in comparison to subsequent cycles. Conclusion: This Phase 1 study of SAR'257 showed an anti-tumor response in a small number of pts from the rrMM and rrNHL cohorts. Due to safety concerns, in particular high rates of EBV and CMV reactivation and recurrent episodes of CRS in the higher dose levels, the study was terminated during dose escalation.

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 &lt; .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.

Introduction In the KarMMa-3 trial (NCT03651128), ide-cel, a BCMA-directed CAR T cell therapy (Tx), significantly improved median progression-free survival (13.3 vs 4.4 mo, HR 0.49, P &lt; 0.001) and overall response rate (71% vs 42%, P &lt; 0.001) vs std regimens in pts with RRMM who were TCE to immunomodulatory (IMiD ®) agents, proteasome inhibitors (PIs), and daratumumab (Rodríguez-Otero NEJM 2023). Early high-grade (gr) cytopenias and severe infections have been reported post-CAR T cell infusion (Logue Blood 2022, Thibaud Blood 2022), and persistent cytopenias and infections can pose clinical challenges in pt care. In this safety analysis of KarMMa-3, we report frequency, kinetics of occurrence, and management of cytopenias and infections post-Tx with ide-cel or std regimens. Methods This international, randomized, multicenter phase 3 trial enrolled pts with RRMM who received 2-4 prior Txs (an IMiD agent, a PI, and daratumumab) and were refractory to the last Tx. Pts were randomized 2:1 to ide-cel or a std regimen (DPd, DVd, IRd, Kd, or EPd) selected by investigator based on prior anti-MM Tx. In the ide-cel arm, pts could have ≤ 1 cycle of optional bridging Tx (BTx) for disease control. Treated population (pop; ide-cel: pts who received leukapheresis [LA], BTx, lymphodepleting chemotherapy, or ide-cel; std regimens: pts who received any dose of study Tx) was used to assess adverse events (AEs), gr 3/4 AEs, and serious AEs. Safety pop (pts who received ide-cel or any dose of std regimens) was used to assess treatment-emergent AEs, AEs of special interest, investigator-identified neurotoxicity/cytokine release syndrome and others. In pts who had documented disease progression on std regimens and then underwent LA to receive ide-cel, only AEs before LA were included. In this analysis, incidence of cytopenias and infections at various time intervals and management, types of infections, and incidence of hypogammaglobulinemia (HGG) were assessed. Results At data cutoff (Oct 3, 2022), median follow-up was 24.1 (range 5.9−41.0) mo in the 386 randomized pts. In the treated pop, 248/249 (99.6%) vs 124/126 (98.4%) pts had any-gr AEs, 234 (94.0%) vs 96 (76.2%) had gr 3/4, and 36 (14.5%) vs 9 (7.1%) had gr 5 in ide-cel vs std regimens arms, respectively. Of the gr 5 AEs, 18/36 and 3/9 had verbatim terms consistent with progressive disease. In the safety pop, incidence of gr 3/4 cytopenias with ide-cel were higher early after infusion but generally resolved over time (196 [87.1%] pts at &lt; 3 mo, 52 [24.1%] pts at 3−&lt; 6 mo, 30 [14.7%] pts at ≥ 6 mo; Table 1) vs std regimens, which showed lower rate of resolution over time. More pts in the ide-cel (16 [7.1%]) vs std regimens arms (3 [2.4%]) had any-gr febrile neutropenia. Cytopenias were mainly managed using colony-stimulating factor in both arms (55.5% and 58.7%, respectively); RBC (48%) and platelet transfusions (32%) were more common in the ide-cel arm. Overall, incidence of gr 3/4 infections was high at &lt; 3 mo and remained consistent over time in both arms (ide-cel: 17 [7.6%] pts at &lt; 3 mo, 18 [8.3%] pts at 3−&lt; 6 mo, 13 [6.4%] pts at ≥ 6 mo; Table 2). Any-gr bacterial infections were more common in the ide-cel vs std regimens arms with higher incidence at &lt; 3 mo (10% vs 6%) but lowered at later timepoints. Incidence of gr ≥ 3 viral infections remained low and consistent with time; fungal infections were uncommon. Deaths due to infections occurred in 3 (1.3%) vs 1 (0.8%) pts at &lt; 3 mo, 0 pts at 3−&lt; 6 mo, and 7 (3.4%) vs 2 (2.6%) pts at ≥ 6 mo in the ide-cel vs std regimens arms, respectively. Indence of any-gr new HGG was higher in the ide-cel vs std regimens arms but decreased over time: 15 (6.7%) vs 2 (1.6%) pts at &lt; 3 mo, 3 (1.4%) vs 1 (0.9%) at 3−&lt; 6 mo, and 5 (2.5%) vs 0 at ≥ 6 mo, respectively; of these, 13 (5.8%) vs 1 (0.8%), 2 (0.9%) vs 1 (0.9%), and 5 (2.5%) vs 0 pts received IV immunoglobulin replacement Tx at the respective time intervals. Incidence rate (% per 100 pt-years, 95% CI) of second primary malignancies remained low and similar between arms (ide-cel, 4.0 [2.4−6.7]; std regimens, 4.4 [1.9−10.7]). Conclusion In KarMMa-3, most severe cytopenias associated with ide-cel occurred early, with a low incidence of prolonged cytopenias; all were largely manageable. Any-gr bacterial infections decreased over time while viral infections remained the same. No new safety concerns were identified for ide-cel; safety profile was consistent with previous reports. Study support 2seventy bio and Celgene, a Bristol-Myers Squibb Company.

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 &lt; 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.