Dhakal, Binod

Abstract Introduction: Multiple myeloma (MM) significantly contributes to global disease burden. To facilitate tailoring of treatment strategies and improved patient (pt) management according to regional differences, there is a need for research on geographical distribution of clinical characteristics that may influence tumor expression and treatment response in RRMM. This study aimed to describe the distribution of prognostic characteristics of pts with RRMM in Europe and the US. Methods: Data were drawn from the Adelphi Real World MM III Disease Specific ProgrammeTM(DSP), a cross-sectional survey, with retrospective chart review, of physicians and their pts with RRMM. The survey was administered to hemato-oncologists and hematologists in EU4 (France, Germany, Italy, Spain) from July to Nov 2021, the UK (May to Nov 2021), and the US (Sep 2020 to Sep 2021). Physician-reported data (collected via DSP pt record forms) for consulting RRMM pts (second-line or later [2L+]) were analyzed to capture demographics, clinical characteristics, and treatment history. Descriptive analyses were performed to assess key variables. Results: In total, 236 physicians provided data on 2037 pts with 2L+ RRMM (n=259 US; n=1778 EU4+UK). Demographic characteristics in the US and EU4+UK were generally similar except there were more White pts in EU4+UK than the US (93%/59%). The mean (standard deviation [SD]) age at diagnosis was 65.8 (7.9) years in the US and 65.9 (9.2) years in EU4+UK, and at the time of data collection (i.e., at the most recent RRMM consultation) mean (SD) age was 69.1 (8.1) years in the US and 70.8 (9.1) years in EU4+UK. Most pts were male (62% in the US and 56% in EU4+UK). Most clinical characteristics were similar between the US and EU4+UK and within regions between White and non-White pts. International Staging System (ISS) stage I/II/III at the time of data collection was 10%/37%/53% in the US and 11%/26%/63% in EU4+UK. There was some variation in other clinical characteristics: ECOG performance status 0–1 at the time of data collection was 80% in the US and 68% in EU4+UK. Bone lesions were experienced by 58% in the US and 65% in EU4+UK, and high-risk cytogenetics were present in 39% in the US and 26% in EU4+UK. The most frequent comorbidities reported at the time of data collection in the US and EU4+UK were hypertension (47%/46%), anemia (24%/26%), hyperlipidemia (19% in both), diabetes (19%/24%), and mild renal disease (12%/18%). Despite some differences in populations, prescribed therapies were broadly similar between regions and between White and non-White within regions. Common 1L therapy classes prescribed in the US and EU4+UK were proteasome inhibitors (PIs) (22%/27%), immunomodulatory drugs (IMDs) (18%/15%), and PI/IMD (59%/51%). Common 2L therapies prescribed in the US and EU4+UK were PIs (15%/18%), IMDs (4%/21%), PI/IMD combination (28%/20%), and IMD/anti-CD38 combination (25%/20%). Common 3L+ therapies in the US and EU4+UK were PIs (24%/14%), IMDs (8%/20%), PI/IMD (26%/21%), and IMD/anti-CD38 (15%/16%). Minor variations in prescribed therapies included rates of stem cell transplantation (22% US/30% EU4+UK), exposure to anti-CD38 (63%/71%), exposure to lenalidomide (88%/92%), and exposure to both lenalidomide and anti-CD38 (56%/66%). The US had higher rates of pts refractory to treatments: anti-CD38 refractory (43% US/31% EU4+UK), lenalidomide refractory (32%/27%), and refractory to both lenalidomide and anti-CD38 (40%/13%). Conclusion: Our study provides critical insights into pts with RRMM across different regions, aligning closely with results from other published large population-based studies. Demographic/clinical characteristics were generally similar across the regions (except proportions of White pts) and between White and non-White pts within regions, including age of diagnosis, ISS staging, and comorbidity burden. Pts were also treated with similar combinations of classes in frontline and second line therapy during the time the study was conducted. Minor variations were seen in level of refractoriness to common therapies, including lenalidomide and anti-CD38. Similarities between the populations enable extrapolation across the regions, to inform treatment strategies.

Abstract Introduction: Multiple myeloma (MM) accounts for nearly 20% of all hematologic cancers in the US and remains a substantial clinical burden, with patients (pts) requiring multiple lines of therapy (LOT). While advances such as BCMA-directed CAR T-cell therapy have improved outcomes, challenges persist, including disease relapse, treatment toxicities (CRS, ICANS, and non-ICANS neurotoxicities), and access. AZD0120 (formerly GC012F) is a first-in-class autologous BCMA/CD19 dual-targeting CAR T-cell therapy using the FasTCAR rapid manufacturing platform that preserves the naive and central memory T-cell phenotypes with marked in vivo proliferative capacity. Phase 1 investigator-initiated trials in China demonstrated deep, durable responses and a favorable safety profile following single-infusion AZD0120 in newly diagnosed and relapsed/refractory MM (RRMM) (Du J, et al. EHA 2024 and ASCO 2023). Here, we report for the first time preliminary phase 1b results from DURGA-1, an ongoing phase 1b/2 clinical trial evaluating the safety and efficacy of AZD0120 in pts with RRMM. Methods: This open-label, single-arm, US-based, multicenter study (NCT05850234) evaluated the safety/tolerability of 2 dose levels (DL) of AZD0120 in pts with RRMM along with preliminary efficacy. Eligible ptswere aged ≥18 y with RRMM (3+ prior LOT [pLOT] including a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody), ECOG PS 0–1, and documented evidence of progressive disease. Exposure to BCMA-directed therapy ≥6 mo with best response of PR or better was permitted. Pts underwent lymphodepletion followed by a single infusion of AZD0120. Pts in DL1 received 1x105 cells/kg; DL2 received 3x105 cells/kg. Dose escalation and recommended phase 2 dose (RP2D) were determined by a safety review committee. Phase 1b primary objectives included safety/tolerability and RP2D determination; secondary objectives included efficacy, cellular kinetics (CK), and pharmacodynamics. Results: As of data cutoff (DCO) on 18 July 2025, a total of 25 pts received infusion of AZD0120 (n=12 DL1; n=13 DL2). The median age was 64 y (range 44–78), median pLOT was 4 (range 3–7), 72% were triple-class refractory, 20% had prior BCMA CAR T-cell therapy, 4% had prior teclistamab, 28% had high-risk cytogenetic features [del(13q), del(17p13), t(4;14), t(14;16), amp(1q)], and 8% had extramedullary plasmacytomas. The median time from apheresis to release was 14 d (range 10–30). Median time from apheresis to infusion was 28 d (range 19–44) with 5 pts receiving bridging therapy. Median follow-up was 1.4 mo (range 0–19.3). No dose-limiting toxicities were reported for either dose. The most common treatment-emergent AEs (TEAEs, any grade) were CRS (64%), neutrophil count decreased (56%), and anemia (32%). The most common grade ≥3 TEAEs were neutrophil count decreased (52%), lymphocyte count decreased (32%), and white blood cell count decreased (32%). CRS was reported in 75% of pts at DL1 (all grade 1) and 54% at DL2 (46% grade 1; 8% grade 2), with no cases of grade ≥3 CRS. Median time to CRS onset (DL1/DL2) was 9 d (range 2–11), with a median duration of 2 d (range 1–4); 12 pts (48%) received tocilizumab for CRS management and 12% received dexamethasone. No cases of ICANS, related non-ICANS neurotoxicity, IEC-colitis, or secondary primary malignancies have been reported. There have been no deaths. For efficacy-evaluable patients (n=15), ORR was 100% (33% sCR, 47% VGPR, 20% PR). CR rates in evaluable pts were 30% in DL1 (n=10) and 40% in DL2 (n=5); median time to response was 0.9 mo for both DLs (range 0.9–1.9 DL1; 0.6–1.8 DL2). All MRD-evaluable pts (n=5 DL1; n=3 DL2; DCO 01 July 2025) were MRD-negative by NGS at a sensitivity of 10-5. Three pts in DL1 with ≥12 mo follow-up maintained MRD negativity. Consistent with robust in vivo expansion, CK analysis from 16 evaluable pts (DCO 12 June 2025) demonstrated a median Tmax of 13 d post-infusion with a median Cmax of 85,266 copies/mg gDNA. Median persistence was 42 d (range 13–273). Updated clinical data with additional follow-up will be presented. Conclusion: Preliminary phase 1b results demonstrated AZD0120 was well tolerated, with a low incidence of serious AEs, no grade ≥3 CRS, and no ICANS. FasTCAR-manufactured AZD0120 had expectedin vivo expansion, which may have resulted in the predictable CRS profile. A single infusion of AZD0120 achieved early, deep responses with 100% MRD negativity from 4L+ triple-class‒exposed pts with RRMM.

Abstract Introduction: Bispecific T-cell engagers (TCE) targeting BCMA (teclistamab, elranatamab) and GPRC5D (talquetamab) are important therapeutic options in relapsed/refractory MM (RRMM). However, data on the independent prognostic impact of individual cytogenetic abnormalities and functional high-risk MM on outcomes with TCEs remains limited. Methods We included RRMM patients treated with BCMA TCEs (teclistamab, elranatamab) and talquetamab across 15 centers in the US. Patients where TCEs were used only as bridging therapy to CAR-T were excluded. High-risk cytogenetic abnormalities (HRCA) included del(17p), t(4;14), t(14;16), 1q gain/amplification (1q21+), del(1p) before initiation of TCE. Functional high-risk disease (FHRMM) was defined as PFS <18 months with frontline therapy. Extramedullary disease (EMD) included visceral or soft tissue disease and excluded paraskeletal disease. Progression-free survival (PFS) was estimated from TCE initiation using the Kaplan–Meier method and compared using the log-rank test. Univariate and multivariable Cox proportional hazards models were used to identify predictors of PFS in the entire cohort and the subcohorts of BCMA TCEs and talquetamab (Talq). Results We analyzed 943 treatment initiations with TCEs in RRMM, comprising 577 BCMA-directed TCEs [teclistamab (n=436) and elranatamab (n=141)] and 366 talquetamab initiations. The median follow-up from TCE initiation was 13.4 months (95% CI: 12.5–14.2) and median age was 68 years (interquartile range 61-75 years). Two ore more HRCAs were noted in 30% of the cohort (34% in Talq vs. 28% in BCMA TCEs, p=0.04), EMD was present in 21% of patients (26% in Talq vs. 18% in BCMA TCEs, p=0.002), and 45.5% of patients had FHRMM (47% in Talq vs. 45% in BCMA TCE, p=0.54). The median prior lines of therapy was 6 (interquartile range: 5-8), with 92% being triple-class refractory (TCR); 60% received prior BCMA-directed therapy (85% in Talq vs. 45% in BCMA TCE, p<0.0001) and 45% had prior CAR-T in 45% (57% in Talq vs. 37% in BCMA TCE, p<0.001). The best overall response rate (ORR) was 67.1 % for the entire cohort (66.4% for BCMA cohort and 68.2% for Talq), with 32.5% patients achieving a ≥ complete response. The median PFS was 7.7 months (95% CI: 6.7–8.6) for the entire cohort, with a median PFS of 10.1 months (95% CI: 7.5-13.4) for teclistamab and 10.1 months (95% CI: 3.9-NR) for elranatamab. In the more heavily pretreated talq cohort, the median PFS was 6.4 months (95% CI: 5.1-7.5). In a univariate analysis (UVA), several HRCAs were associated with inferior PFS−del(17p) (HR 1.59), t(4;14) (HR 1.43), del(1p) (HR 1.54), and ≥2 HRCAs (HR 1.64), all p<0.01. Apart from HRCAs, adverse disease characteristics included FHRMM (HR 1.20) and EMD (HR 1.46); all p<0.05. Among laboratory markers, hemoglobin <9 g/dL (HR 2.10), platelet count <75 ×10⁹/L (HR 1.96), and elevated ferritin (≥600 ng/mL; HR 2.17) (all p<0.01) were prognostic for PFS. ECOG ≥2 (HR 1.62), prior BCMA-directed therapy (HR 1.56), and prior CAR-T (HR 1.44) (all p<0.001) were also associated with inferior PFS. In a multivariable analysis (MVA), prior BCMA therapy (HR 1.72, p<0.0001), ferritin >600 ng/mL (HR 1.68, p<0.0001), hemoglobin <9 g/dL (HR 1.53, p=0.001), ECOG PS ≥2 (HR 1.52, p=0.0009), del(17p) (HR 1.44, p=0.0034) and FHRMM (HR 1.26, p=0.047), were associated with inferior PFS. Within the talq cohort (n=366), EMD (HR 1.64), del(17p) (HR 1.42), del(1p) (HR 1.54), FHRMM (HR 1.34), ECOG ≥2 (HR 1.56), ferritin >600 (HR 1.88), hemoglobin <9 g/dL (HR 1.6), platelet count <75 ×10⁹/L (HR 1.36) and leukopenia <0.25 x 10⁹/L (HR 1.52) were adverse prognostic markers on UVA. A MVA confirmed the independent impact of ferritin >600 ng/mL (HR: 1.77), ECOG ≥2 (HR 1.61) and functional high-risk status (HR 1.52) on PFS, whereas del(17p) and EMD were trending toward significance. Within the BCMA TCE cohort (n=577), prior BCMA therapy (HR 1.9), ferritin >600 (HR 1.79), ECOG ≥2 (HR 1.55), Hb <9 g/dL (HR 1.54), and del(17p) (HR 1.52) were independently associated with inferior PFS on a MVA.Conclusions: In this large real-world cohort of TCE, outcomes varied by fitness, disease biology, and treatment history. The ECOG PS, elevated ferritin, functional high-risk status and del(17p) were consistently associated with inferior PFS. Prior BCMA exposure was an independent risk factor for inferior PFS in the BCMA TCE cohort, but not with talquetamab.

Abstract Background: Multiple myeloma patients face complex barriers to diagnosis, care access, support, and navigation. This study analyzes patient-reported experiences to identify structural gaps and cluster patients into meaningful segments based on their needs and perceptions. Methods: We administered a 48-item anonymous survey to adult myeloma patients at the Medical College of Wisconsin and through national platforms, including the International Myeloma Foundation, Leukemia & Lymphoma Society, and Facebook groups. The survey assessed demographics, treatment experiences, delays, perceived personalization, and barriers to care. We used JMP 17 for analysis and Julius.AI for visualization. Rule based segmentation of structured responses was used to identify distinct patient personas. Chi-square tests assessed associations, with p < 0.05 considered significant. The study was IRB-approved. Results : A total of 320 participants responded between April 25 and June 5, 2025; 289 (90.3%) completed the survey in full. The cohort was predominantly older (55.7%, n=170/305 between 60- 75), White (79.3%, n=241/304), female (58.9%, n=179/304), highly educated (89.5%, n=272/304), and suburban (52.5%, n=159/303). Modal insurance types were Medicare (37.8%) or private insurance (30.9%); 11.2% both. Most (69.7%) reported a smooth treatment start; delays were primarily due to insurance/cost (4%). Using rule-based segmentation of structured responses, we identified three distinct patient personas: (1) Empowered but Unsupported (n=56; 17.5%) who indicated no emotional support barriers, less interest in navigators, but frequent reports of unmet needs such as poor communication. (2) Engaged and Informed (n=105; 32.8%): Highly motivated patients who requested personalized care, clinical trial transparency, or insurance navigation and (3) Delayed and Discouraged (n=35; 10.9%) who reported lower support, diagnostic delays, and a strong perception of race-related disparities. Unclassifiable personas (n=124) were due to missing or neutral responses There was no difference in self identified race across the personas (p = 0.08), but 100% of the Delayed/ Discouraged group believed race played a role in care, compared with 44% of the Engaged/Informed and 21.4% of the Empowered/Unsupported (p < 0.001). Minoritized patients (86.7% Black, 100% other minoritized) were more likely to perceive race as a factor (p = 0.0024). Empowered/Unsupported patients were significantly more likely to request better communication (100%) and empathy (53.6%), while Engaged and Informed patients prioritized clinical trial access (61%). None of the Delayed and Discouraged patients made this request (p < 0.0001). Black respondents most frequently expressed the need for greater empathy (53.7%; p = 0.0012). Those <60 (40.2%, n=33) were more likely to express interest in clinical trials (p=0.03), this interest did not vary by race (p=0.36). Interest in patient navigation did not significantly differ by education level (p = 0.3), suggesting that even highly educated patients may struggle with treatment complexity. Most patients felt their care was personalized (71.1% 207/291), with no differences by race (p = 0.55), but perceptions varied by persona with only 39.1% of Engaged/Informed patients felt their treatment was always tailored, vs. 61.8% of Empowered/Unsupported and 88.6% of Delayed/Discouraged (p < 0.0001), contrasting patients' expectations with the actual delivery of care. Conclusion: Patient-reported experiences reveal distinct personas with differing needs, perceptions and expectations of care. While most patients reported smooth treatment transitions and felt their care was personalized, gaps persist particularly among highly engaged patients who report unmet expectations around communication, personalization, and trial access. Perceptions of racial disparities persist, especially among minoritized groups illuminating the unequal experiences of patients within the myeloma care landscape. These findings stress the importance of segmenting care approaches to align with patient identity, complexity, and support needs in multiple myeloma.

Abstract Background: Prolonged cytopenias are a well-recognized complication following CAR-T therapy, leading to increased morbidity and healthcare utilization. Autologous SCB offers a potential strategy to promote hematologic recovery. We conducted a retrospective multi-institutional analysis across 18 centers comparing outcomes of SCB versus supportive care alone in RRMM patients who experienced prolonged cytopenias >30 days after CAR-T infusion. Methods: Patients were included if they received SCB within 1 year after commercial CAR-T between 6/2021 and 3/2024. To identify matched controls, we reviewed other CAR-T recipients from the same consortium and selected those with an absolute neutrophil count (ANC) of <0.72x109/L and platelet count of <21K at day 30 post-infusion-thresholds representing the 75th percentile of cytopenia severity in the SCB cohort. These criteria ensured control patients had comparable hematologic toxicity but without SCB. Hematologic recovery in the SCB cohort was assessed using the CIBMTR engraftment criteria. For the non-SCB (nSCB) group, cell counts were analyzed cross-sectionally at day 90 post-CAR-T and compared to the SCB cohort with Kruskal Wallis tests. Progression-free survival (PFS) and overall survival (OS) were evaluated using Kaplan Meier methods. Results: Of the 590 CAR-T recipients, 91 patients (15.4%) developed prolonged cytopenias; 39 patients received SCB and 52 did not. SCB patients more frequently had ISS stage III disease (23.1% vs. 11.5%), exrtamedullary disease (59% vs. 46.2%) and penta-refractory status (43.6% vs. 34.6%). The median number of prior lines of therapy was 6 in both cohorts. Thirteen patients (33.3%) in the SCB and 11 (21.2%) in the nSCB received high intensity infusional chemotherapy (DCEP/PACE/HyperCVAD). Pre-CAR-T cytopenias tended to be less frequent in the SCB vs. nSCB cohort: ANC <1000 in 5.1% vs. 13.5%, Hgb <8 in 23.1% vs. 21.2%, and platelets <50K in 28.2% vs. 40.4%. Median plasmacytosis in the bone marrow prior to CAR-T in the SCB group was 35% and 47.5% in the nSCB group. In the SCB cohort, 2 patients harbored DNMT3A mutations, one of whom had CCUS. Ide-cel was administered in 64.8% and cilta-cel in 35.2% of all patients. The rates and grades of cytokine release syndrome did not differ between groups. Six patients (15.4%) had HLH in the SCB group vs. none in the control group. All (100%) SCB patients received growth factor support; 58% also received TPO agonists. In the nSCB group, 43 patients (82.7%) received growth factor, and 16 patients (30.8%) received TPO agonists. Out of 24 pre-SCB bone marrow biopsies available, only 1 patient had relapsed MM while the remainder had hypocellular marrows. Median CD34+ cell dose was 2.93 million/kg (range: 1.76-23.55) administered at a median of 53 days post-CAR-T (range 24-265). All but one patient (97.4%) in the SCB group achieved hematologic recovery; median time to recovery was 24 days (range 9-87). No new toxicities attributable to SCB were observed. On day 90 post CAR-T infusion, SCB patients had higher median ANC (2.12 vs. 1.59x109/L, p=0.277), Hgb (10.6 vs. 8.7g/dL, p=0.002), and platelet counts (135 vs. 35K/L (p<0.001). Minimal residual disease negativity was achieved in 82.4% (SCB) vs. 83.3% (nSCB). Infections occured in 53.8% and 48.1% of SCB and nSCB cohorts. All serious infections occurred prior to SCB. There were 12 deaths in the SCB group (7 from disease progression, 2 from infection, 1 from neurotoxicity (NT), and 1 unknown) and 27 in the nSCB group (22 from progression, 3 from infection, 1 from HLH, 1 from NT). After a median follow-up period of 12.6 months in the SCB cohort and 11.6 months in the nSCB arm, the mPFS was 11.0 months and 8.2 months, respectively. The mPFS was 10.6 months (SCB) and 5.8 months (nSCB) (p=0.216), and 11.0 months (SCB) and 10.9 months (nSCB), for ide-cel and cilta-cel treated-patients, respectively. Median OS was not reached vs.12.3 months in the SCB vs. nSCB groups, respectively. Conclusion: Overall, SCB was safe and effective in promoting rapid hematologic recovery in nearly all patients. Compared to controls, SCB recipeints had significantly higher Hgb and platelet levels by day 90 post-CAR-T infusion. SCB was associated wih a near doubling of PFS in patients who received ide-cel, though interpretation is limited by non-randomized design and small sample size. Further study is needed to optimize paient selection, timing, and integration of SCB into CAR-T care.

Abstract Despite significant therapeutic advances in multiple myeloma (MM), outcomes in patients with plasma cell leukemia (PCL) remain dismal. We conducted a multicenter retrospective analysis of patients with PCL who were treated with the B-cell maturation antigen–directed chimeric antigen receptor T-cell (CAR-T) products idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel). We identified 34 patients; 19 patients received ide-cel and 15 received cilta-cel. With a median follow-up of 11.9 months, the overall median progression-free survival (mPFS) was 9.0 months (95% confidence interval [CI], 4-15) and the median overall survival (mOS) was 13.0 months (95% CI, 8 to not estimable [NE]). The 1-year cumulative incidence of progression or death was 72%, and the 1-year cumulative incidence of death was 47%. Patients who received cilta-cel had a longer mPFS (19.0 months vs 6.0 months) and mOS (>23 months [NE] vs 9.0 months) when compared with those treated with ide-cel. Similarly, the 1-year cumulative incidence of disease progression or death was 37.5% (95% CI, 17.4-68.5) with cilta-cel, whereas all patients treated with ide-cel progressed or died within 12 months of infusion. The rates of hematologic and nonhematologic toxicities were similar between patients treated with cilta-cel and those treated with ide-cel and were consistent with those reported in patients with MM. In this first multicenter study that evaluated patients with PCL who were treated with standard-of-care CAR-T products, we show that CAR-T is safe, feasible, and associated with improved outcomes when compared with historic standards.

Abstract Ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel), 2 B-cell maturation antigen (BCMA)–directed chimeric antigen receptor T-cell (CAR-T) therapies, have transformed outcomes for relapsed/refractory multiple myeloma; however, the 6 to 8 weeks manufacturing time risks disease progression or death in up to 10% of patients. Talquetamab, a G-protein–coupled receptor, family C, group 5, member D (GPRC5D)–targeting bispecific antibody, represents a promising option. We performed a multi-institutional retrospective analysis across 20 centers (18 United States, 2 Germany) evaluating talquetamab as a bridging therapy prior to cilta-cel or ide-cel. Among 134 patients receiving talquetamab, 119 proceeded to CAR-T (n = 98 cilta-cel, n = 21 ide-cel). Reasons for not proceeding (n = 15) included progression (n = 7), manufacturing failure (n = 6), or patient decision (n = 2). Median age was 65 years and had median 5 prior lines of therapy. Notably, 85% would not have met CARTITUDE-1/KarMMa eligibility criteria. Talquetamab was administered for a median 23 days. Toxicity was manageable: no grade ≥3 cytokine release syndrome (CRS), 2% grade 3 immune effector cell–associated neurotoxicity syndrome (ICANS) and grade 1 to 2 talquetamab unique toxicities (70% oral, 38% skin, and 17% nail; 60% resolved). Talquetamab achieved 71% response rate. After CAR-T, 88% responded (54% complete response), with low-grade toxicities (2 grade ≥3 CRS, 1 grade 3 ICANS, and 5% grade ≥3 infections). Two cases of facial palsy and 1 acute myeloid leukemia occurred. Talquetamab correlated with sustained soluble BCMA decline and peak CAR-T expansion around day 14. Talquetamab bridging appears safe, enabling the majority of difficult-to-treat patients to successfully proceed to BCMA CAR-T therapy.

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 .