Koneru, Mythili

Abstract Introduction: Cilta-cel is approved in the US and the EU for the treatment of patients (pts) with lenalidomide-refractory multiple myeloma (MM) after ≥1 prior line of therapy (pLOT), including a proteasome inhibitor and an immunomodulatory agent based on the CARTITUDE-1 (CART-1, NCT03548207) and CARTITUDE-4 (CART-4, NCT04181827) studies. Cilta-cel led to deep and durable responses and significant survival benefit in pts with relapsed/refractory MM (RRMM) after ≥3 pLOT in CART-1. In CART-4, cilta-cel led to a significant overall survival benefit with a higher proportion of pts achieving deep, sustained minimal residual disease negativity vs standard of care in pts with lenalidomide-refractory MM after 1–3 pLOT. We investigated the mechanism of action of cilta-cel by correlating biomarkers from peripheral blood and the bone marrow TME with progression-free survival (PFS) and number of pLOT in pts with RRMM from CART-1 and CART-4. Methods: Biomarker analyses were performed using peripheral blood and bone marrow aspirates (BMAs) collected in both CART-1 and CART-4 studies. Immunophenotyping by flow cytometry was performed using peripheral blood at baseline/time of apheresis in samples from both studies. Immune fitness at baseline was assessed in pts by pLOT and in association with PFS. Gene set enrichment scores were derived from RNA sequencing data of the TME using BMAs. Mixed-effects models were used to identify signatures/pathways modulated over time (day [D] 28 and at 6 months [mo] post infusion vs screening) and in association with PFS and pLOT. Results: In total, 176 CART-4 and 97 CART-1 pts received cilta-cel as study treatment. Immunophenotyping data were available from 248 peripheral blood samples (1 pLOT, n=56; 2 pLOT, n=61; ≥3 pLOT, n=131). At apheresis, CD4+ naïve T cells (%) were higher in pts with 1 or 2 pLOT, compared with those with ≥3 pLOT, while no difference was found in pts with ≥3 pLOT with further breakdown (i.e., 3–4 vs 5–6 vs ≥7 pLOT). Further, higher baseline levels of CD4+ naïve T cells were associated with longer PFS. These data suggest that the negative impact on peripheral immune fitness with the addition of LOT may plateau when pts have received ≥3 pLOT. TME gene expression data were available from 148 BMA samples (screening, n=50; D28, n=50; 6 mo, n=48) from CART-4. Analyses of gene expression signatures suggest depletion of B cells and antibodies at D28 post cilta-cel infusion, with partial recovery at 6 mo. This was corroborated in parallel by flow cytometry and immunoglobulin quantification. Further, elevated expression of genes associated with myeloid cells, including tumor-associated macrophages (TAM, likely M1), and of genes associated with cytotoxic T cells were also observed at D28. Elevated expression of genes associated with B-cell receptors, T-cell differentiation and activation, and cytokine signaling pathways were found at both D28 and 6 mo. Pts with longer PFS (>18 mo) had higher levels of M1 TAM at D28, while those with shorter PFS had higher levels of regulatory T cells and more suppressed interferon pathway genes at 6 mo, suggesting that relapse may be associated with a more suppressive immune response. In pts with fewer pLOT, more profound B-cell depletion on D28, better recovery at 6 mo, and elevated B-cell receptor signaling were inferred from gene expression data. Pts with 1 pLOT also demonstrated higher elevation of M1 TAM expression on D28 from screening as compared with pts with 3 pLOT, similar to what was observed in pts with longer PFS. Conclusions: Correlative biomarker data suggest that longer PFS is associated with better immune fitness at baseline and stronger immune responses post cilta-cel infusion, as observed in peripheral blood and within the TME of pts with RRMM in CART-1 and CART-4. The peripheral immune fitness was more pronounced in pts with 1 and 2 pLOT vs 3 pLOT and beyond, where deterioration plateaued. This suggests the impact of T-cell immune fitness on PFS may be limited beyond the third LOT. Importantly, other covariates, including factors within the immune TME and tumor burden, may play a significant role in balancing this compromised intrinsic T-cell immune fitness at apheresis, thereby contributing to PFS durability after 3 pLOT. Overall, these results support increased benefits in treating pts with MM with cilta-cel in earlier LOTs.

Abstract Introduction: The CARTITUDE-4 study (NCT04181827), which enrolled patients with lenalidomide-refractory multiple myeloma (MM) after 1–3 prior lines of therapy (pLOT), demonstrated a significant benefit of ciltacabtagene autoleucel (cilta-cel) over established triplet regimens. However, the benefit of cilta-cel for patients with standard-risk cytogenetics remains less defined. Here, we report outcomes in patients with standard-risk cytogenetics from the intent-to-treat and as-treated populations in CARTITUDE-4. Methods: InCARTITUDE-4, patients randomized to the cilta-cel arm underwent apheresis and bridging treatment with either pomalidomide, bortezomib, and dexamethasone (PVd) or daratumumab, pomalidomide, and dexamethasone (DPd), followed by lymphodepletion therapy with cyclophosphamide and fludarabine, and then a single cilta-cel infusion. Progression-free survival (PFS) was assessed using a validated computerized algorithm. The intent-to-treat population included 208 patients; 32 patients progressed or died on bridging therapy, resulting in an as-treated population of 176 patients. Patients with high-risk cytogenetics, defined as del(17p), t(14;16), t(4;14), gain/amp(1q) (n=105), or with unknown cytogenetics (n=12), were excluded from the as-treated analysis. The 12-month minimal residual disease (MRD)-negative complete response (CR) was defined per the International Myeloma Working Group criteria as the proportion of participants with CR or better prior to and at 12 months (±3 months), achieving MRD-negative status at 12 months (+3 months) after cilta-cel infusion, as determined by next-generation sequencing (10-5), prior to progressive disease or subsequent anti-myeloma therapy. For the as-treated population, PFS rates were measured from the time of cilta-cel infusion. Results: In CARTITUDE-4, in the intent-to-treat population, at a median follow-up of 33.6 months, patients with standard-risk cytogenetics had a 30-month PFS rate (95% CI) of 71.0% (58.8–80.2) in the cilta-cel arm (N=69) vs 43.2% (31.3–54.5) in the standard-of-care (SOC) arm (N=70). Patients with standard-risk cytogenetics in the as-treated population (n=59) had a 30-month PFS rate of 80.5% (95% CI, 67.2–88.8). In CARTITUDE-1 (NCT03548207), which evaluated cilta-cel in patients with heavily pretreated relapsed/refractory MM (RRMM; ≥3 pLOT), the 30-month PFS rate among patients with standard-risk cytogenetics (negative for del(17p), t(14;16), or t(4;14); n=68) was 59.9% (95% CI, 47.2–70.5). In the CARTITUDE-4 as-treated population with standard-risk cytogenetics, 8 PFS events occurred within 1 year and 4 PFS events beyond 1 year of cilta-cel infusion. Twenty-six patients achieved MRD-negative CR at 12 months after cilta-cel; 100.0% of these patients were progression free at 30 months. Fourteen patients were not evaluable for MRD due to: calibration failure (n=12), no sample availability for testing (n=1), or indeterminate results post baseline (n=1). Conclusions: The PFS rate at 2.5 years for patients with standard-risk RRMM was higher in CARTITUDE-4 compared with CARTITUDE-1, supporting the use of cilta-cel as early as second line in the treatment course. In CARTITUDE-4 (as-treated population), 80.0% of patients with standard-risk cytogenetics were progression free and off treatment at 2.5 years. In patients with standard-risk disease who achieved MRD-negative CR at 1 year, this rate increased to 100.0%. The low rate of progression events in cilta-cel-treated patients with standard-risk cytogenetics shows the profound benefit of a single cilta-cel infusion in this population.

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 .