ABSTRACT
Ciltacabtagene autoleucel (cilta‐cel) has demonstrated excellent efficacy and long‐term disease control in patients with relapsed/refractory multiple myeloma (RRMM). However, a proportion of patients experience early treatment failures. We investigated clinical factors associated with early progression or death (within 12 months) in patients with RRMM receiving standard‐of‐care cilta‐cel across the three Mayo clinic centers. Patients with a follow‐up of at least 12 months or progression or death within 12 months from infusion were included. Of the patients with early treatment failure (n = 52), 69% had progressive disease and 31% had a non‐relapse mortality (NRM) event. In patients without early treatment failure (n = 164), 13% of events were NRM. Among pretreatment factors, prior BCMA‐directed therapy, presence of extramedullary disease and a CAR‐HEMATOTOX score of ≥ 2 were independent predictors of early progression or death. The utilization of cilta‐cel in earlier lines of treatment (1–3 vs. 4 or more) demonstrated comparable PFS (12‐month PFS 73% vs. 77%, p = 0.94). Measurable residual disease positivity in the bone marrow at 3 months (11/197 patients) identified a small but high‐risk group with an increased risk of early treatment failure (OR 5.68; p = 0.012). Patients with less than a complete response on a FDG PET/CT at 3 months also had an increased risk of early treatment failure (OR 11.8; p < 0.0001). Our findings may help identify patients at high‐risk for early adverse outcomes despite receiving highly effective therapy, and support consideration of novel therapeutic strategies within a clinical trial setting.
1. Introduction
Ciltacabtagene autoleucel (cilta‐cel) is a highly effective B‐cell maturation antigen (BCMA)–targeting chimeric antigen receptor (CAR) T‐cell therapy approved in the United States for the treatment of relapsed/refractory multiple myeloma (RRMM). In pivotal studies, cilta‐cel has demonstrated unprecedented depth and durability of response, with a median progression‐free survival (PFS) approaching 36 months [1]. More recently, updated results from the CARTITUDE‐4 trial in patients with 1–3 prior lines of therapy demonstrated a 30‐month PFS rate of approximately 80% among those with standard‐risk cytogenetics, underscoring the transformative impact of this therapy earlier in the disease course [2, 3, 4].
Despite these impressive outcomes, a clinically meaningful minority of patients experience early progression or death following cilta‐cel, representing a particularly high‐risk subgroup. Patients who experience early failure often derive minimal clinical benefit, have limited opportunity for effective salvage therapy, and account for a large proportion of early mortality following CAR T‐cell treatment.
There is limited evidence to suggest that predictors of early treatment failure necessarily overlap with factors associated with late relapses or following immune effector therapies. Identifying determinants of early treatment failure is essential to inform patient selection, optimize pre‐infusion risk stratification, guide the development of rational combination or consolidation strategies, and enable timely consideration of alternative cellular or non–CAR T‐based therapeutic approaches. This is especially important in patients receiving CAR‐T therapy, where non‐relapse mortality (NRM) accounts for a fair proportion of the early treatment failure events [5]. This need is further amplified by the emergence of highly effective immunotherapeutic options. Notably, the combination of teclistamab, a CD3 × BCMA‐directed bi‐specific antibody, with daratumumab has demonstrated an estimated 36‐month PFS rate of 83.4% in relapsed/refractory patients with 1–3 prior lines of therapy, underscoring the potential for rational treatment sequencing in patients at high‐risk of early CAR‐T failure [6].
Against this backdrop, we evaluated a large real‐world cohort to systematically identify clinical and biological factors associated with inferior PFS, with a specific focus on early progression or death (PFS < 12 months), following treatment with cilta‐cel.
2. Methods
2.1. Ethics
This study was conducted in accordance with the Declaration of Helsinki and all methods were performed in accordance with the relevant guidelines and regulations. The Mayo Clinic Institutional Review Board Approval was obtained for conducting the study (25‐000605).
2.2. Data Sources
This is a retrospective study involving the three Mayo Clinic sites in Rochester, MN, Scottsdale, Arizona, and Jacksonville, Florida within the United States. We included patients with RRMM who received standard of care cilta‐cel between 1st February 2022 and 30th November 2024. To identify associative factors for early progression or death, we compared patients who had progressed or died within 12 months (cutoff chosen to identify the time point with 25% of PFS events) termed “early treatment failure” (PFS < 12 months) with patients who were alive and progression‐free at 12 months (PFS ≥ 12 months). Patients who were alive with < 12 months of follow‐up were excluded from this analysis.
Cytogenetics abnormalities were obtained through interphase fluorescence in situ hybridization (FISH) testing within 6 months of infusion. High‐risk cytogenetics abnormalities (HRCA) were defined by the presence of high‐risk IgH translocations including t(4;14), t(14;16) and t(14;20), termed IgH‐HR or the presence of secondary abnormalities del(17p), gain or amplification of 1q (1q+) or del(1p). The impact of the new high‐risk criteria as defined by the new consensus genomic staging (CGS) by the International Myeloma Society (IMS)/International Myeloma Working Group (IMWG) was also explored using an adapted definition (TP53 mutation data and biallelic del(1p) information was not available) [7]. Functional high‐risk (FHR) disease was defined as disease progression within 18 months of commencement of first‐line therapy [8]. Extramedullary disease (EMD) was defined as true bone non‐contiguous plasmacytomas. High disease burden was defined as bone marrow plasmacytosis of ≥ 50% [9, 10] or involved serum free light chain values of ≥ 100 mg/dL. To assess the role of pre‐existing cytopenias and inflammation prior to infusion, the previously validated CAR‐HEMATOTOX score, which incorporates 5 baseline laboratory markers (hemoglobin, absolute neutrophil count, platelet count, C‐reactive protein and serum ferritin), was used as a composite risk factor in our analysis. MRD was determined by either flow cytometry using a Euroflow panel or clonoSEQ with a minimum sensitivity of at least 2 × 10−6 nucleated cells. Cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) were graded according to American Society for Transplantation and Cellular Therapy criteria [11]. Response assessment was based on the 2016 IMWG criteria [12, 13].
2.3. Statistical Methods
Progression‐free survival was defined as the time from CAR‐T infusion to the time of disease progression as defined by the 2016 IMWG criteria or death [13]. Overall survival (OS) was defined as the time from CAR‐T infusion to death or last follow‐up. Time‐to‐event endpoints were calculated using the Kaplan–Meier (KM) method and compared using the log‐rank test. Median follow‐up time was estimated using the reverse KM method. Categorical variables were compared between groups using the chi‐square test or Fisher's exact test, as appropriate. The Cox proportional hazards model was used to estimate hazard ratios for factors associated with progression‐free survival. Binomial logistic regression was used to estimate odds ratios for factors associated with early treatment failure (binary outcome). Variables were first assessed using univariable analysis, and those with p < 0.05 were included in the multivariable model. Variables with p < 0.1 were additionally included if clinically relevant or identified as potential confounders based on prior literature. Selected variables with low counts (n ≤ 10) in either group were excluded from the multivariable model to avoid sparse data bias and unstable parameter estimates.
3. Results
3.1. Patient Characteristics and Outcomes of the Overall Cohort
A total of 232 patients received SOC cilta‐cel between the stated period. Demographics, patient clinical characteristics, treatment history and post‐treatment toxicity are provided in Table 1. The median age was 65 years and 30% were ≥ 70 years of age. Extramedullary disease was present in 18% of patients, 39% had IMS/IMWG CGS‐HR and 28% had FHR disease. The median number of prior lines of therapy was 4 (range 1–14) and median time from frontline therapy to cilta‐cel was 74 (range 7–256) months. In this heavily pre‐treated cohort, 71% of patients were triple‐class refractory, 25% penta‐drug refractory and 5% were exposed to prior BCMA‐directed therapy. Details of the 12 patients with prior BCMA exposure are shown in Table S1. Of the 12 BCMA‐exposed patients, 3 had a prior antibody‐drug conjugate (ADC), 5 had a prior bi‐specific antibody (BsAb) and 4 had prior CAR‐T cell therapy. The median time from BCMA‐directed therapy dose or infusion to cilta‐cel infusion was 12.8 (range 3.7–42.9) months. Of patients who received BsAb or ADC, 6/8 (75%) were deemed refractory to the therapy. Median duration of response for patients who received a prior BCMA‐directed CAR‐T was 8.9 (range 8.3–31.4) months.
TABLE 1.
Baseline patient characteristics of the overall cohort and by early progression defined as < 12 months.
| Overall cohort | No progression or death within 12 months | Early progression or death within 12 months | ||||
|---|---|---|---|---|---|---|
| (n = 232) | (n = 164) | (n = 52) | ||||
| Demographics | ||||||
| Age ≥ 70 years | 70/232 | 30% | 48/164 | 29% | 19/52 | 37% |
| Male sex, N (%) | 126/232 | 54% | 88/164 | 54% | 29/52 | 56% |
| Race, Black or Hispanic, N (%) | 18/232 | 8% | 14/164 | 9% | 2/52 | 4% |
| Disease characteristics | ||||||
| IgG | 130/232 | 56% | 95/164 | 58% | 26/52 | 50% |
| High marrow burden (≥ 50%), N (%) | 49/212 | 25% | 17/150 | 11% | 12/49 | 24% |
| Involved light chain ≥ 100 mg/dL, N (%) | 18/209 | 18% | 7/148 | 5% | 8/46 | 17% |
| Extramedullary disease, N (%) | 41/232 | 18% | 22/164 | 13% | 17/52 | 33% |
| Functional high‐risk (PFS‐1 < 18 m), N (%) | 65/230 | 28% | 47/164 | 29% | 16/51 | 31% |
| IMS/IMWG high‐risk, N (%) | 88/224 | 39% | 59/159 | 37% | 24/50 | 48% |
| 2 or more HRCA | 67/224 | 30% | 42/159 | 26% | 20/50 | 40% |
| LDH > ULN, N (%) | 65/228 | 29% | 43/162 | 27% | 20/51 | 39% |
| MYC‐rearrangement, N (%) | 35/215 | 16% | 22/150 | 15% | 11/50 | 22% |
| Tetraploidy, N (%) a | 21/188 | 11% | 12/127 | 9% | 7/47 | 15% |
| Previous therapy | ||||||
| < 3 prior lines | 29/232 | 13% | 16/164 | 10% | 9/52 | 17% |
| ≥ 4 prior lines | 149/232 | 69% | 115/164 | 70% | 34/52 | 65% |
| Prior ASCT, N (%) | 200/232 | 86% | 144/164 | 88% | 43/52 | 83% |
| Triple‐class refractory, N (%) b | 164/232 | 71% | 110/164 | 67% | 44/52 | 85% |
| Penta‐drug refractory, N (%) c | 58/232 | 25% | 33/164 | 20% | 21/52 | 40% |
| Prior treatment with BCMA‐targeted therapy, N (%) | 12/232 | 5% | 5/164 | 3% | 7/52 | 13% |
| Bridging therapy received, N (%) | 186/232 | 80% | 133/164 | 81% | 42/52 | 81% |
| Response to bridging (PR or better), N (%) | 41/187 | 22% | 29/132 | 22% | 9/42 | 21% |
| Other pre‐infusion variables | ||||||
| CAR‐HEMATOTOX ≥ 2, N (%) d | 79/212 | 37% | 46/149 | 31% | 26/48 | 54% |
| Out of specification infusion, N (%) | 50/232 | 22% | 30/164 | 18% | 17/52 | 33% |
| ECOG PS ≥ 2, N (%) | 13/208 | 7% | 6/144 | 4% | 7/49 | 14% |
| eGFR < 45, N (%) | 19/231 | 9% | 10/154 | 6% | 9/42 | 18% |
Abbreviations: CGS, consensus genomic staging; CRP, C‐reactive protein; ECOG PS, Eastern Cooperative Oncology Group performance status; eGFR, estimated glomerular filtration rate in milliliters per minute per 1.73 m2; HRCA, high‐risk cytogenetic abnormality; IMS, international myeloma society; IMWG, international myeloma working group; IQR, interquartile range; LDH, lactate dehydrogenase; ULN, upper limit of normal.
Tetraploid or near tetraploid clone detected on cytogenetic testing.
Triple‐class therapy includes one proteasome inhibitor, one immunomodulatory drug, and one anti‐CD38 monoclonal antibody.
Penta‐drug therapy includes at least two proteasome inhibitors, at least two immunomodulatory drugs, and one anti‐CD38 monoclonal antibody.
CAR‐HEMATOTOX score is a validated, pre‐lymphodepletion risk‐stratification tool for predicting severe, prolonged hematotoxicity and infection risk comprising 5 markers which include platelet count, absolute neutrophil count, hemoglobin, C‐reactive protein, and serum ferritin.
All patients received fludarabine and cyclophosphamide for lymphodepletion (LD). The out of specification infusion rate was 22% and 80% received bridging therapy. At a median follow up of 17.1 months, the median PFS was 32.5 months, and the median OS was not reached. The estimated 24‐month OS was 77% (Figure S1).
3.2. Impact of Prior Lines of Therapy on PFS With Cilta‐Cel
We first looked at the impact of the number of prior lines of therapy on PFS. In our cohort, 32% (n = 74) of patients had received 1–3 prior lines of therapy. Median follow up time for patients receiving cilta‐cel after 1–3 prior lines (early line) was 14.4 versus 18.4 months in patients receiving cilta‐cel after 4 or more prior lines (later line). Patient receiving cilta‐cel in the earlier line setting (1–3 vs. 4 or more) had a higher proportion of patients with two or more HRCA (41% vs. 25%, p = 0.013), IMS/IMWG CGS‐HR disease (57% vs. 34%, p = 0.02), and a lower proportion with penta‐drug refractoriness (12% vs. 31%, p = 0.002) (Figure S2A). There were no differences in rates of all or high‐grade CRS, ICANS, IEC‐associated hemophagocytic lymphohistiocytosis‐like syndrome (IEC‐HS), IEC‐associated parkinsonism (IEC‐PKS), IEC‐associated nerve palsies or IEC‐associated enterocolitis (IEC‐EC) (Figure S2B). The 3‐month ORR was 96% versus 90% for patients receiving cilta‐cel in the early versus later line, respectively (p = 0.19). The 3‐month MRD negative rate in evaluable patients was 88% in both cohorts (p = 1.00). The proportion of patients with early treatment failure was 26.9% in patients receiving cilta‐cel in the earlier lines versus 22.8% in the later lines (p = 0.51). Progression‐free survival was also comparable among patients treated in the earlier lines versus those treated in the later lines (HR 1.02, 95% CI: 0.61–1.70; p = 0.94) (Figure S2C). In a sensitivity analysis, there was no difference in PFS between the earlier lines and later lines cohort among IMS/IMWG standard‐risk patients (p = 0.43; Figure S2D) and IMS/IMWG high‐risk patients (p = 0.78; Figure S2E).
3.3. Pre‐Infusion Predictors of Early Treatment Failure
We next looked at factors associated with early progression or death (defined as PFS < 12 months), termed “early treatment failure”. The consort diagram demonstrating the inclusion of patients in the analysis cohort is shown in Figure 1. The early treatment failure cohort consisted of 52 (24%) patients who had progressed or died within 12 months. The comparison cohort consisted of 164 patients with > 12 months of follow‐up and a PFS ≥ 12 months. The median follow‐up was 18 months (95% CI: 14–21) in the early treatment failure cohort and 18 months (95% CI: 17–19) in the comparison cohort. Of the 52 patients with early treatment failure, 36 (69%) had progressive disease and 16 (31%) patients had a non‐relapse mortality (NRM) event. Conversely there were 24 progression events in the comparison cohort of which 21 (88%) were progressive disease and 3 (13%) were a NRM event. Patient characteristics of the two groups are described in Table 1. We next calculated odds ratios (OR) comparing baseline parameters within the early progression cohort with the comparison cohort, with selected variables displayed in Table 2A (Table S2 displays all the variables analyzed). On univariate analysis, out‐of‐specification (OOS) product infusion (OR 2.2, 95% CI: 1.08–4.38), impaired renal function (eGFR < 45 mL/min/1.73 m2; OR 3.30, 95% CI: 1.24–8.71), poor performance status (PS ECOG ≥ 2; OR 3.8, 95% CI: 1.21–12.5), the presence of extramedullary disease (OR 3.14, 95% CI: 1.51–6.53), and high disease burden (bone marrow burden ≥ 50%; OR 2.54, 95% CI: 1.11–5.78 or involved free light chain ≥ 100 mg/dL; OR 4.24, 95% CI: 1.44–12.8) were associated with increased odds of early treatment failure. The presence of IMS/IMWG CGS‐HR disease (OR 1.56, 95% CI: 0.82–2.97) was not significantly associated with increased odds of early treatment failure, although a trend was noted for patients harboring two or more HRCA (OR 1.86, 95% CI: 0.95–3.62). On examination of prior‐treatment history, triple‐class (OR 2.7, 95% CI: 1.19–6.13), penta‐drug refractoriness (OR 2.69, 95% CI: 1.37–5.27), and prior BCMA‐exposure (OR 4.95, OR 1.59–16.33) were also associated with increased odds of early treatment failure. Pre‐lymphodepletion, patients with a high CAR‐HEMATOTOX score (defined as ≥ 2) had increased odds of early treatment failure (OR 2.65, 95% CI: 1.36–5.19).
FIGURE 1.
Consort diagram of inclusion of patients into the analytic cohort for predicting early treatment failure. Cilta‐cel, ciltacabtagene autoleucel; PFS, progression‐free survival.
TABLE 2.
Clinical parameters associated with risk of early treatment failure within 12 months. (A) Univariate analysis. (B) Multivariate analysis.
| Risk factors for early treatment failure | A. Univariate analysis | B. Multivariate analysis (n = 193) | ||||
|---|---|---|---|---|---|---|
| Odds ratio | 95% CI | p | Odds ratio | 95% CI | p | |
| ECOG PS ≥ 2 | 3.30 | (1.24–8.71) | 0.018 | |||
| eGFR < 45 | 3.83 | (1.21–12.5) | 0.023 | |||
| Out of specification infusion | 2.17 | (1.08–4.38) | 0.035 | 1.86 | (0.82–4.23) | 0.137 |
| Extramedullary disease | 3.14 | (1.51–6.53) | 0.003 | 2.70 | (1.11–6.55) | 0.028 |
| 2 or more HRCA | 1.86 | (0.95–3.62) | 0.077 | 1.34 | (0.59–3.02) | 0.487 |
| High marrow burden (≥ 50%) | 2.54 | (1.11–5.78) | 0.034 | 2.30 | (0.86–6.12) | 0.096 |
| Triple‐class refractory a | 2.7 | (1.19–6.13) | 0.014 | 1.86 | (0.74–4.65) | 0.184 |
| Prior BCMA therapy | 4.95 | (1.59–16.3) | 0.010 | 4.56 | (1.13–18.3) | 0.033 |
| CAR‐HEMAOTOX score ≥ 2 b | 2.65 | (1.36–5.19) | 0.004 | 2.39 | (1.09–5.24) | 0.030 |
Abbreviations: CGS, consensus genomic staging; ECOG PS, Eastern Cooperative Oncology Group performance status; eGFR, estimated glomerular filtration rate in milliliters per minute per 1.73 m2; IMS, international myeloma society; IMWG, international myeloma working group.
Triple‐class therapy includes one proteasome inhibitor, one immunomodulatory drug, and one anti‐CD38 monoclonal antibody.
CAR‐HEMATOTOX score is a validated, pre‐lymphodepletion risk‐stratification tool for predicting severe, prolonged hematotoxicity and infection risk comprising 5 markers which include platelet count, absolute neutrophil count, hemoglobin, C‐reactive protein, and serum ferritin.
We next included OOS product, the presence of EMD, bone more plasma cell burden (≥ 50% plasma cells), 2 or more HRCA, high pre‐LD CAR‐HEMATOTOX score, triple‐class refractoriness, prior‐BCMA exposure, in a multivariate model (Table 2B). ECOG PS, eGFR, and elevated FLC were not included in the MVA due to low numbers (n ≤ 10 in both groups). Given comparable OR for triple‐class and penta‐drug refractoriness, only the former was included in the MVA due to strong overlap. Noting the trend toward significance for ≥ 2 HRCAs for early treatment failure (p = 0.077) and its established clinical significance, this variable was included in the multivariable analysis. The presence of EMD (adjusted OR 2.70, 95% CI: 1.11–6.55), high CAR‐HEMATOTOX score (adjusted OR 2.39, 95% CI: 1.09–5.24), and prior‐BCMA exposure (adjusted OR 4.56, 95% CI: 1.13–18.3) were found to be independently associated with increased odds of early treatment failure. High bone marrow burden approached statistical significance (OR 2.30; p = 0.096) on the multivariable analysis.
3.4. Post‐Infusion Related Adverse Events
CAR‐T associated toxicities for the overall, early treatment failure and comparison cohorts are summarized in Table 3. The rate of all grade CRS and ICANS was 78% and 11% respectively, and the rate of ≥ grade 3 CRS and ICANS was 1% and 1% respectively. The rate of IEC‐HS was 8%. The rate of delayed neurotoxicity was 11%; IEC‐PKS 5% and IEC‐related nerve palsies (IEC‐NP) 7%, and the rate of IEC‐EC was 5%. Due to a potential for survival bias, we excluded post‐infusion factors from the multivariate analysis.
TABLE 3.
Incidence of CAR‐T cell associated toxicity of the overall cohort and by early progression.
| Overall cohort | No progression or death within 12 months. | Early progression or death within 12 months | p a | ||||
|---|---|---|---|---|---|---|---|
| (n = 232) | (n = 164) | (n = 52) | |||||
| N | % | N | % | N | % | ||
| Post infusion characteristics | |||||||
| Any CRS | 181 | 78% | 128 | 78% | 38 | 73% | 0.763 |
| ≥ Grade 3 | 3 | 1% | 2 | 1% | 1 | 2% | 0.564 |
| ICANS | 26 | 11% | 12 | 7% | 12 | 23% | 0.004 |
| ≥ Grade 3 | 3 | 1% | 0 | 0% | 3 | 6% | 0.013 |
| IEC‐HS | 19 | 8% | 9 | 5% | 9 | 17% | 0.017 |
| Tocilizumab use | 173 | 75% | 119 | 73% | 39 | 75% | 0.858 |
| Repeated Tocilizumab use (≥ 2 doses) | 81 | 35% | 48 | 29% | 24 | 46% | 0.029 |
| Corticosteroid use | 123 | 53% | 85 | 52% | 30 | 58% | 0.525 |
| Anakinra use | 25 | 11% | 12 | 7% | 10 | 19% | 0.019 |
| Peak ALC ≥ 3 × 109/L | 90 | 42% | 74 | 45% | 16 | 31% | 0.077 |
| Delayed toxicity | |||||||
| ALL DNT | 26 | 11% | 17 | 10% | 7 | 13% | 0.613 |
| IEC‐PKS | 11 | 5% | 5 | 3% | 4 | 8% | 0.224 |
| IEC‐NP | 16 | 7% | 13 | 8% | 3 | 6% | 0.777 |
| IEC‐EC | 11 | 5% | 8 | 5% | 3 | 6% | 0.728 |
Abbreviations: ALC, absolute lymphocyte count; CRS, Cytokine release syndrome; ICANS, immune effector cell‐associated neurotoxicity syndrome; IEC, immune effector cell; IEC‐EC, IEC‐associated enterocolitis; IEC‐HS, IEC‐associated hemophagocytic lymphohistiocytosis‐like syndrome; IEC‐NP, IEC‐associated nerve palsy; IEC‐PKS, IEC‐associated parkinsonism.
p value was generated using Fisher's exact test.
When comparing the early treatment failure cohort with the comparison cohort, patients with early treatment failure had higher rates of ICANS and IEC‐HS as well as higher rates of anakinra use or repeated tocilizumab dosing (Table 3). Patients who developed ICANS or IEC‐HS had an inferior PFS compared to patients who did not (Figure 2). The development of delayed neurotoxicity did not significantly affect PFS.
FIGURE 2.
Progression‐free survival (PFS) in patients receiving cilta‐cel based on post‐infusion toxicity. (A) Immune effector cell‐associated neurotoxicity syndrome (ICANS). (B) Immune effector cell‐associated hemophagocytic lymphohistiocytosis‐like syndrome (IEC‐HS). (C) Delayed neurotoxicity (DNT) landmarked at 3 months post‐infusion. [Color figure can be viewed at wileyonlinelibrary.com]
In the analytic cohort (n = 216), there were 19 (9%) cases of NRM where 16 (7%) occurred prior to 12 months and 3 (1%) occurred after 12 months. Nearly one‐third (31%) of early treatment failures were attributable to NRM; whereas 13% of the PFS events were attributable to NRM post the 12‐month follow‐up period. Of the 16 NRM events occurring within the first 12 months after infusion, 5 (32%) were infection‐related deaths, 5 (32%) were related to CAR‐T toxicity [1 with immune effector cell‐related acute inflammatory demyelinating polyradiculopathy (AIDP), 1 with IEC‐associated hemophagocytic lymphohistiocytosis‐like syndrome (IEC‐HS), 1 with IEC‐associated enterocolitis (IEC‐EC) and 2 with IEC‐associated parkinsonism (IEC‐PKS)], 2 (13%) were cardiac‐related deaths, 1 (6%) was from a therapy‐related myeloid neoplasm and 3 were from other causes.
3.5. Prognostic Implications of MRD Negativity
A total of 197 patients were alive and progression free at 3 months post‐infusion with a bone marrow MRD evaluation performed. Bone marrow MRD negative rate of evaluable patients was 94% whilst MRD rate by intention‐to‐treat analysis (including missing evaluation, deaths and progressive disease) was 81%. Among evaluable patients, a 3‐month landmarked PFS analysis demonstrated a markedly inferior PFS among patients with MRD positivity compared to those who were MRD negative (median PFS 11.5 vs. 35.3 months; HR 5.07, 95% CI: 2.37–10.87; p < 0.0001) (Figure 3A).
FIGURE 3.
Progression free survival (PFS) landmarked from 3 months after cilta‐cel infusion based on minimal residual disease (MRD) status at 3 months. (A) Bone marrow MRD negative versus positive. (B) Bone marrow MRD negative CR versus bone marrow MRD negative VGPR versus bone marrow MRD positive. (C) Imaging bone marrow MRD negative versus imaging or bone marrow positive. (D) Proportion of patients with early progression (PFS < 12 months) by MRD status. [Color figure can be viewed at wileyonlinelibrary.com]
There was no significant difference in PFS curves between patients who achieved an MRD‐negative CR or MRD‐negative VGPR at 3 months (median PFS NR vs. 35.3 months; HR 0.89, 95% CI: 0.48–1.63, p = 0.70), whereas patients who were BM MRD positive at 3 months had a significant risk of progression or death versus patients with MRD‐negative CR (HR 5.43, 95% CI: 2.34–12.85, p < 0.0001) and patients with MRD‐negative VGPR (HR 4.82, 95% CI: 2.16–10.76, p < 0.0001) (Figure 3B).
We next looked at the impact of the 3‐month MRD status on early treatment failure among patients who were alive and progression‐free at 3 months after CAR‐T infusion (Figure 3C). Among BM MRD positive patients, 45% had early treatment failure compared to 13% in patients who were BM MRD negative (OR 5.68, 95% CI: 1.60–20.2, p = 0.0120). There was no difference in rates of early treatment failure between BM MRD negative patients who achieved a CR versus VGPR (OR 1.00, 95% CI: 0.40–2.47).
We also assessed the prognostic impact of positron emission tomography (PET)/computed tomography (CT) imaging performed at 3 months. A complete metabolic response (CMR) on PET/CT was defined as a Deauville score of ≤ 3. Among 156 assessable patients with PET/CT performed at the 3‐month mark, 140 (90%) achieved a CMR on PET/CT. Patients who did not achieve a CMR on PET/CT had a significant increased risk of progression or death (HR 3.61, 95% CI: 1.80–7.24) (Figure 3D) and increased odds of early treatment failure (OR 11.8, 95% CI: 4.38–31.9).
At 3 months 145 patients had PET/CT and BM MRD assessment performed of which 130 (89%) were MRD negative and PET CMR, 12 (8%) were either BM MRD positive or less than a CMR on PET/CT and 3 (2%) patients were both MRD positive and less than CMR on PET/CT, with a median PFS (landmarked at 3 months) of 35 versus 19 versus 3 months, respectively (p = 0.002).
4. Discussion
In this large, contemporary real‐world cohort of patients treated with standard‐of‐care cilta‐cel, we confirm the remarkable durability of response reported in clinical trials while, critically, delineating a distinct subset of patients who experience early progression or death and derive limited benefit from CAR T‐cell therapy [1, 3]. Several findings from this analysis refine current understanding of risk after BCMA CAR‐T and have direct implications for patient selection, response assessment, and post‐infusion management.
First, we observed that NRM is a major contributor to the early treatment failure with cilta‐cel. The majority of NRM events with cilta‐cel occurred within 12 months. In our cohort, nearly one‐third of treatment failure events within 12 months were attributable to NRM, with infections and delayed CAR‐T‐related toxicity accounting for the majority of deaths, whereas 13% of the treatment failure events were due to NRM in 13–42 months. These findings reinforce the need for more nuanced pre‐infusion risk stratification, similar to that of a recently published model for large B‐cell lymphoma [14], particularly as CAR‐T therapy is deployed earlier in the disease course and in older patients.
Second, we confirm that prior BCMA‐exposure and EMD remain key determinants in early treatment failure, whilst the impact of high‐risk cytogenetics and functional high‐risk disease may not be as critical [15, 16, 17]. Extramedullary disease, like previous studies, also retained its significant impact on early treatment failure [17, 18, 19]. Extramedullary disease is genomically complex with a highly proliferative phenotype, with a tumor milieu enriched in exhausted effector T‐cells and a microenvironment that likely presents barriers to T‐cell trafficking leading to suboptimal efficacy [20, 21, 22, 23]. Prior BCMA‐directed therapy retained a powerful association with early treatment failure. This observation has important implications for treatment sequencing. As highly active BCMA‐directed bi‐specific antibodies move earlier in therapy, the risk of compromising subsequent CAR‐T efficacy—and specifically increasing the likelihood of early failure—must be carefully weighed [6]. This finding is not surprising, but the magnitude of impact on early treatment failure further supports the strategy to explore alternative non‐BCMA targets for T‐cell engagers and CAR‐T [15, 24, 25, 26]. The REDIRECTT‐2 study, evaluating a combination of Teclistamab and Talquetemab in EMD, demonstrated a 12‐month PFS rate of 61%, and may represent a viable alternative to CAR‐T therapy in the EMD cohort, especially when logistics are a barrier and effective bridging therapy options are not available [27].
Third, a high pre‐LD CAR‐HEMATOTOX score, which uses 5 baseline laboratory biomarkers as surrogates for bone marrow reserve and inflammatory status, was also enriched in the cohort with early treatment failure, highlighting its additional utility, aside from predicting immune‐effector cell associated hematotoxicity [28, 29]. As such, this tool may be used by clinicians for careful patient selection and evaluation prior to CAR‐T therapy.
Fourth, high disease burden prior to lymphodepletion demonstrated a strong association with early treatment failure on univariate analysis with a trend noted on multivariable analysis (p < 0.1), likely not reaching independent significance due to the low numbers. This is an important and potentially actionable finding. High tumor burden is also linked to an increased risk of severe toxicities, including cytokine release syndrome, ICANS, and delayed neurotoxicity, further compromising clinical outcomes [30, 31]. While these findings underscore the critical importance of effective bridging therapy and cytoreduction prior to infusion to optimize tumor control, reduce toxicity risk, and improve the durability of response, we did not identify receipt of bridging therapy or a response to bridging therapy to be associated with lower odds of early treatment failure.
Fifth, this study provides evidence that early BM MRD and PET/CT assessment is a powerful discriminator of both short‐term and long‐term outcomes after CAR‐T therapy [32]. Although bone marrow MRD negativity at 3 months was achieved in the vast majority of evaluable patients, MRD positivity in the absence of disease progression identified a small but exceptionally high‐risk group with five‐fold increased odds of early treatment failure. Importantly, outcomes were comparable between patients achieving MRD‐negative complete response and MRD‐negative VGPR, suggesting adequacy of MRD negativity as an early prognostic marker even in the setting of a small residual M‐protein. Similarly, patients who failed to achieve a CMR on PET/CT at 3 months also displayed markedly higher odds of early treatment failure. These findings support routine early MRD and PET/CT evaluation after CAR‐T and argue against escalation or de‐escalation decisions based solely on serologic response. Notably, traditional high‐risk features such as del(17p), IgH high‐risk translocations, or functional high‐risk disease—long recognized as adverse prognostic markers in myeloma—were not independently associated with early treatment failure. This divergence highlights the importance of explicitly modeling early events, particularly in CAR‐T–treated populations where non‐relapse mortality accounts for a substantial proportion of failures [5, 17].
Lastly, while we compared outcomes for patients treated with cilta‐cel in earlier versus later lines of therapy in keeping within the evolving FDA approval landscape, our findings showed comparable 3‐month ORR, MRD negative rates, and proportion of early treatment failures in patients who received cilta‐cel in earlier lines of therapy (1–3 prior lines) compared to those receiving it in later utilization. This contrasts with the negative impact on outcomes observed in patients with triple‐class refractory disease and prior BCMA exposure, highlighting that in the modern treatment era, refractoriness to specific drug classes may represent a more clinically relevant metric of prior treatment exposure [33].
Collectively, these findings have several practical implications. Patients with EMD, high disease burden, prior BCMA exposure and a high CAR‐HEMATOTOX score should be recognized upfront as being at a higher risk for early CAR‐T failure, intensified surveillance, close monitoring for adverse effects, and potential clinical trial enrollment for alternative immune effector therapy strategies. Early post‐infusion MRD and PET/CT assessment should be incorporated into routine practice to identify patients who may benefit from pre‐emptive intervention [34]. Finally, the negative impact of refractory CRS, ICANS, and IEC‐HS on PFS together with the substantial contribution of NRM to early outcomes underscores the importance of infection prophylaxis, optimizing management of early and delayed toxicities, and careful patient selection, particularly in those with compromised baseline functional status.
Our findings have inherent limitations of a retrospective study. The relatively small sample size may limit power for analyzing the contribution of other risk factors such as poor ECOG PS, impaired renal function and the impact of uncommon events on PFS (i.e., IEC‐PKS and IEC‐EC). Varying institutional practices on toxicity mitigation can also have an impact.
In summary, while cilta‐cel delivers unprecedented benefit for most patients, early progression or death defines a biologically and clinically distinct high‐risk state. Identifying predictors of early failure and integrating MRD and imaging‐based response assessment provides a framework for more personalized CAR‐T utilization and rational sequencing in an increasingly crowded immunotherapeutic landscape.
Author Contributions
K.J.C.L., S.Z., and Y.L.: conceptualization, data curation, writing – original draft. K.J.C.L. and K.D.: performed the statistical analyses. R.P., S.C., K.D., A.D.M.S.C., M.G., L.H., H.S., P.K., M.T., T.K., R.W., J.C., M.B., N.A., P.L.B., U.Y., J.E.W.‐N., S.G., S.K., S.A., R.F., Y.L.: data curation, critical appraisal and writing‐editing the manuscript. All authors made substantial contributions to the acquisition of data, critically revised the manuscript, and gave final approval of the manuscript to be submitted.
Funding
The authors have nothing to report.
Ethics Statement
This study has received Mayo Clinic institutional review board approval. This study was conducted in accordance with all applicable guidelines and regulations.
Consent
Due to the retrospective nature of the research, the requirement for patient informed consent was waived.
Conflicts of Interest
K.J.C.L., S.Z., K.D., A.D.M.S.C., L.H., H.S., P.K., M.T., T.K., R.W., J.C., M.B., N.A., U.Y., J.E.W.‐N., S.G.: no relevant disclosures. R.P.: advisory board role for Sanofi Aventis and Astra Zeneca, research funding from Bristol Myers Squibb Foundation and GlaxoSmithKline. S.C. reports honoraria from Sanofi, Ascentage Pharma, Sobi, Legend Biotech, BMS, Pfizer and institutional research funding from Johnson & Johnson, Takeda, C4 Therapeutics, Abbvie, Ascentage Pharma, AstraZeneca. M.G.: personal fees from Ionis/Akcea, honorarium from Alnylym, personal fees from Prothena, personal fees from Sanofi, personal fees from Janssen, personal fees for Data Safety Monitoring board from Abbvie & Arcellex, fees from Johnson & Johnson, Honoraria for Astra Zeneca, Medscape, Dava Oncology. Alexion. P.K.: Honoraria: Pharmacyclics, Sanofi, BeiGene, MustangBio, AstraZeneca, AbbVie. Consulting or Advisory Role: Sanofi. Research Funding: Amgen, Takeda, Sanofi, AbbVie, GlaxoSmithKline, Sorrento Therapeutics, Karyopharm Therapeutics, Regeneron, Ichnos Sciences, Bristol Myers Squibb/Celgene. P.L.B.: Consultant: Oncopeptidfes. Salarius, Radmetrix, Omeros, CellCentric, AbbVie, Pfizer. S.K.: Consulting or Advisory Role: Takeda, Janssen Oncology, Genentech/Rocher, Abbvie, BMS/Celgene, Pfizer, Regeneron, Sanofi, K36 Therapeutics; travel, accomodation and expenses: Abbvie, pfizer; Research funding: Takeda, Abbvie, Novartis, Sanofi, Janssen Oncology, MedImmune, Roche/Genentech, CARsgen Therapeutics, Allogene Therapeutics, GSK, Regeneron, BMS/Celgene. S.A.: Consulting or Advisory Role: Takeda, BeiGene, GlaxoSmithKline, Sanofi, Pharmacyclics, BMS, Amgen, Janssen, Regeneron, Cellectar. Research Funding: Pharmacyclics, Janssen Biotech, Cellectar, BMS, Amgen, GlaxoSmithKline, AbbVie, Ascentage Pharma, Sanofi. R.F.: consultancy for AbbVie, Adaptive, Amgen, Apple, BMS/Celgene, GSK, Janssen, Karyopharm, Pfizer, RA Capital, Regeneron, Sanofi. Scientific advisory board: Caris Life Sciences. Board of directors: Antengene. Patent for FISH in multiple myeloma. Y.L.: advisory board role for Janssen, Sanofi, BMS, Regeneron, Genentech, Tesserae, Legend, NexT Therapeutics, steering committee for Janssen, Kite/Gilead, research funding from Janssen, BMS, scientific advisory board for Nonimmune, Caribou and sata safety monitor board for Pfizer.
Supporting information
Figure S1: Survival curves for overall cohort. (A) Progression free survival curve by Kaplan‐Meier method with reference line at the 12‐month mark on the x‐axis and upper 25th quartile of the y‐axis. (B) Overall survival by Kaplan‐Meier method.
Figure S2: Analysis by prior lines of therapy, 1–3 prior lines versus ≥ 4 prior lines. (A) Comparisons of disease risk factors by number of prior lines of therapy. (B) Comparisons of treatment related toxicity by number of prior lines of therapy. (C) Progression free survival (PFS) by number of prior lines of therapy. (D) PFS by number of prior lines of therapy among IMS/IMWG defined standard‐risk patients. (E) PFS by number of prior lines of therapy among IMS/IMWG defined high‐risk patients. CRS, Cytokine release syndrome; EMD, extramedullary disease; HR, high‐risk; HRCA, high‐risk cytogenetic abnormality; ICANS, immune effector cell associated neurotoxicity syndrome; IEC, immune effector cell; IEC‐EC, IEC‐associated enterocolitis; IEC‐HS, IEC‐associated hemophagocytic lymphohistiocytosis‐like syndrome; IEC‐NP, IEC‐associated nerve palsy; IEC‐PKS, IEC‐associated parkinsonism; IMS/IMWG‐HR, consensus genomic staging high‐risk as defined by the International Myeloma Society and International Myeloma Working Group.
Table S1: Additional information on the 12 patients with prior BCMA‐exposure.
Table S2: Univariate binomial logistic regression results of all interrogated clinical parameters associated with risk of early treatment failure within 12 months.
Acknowledgments
We would like to thank the Immune Effector Cell Compliance Program managers and data coordinators for their assistance.
Data Availability Statement
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Figure S1: Survival curves for overall cohort. (A) Progression free survival curve by Kaplan‐Meier method with reference line at the 12‐month mark on the x‐axis and upper 25th quartile of the y‐axis. (B) Overall survival by Kaplan‐Meier method.
Figure S2: Analysis by prior lines of therapy, 1–3 prior lines versus ≥ 4 prior lines. (A) Comparisons of disease risk factors by number of prior lines of therapy. (B) Comparisons of treatment related toxicity by number of prior lines of therapy. (C) Progression free survival (PFS) by number of prior lines of therapy. (D) PFS by number of prior lines of therapy among IMS/IMWG defined standard‐risk patients. (E) PFS by number of prior lines of therapy among IMS/IMWG defined high‐risk patients. CRS, Cytokine release syndrome; EMD, extramedullary disease; HR, high‐risk; HRCA, high‐risk cytogenetic abnormality; ICANS, immune effector cell associated neurotoxicity syndrome; IEC, immune effector cell; IEC‐EC, IEC‐associated enterocolitis; IEC‐HS, IEC‐associated hemophagocytic lymphohistiocytosis‐like syndrome; IEC‐NP, IEC‐associated nerve palsy; IEC‐PKS, IEC‐associated parkinsonism; IMS/IMWG‐HR, consensus genomic staging high‐risk as defined by the International Myeloma Society and International Myeloma Working Group.
Table S1: Additional information on the 12 patients with prior BCMA‐exposure.
Table S2: Univariate binomial logistic regression results of all interrogated clinical parameters associated with risk of early treatment failure within 12 months.
Data Availability Statement
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.