Эффективность импульса стволовых клеток (SCB) для химериковой антигенной рецепторной-Т клеточной терапии (CAR-T) в связи с гематологической токсичностью у пациентов с повторной/реактивной множественной миеломой (RRMM)-реальным мировым опытом работы консорциума иммунотерапии США с множественными миеломами.

Key points

Prolonged cytopenias are a common complication following CAR-T cell therapy often requiring extended supportive care

Autologous stem cell boost (SCB) using cryopreserved CD34+ cells was administered to 39 patients across 19 institutions in this retrospective study

Compared to patients who did not receive stem cell boost (SCB), SCB led to higher hemoglobin and platelet levels at day 90 post-CAR-T infusion

The median time to SCB was 53 days post CAR-T, with hematologic recovery rate of 97.4% without the use of conditioning chemotherapy

Median engraftment times following SCB were 13 days for absolute neutrophil count ≥500/μL, 18 days for platelets ≥20,000/ μL, and 24 days for hemoglobin ≥8g/dL

No new toxicities were attributed to SCB suggesting it is a safe and effective strategy to address CAR-T-associated cytopenias

Introduction

CAR-T therapy is an effective commercial therapy available to patients with RRMM [ 1 , 2 ]. In addition to cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), prolonged cytopenias are a well-recognized complication following chimeric antigen receptor T cell (CAR-T) therapy [ 3 – 6 ]. This toxicity has been classified as immune effector cell-associated hematotoxicity (ICAHT) with grading severity based on the depth and duration of neutropenia and thrombocytopenia [ 7 , 8 ]. The causes of cytopenias after CAR-T infusion are multifactorial and not completely understood. In addition to bone marrow suppression from lymphodepletion chemotherapy, CAR-T cell expansion can lead to an intense systemic immune activation which can suppress the bone marrow and delay blood count recovery [ 4 , 9 , 10 ]. Factors such as disease burden and number and type of prior lines of therapy can also result in a compromised hematopoietic reserve less resilient to recovery. While many patients experience count recovery between day 30-90 from CAR-T cell infusion, there is a subpopulation of patients who experience severe and persistent cytopenias [ 3 , 11 – 13 ]. These cytopenias can present major clinical challenges as they can increase the risk of serious infections, bleeding, and need for ongoing transfusions and marrow stimulants. Supportive measures include frequent blood and platelet transfusions, antimicrobial prophylaxis and the use of growth factor such as granulocyte colony-stimulating factor (GCSF) or thrombopoietin agonists. Close monitoring of blood counts is critical as early interventions can prevent serious complications. Autologous stem cell boost (SCB) with cryopreserved CD34+ hematopoietic stem cells may be an alternative to prolonged use of growth factor and transfusion support. Herein, we describe the clinical characteristics, hematopoietic reconstitution, and clinical outcomes in a multi-institutional cohort of patients with RRMM who experienced ICAHT.

Materials and methods

Patients

This was a retrospective analysis of patients with RRMM who experienced ICAHT following commercial BCMA-directed CAR-T infusion between 5/17/2021 and 3/12/2024. To be considered in the SCB category, patients must have received SCB within 1 year of CAR-T infusion. Data was collected from 19 participating institutions of the US Multiple Myeloma Immunotherapy Consortium. Each center obtained institutional review board approval, informed consent per institutional requirements, and the study was conducted according to the Declaration of Helsinki. Collected data included baseline demographics, baseline disease characteristics such as cytogenetic risk (high versus standard), number of prior lines of therapy, bridging therapy, and response to bridging therapy immediately prior to CAR T infusion. High-risk cytogenetics were defined in this study as presence of del17p, t(4;14), or t(14;16) on FISH at any time prior to CAR T infusion.

To identify matched controls with comparable hematologic toxicity, we selected patients with an absolute neutrophil count (ANC) of ≤0.72 × 10 9 /L and platelet count of ≤21 K at day 30 post-infusion-thresholds, representing the 75 th percentile of cytopenia severity in the SCB cohort.

CAR-T

CAR-T-related data included CAR-T product and dose administered, CRS rate and grade, ICANS rate and grade, and overall infection rate. Hematologic variables included cell counts prior to CAR-T infusion, date and dose of SCB, cell counts at day 7, 30, 60, and 90 post CAR-T infusion, and time to cell count recovery following stem cell infusion. In this study, the Center for International Blood and Marrow Research (CIBMTR) definition of cell count recovery was utilized: the first of 3 consecutive days where the absolute neutrophil count (ANC) was ≥ 0.5 × 10 9 /L, the first day where the hemoglobin (Hgb) was ≥8 g/dL without red blood cell transfusion within the previous 7 days, or the first day where platelets were ≥ 20 × 10 9 /L without platelet transfusion within the previous 7 days. For the nSCB group, cell counts were analyzed cross-sectionally at day 60 and 90 post-CAR-T and compared to the SCB cohort. Disease response was assessed according to IMWG response [ 14 ] criteria at approximately day 30-90 post CAR-T infusion.

Statistical Methods

Categorical variables were summarized with frequencies and proportions, while continuous variables were summarized with medians and ranges. Kruskal Wallis tests were used for comparisons between the SCB and nSCB cohorts, comparing cell counts at 90 days after CAR-T infusion. A sensitivity analysis was also conducted on the subgroup of SCB patients with ANC < 0.72 cells/µL and platelets ≤21 ×103/µL (the criteria used to identify the nSCB cohort), as there was no formal protocol to determine who received the SCB in this retrospective analysis. The cell counts of this SCB subgroup were also compared to the nSCB cohort. Time to event outcomes included progression-free survival (PFS) and overall survival (OS). PFS was measured from CAR-T infusion to date of progression or death or censored at last follow-up. OS was measured from CAR-T infusion to date of death or censored at last follow-up. These outcomes were estimated using Kaplan Meier (KM) methods, and medians or landmarks were estimated from the KM curves. Note, select data elements were only available at some sites.

Results

Baseline characteristics

Of the 590 patients who received CAR-T across all sites, 91 patients (15.4%) developed prolonged cytopenias of which 39 patients were administered a SCB. White patients made up 80.2% of the entire cohort and Blacks made up 16.5%. The median age was 65 years (range 39–79) in the SCB cohort and 61 years (range 36-84) in the nSCB cohort. High risk cytogenetics and ISS stage III disease were reported in 33.3% vs. 38.0% and 23.1% vs. 11.5% in the SCB and the nSCB groups, respectively (Table 1 ). Most patients (90.1%) had undergone autologous stem cell transplantation previously in the entire cohort. Forty-three percent of the SCB cohort were penta-refractory compared to 34.6% in the nSCB cohort. Eighty-three percent of patients received bridging therapy, the majority of whom did not attain a partial response or better (78.8% in the SCB group and 68.2% in the nSCB group). No patients achieved a complete response (CR) to bridging therapy in either group. Seventeen patients (51.5%) in the SCB and 7 (16.3%) in the nSCB received infusional chemotherapy (DCEP/PACE/HyperCVAD) (Table 1 ). One patient had received an anti-BCMA antibody drug conjugate (belantamab mafodotin), and one patient had received talquetamab, an anti-GPRC5D bispecific antibody, in the SCB group. In the nSCB arm, 2 patients received belantamab, and one patient received prior ide-cel. Prior to CAR-T infusion, cytopenias were 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 <50 × 10 9 /L in 28.2% vs. 40.4%, respectively (Table 1 ). Median plasmacytosis in the bone marrow prior to CAR-T infusion in the SCB group was 35% (range:1–95), and it was 45% (range: 0–100) in the nSCB group.

CAR-T treatment

Ide-cel was administered in 64.1% (SCB) and 65.4% (nSCB) of patients; the median doses were 417 (range: 253.4–459.7) and 406.1 × 10 6 CAR-positive T cells, respectively. The median doses of cilta-cel were 0.6 (range: 0.41–0.75) and 0.7 × 10 6 CAR+ viable T-cells/kg (range: 0.3-0.8), respectively (Table 2 ). The median baseline ferritin and C reactive protein (CRP) prior to CAR-T infusion were 860 (SCB) vs. 740 (nSCB) and 1.5 (SCB) vs. 1.4 (nSCB), respectively. Only one patient in the SCB group and 4 patients in the nSCB group did not experience cytokine release syndrome (CRS). The rates of CRS were similar between the two groups with the majority experiencing Grade 1 or 2 CRS. There were no grade 4 CRS events. Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 9 patients in each group with only 2 patients experiencing Grade 3 in the nSCB group. Maximum ferritin was 4333 (range: 283–140 166) and 3951 (range: 108–142 013) in the SCB and nSCB, respectively. Nearly all patients in each group received tociluzimab and approximately half the patients in each group received steroids (Table 2 ).

Cytopenias

Of the 91 patients with prolonged cytopenias post CAR-T, 39 received SCB (without conditioning chemotherapy), and 52 did not. Bone marrow biopsy data were only available for the SCB group. Twenty-four patients had biopsies pursued prior to SCB; only 1 patient had relapsed MM, while the remainder were noted to have hypocellular marrow findings without clonal plasma cells. Of note, the patient with relapsed disease did respond to SCB. Two patients harbored DNMT3A mutations on pre-existing bone marrow biopsies, one of whom had a diagnosis of clonal cytopenia of undetermined significance (CCUS) prior to CAR-T. One patient had the discovery of a TP53 mutation on next generation sequencing, though no overt myelodysplasia was reported. The median dose of cryopreserved autologous CD34+ cells administered was 2.9 × 10 6 CD34 cells/kg (range: 1.8–23.6) (Table 3 ). The median time from CAR-T infusion to SCB was 53 days (range: 24–265). All evaluable patients from the SCB cohort received G-CSF (100%), and 22 patients (57.9%) received a thrombopoietin (TPO) agonist in the peri-CAR-T cell therapy period (Table 3 ). Twenty-nine patients continued to receive growth factor support until count recovery even after SCB. In contrast, in the nSCB group, 43 patients (86.0%) received growth factor, and 16 patients (33.3%) received TPO agonists. Table 3 describes the count recovery trends in the SCB group using CAR-T infusion date as day 0. The median time to “engraftment” as per CIBMTR definition from SCB infusion was 24 days (range: 9–87), regardless of whether patients received GCSF only prior to SCB or both before and after boost. The median time to ANC recovery was 13 days (range: 1-87), the median time to Hgb recovery was 24 days (range: 6–57), and the median time to platelet recovery was 18 days (range: 8–57). The overall success rate of SCB in this cohort, defined as ANC ≥ 0.5 ×10 9 /L, platelets ≥20 × 10 9 /L, and Hgb ≥8 g/dL without transfusion dependency, was 97.4%. One patient received a second SCB for persistent neutropenia three months after the first SCB; however, by the time the 2 nd boost was administered, the pt had achieved count recovery. One patient was not evaluable as they died from immune-effector cell hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) before an assessment could be made. Compared to the nSCB cohort, on day 90 post CAR-T infusion, SCB patients had higher median ANC (2.12 vs. 1.59 × 10 9 /L, p = 0.277), Hgb (10.6 vs. 8.7 g/dL, p = 0.002), and platelet counts (135 vs. 35 K/L, p < 0.001) (Table 4 ). In a sensitivity analysis, 23 of 39 patients in the SCB cohort were identified to have ANC ≤ 0.72 cells/µL and platelets ≤21×103/µL at day 30. The cell counts at day 90 in this subgroup were compared to the nSCB cohort, and similar results were found (ANC 2.39 vs 1.59 × 10 9 /L, p = 0.158; Hb 10.7 vs 8.7 g/dL, p = 0.008, platelets 138 vs 35 K/L, p = 0.002) (See Supplemental Table 1 ). In the SCB cohort, there were two admissions related to cytopenias (both due to thrombocytopenia): one for a gastrointestinal bleed and the other for a subdural hematoma, both of which occurred prior to SCB. Of note, there were no reported adverse events related to SCB. No admission data were available for the nSCB group. For the one patient who received talquetamab as bridging therapy, no skin toxicity flare was noted following SCB as was described in a published case report [ 15 ].

Outcomes

The median follow-up period was 12.6 months (range: 1.0–30.1 months) in the SCB cohort and 11.6 months in the nSCB cohort. Out of the entire cohort, 55 patients (60.4%) achieved a complete response (CR), 16 (17.6%) achieved VGPR, 9 (9.9%) achieved a partial response, 4 (4.4%) achieved stable disease, and 7 (7.7%) experienced a best response of disease progression (Table 5 ). Out of the patients with available MRD data, 14 (82.4%) and 15 (83.3%) achieved MRD negativity at 10 -5 in the SCB and nSCB groups, respectively. Twenty-one patients (53.8%) in the SCB group and 25 patients (48.1%) in the nSCB group developed an infection: 10 viral, 10 bacterial, and 1 fungal vs. 12 viral, 9 bacterial, and 3 viral/bacterial co-existing infections, respectively. All infections in the SCB cohort occurred prior to SCB apart from two mild cases of COVID-19.

Median progression-free survival (mPFS) for the SCB cohort was 11 months (95% CI: 7.4–15.2 months) and for the nSCB it was 8.2 months (95% CI: 4.8–11.0 months) (Fig. 1A ) . The mPFS by CAR-T product was 10.6 months (SCB) and 5.8 months (nSCB) for ide-cel (Fig. 1B) and 11 .0 months (SCB) and 10.9 months (nSCB) for cilta-cel (Fig. 1C ). Median OS was not reached in the SCB cohort and 12.3 months in the nSCB (Fig. 2 ). The 12-month OS for the SCB cohort was 68.9% (95% CI: 50.8–81.5%) and was 53.4% for the nSCB cohort (38.9–65.9%) (Fig. 2 ). There were 12 total deaths in the SCB and 27 deaths in the nSCB cohort in the follow-up period: 7 (58.3%) vs. 22 (81.5%) from progressive disease and 2 (16.7%) vs. 3(11.1%) from infection, respectively. Of note, the two patients from the SCB cohort who died from infection had achieved immune reconstitution at the time of death. None of the deaths were related directly to SCB.

Discussion

In this multicenter real-world experience comparing SCB to standard of care in patients with RRMM and prolonged cytopenias following commercial CAR-T therapy, we demonstrate that autologous SCB is a feasible and effective strategy to promote hematopoietic recovery. Notably, 97.4% of patients in the SCB group achieved hematologic recovery by CIBMTR criteria with median times to neutrophil, Hgb, and platelet recovery of 13, 24, and 18 days, respectively, from the time of boost. Our findings align with previous studies that have reported the effectiveness of SCB. For instance, a study by Davis et al. evaluated the role of autologous SCB in 19 RRMM patients. The study demonstrated a 92% success rate in hematopoietic recovery, with a median time to neutrophil and platelet recovery of 16 and 18 days, respectively [ 16 ]. Notably, some of these patients were also included in the retrospective analysis reported in this manuscript, allowing for expanded assessment of outcomes in this cohort. Similar results were also corroborated in a separate multicenter retrospective analysis by Mohan et al. that reported a 95% success rate in hematopoietic recovery among 16 RRMM patients [ 17 ]. In a study presented at the American Society of Hematology 2024 annual meeting investigating the use of SCB, the rate of ICAHT was 58% at day 21 from CAR-T infusion, and the 12-month PFS and OS rates were 67.6% and 88.3%, respectively. On multivariate analysis, the use of SCB and the presence of ICAHT at day 21 were not associated with inferior PFS and OS [ 18 ].

In this analysis, SCB was well tolerated with no adverse events attributed to the procedure. Infection rates were high in both the SCB and nSCB cohorts reflecting the underlying immunosuppressive nature of CAR-T therapy, though none were directly linked to the SCB itself. In fact, all serious infections in the SCB cohort occurred prior to the stem cell infusion, and the two reported readmissions in this group were related to pre-existing cytopenia-related complications rather than the intervention. Of note, 6 patients had pre-existing IEC-HS prior to SCB infusion, one of whom eventually died from organ failure. In a recent publication, a fatal rebound of IEC-HS following SCB was reported in 2 patients following resolution of initial IEC-HS [ 19 ]. The doses of stem cells infused were high in this report published in Blood Advances (13.4 × 10 6 CD34+ cells/kg and 20.8 × 10 6 CD34+ cells/kg). No rebound IEC-HS was witnessed in our study.

Of note, only one patient did not achieve count recovery after stem cell boost. This patient received 5 prior lines of therapy, was administered belantamab mafodotin as a bridging agent, and received a stem cell dose of 4.81 × 106 CD34 cells/kg.

In terms of disease response, SCB did not compromise anti-myeloma efficacy. Rates of complete remission, very good partial remission, and minimal disease negativity were comparable between SCB and nSCB groups. This is consistent with the hypothesis that SCB serves primarily as a supportive tool without interfering with the immune effects of CAR-T.

Survival data stratified by CAR-T product noted a mPFS that was numerically higher in the SCB/ide-cel cohort compared to the nSCB/ide-cel (10.6 months vs 5.8 months), though this did not reach statistical significance. It is important to note that a survival bias exists favoring the SCB arm in that patients needed to survive long enough to receive a stem cell boost which may explain the above phenomenon. Nonetheless, the 10.6 month mPFS in the ide-cel/SCB cohort compares favorably to the mPFS of 8.8 months reported in the pivotal KarMMA trial and 8.9 months observed in our real-world consortium analysis by Hansen et al. [ 5 , 20 ]. In contrast, for patients receiving cila-cel, the mPFS was comparable between SCB and nSCB groups (11 months each), shorter than the 12.5 months reported in the Hansen et al. real-world analysis, and notably shorter than the 34.9 months observed in the CARTITUDE-1 trial [ 2 ]. This discrepancy likely reflects the high-risk, real-world nature of our study cohort-including a high proportion of patients with high-risk features and treated with aggressive bridging therapy.

Notably, a large proportion of patients in this real-world retrospective analysis received intensified infusional chemotherapy as bridging therapy prior to CAR-T infusion. This is an important consideration, as such intensive bridging regimens may not only be an adverse risk factor reflective of advanced/refractory myeloma with high tumor burden but also may contribute directly to prolonged cytopenias post CAR-T therapy. Infusional alkylator-based chemotherapy as bridging therapy has already been identified by this consortium as an adverse risk factor associated with impaired PFS and OS [ 21 ]. Given this risk, careful deliberation is warranted when selecting bridging strategies, particularly in patients without previously collected and cryopreserved autologous stem cells. This also further underscores the need to consider the use of CAR-T cell therapy in earlier lines of therapy before patients are refractory to less-intensive bridging therapy options. The optimal dose of stem cells required for effective hematologic recovery in this setting remains undefined. In our cohort, stem cell doses ranged from 1.8 to 23.6 million CD34+ cells/kg, yet nearly all evaluable patients achieved count recovery. These findings suggest that even lower doses–may be feasible for successful engraftment.

The optimal timing for SCB after CAR-T also remains uncertain, though the authors of this manuscript suggest it be administered at least 30 days after CAR-T infusion. This interval not only permits initial evaluation of endogenous count recovery but also provides a window to conduct additional diagnostic assessments–such as bone marrow biopsy–to rule out confounding factors like disease progression, active infection, or underlying bone marrow pathology. Given that these patients are typically heavily pretreated, many may harbor clonal hematopoiesis of indeterminate potential, CCUS, or even subclinical myelodysplastic syndrome. Administering the boost after this 30-day time point helps ensure that persistent cytopenias are truly due to treatment effects rather than other pathological processes, thereby guiding more precise clinical decision-making. It is also noted that SCB was done in each of these patients without the use of conditioning chemotherapy, which confirms that chemotherapy is not needed for engraftment of stem cells in this setting. The safety profile of SCB observed here supports its broader use.

While our findings are compelling, several limitations should be acknowledged. The retrospective nature of the study limited our ability to retrieve certain data, such as hematologic recovery dates in the nSCB group or granular data around duration and number of transfusions or growth factor administered, as some patients returned to their local oncologist and had blood work that was not recorded. Comparing blood counts on days 30, 60, and 90 appears to be the most feasible approach with the available data. Furthermore, this retrospective data did not allow us to further explore why some patients did not receive SCB despite severe cytopenia. The bone marrow data were incomplete in the control group, limiting our ability to compare underlying marrow reserve or clonal hematopoiesis between cohorts. Another limitation of our study is the fact that some of the patients included in this analysis were also reported in a previously published study by Davis et al., also examining stem cell boosts following CAR-T cell therapy. This overlap and the small sample size may affect the generalizability of our findings and should be considered when interpreting the results. Finally, the study was not powered to detect differences in long-term survival, particularly since many deaths in both groups were driven by disease progression rather than cytopenia-related complications.

An important area of future investigation would be a cost-effectiveness analysis comparing stem cell boosts to alternative supportive care strategies, such as prolonged use of GCSF and TPO agonists. A study incorporating economic modeling could help determine the most resource-efficient approach to managing ICAHT. Furthermore, other factors influencing decision-making include insurance coverage. While many insurance providers, including Medicare, cover certain stem cell procedures, coverage for SCB post CAR-T therapy may not be explicitly defined.

Given the absence of established guidelines for the use of SCB post CAR-T therapy, the authors recognize a need for expert-driven recommendations to assist clinical decision-making. In response, a proposed consensus table has been developed based on the collective experience of participating institutions (Table 6 ). While not a substitute for future prospective studies, these expert suggestions aim to provide practical guidance regarding patient selection, timing, and supportive care strategies, and to serve as an initial framework for centers managing patients with complications from CAR-T.

In conclusion, this study provides some of the strongest real-world evidence to date supporting the use of SCB in RRMM patients with delayed hematologic recovery after commercial CAR-T therapy without compromising anti-myeloma efficacy. Prospective studies are warranted to further refine patient selection criteria and to determine whether early SCB administration could preempt complications and reduce healthcare utilization.

Supplementary information

Supplementary information

Acknowledgements

The authors thank the patients and clinical teams across the participating institutions within the consortium for their contributions to this study. No external funding was received for the conduct or analysis of this research.

Author contributions

CV designed the study, abstracted data and wrote the manuscript, MR analyzed the data, created the tables, reviewed and approved the manuscript. J.A.D, HH, TM, AK, D.W.S, CW, D.K.H, OC, LS, JB, AA, L.D.A Jr, BD, M.M.H, SR, AL-C, DS, PF, SP, JK, YL, SS, KP, MK, SM, and C.J.F. abstracted the data, contributed and approved the final version of the manuscript for submission.

Data availability

The data support the findings of this study were obtained from a multi-institutional consortium of participating centers and are not publicly available due to patient privacy, institutional date use agreements, and regulatory considerations. Only de-identified individual participant data was used in this analysis. Individual participant data will not be shared.

Competing interests

CV reports research funding from Janssen, Kite Pharma, K36 Therapeutics, Arcellx; consulting or advisory role for Janssen. JAD reports consulting or advisory role for Janssen. HH reports consulting or advisory role for Janssen, Amgen, and Karyopharm. TGM reports receiving research funding from Sanofi, Amgen, and Janssen Oncology, and serving as a consultant or in an advisory role for GlaxoSmithKline and Legend Biotech. AK reports research funding from Bristol Myers Squibb and AstraZeneca. DWS reports serving in an advisory role or as consultant for Janssen, Bristol Myers Squibb, GlaxoSmithKline, Sanofi, Legend Biotech, Opna Bio, Pfizer, AbbVie, AstraZeneca, and Genentech, and receiving research support from Pfizer. CBW Pfizer: Consultancy; Jazz: Research Funding. DKH reports research funding from Bristol-Myers Squibb, Karyopharm, Kite Pharma, and Adaptive Biotech; Consulting or advisory role for Bristol Myers Squibb, Janssen, Legend Biotech, Pfizer, Kite Pharma, and Karyopharm. O.C.P. reports serving as a consultant or in an advisory role for Bristol Myers Squibb, Janssen, and Legend Biotech. L.S. reports serving as a consultant for Bristol Myers Squibb. AA reports research funding from Abbvie, Adaptive Biotech, K36 Therapeutics, Janssen, Regeneron; Consulting or advisory role for Karyopharm, Bristol Myers Squibb, Janssen, Pfizer and Sanofi. LDA Jr reports research funding from Bristol Myers Squibb, AbbVie, Janssen, and Cellectar; and consulting or serving in an advisory role for or receiving honoraria from Celgene, Janssen, Amgen, Bristol Myers Squibb, GSK, AbbVie, BeiGene, Cellectar, Sanofi, Karyopharm, Pfizer, and Prothena. BD reports serving as a consultant or in advisory role for Bristol Myers Squibb, Janssen, Genentech, Kite Pharma, Pfizer, Arcellx, Karyopharm, ECor1, Takeda, and Natera, and receiving research funding from Bristol Myers Squibb, Janssen, Arcellx, CARsgen, C4 Therapeutics, and Sanofi. SR reports serving as a consultant for Pfizer and Prothena Biosciences and receiving research funding from Nexcella Inc, Poseida Therapeutics, and Janssen. DS Sanofi: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Jansen: Membership on an entity’s Board of Directors or advisory committees. PAF reports serving as a consultant for Janssen and Sanofi and receiving research funding from Karyopharm. JK reports serving as a consultant for GPCR Therapeutics, Janssen, Prothena, and Legend Biotech, and receiving research funding from Prothena, Ascentage, Janssen, Karyopharm, and GPCR Therapeutics. YL reports serving as a consultant for Janssen, Legend, Celgene, Sanofi, Bristol Myers Squibb, Pfizer, Regeneron, Genentech, NexImmune, and Caribou Biosciences, and receiving research funding from Janssen, Celgene, and Bristol Myers Squibb. SS reports receiving research support from Magenta Therapeutics, Bristol Myers Squibb, Allogene, Janssen, Novartis, and AbbVie, and serving on the advisory board or as a consultant for Bristol Myers Squibb, Janssen, Sanofi, Oncopeptides, Takeda, Regeneron, AbbVie, Pfizer, BioLineRx, Legend, and Kite Pharma. KKP reports serving as a consultant for Bristol Myers Squibb, Janssen, AstraZeneca, Legend Biotech, Kite Pharma, Genentech, AbbVie, Sanofi, Caribou Biosciences, Takeda, Regeneron, and Poseida. SM reports serving as a consultant for Janssen and Pfizer; receiving honoraria from Pfizer; and owning stock in AbbVie. CJF reports consulting or advisory role for Janssen, research funding from Janssen and Regeneron. Remaining authors with no potential conflicts of interest.

Footnotes

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Supplementary information

The online version contains supplementary material available at 10.1038/s41408-026-01469-z.

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Associated Data

Supplementary Materials

Supplementary information

Data Availability Statement

The data support the findings of this study were obtained from a multi-institutional consortium of participating centers and are not publicly available due to patient privacy, institutional date use agreements, and regulatory considerations. Only de-identified individual participant data was used in this analysis. Individual participant data will not be shared.