Функциональное заболевание с повышенным риском связано с плохими результатами лечения нескольких миеломы с помощью клеточной терапии CAR.

Introduction

Prognostic models and risk stratification for multiple myeloma (MM) have historically relied upon international staging system (ISS) criteria [ 1 ] and presence of high-risk chromosomal abnormalities, usually at the time of diagnosis [ 2 ]. However, in a subset of patients, aggressive disease biology only becomes evident after failure of frontline therapy, classifying these patients as functionally high-risk MM based on a dynamic assessment. While the timing of early relapse varies between studies, functionally high-risk disease has been defined as disease progression within 18–24 months of treatment initiation and or disease progression within 12 months of frontline autologous stem cell transplant [ 3 – 6 ]. These studies have uniformly shown that functionally high-risk disease is associated with inferior survival outcomes regardless of cytogenetics and ISS stage [ 3 – 6 ].

With impressive efficacy and reasonable safety seen in pivotal clinical trials, two B cell maturation antigen (BCMA) directed chimeric antigen receptor (CAR) T-cell products, idecabtagene vicleucel (ide-cel) [ 7 ] and ciltacabtagene autoleucel (cilta-cel) [ 8 ], initially emerged as viable treatment options for patients with triple-class relapsed-refractory multiple myeloma (RRMM) with at least four prior lines of therapy. In fact, after showing superiority over standard of care chemotherapy combinations when used for early relapse, both products have now been approved for RRMM after only 1–2 prior lines of therapy [ 9 , 10 ]. CARTITUDE-4 [ 10 ] study demonstrated that cilta-cel compared to standard of care chemotherapy had a nearly 30% higher rate of 12-month progression-free survival (PFS). Importantly, when compared to traditional salvage chemotherapy for patients with functionally high-risk MM, cilta-cel maintained its superior efficacy with outcomes similar to those seen with functionally non high-risk disease [ 11 ]. While all patients with lenalidomide-refractory disease are eligible to receive cilta-cel at first relapse, patients may choose alternative chemotherapy options based on indolent disease biology, concerns related to long-term toxicities, presence of comorbidities, lack of caregiver support, and personal preference. For such patients, whether CAR T-cell therapy can still overcome the negative prognostic impact of functionally high-risk disease in the later lines of therapy and hence be delayed until such time remains unknown. To address this question, we conducted a single-center retrospective study evaluating the outcomes of functionally high-risk MM patients receiving CAR T-cell therapy beyond second relapse.

Methods

We performed a retrospective review of electronic medical records of all patients with triple-class-exposed RRMM who had received BCMA-directed CAR T-cell therapy including cilta-cel, ide-cel, orvacabtagene autoleucel (orva-cel) from 03/2018 until 4/2025 at the Memorial Sloan Kettering Cancer Center (Fig. 1 ). All patients who had received at least two prior lines of therapy prior to CAR T were included in the efficacy and safety analyses. Patients were divided into two groups, functional high-risk and non high-risk, where functional high-risk MM was defined as progression of disease <24 months of frontline therapy. After leukapheresis, patients received bridging chemotherapy at the discretion of the treating physician. Cyclophosphamide 300 mg/m 2 and fludarabine 30 mg/m 2 were used once daily as lymphodepleting chemotherapy on days -5, -4, and -3 before CAR T infusion. Fludarabine dose was adjusted based on creatinine clearance per institutional protocol. Treatment of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were per institutional guidelines, as were the infectious disease prophylaxis and supportive care measures including the use of growth factors, antimicrobials, and intravenous immune globulins (IVIG).

Data collection

We reviewed electronic medical records for baseline demographic and descriptive variables, response data, and treatment-related adverse events. Responses to therapy were determined using the International Myeloma Work Group (IMWG) criteria [ 12 ]. CRS and ICANS were graded based on American Society for Transplantation and Cellular Therapy criteria [ 13 ]. Other hematologic and non-hematologic adverse events were graded based on the CTCAE v5.0 criteria. The primary objective of the study was to determine efficacy outcomes including best overall response rates (ORR), PFS, and overall survival (OS) in the functionally high risk and non high-risk patients. Key secondary outcomes included the incidence and severity of hematologic and non-hematologic toxicities including CRS, ICANS, cytopenias, and infections. Extramedullary disease (EMD) in this study was defined as bone-independent tumors of plasma cells growing at anatomic sites outside of the bone marrow prior to CAR T infusion. High-risk cytogenetics were defined as the presence of genomic aberrations such as deletion (17p), t(4;14), and or t(14;16) on fluorescence in situ hybridization (FISH) testing prior to CAR T. High disease burden was defined as bone marrow plasma cell percentage (immune histochemical analysis) of ≥50% prior to CAR T infusion. For PFS, time was calculated from treatment initiation to progression or death due to any cause, whichever occurred first. For OS, time was calculated from treatment initiation to death due to any cause. Patients were censored at the time of last follow up.

Statistical analysis

Data are presented as count with percentage for categorical variables and as median with range for continuous variables. Categorical variables were compared between the two groups using the chi-square or Fisher exact test , and continuous variables were compared using the Mann–Whitney U test. The Kaplan–Meier (KM) method was used to examine PFS and OS. Cox proportional hazard regression analysis was performed to show the impact of functional high-risk disease on PFS and OS with univariable and multivariable analyses . Important factors analyzed and adjusted for in the univariable and multivariable analyses included CAR-T product, age >70 years, Eastern Cooperative Oncology Group (ECOG) performance status, prior BCMA therapy, presence of high-risk cytogenetics, high disease burden, EMD, and number of prior lines of therapy. All statistical analyses were performed using R 4.3.2.

Results

At the time of study cutoff in 7/2025, a total of 208 patients were treated with CAR T (Fig. 1 ) with 117 (56%) functionally high-risk and 91 (44%) functionally non high-risk patients. Patient, disease, and treatment characteristics are described in Table 1 . Notably, with a median patient age of 65 (58–71) years, 74 (36%) patients were ≥70 years of age. A total of 135 (65%), 45 (22%), and 28 (13%) patients had received cilta-cel, ide-cel, and orva-cel, respectively. A vast majority of patients (97%) had ECOG performance status 0-1. The cohort included 68 (33%) patients with EMD, 35 (17%) with high disease burden, and 104 (53%) with high-risk cytogenetics. A total of 159 patients (76%) received bridging therapy prior to CAR T. With a median of 5 (2–14) prior lines of therapy, 188 (90%) patients had received prior autologous stem cell transplant (ASCT), all patients were triple-class exposed, and 139 (67%) were penta-drug exposed. While a majority (86%) of the patients were daratumumab refractory, 32 (15%) patients had received prior BCMA-directed therapy. Prior BCMA-directed therapy included antibody drug conjugates (8.2%), bispecific antibodies (5.3%), and CAR-T cell therapy (2.0%). Within the functionally high-risk group, 55 (47%) patients had disease progression within 12 months of frontline therapy. Of the 188 patients who had received prior ASCT, 75 (40%) had progressed within 12 months of transplant, 13 (14%) in the non high-risk and 62 (53%) in the functionally high-risk group ( p ≤ 0.001), respectively. The baseline patient and disease characteristics were well balanced between the two groups except that functionally high-risk patients had higher rates of EMD (39% versus (vs) 24%, p = 0.024), more frequent use of quadruplets as frontline therapy (15% vs 6%, p = 0.047), higher incidence of disease progression within 12 months of ASCT (53% vs 14%, p ≤ 0.001), and shorter median time from autologous transplant to CAR T (29 vs 70 months, p < 0.001) compared to the non high-risk group. Details of the frontline therapies are highlighted in Supplementary Table 1 .

Efficacy

With the median follow-up of 19 (95% confidence interval (CI): 17–22, reverse KM estimate) months for the entire patient population, the best ORR was 86%, 33 (16%) achieving stringent complete remission, 70 (34%) complete remission, 53 (25%) very good partial remission, and 22 (11%) partial remission as illustrated in Fig. 2 . When stratified by CAR T product, best ORR for cilta-cel, ida-cel, and orva-cel were 91%, 62% and 96%, respectively. No differences were seen in the best ORR (87% vs 84%, p = 0.5) between the functionally high-risk and non high-risk groups. With a median follow-up of 19 months, median PFS was 12 (95% CI: 9.9–14) months with 12-month PFS of 48% (95% CI: 41–56%) (Fig. 3A ) for the entire population. The median PFS were 11 (95% CI: 8.3–14) and 13 (95% CI: 11–Not Reached [NR]) months ( p = 0.15) with 12-month PFS of 45% (95% CI: 36–56%) and 52% (95% CI: 42–65%) in the functionally high-risk and non high-risk groups, respectively (Fig. 3B ). Within the functionally high-risk group, median PFS for patients with disease progression within 12 months and 12–24 months of frontline therapy were 9.9 (95% CI: 7.7–19) and 12 (95% CI: 6.8–16) months ( p = 0.3) with 12-month PFS of 47% (95% CI: 34–63%) and 43% (95% CI: 31–60%), respectively (Fig. 3C ). In multivariable analysis adjusting for functionally high-risk disease, age, prior lines of therapy, progression within 12 months of ASCT, and high-risk cytogenetics, stratified by CAR T product; prior BCMA-directed therapy (hazard ratio (HR) 2.23, 95% CI: 1.31–3.80, p = 0.003), presence of EMD (HR 2.59, 95% CI: 1.71–3.94, p < 0.001), and high disease burden (HR 2.09, 95% CI: 1.33–3.30, p = 0.001) were associated with inferior PFS as highlighted in Table 2A . At the data cutoff, median OS was 47 (95% CI: 37–NR) months with 12-month OS of 82% (95% CI: 77–88%) for the entire patient population (Fig. 3D ). The median OS was 34 (95% CI: 25–NR) and 55 (95% CI: 51–NR) months ( p = 0.025), with 12-month OS of 79% (95% CI: 72–87%) and 86% (95% CI: 79–94) in the functionally high-risk and non high-risk groups, respectively (Fig. 3E ). Within the functionally high-risk group, median OS for patients with disease progression within 12 months and 12–24 months of frontline therapy were 29 (95% CI: 21–NR) and 34 (95% CI: 25–NR) months ( p = 0.08), with 12-month OS of 80% (95% CI: 70–92%) and 78% (95% CI: 68–90%), respectively (Fig. 3F ). In multivariable analysis adjusting for functionally high-risk disease, age, prior lines of therapy, high-risk cytogenetics and prior BCMA-directed therapy, stratified by product; presence of EMD (HR 2.83, 95% CI: 1.58–5.07, p < 0.001), and high disease burden (HR 1.84, 95% CI: 1.02–3.33, p = 0.044) were associated with inferior OS as highlighted in Table 2B .

Safety

Details of hematologic and non-hematologic toxicities are highlighted in Table 3 . Notably, CRS was observed in 162 (78%) patients with 5 (2%) patients experiencing grade 3+ events. ICANS was observed in 20 (10%) patients with 5 (2%) experiencing grade 3+ events. Infectious events within first 90 days of CAR T were noted in 101 (49%) patients with 17% of the patients experiencing grade 3+ infections. Persistent grade 3+ cytopenias at day 90 after CAR T were accounted for by 8 patients with anemia (4%), 22 patients with neutropenia (11%), and 30 patients with thrombocytopenia (14%). A total of 83 (40%) patients had hypogammaglobulinemia (IgG < 500 ug/L) at time of lymphodepletion and 141 (68%) had hypogammaglobulinemia at day 90 post CAR T. There were no significant differences in the safety outcomes except for higher rates of grade 3 ICANS (4% vs 0%, p = 0.032) in patients with functionally high-risk disease. A total of 60 patients had died at the time of data cut off with disease progression (75%) followed by infections (10%) being the most common causes of death. Treatment-related mortality was observed in 4 (3%) patients in the functionally high-risk group and 2 (2%) patients in the non high-risk group.

Discussion

Clinical trials like CARTITUDE-4 evaluating the role of CAR T-cell therapy in early relapse (1-2 prior lines of therapy) established that the poor prognostic impact of functionally high-risk disease can be overcome by the use of CAR T in earlier lines of therapy [ 10 ]. CARTITUDE-4 demonstrated that cilta-cel in early lines of therapy significantly improved outcomes in patients with functionally high-risk multiple myeloma, defined as early relapse after initial therapy. At a median follow-up of 33.6 months, cilta-cel showed consistent benefit across high-risk subgroups, including patients with high-risk cytogenetics and those with early disease progression. Similarly, for patients with functionally high-risk disease (early relapse ≤12 months after autologous stem cell transplantation or initial therapy), cilta-cel demonstrated exceptional efficacy in the CARTITUDE-2 cohort B study. In this population, the overall response rate was 100%, with 90% achieving complete response or better, and 93% of evaluable patients achieving MRD negativity. Similarly, a real-world analysis of 312 patients who received quadruplet induction therapy and ASCT with disease progression within 36 months of frontline therapy had reduced 2PFS (HR 2.92, 95% C.I. 1.27–2,67, P = 0.012) and OS (HR 6.66, 95% C.I. 1.56–28.47, P = 0.011). Better outcomes were associated with the use of T-cell redirecting therapy as the second line of treatment, with a 12-month 2PFS rate of 90% compared to 23% for patients treated with and without T-cell redirecting therapy (ASH 2025 abstract 1037). With an evolving treatment landscape of safe and highly effective chemoimmunotherapy combinations, logistic concerns related to leukapheresis, medical comorbidities, and caregiver availability, not all patients are ideal candidates or in dire need of CAR T at the time of first relapse [ 14 ]. However, whether CAR T can still negate the negative impact of functionally high-risk disease when used as later line of therapy remains unclear, raising the need for this patient population to be studied in real-world settings. With a median of 5 prior lines of therapy, all patients being triple-class exposed, and vast majority CD38 monoclonal antibody refractory, to our knowledge, this is the first real-world study evaluating the outcomes of CAR T as late line of therapy in functionally high-risk patients. Compared to the functionally high-risk patients, non high-risk patients had lower rates of early progression (<12 months) from ASCT, longer time from frontline therapy to CAR T infusion, and lower rates of EMD. However, all other known predictors of efficacy including type of CAR T product, rates of prior BCMA-directed therapy, high-risk cytogenetics, and high disease burden were similar between the two groups. The study demonstrated inferior survival outcomes in patients with functionally high-risk disease, establishing its negative prognostic impact on outcomes with use of CAR T as late-line therapy, and underscoring the significance of utilizing CAR T as early as first relapse in patients with disease progression within 24 months of frontline therapy. The study highlights that patients receiving CAR T at a later relapse should receive appropriate counseling regarding expected durability of responses. Importantly, consideration should be given to close surveillance for impending relapse as well as consolidation therapies post CAR T to prolong durability of responses in this patient population. Moreover, future clinical trials evaluating the role of novel therapies and combinations including bispecific antibodies, immune modulators, and dual targeting CAR T need to prioritize functionally high-risk MM as an area of unmet need.

The definition of functionally high-risk disease utilized for exploring the role of CAR T in clinical trials has largely been extrapolated from historical non-cellular therapy-based treatments and predates the widespread utilization of CD38 monoclonal antibody-based treatments [ 3 – 6 ]. Moreover, the definition is variable based on timing of relapse from frontline therapy and ASCT [ 15 ]. In this regard, our study included only triple-class-exposed patients many of whom were CD38 monoclonal antibody refractory, one third had relapsed within a year of ASCT, and hence was enriched for a high-risk patient population with a more contemporary treatment exposure. While disease progression within 24 months of frontline therapy was associated with inferior outcomes, further stratification comparing disease progression within 12 months and between 12 and 24 months of frontline therapy was not associated with any significance difference in outcomes. This highlights the significance of disease progression within 24 months of frontline therapy (POD24) as a benchmark for high-risk disease biology for future trials evaluating CAR T and bispecific antibodies in earlier lines of treatment. Moreover, POD24 may allow us to identify patients for post CAR T interventions including close surveillance for relapse, initiation of salvage therapy at the earliest signs of disease progression, and consideration of consolidation/maintenance therapy in future clinical trials.

In our study, after adjusting for all significant covariates, presence of EMD, high disease burden, and prior BCMA therapy as per previous reports [ 16 , 17 ] continue to be associated with inferior PFS and OS. With an improvement in survival outcomes in the era of novel therapeutics, there is an increasing incidence of EMD in relapsed refractory settings and our cohort was enriched for patients with active EMD prior to CAR T. EMD is considered a high-risk disease feature associated with early progression and overall poor prognosis after BCMA-directed CAR T [ 18 , 19 ] as well as other traditional plasma cell directed therapies [ 20 ]. Tumor-driven inhibition of T cell function likely contributes to the effector target disparity, as large tumors seen in EMD require more robust activation of host T cells for deep and durable responses. While this highlights the potential role of cytotoxic chemotherapy and or radiotherapy for maximum debulking prior to CAR T, the overall goal of effective disease control might not be attainable in many of the patients. Hence, there remains a need to identify and treat functionally high-risk patients with CAR T prior to the emergence of EMD as well as develop post CAR T consolidation strategies to optimize outcomes in those with active EMD.

It has been previously shown that a high tumor burden as measured by metabolic tumor volume is associated with worse efficacy outcomes among patients with large cell lymphoma [ 21 ] as well as RRMM receiving CAR T-cell therapy [ 22 ]. These patients with high disease burden have immune dysregulation characterized by significantly higher levels of serum inflammatory markers and tumor interferon signaling leading to poor CAR T-cell expansion and persistence explaining inferior outcomes in comparison to patients who had a lower baseline state of inflammation [ 23 ]. While we did not study specific inflammatory cytokines or tumor microenvironment for our patient population, routine assessment of disease burden with bone marrow biopsies and imaging prior to lymphodepletion continues to have utility as a predictive marker of inferior outcomes.

Similarly, the inferior efficacy seen in patients with prior BCMA exposure in our cohort has been previously demonstrated as a risk factor for early progression [ 24 ] post CAR T and could potentially be explained by emergence of clones with structural or functional loss of BCMA [ 25 , 26 ] or terminally differentiated exhausted T cell phenotype [ 27 ]. While it seems prudent to avoid exposure to BCMA-targeted therapy as the last line of treatment prior to CAR T infusion, it is not always feasible to avoid such treatment for late-line triple-class RRMM patients in need of urgent therapy. Hence, use of CAR T at first relapse in functionally high-risk patients where more viable non-BCMA-directed therapy-based holding and bridging treatments are available may help negate the negative impact of prior treatment. While there has been no direct head-to-head comparison between different the three different CAR-T products in the pivotal clinical trials, there has been real-world evidence-based comparison [ 28 ] highlighting the superior efficacy and survival with cilta-cel for RRMM. Hence, in our study, multivariate analyses were performed after adjusting for CAR T product.

Limitations of our study include its retrospective design and relatively small sample size. However, being a single-center study, management of these patients was more standardized according to the institutional guidelines, and safety and efficacy outcomes were similar to the previously published real-world evidence. Some of the more informative predictors of outcomes including serum soluble BCMA levels and metabolic tumor volume could not be reported, but all clinically relevant variables were accurately captured and evaluated in multivariable analyses. Response assessment was per investigator discretion, but all data underwent peer-based quality check for completeness and internal consistencies. Comprehensive imaging at regular time intervals and bone marrow-based minimal residual disease (MRD) assessments were not always obtained. While MRD assessment has prognostic value, its clinical utility for heavily pretreated RRMM remains unknown. Overall, despite these limitations, our data represent a real-world population and answer important clinical questions regarding the use of CAR T in functionally high-risk patients. Our findings need to be further investigated with focus on outcomes of functionally high-risk RRMM with CAR T in clinical trials and registry-based real-world evidence. Moreover, a matched adjusted comparison analysis of functionally high-risk patients receiving CAR T as early vs late-line therapy will help confirm the findings of our study.

In summary, functionally high-risk MM patients receiving CAR T as late line of therapy have inferior survival outcomes compared to those with non-high-risk disease, underscoring the poor prognostic impact of disease progression <24 months from frontline therapy. This association was largely driven by active EMD and high disease burden at the time of CAR T, highlighting the potential benefit of utilizing CAR T as an early line of therapy for functionally high-risk patients.

Supplementary information

Supplement

Author contributions

TS and HH designed the study. TS led chart review and data collection. TF assists in database organization and review. RF, EJ, and KM, assisted in data collection. AD, DN, HH, and TS performed statistical analysis. HH and TS wrote the manuscript. SR and SM are team leads and oversaw the project. FM, AL, CT, GS, NK HL, MM, MS, HH, KM, US, MH, SG, and SU reviewed the manuscript and provided feedback on the study.

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

AL reports nonfinancial support from Pfizer; grants and personal fees from Janssen, outside the submitted work; serves on the Data Safety Monitoring Board for ArcellX and also has a patent US20150037346A1 with royalties paid. CT reports research funding from Janssen and Takeda, personal fees from MJH Life Sciences, and has received honoraria for consultancy/participated in the advisory boards for Janssen and Sanofi. GS receives research funding from Janssen, Amgen, BMS, Beyond Spring; serves on the data safety monitoring board (DSMB) for ArcellX; and receives research funding to the institution from Janssen, Amgen, BMS, Beyond Spring, and GPCR. NK reports research funding through Amgen, Janssen, Epizyme, AbbVie; consults for Clinical Care Options, OncLive, and Intellisphere Remedy Health; and participated in advisory board for Janssen and MedImmune. HL has served as a paid consultant for AbbVie, Immix Biopharma, Legend Biotech, Alexion, Prothena, and has received research funding from Nexcella, Janssen, Alexion, Protego, and Prothena. MS served as a paid consultant for McKinsey & Company, Angiocrine Bioscience, Inc., and Omeros Corporation; received research funding from Angiocrine Bioscience, Inc., Omeros Corporation, Amgen Inc., Bristol Myers Squibb, and Sanofi; served on ad hoc advisory boards for Kite - A Gilead Company, and Miltenyi Biotec; and received honoraria from i3Health, Medscape, CancerNetwork, and IDEOlogy. HH reports grants from Celgene, Takeda, and Janssen, outside the submitted work. KM reports grant support from ASH, MMRF, and IMS. US reports research support from Celgene/Bristol Myers Squibb and Janssen; personal fees from ACCC, MashUp MD, Janssen Biotech, Sanofi, Bristol Myers Squibb, MJH LifeSciences, Intellisphere, Phillips Gilmore Oncology Communications, i3 health, and RedMedEd; and nonfinancial support from the ASH Clinical Research Training Institute and TREC Training Workshop (R25CA203650; PI: Melinda Irwin). MH reports research funding from GlaxoSmithKline, BeiGene, AbbVie, and Daiichi Sankyo, and has received honoraria for consultancy/participated in the advisory boards for Curio Science LLC, Intellisphere LLC, Bristol Myers Squibb, Janssen and GlaxoSmithKline. SAG reports personal fees and advisory role (scientific advisory board) from Actinium, Celgene, Bristol Myers Squibb, Sanofi, Amgen, Pfizer, GlaxoSmithKline, JAZZ, Janssen, Omeros, Takeda, and Kite, outside the submitted work. SZU received research funding from Amgen, AbbVie, Array Biopharma, BMS, Celgene, Gilead, GSK, Janssen, Merck, Pharmacyclics, Sanofi, Seattle Genetics, SkylineDX, and Takeda, is a Consultant to AbbVie, Amgen, BMS, Celgene, EdoPharma, Genentech, Gilead, GSK, Gracell, Janssen, Oncopeptides, Pfizer, Sanofi, Seattle Genetics, SecuraBio, SkylineDX, Takeda, TeneoBio, and is also a Speaker with Amgen, BMS, Janssen, Sanofi. Bristol Myers Squibb, Sanofi, Amgen, Pfizer, GlaxoSmithKline, JAZZ, Janssen, Omeros, Takeda, and Kite, outside the submitted work. SM reports research funding from the NCI, Janssen Oncology, Bristol Myers Squibb, Allogene Therapeutics, Fate Therapeutics, Caribou Therapeutics, and Takeda Oncology and has received consulting fees from EviCore, Optum, BioAscend, Janssen Oncology, Bristol Myers Squibb, AbbVie, HMP Education, and Legend Biotech, and honoraria from OncLive, Physician Education Resource, MJH Life Sciences, and Plexus Communications. HH reports consultancy for Karyopharm, Amgen, and Janssen. TS, SR, TF, RF, EJ, KM, FM, MM, AD, DN, have no conflicts of interest to disclose.

Ethics approval and consent to participate

The Institutional Review Board granted approval for the study, including a waiver of informed consent (IRB #23-070). Furthermore, the study adhered to the ethical principles outlined in the Declaration of Helsinki.

Footnotes

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

These authors contributed equally: Hamza Hashmi, Tara Sebastian, Sridevi Rajeeve.

These authors jointly supervised this work: Sham Mailankody, Saad Z. Usmani.

Supplementary information

The online version contains supplementary material available at 10.1038/s41408-026-01494-y.

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Associated Data

Supplementary Materials

Supplement

Data Availability Statement

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.