Annals of hematology · 2026
Ранняя глубокая реакция на цилта-целл, как на 2-ую терапию CAR T-Cell после переплетения на базе CELMOD для продвинутой множественной миеломы.
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Niklas Henrik, Bold Anna, Völkl Simon, Lang Nicola, Truger Marietta, Wendelin Knut, Strifler Susanne, Gärtner Johannes, Knop Stefan
Аннотация
В качестве новаторского и высокоэффективного метода лечения пациентов с множественным миелом (RRMM) реанимированным/отверженным антигенным рецептором (CAR) была разработана абстрактная антигенная терапия (CAR). Этот эффект основан на переориентации модифицированных Т-клеток на плазменные клетки, выражающие целевые антигены, в частности B антигены созревания клеток (BCMA). Несмотря на высокий уровень первоначальных ответов, рецидив заболеваний по-прежнему является серьезной клинической проблемой. Терапевтические опционы после прохождения предыдущей терапии на Т-клеток BCMA ограничены, и прогнозы часто являются неудовлетворительными. Мы сообщаем о 58-летнем мужчине с высокой степенью риска ига каппой, множественной миеломой, который прошел интенсивную предварительную терапию и получил идекабаген вклейкелел в качестве шестой линии терапии, что привело к глубокой реакции, которая длилась примерно один год. После развития болезни пациент получил переходную терапию с мезигдомидом, карфильцомибом и дексаметазоном, за которым последовала вторая инфильтрация CAR-клетки с управлением BCMA с использованием цитакабтагена автолейкеля. Предыдущая последовательность генома подтвердила сохранение экспрессии BCMA. Токсичность, связанная с лечением, поддается регулированию, включая цитокиновый синдром второго сорта и продолжительные цитопенсии, без признаков нейротоксичности. Этот случай дает дополнительные знания о том, что повторное лечение с помощью терапии ЦАР-клетки, ориентированной на БЦМА, может быть практически осуществимым и клиническим образом эффективным в случае сильно обработанной множественной миэломы, особенно после длительного реагирования на первоначальную терапию ЦАР-клетки. Связанная терапия и использование альтернативной конструкции Т-клеток ЦАР могут привести к дальнейшему улучшению результатов. Для определения оптимального отбора и последовательности лечения пациентов в таких условиях необходимы перспективные исследования.
Оригинал публикации
Early deep response to cilta-cel as 2nd CAR T-Cell therapy after CELMoD-based bridging for advanced multiple myeloma.
AbstractChimeric antigen receptor (CAR) T-cell therapy has emerged as an innovative and highly effective treatment option for patients with relapsed/refractory multiple myeloma (RRMM). This effect is based on redirecting modified T-cells towards plasma cells expressing target antigens, specifically B cell maturation antigen (BCMA). Despite high initial response rates, disease relapse remains a major clinical challenge. Therapeutic options after progression following prior BCMA-directed CAR T-cell therapy are limited, and prognosis is often poor. We report on a 58-year-old male with high-risk IgA kappa multiple myeloma who was heavily pretreated and received idecabtagene vicleucel as sixth-line therapy, achieving a deep response lasting for approximately one year. Following disease progression, the patient received bridging therapy with mezigdomide,carfilzomib, and dexamethasone, followed by a second BCMA-directed CAR T-cell infusion using ciltacabtagene autoleucel. Previous whole genome sequencing had confirmed preserved BCMA expression.Early post-infusion assessment showed a rapid and profound response, with marked declines in serum IgA and free kappa light chains, accompanied by robust CAR T-cell expansion. Treatment-related toxicities were manageable, including grade II cytokine release syndrome and prolonged cytopenias, without evidence of neurotoxicity.This case provides additional knowledge that retreatment with BCMA-directed CAR T-cell therapy may be feasible and clinically effective in heavily pretreated multiple myeloma, particularly after a durable response to initial CAR T-cell therapy. Bridging therapy and the use of an alternative CAR T-cell construct may further improve outcomes. Prospective studies are needed to define optimal patient selection and treatment sequencing in this setting.
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Introduction
Multiple myeloma is a clonal plasma cell malignancy that, despite substantial therapeutic progress with proteasome inhibitors, immunomodulatory agents, monoclonal antibodies, and autologous stem cell transplantation, remains incurable [ 1 , 2 ]. High-risk cytogenetic abnormalities, including t(4;14), del(17p), and 1q21 gain, are associated with early relapse and poor outcomes under conventional treatment [ 3 ].
CAR T-cell therapy targeting B-cell maturation antigen (BCMA) has emerged as a highly effective option for heavily pretreated patients. Two constructs are currently approved: idecabtagene vicleucel (ide-cel), based on a murine-derived scFv, and ciltacabtagene autoleucel (cilta-cel), which uses two llama-derived single-domain antibodies against distinct BCMA epitopes [ 4 , 5 ]. Despite high initial response rates, most patients eventually relapse, and therapeutic options thereafter remain limited.
Retreatment with a second BCMA-directed CAR T-cell infusion is emerging as one such option, particularly after a durable response to the first infusion, though data remain scarce [ 6 , 7 ]. Cereblon E3 ligase modulators such as mezigdomide represent a further option in this setting, with response rates of 30–50% reported in heavily pretreated patients in early-phase trials [ 8 , 9 ]. Here, we report a case of successful retreatment with cilta-cel following mezigdomide-based bridging therapy, highlighting the role of target antigen preservation and CAR T-cell expansion as key factors influencing therapeutic efficacy.
Case presentation
Our male patient was diagnosed with ISS stage II IgA kappa multiple myeloma in August 2016 at age 58, with a history of prostate carcinoma (pT2c, pN0) cured by radical prostatectomy in 2015.
Laboratory assessment revealed an M-protein of 42 g/L, anemia (Hb 10.5 g/dL), and normal renal function. Bone marrow biopsy showed 60% clonal plasma cells (CD38⁺, CD138⁺, CD19⁻, CD45low, CD56⁺, kappa-restricted). Cytogenetics revealed del(13q) and t(4;14), consistent with high-risk disease [ 3 ]. Staging was ISS II/R-ISS II; the full treatment timeline is shown in Table 1 .
Table 1 Chronological overview of treatment lines and clinical outcomes. VCD, bortezomib, cyclophosphamide, dexamethasone; HDM, high-dose melphalan; ASCT, autologous stem cell transplantation; DVd, daratumumab, bortezomib, dexamethasone; KRd, carfilzomib, lenalidomide, dexamethasone; IsaPd, isatuximab, pomalidomide, dexamethasone; Flu/Cy, fludarabine/cyclophosphamide; ide-cel, idecabtagene vicleucel; cilta-cel, ciltacabtagene autoleucel; VGPR, very good partial response; CR, complete remission; N.a., not applicable Treatment line Start Therapy Best Response Reason for Discontinuation for treatments with continued schedule 1 2016 VCD → HDM/ASCT → lenalidomide maintenance Remission (~ 3 years) Serological relapse 2 2019 Bortezomib Response not specified Progressive disease 3 2019/2020 DVd Response not specified Progressive disease 4 2020/2021 KRd Disease control COVID-19 infection; subsequent progression 5 2021 IsaPd Stable disease Progressive disease 6 Oct 2022 Lymphodepletion (Flu/Cy) → ide-cel Complete remission (~ 12 months) N.a. 7 Apr 2024 Carfilzomib (CAR-CAR program) Stable disease Progressive disease 8 Aug 2024 Experimental antibody-drug conjugate Minor response Progression; grade III neutropenia and pneumonia 9 Jan 2025 Mezigdomide + Kd (bridging) Partial response Planned second CAR T-cell therapy 10 Dec 2025 Lymphodepletion (Flu/Cy) → cilta-cel VGPR → ongoing serological CR (> 6 months) N.a.
Table 1 Chronological overview of treatment lines and clinical outcomes. VCD, bortezomib, cyclophosphamide, dexamethasone; HDM, high-dose melphalan; ASCT, autologous stem cell transplantation; DVd, daratumumab, bortezomib, dexamethasone; KRd, carfilzomib, lenalidomide, dexamethasone; IsaPd, isatuximab, pomalidomide, dexamethasone; Flu/Cy, fludarabine/cyclophosphamide; ide-cel, idecabtagene vicleucel; cilta-cel, ciltacabtagene autoleucel; VGPR, very good partial response; CR, complete remission; N.a., not applicable Treatment line Start Therapy Best Response Reason for Discontinuation for treatments with continued schedule 1 2016 VCD → HDM/ASCT → lenalidomide maintenance Remission (~ 3 years) Serological relapse 2 2019 Bortezomib Response not specified Progressive disease 3 2019/2020 DVd Response not specified Progressive disease 4 2020/2021 KRd Disease control COVID-19 infection; subsequent progression 5 2021 IsaPd Stable disease Progressive disease 6 Oct 2022 Lymphodepletion (Flu/Cy) → ide-cel Complete remission (~ 12 months) N.a. 7 Apr 2024 Carfilzomib (CAR-CAR program) Stable disease Progressive disease 8 Aug 2024 Experimental antibody-drug conjugate Minor response Progression; grade III neutropenia and pneumonia 9 Jan 2025 Mezigdomide + Kd (bridging) Partial response Planned second CAR T-cell therapy 10 Dec 2025 Lymphodepletion (Flu/Cy) → cilta-cel VGPR → ongoing serological CR (> 6 months) N.a.
Chronological overview of treatment lines and clinical outcomes. VCD, bortezomib, cyclophosphamide, dexamethasone; HDM, high-dose melphalan; ASCT, autologous stem cell transplantation; DVd, daratumumab, bortezomib, dexamethasone; KRd, carfilzomib, lenalidomide, dexamethasone; IsaPd, isatuximab, pomalidomide, dexamethasone; Flu/Cy, fludarabine/cyclophosphamide; ide-cel, idecabtagene vicleucel; cilta-cel, ciltacabtagene autoleucel; VGPR, very good partial response; CR, complete remission; N.a., not applicable
The patient received VCD induction, HDM/ASCT, and lenalidomide maintenance, followed after serological relapse in 2019 by bortezomib monotherapy and DVd. Subsequent regimens included KRd (discontinued due to COVID-19 infection with progression) and IsaPd, achieving stable disease.
In October 2022, the patient received lymphodepletion followed by ide-cel, complicated by grade I CRS and prolonged cytopenia requiring intermittent G-CSF. Referred to our center in January 2023, he had negative serum immunofixation with unconfirmed CAR T-cell persistence. By April 2023, early polyclonal immune reconstitution was accompanied by severe T-cell depletion (CD4⁺ 105/µL). Low-level serological relapse became detectable in November 2023; PET/CT in January 2024 showed stable osteolytic lesions without metabolic activity. In April 2024, carfilzomib monotherapy was given within the “CAR-CAR program”, aiming to enhance CAR T-cell recognition via increased BCMA expression [ 10 ], resulting in stable disease.
By July 2024, disease activity was increasing. WGS and FISH (March 2024) confirmed presence of a clonal population with 1q gain, t(4;14), 13q deletion, and a KRAS missense mutation; BCMA (TNFRSF17) remained unaltered with normal expression, and IGH::NSD2 fusion with NSD2 overexpression was confirmed. The longitudinal course of M-protein, IgA, and free kappa light chains is shown in Fig. 1 .
Fig. 1 Longitudinal course of IgA and κ free light chain levels over the disease trajectory. Lines represent serum concentrations (IgA in g/L, κ free light chains in mg/L). Bars indicate treatment phases
Longitudinal course of IgA and κ free light chain levels over the disease trajectory. Lines represent serum concentrations (IgA in g/L, κ free light chains in mg/L). Bars indicate treatment phases
The patient was enrolled in an early-phase trial of an experimental antibody-drug conjugate in August 2024. Baseline bone marrow showed 70% plasma cell infiltration with persistent high-risk cytogenetics. He achieved minor remission for two cycles but was withdrawn after cycle 4 due to progression and ≥grade 3 neutropenia/pneumonia; immunohistochemistry at that time confirmed 80% plasma cell infiltration with strong BCMA expression despite prior ide-cel exposure.
In January 2025, mezigdomide/carfilzomib/dexamethasone became available and was initiated as bridging therapy to reduce tumor burden ahead of a second BCMA-directed CAR T-cell infusion. Despite treatment interruptions from viral infections and grade 3 neutropenia, the patient achieved a partial response, underscoring the efficacy of mezigdomide-based bridging in this heavily pretreated, high-risk setting.
Following apheresis in July 2025 and continued Kd/mezigdomide bridging until November 2025, bone marrow still showed 50–70% plasma cell infiltration despite serological partial remission; WGS/FISH again confirmed high-risk features with preserved BCMA. PET/CT showed only low metabolic activity in known lesions without extramedullary disease.
After fludarabine/cyclophosphamide lymphodepletion, the patient received cilta-cel in December 2025 (baseline IgA 1,529 mg/dL, free kappa light chains 1,103 mg/L), with robust CAR T-cell expansion confirmed on days + 7 and + 14. An early response followed: by day + 3, a VGPR per IMWG criteria had been achieved, and by April 2026, immunofixation was negative. CAR⁺ T-cell s increased from 3.73% (0.9 cells/µL) at day + 7 to 31.72% (187.1 cells/µL) at day + 14, becoming undetectable (< 0.05%) by day + 57. Toxicity was limited to grade II CRS and prolonged cytopenias, without neurotoxicity. Preserved BCMA expression supported the biological rationale for retreatment.
More than 6 months after the second CAR T-cell therapy, the patient shows no serological evidence of disease and polyclonal plasma cell reconstitution — highlighting the efficacy and potential of repeat BCMA-directed CAR T-cell therapy in carefully selected patients.
Discussion
Rationale for second CAR T-cell therapy
Relapse of multiple myeloma remains a major challenge after BCMA-directed CAR T-cell therapy, and treatment options thereafter are limited. Retreatment with a second BCMA-directed CAR T-cell product is considered to carry additional risks, including antigen loss, T-cell exhaustion, and cumulative toxicity, with supporting data remaining limited [ 11 , 12 ]. However, a growing body of evidence indicates that retreatment can still achieve meaningful disease control in selected patients, particularly if the initial CAR T-cell therapy resulted in a response lasting more than six months [ 12 – 14 ]. This criterion was fulfilled in our patient, who achieved a deep and durable response of approximately one year to idecabtagene vicleucel, supporting the rationale for a second infusion with a different product in light of preserved organ function and good overall condition (ECOG 1). A brief attempt to reactivate the persisting ide-cel product via proteasome inhibition (CAR-CAR approach) achieved only stable disease, likely reflecting limited persistence of the initial CAR T-cell product [ 10 ]. Based on this rationale and published precedents (Table 2 ), the decision was made to proceed with cilta-cel as a second BCMA-directed CAR T-cell infusion.
Table 2 Summary of published cases and cohorts on sequential CAR T-cell therapy (1st → 2nd CAR T), including prior treatment lines, response, toxicity, and outcomes, compared with the present case Study
n
1st → 2nd CAR T Prior lines before 2. CAR T Response (1st → 2nd CAR T) Toxicity (2nd CAR T) Outcome Reyes et al., Blood Adv 2024 [ 11 ] – mixed (retreatment cohort) – variable – Retreatment = best salvage option, esp. if DOR > 6 mo after 1st CAR T Mobascher et al., Ann Hematol 2025 [ 12 ] 1 ide-cel → cilta-cel 7th LOT PR (not durable) → sCR Grade 2 CRS, no ICANS Ongoing sCR (13 mo) Richardson et al., Blood Adv 2025 [ 13 ] 10 ide-cel → cilta-cel – DOR to ide-cel predictive → ORR 100% (≥ VGPR), 60% MRD-neg No increase vs. 1st CAR T; no new signal 64.8% PFS at 6 mo; short DOR after ide-cel → early relapse Attar et al., Blood 2025 [ 14 ] 9 mixed BCMA CAR-T → cilta-cel – variable – 7/9 responded (3 CR, 3 VGPR, 1 PR); median PFS 31 mo Present case 1 ide-cel → cilta-cel 9th LOT CR (~ 12 mo) → VGPR by d + 3, IFE-neg by month 4 Grade I–II CRS both infusions, no ICANS Ongoing molecular remission (> 6 mo)
Table 2 Summary of published cases and cohorts on sequential CAR T-cell therapy (1st → 2nd CAR T), including prior treatment lines, response, toxicity, and outcomes, compared with the present case Study
n
1st → 2nd CAR T Prior lines before 2. CAR T Response (1st → 2nd CAR T) Toxicity (2nd CAR T) Outcome Reyes et al., Blood Adv 2024 [ 11 ] – mixed (retreatment cohort) – variable – Retreatment = best salvage option, esp. if DOR > 6 mo after 1st CAR T Mobascher et al., Ann Hematol 2025 [ 12 ] 1 ide-cel → cilta-cel 7th LOT PR (not durable) → sCR Grade 2 CRS, no ICANS Ongoing sCR (13 mo) Richardson et al., Blood Adv 2025 [ 13 ] 10 ide-cel → cilta-cel – DOR to ide-cel predictive → ORR 100% (≥ VGPR), 60% MRD-neg No increase vs. 1st CAR T; no new signal 64.8% PFS at 6 mo; short DOR after ide-cel → early relapse Attar et al., Blood 2025 [ 14 ] 9 mixed BCMA CAR-T → cilta-cel – variable – 7/9 responded (3 CR, 3 VGPR, 1 PR); median PFS 31 mo Present case 1 ide-cel → cilta-cel 9th LOT CR (~ 12 mo) → VGPR by d + 3, IFE-neg by month 4 Grade I–II CRS both infusions, no ICANS Ongoing molecular remission (> 6 mo)
Summary of published cases and cohorts on sequential CAR T-cell therapy (1st → 2nd CAR T), including prior treatment lines, response, toxicity, and outcomes, compared with the present case
Preserved BCMA expression supported the choice of a structurally distinct second product
Ide-cel and cilta-cel differ primarily in their antigen-binding domains: cilta-cel incorporates two BCMA-binding single-domain antibodies, potentially enhancing tumor recognition even with heterogeneous BCMA expression [ 6 ]. High-risk cytogenetic features (t(4;14), 1q21 gain) were present at diagnosis [ 3 ], yet comprehensive molecular analysis before the second CAR T-cell infusion revealed no genomic alterations in the BCMA-encoding gene (TNFRSF17) and preserved TNFRSF17 expression at RNA level, comparable to CAR T-cell-naïve patients, and confirmed by strong BCMA expression on immunohistochemistry [ 15 , 16 ]. These findings excluded antigen loss as a potential mechanism of resistance, consistent with reports that preserved BCMA expression is a prerequisite for successful CAR T-cell therapy even in high-risk disease [ 16 – 18 ]. Tumor heterogeneity and the incompletely understood mechanisms underlying BCMA loss mean that confirmed target antigen integrity, while reassuring, cannot yet reliably predict response to a second BCMA-directed CAR T-cell infusion [ 15 , 17 ]. This is illustrated by preliminary data from Attar et al., who reported outcomes in a cohort of nine patients receiving cilta-cel after prior BCMA-directed CAR T-cell therapy, with responses in 7/9 patients despite variable antigen status, providing additional albeit still limited evidence in this setting [ 19 ]. A structurally distinct second product may additionally help overcome resistance mechanisms such as pre-existing anti-CAR immunity, although clinical evidence for this remains limited [ 20 ]. Consistent with this rationale, cilta-cel has been associated with deeper and more durable responses than ide-cel in heavily pretreated patients, albeit potentially at the cost of increased toxicity [ 6 , 21 ].
Safety of repeat CAR T-cell therapy
In our patient, both CAR T-cell treatments were complicated by low-grade cytokine release syndrome (CRS) and prolonged cytopenias consistent with prior reports in heavily pretreated patient populations [ 22 , 23 ].
A key factor enabling repeat CAR T-cell therapy in this case was the preservation of organ function throughout the disease course. This allowed for the safe administration of repeat lymphodepleting chemotherapy followed by CAR T-cell infusion. These observations underscore the critical importance of careful patient selection when considering CAR T-cell retreatment.
Conclusion
This case illustrates that repeat BCMA-directed CAR T-cell therapy, prepared for by CELMoD-based bridging, a structurally distinct second product, and molecular confirmation of BCMA integrity, can achieve meaningful disease control even in heavily pretreated, high-risk multiple myeloma.
Multiple myeloma is a clonal plasma cell malignancy that, despite substantial therapeutic progress with proteasome inhibitors, immunomodulatory agents, monoclonal antibodies, and autologous stem cell transplantation, remains incurable [ 1 , 2 ]. High-risk cytogenetic abnormalities, including t(4;14), del(17p), and 1q21 gain, are associated with early relapse and poor outcomes under conventional treatment [ 3 ].
CAR T-cell therapy targeting B-cell maturation antigen (BCMA) has emerged as a highly effective option for heavily pretreated patients. Two constructs are currently approved: idecabtagene vicleucel (ide-cel), based on a murine-derived scFv, and ciltacabtagene autoleucel (cilta-cel), which uses two llama-derived single-domain antibodies against distinct BCMA epitopes [ 4 , 5 ]. Despite high initial response rates, most patients eventually relapse, and therapeutic options thereafter remain limited.
Retreatment with a second BCMA-directed CAR T-cell infusion is emerging as one such option, particularly after a durable response to the first infusion, though data remain scarce [ 6 , 7 ]. Cereblon E3 ligase modulators such as mezigdomide represent a further option in this setting, with response rates of 30–50% reported in heavily pretreated patients in early-phase trials [ 8 , 9 ]. Here, we report a case of successful retreatment with cilta-cel following mezigdomide-based bridging therapy, highlighting the role of target antigen preservation and CAR T-cell expansion as key factors influencing therapeutic efficacy.
Case presentation
Our male patient was diagnosed with ISS stage II IgA kappa multiple myeloma in August 2016 at age 58, with a history of prostate carcinoma (pT2c, pN0) cured by radical prostatectomy in 2015.
Laboratory assessment revealed an M-protein of 42 g/L, anemia (Hb 10.5 g/dL), and normal renal function. Bone marrow biopsy showed 60% clonal plasma cells (CD38⁺, CD138⁺, CD19⁻, CD45low, CD56⁺, kappa-restricted). Cytogenetics revealed del(13q) and t(4;14), consistent with high-risk disease [ 3 ]. Staging was ISS II/R-ISS II; the full treatment timeline is shown in Table 1 .
Table 1 Chronological overview of treatment lines and clinical outcomes. VCD, bortezomib, cyclophosphamide, dexamethasone; HDM, high-dose melphalan; ASCT, autologous stem cell transplantation; DVd, daratumumab, bortezomib, dexamethasone; KRd, carfilzomib, lenalidomide, dexamethasone; IsaPd, isatuximab, pomalidomide, dexamethasone; Flu/Cy, fludarabine/cyclophosphamide; ide-cel, idecabtagene vicleucel; cilta-cel, ciltacabtagene autoleucel; VGPR, very good partial response; CR, complete remission; N.a., not applicable Treatment line Start Therapy Best Response Reason for Discontinuation for treatments with continued schedule 1 2016 VCD → HDM/ASCT → lenalidomide maintenance Remission (~ 3 years) Serological relapse 2 2019 Bortezomib Response not specified Progressive disease 3 2019/2020 DVd Response not specified Progressive disease 4 2020/2021 KRd Disease control COVID-19 infection; subsequent progression 5 2021 IsaPd Stable disease Progressive disease 6 Oct 2022 Lymphodepletion (Flu/Cy) → ide-cel Complete remission (~ 12 months) N.a. 7 Apr 2024 Carfilzomib (CAR-CAR program) Stable disease Progressive disease 8 Aug 2024 Experimental antibody-drug conjugate Minor response Progression; grade III neutropenia and pneumonia 9 Jan 2025 Mezigdomide + Kd (bridging) Partial response Planned second CAR T-cell therapy 10 Dec 2025 Lymphodepletion (Flu/Cy) → cilta-cel VGPR → ongoing serological CR (> 6 months) N.a.
Table 1 Chronological overview of treatment lines and clinical outcomes. VCD, bortezomib, cyclophosphamide, dexamethasone; HDM, high-dose melphalan; ASCT, autologous stem cell transplantation; DVd, daratumumab, bortezomib, dexamethasone; KRd, carfilzomib, lenalidomide, dexamethasone; IsaPd, isatuximab, pomalidomide, dexamethasone; Flu/Cy, fludarabine/cyclophosphamide; ide-cel, idecabtagene vicleucel; cilta-cel, ciltacabtagene autoleucel; VGPR, very good partial response; CR, complete remission; N.a., not applicable Treatment line Start Therapy Best Response Reason for Discontinuation for treatments with continued schedule 1 2016 VCD → HDM/ASCT → lenalidomide maintenance Remission (~ 3 years) Serological relapse 2 2019 Bortezomib Response not specified Progressive disease 3 2019/2020 DVd Response not specified Progressive disease 4 2020/2021 KRd Disease control COVID-19 infection; subsequent progression 5 2021 IsaPd Stable disease Progressive disease 6 Oct 2022 Lymphodepletion (Flu/Cy) → ide-cel Complete remission (~ 12 months) N.a. 7 Apr 2024 Carfilzomib (CAR-CAR program) Stable disease Progressive disease 8 Aug 2024 Experimental antibody-drug conjugate Minor response Progression; grade III neutropenia and pneumonia 9 Jan 2025 Mezigdomide + Kd (bridging) Partial response Planned second CAR T-cell therapy 10 Dec 2025 Lymphodepletion (Flu/Cy) → cilta-cel VGPR → ongoing serological CR (> 6 months) N.a.
Chronological overview of treatment lines and clinical outcomes. VCD, bortezomib, cyclophosphamide, dexamethasone; HDM, high-dose melphalan; ASCT, autologous stem cell transplantation; DVd, daratumumab, bortezomib, dexamethasone; KRd, carfilzomib, lenalidomide, dexamethasone; IsaPd, isatuximab, pomalidomide, dexamethasone; Flu/Cy, fludarabine/cyclophosphamide; ide-cel, idecabtagene vicleucel; cilta-cel, ciltacabtagene autoleucel; VGPR, very good partial response; CR, complete remission; N.a., not applicable
The patient received VCD induction, HDM/ASCT, and lenalidomide maintenance, followed after serological relapse in 2019 by bortezomib monotherapy and DVd. Subsequent regimens included KRd (discontinued due to COVID-19 infection with progression) and IsaPd, achieving stable disease.
In October 2022, the patient received lymphodepletion followed by ide-cel, complicated by grade I CRS and prolonged cytopenia requiring intermittent G-CSF. Referred to our center in January 2023, he had negative serum immunofixation with unconfirmed CAR T-cell persistence. By April 2023, early polyclonal immune reconstitution was accompanied by severe T-cell depletion (CD4⁺ 105/µL). Low-level serological relapse became detectable in November 2023; PET/CT in January 2024 showed stable osteolytic lesions without metabolic activity. In April 2024, carfilzomib monotherapy was given within the “CAR-CAR program”, aiming to enhance CAR T-cell recognition via increased BCMA expression [ 10 ], resulting in stable disease.
By July 2024, disease activity was increasing. WGS and FISH (March 2024) confirmed presence of a clonal population with 1q gain, t(4;14), 13q deletion, and a KRAS missense mutation; BCMA (TNFRSF17) remained unaltered with normal expression, and IGH::NSD2 fusion with NSD2 overexpression was confirmed. The longitudinal course of M-protein, IgA, and free kappa light chains is shown in Fig. 1 .
Fig. 1 Longitudinal course of IgA and κ free light chain levels over the disease trajectory. Lines represent serum concentrations (IgA in g/L, κ free light chains in mg/L). Bars indicate treatment phases
Longitudinal course of IgA and κ free light chain levels over the disease trajectory. Lines represent serum concentrations (IgA in g/L, κ free light chains in mg/L). Bars indicate treatment phases
The patient was enrolled in an early-phase trial of an experimental antibody-drug conjugate in August 2024. Baseline bone marrow showed 70% plasma cell infiltration with persistent high-risk cytogenetics. He achieved minor remission for two cycles but was withdrawn after cycle 4 due to progression and ≥grade 3 neutropenia/pneumonia; immunohistochemistry at that time confirmed 80% plasma cell infiltration with strong BCMA expression despite prior ide-cel exposure.
In January 2025, mezigdomide/carfilzomib/dexamethasone became available and was initiated as bridging therapy to reduce tumor burden ahead of a second BCMA-directed CAR T-cell infusion. Despite treatment interruptions from viral infections and grade 3 neutropenia, the patient achieved a partial response, underscoring the efficacy of mezigdomide-based bridging in this heavily pretreated, high-risk setting.
Following apheresis in July 2025 and continued Kd/mezigdomide bridging until November 2025, bone marrow still showed 50–70% plasma cell infiltration despite serological partial remission; WGS/FISH again confirmed high-risk features with preserved BCMA. PET/CT showed only low metabolic activity in known lesions without extramedullary disease.
After fludarabine/cyclophosphamide lymphodepletion, the patient received cilta-cel in December 2025 (baseline IgA 1,529 mg/dL, free kappa light chains 1,103 mg/L), with robust CAR T-cell expansion confirmed on days + 7 and + 14. An early response followed: by day + 3, a VGPR per IMWG criteria had been achieved, and by April 2026, immunofixation was negative. CAR⁺ T-cell s increased from 3.73% (0.9 cells/µL) at day + 7 to 31.72% (187.1 cells/µL) at day + 14, becoming undetectable (< 0.05%) by day + 57. Toxicity was limited to grade II CRS and prolonged cytopenias, without neurotoxicity. Preserved BCMA expression supported the biological rationale for retreatment.
More than 6 months after the second CAR T-cell therapy, the patient shows no serological evidence of disease and polyclonal plasma cell reconstitution — highlighting the efficacy and potential of repeat BCMA-directed CAR T-cell therapy in carefully selected patients.
Discussion
Rationale for second CAR T-cell therapy
Relapse of multiple myeloma remains a major challenge after BCMA-directed CAR T-cell therapy, and treatment options thereafter are limited. Retreatment with a second BCMA-directed CAR T-cell product is considered to carry additional risks, including antigen loss, T-cell exhaustion, and cumulative toxicity, with supporting data remaining limited [ 11 , 12 ]. However, a growing body of evidence indicates that retreatment can still achieve meaningful disease control in selected patients, particularly if the initial CAR T-cell therapy resulted in a response lasting more than six months [ 12 – 14 ]. This criterion was fulfilled in our patient, who achieved a deep and durable response of approximately one year to idecabtagene vicleucel, supporting the rationale for a second infusion with a different product in light of preserved organ function and good overall condition (ECOG 1). A brief attempt to reactivate the persisting ide-cel product via proteasome inhibition (CAR-CAR approach) achieved only stable disease, likely reflecting limited persistence of the initial CAR T-cell product [ 10 ]. Based on this rationale and published precedents (Table 2 ), the decision was made to proceed with cilta-cel as a second BCMA-directed CAR T-cell infusion.
Table 2 Summary of published cases and cohorts on sequential CAR T-cell therapy (1st → 2nd CAR T), including prior treatment lines, response, toxicity, and outcomes, compared with the present case Study
n
1st → 2nd CAR T Prior lines before 2. CAR T Response (1st → 2nd CAR T) Toxicity (2nd CAR T) Outcome Reyes et al., Blood Adv 2024 [ 11 ] – mixed (retreatment cohort) – variable – Retreatment = best salvage option, esp. if DOR > 6 mo after 1st CAR T Mobascher et al., Ann Hematol 2025 [ 12 ] 1 ide-cel → cilta-cel 7th LOT PR (not durable) → sCR Grade 2 CRS, no ICANS Ongoing sCR (13 mo) Richardson et al., Blood Adv 2025 [ 13 ] 10 ide-cel → cilta-cel – DOR to ide-cel predictive → ORR 100% (≥ VGPR), 60% MRD-neg No increase vs. 1st CAR T; no new signal 64.8% PFS at 6 mo; short DOR after ide-cel → early relapse Attar et al., Blood 2025 [ 14 ] 9 mixed BCMA CAR-T → cilta-cel – variable – 7/9 responded (3 CR, 3 VGPR, 1 PR); median PFS 31 mo Present case 1 ide-cel → cilta-cel 9th LOT CR (~ 12 mo) → VGPR by d + 3, IFE-neg by month 4 Grade I–II CRS both infusions, no ICANS Ongoing molecular remission (> 6 mo)
Table 2 Summary of published cases and cohorts on sequential CAR T-cell therapy (1st → 2nd CAR T), including prior treatment lines, response, toxicity, and outcomes, compared with the present case Study
n
1st → 2nd CAR T Prior lines before 2. CAR T Response (1st → 2nd CAR T) Toxicity (2nd CAR T) Outcome Reyes et al., Blood Adv 2024 [ 11 ] – mixed (retreatment cohort) – variable – Retreatment = best salvage option, esp. if DOR > 6 mo after 1st CAR T Mobascher et al., Ann Hematol 2025 [ 12 ] 1 ide-cel → cilta-cel 7th LOT PR (not durable) → sCR Grade 2 CRS, no ICANS Ongoing sCR (13 mo) Richardson et al., Blood Adv 2025 [ 13 ] 10 ide-cel → cilta-cel – DOR to ide-cel predictive → ORR 100% (≥ VGPR), 60% MRD-neg No increase vs. 1st CAR T; no new signal 64.8% PFS at 6 mo; short DOR after ide-cel → early relapse Attar et al., Blood 2025 [ 14 ] 9 mixed BCMA CAR-T → cilta-cel – variable – 7/9 responded (3 CR, 3 VGPR, 1 PR); median PFS 31 mo Present case 1 ide-cel → cilta-cel 9th LOT CR (~ 12 mo) → VGPR by d + 3, IFE-neg by month 4 Grade I–II CRS both infusions, no ICANS Ongoing molecular remission (> 6 mo)
Summary of published cases and cohorts on sequential CAR T-cell therapy (1st → 2nd CAR T), including prior treatment lines, response, toxicity, and outcomes, compared with the present case
Preserved BCMA expression supported the choice of a structurally distinct second product
Ide-cel and cilta-cel differ primarily in their antigen-binding domains: cilta-cel incorporates two BCMA-binding single-domain antibodies, potentially enhancing tumor recognition even with heterogeneous BCMA expression [ 6 ]. High-risk cytogenetic features (t(4;14), 1q21 gain) were present at diagnosis [ 3 ], yet comprehensive molecular analysis before the second CAR T-cell infusion revealed no genomic alterations in the BCMA-encoding gene (TNFRSF17) and preserved TNFRSF17 expression at RNA level, comparable to CAR T-cell-naïve patients, and confirmed by strong BCMA expression on immunohistochemistry [ 15 , 16 ]. These findings excluded antigen loss as a potential mechanism of resistance, consistent with reports that preserved BCMA expression is a prerequisite for successful CAR T-cell therapy even in high-risk disease [ 16 – 18 ]. Tumor heterogeneity and the incompletely understood mechanisms underlying BCMA loss mean that confirmed target antigen integrity, while reassuring, cannot yet reliably predict response to a second BCMA-directed CAR T-cell infusion [ 15 , 17 ]. This is illustrated by preliminary data from Attar et al., who reported outcomes in a cohort of nine patients receiving cilta-cel after prior BCMA-directed CAR T-cell therapy, with responses in 7/9 patients despite variable antigen status, providing additional albeit still limited evidence in this setting [ 19 ]. A structurally distinct second product may additionally help overcome resistance mechanisms such as pre-existing anti-CAR immunity, although clinical evidence for this remains limited [ 20 ]. Consistent with this rationale, cilta-cel has been associated with deeper and more durable responses than ide-cel in heavily pretreated patients, albeit potentially at the cost of increased toxicity [ 6 , 21 ].
Safety of repeat CAR T-cell therapy
In our patient, both CAR T-cell treatments were complicated by low-grade cytokine release syndrome (CRS) and prolonged cytopenias consistent with prior reports in heavily pretreated patient populations [ 22 , 23 ].
A key factor enabling repeat CAR T-cell therapy in this case was the preservation of organ function throughout the disease course. This allowed for the safe administration of repeat lymphodepleting chemotherapy followed by CAR T-cell infusion. These observations underscore the critical importance of careful patient selection when considering CAR T-cell retreatment.
Conclusion
This case illustrates that repeat BCMA-directed CAR T-cell therapy, prepared for by CELMoD-based bridging, a structurally distinct second product, and molecular confirmation of BCMA integrity, can achieve meaningful disease control even in heavily pretreated, high-risk multiple myeloma.