Second CAR T-Cell Infusion Hits Myeloma After CELMoD Bridging

A case report from German hematologists suggests that patients with advanced multiple myeloma may still benefit from a second BCMA-directed CAR T-cell therapy, even after their disease has progressed following a first such treatment. The report, published in Annals of Hematology, describes a heavily pretreated 58-year-old man with high-risk IgA kappa myeloma who achieved a rapid and profound response after receiving ciltacabtagene autoleucel as his second CAR T-cell infusion, preceded by bridging therapy combining the CELMoD agent mezigdomide with carfilzomib and dexamethasone.

CAR T-cell therapy has reshaped the treatment landscape for relapsed and refractory multiple myeloma. The approach involves collecting a patient’s own T-lymphocytes, engineering them in the laboratory to express a chimeric antigen receptor that recognizes a specific target on cancer cells, expanding the modified cells to large numbers, and reinfusing them into the patient. In myeloma, the preferred target is B cell maturation antigen, or BCMA, a protein abundantly expressed on malignant plasma cells. Two such products, idecabtagene vicleucel and ciltacabtagene autoleucel, have demonstrated high initial response rates in clinical trials and are now established options for patients whose disease has exhausted conventional therapies.

Despite those impressive early results, a major clinical challenge looms: relapse. Most patients who respond to BCMA-directed CAR T-cell therapy eventually experience disease progression, and once that happens, therapeutic options become scarce and prognosis is often poor. Whether a second BCMA-directed CAR T-cell infusion can work after the first one has failed has remained an open question, complicated by concerns that the tumor may have evolved mechanisms of immune escape, including loss or downregulation of the BCMA target itself.

The newly reported case offers a carefully documented data point. The patient had high-risk IgA kappa multiple myeloma and had undergone extensive prior treatment. Idecabtagene vicleucel was administered as his sixth line of therapy, and it produced a deep response lasting approximately one year. When his disease subsequently progressed, the clinical team faced the dilemma of how to bridge him to a potential second cellular therapy while keeping the myeloma under control. Notably, whole genome sequencing performed earlier had confirmed that his myeloma cells still expressed BCMA, providing a molecular rationale for retargeting the same antigen with a different CAR construct.

As bridging therapy, the patient received a combination of mezigdomide, carfilzomib, and dexamethasone. Mezigdomide belongs to the CELMoD class, a new generation of molecular glue degraders that bind cereblon and induce the degradation of proteins central to myeloma cell survival, including Ikaros and Aiolos. This combination rapidly reduced disease burden and allowed the team to proceed with a second BCMA-directed CAR T-cell infusion, this time using ciltacabtagene autoleucel, a product distinguished by a multi-targeting CAR design intended to enhance antigen recognition and reduce tumor escape.

Early post-infusion assessment showed a swift and profound response. Marked declines in serum IgA and free kappa light chains, key myeloma biomarkers, were observed, accompanied by robust expansion of the infused CAR T-cells in the patient’s circulation. The rapidity and depth of the response are particularly notable given the extensive prior treatment and the fact that the patient had already received one BCMA-directed product. The case demonstrates that preserved BCMA expression, confirmed molecularly before retreatment, may help identify patients likely to respond to a second BCMA-targeted cellular therapy.

treatment-related toxicities were described as manageable. The patient experienced grade II cytokine release syndrome, a common inflammatory side effect of CAR T-cell therapy mediated by immune signaling molecules released during T-cell activation, as well as prolonged cytopenias, a reduction in blood cell counts that persisted beyond the expected window. Importantly, there was no evidence of neurotoxicity, another recognized risk of CAR T-cell therapy. These findings reinforce the notion that carefully monitored retreatment can be delivered with an acceptable safety profile even in a heavily pretreated patient.

The authors emphasize that this single case provides additional knowledge rather than definitive proof. It suggests that retreatment with BCMA-directed CAR T-cell therapy may be feasible and clinically effective in heavily pretreated multiple myeloma, particularly in patients who achieved a durable response to their initial CAR T-cell infusion. The combination of bridging therapy to reduce tumor burden and the use of an alternative CAR T-cell construct may further improve outcomes by minimizing disease progression during manufacturing and by presenting the tumor with a different engineered receptor.

The report also highlights the growing role of genomic characterization in treatment planning. In this case, prior whole genome sequencing confirmed preserved BCMA expression, giving clinicians the confidence to pursue a second BCMA-directed approach rather than switching to an alternative target. As sequencing becomes more widely available, such molecular assessments may become a standard part of the decision-making process for patients considering CAR T-cell re-treatment.

Prospective studies will be needed to define optimal patient selection and treatment sequencing in this setting, the authors conclude. Key questions include which patients are most likely to benefit from a second BCMA-directed infusion, the ideal choice and duration of bridging therapy, and whether alternative CAR constructs truly outperform reinfusion of the original product. For now, this case adds to a small but growing body of evidence that a second CAR T-cell chance may be possible for some patients with advanced multiple myeloma.

Subject of Research: Retreatment with BCMA-directed CAR T-cell therapy after CELMoD-based bridging in relapsed multiple myeloma

Article Title: Early deep response to cilta-cel as 2nd CAR T-Cell therapy after CELMoD-based bridging for advanced multiple myeloma

Article References: Niklas, H., Bold, A., Völkl, S., Lang, N., Truger, M., Wendelin, K., Strifler, S., Gärtner, J., & Knop, S. (2026). Early deep response to cilta-cel as 2nd CAR T-Cell therapy after CELMoD-based bridging for advanced multiple myeloma. Annals of Hematology. https://doi.org/10.1007/s00277-026-07278-5

Image Credits: AI Generated

DOI: 10.1007/s00277-026-07278-5

Keywords: multiple myeloma, CAR T-cell therapy, BCMA, ciltacabtagene autoleucel, idecabtagene vicleucel, mezigdomide, CELMoD, bridging therapy, relapsed refractory myeloma, cytokine release syndrome, immunotherapy, cell therapy