Introduction
Idecabtagene vicleucel (ide-cel), a B-cell maturation antigen (BCMA) targeting chimeric antigen receptor T-cell (CAR-T cell) therapy, has been shown to improve outcomes in patients with relapsed/refractory (RR) multiple myeloma (MM) refractory to most standard therapies, such as proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and anti-CD38 antibodies. In the KarMMa trial ( 1 ), ide-cel showed strong and durable responses in heavily pretreated patients with RR MM. Furthermore, in the KarMMa-3 trial ( 2 , 3 ), a randomized phase 3 trial targeting patients with RR MM who had received 2 to 4 prior lines of therapy, ide-cel therapy resulted in a favorable progression-free survival (13.8 months vs 4.4 months, and hazard ratio: 0.49) compared to standard therapy. However, in this study, among the 249 patients who received a collection of peripheral blood (PB) mononuclear cells, termed leukapheresis, for ide-cel construction, eight patients could not receive an infusion of ide-cel, four patients had adverse events during bridging therapy, and the other four patients had disease progression. To date, few studies have focused on patients who fail to receive CAR-T cell infusions because of disease progression. We herein report the characteristics of patients who did not receive ide-cel therapy after leukapheresis.
Between July 2022 and March 2024, 34 patients underwent leukapheresis for ide-cel production at the Nagoya City University Hospital. Among them, 28 patients successfully received ide-cel therapy, 1 patient received an out-of-specification product, 1 patient experienced production failure, and 4 patients did not receive ide-cel therapy due to disease progression ( Fig. 1 ). This study focused on four patients who discontinued ide-cel therapy because of disease progression. The baseline characteristics of the patients are shown in Fig. 2 .
Case Reports
Case 1
Case 1 involved a 70-year-old woman with no specific medical history. She presented with bone pain and was diagnosed with MM [non-secretory type, International Staging System (ISS) 3, Revised-ISS (R-ISS) 3, myeloma-defining event (MDE), multiple bone lesions, anemia, and hypercalcemia]. A cytogenetic analysis revealed cyclin D1 (CCND1)-IgH translocation t(11;14) by fluorescence in situ hybridization (FISH) analysis, and complex karyotype abnormalities were detected by a G-band analysis. Although three cycles of lenalidomide (Len) and dexamethasone (Dex) (Ld) therapy followed by three cycles of daratumumab (Dara) plus Ld therapy were performed, anemia and thrombocytopenia, signs of disease progression, worsened.
As second-line therapy, bortezomib (Bor) plus pomalidomide (Pom) and Dex (BPD) therapy was administered, but she eventually became refractory after seven cycles of treatment and acquired a high lactate dehydrogenase (LDH) level, thrombocytopenia, and appearance of plasma cells (PCs) in the PB (13%). As third-line therapy, four cycles of Bor plus doxorubicin and Dex therapy and two cycles of Bor plus cyclophosphamide (C) and Dex (BCD) therapy were performed; however, disease progression, represented as severe thrombocytopenia with a high ratio of PCs, did not improve. To overcome disease progression, fourth-line therapy (elotuzumab plus PD therapy) was administered. During this therapy, disease progression in the central nervous system (CNS), represented by diplopia and PCs in the cerebrospinal fluid, was observed. After four intrathecal injections (methotrexate and cytarabine), she achieved remission of the CNS disease. However, new lesions, hepatic tumors, and left axillary lymphadenopathy were observed ( Fig. 3 ).
To initiate CAR-T cell therapy, a performance status (PS) of 1 was confirmed. She underwent leukapheresis and consequently received the carfilzomib (Car) plus LD regimen as a bridging therapy. A reevaluation of the cytogenetic analysis of MM cells showed a complex karyotype with 1q21 amplification ( Fig. 2 ). After 15 days of bridging therapy, marked disease progression, elevation of LDH (1,367 U/L) and aspartate aminotransferase (AST) (67 U/L) levels, and circulating high levels of PCs in the peripheral blood (25%) were observed. Doxorubicin plus Bor plus Dex (BD) therapy was initiated the following day ( Fig. 4 ). However, 26 days after leukapheresis, the patient died due to disease progression. In an overview, no treatment interval was achieved during any course of MM treatment ( Fig. 3 ).
Case 2
Case 2 involved a 70-year-old man with a history of type 2 diabetes mellitus and urolithiasis. The patient presented with bone pain and was diagnosed with MM (non-secretory type, ISS 3, R-ISS 3, MDE: multiple bone lesions, anemia, renal failure, and hypercalcemia). A cytogenetic analysis revealed CCND1-IgH translocation according to FISH. After induction therapies, 1 cycle of BD and 4 cycles of BLD therapy, he achieved complete remission (CR) and received high-dose chemotherapy, 200 mg/m 2 of melphalan, followed by autologous stem cell transplantation. Consequently, he received ixazomib maintenance therapy. After 11 cycles of maintenance therapy, severe thrombocytopenia was observed, and disease relapse was considered based on the high ratio of PC occupation in the bone marrow.
As second-line therapy, he received Dara plus LD therapy. After six cycles of salvage therapy, thrombocytopenia progression and renal failure were observed, and the patient was considered to have treatment failure. Three cycles of Car plus PD therapy were administered as a third-line therapy. However, new extramedullary or plasmacytoma lesions located in the pleura and neighboring Th4/Th5 were observed. After radiation therapy (20 Gy/5 fractions) of these lesions, he received further salvage regimens, isatuximab plus Car+Dex therapy, and C plus PD (PCD) therapy ( Fig. 3 ). However, he eventually became refractory to these therapies, presenting with severe thrombocytopenia and a highly elevated LDH level.
For CAR-T cell therapy, a PS score of 1 was confirmed. He underwent leukapheresis followed by bridging therapy. After 15 days of leukapheresis, he experienced a seizure, suggesting disease progression with CNS involvement. The patient died of disease progression 34 days after leukapheresis ( Fig. 4 ). Similar to Case 1, no treatment-free interval was observed during the treatment course ( Fig. 3 ).
Case 3
Case 3 was that of a 68-year-old man with no significant medical history. The patient presented with lumbago and was diagnosed with MM (IgG kappa type, ISS 1, R-ISS 1, MDE: multiple bone lesions). After treatment with Bor-containing therapies, including doxorubicin and BD regimen (three cycles), Bor monotherapy (six cycles), and thalidomide plus melphalan and prednisolone (three cycles), he achieved stringent CR and achieved long-term remission for four years. Upon relapse with bone disease, the patient received Ld therapy (24 cycles), ixazomib plus Ld therapy (20 cycles), elotuzumab and PD therapy (3 cycles), and Car and Dex therapy (4 cycles). However, disease progression in the cervical vertebra (C1) was observed, necessitating involved-field RT.
For the next salvage therapy, he received four regimens, four cycles of isatuximab plus PD therapy, one cycle of Car and Dex therapy, four cycles of ixazomib and Dex therapy, and six cycles of the Dara plus BCD regimen. Despite these therapies, no clinical response was achieved and disease progression was confirmed by new bone lesions. In a reexamination of his cytogenetic abnormalities, a deletion(17p) was observed by FISH ( Fig. 2 ).
To initiate CAR-T cell therapy, a PS score of 2 due to bone pain was confirmed. The patient underwent leukapheresis followed by bridging therapy (BCD). Eleven days after leukapheresis, he developed generalized pain with progression of bone lesions and showed a poor PS score of 4. The treatment plan was switched to doxorubicin plus BD therapy, but his calcium levels increased and his level of consciousness declined. The treatment approach was changed to best supportive care, and the patient died 52 days after leukocyte apheresis ( Fig. 4 ).
Case 4
Case 4 was that of a 77-year-old man with no specific medical history. He presented with fatigue and was diagnosed with MM (IgA lambda type, ISS ≥2, R-ISS ≥2, MDE: anemia). No high-risk cytogenetic abnormalities were detected. As initial therapy, LD was administered; however, this was discontinued because of drug fever. Next, 4 regimens of therapies, 13 cycles of BCD therapy, 3 cycles of Dara plus Car and Dex regimen, 5 cycles of Dara plus PD therapy, and 5 cycles of doxorubicin and BD therapy were administered.
After disease relapse, PS score of 1 was confirmed. He underwent leukapheresis for the manufacture of the ide-cel and received BD as bridging therapy. Forty-one days after leukapheresis, he experienced septic shock and had a PS score of 4; thus, bridging therapy was discontinued. The patient died of disease progression 101 days after leukapheresis ( Fig. 4 ).
Discussion
At our institution, 33 patients underwent leukapheresis for ide-cel therapy before bispecific antibodies became available. Disease progression during bridging therapy occurred in all 4 patients who ultimately did not receive ide-cel infusion (100%), as well as in 15 (53%) of the 28 patients who proceeded to infusion. By comparison, dropout rates in previous studies were lower: 3.2% (8 of 249 underwent leukapheresis) in the KarMMa-3 trial (due to adverse events or disease progression) ( 2 , 3 ); 14.1% (16 of 113) in CARTITUDE-1 (due to early withdrawal, progression, or death) ( 4 ); and 7.0% (12 of 171) reported in a real-world study by Hansen et al. (due to progression or death) ( 5 ). The relatively high leukapheresis-to-infusion failure rate in our cohort may reflect the initial CAR-T indication requiring ≥3 prior lines of therapy. Consequently, our patients were heavily pretreated (with many penta-refractory cases), making disease control during bridging challenging.
Hansen et al. reported that patients with a poor PS score (≥2), advanced R-ISS stage, or high tumor burden (≥50% CD138-positive plasma cells in the bone marrow prior to ide-cel infusion) were significantly more likely to develop grade ≥3 cytokine release syndrome ( 5 ). They also found that extramedullary disease, prior BCMA-targeted therapy, and penta-refractoriness were significantly associated with a shortened progression-free survival. Furthermore, Ailawadhi et al. demonstrated that a greater number of prior treatment lines was associated with an increased dropout rate between leukapheresis and ide-cel infusion ( 2 ), suggesting that earlier introduction of CAR-T therapy may be preferable.
Thrombocytopenia in leukapheresis has also been reported as an important predictor of poor cell collection and prolonged cytopenia after CAR-T cell infusion ( 6 ). In our cohort, among the four patients who could not undergo ide-cel infusion, only one had a platelet count below the guideline's exclusion threshold (＜100×10 9 /L) at leukapheresis. Platelet counts at leukapheresis for Cases 1-4 were 100×10 9 /L, 48×10 9 /L, 360×10 9 /L, and 120×10 9 /L, respectively, indicating that thrombocytopenia was not consistently severe. These observations suggest that thrombocytopenia should be carefully evaluated as a potential determinant for successful ide-cel manufacturing and subsequent infusion eligibility.
Consistent with the findings of Hansen et al., 75% of real-world patients did not meet the KarMMa trial eligibility criteria ( 5 ), and several patients in our cohort also fell short of certain trial-based thresholds (e.g., peripheral blood counts and performance status). Nevertheless, all of our patients met the eligibility criteria of the Guidelines for the Appropriate Use of CAR-T Cell Therapy, and none were excluded on that basis. Notably, Case 1 was deemed eligible for leukapheresis after achieving disease control with intrathecal chemotherapy; thus, this case met no exclusion criteria in the guidelines.
We compared prognostic factors between patients who failed to proceed with ide-cel infusion (n=4) and those who were infused, examining circulating plasma cells, extramedullary disease at leukapheresis, and renal impairment. Given the small sample size of non-infused patients, none of these factors showed a statistically significant difference. Notably, however, two of the four non-infused patients had a non-secretory myeloma subtype with cytogenetic abnormalities, such as t(11;14) and complex karyotypes.
When we focused on two patients with non-secretory type and t(11;14), these patients had three issues: shorter duration of response to each regimen after the second relapse/refractory status, rapid progression of disease, and no treatment-free interval for two years just before leukapheresis. Furthermore, early tumor death was observed after leukapheresis. In general, the non-secretory type is a rare subtype of MM (3-4% of all MM patients) ( 7 ) and is often observed in t(11;14) (about 60-80% of all MM patients) ( 8 ). When limited to reports analyzing patients with autologous transplantation, t(11;14) patients with additional cytogenetic abnormalities had particularly poor outcomes compared to other patients, such as t(4;14) patients ( 9 ). In our two patients who failed to receive ide-cel infusion after leukapheresis and harbored t(11;14), one showed an acquired additional complex karyotype abnormality, and the other had an unevaluable cytogenetic examination due to a dry tap, which was considered to be myelofibrosis. Although few studies have analyzed the efficacy of novel immune cell therapies, such as CAR-T cell therapy and bispecific antibodies, for patients with non-secretory type and harboring (11;14), the early use of immune cell therapies would be desirable for these patients before the acquisition of multiple drug resistance and the development of serious and rapid disease progression.
Similarly, disease control during bridging therapy is important to prevent treatment failure of the ide-cel therapy. To avoid disease progression and maintain a well-controlled disease status of MM, effective treatment strategies should be selected as bridging therapy during the manufacture of the ide-cel product. Of the 4 patients who discontinued ide-cel therapy after leukapheresis, all (100%) were refractory to 3 class agents (PI, IMiDs, and anti-CD38 antibody), defined as triple-refractory, and 3 patients (75%) were refractory to 5 drugs, including Len, Pom, Bor, Car, and Dara or isatuximab, defined as penta-refractory. Previous studies have reported that patients who were triple- or penta-refractory had poor outcomes ( 10 ) related to failure to receive ide-cel infusion after leukapheresis ( 1 , 2 ).
As an effective treatment strategy, it is crucial to reserve PI and IMiDs, such as Car and Pom, for first-line use during bridging therapy, rather than administering them in prior treatments. In addition, bispecific antibodies (e.g., teclistamab and talquetamab) have shown markedly increased response rates during bridging (overall response rate: 100% vs. 46% with conventional regimens) ( 11 ), making them promising options. Because some patients die from rapid disease progression during CAR-T cell manufacturing, optimizing bridging therapy is critical to ensure that patients remain eligible for infusion. We propose that bridging regimens incorporating bispecific antibodies or other novel agents are necessary to maintain disease control until the CAR-T cells are ready.
In conclusion, evaluating the risk factors for rapid disease progression in MM, including high-risk cytogenetic abnormalities, extramedullary disease, and other clinical implications, such as non-secretory type with t(11;14), is critical for adopting ide-cel therapy in the early disease phase after a relapse or when patients become refractory to standard therapies. Furthermore, effective bridging therapy to control MM disease status is warranted to avoid missing the appropriate timing of the ide-cel infusion after leukapheresis.
Author’s disclosure of potential Conflicts of Interest (COI).
Dr. Iida received honoraria from Sanofi, Takeda Pharmaceutical, Janssen Pharmaceutical, Ono Pharmaceutical, Bristol-Myers Squibb, Pfizer Japan, and AstraZeneca. He also received research funding from Sanofi, Takeda Pharmaceutical, Janssen Pharmaceutical, Ono Pharmaceutical, Bristol-Myers Squibb, Pfizer Japan, Daiichi Sankyo, Amgen, AbbVie, Caelum Biosciences, Shionogi, GlaxoSmithKline, Celgene, and Chugai Pharmaceutical.
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