Real-life experiences with CAR T-cell therapy with idecabtagene vicleucel (ide-cel) for triple-class exposed relapsed/refractory multiple myeloma patients

Retrospective analysis of consecutive patients with triple-class exposed RRMM treated with commercial ide-cel at the University Hospital of Bern, Switzerland. Eligible patients for treatment indication had progressive disease (PD), according to the International Myeloma Working Group (IMWG) response criteria [17], following at least 3 previous treatment lines and had exposure to at least one proteasome inhibitor, one immunomodulatory agent and one anti-CD38 antibody. Further eligibility criteria were an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 at time point of treatment indication and adequate organ function, no age restrictions were defined. In patients fit to receive CAR T-cell therapy, ide-cel was prioritized over bispecific antibodies. The retrospective data collection and analysis was performed in accordance with local laws and regulations and all patients provided written informed consent.

MM disease responses were assessed based on bone marrow (BM) examinations and serological parameters following the IMWG standard and minimal residual disease (MRD) response criteria [17, 18]. MRD was assessed by multiparameter flow cytometry, reaching a minimal sensitivity of 1 in 10⁵ nucleated cells or higher. Toxicities were registered following the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading for CRS and immune effector-cell associated neurologic toxicities [19], and the Common Terminology Criteria for Adverse Events (CTCAE CTCAE) version 5.0 (https://​ctep.​cancer.​gov/​protocoldevelopm​ent/​electronic_​applications/​docs/​ctcae_​v5_​quick_​reference_​5x7.​pdf) for the remaining adverse events.

In previous work, we established a ddPCR assay for quantification of sequences of the intracellular domain of the bb2121 CAR-T construct. Briefly, primers and probes targeting the intracellular junction sequence between the effector (4-1BB) and co-stimulatory (CD3z) domains, were designed [23]. We performed longitudinal monitoring of circulating CAR T copies per μg of cell-free DNA (cfDNA) during up to 12 weeks following ide-cel infusion. Patients with a CAR T expansion over 10⁵ copies/μg cfDNA were defined as expanders. sBCMA plasma levels were monitored 2 to 3 times/weekly during the first week after ide-cel infusion, then every 2 week and finally every 30–60 days, and up to 120 days, as previously described [23]. For sBCMA assessment, the human BCMA/TNFRSF17 ELISA Kit (EH41RB, Thermo Fisher Scientific, Waltham, MA, USA) was used. ELISA assays were performed following the manufacturer’s instructions and mean values of triplicate measurements were plotted for each sample.

The first 16 consecutive RRMM patients treated with ide-cel at the University Hospital of Bern, Switzerland, between June and October 2022, have been included in this retrospective analysis. Median age was 69 (57 – 83) years, six (38%) patients had high-risk cytogenetic alterations, three (19%) patients had an initial R-ISS stage III and 5 (31%) extramedullary disease. Median number of previous treatment lines was 6 (3–12), including bridging therapies. Five (31%) patients had high tumor burden, defined as = / > 50% plasma cell BM infiltration, previous to ide-cel treatment. 16/16 patients (100%) had received at least one course of HDCT and ASCT. 1/16 (6%) patient additionally received a previous allogenic stem cell transplantation. No patients received previous therapy with bispecific antibodies. Patient baseline characteristics are summarized in Table 1.

Overall production success rate was 88%; one (6%) patient received an out-of-specification (OOS) product, one (6%) patient required a second apheresis due to insufficient production quality. Median time from lymphapheresis to ide-cel infusion for the whole cohort was 7 (7–11) weeks. Median duration of hospitalization for ide-cel treatment was 18 (16–41) days. Preliminary response data are available from all 16 patients, assessed in a first BM aspirate performed at a median of 12 (10–35) days after ide-cel infusion and with a second BM aspirate at 10–12 weeks (3 months assessment). In one (6%) patient with prolonged hematologic toxicity, the 3 months BM assessment was performed earlier, at 9 weeks follow-up. The objective response rate (ORR) for the entire cohort was 75% in the initial assessment and 69% at 3 months assessment. At 3 months follow-up, seven (44%) patients achieved an MRD negative complete response (MRDneg CR) or stringent complete response (sCR), one (6%) patient a complete response (CR), three (19%) patients a very good partial response (VGPR), and five (31%) showed progressive disease (PD). Interestingly, two patients with CR and PR, respectively, in the first BM assessment, showed MRD negativity at the 3 months assessment (Fig. 1A, B). Despite sample size limitations, 4/6 (67%) patients with high-risk cytogenetics showed PD after treatment with ide-cel, while only 1/10 (10%) patients with standard-risk cytogenetics showed PD. No negative correlation with presence of extramedullary disease was observed. Median follow-up was 5.7 months (r: 0.6–9.0).

Observed adverse event profile was similar to previously published trial data [9]. CRS occurred in 15 patients (94%: 88% grade 1, 6% grade 2, no grade 3/4) and ICANS occurred uniquely in one patient (6% grade 2, no grade 1/3/4). Median time to CRS onset was 0 days (r: 0–2). Serum IL-6 levels correlated with CRS onset. Following CRS onset, median time to IL-6 peak-level was 3 days (r: 1–36) and median peak value 2131 pg/ml (r: 96–16,189). 15 (94%) patients required at least one dose of tocilizumab, 2 (13%) patients required the addition of dexamethasone, and 1 (6%) patient required siltuximab due to ICANS grade 2. In this patient, onset of ICANS occurred 8 days after ide-cel infusion. Hematologic toxicity was observed in all patients. Any grade of anemia occurred in 16 patients (100%: 6% grade 1, 6% grade 2, 88% grade 3), neutropenia in 16 (100%: 31% grade 3, 69% grade 4) and thrombocytopenia in 15 (94%: 19% grade 2, 19% grade 3 and 56% grade 4). Febrile neutropenia occurred in 11 (69%) patients, and infections with identification of a germ in 5 (31%) (Fig. 2A). Median onset of hematologic toxicity presented at day -5 before ide-cel administration for anemia, starting during conditioning chemotherapy, at day -1 for neutropenia and at day 0 for thrombocytopenia. Median duration of anemia was 35 days (r: 10–177), of neutropenia 18 days (r: 2–176) and of thrombocytopenia 60 days (r: 14–184) (Fig. 2B). Prolonged hematologic toxicity with anemia, neutropenia and/or thrombocytopenia of at least grade 3 persisting 3 months post-treatment with ide-cel occurred in 4/16 (25%) patients. One of the 6 patients presented a severe biphasic pancytopenia, with late-onset peak detected at day 36 post-ide-cel infusion and still ongoing at 11 weeks follow-up. BM examination in this patient showed a sCR and an aplastic BM. To date, the patient continues receiving regular transfusions, granulocyte-colonies stimulating factors, as well as supplementation with vitamin B12 and folic acid. Other common non-hematological toxicities were elevated ALT (38%: 19% grade 1, 13% grade 2, 6% grade 3, no grade 4), elevated AST (38%: 31% grade 1, 6% grade 3, no grade 2/4). One patient had a colitis (6%, grade 3) and another patient a disseminated intravascular coagulation (DIC) (6%, grade 3) (Fig. 2A). Hepatotoxicity, colitis and DIC resolved to baseline. One patient presented multi-factorial physical deterioration despite confirmed sCR in early BM biopsy and lack of infectious complications. Following patient’s wish, supportive therapy was interrupted, and the patient died 10 weeks after ide-cel treatment.

Longitudinal monitoring in peripheral blood of circulating CAR T copies per μg of cfDNA up to 12 weeks following ide-cel infusion is represented in Fig. 3A (responders) and 3B (non-responders). CAR T expansion peak was observed between week 1 and 3 for most patients. 8/16 patients (50%) achieved expansion over 10⁵ copies/μg cfDNA. 8/8 (100%) expanders vs 3/8 (38%) non-expanders had an objective response, 5/8 (63%) expanders vs 2/8 (25%) non-expanders had a sCR, and all patients with PD showed a CAR T expansion under 10⁵ copies/μg cfDNA (Fig. 3C). sBCMA plasma levels following ide-cel infusion are available all 16 patients, with nadir sBCMA levels observed between week + 8 and + 12 following ide-cel infusion. Non-responders showed typically lack of decrease or plateau sBCMA levels. In responders, however, high inter-patient variability regarding timing of sBCMA decrease was observed (Fig. 4A, B).

A 75-year-old female patient with IgA kappa multiple myeloma, initial R-ISS Stage II, and with PD after previous 12 treatment lines, including HD-CT and ASCT. Previous to ide-cel therapy, a 12^th treatment line with belantamab mafodotin, carfilzomib and dexamethasone was performed, with lack of tumor response. BM biopsy before ide-cel treatment showed a 30% infiltration and a pleural biopsy confirmed presence of pleural extramedullary disease. 12 days after ide-cel infusion, patient reported progressive dyspnea, and thorax computer tomography revealed progression of the pleural infiltrative mass (70 × 48 mm, previous size 68 × 47 mm), as well as of the associated pleural effusion. Cytology and flow cytometry of pleural effusion confirmed presence of aberrant plasma cells (26.5%). 4 weeks following ide-cel infusion a slight reduction of the pleural mass could be radiographically documented (65 × 43), remaining stable 8 weeks after ide-cel (Fig. 5A, B, C). An additional radiotherapy to the pleural mass was performed. Early BM response assessment showed a PR and 3 months assessment a sCR.