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

BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment landscape of relapsed/refractory multiple myeloma (RRMM), leading to unprecedented responses in this patient population. Idecabtagene vicleucel (ide-cel) has been recently approved for treatment of triple-class exposed RRMM. We report real-life experiences with the commercial use of ide-cel in RRMM patients. METHODS: We performed a retrospective analysis of the first 16 triple-class exposed RRMM patients treated with ide-cel at a single academic center. We assessed toxicities, response to treatment, CAR T expansion and soluble BCMA (sBCMA) levels. RESULTS: We identified 16 consecutive RRMM patients treated with ide-cel between 06-10/2022. Median age was 69 years, 6 (38%) patients had high-risk cytogenetics, 3 (19%) R-ISS stage III, and 5 (31%) extramedullary disease. Median number of previous treatment lines was 6 (3-12). Manufacturing success rate was 88% (6% required second lymphapheresis, 6% received an out-of-specification product). At 3 months, the overall response rate (ORR) was 69% (44% sCR, 6% CR, 19% VGPR). Cytokine release syndrome (CRS) occurred in 15 (94%) patients (88% G1, 6% G2), immune effector-cell associated neurotoxicity syndrome (ICANS) in 1 (6% G1), febrile neutropenia in 11 (69%), and infections in 5 (31%). Prolonged hematologic toxicity occurred in 4/16 (25%) patients. Other non-hematological toxicities were elevated hepatic enzymes (38%), colitis (6%, G3) and DIC (6%, G2). Responses were more frequent in patients with higher CAR T expansion (100% vs 38%), and lack of decrease or plateau of sBCMA levels was typically observed in non-responders. CONCLUSIONS: We report one of the first cohorts of RRMM treated with commercial ide-cel. The ORR was 69% and safety profile was manageable, but prolonged hematologic toxicity still represents a major challenge. Responses correlated with in vivo CAR T cell expansion, underlining the need of further research to optimize CAR T expansion.

Idecabtagene vicleucel (ide-cel) CAR T-cell therapy for relapsed and refractory multiple myeloma.

Idecabtagene vicleucel (ide-cel), a novel chimeric antigen receptor (CAR) T-cell therapy targeting B-cell maturation antigen (BCMA), has recently gained approval by the US FDA for relapsed and refractory multiple myeloma (RRMM) after multicenter trials have demonstrated unprecedented results in this difficult-to-treat subgroup of patients. As the first CAR T-cell product approved for myeloma, ide-cel is poised to become a practice-changing treatment option. This first-in-class therapeutic offers hope for more durable remissions, as well as better quality of life, following a single infusion in a group of patients that previously had little hope. This paper reviews the ide-cel product in terms of design, pharmacology, efficacy and toxicity as described in studies reported to date.

Lay abstract Idecabtagene vicleucel (ide-cel) is a novel therapy using a patient's own T cells that have been genetically modified to force them to recognize a target antigen called BCMA that is present on myeloma and plasma cells but not on other normal cells. This therapy, known as CAR T-cell therapy, has recently gained approval by the US FDA for relapsed multiple myeloma after clinical trials have demonstrated unprecedented results in this difficult-to-treat subgroup of patients who have failed at least four prior lines of therapy. As the first CAR T-cell product approved for myeloma, ide-cel is poised to become a practice-changing treatment option. This first-in-class therapeutic offers hope for more durable remissions, as well as a longer and better quality of life, following a single infusion. This paper reviews the ide-cel product in terms of design, pharmacology, efficacy and toxicity as described in studies reported to date.

Impact of Previous Allogeneic Hematopoietic Stem Cell Transplantation on Chimeric Antigen Receptor (CAR) T Cell Treatment for Relapsed/Refractory Multiple Myeloma.

BACKGROUND: Anti-BCMA-directed chimeric antigen receptor (CAR) T cells are effective treatment for patients with refractory/relapsed multiple myeloma (RRMM). However, little is known about the impact of previous allogeneic hematopoietic stem cell transplantation (allo-HSCT) on lymphocyte collection for production of CAR T cells and subsequent treatment with CAR T cells. PATIENTS AND METHODS: We performed a retrospective analysis of cellular composition of lymphocyte collections, CAR T cell expansion and treatment outcomes of RRMM patients undergoing therapy with idecabtagene vicleucel (ide-cel) with and without history of allo-HSCT. 27 patients (11/27 female) with median age 63 (range 39-75) years were analyzed. Five patients (19%) had the history of allo-HSCT median of 5.5 years before ide-cel. RESULTS: Prior to apheresis, the white blood cell, absolute lymphocyte counts, CD3+ cells and monocytes did not differ in patients with and without prior allo-HSCT. We also noticed no differences in the collected CD3+ yields or cellular compositions of lymphocyte collections. One year after ide-cel infusion, the progression-free survival and overall survival of patients with and without previous allo-HSCT did not differ with 60% and 45% respectively (P = .58) and 66.7% and 74% respectively (P = .84). The highest expansion of CAR T was detected between day 7 after infusion and showed no difference regarding previous allo-HSCT (P = .71). No graft-versus-host disease during the follow-up was detected. CONCLUSION: Our data confirm that the treatment with ide-cel is feasible for patients with prior allo-HSCT. Furthermore, allo-HSCT did not influence cellular composition of lymphocyte collections, clinical outcome or in vivo expansion of ide-cel.

Early Chimeric Antigen Receptor T Cell Expansion Is Associated with Prolonged Progression-Free Survival for Patients with Relapsed/Refractory Multiple Myeloma Treated with Ide-Cel: A Retrospective Monocentric Study.

The outcomes of patients with relapsed and refractory multiple myeloma (RRMM) previously treated with the 3 main classes of myeloma therapy-immunomodulatory drugs, proteasome inhibitors, and anti-CD38 antibodies-remain poor. Recently, based on the phase II pivotal KarMMa trial showing prolonged overall survival (OS) and progression-free survival (PFS) in heavily treated patients, idecabtagene vicleucel (ide-cel), a B cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T cell therapy (CAR-T) product, was approved in the United States for the treatment of RRMM. In France, since June 2021, an early access program has authorized the use of ide-cel in the setting of RRMM (defined as progressive myeloma after at least 3 previous regimens, including the 3 main antimyeloma therapies). We report the first French experience through this early access program in a retrospective study of 24 consecutive patients treated with ide-cel at our institution. The patients were evaluated according to International Myeloma Working Group criteria and by positron emission tomography computed tomography (PET-CT) at 1, 3, 6, 9, and 12 months after ide-cel infusion. Most patients had adverse cytogenetic abnormalities, and RRMM with triple-refractory drugs were seen in 79%. Bridging therapy was required for 19 of 24 patients. Before CAR-T cell infusion, lymphodepletion with fludarabine and cyclophosphamide was systematically performed. The median follow-up was 15.2 months. At 3 months after ide-cel infusion, 92% of patients achieved at least a partial response, and 50% achieved a complete response or better (≥CR). At 6 months, 70% of patients had a persistent ≥CR. At 3 and 6 months, bone marrow minimal residual disease (10-6 level) was undetectable in 79% and 75% of patients, respectively. At 6 months, CR as assessed by PET-CT was achieved in 15 of 20 patients (75%). The median PFS was 14.8 months, and median OS was not reached. Notably, an expansion of circulating CAR-T cells to >180/mm3 after infusion was strongly associated with prolonged PFS. Additionally, the level of soluble BCMA measured before infusion was identified as a prognostic factor for PFS, likely correlated to the tumor burden. Grade 1-2 cytokine release syndrome (CRS) occurred in 22 of 24 patients (92%). Only 1 patient (4%) experienced grade ≥3 CRS. The occurrence of neurologic toxicity was infrequent (12.5%) and reversible in all cases. Hematologic toxicity was relatively common, and secondary hypogammaglobulinemia occurred in most patients. Infections (mostly viral) were frequent but most often nonsevere. This study echoes the promising results of the KarMMa trial and identifies possible prognostic indicators in RRMM patients treated with ide-cel, potentially refining treatment strategies and improving outcomes in this challenging context.

Impact of extramedullary multiple myeloma on outcomes with idecabtagene vicleucel.

Idecabtagene vicleucel (Ide-cel) has demonstrated excellent efficacy and durable responses in patients with relapsed/refractory multiple myeloma (RRMM). However, the outcomes with ide-cel in patients with extramedullary disease (EMD) remain incompletely characterized. We included patients with RRMM treated with ide-cel between May 2021 and April 2023 across 11 US academic institutions. Visceral or soft tissue lesions non-contiguous from bone was classified as EMD. Time-to-event analyses were performed from date of ide-cel infusion. Among 351 patients, 84 (24%) had EMD prior to infusion. The median follow-up from ide-cel infusion was 18.2 months (95% CI: 17-19.3). The day 90 overall response rates (ORR) were 52% vs. 82% for the EMD and non-EMD cohorts, respectively (p < 0.001). The median progression-free survival (PFS) was 5.3 months (95% CI: 4.1-6.9) for the EMD cohort vs. 11.1 months (95% CI: 9.2-12.6; p < 0.0001) for the non-EMD cohort. In a multivariable analysis, EMD was an independent predictor of inferior PFS [hazard ratio 1.5 (1.1-2.2), p = 0.02]. The median overall survival was 14.8 months [95% CI: 9-Not reached (NR)] vs. 26.9 months (26.3 vs. NR, p = 0.006) for the EMD and non-EMD cohorts, respectively. Extramedullary disease represents an independent predictor of inferior day 90 ORR and PFS among patients treated with ide-cel.

Optimizing the CAR T-Cell Therapy Experience in Multiple Myeloma: Clinical Pearls From an Expert Roundtable.

Chimeric antigen receptor T-cell (CAR-T) therapies offer substantial advancement in the treatment of multiple myeloma (MM). However, the CAR-T therapy process involves complex decision-making that is informed by many variables. This review aims to provide an overview of the patient selection and administration process for CAR-T therapy for MM from the perspective of experienced healthcare providers (HCPs), including considerations for each step in the CAR-T therapy process. Referring HCPs should initiate conversations with HCPs at CAR-T capable centers earlier in the treatment journey, even before patients are eligible for CAR-T therapy, particularly for patients from underserved populations and patients with high-risk disease, to ensure adequate time for logistical planning and patient education. Patient selection for CAR-T therapy may be guided by factors such as performance status, rate of disease progression, and logistical considerations. Some anticancer therapies may affect T-cell fitness and therefore impact CAR-T manufacturing and patient outcomes; however, additional research is needed to confirm this in MM. Bridging therapies should be tailored to the needs of the patient and ideally halted 1 week or longer before CAR-T infusion, contingent upon the agent(s) used. Lymphodepletion regimens may need to be modified for patients with renal insufficiency. Collaboration with HCPs at both the treating and referring centers is important to optimize coordinated care of patients. Collaboration with and guidance from experienced HCPs throughout patient selection, referral, and CAR-T administration is instrumental in optimizing patient outcomes as access to CAR-T therapies expands.

"Waitlist mortality" is high for myeloma patients with limited access to BCMA therapy.

Background: The first-in-class approved BCMA CAR-T therapy was idecabtagene vicleucel (ide-cel), approved in March 2021, for RRMM patients who progressed after 4 or more lines of therapy. Despite the promising outcomes, there were limited apheresis/production slots for ide-cel. We report outcomes of patients at our institution who were on the "waitlist" to receive ide-cel in 2021 and who could not secure a slot. Methods: We conducted a retrospective review of RRMM patients evaluated at the University of Kansas Cancer Center for ide-cel from 3/2021-7/2021. A retrospective chart review was performed to determine patient and disease characteristics. Descriptive statistics were reported using medians for continuous variables. Survival analysis from initial consult was performed using Kaplan-Meier Survival estimator. Results: Forty patients were eligible and were on the "waitlist" for CAR-T. The median follow-up was 14 months (2-25mo). Twenty-four patients (60%) secured a production slot and 16 (40%) did not. The median time from consult to collection was 38 days (8-703). The median time from collection to infusion was 42 days (34-132 days). The median overall survival was higher in the CAR-T group (NR vs 9 mo, p<0.001). Conclusions: Many patients who were eligible for ide-cel were not able to secure a timely slot in 2021. Mortality was higher in this group, due to a lack of comparable alternatives. Increasing alternate options as well as improvement in manufacturing and access is an area of high importance to improve RRMM outcomes.

Recent Advances in the Use of Chimeric Antigen Receptor-Expressing T-Cell Therapies for Treatment of Multiple Myeloma.

INTRODUCTION: Chimeric antigen receptor T cell (CAR-T) therapies have revolutionized the treatment paradigm for heavily pretreated B-cell malignancies such as large B-cell lymphoma. There is a major unmet need for effective treatments for heavily pretreated relapsed/refractory multiple myeloma (RRMM), for which many CAR-T therapies are under active clinical investigation. Goal of the review: This review provides an overview of recently updated clinical trial data and indirect treatment comparison analyses regarding two clinically advanced CAR-T therapies, idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel). DISCUSSION: Recently presented data after prolonged follow-up periods for ide-cel (KarMMa) and cilta-cel (CARTITUDE-1) have demonstrated that both therapies have the potential to elicit responses in individuals with heavily pretreated RRMM. Indirect treatment comparisons between cilta-cel and ide-cel suggest cilta-cel is associated with deeper and more durable responses than ide-cel in triple class-exposed RRMM; however, these types of comparisons have limitations and direct head-to-head trials are needed to confirm these findings. Additional indirect treatment comparisons conducted separately for ide-cel and cilta-cel have demonstrated that these CAR-T therapies hold promise for substantial clinical benefit relative to currently available treatments for RRMM. Further considerations, including safety profiles and real-world treatment considerations, are also discussed. CONCLUSION: Data collected to date support CAR-T therapies holding substantial promise for patients with heavily pretreated RRMM relative to other currently available therapies. Additional real-world data will help provide further insights into the comparative efficacy and safety profiles of these treatments in RRMM as these treatments become more widely available.

Idecabtagene vicleucel for relapsed/refractory multiple myeloma: a review of recent advances.

The introduction of new classes of drugs for the treatment of multiple myeloma (MM) in the past 2 decades, such as proteasome inhibitors, immunomodulators and anti-CD38 monoclonal antibodies, coupled with autologous stem cell transplantation, has approximately doubled the 5-year survival rate of MM patients. However, the patients eventually relapse and/or become resistant to the drugs and treatment. The recent emergence of anti-B-cell maturation antigen (BCMA) therapies, especially chimeric antigen receptor T-cell (CAR-T) immunotherapy targeting BCMA, holds great prospect in MM treatment. In this article, we review in detail the advances of idecabtagene vicleucel (ide-cel, bb-2121), the first CAR-T therapy targeting BCMA for treating relapse or refractory MM approved by the U.S. Food and Drug Administration (FDA) in 2021, including the preclinical study and phase I and II clinical trials. Also, it is predicted in this review that despite its amazing clinical efficacy and relatively lower toxicity, a lot of challenges and unsolved problems for ide-cel therapy remain in the way ahead.