Oncology
Multiple Myeloma
Bridging Therapy Prior to Chimeric Antigen Receptor T-Cell Therapy in Patients With Multiple Myeloma
Overview
Since the manufacturing of chimeric antigen receptor (CAR) T-cell therapy takes time, bridging therapy is often delivered to ensure that the disease is controlled until the CAR T-cell treatment is infused. Such therapy is common today, but the need for it may not be as great in the future.
Expert Commentary
Kenneth C. Anderson, MD
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“The use of CAR T-cell therapy in earlier disease settings, as well as the development of products with shorter production times, will dramatically reduce the need for bridging therapy in the future.”
CAR T cells are the best option for many—if not most—patients with far advanced multiple myeloma (eg, penta-refractory disease) due to the impressive responses that have been observed with treatment. Importantly, CAR T cells can be used in many patients, including older individuals and those with comorbidities who are not eligible for high-dose therapy and autologous stem cell transplantation. A 98% response rate with a durability of at least 2 years has been reported for ciltacabtagene autoleucel, and a durability of approximately 1 year has been reported for idecabtagene vicleucel with the currently recommended dose range. Both treatments are associated with minimal residual disease negativity in a substantial number of patients, and this portends favorably for a more prolonged response.
Because the production of CAR T cells can take up to 3 to 4 weeks, the majority of patients who receive CAR T-cell therapy require bridging therapy, which is administered after the T cells have been harvested to control the patient’s multiple myeloma until the CAR T-cell product is ready for infusion. The choice of bridging therapy should be individualized and is, to some extent, predicated on the patient's prior treatment(s) and whether their most recent regimen is controlling their multiple myeloma. The most important point to emphasize is that there is no one universal bridging regimen; therapy is used simply to maintain control of the patient's multiple myeloma during that waiting period.
One example of individualizing bridging therapy involves the consideration of the target (ie, BCMA). Since other BCMA-directed therapies such as belantamab mafodotin or the bispecific T-cell engager teclistamab are available and may have been used, the inclusion of a wash-out period may be considered to allow for the upregulation of BCMA expression prior to administering another BCMA-directed therapy.
CAR T-cell therapies are now being evaluated in clinical trials examining their use earlier in the course of therapy, including for earlier relapses and even in the frontline setting. Such early use will lessen the need for intense bridging therapy because the disease is at a stage that can be more easily controlled. The development of products and strategies that involve the production of CAR T cells in a much shorter period of time (ie, 5-7 days rather than 3-4 weeks) will also impact the need for bridging therapy.
At the 63rd American Society of Hematology (ASH) Annual Meeting and Exposition in 2021 and the 64th ASH Annual Meeting and Exposition in 2022, Sperling et al and Costa et al, respectively, reported the preliminary results of the reinfusion of a small number of CAR T cells into patients after only a few days. The concept is to infuse a smaller number of cells and let the expansion happen in the patient with multiple myeloma, rather than letting the expansion occur over a period of weeks outside of the patient. Infusing fewer cells creates the potential for a reduced side-effect burden, and, thus far, the efficacy appears to be quite remarkable. The use of CAR T-cell therapy in earlier disease settings, as well as the development of products with shorter production times, will dramatically reduce the need for bridging therapy in the future.
References
Amini L, Silbert SK, Maude SL, et al. Preparing for CAR T cell therapy: patient selection, bridging therapies and lymphodepletion. Nat Rev Clin Oncol. 2022;19(5):342-355. doi:10.1038/s41571-022-00607-3
Anderson LD Jr, Munshi NC, Shah N, et al. Idecabtagene vicleucel (ide-cel, bb2121), a BCMA-directed CAR T cell therapy, in relapsed and refractory multiple myeloma: updated KarMMa results. J Clin Oncol. 2021;39(suppl 15):8016. doi:10.1200/JCO.2021.39.15_suppl.8016
Bansal R, Baksh M, Larsen JT, et al. Prognostic value of early bone marrow MRD status in CAR-T therapy for myeloma. J Clin Oncol. 2022;40(suppl 16):8022. doi:10.1200/JCO.2022.40.16_suppl.8022
Berdeja JG, Madduri D, Usmani SZ, et al. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study [published correction appears in Lancet. 2021;398(10307):1216]. Lancet. 2021;398(10297):314-324. doi:10.1016/S0140-6736(21)00933-8
Bhaskar ST, Dholaria BR, Sengsayadeth SM, Savani BN, Oluwole OO. Role of bridging therapy during chimeric antigen receptor T cell therapy. EJHaem. 2021;3(suppl 1):39-45. doi:10.1002/jha2.335
Cohen AD, Mateos M-V, Cohen YC, et al. Efficacy and safety of cilta-cel in patients with progressive multiple myeloma after exposure to other BCMA-targeting agents. Blood. 2023;141(3):219-230. doi:10.1182/blood.2022015526
Costa LJM, Kumar SK, Atrash S, et al. Results from the first phase 1 clinical study of the B-cell maturation antigen (BCMA) NEX T chimeric antigen receptor (CAR) T cell therapy CC-98633/BMS-986354 in patients (pts) with relapsed/refractory multiple myeloma (RRMM) [abstract 566]. Abstract presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA.
Dhodapkar KM, Cohen AD, Kaushal A, et al. Changes in bone marrow tumor and immune cells correlate with durability of remissions following BCMA CAR T therapy in myeloma. Blood Cancer Discov. 2022;3(6):490-501. doi:10.1158/2643-3230.BCD-22-0018
Martin T, Usmani SZ, Berdeja JG, et al. Ciltacabtagene autoleucel, an anti–B-cell maturation antigen chimeric antigen receptor T-cell therapy, for relapsed/refractory multiple myeloma: CARTITUDE-1 2-year follow-up. J Clin Oncol. 2022 Jun 4;JCO2200842. doi:10.1200/JCO.22.00842
Moreau P, Garfall AL, van de Donk NWCJ, et al. Teclistamab in relapsed or refractory multiple myeloma. N Engl J Med. 2022;387(6):495-505. doi:10.1056/NEJMoa2203478
Munshi NC, Paiva B, Martin T, et al. Efficacy outcomes and characteristics of patients with multiple myeloma (MM) who achieved sustained minimal residual disease negativity after treatment with ciltacabtagene autoleucel (cilta-cel) in CARTITUDE-1 [abstract 2030]. Abstract presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA.
Rendo MJ, Joseph JJ, Phan LM, DeStefano CB. CAR T-cell therapy for patients with multiple myeloma: current evidence and challenges. Blood Lymphat Cancer. 2022;12:119-136. doi:10.2147/BLCTT.S327016
Sperling AS, Nikiforow S, Nadeem O, et al. Phase I study of PHE885, a fully human BCMA-directed CAR-T Cell therapy for relapsed/refractory multiple myeloma manufactured in <2 days using the T-Charge™ platform [abstract 3864]. Abstract presented at: 63rd American Society of Hematology Annual Meeting and Exposition; December 10-14, 2021; Atlanta, GA.
Usmani SZ, Berdeja JG, Madduri D, et al. Updated CARTITUDE-1 results of ciltacabtagene autoleucel, a B-cell maturation antigen–directed chimeric antigen receptor T cell therapy, in relapsed/refractory multiple myeloma. HemaSphere. 2021;5(suppl 2):451.
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