Iranian Journal of Medical Sciences

Iranian Journal of Medical Sciences

Current Issue

By Issue

By Author

By Subject

Author Index

Keyword Index

About Journal

Aims and Scope

Journal Team

Publication Ethics

Indexing and Abstracting

Related Links

Peer Review Process

Journal Metrics

Advancing Multiple Myeloma Immunotherapy: A Review of Chimeric Antigen Receptor T-Cell and Bispecific T-Cell Engagers Cell Therapies in Revolutionizing Treatment

Articles InPress

Document Type : Review Article

Authors

1 PES Institute of Medical Sciences and Research, Kuppam, India

2 Mayo Clinic, Rochester, MN, United States of America

3 Liaquat National Hospital & Medical College, Karachi, Pakistan

4 Indira Gandhi Medical College and Hospital, Shimla, India

5 University College of Medical Sciences, New Delhi, India

6 Penn State Health Milton S. Hershey Medical Center, Pennsylvania, United States of America

10.30476/ijms.2024.101739.3446

Abstract

Multiple Myeloma (MM) is a hematologic malignancy characterized by clonal plasma cell development, leading to serious complications. Despite traditional treatments, MM remains incurable, necessitating innovative therapeutic approaches. Chimeric Antigen Receptor (CAR) T-cell therapy and Bispecific T-cell engagers (BiTEs) are emerging immunotherapies showing promise in MM treatment. CAR T-cell therapy involves modifying patient T-cells to target specific antigens, primarily B Cell Maturation Antigen (BCMA). BiTEs, on the other hand, are non-IgG-like bispecific antibodies designed to engage both CD3 and tumor-associated antigens. These therapies exhibit impressive efficacy in clinical trials, leading to FDA approvals for specific MM patient populations. Despite their successes, these therapies come with unique challenges and adverse effects, such as cytokine release syndrome (CRS) and neurotoxicity. This narrative review explores the mechanisms, efficacy, challenges, and potential benefits of CAR T-cell and BiTE therapies for MM patients, shedding light on their roles in addressing this complex disease.

Keywords

References
  1. Cowan AJ, Green DJ, Kwok M, Lee S, Coffey DG, Holmberg LA, et al. Diagnosis and Management of Multiple Myeloma: A Review. JAMA. 2022;327:464-77. doi: 10.1001/jama.2022.0003. PubMed PMID: 35103762.
  2. Padala SA, Barsouk A, Barsouk A, Rawla P, Vakiti A, Kolhe R, et al. Epidemiology, Staging, and Management of Multiple Myeloma. Med Sci (Basel). 2021;9. doi: 10.3390/medsci9010003. PubMed PMID: 33498356; PubMed Central PMCID: PMCPMC7838784.
  3. Rajkumar SV. Multiple myeloma: 2020 update on diagnosis, risk-stratification and management. Am J Hematol. 2020;95:548-67. doi: 10.1002/ajh.25791. PubMed PMID: 32212178.
  4. Janssens R, Lang T, Vallejo A, Galinsky J, Plate A, Morgan K, et al. Patient Preferences for Multiple Myeloma Treatments: A Multinational Qualitative Study. Front Med (Lausanne). 2021;8:686165. doi: 10.3389/fmed.2021.686165. PubMed PMID: 34295912; PubMed Central PMCID: PMCPMC8289885.
  5. Zhang X, Zhu L, Zhang H, Chen S, Xiao Y. CAR-T Cell Therapy in Hematological Malignancies: Current Opportunities and Challenges. Front Immunol. 2022;13:927153. doi: 10.3389/fimmu.2022.927153. PubMed PMID: 35757715; PubMed Central PMCID: PMCPMC9226391.
  6. Soekojo CY, Chng WJ. Treatment horizon in multiple myeloma. Eur J Haematol. 2022;109:425-40. doi: 10.1111/ejh.13840. PubMed PMID: 35880395.
  7. Mikkilineni L, Kochenderfer JN. Chimeric antigen receptor T-cell therapies for multiple myeloma. Blood. 2017;130:2594-602. doi: 10.1182/blood-2017-06-793869. PubMed PMID: 28928126; PubMed Central PMCID: PMCPMC5731088.
  8. Carpenter RO, Evbuomwan MO, Pittaluga S, Rose JJ, Raffeld M, Yang S, et al. B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma. Clin Cancer Res. 2013;19:2048-60. doi: 10.1158/1078-0432.CCR-12-2422. PubMed PMID: 23344265; PubMed Central PMCID: PMCPMC3630268.
  9. Bu DX, Singh R, Choi EE, Ruella M, Nunez-Cruz S, Mansfield KG, et al. Pre-clinical validation of B cell maturation antigen (BCMA) as a target for T cell immunotherapy of multiple myeloma. Oncotarget. 2018;9:25764-80. doi: 10.18632/oncotarget.25359. PubMed PMID: 29899820; PubMed Central PMCID: PMCPMC5995247.
  10. van de Donk N, Usmani SZ, Yong K. CAR T-cell therapy for multiple myeloma: state of the art and prospects. Lancet Haematol. 2021;8:e446-e61. doi: 10.1016/S2352-3026(21)00057-0. PubMed PMID: 34048683.
  11. Perez P, Hoffman RW, Shaw S, Bluestone JA, Segal DM. Specific targeting of cytotoxic T cells by anti-T3 linked to anti-target cell antibody. Nature. 1985;316:354-6. doi: 10.1038/316354a0. PubMed PMID: 3160953.
  12. Brinkmann U, Kontermann RE. The making of bispecific antibodies. MAbs. 2017;9:182-212. doi: 10.1080/19420862.2016.1268307. PubMed PMID: 28071970; PubMed Central PMCID: PMCPMC5297537.
  13. Einsele H, Borghaei H, Orlowski RZ, Subklewe M, Roboz GJ, Zugmaier G, et al. The BiTE (bispecific T-cell engager) platform: Development and future potential of a targeted immuno-oncology therapy across tumor types. Cancer. 2020;126:3192-201. doi: 10.1002/cncr.32909. PubMed PMID: 32401342.
  14. Du J, Zhuang J. Major advances in the treatment of multiple myeloma in American Society of Hematology annual meeting 2020. Chronic Dis Transl Med. 2021;7:220-6. doi: 10.1016/j.cdtm.2021.08.003. PubMed PMID: 34786541; PubMed Central PMCID: PMCPMC8579022.
  15. Teoh PJ, Chng WJ. CAR T-cell therapy in multiple myeloma: more room for improvement. Blood Cancer J. 2021;11:84. doi: 10.1038/s41408-021-00469-5. PubMed PMID: 33927192; PubMed Central PMCID: PMCPMC8085238.
  16. Kegyes D, Constantinescu C, Vrancken L, Rasche L, Gregoire C, Tigu B, et al. Patient selection for CAR T or BiTE therapy in multiple myeloma: Which treatment for each patient? J Hematol Oncol. 2022;15:78. doi: 10.1186/s13045-022-01296-2. PubMed PMID: 35672793; PubMed Central PMCID: PMCPMC9171942.
  17. Wang Z, Chen C, Wang L, Jia Y, Qin Y. Chimeric antigen receptor T-cell therapy for multiple myeloma. Front Immunol. 2022;13:1050522. doi: 10.3389/fimmu.2022.1050522. PubMed PMID: 36618390; PubMed Central PMCID: PMCPMC9814974.
  18. Choi T, Kang Y. Chimeric antigen receptor (CAR) T-cell therapy for multiple myeloma. Pharmacol Ther. 2022;232:108007. doi: 10.1016/j.pharmthera.2021.108007. PubMed PMID: 34582835; PubMed Central PMCID: PMCPMC8930424.
  19. 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;12:119-36. doi: 10.2147/BLCTT.S327016. PubMed PMID: 36060553; PubMed Central PMCID: PMCPMC9439649.
  20. Alhallak K, Sun J, Jeske A, Park C, Yavner J, Bash H, et al. Bispecific T Cell Engagers for the Treatment of Multiple Myeloma: Achievements and Challenges. Cancers (Basel). 2021;13. doi: 10.3390/cancers13122853. PubMed PMID: 34201007; PubMed Central PMCID: PMCPMC8228067.
  21. Yu B, Jiang T, Liu D. BCMA-targeted immunotherapy for multiple myeloma. J Hematol Oncol. 2020;13:125. doi: 10.1186/s13045-020-00962-7. PubMed PMID: 32943087; PubMed Central PMCID: PMCPMC7499842.
  22. Cho SF, Yeh TJ, Anderson KC, Tai YT. Bispecific antibodies in multiple myeloma treatment: A journey in progress. Front Oncol. 2022;12:1032775. doi: 10.3389/fonc.2022.1032775. PubMed PMID: 36330495; PubMed Central PMCID: PMCPMC9623099.
  23. Mullard A. FDA approves first CAR T therapy. Nat Rev Drug Discov. 2017;16:669. doi: 10.1038/nrd.2017.196. PubMed PMID: 28959944.
  24. Munshi NC, Anderson LD, Jr., Shah N, Madduri D, Berdeja J, Lonial S, et al. Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma. N Engl J Med. 2021;384:705-16. doi: 10.1056/NEJMoa2024850. PubMed PMID: 33626253.
  25. Vogl DT, Dingli D, Cornell RF, Huff CA, Jagannath S, Bhutani D, et al. Selective Inhibition of Nuclear Export With Oral Selinexor for Treatment of Relapsed or Refractory Multiple Myeloma. J Clin Oncol. 2018;36:859-66. doi: 10.1200/JCO.2017.75.5207. PubMed PMID: 29381435; PubMed Central PMCID: PMCPMC6905485.
  26. Chari A, Vogl DT, Gavriatopoulou M, Nooka AK, Yee AJ, Huff CA, et al. Oral Selinexor-Dexamethasone for Triple-Class Refractory Multiple Myeloma. N Engl J Med. 2019;381:727-38. doi: 10.1056/NEJMoa1903455. PubMed PMID: 31433920.
  27. Martin T, Usmani SZ, Berdeja JG, Agha M, Cohen AD, Hari P, 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. 2023;41:1265-74. doi: 10.1200/JCO.22.00842. PubMed PMID: 35658469; PubMed Central PMCID: PMCPMC9937098.
  28. Rodriguez-Otero P, Ailawadhi S, Arnulf B, Patel K, Cavo M, Nooka AK, et al. Ide-cel or Standard Regimens in Relapsed and Refractory Multiple Myeloma. N Engl J Med. 2023;388:1002-14. doi: 10.1056/NEJMoa2213614. PubMed PMID: 36762851.
  29. Berdeja JG, Madduri D, Usmani SZ, Jakubowiak A, Agha M, Cohen AD, 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. Lancet. 2021;398:314-24. doi: 10.1016/S0140-6736(21)00933-8. PubMed PMID: 34175021.
  30. Martin T, Usmani SZ, Schecter JM, Vogel M, Jackson CC, Deraedt W, et al. Matching-adjusted indirect comparison of efficacy outcomes for ciltacabtagene autoleucel in CARTITUDE-1 versus idecabtagene vicleucel in KarMMa for the treatment of patients with relapsed or refractory multiple myeloma. Curr Med Res Opin. 2021;37:1779-88. doi: 10.1080/03007995.2021.1953456. PubMed PMID: 34256668.
  31. Bishop MR, Dickinson M, Purtill D, Barba P, Santoro A, Hamad N, et al. Second-Line Tisagenlecleucel or Standard Care in Aggressive B-Cell Lymphoma. N Engl J Med. 2022;386:629-39. doi: 10.1056/NEJMoa2116596. PubMed PMID: 34904798.
  32. Kamdar M, Solomon SR, Arnason J, Johnston PB, Glass B, Bachanova V, et al. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results from an interim analysis of an open-label, randomised, phase 3 trial. Lancet. 2022;399:2294-308. doi: 10.1016/S0140-6736(22)00662-6. PubMed PMID: 35717989.
  33. Locke FL, Miklos DB, Jacobson CA, Perales MA, Kersten MJ, Oluwole OO, et al. Axicabtagene Ciloleucel as Second-Line Therapy for Large B-Cell Lymphoma. N Engl J Med. 2022;386:640-54. doi: 10.1056/NEJMoa2116133. PubMed PMID: 34891224.
  34. San-Miguel J, Dhakal B, Yong K, Spencer A, Anguille S, Mateos MV, et al. Cilta-cel or Standard Care in Lenalidomide-Refractory Multiple Myeloma. N Engl J Med. 2023;389:335-47. doi: 10.1056/NEJMoa2303379. PubMed PMID: 37272512.
  35. Topp MS, Duell J, Zugmaier G, Attal M, Moreau P, Langer C, et al. Anti-B-Cell Maturation Antigen BiTE Molecule AMG 420 Induces Responses in Multiple Myeloma. J Clin Oncol. 2020;38:775-83. doi: 10.1200/JCO.19.02657. PubMed PMID: 31895611.
  36. Moreau P, Garfall AL, van de Donk N, Nahi H, San-Miguel JF, Oriol A, et al. Teclistamab in Relapsed or Refractory Multiple Myeloma. N Engl J Med. 2022;387:495-505. doi: 10.1056/NEJMoa2203478. PubMed PMID: 35661166; PubMed Central PMCID: PMCPMC10587778.
  37. Chari A, Minnema MC, Berdeja JG, Oriol A, van de Donk N, Rodriguez-Otero P, et al. Talquetamab, a T-Cell-Redirecting GPRC5D Bispecific Antibody for Multiple Myeloma. N Engl J Med. 2022;387:2232-44. doi: 10.1056/NEJMoa2204591. PubMed PMID: 36507686.
  38. Cohen YC, Moreau P, Tolbert J, Qin X, Ma X, Vieyra D, et al. MonumenTAL-3: Phase 3 trial of talquetamab+ daratumumab±pomalidomide versus daratumumab+ pomalidomide+ dexamethasone in relapsed/refractory multiple myeloma following≥ 1 prior line of therapy. Blood. 2022;140:4418-9. doi: 10.1182/blood-2022-162733.
  39. Lesokhin AM, Richter J, Trudel S, Cohen AD, Spencer A, Forsberg PA, et al. Enduring responses after 1-year, fixed-duration cevostamab therapy in patients with relapsed/refractory multiple myeloma: early experience from a phase I study. Blood. 2022;140:4415-7. doi: 10.1182/blood-2022-157547.
  40. Mohty M, Tomasson MH, Arnulf B, Bahlis NJ, Rodríguez-Otero P, Martinez-Lopez J, et al. S196: Elranatamab, A B-Cell Maturation Antigen (BCMA)-Cd3 Bispecific Antibody, For Patients with Relapsed/Refractory Multiple Myeloma: Extended Follow Up and Biweekly Administration from Magnetismm-3. HemaSphere. 2023;7:e1309654. doi: 10.1097/01.hs9.0000967696.13096.54.
  41. Bahlis NJ, Tomasson MH, Mohty M, Niesvizky R, Nooka AK, Manier S, et al. Efficacy and safety of elranatamab in patients with relapsed/refractory multiple myeloma naïve to B-cell maturation antigen (BCMA)-directed therapies: results from cohort a of the magnetismm-3 study. Blood. 2022;140:391-3. doi: 10.1182/blood-2022-162440.
  42. Kumar S, Bachier CR, Cavo M, Corradini P, Delforge M, Janowski W, et al. CAMMA 2: A phase I/II trial evaluating the efficacy and safety of cevostamab in patients with relapsed/refractory multiple myeloma (RRMM) who have triple-class refractory disease and have received a prior anti-B-cell maturation antigen (BCMA) agent. American Society of Clinical Oncology. 2023. doi: 10.1200/JCO.2023.41.16_suppl.TPS8064.
  43. Ludwig H, Terpos E, van de Donk N, Mateos MV, Moreau P, Dimopoulos MA, et al. Prevention and management of adverse events during treatment with bispecific antibodies and CAR T cells in multiple myeloma: a consensus report of the European Myeloma Network. Lancet Oncol. 2023;24:e255-e69. doi: 10.1016/S1470-2045(23)00159-6. PubMed PMID: 37269857.
  44. Kapinos KA, Hu E, Trivedi J, Geethakumari PR, Kansagra A. Cost-Effectiveness Analysis of CAR T-Cell Therapies vs Antibody Drug Conjugates for Patients with Advanced Multiple Myeloma. Cancer Control. 2023;30:10732748221142945. doi: 10.1177/10732748221142945. PubMed PMID: 36651055; PubMed Central PMCID: PMCPMC9869188.
  45. Subklewe M. BiTEs better than CAR T cells. Blood Adv. 2021;5:607-12. doi: 10.1182/bloodadvances.2020001792. PubMed PMID: 33496755; PubMed Central PMCID: PMCPMC7839370.
  46. Du Z, Zhu S, Zhang X, Gong Z, Wang S. Non-Conventional Allogeneic Anti-BCMA Chimeric Antigen Receptor-Based Immune Cell Therapies for Multiple Myeloma Treatment. Cancers (Basel). 2023;15. doi: 10.3390/cancers15030567. PubMed PMID: 36765526; PubMed Central PMCID: PMCPMC9913487.
  47. Usmani SZ, Karlin L, Benboubker L, Nahi H, San-Miguel J, Trancucci D, et al. Durability of responses with biweekly dosing of teclistamab in patients with relapsed/refractory multiple myeloma achieving a clinical response in the majesTEC-1 study. American Society of Clinical Oncology. 2023. doi: 10.1016/S2152-2650(23)01410-6.
  48. Center for Drug Evaluation and Research [Internet]. Talquetamab-tgvs for relapsed or refractory multiple myeloma. U.S. Food and Drug Administration. [Cited 10 August 2023]. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-talquetamab-tgvs-relapsed-or-refractory-multiple-myeloma
  49. Hua G, Scanlan R, Straining R, Carlson DS. Teclistamab-cqyv: The First Bispecific T-Cell Engager Antibody for the Treatment of Patients With Relapsed or Refractory Multiple Myeloma. J Adv Pract Oncol. 2023;14:163-71. doi: 10.6004/jadpro.2023.14.2.7. PubMed PMID: 37009408; PubMed Central PMCID: PMCPMC10062534.
  50. Hansen DK, Sidana S, Peres LC, Colin Leitzinger C, Shune L, Shrewsbury A, et al. Idecabtagene Vicleucel for Relapsed/Refractory Multiple Myeloma: Real-World Experience From the Myeloma CAR T Consortium. J Clin Oncol. 2023;41:2087-97. doi: 10.1200/JCO.22.01365. PubMed PMID: 36623248; PubMed Central PMCID: PMCPMC10082273.
  51. van de Donk NWCJ, Garfall A, Benboubker L, Uttervall K, Groen K, Rosiñol Dachs L, et al. P911: Evaluation of Prophylactic Tocilizumab (TOCI) For the Reduction of Cytokine Release Syndrome (CRS) To Inform the Management of Patients (Pts) Treated with Teclistamab In Majestec-1. HemaSphere. 2023;7:e43149cb. doi: 10.1097/01.HS9.0000970548.43149.cb.
  52. van de Donk NW, Moreau P, Garfall AL, Bhutani M, Oriol A, Nooka AK, et al. Long-term follow-up from MajesTEC-1 of teclistamab, a B-cell maturation antigen (BCMA) x CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma (RRMM). American Society of Clinical Oncology. 2023. doi: 10.1016/S2152-2650(23)00857-1.
Iranian Journal of Medical Sciences

Articles InPress, Corrected Proof
Available Online from 05 October 2024
Files
History
  • Received: 25 February 2024
  • Revised: 16 May 2024
  • Accepted: 07 July 2024
Share
How to cite
Statistics