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Role of CARVYKTI® in the treatment of Multiple Myeloma



Multiple myeloma (MM) is one of the most common haematological cancers, with an incidence rate of 10%. As per the GLOBOCON 2022 update, the age standardised rate (ASR) of mortality was 1.1 of 100,000 people globally. The majority of MM cases originate from a precancerous asymptomatic stage known as monoclonal gammopathy of undetermined significance (MGUS) or an advanced intermediate asymptomatic stage called smoldering multiple myeloma (SMM). It is estimated that 5% of the population aged 50 or older have MGUS stage and SMM is found in approximately 0.5% of population above the age of 40 (1,2).

The understanding of the pathophysiology and the application of therapies such as monoclonal antibodies, proteasome inhibitors, immunomodulatory medications, and nuclear export inhibitors have improved the prognosis for individuals with MM. However, novel therapeutic methods are need of the hour for relapsed or refractory (RRMM) patients with drug resistance, extramedullary disease or high-risk cytogenetic abnormalities such TP53 mutation, del (17p), gain (1q), and t (4;14). These individuals have poor prognoses and frequent clonal evolution (3).


Chimeric Antigen Receptor (CAR) T cell therapy


Over the past twenty years, the treatment of haematological malignancies has been greatly improved by CAR-T cell therapy. With co-stimulatory domains added to higher-generation designs for enhanced T cell persistence and anti-tumour activity, CAR-T cells are designed to target overexpressed tumour cell surface antigens. In the USA, there are now six CAR-T cell treatments that have received FDA approval. Due to its increased efficacy, low degree of toxicity, and capacity to induce treatment-free remission, CAR-T cell therapy has been shown through long-term data studies to be effective in the management of haematological tumours (4,5).


Ciltacabtagene autoleucel (CARVYKTI®)


T cells from the patient is genetically altered to produce CARs as part of the personalized therapy known as CARVYKTI® containing Ciltacabtagene autoleucel. The B cell maturation antigen (BCMA) on the MM cells can then be bound by the CAR, causing the cells to be destroyed. Adult patient’s refractory to lenalidomide who have undergone at least one previous line of therapy consisting of an immunomodulatory drug and a proteasome inhibitor may be considered candidates for this treatment. With the FDA approval, Ciltacabtagene autoleucel is now the only medicine that targets the BCMA and is authorised for the treatment of MM patients, even at the initial relapse (6).


Clinical Evidence - CARTITUDE-1


Based on the CARTITUDE-1 study, the FDA approved the use of Ciltacabtagene autoleucel in February 2022 for patients with relapsed or resistant MM following four or more lines of treatment. The study found a complete response rate of 67%, an overall response rate of 97%, a 12 months overall survival rate of 89%, and a progression-free rate of 77% (See Figure 1). The study also reported an improvement in health-related-quality-of-life (7,8). The outcomes of the research conducted on Chinese (CARTIFAN-1) and Japanese (CARTITUDE-1) patients provided similar results (9,10).


Clinical Evidence - CARTITITUDE-4


The efficacy of Ciltacabtagene autoleucel was compared to standard care group (Pomalidomide, Bortezomib, and Dexamethasone (PVd) or Daratumumab, Pomalidomide, and Dexamethasone (DPd)) in the CARTITUDE-4 Phase 3 study. Progression-free survival (PFS) was the primary outcome (11). 


In the standard-care group, the median PFS was 11.8 months, while it was not achieved in the Ciltacabtagene autoleucelgroup. PFS was 75.9% at 12 months in the Ciltacabtagene autoleucel group, whereas it was 48.6% in the standard-care group (11). 


CAR-T versus Non-CAR-T therapies


A trial comparing three non-CAR-T therapies (DREAMM-2, STORM Part 2, and HORIZON) with CARTITUDE-1 was conducted using MAICs. [D1] Following adjustment, Ciltacabtagene autoleucel-treated patients had 3.1-fold increase in ORR, 10.3-fold increase in CR, 74% reductions in disease progression, and 47% reduction in the risk of mortality (12). 

A similar trial compared physician-selected medicine with Ciltacabtagene autoleucel (CARTITUDE-1) was conducted by including an external control arm from patients enrolled in continued follow-up trials with daratumumab (POLLUX, CASTOR, and EQUULEUS). The results reaffirmed Ciltacabtagene autoleucel's superiority (13).


Conclusion


Ciltacabtagene autoleucel has shown remarkable efficacy in treating relapsed or refractory multiple myeloma, outperforming traditional therapies. With impressive response rates, extended progression-free survival, and enhanced overall survival, Ciltacabtagene autoleucel represents a significant advancement in multiple myeloma treatment. Its ability to deliver profound, lasting responses and improved quality of life highlights its transformative potential for patients with advanced disease.


About the Author


Ms. Tanvi Goel is a Medical Writer with a master’s degree in pharmaceutical science. Tanvi has experience in scientific and regulatory writing and is eager to learn more about novel pharmacological agents. 


Reference


  1. Ferlay J, Colombet M, Soerjomataram I, et al. Cancer statistics for the year 2020: An overview. Int J Cancer. 2021 Apr 5. 

  2. Rajkumar SV. Multiple myeloma: 2024 update on diagnosis, risk-stratification, and management. Am J Hematol. 2024 Sep;99(9):1802-1824. 

  3. Zhang X, Zhang H, Lan H, et al. CAR-T cell therapy in multiple myeloma: Current limitations and potential strategies. Front Immunol. 2023 Feb 20;14:1101495. 

  4. Chohan KL, Siegler EL, Kenderian SS. CAR-T Cell Therapy: the Efficacy and Toxicity Balance. Curr Hematol Malig Rep. 2023 Apr;18(2):9-18. doi: 10.1007/s11899-023-00687-7. Epub 2023 Feb 10. 

  5. Cappell KM, Kochenderfer JN. Long-term outcomes following CAR T cell therapy: what we know so far. Nat Rev Clin Oncol. 2023 Jun;20(6):359-371. 

  6. CARVYKTI® is the First and Only BCMA-Targeted Treatment Approved by the U.S. FDA for Patients with Relapsed or Refractory Multiple Myeloma Who Have Received at Least One Prior Line of Therapy. Available at: https://www.jnj.com/media-center/press-releases/carvykti-is-the-first-and-only-bcma-targeted-treatment-approved-by-the-u-s-fda-for-patients-with-relapsed-or-refractory-multiple-myeloma-who-have-received-at-least-one-prior-line-of-therapy#:~:text=CARVYKTI%20%C2%AE%20%28cilta-cel%29%20received%20U.S.%20Food%20and%20Drug,immunomodulatory%20agent%2C%20and%20who%20are%20refractory%20to%20lenalidomide Accessed on: 01 September 2024 

  7. 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. Lancet. 2021 Jul 24;398(10297):314-324. 

  8. Martin T, Lin Y, Agha M, et al. Health-related quality of life in patients given ciltacabtagene autoleucel for relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b-2, open-label study. Lancet Haematol. 2022 Dec;9(12):e897-e905. 

  9. Mi JQ, Zhao W, Jing H, et al. Phase II, Open-Label Study of Ciltacabtagene Autoleucel, an Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor-T-Cell Therapy, in Chinese Patients With Relapsed/Refractory Multiple Myeloma (CARTIFAN-1). J Clin Oncol. 2023 Feb 20;41(6):1275-1284. 

  10. Ri M, Suzuki K, Ishida T, et al. Ciltacabtagene autoleucel in patients with relapsed/refractory multiple myeloma: CARTITUDE-1 (phase 2) Japanese cohort. Cancer Sci. 2022 Dec;113(12):4267-4276. 

  11. Alsdorf W, Diels J, Ghilotti F, et al. Efficacy of CARVYKTI in CARTITUDE-4 versus other conventional treatment regimens for lenalidomide-refractory multiple myeloma using inverse probability of treatment weighting. J Comp Eff Res. 2024 Sep;13(9):e240080. 

  12. Weisel K, Krishnan A, Schecter JM, et al. Matching-Adjusted Indirect Treatment Comparison to Assess the Comparative Efficacy of Ciltacabtagene Autoleucel in CARTITUDE-1 Versus Belantamab Mafodotin in DREAMM-2, Selinexor-Dexamethasone in STORM Part 2, and Melphalan Flufenamide-Dexamethasone in HORIZON for the Treatment of Patients With Triple-Class Exposed Relapsed or Refractory Multiple Myeloma. Clin Lymphoma Myeloma Leuk. 2022 Sep;22(9):690-701. 

  13. Weisel K, Martin T, Krishnan A, et al. Comparative Efficacy of Ciltacabtagene Autoleucel in CARTITUDE-1 vs Physician's Choice of Therapy in the Long-Term Follow-Up of POLLUX, CASTOR, and EQUULEUS Clinical Trials for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma. Clin Drug Investig. 2022 Jan;42(1):29-41. 

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