Innovations in the Treatment of Relapsed or Refractory Multiple Myeloma: BCMA-Targeted CAR T-Cell Therapies
Multiple myeloma (MM) is a hematological malignancy resulting from the abnormal accumulation of plasma cells. It constitutes approximately 10% of all hematological cancers.1 The disease unfolds through a spectrum of stages, from monoclonal gammopathy of undetermined significance to smoldering MM, which can then progress to active MM and, in severe instances, plasma cell leukemia. This progression is associated with genomic clonal expansion and evolution as well as immunosuppression in the bone marrow milieu.2 Diverse immune mechanisms — including disruptions within B cells, T cells, and natural killer cells; deficiencies in antigen presentation; and the activation of transforming growth factor-β — orchestrate the propagation of MM cells, resulting in suppressed interleukin-2 production and subsequent T cell inhibition, all of which contribute to the development of impaired tumor-specific immune response.1 MM represents 2% of both cancer diagnoses and deaths in the United States, and its incidence has risen by 40% in the US and 126% globally since 1990. The incidence and mortality from MM in the US are available in Figure 1.3
Therapeutic Challenges
While traditional approaches like surgery, radiotherapy, and chemotherapy have improved outcomes for patients with MM, the challenge of achieving a comprehensive treatment strategy for patients with relapsed and refractory MM (RRMM) remains.1
In the management of RRMM, the current standard of care is a multidrug regimen that potentially incorporates a proteasome inhibitor, an immunomodulatory drug, a monoclonal antibody (mAb), and a corticosteroid. However, patients may become resistant to these treatments, leading to less response depth and durability with each successive line of therapy (LoT). This challenge is particularly pronounced for patients who are refractory to multiple drug classes, who experience suboptimal outcomes; 1 study found that patients with RRMM who were refractory to fewer than 3 prior LoT had a median overall survival (OS) of 11.2 months, while patients who were refractory to 5 or more treatments had an OS of 5.6 months.4
Revolutionizing the MM Treatment Landscape
Therapeutic mAbs, such as daratumumab and elotuzumab, play a crucial role in the treatment of MM through their ability to activate immune effectors, which then eliminate target MM cells through host defense mechanisms, such as antibody-dependent cell cytotoxicity, complement-dependent cytotoxicity, and antibody-dependent cell-mediated phagocytosis. The advent of mAbs marked a transformative shift in the MM treatment paradigm, and these therapies demonstrate high efficacy and durability. However, the molecules targeted by daratumumab and elotuzumab, including activated B and T lymphocytes, monocytes, natural killer cells, and other effector cells, are also expressed on normal tissues. Natural killer cell depletion following daratumumab treatments may reduce its continued efficacy, and the nonspecific toxicity of these drugs also limits their clinical utility.2
Personalized immunotherapy using chimeric antigen receptor (CAR) T-cell therapy has emerged as an extremely promising avenue for the treatment of RRMM. CAR T-cell therapy involves the genetic modification of a patient’s own T cells to recognize and eliminate malignant plasma cells.4 Recently, B cell maturation antigen (BCMA)-targeted CAR T-cell therapies have emerged as a focal point for novel immunotherapeutic approaches. BCMA is a cell-surface receptor exclusively presented on the surface of B cell lineage cells, where it plays an important role in B cell development, survival, proliferation, and differentiation into plasma cells. BCMA exhibits variable expression, is notably heightened in cancerous B cells, and has also been demonstrated to play an important role in the development of several hematological malignancies; notably, BCMA is overexpressed in all MM, and it has been established that BCMA plays a key role in the pathogenesis of MM.5 The combination of these factors makes BMCA an extremely compelling target for MM therapies, and several studies of BMCA-targeted CAR T-cell therapies for patients with RRMM have reported remarkable overall response rates (ORR) of over 80%.2
The demonstrated success of BMCA-targeted CAR T-cell therapies has led to the approval by the US Food and Drug Administration (FDA) of 2 drugs for patients with RRMM: idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel).6,7
BMCA-Targeted Therapies for RRMM
Ide-cel is a second-generation CAR T-cell therapy.8 It was the first cellular therapy approved for treatment of RRMM.6 Ide-cel was approved based on the results of the phase 2 KarMMa trial (ClinicalTrials.gov identifier: NCT03361748), which involved 128 patients with a median of 6 prior LoT; significantly, 84% of patients in the KarMMa trial were triple-class refractory. In this trial, ide-cel showcased impressive efficacy, achieving an ORR of 73% across all treated patients and an even higher 81% in those receiving the highest dose (450 x 106). Complete response (CR) rates were also notable, with 33% of all patients and 39% of patients receiving the highest dose achieving CR and a median time to first response of 1 month. Median progression-free survival (PFS) was 8.8 months in all patients and 12.1 months in patients receiving the highest dose, and the median OS was 24.8 months. While 84% of all patients and 96% of patients receiving the highest dose experienced cytokine release syndrome (CRS), the majority were classified as only grade 1 or 2, with fewer than 6% of patients experiencing CRS at grade 3 or above. Neurological complications were reported in 18% of patients, but these events were also mostly classified as grade 1 or 2. However, cytopenia was a frequently observed complication of treatment, and it was not found to be dose-related.8
Cilta-cel is another second-generation CAR T-cell therapy. It was approved based on the remarkable outcomes of the CARTITUDE-1 study (ClinicalTrials.gov identifier: NCT03548207),7,8 which included 97 patients with a median of 6 prior LoT, of whom 87.6% were triple-class refractory. In this study, cilta-cel exhibited remarkable efficacy, demonstrating an ORR of 97.9%, with 82.5% of patients achieving a stringent complete response (sCR). The response to cilta-cel was also found to be highly durable, with a 2-year PFS of 60.5% and a 2-year OS of 71% in patients who had achieved sCR. However, neutropenia was present in 96% of patients receiving cilta-cel, and 95% of these patients experienced neutropenia at grade 3 or higher. CRS was also present in 95% of patients, mostly at grade 1 or 2. Neurological events were reported in slightly more than 20% of patents, including 16 presenting with immune effector cell-associated neurotoxicity syndrome.8
Comparisons of Ide-cel and Cilta-cel
While both ide-cel and cilta-cel demonstrate high response rates and durable responses, some differences between them should be taken into account when deciding on the best choice of treatment. They are both genetically engineered autologous second-generation CAR T-cell agents with anti-BCMA antibodies in the ectodomain to direct against BCMA antigens, but ide-cel contains a single mouse-derived binding domain to target only 1 epitope of the BMCA antigen, while cilta-cel has a unique CAR design expressing 2 camelid heavy chains of mAbs to bind with 2 separate epitopes of the BCMA antigen. Cilta-cel, therefore, has higher target-cell binding avidity, enhanced activity, and lowered immunogenicity compared to ide-cel.5
A head-to-head clinical trial comparing the efficacy of ide-cel and cilta-cel has yet to be performed, but a matching-adjusted indirect comparison study found that cilta-cel was associated with statistically significant improvements in ORR, CR, duration of response, and PFS over ide-cel; it also found that cilta-cel demonstrated improved OS, but this finding had a confidence interval overlapping 1.9 More information on ide-cel and cilta-cel can be found in Table 1.10,11
Ongoing Trials
The effectiveness of ide-cel is being evaluated in 2 ongoing studies: KarMMa-2 (ClinicalTrials.gov identifier: NCT030601078), which is estimated to be completed by the end of 2030, and a study of whether ide-cel (bb2121) can be made from people with MM who have had a hematopoietic cell transplant (ClinicalTrials.gov identifier: NCT05393804).
Cilta-cel’s efficacy continues to be explored in ongoing trials, such as CARTITUDE-2 (ClinicalTrials.gov identifier: NCT04133636), CARTITUDE-4 (ClinicalTrials.gov identifier: NCT04181827), CARTITUDE-5 (ClinicalTrials.gov identifier: NCT04923893), and CARTITUDE-6 (ClinicalTrials.gov identifier: NCT05257083). Patients from these trials will also be monitored for up to 15 years in the CARTinue study (ClinicalTrials.gov identifier: NCT050201781) to evaluate long-term efficacy and safety.
References
1. Mishra AK, Gupta A, Dagar G, et al. CAR-T-cell therapy in multiple myeloma: B-cell maturation antigen (BCMA) and beyond. Vaccines (Basel). 2023;11(11):1721. doi:10.3390/vaccines11111721
2. Tai YT, Anderson KC. B cell maturation antigen (BCMA)-based immunotherapy for multiple myeloma. Expert Opin Biol Ther. 2019;19(11):1143-1156. doi:10.1080/14712598.2019.1641196
3. Padala SA, Barsouk A, Barsouk A, et al. Epidemiology, staging, and management of multiple myeloma. Med Sci (Basel). 2021;9(1):3. doi:10.3390/medsci9010003
4. 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;41(6):1265-1274. doi:10.1200/JCO.22.00842
5. Chekol Abebe E, Yibeltal Shiferaw M, Tadele Admasu F, Asmamaw Dejenie T. Ciltacabtagene autoleucel: the second anti-BCMA CAR T-cell therapeutic armamentarium of relapsed or refractory multiple myeloma. Front Immunol. 2022;13:991092. doi:10.3389/fimmu.2022.991092
6. FDA approves idecabtagene vicleucel for multiple myeloma. News release. US Food and Drug Administration. March 29, 2021. Accessed January 31, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-idecabtagene-vicleucel-multiple-myeloma
7. FDA approves ciltacabtagene autoleucel for relapsed or refractory multiple myeloma. News release. US Food and Drug Administration. March 7, 2022. Accessed January 31, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ciltacabtagene-autoleucel-relapsed-or-refractory-multiple-myeloma
8. Rodriguez-Otero P, San-Miguel JF. Cellular therapy for multiple myeloma: what’s now and what’s next. Hematology Am Soc Hematol Educ Program. 2022;2022(1):180-189. doi:10.1182/hematology.2022000396
9. Martin T, Usmani SZ, Schecter JM, 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(10):1779-1788. doi:10.1080/03007995.2021.1953456
10. Abecma®. Prescribing information. Celgene Corporation/Bristol-Myers Squibb Company; 2021. Accessed January 26, 2024. https://packageinserts.bms.com/pi/pi_abecma.pdf
11. Carvykti®. Prescribing information. Janssen Biotech, Inc; 2022. Accessed January 26, 2024. https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/CARVYKTI-pi.pdf
Published by Haymarket’s Clinical Content Hub. The editorial staff of Oncology Nurse Advisor had no role in this content‘s production.
Reviewed February 2024
