Exploring the Frontier:CAR-T Trials for Multiple Myeloma and Their Transformative Impact
Exploring the Frontier:CAR-T Trials for Multiple Myeloma and Their Transformative Impact
Multiple myeloma (MM) treatment has made remarkable progress over the past two decades, significantly improving patient survival, but the disease is still considered incurable. Therefore, new treatment strategies are urgently needed. CAR-T cell therapy may be the most promising immunotherapy for cancer treatment in general and MM treatment in particular.
Indeed, CAR-T cell therapy, which has become the “hope of the village” for MM patients, has lived up to expectations, showing unprecedented high response rates in multiple clinical trials. This has led to the approval of two BCMA-targeted CAR-T cell products, idecabtagene vicleucel (Ide-cel) and ciltacabtagene autoleucel (Cilta-cel), for treating relapsed/refractory multiple myeloma in patients who have undergone complex prior therapies.
Since then, CAR-T cell therapy for multiple myeloma (MM) has received increasing attention from people inside and outside the industry. Recently, Strassl I et al. from Ordensklinikum Linz Hospital in Austria published a review article titled “The preclinical discovery and clinical development of ciltacabtagene autoleucel (Cilta-cel) for the treatment of multiple myeloma” in the journal Expert Opinion on Drug Discovery. The article reviews the development history of CAR-T cells (with a focus on Cilta-cel), summarizes the latest clinical data on Cilta-cel, and discusses strategies to further improve its potency and reduce its toxicity.
BCMA has become a major target for CAR-T cell therapy in multiple myeloma
BCMA (B-cell maturation antigen, also known as CD269 or TNFRSF17) has become a major target for CAR-T cell therapy in multiple myeloma patients. It is a receptor for the APRIL ligand and is expressed on late memory B cells, short-lived plasmablasts, and long-lived plasma cells. BCMA is highly expressed on MM cells compared to normal plasma cells and promotes tumor cell growth, drug resistance, and immunosuppression in the bone marrow microenvironment.
In 2016, the first clinical trial of BCMA-targeted CAR-T cell therapy reported promising activity in two MM patients.
On March 27, 2021, the U.S. Food and Drug Administration (FDA) approved idecabtagene vicleucel (Ide-cel) developed by Bristol-Myers Squibb and Bluebird BIO; on February 28, 2022, the FDA approved the second BCMA-targeted CAR-T cell therapy – ciltacabtagene autoleucel (Cilta-cel). Both CAR-T cells were approved for treating adult patients with relapsed/refractory multiple myeloma who had received ≥4 prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. Therefore, both Ide-cel and Cilta-cel are theoretically available for commercial use.
Molecular structure of Cilta-cel: unique bispecific design for stronger cancer cell affinity
Cilta-cel consists of an extracellular domain, a transmembrane domain, and an intracellular domain. The extracellular domain of Cilta-cel contains two camelid single-domain antibodies linked by a flexible hinge region, targeting two different epitopes of the BCMA antigen. Unlike Ide-cel, which targets only one epitope, Cilta-cel’s unique bispecific design aims to enhance its high affinity for BCMA-expressing cancer cells, thereby increasing anti-MM activity and reducing immunogenicity.
The latest clinical data on Cilta-cel
LEGEND-2 trial
Cilta-cel (formerly known as LCAR-B38M) was first evaluated in the domestic phase 1 LEGEND-2 clinical trial [NCT03090659]. Prior to infusion, MM patients had received an average of three lines of therapy.
The results showed that 65 out of 74 patients responded to the therapy, with an objective response rate (ORR) of 88%. Fifty-four patients (73%) achieved a complete response (CR). Of the 40 minimal residual disease (MRD)-evaluable patients, 39 (97.5%) achieved MRD negativity, including 35 patients who achieved a stringent complete response (sCR).
In terms of safety, 91.9% of patients experienced cytokine release syndrome (CRS), with 8.1% experiencing grade ≥3 CRS, and one patient died due to CRS; one patient experienced grade 1 neurotoxicity. There were no signs or symptoms of parkinsonism. Four patients reported secondary primary malignancies (SPMs).
The latest survival data, with a median follow-up of 65.4 months, showed that 44.6% (n = 33/74) of patients were still alive, and 16.2% (n = 12/74) were progression-free. The 5-year progression-free survival (PFS) rate was 21.7%, and the 5-year overall survival (OS) rate was 49.1%. The median overall survival reached 55.8 months for the first time at the data cutoff date.
CARTITUDE-1 (MMY2001) trial
The CARTITUDE-1 trial [NCT03548207] was a single-arm phase 1b/2 study that ultimately led to the approval of Cilta-cel. The trial enrolled a total of 113 MM patients who had undergone complex prior therapies, with 97 patients having received an average of 6 prior lines of therapy, and 87.6% being triple-refractory (refractory to a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 mAb).
The latest follow-up results from CARTITUDE-1 (median follow-up of 33.4 months) showed that Cilta-cel achieved unprecedented levels of response rates and response durability: the objective response rate (ORR) was 97.9% (with 82.5% achieving a complete response); the median progression-free survival (PFS) was 34.9 months, and the median overall survival (OS) was not reached. An estimated 62.9% of patients were expected to be alive at the 3-year follow-up. Among the 57 (59%) MRD-evaluable patients, 53 (93%) achieved MRD negativity.
In terms of safety, 92 out of 97 patients (95%) experienced CRS, with all cases resolving except for one grade 5 CRS and hemophagocytic lymphohistiocytosis (HLH). Twenty patients (21%) experienced neurotoxicity. Hematologic adverse events were relatively common. There were 14 deaths in the study, 6 due to treatment-related adverse events, 5 due to disease progression, and 3 due to adverse events unrelated to treatment.
Overall, Cilta-cel achieved the longest progression-free survival to date – nearly 3 years – in treating heavily pretreated MM patients.
CARTITUDE-2 (MMY2003) trial
The ongoing phase 2 CARTITUDE-2 trial [NCT04133636] with multiple cohorts evaluated the use of Cilta-cel at earlier treatment stages than CARTITUDE-1. All participants received a single infusion of Cilta-cel (target dose of 0.75 × 10^6 viable CAR-positive T cells/kg) after lymphodepletion. The primary endpoint was MRD negativity at the 10^-5 threshold.
In cohort A, 20 MM patients who had received 1-3 prior lines of therapy and were Lenalidomide-refractory received Cilta-cel infusion. The latest follow-up results (median follow-up of 29.9 months) showed that the MRD negativity rate was 100% in 17 evaluable patients, the objective response rate (ORR) was 95% (≥90% complete response, ≥95% very good partial response), with a median time to first response and best response of 1 month and 3.3 months, respectively.
Responses continued to deepen over time. The median progression-free survival (PFS) was not reached. The median PFS rate at 24 months was 75%.
In terms of safety, CRS was mainly grade 1/2, with 2 patients experiencing grade 3/4 CRS. No movement and neurocognitive treatment-emergent adverse events (MNTs) were observed. Three patients experienced other late neurotoxicities (peripheral neuropathy, anosmia, facial palsy). One death was attributed to COVID-19/pneumonia (treatment-related), three deaths were due to disease progression, and one death was due to sepsis (unrelated to treatment).
Cohort B studied the activity of Cilta-cel in high-risk functional multiple myeloma patients (n = 19) who relapsed within 12 months after receiving standard therapy. The latest follow-up results (median follow-up of 27.9 months) showed that 93% (14/15) of the MRD-evaluable patients achieved MRD negativity, and the objective response rate (ORR) was 100% (≥100% representing a very good partial response; ≥90% representing a complete response). The median time to first response was 0.95 months, and the median time to best response was 5.1 months. The median progression-free survival (PFS) was not reached. The 24-month PFS rate was 73.3%, and the 12-month PFS rate was 90%.
In terms of safety, the most common adverse events were hematological toxicities (grade 3/4). CRS occurred in 84.2% of patients (1 case was grade 4). Immune effector cell-associated neurotoxicity syndrome (ICANS; grade 1) and other neurotoxicities (grade 3/4) occurred in 5.3% of patients, respectively. Three patients died due to disease progression.
In Cohort C, patients had progressive disease despite receiving proteasome inhibitors, immunomodulatory drugs, anti-CD38 antibodies, and non-cellular anti-BCMA immunotherapy. After receiving Cilta-cel treatment, the overall MRD negativity rate was 35%; the ORR was 60%. The median duration of response and median PFS were 11.5 months and 9.1 months, respectively.
The most common adverse events were hematological toxicities. CRS occurred in 12 patients (60%) (all grade 1-2); 4 cases of ICANS occurred (2 cases were grade 3-4); no Parkinsonism was observed. Seven patients died (3 due to disease progression, 4 due to adverse events).
Cartitude-4 (MMY3002) Trial
In the results from the global, multicenter phase 3 trial [NCT04181827] with a median follow-up of 15.9 months, Cilta-cel demonstrated significant superiority over standard therapy (pomalidomide/bortezomib/dexamethasone or daratumumab/pomalidomide/dexamethasone) in lenalidomide-refractory multiple myeloma patients (who had received 1-3 prior lines of therapy).
In terms of efficacy, the 12-month PFS rates were 76% for the Cilta-cel group and 49% for the standard therapy group, with median PFS of not reached (NR) and 11.8 months, respectively (HR=0.26). The ORRs were 99.4% and 67%; the CR rates were 86.4% and 22%, respectively. The MRD negativity rate was 60.6% in the Cilta-cel group and 15.6% in the standard therapy group, with an odds ratio of 8.7 and a hazard ratio of 2.2.
Although overall survival data are not yet mature, the hazard ratio of 0.78 supports the efficacy of Cilta-cel treatment.
In terms of safety, CRS occurred in 76.1% of patients (mostly grade 1/2, with only 2 patients having grade 3), and ICANS was limited to 4.5% of patients, with grades 1/2. Other neurotoxicities were observed in 17% of patients, with a higher incidence, including cranial nerve palsies (9.1%), peripheral neuropathy (2.8%), and one MNT event.
These data demonstrating favorable efficacy in the CARTITUDE-4 trial suggest that Cilta-cel is likely to become the new standard of care for lenalidomide-refractory multiple myeloma patients at first relapse, with anticipated approval in this setting by 2024.
CARTIFAN-1 Trial
The pivotal phase 2 CARTIFAN-1 trial [NCT03758417] evaluated the efficacy and safety of Cilta-cel in treating relapsed/refractory multiple myeloma patients in China who had received ≥3 prior lines of therapy, including immunomodulatory drugs and proteasome inhibitors.
In terms of efficacy, at a median follow-up of 18 months, the ORR was 89.6%, with a median time to first response of approximately 1 month; over 77.1% achieved a complete response. The PFS rate and overall survival (OS) rate were 66.8% and 78.7%, respectively.
Hematological toxicities were common. CRS occurred in 97.9% of patients (35.4% were grade 3/4), and two patients experienced neurotoxicity (grade 1 and grade 2, respectively). Infections occurred in 85.4% of patients (37.5% were grade 3/4).
Ongoing Phase 3 CARTITUDE-6 Trial
The randomized phase 3 CARTITUDE-6 trial [NCT05257083] aims to compare Cilta-cel infusion after daratumumab, pomalidomide, lenalidomide, and dexamethasone (Dara-VRd) versus autologous stem cell transplantation after Dara-VRd in newly diagnosed multiple myeloma (NDMM) patients. This study is currently recruiting.
Comparison of Cilta-cel with Other Treatments
Several studies have indirectly compared the data for Cilta-cel from the CARTITUDE-1 trial with real-world data from the MAMMOTH and prospective LocoMMotion studies, as well as data from the Flatiron Health database. These studies revealed significant advantages for Cilta-cel in terms of overall survival, progression-free survival, time to next treatment (TTNT), and objective response rates compared to other treatment options.
Adverse Events Associated with Cilta-cel and Management Strategies
CAR-T-cell therapies have specific toxicities, primarily cytokine release syndrome (CRS) and neurotoxicity. In the various studies of Cilta-cel, the incidence of CRS ranged from 60.0% to 97.9%; in most studies, the incidence of adverse events ≥ grade 3 was below 10.0%. ICANS presentations were mostly mild and resolved within days without residual effects.
In contrast, late neurotoxicities were almost unpredictable, partially irreversible, and difficult to treat. Compared to Ide-cel, Parkinsonism-like symptoms were more likely to be observed after Cilta-cel treatment. These neurotoxicity events, known as movement and neurocognitive treatment-emergent adverse events (MNTs), can lead to irreversible neurological conditions and severely impact daily living. Interventions such as carbidopa/levodopa were ineffective in symptom improvement; however, measures to reduce CAR-T-cell activity (such as cyclophosphamide or intrathecal chemotherapy) have shown efficacy in individual cases.
Additionally, some studies also reported cranial nerve palsies, particularly facial nerve palsy, and peripheral neuropathy. These neurotoxicities are life-threatening, long-lasting, and irreversible. They cannot be accurately predicted and may occur in patients without risk factors, necessitating close monitoring by physicians.
The incidence of secondary primary malignancies (SPMs) varied across studies, with most reporting rates below 10%. Recent reports of lymphomas following CAR-T-cell therapies targeting BCMA and CD19 have prompted an FDA warning. Lifelong monitoring and screening for secondary malignancies, as well as testing for CAR-Transgenes in case of T-cell lymphomas, are recommended.
Another emerging and concerning adverse reaction after CAR-T-cell therapy is immune effector cell-associated hemophagocytic lymphohistiocytosis (IEC-HS). Common manifestations of IEC-HS include elevated ferritin, elevated liver transaminases, and decreased phagocytes in the bone marrow or other tissues. It typically occurs after CRS. Anakinra and corticosteroids can be used for treatment; in severe cases, ruxolitinib or emapalumab may also be used.
In addition to these CAR-T-cell-specific toxicities, hematological toxicities are also common, including neutropenia, lymphopenia, and thrombocytopenia, which may persist for an extended period in some cases. Due to leukopenia and hypogammaglobulinemia, hematological toxicities may lead to frequent and potentially life-threatening infections. Autologous stem cell therapy can promote hematopoietic recovery after CAR-T-cell treatment in patients with relapsed/refractory multiple myeloma and may be an effective treatment for hematological toxicities and their infectious complications.
Conclusion
With the approval of the first CAR-T-cell product, a new generation of immunotherapies is transforming the treatment landscape for MM. In the pivotal CARTITUDE-1 trial, Cilta-cel achieved unprecedented response rates in heavily pretreated MM patients, with these results being truly encouraging. This further led to the approval of Cilta-cel in 2022 for the treatment of RRMM, with ≥4 (FDA) and ≥3 (EMA) prior lines of therapy, including proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies. Recent data have also confirmed the effectiveness of these findings in real-world applications. Additionally, Cilta-cel is gradually becoming the new standard for early treatment of MM.
In the not-too-distant future, CAR-T-cells are likely to become part of frontline treatment for high-risk MM patients and may even surpass autologous stem cell transplantation in newly diagnosed MM. Despite current limitations, including durability concerns, toxicities, high costs, and poor accessibility, for patients without high-risk features, CAR-T-cell therapy has made long-term disease-free survival and potential cure a possibility for MM.
References
Strassl, Irene, and Klaus Podar. “The preclinical discovery and clinical development of ciltacabtagene autoleucel (Cilta-cel) for the treatment of multiple myeloma.” Expert opinion on drug discovery vol. 19,4 (2024): 377-391. doi:10.1080/17460441.2024.2319672
Content Source:细胞知聊