Feature: B-Cell Maturation Antigen Targeting CAR T-Cell Therapy in Relapsed/Refractory Multiple Myeloma

Abigail Shockley, PharmD
PGY2 Hematology/Oncology Pharmacy Resident
Medical University of South Carolina
Charleston, SC

James Davis, PharmD, BCOP
Assistant Professor – MUSC College of Pharmacy
Malignant Hematology Clinical Pharmacy Specialist
Medical University of South Carolina
Charleston, SC

Background
Multiple myeloma is characterized by malignant proliferation of plasma cells in the bone marrow.^1-4 These abnormal plasma cells overproduce immunoglobulins causing protein accumulation, bone marrow failure, bone destruction, and end-organ damage.¹ Multiple myeloma is the second most common hematologic cancer and accounts for 1.8% of all cancers with an estimated 32,000 new cases in the United States in 2020, and more than 12,000 deaths.^2-4 Although many patients obtain deep and durable remissions with induction therapy, relapse is inevitable in this incurable disease.

There are many available treatments for relapsed/refractory (R/R) disease but ideal sequencing remains a challenge. The National Comprehensive Cancer Network (NCCN) guidelines contain nine different preferred category 1 treatment regimens for these patients.⁴ These treatment combinations consist of multiple agents including: antiCD38 monoclonal antibodies, proteasome inhibitors, immunomodulatory agents, and corticosteroids. With each relapse and subsequent treatment, progression-free survival (PFS) and overall survival (OS) outcomes become shorter.^4,5 The poor prognoses of these patients have led researchers to investigate novel treatment modalities, including chimeric antigen receptor (CAR) T-cell therapy.

CAR T-cell therapy is a type of treatment in which a patient’s T cells are genetically modified in a laboratory to express a CAR that is specifically designed to target select cancer cells’ surface markers. This process is initiated by collecting T-cells from the patient’s blood via leukapheresis. The collected T-cells are then sent to a manufacturing lab for CAR attachment and proliferation. This process generally takes between 4 to 6 weeks. Once the T-cells meet manufacturing specification, the cells are shipped back to the medical center for infusion into the patient. Prior to cell infusion, the patient undergoes lymphodepleting chemotherapy in order to make a favorable environment for T-cell expansion and persistence. After the infusion, the CAR T-cells target, attack, and destroy the cancer.¹

B-cell maturation antigen (BCMA) is a cell surface protein that is a member of the tumor necrosis factor (TNF) receptor family primary expressed on plasma cells. BCMA regulates the maturation of B-cells into plasma cells. Multiple myeloma cells have been shown to overexpress BCMA which leads to malignant plasma cell survival.⁶ BCMA is also undetectable in naïve B-cells, hematopoietic stem cells, and normal non-hematologic tissues. This unique expression of BCMA on myeloma cells has allowed researchers to develop BCMA targeted therapies for myeloma while being able to reduce off-target toxicities.^1,6

Recently, efficacy and safety outcomes of two BCMA targeting CAR T-cell therapies, idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) were published.^7,8 Here, we summarize and discuss the literature for these novel BCMA targeting CAR T-cell therapies.

KarMMa: Idecabtagene Vicleucel

KarMMa was an open-label, multicenter, phase 2 trial that sought to confirm the safety and efficacy of idecabtagene vicleucel in patients with R/R multiple myeloma. One hundred twenty-eight patients aged 33-78 years (median 61) received one infusion of ide-cel at a target dose of 150x106, 300x106, or 450x106 per kilogram CAR-positive T-cells 2 days after receiving lymphodepleting chemotherapy. The median lines of therapy prior to study enrollment were 6 (3-16). Sixteen percent of patients had Revised–International Staging System (R-ISS) stage III disease and 35% had high-risk cytogenetic abnormalities defined as del(17p), t(4;14), or t(14;16). Patients were excluded if they had evidence of plasma cell leukemia, previous allogeneic hematopoietic stem cell transplantation, and/or central nervous system disease.⁷

The primary endpoint was overall response rate (ORR). The secondary endpoint was complete response (CR) or stringent CR (sCR) rates. At a median follow-up of 13.3 months, 73% of patients met the primary outcome of ORR (95% CI 66-81; p<0.001) with 33% obtaining a CR or better. Twenty-six percent of the patients achieved minimal residual disease (MRD) negative status. The median duration of response (DOR) was 10.7 months (95% CI 9.0- 11.3). Median PFS and OS were 8.8 months (95% CI 5.6-11.6) and 19.4 months (95% CI 18.2-could not be estimated), respectively.⁷

Treatment related toxicity was reported in all patients receiving treatment with 99% of patients experiencing a grade ≥3 adverse reaction. The most common high-grade toxicities were neutropenia (89%), anemia (60%), thrombocytopenia (52%), and infections (22%). Other notable toxicities included cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Eighty-four percent of patients experienced low-grade CRS with 5% of patients experiencing grade ≥3 toxicity. The median time to onset of CRS was 1 day (1-12), with a median duration of 5 days (1-63). Eighteen percent of patients experienced ICANS, with 3% of patients experiencing grade ≥3 neurotoxicity. Median time to onset for ICANS was 2 days (1-10), with a median duration of 3 days (1-26).

On March 26, 2021, the FDA granted idel-cel accelerated approval for adult patients with R/R myeloma after 4 or more lines of therapy, including an immunomodulatory agent, a proteasome 4 inhibitor, and an anti-CD38 antibody, based on the results of KarMMa trial.⁷ The NCCN also added idecabtagene vicleucel as a category 2A recommendation based on this approval.^4,7

CARTITUDE-1: Ciltacabtagene Autoleucel

CARTITUDE-1 is a multicenter, open-label, single arm, phase 1b/2 trial that evaluates dosing, safety, and efficacy of ciltacabtagene autoleucel in patients with R/R multiple myeloma. Ninety-seven patients aged 56-68 (median 61) received cilta-cel at a target dose of 0.75x106 CAR-positive T-cells per kilogram after lymphodepleting chemotherapy. Patients were required to have failed previous treatment with at least 3 lines of therapy with the median lines of therapy prior to study enrollment being 6 (4-8). Fourteen percent of patients had R-ISS stage III disease and 24% had high-risk cytogenetic abnormalities defined as del (17p), t(4;14), or t(14;16). Patients were excluded if they had previous CAR T-cell or BCMA targeting therapy.⁸

The primary endpoints were safety, dose confirmation, and ORR. Secondary endpoints were CR, sCR, DOR, PFS, MRD-negativity rate, and OS. At a median follow-up of 12.4 months, 97% of patients met the primary outcome of ORR (95% CI 91.2–99.4; p<0.001) with 67% obtaining a sCR. Ninety-three percent of patients achieved MRD negative status. The median DOR (15.9-not estimable) and PFS (16.8-not estimable) were not reached. 12-month OS was 89% (80.2-93.5).⁸ A 24-month update presented at the 2021 American Society of Hematology Annual Meeting, confirmed these results with ORR in 97.9% of patients with 82.5% maintaining a sCR. 24-month PFS and OS were 60.5% and 74%, respectively.⁹

Treatment related toxicity was reported in all patients receiving treatment with 99% of patients experiencing a grade ≥3 adverse reaction. The most common high-grade toxicities were neutropenia (95%), anemia (68%), thrombocytopenia (60%), and infections (20%). Ninety-five percent of patients experienced low-grade CRS with 4% of patients experiencing grade ≥3 toxicity. The median time to onset of CRS was 7 days (IQR 5-8), with a median duration of 4 days (IQR 3-6). One patient died due to grade 5 CRS in combination with hemophagocytic lymphohistiocytosis (HLH). Twenty-one percent of patients experienced neurotoxicity with 9% of patients experiencing grade ≥3 events. Median time to onset was 8 days (IQR 6-8), with a median duration of 4 days (IQR 6-8). Eight percent of patients experienced delayed high-grade neurotoxicity not described by ICANS diagnostic criteria. These events included parkinsonian-like movement disorders, cranial nerve paralysis, and neuropathy. Fifty percent of these patients’ neurotoxicity did not resolve and one patient death occurred from a grade five event.⁸

The manufacturer anticipated a decision from the FDA on the accelerated approval of cilta-cel in the fourth quarter of 2021; however, the FDA’s decision was recently postponed until the first quarter of 2022.¹⁰ There are other ongoing trials using cilta-cel in combination with other anti-myeloma therapies as well as in earlier treatment lines for patients with multiple myeloma.

Treatment Considerations:

Advantages
There are many advantages of the utilization of CAR T-cell therapy in R/R myeloma patients. In comparison to other chemotherapy regimens, which require multiple infusions administered at pre-defined intervals, CAR T-cell therapy works with the immune system to provide a deep response after a single infusion. CAR T-cells may provide heavily pre-treated patients a substantial treatment-free interval during remission. For these reasons many patients report to have improved quality of life following ide-cel infusion.¹¹ BCMA targeting CAR T-cell therapies can offer many patients previously thought to have run out of treatment choices the option of prolonged, treatment-free survival.

Toxicity
CAR T-cell therapy is associated with significant toxicities including CRS, neurotoxicity, prolonged cytopenias, and infections.^7,8 Due to ide-cel’s CRS and neurotoxicity there is a risk evaluation and mitigation strategy (REMS) program which ensures that hospitals and their associated clinics that dispense this CAR T-cell therapy are certified to manage CRS and neurotoxicity and have access to tocilizumab, a medication approved to manage these toxicities.⁷ These toxicities also make CAR T-cell therapy challenging to administer safely in frail patients, those with high disease burden, and those who are heavily pretreated. Treatments of these toxicities are improving, however, patients are still required to receive CAR T-cell therapy and monitoring at large tertiary medical centers. An advantage of cilta-cel’s delayed CRS and neurotoxicity may potentially allow for outpatient administration and better reimbursement, though, these delayed toxicities may pose a challenge to successful long-term follow-up. Many ongoing studies are working to overcome CAR T-cell toxicity through modifications of CAR T-cell constructs. Methods to mitigate toxicity include utilizing suicide switch mechanisms, dual target antigen recognition, synthetic notch receptors, inhibitory CARs, bispecific T-cell engagers, and more.¹²

Therapeutic Resistance and Duration of Response

The limited duration of responses to CAR T-cell therapy suggests that current constructs may be vulnerable to resistance. The mechanisms behind resistance and therapeutic failure are poorly understood.¹³ Ide-cel’s short persistence is thought to be due to the lack of ability to produce a robust response by memory T-cells. In ongoing trials, ide-cel’s CAR construct is being studied with the addition of a phosphoinositide 3-kinase inhibitor during the CAR T-cell expansion phase. This is hypothesized to enhance the drug product’s memory in hopes to provide a more durable response.¹⁴

Cilta-cel’s increased durability may be due to improved binding affinity. Cilta-cel expresses two BCMA-targeting single-domain antibodies and a CD3-41BB co-stimulatory domain to optimize T-cell activation and proliferation.8 Additionally, future research to mitigate antigen escape is currently underway. Antigen escape can occur as CAR T-cells are targeting a specific antigen, thus applying selective pressure on malignant clones that do not express that target. This ultimately results in disease relapse due to the replication of the surviving clones. It is thought that this mechanism of resistance can be mitigated through dual targeting via selection of multiple antigens.¹⁵

Accessibility

Access to BCMA targeting CAR T-cell products remains limited. At this time, ide-cel is the only currently FDA approved CAR T-cell therapy for multiple myeloma and manufacturing slots have not been able to keep up with prescriber demand. Cilta-cel approval has been delayed and roll-out may take months due to the anticipated REMS requirements.¹⁰ Additionally, patients must meet many requirements prior to receiving therapy. Patients must have good social support, access to a tertiary medical center for monitoring, be fit enough to make it through the 4-to-6-week manufacturing process, and have insurance approval. The costs of these therapies are substantial for both the institution and patient. It is estimated that the average cost for CAR T-cell therapy is approximately 700,000 dollars and can increase to over 2 million dollars depending on the extent of monitoring and treatment of toxicities.¹⁶

Cilta-cel’s delayed toxicity profile may potentially allow outpatient administration, thereby increasing access and potentially increasing insurance reimbursement. Allogeneic or “off the shelf” CAR T-cell products are also under investigation and may improve product-to-vein time, eliminating the need for leukapheresis, and potentially lowering costs.^13,17 Ongoing BCMA targeting CAR T-cell therapies can be seen in Table 1.

Conclusion

CAR T-cell therapy has revolutionized the treatment of R/R multiple myeloma. Both the KarMMa and CARTITUDE-1 trials showed improved survival outcomes in this difficult to treat patient population. Ide-cel has also demonstrated increased quality of life. Among these BCMA targeting CAR T-cell therapies, cilta-cel seems to have the highest response rates; however, caution should be used when comparing results between trials. These novel cellular therapies provide heavily pre-treated patients with promising options. As data mature and these therapies become more accessible, BCMA targeting CAR T-cell therapy will likely become more frequently incorporated into the multiple myeloma treatment paradigm.

Table 1. Ongoing Trials of BCMA Targeting CAR T-cell Therapy

ASCT: autologous stem cell transplant; CAR: chimeric antigen receptor; MM: multiple myeloma; R/R: relapsed/refractory; MRD: minimal residual disease.

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