What is the role of Chimeric Antigen Receptor T (CART) cells in Multiple Myeloma (MM)?

From the Guidelines

CAR-T cell therapy is a highly effective treatment for multiple myeloma (MM), particularly for patients with relapsed or refractory disease, with response rates of up to 73% and complete response rates of up to 33% 1.

Key Points

• The most effective CAR-T cell therapies for MM target B-cell maturation antigen (BCMA), which is highly expressed on myeloma cells.
• Currently approved BCMA-targeted CAR-T therapies include idecabtagene vicleucel (Abecma) and ciltacabtagene autoleucel (Carvykti), both showing impressive response rates in heavily pretreated patients.
• Typical dosing ranges from 300-460 million CAR-T cells administered as a single infusion after lymphodepletion with fludarabine and cyclophosphamide.
• Patients require hospitalization for monitoring after infusion, typically for 7-14 days.
• Common side effects include cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), which are managed with tocilizumab and corticosteroids.

Efficacy and Safety

• In a phase II study, idecabtagene vicleucel demonstrated a response rate of 73% and a complete response rate of 33% in heavily pretreated patients with MM 1.
• The median time to response was 1 month and the median time to a complete response or better was 2.8 months.
• High response rates (>50%) were found in several examined subgroups, including older patients, patients with high-risk cytogenetic abnormalities, pentarefractory disease, and high tumor burden.

Recommendations

• Idecabtagene vicleucel is a recommended option for patients with MM who have received at least 4 prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor (PI), and an immunomodulatory drug (IMiD) 1.
• Patients should be closely monitored for adverse events, including cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, and managed with tocilizumab and corticosteroids as needed.

From the FDA Drug Label

ABECMA is a BCMA-directed genetically modified autologous T cell immunotherapy product consisting of a patient's own T cells that are harvested and genetically modified ex vivo through transduction with an anti-BCMA02 chimeric antigen receptor (CAR) lentiviral vector (LVV). The CAR construct includes an anti-BCMA scFv-targeting domain for antigen specificity, a transmembrane domain, a CD3-zeta T cell activation domain, and a 4-1BB costimulatory domain Antigen-specific activation of ABECMA results in CAR-positive T cell proliferation, cytokine secretion, and subsequent cytolytic killing of BCMA-expressing cells.

CART cell in MM: ABECMA is a chimeric antigen receptor (CAR)-positive T cell therapy targeting B-cell maturation antigen (BCMA), which is expressed on the surface of normal and malignant plasma cells.

• The mechanism of action of ABECMA involves the binding of the CAR-positive T cells to BCMA-expressing target cells, leading to signaling initiated by CD3ζ and 4-1BB domains, and subsequent CAR-positive T cell activation.
• Key points:
  • ABECMA is a genetically modified autologous T cell immunotherapy product.
  • The CAR construct targets BCMA-expressing cells.
  • Antigen-specific activation of ABECMA results in CAR-positive T cell proliferation and cytolytic killing of BCMA-expressing cells.
  • ABECMA can persist in peripheral blood for up to 1 year post-infusion. 2 2 2

From the Research

CART Cell Therapy in Multiple Myeloma

• CART cell therapy has shown promising results in the treatment of multiple myeloma (MM), with several studies demonstrating its efficacy and safety 3, 4, 5, 6, 7.
• The most common target for CART cell therapy in MM is B-cell maturation antigen (BCMA), which is preferentially expressed by mature B lymphocytes and has been associated with MM in preclinical models and humans 3, 4, 5, 6, 7.
• Studies have shown that BCMA-targeted CART cell therapy can produce high response rates, with pooled overall response rates ranging from 77% to 78% and complete response rates ranging from 37% to 38% 6.
• However, CART cell therapy can also be associated with serious side effects, including cytokine release syndrome (CRS) and neurologic toxicity, with pooled grade 3-4 rates ranging from 14% to 13% 6.
• Strategies to improve CART cell function and reduce toxicity are being explored, including targeting dual antigens, enhancing cell longevity through genetic modification, and eliminating the immunosuppressive tumor microenvironment 4, 5, 7.

Efficacy and Safety of CART Cell Therapy

• A systematic review and meta-analysis of 23 studies found that CART cell therapy was associated with a pooled overall response rate of 77%, a complete response rate of 37%, and a minimal residual disease (MRD) negativity rate of 78% 6.
• The same study found that the pooled relapse rate of responders was 38% and the median progression-free survival was 8 months 6.
• Another study found that BCMA-targeted CART cell therapy was associated with a high response rate and durable responses, with some patients achieving complete remission 3.

Future Directions

• Further studies are needed to determine the optimal target for CART cell therapy in MM, as well as to explore strategies to improve CART cell function and reduce toxicity 4, 5, 7.
• The development of universal allogeneic CART cells and bispecific antibodies may also provide new treatment options for patients with MM 4, 7.
• Additionally, studies are needed to determine which patients are most likely to benefit from CART cell therapy and to identify biomarkers that can predict response to treatment 7.