How CARVYKTI^® Works¹

Multiple myeloma is the second most common hematological malignancy in the United States.
It is characterized by the abnormal accumulation of plasma cells in the bone marrow and excessive production of monoclonal immunoglobulins.
The malignant plasma cells highly express B cell maturation antigen, or BCMA, which has been associated with progression of multiple myeloma.

BCMA is a transmembrane protein belonging to the tumor necrosis factor receptor superfamily, crucial for the viability of long-lived plasma cells.
Its activation leads to the upregulation of genes involved in growth, survival, immunosuppression, metastasis, angiogenesis and osteoclast activation.
Due to its overexpression by malignant plasma cells, but limited expression in other tissues, BCMA is a desired target for multiple myeloma therapy.

Chimeric antigen receptor T cell therapy, known as CAR-T, is an approach in anticancer therapy in which patient’s own T cells are genetically engineered to express a receptor to target specific proteins on the surface of cancer cells.
CARs contain 3 main elements that can be customized to target tumor cells in a disease-specific manner to maximize the CAR T-cell response.
The extracellular domain of CAR is essential for ligand recognition. It is usually designed to contain single domains of tumor antigen-reactive antibodies.
Inside the cell, the CAR has a T cell activation domain. Included in this is a costimulatory domain, which serves in the T cell activation and function.

CARVYKTI® (ciltacabtagene autoleucel) is a B-cell maturation antigen (BCMA)-directed genetically modified autologous T-cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory multiple myeloma, who have received at least 1 prior line of therapy, including a proteasome inhibitor, an immunomodulatory agent, and are refractory to lenalidomide.
The CARVYKTI® CAR protein features two BCMA-targeting single domain antibodies designed to confer high avidity against human BCMA.
Clinical relevance of the two distinct binding domains is not known. It also contains a 4-1BB co-stimulatory domain and a CD3ζ cytoplasmic domain.
Upon binding to BCMA-expressing cells, the CAR promotes T cell activation, expansion and elimination of target cells.
In vitro studies with CARVYKTI®, manufactured from healthy donors, and patients with Multiple Myeloma, showed no evidence of cytokine independent growth.
After a single infusion of ciltacabtagene autoleucel, expansion of CAR-positive T cells coincided with decreases of serum soluble BCMA, serum M-protein and/or free light chains.