Last updated on:December 10th, 2022
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Multiple myeloma is a type of bone marrow cancer caused by the malignant transformation and uncontrolled proliferation of a subset of the plasma cells (antibody-producing cells). These events stem from the dysregulation of proteins that control the cell cycle—and thus, cell proliferation. The malignant cells and their products cause deleterious effects to organs including bones, bone marrow and the kidneys; a variety of mechanisms are postulated to be involved, including bone marrow infiltration by the abnormal cells and organ damage secondary to monoclonal proteins and free light chains. Although multiple myeloma cells tend to proliferate in and infiltrate the bone marrow, malignant cells may circulate into the peripheries.
Genetic causes of multiple myeloma
Multiple myeloma is often associated with genetic aberrations. While the causes of such changes are not always clear, genetic predisposition is thought to play a role in many cases. Other risk factors include aging, radiation, and exposure to chemicals such as benzene. These aberrations usually affect genes coding for antibodies and include gene translocations from one chromosome to another or the gain of odd-numbered chromosomes. Patient survival is variable and usually dependent on the type of genetic aberration. The gain of odd-numbered chromosomes is usually associated with a better prognosis than the translocation of genes coding for antibodies.
Relapsed refractory multiple myeloma (RRMM)
Relapsed refractory multiple myeloma (RRMM) is a subtype of multiple myeloma with a poor prognosis and decreased survival rates. It is characterized by disease recurrence after treatment, which generally includes inhibitors of the proteasome (a protein-degrading molecular complex), immunomodulatory drugs, and monoclonal antibodies against CD38 (a protein on the surface of plasma cells). Alternative therapeutic strategies have shown higher efficacy. These strategies include antibodies against other plasma cell proteins as well as chimeric antigen receptor T-cell (CAR-T) therapies, which utilize genetically modified T-cells from the same patient to find and destroy malignant cells carrying a specific molecule on their surface.
CAR-T cell therapies against RRMM
In CAR-T therapies, T-cells are obtained from patient blood and infected with genetically modified viruses coding for a chimeric antigen receptor. The T-cell chimeric antigen receptor utilized in gene therapy against RRMM contains the intracellular 4-1BB and CD3-zeta molecules, a transmembrane linker region, and an extracellular region that recognizes the B-cell maturation antigen (BCMA). The 4-1BB and CD3-zeta molecules have co-stimulatory and signaling functions, respectively, promoting T-cell fitness, expansion, and activity against malignant plasma cells. The BCMA-recognizing region provides specificity against malignant plasma cells. Upon being returned to the patient, these modified T-cells are able to recognize malignant plasma cells through their BCMA. The interaction between the two cell types triggers the release of cytotoxic molecules that result in the destruction of the plasma cell.
B-cell maturation antigen (BCMA)
The B-cell maturation antigen (BCMA) is a protein found exclusively and uniformly on malignant plasma cells. It has an essential role in their differentiation into malignant cells and subsequent proliferation, being important for their survival. These features make it an ideal drug target for RRMM.
There are two CAR-T cell therapies currently approved by the Food and Drug Administration (FDA) of the United States for the treatment of adult patients with RRMM: idecabtagene vicleucel and ciltacabtagene autoleucel. In both therapies, patient T-cells are genetically modified to produce a chimeric antigen receptor able to neutralize malignant plasma cells.