Multiple myeloma is a cancer that begins in the plasma cells, a type of white blood cell found in the bone marrow. Normal plasma cells produce antibodies that help fight infections. In multiple myeloma, these plasma cells become cancerous and multiply uncontrollably, crowding out healthy blood-forming cells and producing abnormal proteins called M proteins. This overgrowth can lead to various complications, including bone damage, low blood counts, and kidney problems. Immunotherapy represents a modern treatment approach that harnesses the body’s own immune system to recognize and eliminate these cancerous plasma cells.
Understanding Immunotherapy Approaches
Immunotherapy works by utilizing the body’s immune system to identify and destroy cancer cells. Unlike traditional treatments such as chemotherapy, which directly attack fast-growing cells, immunotherapy aims to empower the immune system to do the fighting. Cancer cells often develop ways to evade immune detection, either by hiding or by sending signals that tell immune cells to ignore them.
Immunotherapy strategies counteract these evasion tactics by either boosting the immune system’s natural ability to recognize and target cancer cells or by making the cancer cells more visible to immune cells.
Targeted Antibody Therapies
Targeted antibody therapies use specially engineered antibodies to fight multiple myeloma. These laboratory-created proteins are designed to bind to specific targets on myeloma cells or immune cells, initiating various mechanisms to destroy the cancer.
Monoclonal antibodies are a type of targeted antibody therapy that can directly bind to proteins on the surface of multiple myeloma cells. Daratumumab, for instance, targets CD38, a protein found in high numbers on myeloma cells. Once daratumumab binds to CD38, it can trigger cancer cell destruction through several ways, including complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP). CDC activates a protein system that directly damages cancer cells, while ADCC and ADCP involve immune cells like natural killer (NK) cells and macrophages recognizing and destroying antibody-coated cancer cells.
Elotuzumab is another monoclonal antibody that targets SLAMF7, a protein widely expressed on multiple myeloma cells and NK cells. It primarily induces ADCC, flagging myeloma cells for destruction by NK cells. It also enhances NK cell activity against myeloma cells by binding to SLAMF7. Isatuximab is an anti-CD38 monoclonal antibody. It binds to CD38, inducing direct cancer cell death through apoptosis, and triggering CDC, ADCC, and ADCP. Isatuximab may also sensitize T-cells against CD38-expressing cells.
Bispecific T-cell engagers (BiTEs) represent a newer class of engineered antibodies. These innovative antibodies have two “arms”: one arm binds to a specific protein on the surface of a multiple myeloma cell, and the other arm binds to CD3, a protein found on the surface of T-cells. This dual binding brings the T-cell and the myeloma cell into close proximity. Once brought together, the T-cell is activated and redirected to specifically attack and kill the myeloma cell. Teclistamab and elranatamab are examples of BiTEs that target B-cell maturation antigen (BCMA) on myeloma cells and CD3 on T-cells. Talquetamab is another BiTE that targets GPRC5D on myeloma cells and CD3 on T-cells, offering another approach to T-cell redirection.
Cellular Immunotherapies
Cellular immunotherapies, particularly CAR T-cell therapy, represent a highly advanced approach to treating multiple myeloma. This therapy involves genetically modifying a patient’s own T-cells to specifically target and destroy cancer cells. The process begins with apheresis, where a patient’s T-cells are collected from their blood.
These T-cells are then genetically engineered in a laboratory to express a Chimeric Antigen Receptor (CAR) on their surface. This CAR is designed to recognize a specific protein, or antigen, on multiple myeloma cells, often B-cell maturation antigen (BCMA). The CAR acts like a homing device, allowing the modified T-cells to precisely identify cancer cells.
Once modified and expanded, these T-cells are infused back into the patient. These reinfused CAR T-cells circulate, seeking and binding to myeloma cells. Upon binding, they activate, proliferate, and destroy the cancerous plasma cells. Idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) are two approved CAR T-cell therapies for multiple myeloma that target BCMA. Cilta-cel is unique as it expresses single-domain antibodies directed against two distinct epitopes of the BCMA target antigen, potentially enhancing its binding and efficacy.
Patient Considerations
Immunotherapy for multiple myeloma is typically administered through intravenous infusion, though some therapies may involve subcutaneous injection. CAR T-cell therapy is generally a single administration, following a period of T-cell collection and modification. The administration schedule for targeted antibody therapies and bispecific T-cell engagers varies depending on the specific drug and treatment plan.
Patients undergoing immunotherapy may experience various side effects, which result from the immune system’s heightened activity. Common general side effects include fatigue, infusion reactions (especially during initial treatments), and an increased risk of infection and inflammation in areas like the skin, lungs, or colon.
For cellular immunotherapies like CAR T-cell therapy and bispecific antibodies, more specific side effects are observed. Cytokine release syndrome (CRS) is a common reaction causing fever, chills, headache, and muscle aches, resulting from the rapid release of inflammatory molecules by activated immune cells. Immune effector cell-associated neurotoxicity syndrome (ICANS) is another potential side effect, manifesting as confusion, difficulty speaking, or seizures. Close monitoring during and after treatment is crucial for managing these side effects, with healthcare teams prepared to intervene with medications like tocilizumab, an anti-IL-6 monoclonal antibody, or corticosteroids to mitigate severe reactions.