Multiple myeloma is a cancer of plasma cells, a type of white blood cell found in the bone marrow. Normally, these cells produce antibodies to fight infections. In multiple myeloma, these plasma cells become cancerous and multiply uncontrollably, leading to health complications. CD38 antibody therapies target these malignant cells, representing a significant treatment advancement.
Understanding Multiple Myeloma
Plasma cells reside in the bone marrow, the soft, inner part of certain bones where blood cells are made. Normally, they are part of the immune system, producing antibodies to combat infections. When these cells become cancerous, they are called myeloma cells. Their excessive growth in the bone marrow displaces healthy blood-forming cells.
This overgrowth leads to low blood counts, including anemia (low red blood cells, causing fatigue), thrombocytopenia (low platelets, increasing bleeding risk), and leukopenia (low white blood cells, raising infection risk). Abnormal plasma cells also produce faulty antibodies, which can cause kidney issues and thickened blood. Myeloma cells can also form tumors in the bone marrow or soft tissue, leading to bone damage and weakening bones, often visible as fractures or lesions on X-rays.
How CD38 Antibodies Target Myeloma Cells
CD38 is a protein highly expressed on the surface of multiple myeloma cells, making it an attractive therapeutic target. Although CD38 is also present on some normal immune cells, its much higher concentration on myeloma cells allows for targeted treatment.
CD38 antibodies bind specifically to this protein on the myeloma cell surface, triggering multiple mechanisms to destroy cancer cells. One primary method is antibody-dependent cellular cytotoxicity (ADCC), where the antibody flags myeloma cells for destruction by natural killer (NK) cells, a type of immune cell. NK cells then release toxic substances that create pores in the cancer cell membrane, leading to cell death.
Another mechanism is complement-dependent cytotoxicity (CDC), where antibody binding activates the complement system, a group of blood proteins that directly punch holes in the myeloma cell membrane, causing cell lysis. Antibody-dependent cellular phagocytosis (ADCP) also occurs, where immune cells like macrophages recognize and engulf antibody-coated myeloma cells. These antibodies can also have immunomodulatory effects by eliminating CD38-positive immune-suppressing cells, enhancing the body’s anti-tumor immune response.
Specific CD38 Antibody Medications
Two main CD38 antibody medications are approved for multiple myeloma: Daratumumab (brand names Darzalex, Darzalex Faspro) and Isatuximab (brand name Sarclisa). These medications are administered intravenously, meaning they are given directly into a vein. Daratumumab was the first monoclonal antibody approved for multiple myeloma, initially for patients who had received prior therapies. It is now used alone or in combination with other anti-myeloma drugs.
Daratumumab can be combined with various regimens, such as lenalidomide and dexamethasone, or bortezomib and dexamethasone. A subcutaneous formulation, Darzalex Faspro, has also been approved, allowing for shorter administration. Isatuximab is another CD38-targeting antibody. It is typically administered in combination with other agents like pomalidomide and dexamethasone, or carfilzomib and dexamethasone, for patients who have received prior treatments.
What to Expect During CD38 Antibody Treatment
CD38 antibody treatments are given as intravenous infusions in a medical facility. The frequency and duration of infusions vary based on the specific medication and treatment regimen. For example, Daratumumab monotherapy often starts with weekly infusions for the first 8 weeks, then every two weeks for the next 16 weeks, and finally monthly thereafter until disease progression. Initial infusions can be lengthy, with the first Daratumumab infusion taking around 7 hours, gradually decreasing for subsequent infusions. Isatuximab infusions also vary in duration, with the first infusion typically lasting about 3 hours and 20 minutes, reducing to 75 minutes for later infusions.
Patients commonly experience infusion-related reactions, especially during the first few doses. These reactions can include symptoms like nasal congestion, throat irritation, cough, chills, and nausea. To manage these, patients often receive premedications such as corticosteroids, antihistamines, and acetaminophen before each infusion. If a reaction occurs, the infusion may be paused or slowed down, and supportive care might be provided.
Other potential side effects can include fatigue, nausea, diarrhea, and low blood counts, such as neutropenia (low white blood cells). Low blood counts can increase the risk of infections, and patients may be monitored for symptoms like fever or cough. Patients should communicate any side effects to their healthcare team, as management strategies can help alleviate symptoms and ensure treatment continues safely. Additionally, CD38 antibodies can interfere with certain blood tests, such as blood compatibility testing for transfusions, so healthcare providers will take precautions like pre-screening blood types.