Teclistamab and talquetamab are treatments for relapsed or refractory multiple myeloma (MM). These therapies are bi-specific T-cell engagers (BsAbs), a class of engineered antibodies that harness the body’s immune system to fight cancer. They are approved for patients who have received multiple prior lines of therapy that failed to control the disease. These agents offer new options by providing a mechanism to target and destroy myeloma cells.
Understanding the Mechanism and Targets
These treatments function as molecular bridges, connecting the patient’s immune cells and the cancer cells. Each drug is a bi-specific antibody with two arms. One arm binds to the CD3 protein found on the surface of T-cells. The other arm attaches to a distinct target protein highly expressed on the surface of multiple myeloma cells. This dual binding redirects the T-cell to the cancer cell, triggering it to release toxic substances that destroy the malignant cell.
The difference between the two therapies lies in the specific target on the myeloma cell. Teclistamab targets B-cell maturation antigen (BCMA), which is expressed almost exclusively on plasma cells, including myeloma cells. Its presence on the cancer cells makes BCMA an ideal landing spot for the drug to initiate the immune response. BCMA-directed therapies have shown high rates of deep and durable responses in heavily pretreated patients.
Talquetamab targets a different protein: G-protein coupled receptor class C group 5 member D (GPRC5D). This target is highly expressed on myeloma cells but is largely absent from healthy cells in the bone marrow, making it a selective target. Targeting GPRC5D offers an alternative, especially for patients whose cancer cells have stopped producing BCMA or who have progressed after BCMA-directed therapy. Targeting a distinct antigen like GPRC5D helps overcome resistance mechanisms that can develop during treatment.
Treatment Protocol and Administration
The administration of these bi-specific antibodies follows a structured protocol designed to manage the powerful immune reaction they generate. Both teclistamab and talquetamab are administered via subcutaneous injection, often in the abdomen or thigh. This route of administration is more convenient than prolonged intravenous infusions.
A feature of the treatment regimen is the use of “step-up dosing” at the start of therapy. This involves administering small, escalating doses over several days before the full treatment dose. This gradual increase is a safety measure intended to slowly activate the T-cells and mitigate the risk of a sudden, severe immune response. For teclistamab, the step-up phase typically involves two lower doses given a few days apart, followed by the first full treatment dose.
Due to the risk of immediate adverse reactions, patients must remain under close observation after each step-up dose. For teclistamab, monitoring for 48 hours after each step-up dose is commonly recommended. Following this initial phase, the maintenance dose is typically given weekly. For patients who achieve a strong response, the dosing frequency may be reduced to every two weeks after a certain period, such as six months.
Managing Safety and Adverse Events
Since these drugs powerfully activate the immune system, the primary risk is a systemic inflammatory reaction known as Cytokine Release Syndrome (CRS). CRS occurs when activated T-cells rapidly release large amounts of inflammatory molecules (cytokines) into the bloodstream. Symptoms of CRS are generally flu-like and can include fever, chills, fatigue, rapid heart rate, and low blood pressure.
CRS is a common event with this class of therapy, occurring in a majority of patients, although it is usually low-grade (Grade 1 or 2) and manageable. The step-up dosing schedule is the primary strategy for reducing the severity of CRS. Patients are also given pre-medications like corticosteroids and acetaminophen before each step-up dose. If CRS occurs, it is typically managed with supportive care and, in more severe cases, an anti-inflammatory medication like tocilizumab.
Another serious, though less frequent, adverse event is Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS). ICANS involves neurological symptoms that can range from mild confusion, difficulty speaking, or tremors to more severe issues like seizures. The onset of ICANS often occurs within the first few days after treatment, sometimes concurrently with CRS.
Beyond these immune-related complications, both drugs carry a risk of infections and hematologic toxicities, such as low blood counts (neutropenia and anemia). Talquetamab, due to its GPRC5D target, can also cause unique side effects related to GPRC5D expression on healthy cells, including skin, nail, and oral toxicities. Skin-related events, such as skin exfoliation and dry skin, affect many patients, and changes to the nails and a diminished sense of taste are also reported. These drugs are subject to strict regulatory monitoring programs, such as Risk Evaluation and Mitigation Strategies (REMS) in the US, which mandate specific training and safety protocols for healthcare providers to manage these complex side effects.