Teclistamab is a treatment for relapsed or refractory multiple myeloma, a cancer of plasma cells. It is a form of immunotherapy, a treatment that uses the body’s immune system to combat cancer. A frequent side effect of this therapy is Cytokine Release Syndrome (CRS), an intense inflammatory response that can occur as a result of the treatment’s effect on immune cells.
The Mechanism Behind Teclistamab and CRS
Teclistamab is a type of medication known as a bispecific T-cell engager (BiTE) antibody. It functions as a biological “matchmaker,” connecting two different cells. One end of the teclistamab molecule attaches to a protein called CD3 on the surface of T-cells, while the other end binds to the B-cell maturation antigen (BCMA) on multiple myeloma cells.
This connection activates the T-cell, instructing it to recognize and destroy the myeloma cell. When this happens on a large scale, the activated T-cells release a massive amount of inflammatory signaling molecules known as cytokines. This flood of cytokines into the bloodstream triggers a systemic inflammatory response, which is the collection of symptoms known as CRS.
Recognizing the Signs and Symptoms of CRS
The signs of Cytokine Release Syndrome can vary widely, from mild, flu-like reactions to severe, life-threatening conditions. Symptoms typically begin within the first few days after receiving the teclistamab infusion. Initial symptoms often include fever, chills, fatigue, headache, and muscle or joint pain.
As the syndrome progresses, individuals may experience a drop in blood pressure, known as hypotension, or a rapid heartbeat, called tachycardia. More severe signs can involve the respiratory system, leading to shortness of breath or decreased oxygen levels in the blood, a condition called hypoxia.
To standardize care, doctors classify the severity of CRS using a grading system. Grade 1 CRS might only involve a fever that can be managed with standard fever-reducing medications. Higher grades, such as 2, 3, or 4, are defined by more serious issues like hypotension requiring intravenous fluids or hypoxia necessitating supplemental oxygen. This grading helps guide the medical team in applying the appropriate level of intervention.
Monitoring and Risk Mitigation Strategies
To reduce the risks associated with teclistamab, proactive measures are integrated into the treatment plan. A primary strategy is the “step-up dosing” schedule. Patients receive two smaller, introductory doses over several days before the first full treatment dose is administered. This incremental approach allows the immune system to acclimate to the drug more gradually, which can lessen the intensity of the subsequent cytokine release.
This method has been shown to reduce both the likelihood and the potential severity of CRS. Because the highest risk for CRS is during this initial dosing period, patients are hospitalized for monitoring. This allows for immediate medical intervention if symptoms appear. Patients also receive premedications before each dose, including corticosteroids, antihistamines, and fever reducers, to help suppress the initial inflammatory response.
Management of Active CRS
Once a patient is diagnosed with CRS, the treatment approach is linked to the assigned grade of severity. For mild, Grade 1 CRS, management is supportive. This involves using medications to control the fever and providing intravenous fluids to maintain hydration and blood pressure.
For moderate to severe CRS, classified as Grade 2 or higher, more targeted therapies are required. A medication used is tocilizumab, an antibody that works by blocking the receptor for a specific cytokine called interleukin-6 (IL-6). Since IL-6 is a major driver of the inflammatory cascade in CRS, blocking its effects can quickly reverse many of the symptoms.
In cases where CRS is severe or does not respond adequately to tocilizumab, corticosteroids are administered. These anti-inflammatory drugs can help suppress the widespread immune activation that underlies the syndrome.
Associated Neurological Events (ICANS)
A distinct, but related, side effect of teclistamab is Immune Effector Cell-Associated Neurotoxicity Syndrome, or ICANS. This condition affects the brain and nervous system and can develop either alongside CRS or independently. The cause is thought to be related to inflammatory cytokines crossing the blood-brain barrier and causing inflammation within the central nervous system.
Patients and caregivers should watch for neurological symptoms, which can include confusion, difficulty with speaking or writing (aphasia and dysgraphia), headaches, tremors, or significant drowsiness. In more severe instances, ICANS can lead to seizures or a decreased level of consciousness.
To detect these changes early, healthcare providers perform regular neurological assessments. These simple checks might involve asking the patient to state their name and the current date or to write a short sentence. If ICANS is diagnosed, the primary treatment involves the use of corticosteroids to reduce the inflammation in the brain and manage the neurological symptoms.