What Is Cytokine Release Syndrome (CRS)?

Cytokine release syndrome (CRS) is a condition that occurs when the immune system is highly activated, leading to the rapid and excessive release of cytokines into the bloodstream. Cytokines are small proteins that play a crucial role in regulating immune responses and inflammation. In normal circumstances, cytokines are released in a controlled manner to combat infections. However, in CRS, the sudden and uncontrolled release of large amounts of cytokines can trigger a severe, systemic inflammatory response known as a "cytokine storm," and it can be potentially life-threatening.

During a cytokine storm, the overactivated immune system can cause widespread inflammation and damage to healthy tissue and organs throughout the body. The symptoms of CRS can range from mild, flu-like symptoms to more severe complications such as high fever, low blood pressure, difficulty breathing, and multi-organ failure. CRS is a recognized complication of certain T-cell-engaging (TCE) immunotherapies, such as CAR T-cell and bispecific therapy, and can occur with a severe infection, such as COVID-19.

Prompt diagnosis and management of CRS are essential to prevent serious complications and improve patient outcomes. 

What Are Multiple Myeloma Drugs That May Cause CRS?

• ABECMA® (idecabtagene vicleucel)
• CARVYKTI® (ciltacabtagene autoleucel)
• ELREXFIO® (elranatamab-bcmm)
• TALVEY™ (talquetamab)
• TECVAYLI™ (teclistamab-cqyv)

What Are the Symptoms of Cytokine Release Syndrome?

CRS can occur within hours to days following treatment with TCE immunotherapy. Symptoms of CRS may include some or all of the following:

• fever
• chills, uncontrollable shaking (rigors) 
• difficulty breathing 
• dizziness or lightheadedness 
• nausea 
• headache 
• tachycardia (fast heartbeat) 
• low blood pressure 
• fatigue 

How Is Cytokine Release Syndrome Managed? 

The degree of CRS is graded on a scale of 1-4, with 1-2 being mild and 3-4 being severe to life-threatening. Management is based on grade of CRS.  

Prevention is the first step in managing CRS. Bispecific medications use a “step-up” dose schedule when the medication is first being introduced to the body. This allows a person’s immune system to slowly become familiar with the medication to prevent an overreaction of the immune system. Premedication with tocilizumab before receiving bispecifics and CAR T-cell therapy is also being used in clinical trials. 

Treatment is based on the type of symptoms and how severe they are. Typically, supportive care is provided, such as fluids, oxygen, and medications to manage fever and inflammation (grade 1-2). If symptoms become more severe, medications may be necessary to control the overactive immune response and limit the damaging effects of the cytokine storm (grade 3-4). Commonly used medications to manage more severe or life-threatening CRS are tocilizumab alone or combined with steroids.