T-cell-directed therapies designed to treat multiple myeloma have certain side effects that are still being revealed as more and more patients use these treatments. 

In today’s article, we are highlighting the most important parts of Dr. Kara Cicero’s presentation to the myeloma community at the Seattle Round Table on October 14, 2023. 

In this presentation, she shares about the natural function of T-cells and how side effects from new T-cell-directed therapies for myeloma are affecting patients. 

The Natural Function of T-Cells 

T-cells are a part of our adaptive immune system. Our bodies create many different types of T-cells, each with the ability to detect specific viruses, infections, or errors within our bodies. 

When a T-cell sees something that shouldn’t be there, like a virus, the specific T-cell created to attack said virus will be activated. These cells create inflammatory signals to be released to target said virus with the end goal of eliminating the virus from the body. 

These inflammatory signals can often present as fever, chills, body aches, and pain, etc. which we commonly associate as “symptoms” of said virus or infection like the flu. In reality, in our body’s physiological response to eliminating the disease.  
 

CAR-T Cells 

In the CAR T-cell Therapy that we are familiar with within myeloma treatment, a patient’s blood is taken and their T-cells are engineered to specifically recognize and destroy myeloma. 

In both current FDA-approved CAR T-cell therapies, BCMA is the specific target of the myeloma cells that the T-cells are engineered to detect and eliminate.  

Some of the side effects from these therapies that will be presented throughout this article (and Dr. Cicero’s presentation) can be seen as similar to the physiological responses our body has when fighting the flu or a different virus. 
 

T-Cell Engaging Bispecific Antibodies 

Bispecific Antibody therapies take the T-cells of a myeloma patient closer to the myeloma cells and activate the T-cells in a similar way that the immune system would do for a different virus. This, too, can obviously cause a physiological reaction in the same way that a flu, infection, or other illness could cause in the body. 

Reactions to the CAR T-Cell Therapy in Today’s Myeloma 

The CAR T-therapies today have side effects that can be quite serious. 

In the KarMMa-3 ide-cel trial of 376 patients, almost every person (99%) had some kind of toxicity due to the treatment. You can see the breakdown below. 

• Hematologic event: neutropenia (78%), anemia (66%), thrombocytopenia (54%)
• Gastrointestinal event: nausea (45%), diarrhea (34%), constipation (27%)
• Other events: infection (58%), fatigue (28%), headache (24%)
• CRS (cytokine release syndrome): 88%, grade 3-5 CRS was only in 5%
• ICANS: 15%

In the CARTITUDE-4 cilta-cel trial of 416 patients, every single patient (100%) experienced some level of toxicity due to the treatment. 

• Hematologic event: neutropenia (89%), anemia (54%), thrombocytopenia (54%) 
• Gastrointestinal event: nausea (43%), diarrhea (33%), constipation (25%)
• Other events: infection (62%), fatigue (28%), headache (26.4%) 
• CRS (cytokine release syndrome): 76.1%, grade 3-5 CRS was 1.1% 
• ICANS: 19.3%  

What is Cytokine Release Syndrome (CRS)? 

It’s a systemic inflammatory response. The T cell stimulation causes a cytokine storm, and there are manifestations of similar flu-like illness such as CRS. Any organ can be involved (decreased blood pressure, kidney and/or lung involvement requiring intervention, etc. as the CRS becomes more serious. 

The predictors of severity include: 

• Initial disease burden 
  • If one has a lot of myeloma cells prior to CAR T, the higher their risk of developing serious CRS. Bridging therapy (such as chemotherapy) can be used before CAR T to lower this risk. 
• Strength of T cell activation and degree of T cell expansion 
  • Dictated by the actual CAR themselves- how strong it’s binding to the myeloma cell and how fast it’s moving through your body 

The treatment of CRS depends on the severity of the CRS. The treatment approach for mild cytokine release syndrome (Grades 1-2, the most common grades) is to treat the manifesting symptoms. 

Antihistamines (Zyrtec, Benadryl, Claritin, etc.), antipyretics (ibuprofen, acetaminophen), fluids, and antibiotics are used to treat symptoms that are caused by the CRS themselves. 

Severe CRS’s treatment approach is to treat the CRS itself. One of the cytokines causing the cytokine storm within your body is called IL-6. Tocilizumab (commonly known as Toci) is used to block IL-6. Steroids and supplemental oxygen are also used to treat severe levels of CRS. 

Although severe CRS can be scary, when recognized and treated early, it’s often preventable and reversible.

What is ICANS (Immune effector Cell-Associated Neurotoxicity Syndrome)?

When the T-cells are expanding throughout the body, seeking for myeloma cells, they cross the blood-brain barrier.

This barrier is separating our central nervous system (brain and spinal cord) from the rest of our body and the outside world. When the CAR-T cells cross the blood-brain barrier, they disrupt it.

ICANS is less understood than CRS in general, but the hypothesis is that the cytokines are able to enter the central nervous system space and there is able to be some toxic effects on our brain itself. 

Symptoms of ICANS are: 

• Mild confusion
• Headaches 
• Impaired fine motor skills (handwriting impaired) 
• Hallucinations
• Physical weakness 
• Cranial nerve palsies (can cause partial weakness or paralysis of certain areas) 
• Seizures 
• Somnolence (drowsiness or desire to fall asleep) 

The main way of treating ICANS is through the use of steroids. 

Reactions to the Bispecific Antibody Therapy in Today’s Myeloma 

Bispecific antibody therapies, as mentioned earlier, also use T-cells as part of their mechanism of action and, therefore, also result in similar side effects as CAR T-cell therapy. 

In the MajesTEC-1 (teclistimab) study of 165 patients, 100% of patients had adverse events. 

• Hematologic events: neutropenia (70%), anemia (52.1%), thrombocytopenia (40%)
• Gastrointestinal event: nausea (27%), diarrhea (47%), constipation (34%) 
• Other events: infection (76%), fatigue (46%), headache (39%) 
• CRS (cytokine release syndrome): 72%, grade 3-4 only 0.6%
• ICANS (14.5%)

In the MagnetisMM-3 (elranatamab) study of 123 patients, 100% of patients had an adverse event.

• Hematologic events: neutropenia (70%), anemia (52.1%), thrombocytopenia (40%)
• Gastrointestinal event: nausea (27%), diarrhea (47%), constipation (34%) 
• Other events: infection (76%), fatigue (46%), headache (39%) 
• CRS (cytokine release syndrome): 72%, no grade 3-4 
• ICANS: (3.4%) 

In the MonumenTAL-1 (talquetamab) study of 176 patients, 100% of patients had adverse events.  

• Hematological: neutropenia (67%), anemia (60%), thrombocytopenia (37%)
• Gastrointestinal event: nausea (30%), diarrhea (30%), constipation (7%) 
• Other events: infection (47%), fatigue (33%), headache (20%)
• CRS (cytokine release syndrome): 77%), grade 3-4 3%
• ICANS (3.3%) 

An interesting point to note is that talquetamab causes significant skin and taste problems. Peeling, itching, and skin darkening are prevalent. Many patients see significant changes to their nails and/or lose their sense of taste and feel a strange physiological change in their tongue. 

BCMA-targeted bispecifics are more likely to cause infection than other targeted therapies like GPRC5D and FcRH5.

The main cause of the high infection for bispecific antibodies is the continual administration of the therapy. The longer that one receives bispecifics, the higher the infection risk rate. Prophylaxis measures are taken to help prevent and manage these infections, such as antibiotics and IVIG. 

ICANS is less likely to occur in bispecific antibody therapy, although it is occasionally seen as seen in the lists above. This is because the T-cells are less likely to cross the blood/brain barrier than CAR-T cells. ICANS usually appear as headaches versus the more severe presentations in bispecific antibodies. 

Conclusion 

The main symptoms of immunotherapy in multiple myeloma are CRS (cytokine release syndrome), ICANS (immune effector cell neurotoxicity syndrome), infections, and more.

These symptoms are often reversible and easy to manage, but you, your caregiver, and your healthcare team should be aware of these risks and continually monitor for signs of these side effects. 

For more of this excellent presentation from Dr. Kara Cicero, watch the video below: