Bispecific Antibodies: Early Side Effects

Bispecific antibodies are a promising treatment for myeloma, but they can cause early side effects, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).

• Bispecific antibodies have two arms, one targeting myeloma cells and the other engaging immune cells to destroy myeloma.
• Early side effects, typically within the first month of therapy, may include CRS and ICANS.
• CRS is an immune system overreaction, classified into grades 1 to 4, with symptoms like fever and blood pressure changes. Most CRS cases are manageable.
• CRS usually occurs within the first few doses of bispecifics, often requiring hospital admission for observation.
• Neurological side effects, including ICANS, can manifest as speech difficulties, tremors, confusion, or coma and occur less frequently than CRS.
• Patients may undergo basic tests to monitor ICANS, such as walking, writing, and answering questions.
• Less than 10% of patients receiving bispecific antibodies experience ICANS, usually in the first few weeks.
• Treatment for ICANS may involve fluids, steroids, and tocilizumab.
• The effects of bispecific antibodies may vary based on a person's race or ethnicity.
• Prophylactic measures, such as using tocilizumab to prevent CRS and ICANS, are being tested.
• Ongoing research aims to maximize the benefits of bispecific antibodies while minimizing side effects in myeloma treatment.

Throughout this series, we've been exploring a novel way of treating myeloma using bispecific antibodies or bispecifics. These remarkable new drugs have two arms; one that hooks onto the myeloma cell and the other that engages a local immune cell, usually a T-cell, to help destroy the myeloma. These are highly effective treatments, but like all therapies, they do come with some potential side effects. In this video, I will review the early side effects or those we typically see within the first month of starting therapy. Complications can occur right after patients receive their first dose of a bispecific antibody. I will focus on the two most common effects. Cytokine Release Syndrome are CRS, and Immune Effector Cell-Associated Neurotoxicity Syndrome or ICANS.

Cytokine Release Syndrome. When T-cells are engaged, the body can have a systemic reaction called Cytokine Release Syndrome or CRS for short. It's like an overreaction of the immune system to the immunotherapy given. We classify it Grade 1 to 4, or Grade 1, 2, 3, and 4, based on the key symptoms and signs of fever and blood pressure. Grade 3 and 4 CRS require admission to hospital in an intensive care unit as patients need medications to boost their blood pressure. Thankfully, most CRS with bispecifics is grade one or grade two, and can be managed rapidly, although usually in hospital or at least an observation unit. CRS typically occurs with the first few doses of a bispecific. Indeed, most bispecifics will have a step-up dosing strategy to give the patient a very low dose of the drug to reduce the risk of CRS. This step up dosing may be given over several days, often in a hospital or in a dedicated observation unit. Some centers may do some of this entirely as an outpatient, so it is critical that patients and their care partners be aware of the potential side effects so they can be communicated to the healthcare team.

What should patients and their care partners expect early on when receiving a bispecific antibody? Well, most centers will admit their patients for at least five to seven days. Some may even have specialized units. The length of admission and observation will vary and could be planned for up to two weeks. This, of course, could even be longer if a patient develops CRS. Most CRS will occur within the first few doses, and it is often signaled with fever. Approximately 50% of patients will need treatment of that fever. Options for treatment include close observation, fluids, a drug called tocilizumab or toci for short, and steroids. Local institutional practices vary as to when each of these approaches may be employed.

The second side effect we watch carefully for is a neurological one. Although we see this less commonly than we do with CAR-T cell therapy, we can see varied and different effects on the neurological system of a patient, often called neurotoxicity. One in particular we watch for is ICANS or Immune Effector Cell-Associated Neurotoxicity Syndrome. This side effect can manifest as really any neurological symptom. Most common ones include difficulty speaking, tremor, confusion, and even coma. These can become more severe if not treated, so we are careful to watch for these. Patients and their care partners may be involved in performing basic testing to monitor for ICANS in the form of the ICE score, patients may be asked to walk, write, and answer basic questions to assess their status. Thankfully, ICANS occurs in less than 10% of patients receiving bispecific antibodies and tends to happen in the first few weeks. The most commonly used treatments include fluids, steroids, and tocilizumab.

Importantly, we are beginning to learn that these effects may also be different based on a person's race or ethnicity. As we treat more patients and understand these immunotherapies better, we will have more optimal ways to manage all patients being treated with bispecifics. Looking to the future, we may even become more aggressive in trying to prevent CRS and ICANS in the form of prophylaxis or prevention with drugs like Tocilizumab, this is being tested now. All drugs in myeloma go through an evolution to maximize their benefit and reduce their toxicity. We are going through that process now with bispecific antibodies, so our patients can have the greatest benefit and the least side effects.