Bispecific Antibodies for Myeloma Treatment

One of the newest classes of drugs in multiple myeloma is a group of therapies known as bispecific antibodies. They are a form of immunotherapy where we can engage a patient’s own immune system to fight their myeloma. They are also known as bispecific T-cell engagers or bispecifics. 

They are similar to monoclonal antibodies that we have described before. How exactly? Bispecifics, like monoclonal antibodies, can attach to a myeloma cell by something on the cell’s surface – an antigen. But they are also different than monoclonal antibodies. Bispecifics have a second arm that can engage a local immune cell to activate it to destroy the myeloma cell.  

That is why they are called “Bi-” specific, because they have two arms. One arm hooks on to the myeloma cell, and the other arm hooks on to a local immune cell, usually a T cell.  

This dual effect is very important. It leverages the action of a monoclonal antibody in identifying the target on the myeloma cell. Also, it engages more of the immune system by activating a nearby T cell. We know that T cells are white cells that essentially function as soldier cells that can be activated to destroy other cells. When we perform CAR T-cell therapy (Chimeric Antigen T cell therapy), we remove T cells from patients. Then, we “train” or manufacture these T-cells to recognize and attack myeloma cells once we give them back to patients. With bispecific antibodies, we simply deliver a drug that brings together the myeloma cell and a local T cell to engage it. 

This means that patients do not need to have their T cells collected, but we give the drug directly to the patient “off the shelf.”  

That way, the bispecific antibody can work immediately to treat the patient’s multiple myeloma.  

These agents can be given intravenously or subcutaneously (in the skin). They are usually given in a “step-up” dosing strategy, meaning lower doses are given for the first few times to reduce the risk of side effects.  

They must be given at an approved institution. Some centers administer bispecifics as an inpatient procedure, while others do so as an outpatient procedure. When given as outpatient care, remote monitoring is used to detect potential side effects. 

Several bispecific antibodies have been approved, and many more are being developed. One of the important differentiators of these treatments is the target, or antigen, that they adhere to on the cell surface. The most common target is BCMA or B Cell Maturation Antigen. Other targets include GPRC5D and FcRH5. I discuss those other targets in another “Myeloma Made Simple” video. 

There is a lot of excitement about these agents. One reason is their overall response rate. There is variability between the different bispecifics, but in general, response rates range from approximately 60% to 75% in patients with very heavily pretreated myeloma. 

At present, three approved bispecific antibodies are teclistamab (also known as Tecvayli™), talquetamab (or, Talvey™) and elranatamab (Elrexfio™). 

Each of these is approved for patients who have had at least 4 lines of prior therapy, including a proteasome inhibitor, an immunomodulatory agent, and a monoclonal antibody.  

Bispecific antibodies have unique side effects. As with CAR T-cell therapy, patients can experience Cytokine Release Syndrome (or, CRS), especially when first being treated. To reduce the risk of CRS, some bispecific agents have a lower “step-up” dose. CRS often starts with a low-grade fever, but it can progress to low blood pressure, requiring in-hospital monitoring.  

CRS can range from Grade 1 to 4. Most CRS with bispecifics is only Grade 1 or 2, but patients must be monitored carefully to prevent progression to a higher grade. CRS may be treated with agents such as tocilizumab, steroids, and supportive care. Most CRS occurs within the first week of the first dose of a bispecific antibody. 

Another potential side effect is a neurological one called ICANS, or Immune Effector Cell Associated Neurotoxicity Syndrome. This tends to occur later than CRS. ICANS may include almost any neurological symptom like confusion, headache, or seizures. It is usually treated with steroids and supportive care. 

[Common side effects include Cytokine Release Syndrome (CRS), Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS), low blood counts, low immunoglobulin levels, and infections, which require close monitoring and management.] 

Later effects of bispecific antibodies include low blood counts, low immunoglobulin levels (namely IgG), infections, and neurological symptoms. Patients should be monitored closely, especially as unusual infections can occur in patients on this treatment. Often patients will require IVIG (intravenous IgG) due to their low immunoglobulin levels. The dosing frequency of the drug may also be reduced.  

In summary, bispecific antibodies are a novel form of immunotherapy where we can bring together a myeloma cell and a T cell to treat a patient’s myeloma. They are highly effective in heavily pretreated patients. Yet, we must manage the side effects, especially the early ones like CRS and ICANS. Many more bispecifics are being developed and will become standard therapy for myeloma patients at all stages of the disease course.