Bispecific Antibodies — The Thunderdome of Myeloma

“Bispecific antibodies have become an amazing resource in the relapse refractory myeloma world,” Dr. Joshua Richter, an associate professor of medicine at the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, and the director of myeloma at the Blavatnik Family Chelsea Medical Center at Mount Sinai, tells SurvivorNet Connect.

These antibodies have revolutionized the treatment landscape for multiple myeloma, offering new hope for patients in advanced stages of this disease. Currently, three bispecific antibodies are approved for use in the management of multiple myeloma: teclistamab (brand name Tecvayli), elranatamab (brand name Elrexfio), and talquetamab (brand name Talvey).

These therapies target specific antigens on myeloma cells while simultaneously engaging the immune system, notably T cells, to attack the cancer.

Approved Bispecific Antibodies

1. Teclistamab – This bispecific antibody targets B cell maturation antigen (BCMA) and CD3. BCMA is highly expressed on myeloma cells, making it a prime target for therapeutic intervention. Teclistamab engages T cells through the CD3 receptor, leading to the targeted destruction of cancerous cells.
2. Elranatamab – Like teclistamab, elranatamab also targets BCMA and CD3, utilizing a similar mechanism of action. This dual engagement amplifies the body’s natural immune response against myeloma cells.
3. Talquetamab – Talquetamab differs slightly from the other two bispecific antibodies, as it targets GPRC5D, a receptor that is abundantly expressed in myeloma cells, and CD3. The engagement of CD3 facilitates T-cell activation, resulting in the death of myeloma cells.

“Elrexfio is one of our FDA approved BCMA bispecific antibodies along with Teclistamab (Tecvayli). If you look at the efficacy and tolerability data for Elrexfio and Tecvayli, they’re pretty much the same thing. There are a few subtle differences, mostly in the realm of administration,” says Dr. Richter.

“Elranatamab has a shorter step up time, only five days as opposed to seven days. For Teclistamab, it’s fixed dose. So it’s a flat dose for everyone, not a weight-based dosing schedule. But essentially whichever one you can get is the right drug. If your care team can get you a Elrexfio, that’s the right drug. If they can only get you Teclistamab, that’s the right drug. Both are extremely effective in relapse myeloma,” he adds.

Administration of Bispecific Antibodies

In the United States, the administration of bispecific antibodies for myeloma occurs under strict regulatory oversight. All three approved bispecific antibodies are prescribed through restricted programs known as Risk Evaluation and Mitigation Strategy (REMS) programs, designed to closely monitor for severe adverse events. Patients receive these therapies subcutaneously, with gradually increasing doses over the first week. This gradual dose escalation helps mitigate some of the more severe side effects associated with these potent agents.

“One of the issues is the upfront administration, with the concerns for Cytokine Release Syndrome and Immune Effector  Cell-Associated Neurotoxicity Syndrome (ICANS). Patients often need to be admitted to the hospital for up to a week for the step up dosing,” says Dr. Richter.

“This is a lot easier in an academic setting where we have all of these things set up and both practice and hospital are one in the same. This is a much more complicated issue in the community. And one of the things I want to make clear is that we are happy to partner with the community at any and all of the academic centers that treat myeloma. If you have a patient that you think is ideal for a bispecific antibody, but you’re concerned about the initial step up, send them to us. We can give them that initial step up in the hospital and send them back to you for routine continual care after that initial StepUp is done. So we need to kind of work from all standpoints to cover everyone,” he adds.

Following the initial dose escalation, patients are typically placed on weekly or bi-weekly dosing schedules. The decision on dosing frequency depends on the patient’s response to treatment and overall tolerance. Importantly, patients are monitored closely for at least 48 hours after each dose escalation to detect and manage any emerging toxicities.

Key Safety Considerations

As with all potent cancer therapies, bispecific antibodies come with a range of adverse effects that healthcare professionals must be aware of. Early recognition and management of these side effects are crucial for minimizing their impact and ensuring that patients can continue to benefit from these therapies.

Teratogenicity

Bispecific antibodies can cause harm to fetuses, making them contraindicated in pregnant patients or those planning to become pregnant. Additionally, patients who are breastfeeding should avoid these therapies due to the potential for harm to infants. As a result, strict precautions must be taken to ensure that patients are not pregnant when they start treatment, and contraceptive measures must be in place during treatment.

Cytokine Release Syndrome (CRS)

Cytokine release syndrome is one of the most serious potential side effects associated with bispecific antibodies. CRS results from a systemic immune response, with symptoms that can include high fever, flu-like symptoms, hypotension, and changes in mental status. In severe cases, CRS can be life-threatening.

Treatments for CRS may include the use of tocilizumab, an interleukin-6 (IL-6) inhibitor, along with corticosteroids to dampen the inflammatory response. Preventive measures, including pretreatment with corticosteroids, histamine-1 receptor antagonists, and antipyretics, can help reduce the risk of CRS occurring after the administration of bispecific antibodies.

Neurologic Toxicities

Although less common than CRS, neurologic toxicities can still pose a significant risk to patients receiving bispecific antibodies. Immune effector cell-associated neurotoxicity syndrome (ICANS) is the most concerning neurologic side effect, leading to changes in mental status, confusion, behavioral alterations, and speech abnormalities.

Because of the potential severity of ICANS, healthcare professionals must remain vigilant for early signs of neurologic complications in their patients. Dose adjustments or interruptions may be required to manage ICANS, and detailed recommendations for dose modifications are included in the prescribing information for each bispecific antibody.

Hepatotoxicity

Bispecific antibodies can also cause liver damage, necessitating regular monitoring of liver function during treatment. Before starting therapy, baseline liver enzyme levels and bilirubin should be measured. These tests should be repeated throughout treatment, particularly if patients develop any signs of hepatotoxicity, such as jaundice or elevated liver enzymes.

Infection Risk and Antimicrobial Prophylaxis

Severe and even fatal infections have been reported in patients treated with bispecific antibodies. Given the immunosuppressive effects of these therapies, patients should not start treatment if they have an active infection. Prophylactic measures are necessary to minimize the risk of serious infections. One standard precaution is to offer antiviral prophylaxis to prevent the reactivation of herpes zoster, following local guidelines for patient management.

Local Injection Site Reactions

Approximately one-quarter of patients treated with bispecific antibodies experience local reactions at the injection site. These reactions are generally mild and include redness, swelling, and tenderness at the injection site. However, healthcare providers should monitor patients for any signs of infection or more severe complications.

Additional Adverse Effects Associated with Talquetamab

While all bispecific antibodies have a similar overall safety profile, talquetamab has been associated with unique adverse effects that healthcare providers must be aware of. These include:

• Skin and Nail Toxicities: The majority of patients treated with talquetamab experience skin and nail changes, which may range from mild (grade 1 or 2) to severe. Skin reactions can include maculopapular rash, erythematous rash, xerosis (dry skin), and pruritus (itching). Patients should be monitored for skin toxicities, and appropriate supportive measures should be employed to alleviate discomfort.
• Oral Toxicity and Weight Loss: Talquetamab is also linked to oral toxicities and significant weight loss in many patients. Symptoms may include oral sores, changes in taste, and difficulty eating, which can contribute to malnutrition if not addressed early. Patients should be encouraged to report any oral issues promptly, and early intervention is crucial, as some of these toxicities may not be reversible.