Navigating the Challenges of Bispecific Antibodies in Relapsed and Refractory Multiple Myeloma

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Bispecific antibodies have changed the treatment landscape for relapsed and refractory (R/R) multiple myeloma (MM) by offering a promising alternative to traditional treatment, including autologous stem cell transplantation and chimeric antigen receptor (CAR) T-cell therapies. However, bispecific therapies also come with challenges related to administration protocols, adverse effects (AEs), and logistical complexities, particularly within clinical pharmacy practice.

There are 3 bispecific antibodies—talquetamab (Talvey; Janssen Biotech, Inc), teclistamab (Tecvayli; Janssen Biotech, Inc), and elranatamab (Elrexfio; Pfizer Inc)—that have demonstrated benefit in targeting specific antigens, such as BCMA and GPRC5D, for the treatment of MM. A panel discussion at a Pharmacy Times Clinical Forum in Chicago, Illinois, moderated by Gabriel Hinojosa, PharmD, BCOP, shed light on best practices, barriers, and strategies for implementing these bispecific antibodies in R/R MM care.

“Right now, all 3 of these agents are recommended after at least 4 prior lines. So, this is all in [the] fifth line, and all must be triple-class refractory. In contrast, our CAR T-cell therapies now, hot off the press this year, are getting moved even earlier with [ciltacabtagene autoleucel (Carvykti; Janssen Biotech, Inc) being as early as second line and [idecabtagene vicleucel (Abecma; Celgene Corporation and 2seventy bio, Inc)] in the third-line setting,” said Hinojosa, a clinical pharmacy specialist in the Division of Hematology and Oncology at UT Southwestern Medical Center in Dallas, Texas. “That has taken some of the question out for sequencing if you’re using CAR T in those early lines. But for our patients [who] do still get to [the] fifth line, sequencing between CAR T and bispecifics can be complicated.”

The Promise of Bispecific Antibodies in R/R MM

Bispecific antibodies target 2 antigens simultaneously, a mechanism of action that distinguishes these therapies from traditional monoclonal antibodies and CAR T-cell therapies, Hinojosa explained during the Clinical Forum discussion. In R/R MM, bispecifics primarily target BCMA, a protein highly expressed on the surface of malignant plasma cells, and GPRC5D, a protein associated with MM cell survival.

One key advantage of bispecific antibodies is their ability to bypass the long manufacturing timelines and complex logistics associated with CAR T-cell therapies. Unlike CAR T, which requires personalized T-cell extraction, modification, and reinfusion, bispecific antibodies can be administered more rapidly, allowing faster patient access to treatment.

Toxicity Management and Patient Monitoring

The administration of bispecific antibodies for patients with MM requires vigilant monitoring for AEs, particularly cytokine release syndrome (CRS) and neurotoxicity. CRS is a common complication associated with immunotherapies, including bispecific antibodies, and is characterized by systemic inflammation resulting from the activation of immune cells. Neurotoxicity, including immune effector cell–associated neurotoxicity syndrome (ICANS), is another critical concern that can complicate treatment.

The clinical management of CRS and ICANS can be challenging, but it is essential for ensuring patient safety. Hinojosa emphasized that most CRS cases associated with bispecific antibodies are mild to moderate, making them manageable in outpatient settings. This is an important consideration, as many patients with R/R MM receive bispecific antibody therapies through outpatient administration, reducing the strain on inpatient resources. However, severe CRS cases may still necessitate hospitalization and intensive monitoring.

“All 3 of these agents do carry risk for CRS and ICANS like all of our cellular therapies,” Hinojosa said. “Because of that, they do have [Risk Evaluation and Mitigation Strategies (REMS)] program requirements. We have step-up dosing for these to minimize that risk of CRS. There are recommendations for that step-up dosing to be done inpatient, although more centers are starting to do step-up dosing outpatient with close monitoring. That inpatient observation for at least 48 hours after each step-up dose is still on label, but we’re seeing more centers consider doing this outpatient.”

Step-up dosing protocols involve patients receiving a gradually increasing dose over several treatment cycles. According to the panelists, institutions such as the University of Chicago and City of Hope Chicago have integrated step-up dosing protocols into their electronic health records (EHRs), ensuring that each dose is verified before administration, which reduces the risk of dosing errors and ensures CRS resolution before advancing to higher doses.

Infection prevention also emerged as a critical theme, with panelists debating the role of intravenous immunoglobulin (IVIG). Jennifer Collins, PharmD, BCOP, a PGY-2 hematology/oncology pharmacy residency director at UChicago Medicine, outlined her institution’s approach, which includes monthly IVIG administration for patients with IgG levels below 400 mg/dL. However, Hinojosa, an IVIG skeptic, challenged the efficacy of broad usage.

“Why wait for levels to drop? Preventing infections proactively is often advocated, but the evidence for routine IVIG in all cases isn’t compelling,” Hinojosa said.

Variability in Clinical Practices and Therapeutic Sequencing

A recurring theme during the panel discussion was the variability in how different institutions approach the use of bispecific antibodies in R/R MM, reflecting differences in resources, patient demographics, and institutional protocols. For example, some centers may prioritize CAR T-cell therapies early in treatment due to their high efficacy, whereas others opt for bispecific antibodies as firstline therapies, particularly in high-risk patients or those who have experienced rapid relapse.

During the discussion, Hinojosa asked panelists about the factors driving the choice between teclistamab and elranatamab, specifically whether payer, provider, or patient preference plays a dominant role. According to Connor Roth, PharmD, a hematology/oncology pharmacy specialist at Franciscan Alliance in Chicago, patient preference can play a significant role in therapeutic selection. For patients, the need to travel or the need for caregiver support for a particular treatment can impact preference. For example, teclistamab is typically administered every week for the first 2 cycles, after which the treatment schedule may switch to biweekly dosing. In contrast, elranatamab offers a flat dosing schedule, making it an attractive option for the outpatient setting with a reduced need for hospitalvisits; this may pose a significant advantage for some patients based on their ability to travel to and from the treatment center and their ability to take time off work.

However, despite the logistical benefits of some bispecifics, clinical experience and institutional preferences can often drive the selection of one therapy over another, according to the panelists. At City of Hope, for instance, teclistamab was initially favored due to provider familiarity, but the institution has since adopted both teclistamab and elranatamab to expand therapeutic coverage, explained Erica Marchese, PharmD, MHA, BCPS, BCOP, director of pharmacy at City of Hope Chicago. At Franciscan Alliance, Roth noted that teclistamab is often considered for patients with specific disease characteristics, and elranatamab is often considered for those with refractory disease.

Kaitlin Kelly, PharmD, a clinical pharmacy specialist in hematology/oncology (multiple myeloma and lymphoma) at the University of Chicago, raised concerns about provider-dependent practices, which can lead to variability in patient care. Kelly explained further that her institution is working toward a standardized approach, leveraging elranatamab’s operational advantages, such as reduced drug waste and ease of preparation, to build consensus among providers.

Overcoming Logistical Barriers in Clinical Pharmacy Practice

One significant challenge in implementing bispecific antibodies in clinical practice is coordinating care across multiple settings, especially when dealing with outpatient administration. Within REMS programs, bispecific antibodies require careful oversight to ensure compliance with safety standards. These programs often necessitate additional documentation and coordination between pharmacy teams, clinical providers, and nursing staff.

The panelists discussed the importance of centralizing REMS oversight and creating streamlined workflows for medication safety. For example, the University of Chicago has employed dedicated REMS coordinators to oversee compliance and training, ensuring all staff members know the potential risks and management strategies associated with bispecific antibodies.

At City of Hope Chicago, Marchese advocated embedding REMS requirements directly into EHR workflows to ensure seamless integration and reduce patient care delays. Additionally, Marchese noted that although REMS requirements for dose-by-dose verification were initially stringent at her institution, current adaptations have allowed for more efficient workflows without compromising safety. The panelists concurred that flexibility in dosing schedules and

robust communication among care teams are vital for optimizing patient outcomes.

Collins noted that a lack of pharmacist involvement can be a challenge at UChicago Medicine community sites. “I think one of our biggest barriers with our community sites is, and I’m not saying this because I’m in a room of pharmacists, but it’s really the lack of presence of pharmacists at our sites or community sites,” Collins said. “I think the oncologist just can’t navigate how to set up any type of [REMS] program like this without a pharmacist. Then lack of education just for our nursing staff. I do think having a pharmacist there to really build this program up is essential.”

Another operational challenge discussed was the management of step-up dosing protocols. According to the panelists, some institutions have developed systems within their EHRs that separate treatment days and track the clearance of each dose, ensuring that the CRS resolution is documented before proceeding to subsequent doses. This approach improves patient safety and ensures all team members know the patient’s treatment progress.

The Role of Education and Standardized Protocols

Education and training are crucial components of managing bispecific antibodies effectively, according to the panelists. Ensuring that all care team members, including pharmacists, nurses, and physicians, are well versed in each therapy’s administration protocols, AEs, and management strategies is key to improving patient outcomes. Integrating educational materials into clinical workflows and ensuring clear communication among interdisciplinary teams helps standardize care and prevent errors.

At the institutional level, pharmacists are often responsible for educating staff on the potential toxicities of bispecific antibodies and ensuring that appropriate preventive measures, such as premedication strategies for CRS, are in place. For example, many institutions have established protocols for managing AEs such as dysgeusia and weight loss, which are more prevalent with talquetamab therapy, by using a combination of dietary support and symptom management strategies. Educating staff on this protocol can be an essential part of the pharmacist’s role in collaboration with other care team members, the panelists explained.

Collaborating Across Institutions and Optimizing Patient Access

The discussion also touched on the importance of collaboration between academic and community oncology centers in facilitating patient access to bispecific antibodies. In many cases, community sites face logistical challenges in stocking and administering these complex therapies, particularly considering the high cost and limited availability of certain supportive medications, such as tocilizumab (Actemra; Genentech, Inc), which is used to manage CRS. To address these challenges, some institutions have developed formal referral pathways to ensure that patients can be referred to academic centers for the more intensive phases of treatment, such as the initial step-up dosing, before returning to community care for ongoing therapy.

Successful partnerships between academic and community practices require proactive engagement and flexibility, according to the panelists. Regular meetings and iterative protocol adjustments ensure that community sites feel confident and capable of managing complex therapies. For example, one institution developed a “subprotocol” tailored to a specific community site’s needs, reflecting a commitment to compromise and collaboration.

The role of technology in improving communication and coordination between institutions was also highlighted. EHRs and telemedicine services can bridge gaps between academic and community centers, ensuring that patient information is easily shared and that care continuity is maintained. Text and email communication between attending physicians can also streamline urgent decision-making, and dedicated efforts to formalize these interactions improve efficiency and scalability.

Looking Forward

As bispecific antibodies continue to evolve as a treatment option for R/R MM, clinical pharmacy practices must adapt to meet the challenges posed by these novel therapies. Although bispecific antibodies offer significant advantages over other treatments, their use requires meticulous patient monitoring, robust institutional protocols, and high collaboration across health care teams and institutions. By addressing these challenges, oncology pharmacy teams support optimizing the use of bispecific therapies, improving patient outcomes, and advancing the care of individuals with R/R MM.