Redefining Readiness: Are We Prepared for the Bispecific Era in Multiple Myeloma? | Written Recap

Zahra Mahmoudjafari, Pharm.D., MBA, is a clinical pharmacy manager in the Division of Hematologic Malignancies and Cellular Therapeutics at the University of Kansas Health System in Kansas City, Kansas. In this Managed Healthcare Executive K-Cast video series, Mahmoudjafari discussed a wide range of issues concerning bispecific antibodies as treatment of multiple myeloma, including their relationship to CAR-T therapy, formulary placement, some of the operational and financial challenges they pose and safety and toxicity issues.

Transformative treatment

The emergence of bispecific antibodies has transformed the treatment landscape for relapsed/refractory multiple myeloma by offering an immediate and accessible, off-the-shelf immunotherapy for patients with multiple myeloma, Mahmoudjafari said. Bispecific antibodies can “generate deep responses in patients with limited options,” she noted. Moreover, unlike CAR-T therapy, which is often personalized and requires weeks of manufacturing, bispecific antibodies can be administered fairly quickly, said Mahmoudjafari, a time difference crucial for patients with aggressive or symptomatic disease progression.

Bispecific antibodies have a dual-binding mechanism that typically involves binding to the CD3 protein complex on T cells and the B-cell maturation antigen (BCMA) on myeloma cells, Mahmoudjafari explained. Patients do not need lymphodepleting chemotherapy, frequently seen in CAR-T therapy, which, Mahmoudjafari said, is “especially impactful in those patients who aren’t candidates or have progressed after CAR-T therapy. In addition, real-world and emerging clinical trial data have shown that the BCMA-targeted bispecific antibodies retain activity in patients who previously received other BCMA-targeted therapies. The responses may be somewhat attenuated compared with BCMA-naïve populations, Mahmoudjafari said, but “the efficacy remains clinically meaningful.” She said that at her center, they have seen objective response rates ranging from 40% to 50% in patients treated with teclistamab [Tecvayli] with prior exposure to BCMA-targeted treatment. “This opens up some significant sequencing possibilities and positions bispecifics as a valuable bridge or follow-up strategy post CAR-T,” she said. The ability to retarget the same antigen through different mechanisms “gives us the flexibility in designing salvage regimens while managing that antigen-specific activity,” Mahmoudjafari added.

Forms of BCMA treatment

The BCMA-targeted therapies have become a cornerstone in the treatment of relapsed refractory multiple myeloma, explained Mahmoudjafari. But the three BCMA-directed modalities — CAR-T therapy, bispecific antibodies, and antibody-drug conjugates — vary significantly in how they are administered, their efficacy, their toxicity profiles and the logistical issues they pose.

CAR-T therapies have some of the highest response rates and depth of responses in relapsed/refractory melanoma, with a median progression-free survival of nine to
12 months. Real-world data have shown that the outcomes are durable, according to Mahmoudjafari.

Mahmoudjafari said the bispecific antibodies have the advantage of immediate treatment initiation, which makes them suitable for rapidly progressing disease patients who can’t wait for CAR-T therapy. Data from clinical trials have shown an overall response rate of 60% to 75%, a complete response rate of 25% to 40%, and progression-free survival ranging from seven to 12 months.

Clinical trial data for belantamab mafodotin (Blenrep), an antibody-drug conjugate, have demonstrated a more modest overall response rate, Mahmoudjafari said. The drug is no longer on the market after failing to show superiority on primary end points in a confirmatory trial, she said. She noted, though, that the FDA is reviewing data from the DREAMM-7 and DREAMM-8 trials and that it might be reapproved.

Mahmoudjafari compared the safety and toxicity of the three modalities. CAR-T therapy is often associated with the highest-grade cytokine release syndrome (CRS) and immune cell-associated neurotoxicity syndrome (ICAN), she said, often requiring significant care and prolonged hospitalization. The risk of prolonged cytopenia and infections is also high, requiring significant infrastructure and 24/7 access to care and postinfusion monitoring capabilities.

With the bispecifics, CRS and ICAN are still a concern, but they tend to be lower grade, Mahmoudjafari said. Patients are pretreated with corticosteroids, and the side effects tend to be more predictable because of step-up dosing. Infection remains a significant risk, and patients often require intravenous immunoglobulin replacement therapy and close monitoring.

Mahmoudjafari said the concern with belantamab mafodotin is the significant ocular toxicities that require extensive monitoring.

NCCN guidelines

The National Comprehensive Cancer Network (NCCN) guidelines are a “vital framework” for both clinicians and payers to guide evidence-based treatment sequencing in multiple myeloma, Mahmoudjafari said. But when it comes to novel immunotherapies, such as bispecific antibodies and CAR-T therapy, there is some flexibility that often creates gray areas for interpretation, she said.

Currently, NCCN assigns a category 1 recommendation (its highest) to CAR-T therapy for patients with multiple myeloma who have received at least four prior lines of treatment, Mahmoudjafari said. She said that bispecific antibodies such as teclistamab, elranatamab (Elrexfio), and the newly approved linvoseltamab (Lynozfic) are recommended for similarly heavily pretreated patients, although their exact placement is evolving. One CAR-T has a second-line indication, but all the bispecific antibodies are recommended after four prior lines. NCCN likely ranks CAR-T higher than the bispecific antibodies because of the lack of long-term efficacy data about the bispecific antibodies, she said.

“Because NCCN can be a little gray, institutions like mine are developing internal treatment pathways that look at prioritizing bispecifics for patients who are not candidates for CAR-T or have relapsed post CAR-T,” Mahmoudjafari said.

She stressed the importance of educational strategies that focus on caregivers as well as patients. Education should include the rationale for choosing treatment with bispecific therapies and training so that patients and caregivers can recognize the early signs of CRS (fever, fatigue, hypotension) and ICAN (confusion, tremors, difficulty speaking).

The future

Mahmoudjafari praised the pace of innovation in treating multiple myeloma with the advent of the bispecific antibodies and novel combinations in the pipeline. The recent approval of linvoseltamab increases choice among the bispecific antibodies. She said linvoseltamab has shown higher overall response rates, even in heavily pretreated patients, just like the other agents in the class. It also has a step-up dosing schedule and a safety profile that may reduce hospitalization, enhancing the feasibility for outpatient administration. For payers, it allows a conversation about whether all should be covered equally or if there should be some referencing.

Mahmoudjafari said novel combinations of bispecific antibodies, such as talquetamab and teclistamab, introduce a dual-targeted strategy, which may offer enhanced efficacy and potentially help delay resistance development. “But from a payer perspective, the cost of care per patient remains a major concern, especially as patients are now living longer and moving through multiple lines of care,” she said. “So truly, we really need some cost-effective analysis and patient-reported outcome data to support value-based contracting in this space.”