What might be the future applications for BCMA-directed bispecific antibodies in MM and other plasma cell dyscrasias?

The Multiple Myeloma Hub spoke with Sagar Lonial, Winship Cancer Institute of Emory University, Atlanta, US. We asked, What might be the future applications for B-cell maturation antigen (BCMA)-directed bispecific antibodies in multiple myeloma (MM) and other plasma cell dyscrasias?

In this interview, Sagar Lonial discussed the expanding role of BCMA-directed bispecific antibody therapies beyond relapsed/refractory MM, including their potential applications in high-risk smoldering MM and light chain (AL) amyloidosis. Lonial also evaluated emerging strategies for optimizing dosing schedules, enhancing the patient experience, and mitigating treatment resistance. 

Key learnings

• BCMA-directed bispecific antibodies are currently under investigation as a novel therapeutic approach for patients with high-risk smoldering MM, a population with limited treatment options and a significant unmet need.

• Ongoing clinical trials are evaluating the role of BCMA-directed bispecific antibodies in high-risk smoldering MM and aim to determine whether early intervention with bispecific antibodies can delay progression to symptomatic MM.¹

• In AL amyloidosis, where tumor burden is generally lower, BCMA-directed bispecifics are being explored as a strategy to achieve measurable residual disease (MRD) negativity with shorter treatment durations compared to conventional regimens. This approach could potentially lead to faster responses while reducing cumulative toxicity.²

• The lower tumor burden observed in smoldering MM and AL amyloidosis presents an opportunity to optimize treatment duration. The overarching goal is to reduce the frequency of treatment and improve tolerability, without compromising efficacy.^1,2

• One of the primary challenges in bispecific antibody therapy is defining the optimal dosing schedule and, particularly, determining whether treatment can be safely discontinued after achieving sustained MRD negativity. Optimizing dosing is important in diseases with lower tumor burden, where prolonged therapy may not be necessary and could increase the risk of adverse events.³

• Reducing continuous dosing and allowing discontinuation of treatment could improve patients’ quality of life while also helping to mitigate resistance mechanisms, such as mutations in BCMA.

• There are also ongoing clinical trials evaluating BCMA-directed bispecifics in combination regimens for newly diagnosed multiple myeloma and early relapse settings. 

• A shift towards individualized, response-adapted dosing intervals is also being explored; adaptive dosing could facilitate improved immune system recovery, reduce infectious complications, and further improve treatment tolerability.

• To improve treatment convenience and quality of life for patients, strategies such as home-based or community administration of BCMA-directed bispecifics are being evaluated, including in the ERICA trial (NCT06015542) where self-administration of elranatamab in patients with relapsed/refractory MM is being evaluated.⁴

• The proactive administration of tocilizumab is being evaluated at the Winship Cancer Institute of Emory University to mitigate cytokine release syndrome and enable outpatient administration of BCMA-directed bispecifics.

• BCMA-directed bispecific antibodies therefore offer a promising approach to achieving deep, durable responses in plasma cell dyscrasias, with evolving strategies focused on minimizing treatment duration, enhancing tolerability, and enabling treatment-free intervals guided by MRD status.