Belantamab mafodotin combination therapies in early RRMM

During the Multiple Myeloma Hub Steering Committee Meeting in November 2024, key opinion leaders met to discuss belantamab mafodotin combination therapies for early relapsed/refractory multiple myeloma (RRMM), with a focus on patient-specific considerations when developing personalized treatment plans. The discussion included emerging data from recent clinical trials; the integration of novel therapies, such as B-cell maturation antigen (BCMA)-directed therapies; and the challenges of selecting appropriate regimens based on patient and disease characteristics.

The meeting opened with a presentation by María-Victoria Mateos on the safety, efficacy, and positioning of novel combinations of belantamab-based regimens, BCMA-directed chimeric antigen receptor (CAR) T-cell therapies, and bispecific antibodies in various patient scenarios. Following this presentation, Mateos chaired a Q&A session featuring Sagar Lonial, Paul Richardson, Shaji Kumar, Hermann Einsele, Heinz Ludwig, Bruno Paiva, Meral Beksaç, Elena Zamagni, Sonja Zweegman, Morie Gertz, and Miles Prince.

Presentation

Efficacy and safety of belantamab-based combinations

• DREAMM-7 (NCT04246047): Belantamab combined with bortezomib and dexamethasone (Bela-Vd) demonstrated superior progression-free survival (PFS) of 36.6 months compared to 13.4 months for daratumumab-Vd, along with an overall survival (OS) benefit, particularly in lenalidomide-refractory and high-risk cytogenetic subgroups.
• DREAMM-8 (NCT04484623): Belantamab in combination with pomalidomide and dexamethasone (Bela-Pd) showed significant improvements in PFS and increased durability of response compared with pomalidomide and dexamethasone alone, with consistent efficacy observed across subgroups.
• Ocular toxicities were common; however, they were manageable with dose adjustments;  extended dosing intervals effectively reduced ocular toxicity without compromising efficacy.

Challenges in selecting therapies

• Determining the optimal sequencing of BCMA-targeted treatments including belantamab-based combinations, CAR T-cell therapies, and bispecific antibodies, depends on multiple factors, such as age, transplant eligibility, and prior treatments.
• Additional considerations include efficacy, safety data, accessibility, and patient preferences.

Advantages of belantamab-based combinations

• Practical benefits include off-the-shelf availability, manageable toxicity, and no requirement for hospitalization.
• Reduced dose intensity and extended intervals may help mitigate ocular toxicity concerns while maintaining efficacy.
• Extended dosing intervals also improve the patient experience, it is less intrusive on daily life.

Discussion

• Data on prior BCMA-targeted antibody-drug conjugate (ADC) exposure and response to CAR T-cell therapy show varied outcomes, with some studies reporting reduced efficacy; however, real-world experience does not always substantiate this finding.
• Longer intervals between BCMA-targeted therapies (>6 months) appear to improve outcomes.
• Patients pretreated with BCMA-directed bispecific antibodies or ADCs often have poorer outcomes when immediately retreated with BCMA-targeted therapies. Retreatment strategies could benefit from an assessment of BCMA expression before proceeding.
• CAR T-cell therapy may be more effective earlier in the treatment course due to better T-cell fitness and lower tumor burden. Using CAR T-cell therapy later can preserve treatment-free intervals, but may be less effective due to T-cell exhaustion and antigen loss.
• For heavily pretreated patients, ADCs remain a viable option as they are less reliant on T-cell fitness.
• Belantamab mafodotin demonstrates efficacy in later line settings due to its mechanism of action, which is less impacted by T-cell exhaustion.
• ADCs provide a valuable alternative in settings where CAR T-cell therapy and bispecifics are not available, particularly in resource-limited settings.
• The sequencing of BCMA-targeted therapies requires individualized approaches based on patient characteristics, treatment history, and resource availability.