The clinical journey of belantamab mafodotin in relapsed or refractory multiple myeloma: lessons in drug development
Abstract Patients with relapsed/refractory multiple myeloma (RRMM) have a poor prognosis and a need remains for novel effective therapies. Belantamab mafodotin, an anti–B-cell maturation antigen antibody-drug conjugate, was granted accelerated/conditional approval for patients with RRMM who have rec...
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| Format: | Article |
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Nature Publishing Group
2025-02-01
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| Series: | Blood Cancer Journal |
| Online Access: | https://doi.org/10.1038/s41408-025-01212-0 |
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| author | Pralay Mukhopadhyay Hesham A. Abdullah Joanna B. Opalinska Prani Paka Eric Richards Katja Weisel Suzanne Trudel Maria-Victoria Mateos Meletios Athanasios Dimopoulos Sagar Lonial |
| author_facet | Pralay Mukhopadhyay Hesham A. Abdullah Joanna B. Opalinska Prani Paka Eric Richards Katja Weisel Suzanne Trudel Maria-Victoria Mateos Meletios Athanasios Dimopoulos Sagar Lonial |
| author_sort | Pralay Mukhopadhyay |
| collection | DOAJ |
| description | Abstract Patients with relapsed/refractory multiple myeloma (RRMM) have a poor prognosis and a need remains for novel effective therapies. Belantamab mafodotin, an anti–B-cell maturation antigen antibody-drug conjugate, was granted accelerated/conditional approval for patients with RRMM who have received at least 4 prior lines of therapy, based on response rates observed in DREAMM-1/DREAMM-2. Despite the 41% response rate and durable responses observed with belantamab mafodotin in the Phase III confirmatory DREAMM-3 trial, the marketing license for belantamab mafodotin was later withdrawn from US and European markets when the trial did not meet its primary endpoint of superiority for progression-free survival compared with pomalidomide and dexamethasone. This review reflects on key lessons arising from the clinical journey of belantamab mafodotin in RRMM. It considers how incorporating longer follow-up in DREAMM-3 may have better captured the clinical benefits of belantamab mafodotin, particularly given its multimodal, immune-related mechanism of action with responses deepening over time. A non-inferiority hypothesis may have been more appropriate rather than superiority in the context of a monotherapy versus an active doublet therapy. Further, anticipation of, and planning for, non-proportional hazards arising from response heterogeneity may have mitigated loss of statistical power. With the aim of improving the efficacy of belantamab mafodotin, other Phase III trials in the RRMM development program (DREAMM-7 and DREAMM-8) proceeded to evaluate the synergistic potential of combination regimens in earlier lines of treatment. The aim was to increase the proportion of patients responding to belantamab mafodotin (and thus the likelihood of seeing a clear separation of the progression-free survival curve versus comparator regimens). Protocol amendments reflecting DREAMM-3 learnings could also be implemented prospectively on the combinations trials to optimize the follow-up duration and mitigate risk. The wider implications of the lessons learned for clinical research in RRMM and in earlier treatment settings are discussed. |
| format | Article |
| id | doaj-art-e9acc5143e2743b68c74d2d9721a4b12 |
| institution | Kabale University |
| issn | 2044-5385 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Publishing Group |
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| series | Blood Cancer Journal |
| spelling | doaj-art-e9acc5143e2743b68c74d2d9721a4b122025-02-09T12:13:02ZengNature Publishing GroupBlood Cancer Journal2044-53852025-02-0115111110.1038/s41408-025-01212-0The clinical journey of belantamab mafodotin in relapsed or refractory multiple myeloma: lessons in drug developmentPralay Mukhopadhyay0Hesham A. Abdullah1Joanna B. Opalinska2Prani Paka3Eric Richards4Katja Weisel5Suzanne Trudel6Maria-Victoria Mateos7Meletios Athanasios Dimopoulos8Sagar Lonial9GSKGSKGSKGSKGSKUniversity Medical Center of Hamburg-EppendorfPrincess Margaret Cancer CentreUniversity Hospital of Salamanca/IBSAL/CIC/CIBERONCDepartment of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens School of MedicineWinship Cancer Institute, Emory University HospitalAbstract Patients with relapsed/refractory multiple myeloma (RRMM) have a poor prognosis and a need remains for novel effective therapies. Belantamab mafodotin, an anti–B-cell maturation antigen antibody-drug conjugate, was granted accelerated/conditional approval for patients with RRMM who have received at least 4 prior lines of therapy, based on response rates observed in DREAMM-1/DREAMM-2. Despite the 41% response rate and durable responses observed with belantamab mafodotin in the Phase III confirmatory DREAMM-3 trial, the marketing license for belantamab mafodotin was later withdrawn from US and European markets when the trial did not meet its primary endpoint of superiority for progression-free survival compared with pomalidomide and dexamethasone. This review reflects on key lessons arising from the clinical journey of belantamab mafodotin in RRMM. It considers how incorporating longer follow-up in DREAMM-3 may have better captured the clinical benefits of belantamab mafodotin, particularly given its multimodal, immune-related mechanism of action with responses deepening over time. A non-inferiority hypothesis may have been more appropriate rather than superiority in the context of a monotherapy versus an active doublet therapy. Further, anticipation of, and planning for, non-proportional hazards arising from response heterogeneity may have mitigated loss of statistical power. With the aim of improving the efficacy of belantamab mafodotin, other Phase III trials in the RRMM development program (DREAMM-7 and DREAMM-8) proceeded to evaluate the synergistic potential of combination regimens in earlier lines of treatment. The aim was to increase the proportion of patients responding to belantamab mafodotin (and thus the likelihood of seeing a clear separation of the progression-free survival curve versus comparator regimens). Protocol amendments reflecting DREAMM-3 learnings could also be implemented prospectively on the combinations trials to optimize the follow-up duration and mitigate risk. The wider implications of the lessons learned for clinical research in RRMM and in earlier treatment settings are discussed.https://doi.org/10.1038/s41408-025-01212-0 |
| spellingShingle | Pralay Mukhopadhyay Hesham A. Abdullah Joanna B. Opalinska Prani Paka Eric Richards Katja Weisel Suzanne Trudel Maria-Victoria Mateos Meletios Athanasios Dimopoulos Sagar Lonial The clinical journey of belantamab mafodotin in relapsed or refractory multiple myeloma: lessons in drug development Blood Cancer Journal |
| title | The clinical journey of belantamab mafodotin in relapsed or refractory multiple myeloma: lessons in drug development |
| title_full | The clinical journey of belantamab mafodotin in relapsed or refractory multiple myeloma: lessons in drug development |
| title_fullStr | The clinical journey of belantamab mafodotin in relapsed or refractory multiple myeloma: lessons in drug development |
| title_full_unstemmed | The clinical journey of belantamab mafodotin in relapsed or refractory multiple myeloma: lessons in drug development |
| title_short | The clinical journey of belantamab mafodotin in relapsed or refractory multiple myeloma: lessons in drug development |
| title_sort | clinical journey of belantamab mafodotin in relapsed or refractory multiple myeloma lessons in drug development |
| url | https://doi.org/10.1038/s41408-025-01212-0 |
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