Unique Toxicities of Novel Myeloma Therapies: Focus on Belantamab Mafodotin, Talquetamab, and Selinexor

Authors

  • Jesse Shustik, MD, FRCPC Department of Medical Oncology, BC Cancer-Surrey Centre, Surrey, B.C.

DOI:

https://doi.org/10.58931/cht.2025.4379

Abstract

Recent survival improvements in patients with multiple myeloma are attributable largely to the introduction of three main drug classes, immunomodulatory drugs (IMIDs), proteasome inhibitors, and anti-CD38 monoclonal antibodies. However, the majority of patients will inevitably develop resistance to all three drug classes, and survival in this setting has been historically poor.

Several novel therapeutic classes exploiting new mechanisms of action (e.g., chimeric antigen receptor (CAR)-T cell therapy, bispecific antibodies, antibody-drug conjugates (ADC), and selective inhibitors of nuclear export) have shown high levels of activity in relapsed myeloma and promise to transform the treatment landscape. However, these therapies have been associated with distinct toxicity profiles, with adverse effects that are uncommonly observed with conventional antimyeloma therapies. Given improvements in long-term disease control and survival with current therapies, treatment-related toxicity represents an increasingly important health burden in patients with myeloma, and the development of effective toxicity management strategies is required to minimize complications and ensure preserved quality of life.

Author Biography

Jesse Shustik, MD, FRCPC, Department of Medical Oncology, BC Cancer-Surrey Centre, Surrey, B.C.

Dr. Jesse Shustik is a hematologist-oncologist practicing at BC Cancer‑Surrey Centre in British Columbia. His primary clinical interest is in lymphoid malignancies and multiple myeloma, and he has been active in myeloma clinical trials at his centre. He is the site representative for the Canadian Myeloma Research Group at his at his centre and has been a provincial lead for the BC Cancer myeloma program.

References

Malard F, Neri P, Bahlis NJ, Terpos E, Moukalled N, Hungria VTM, et al. Multiple myeloma. Nat Rev Dis Primers. 2024;10(1):45. doi: 10.1038/s41572-024-00529-7. DOI: https://doi.org/10.1038/s41572-024-00529-7

Visram A, De La Torre A, White D, Su J, Masih-Khan E, Chu M, et al. Real world data on outcomes of anti-CD38 antibody treated, including triple class refractory, patients with multiple myeloma: a multi-institutional report from the Canadian Myeloma Research Group (CMRG) Database. Blood Cancer J. 2023;13(1):181. doi: 10.1038/s41408-023-00946-z. DOI: https://doi.org/10.1038/s41408-023-00946-z

Mateos MV, Weisel K, De Stefano V, Goldschmidt H, Delforge M, Mohty M, et al. LocoMMotion: a prospective, non-interventional, multinational study of real-life current standards of care in patients with relapsed and/or refractory multiple myeloma. Leukemia. 2022;36(5):1371-1376. doi: 10.1038/s41375-022-01531-2. DOI: https://doi.org/10.1038/s41375-022-01531-2

Van de Donk NWCJ, Zweegman S. T-cell-engaging bispecific antibodies in cancer. Lancet. 2023;402(10396):142-158. doi: 10.1016/S0140-6736(23)00521-4.. DOI: https://doi.org/10.1016/S0140-6736(23)00521-4

Neri P, Leblay N, Lee H, Gulla A, Bahlis NJ, Anderson KC. Just scratching the surface: novel treatment approaches for multiple myeloma targeting cell membrane proteins. Nat Rev Clin Oncol. 2024;21(8):590-609. doi: 10.1038/s41571-024-00913-y. DOI: https://doi.org/10.1038/s41571-024-00913-y

Lonial S, Lee HC, Badros A, Trudel S, Nooka AK, Chari A, et al. Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study. Lancet Oncol. 2020;21(2):207-221. doi: 10.1016/S1470-2045(19)30788-0. DOI: https://doi.org/10.1016/S1470-2045(19)30788-0

Dimopoulos MA, Hungria VTM, Radinoff A, Delimpasi S, Mikala G, Masszi T, et al.. Efficacy and safety of single-agent belantamab mafodotin versus pomalidomide plus low-dose dexamethasone in patients with relapsed or refractory multiple myeloma (DREAMM-3): a phase 3, open-label, randomised study. Lancet Haematol. 2023;10(10):e801-e812. doi: 10.1016/S2352-3026(23)00243-0. DOI: https://doi.org/10.1016/S2352-3026(23)00243-0

Hungria V, Robak P, Hus M, Zherebtsova V, Ward C, Ho PJ,et al. Belantamab mafodotin, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2024;391(5):393-407. doi: 10.1056/NEJMoa2405090. DOI: https://doi.org/10.1056/NEJMoa2405090

Dimopoulos MA, Beksac M, Pour L, Delimpasi S, Vorobyev V, Quach H, et al. Belantamab Mafodotin, Pomalidomide, and dexamethasone in multiple myeloma. N Engl J Med. 2024;391(5):408-421. doi: 10.1056/NEJMoa2403407.. DOI: https://doi.org/10.1056/NEJMoa2403407

Hungria V, Robak P, Hus M, Zherebtsova V, Ward C, Ho PJ, et al. Belantamab mafodotin, bortezomib, and dexamethasone vs daratumumab, bortezomib, and dexamethasone in relapsed/refractory multiple myeloma: overall survival analysis and updated efficacy outcomes of the phase 3 Dreamm-7 trial. Blood 2024;144(Supplement 1):772. DOI: https://doi.org/10.1182/blood-2024-200336

Lee V, Hultcrantz M, Petrone S, Lewis EW, Banna H, Lichtman E, et al. Characterization of belantamab mafodotin-induced corneal changes in patients with multiple myeloma. JAMA Ophthalmol. 2025;143(6):507-514. doi: 10.1001/jamaophthalmol.2025.1008. DOI: https://doi.org/10.1001/jamaophthalmol.2025.1008

Trudel S, McCurdy A, Louzada ML, Parkin S, White D, Chu MP, et al. Belantamab mafodotin, pomalidomide and dexamethasone in refractory multiple myeloma: a phase 1/2 trial. Nat Med. 2024;30(2):543-551. doi: 10.1038/s41591-023-02703-y. DOI: https://doi.org/10.1038/s41591-023-02703-y

Terpos E, Trudel S, Mateos MV, Alejandre N, Colby K, Dimopoulos MA, et al. Practical guidance on clinical management of belantamab mafodotin-associated ocular events. Am J Hematol. 2025;100(10):1839-1850. doi: 10.1002/ajh.70015. DOI: https://doi.org/10.1002/ajh.70015

Mateos MV, Trudel S, Quach H, Robak P, Beksac M, Pour L, et al. Modification of belantamab mafodotin dosing to balance efficacy and tolerability in the DREAMM-7 and DREAMM-8 trials. Blood Adv. 2025:bloodadvances.2025016949. doi: 10.1182/bloodadvances.2025016949. Epub ahead of print. DOI: https://doi.org/10.1182/bloodadvances.2025016949

E. Terpos, M. Gavriatopoulou, I. Ntanasis- Stathopoulos, et al., Evaluation of a novel method guiding belantamab mafodotin dosing in multiple myeloma based on a patient-reported questionnaire. 2024 ASCO Annual Meeting; Abstract 7530. DOI: https://doi.org/10.1200/JCO.2024.42.16_suppl.7530

BLENREP Product Monograph; Date of Authorization: September 26th, 2025; https://ca.gsk.com/media/j3dnbhae/blenrep.pdf

Terpos E, Gavriatopoulou M, Ntanasis-Stathopoulos I, Malandrakis P, Fotiou D, Migkou M, et al. Belantamab mafodotin, lenalidomide and dexamethasone in transplant-ineligible patients with newly diagnosed multiple myeloma: part 1 results of a phase I/II study. Haematologica. 2024;109(8):2594-2605. doi: 10.3324/haematol.2023.284347. DOI: https://doi.org/10.3324/haematol.2023.284347

Rodriguez-Otero P, van de Donk NWCJ, Pillarisetti K, Cornax I, Vishwamitra D, Gray K, et al. GPRC5D as a novel target for the treatment of multiple myeloma: a narrative review. Blood Cancer J. 2024;14(1):24. doi: 10.1038/s41408-023-00966-9. DOI: https://doi.org/10.1038/s41408-023-00966-9

Chari A, Minnema MC, Berdeja JG, Oriol A, van de Donk NWCJ, Rodríguez-Otero P, et al. Talquetamab, a T-cell-redirecting GPRC5D bispecific antibody for multiple myeloma. N Engl J Med. 2022;387(24):2232-2244. doi: 10.1056/NEJMoa2204591. DOI: https://doi.org/10.1056/NEJMoa2204591

Chari A, Touzeau C, Schinke C, Minnema MC, Berdeja JG, Oriol A, et al. Safety and activity of talquetamab in patients with relapsed or refractory multiple myeloma (MonumenTAL-1): a multicentre, open-label, phase 1-2 study. Lancet Haematol. 2025;12(4):e269-e281. doi: 10.1016/S2352-3026(24)00385-5. DOI: https://doi.org/10.1016/S2352-3026(24)00385-5

Chari A, Krishnan A, Rasche L, Ye JC, Garfall A, Popat R, et al. Clinical management of patients with relapsed/refractory multiple myeloma treated with talquetamab. Clin Lymphoma Myeloma Leuk. 2024;24(10):665-693.e14. doi: 10.1016/j.clml.2024.05.003. DOI: https://doi.org/10.1016/j.clml.2024.05.003

Rodriguez-Otero P, Usmani S, Cohen AD, van de Donk NWCJ, Leleu X, Gállego Pérez-Larraya J, et al. International Myeloma Working Group immunotherapy committee consensus guidelines and recommendations for optimal use of T-cell-engaging bispecific antibodies in multiple myeloma. Lancet Oncol. 2024;25(5):e205-e216. doi: 10.1016/S1470-2045(24)00043-3. DOI: https://doi.org/10.1016/S1470-2045(24)00043-3

Chari A, Oriol A, Krishnan A, et al. Efficacy and safety of less frequent/lower intensity dosing of talquetamab in patients with relapsed/refractory multiple myeloma: results from the phase 1/2 MonumenTAL-1 study. Blood 2023;142(suppl 1):1010. DOI: https://doi.org/10.1182/blood-2023-181228

Gavriatopoulou M, Chari A, Chen C, Bahlis N, Vogl DT, Jakubowiak A, et al. Integrated safety profile of selinexor in multiple myeloma: experience from 437 patients enrolled in clinical trials. Leukemia. 2020;34(9):2430-2440. doi: 10.1038/s41375-020-0756-6. DOI: https://doi.org/10.1038/s41375-020-0756-6

Chari A, Vogl DT, Gavriatopoulou M, Nooka AK, Yee AJ, Huff CA, et al. Oral selinexor-dexamethasone for triple-class refractory multiple myeloma. N Engl J Med. 2019;381(8):727-738. doi: 10.1056/NEJMoa1903455. DOI: https://doi.org/10.1056/NEJMoa1903455

Grosicki S, Simonova M, Spicka I, Pour L, Kriachok I, Gavriatopoulou M, et al. Once-per-week selinexor, bortezomib, and dexamethasone versus twice-per-week bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a randomised, open-label, phase 3 trial. Lancet. 2020;396(10262):1563-1573. doi: 10.1016/S0140-6736(20)32292-3. DOI: https://doi.org/10.1016/S0140-6736(20)32292-3

Nooka AK, Costa LJ, Gasparetto CJ, Richardson PG, Siegel DS, Chari A, et al. Guidance for use and dosing of selinexor in multiple myeloma in 2021: consensus from International Myeloma Foundation expert roundtable. Clin Lymphoma Myeloma Leuk. 2022;22(7):e526-e531. doi: 10.1016/j.clml.2022.01.014. DOI: https://doi.org/10.1016/j.clml.2022.01.014

Mikhael J, Noonan KR, Faiman B, Gleason C, Nooka AK, Costa LJ, et al. Consensus recommendations for the clinical management of patients with multiple myeloma treated with selinexor. Clin Lymphoma Myeloma Leuk. 2020;20(6):351-357. doi: 10.1016/j.clml.2019.12.026. DOI: https://doi.org/10.1016/j.clml.2019.12.026

Jagannath S, Delimpasi S, Grosicki S, Van Domelen DR, Bentur OS, Špička I, et al. Association of selinexor dose reductions with clinical outcomes in the BOSTON study. Clin Lymphoma Myeloma Leuk. 2023;23(12):917-923.e3. doi: 10.1016/j.clml.2023.08.018. DOI: https://doi.org/10.1016/j.clml.2023.08.018

Gasparetto C, Schiller GJ, Tuchman SA, Callander NS, Baljevic M, Lentzsch S, et al. Once weekly selinexor, carfilzomib and dexamethasone in carfilzomib non-refractory multiple myeloma patients. Br J Cancer. 2022;126(5):718-725. doi: 10.1038/s41416-021-01608-2. DOI: https://doi.org/10.1038/s41416-021-01608-2

White DJ, Chen CI, Baljevic M, et al. Once weekly oral selinexor, pomalidomide, and dexamethasone in relapsed refractory multiple myeloma. Blood 2021;138:2748. DOI: https://doi.org/10.1182/blood-2021-148759

Published

2025-12-08

How to Cite

1.
Shustik J. Unique Toxicities of Novel Myeloma Therapies: Focus on Belantamab Mafodotin, Talquetamab, and Selinexor. Can Hematol Today [Internet]. 2025 Dec. 8 [cited 2026 Jan. 2];4(3):24–35. Available from: https://canadianhematologytoday.com/article/view/4-3-Shustik

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