Belantamab: A Comprehensive Overview

1. Background study

In both relapsed and refractory categories, patients with multiple myeloma (MM), a blood malignancy, do not show any improvement or at least a minor response after sixty days of starting treatment [1]. With an occurrence of 4.5 to 6 per 100,000 yearly, MM accounts for 1.8% of all new cancer cases and 2.1% of all cancer-related deaths in the United States each year [2]. MM presently has 160,000 cases and a 106,000 fatality rate globally [3]. Although it is typically incurable, survival rates have increased over the past few decades due to new treatment development [4]. When treating MM, Belantamab mafodotin, a monoclonal antibody treatment, has demonstrated significant effectiveness and safety [5].  

2. Target and its mechanism

Targeting B-cell maturation antigen (BCMA) protein, which is expressed on the myeloma cell surface, Belantamab mafodotin as an earlier ADC (Antibody-drug conjugate) that works against BCMA in the MM management [6]. It coupled with MMAF (Monomethyl auristatin F), a solid microtubule-disrupting factor, results in cell death [7]. After binding with BCMA, Belantamab induces ADCC (Antibody-dependent cellular cytotoxicity) and ADCP (Antibody-dependent cellular phagocytosis) by inhibiting BCMA receptor signalling and microtubule polymerization [8,9].  

3. Medicinal usage 

The FDA (Food and Drug Administration) approved Belantamab as the first targeted antibody therapy in 2020 for the treatment of multiple myeloma (Relapsed or Refractory) in adult patients who have already been treated with current medicines, such as immunomodulatory drugs, proteasome inhibitors, and anti-CD38 monoclonal antibodies [10]. 

4. Clinical study results

According to Lonial et al., Belantamab reported a total rate of 32% positive response and an average treatment period of 11 months with MM patients who were previously pretreated during the phase II DREAMM-2 trial [11]. Comparing Belantamab to Pomalidomide and dexamethasone (low-dose), recent clinical studies demonstrated significant progress in survival incidence during the phase III DREAMM-3 trial [12, 13]. 

5. Side effects

Patients-administered Belantamab shows some frequent side effects, such as reduced platelets, corneal illness, diminished vision, anaemia, pyrexia, and fetal danger [7]. According to the toxicity profile, eye toxicity affected 44% of patients and reported 33.3% of patients associated with keratopathy grade 2-3 (Fluctuations in visual acuteness) [14, 15].

6. Molecular engineering and development

Belantamab has been manufactured using a humanized anti-BCMA antibody technique, conjugating MMAF through a non-cleanable linker [5]. The drug-and-antibody ratio is 4:1 [16]. 

7. Potential drug interactions

Other medications, including OATP (Organic anion transporting polypeptide) and P-glycoprotein (P-gp) transporters-oriented drugs, also collaborated with Belantamab in treating MM [7]. However, combined dose of Belantamab with CYP3A4 inhibitors may raise the likelihood of adverse side effects [17]. 

8. New prospective uses

It is also studied with several drugs, such as Lenalidomide, Bortezomib, and Pembrolizumab, in treating multiple myeloma [11, 13]. Additionally, Belantamab is also being investigated as a possible medication for BCMA-expressing malignancy treatment [14].  

9. Other antibodies in clinical development

Despite Belantamab, numerous other anti-BCMA agents, such as AMG 701, CC-99712, and MEDI2228, are being studied clinically for MM treatment [19].  Although the mechanisms of action of many medicines are similar, their pharmacokinetic properties and safety issues may vary [20]. 

Ichorbio is a high-quality manufacturer of biosimilars and has developed a Belantamab biosimilar. Find the product: https://ichor.bio/belantamab-biosimilar-research-grade

References:

1. Bhatt P, Kloock C, Comenzo R. Relapsed/Refractory Multiple Myeloma: A Review of Available Therapies and Clinical Scenarios Encountered in Myeloma Relapse. Curr Oncol. 2023 Feb 15;30(2):2322-2347. 

2. Padala SA, Barsouk A, Barsouk A, Rawla P, Vakiti A, Kolhe R, Kota V, Ajebo GH. Epidemiology, Staging, and Management of Multiple Myeloma. Med Sci (Basel). 2021 Jan 20;9(1).

3. Ludwig H, Novis Durie S, Meckl A, Hinke A, Durie B. Multiple Myeloma Incidence and Mortality Around the Globe; Interrelations Between Health Access and Quality, Economic Resources, and Patient Empowerment. Oncologist. 2020 Sep;25(9): e1406-e1413. 

4. clinicaltrials.gov/study/NCT03514121 [Extracted information on 28 April 2024]

5. Morè S, Offidani M, Corvatta L, Petrucci MT, Fazio F. Belantamab Mafodotin: From Clinical Trials Data to Real-Life Experiences. Cancers (Basel). 2023 May 27;15(11):2948. 

6. Matula Z, Uher F, Vályi-Nagy I, Mikala G. The Effect of Belantamab Mafodotin on Primary Myeloma-Stroma Co-Cultures: Asymmetrical Mitochondrial Transfer between Myeloma Cells and Autologous Bone Marrow Stromal Cells. Int J Mol Sci. 2023 Mar 10;24(6):5303. 

7. Lassiter G, Bergeron C, Guedry R, Cucarola J, Kaye AM, Cornett EM, Kaye AD, Varrassi G, Viswanath O, Urits I. Belantamab Mafodotin to Treat Multiple Myeloma: A Comprehensive Review of Disease, Drug Efficacy and Side Effects. Curr Oncol. 2021 Jan 21;28(1):640-660. 

8. Fu Z., Li S., Han S., Shi C., Zhang Y. Antibody-drug conjugate: The “biological missile” for targeted cancer therapy. Signal Transduct. Target. Ther. 2022; 7:93. 

9. Martino, E. A., Bruzzese, A., Iaccino, E., Labanca, C., Mendicino, F., Mimmi, S., … Gentile, M. (2023). Belantamab mafodotin in multiple myeloma. Expert Opinion on Biological Therapy, 23(11), 1043–1047. 

10. Baines AC, Ershler R, Kanapuru B, Xu Q, Shen G, Li L, Ma L, Okusanya OO, Simpson NE, Nguyen W, Theoret MR, Pazdur R, Gormley NJ. FDA Approval Summary: Belantamab Mafodotin for Patients with Relapsed or Refractory Multiple Myeloma. Clin Cancer Res. 2022 Nov 1;28(21):4629-4633. 

11. Lonial S, Lee HC, Badros A, Trudel S, Nooka AK, Chari A, Abdallah AO, Callander N, Lendvai N, et al. Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study. Lancet Oncol. 2020 Feb;21(2):207-221. 

12. Dimopoulos MA, Hungria VTM, Radinoff A, Delimpasi S, Mikala G, Masszi T, Li J, Capra M, 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 Oct;10(10): e801-e812. 

13. Trudel, S., McCurdy, A., Louzada, M.L. et al. Belantamab mafodotin, pomalidomide and dexamethasone in refractory multiple myeloma: a phase 1/2 trial. Nat Med 30, 543–551 (2024). 

14. Ntanasis-Stathopoulos I, Malandrakis P, Fotiou D, Migkou M, Theodorakakou F, et al. Real-World Effectiveness and Safety of Belantamab Mafodotin Monotherapy in Triple-Class Refractory Multiple Myeloma. Int J Mol Sci. 2023 Jul 23;24(14):11829. 

15. Popat R, Warcel D, O'Nions J, Cowley A, Smith S, Tucker WR, Yong K, Esposti SD. Characterization of response and corneal events with extended follow-up after belantamab mafodotin (GSK2857916) monotherapy for patients with relapsed multiple myeloma: a case series from the first-time-in-human clinical trial. Haematologica. 2020 May;105(5): e261-e263. 

16. Xing L, Liu Y, Liu J. Targeting BCMA in Multiple Myeloma: Advances in Antibody-Drug Conjugate Therapy. Cancers (Basel). 2023 Apr 11;15(8):2240. 

17. Iida S, Sunami K, Mishima Y, Fujii T, Kato H, Terao T, Matsuzawa Y, Matsubara M, Crossman T, Kremer BE, Gupta I. Safety, pharmacokinetics, and efficacy of belantamab mafodotin monotherapy in Japanese patients with relapsed or refractory multiple myeloma: DREAMM-11. Int J Hematol. 2023 Nov;118(5):596-608. 

18. de la Rubia J, Alonso R, Clavero ME, Askari E, García A, Antón C, Fernández M, Escalante F, García A, et al. Belantamab Mafodotin in Patients with Relapsed/Refractory Multiple Myeloma: Results of the Compassionate Use or the Expanded Access Program in Spain. Cancers (Basel). 2023 May 29;15(11):2964. 

19. Sammartano V, Franceschini M, Fredducci S, Caroni F, Ciofini S, Pacelli P, Bocchia M, Gozzetti A. Anti-BCMA novel therapies for multiple myeloma. Cancer Drug Resist. 2023 Mar 22;6(1):169-181. 

20. Chang HP, Le HK, Shah DK. Pharmacokinetics and Pharmacodynamics of Antibody-Drug Conjugates Administered via Subcutaneous and Intratumoral Routes. Pharmaceutics. 2023 Apr 3;15(4):1132.