Jiménez-Ochoa MA, Lozano-Jaramillo DA

Language: Spanish
References: 25
Page: 70-78
PDF size: 307.00 Kb.

ABSTRACT

Isatuximab is a monoclonal IgG1 antibody that binds to the glycoprotein CD38 expressed in multiple myeloma cells. The activation of the CD38 receptor leads to generation of adenosin, an immunosuppressor that favors neoplastic proliferation. The main mechanisms of action include enzymatic inhibition, indirect cytotoxicity, direct cytotoxicity, and immunomodulatory effects. The main differences with daratumumab are the binding to another epitope and the internalization of the CD38 receptor. As it is today, two randomized phase 3 clinical studies have demonstrated efficacy of isatuximab in the treatment of multiple myeloma relapsed or refractory (R/R). The ICARIA study compared isatuximab-pomalidomide-dexamethasone (Isa-Pd) vs pomalidomide-dexamethasone (Pd). The mean progression free survival was superior for the Isa-Pd group with 11.5 months (IC95% 8.9-13.9) vs Pd with 6.5 months (IC95% 4.5-8.3). Sixty percent of the patients with Isa-Pd reached a partial response, compared with 35% in the Pd group. The IKEMA study compared the combinations isatuximab-carfilzomib-dexamethasone (Isa-Kd) vs carfilzomib-dexamethasone (Kd). The progression free survival at two years was superior with Isa-Kd (68.9% vs 45.7%). Eighty-seven percent with Isa-Kd reached a response regardless of the grade. Infusionrelated reactions were the most common adverse events in both studies. The use of isatuximab in patients with multiple myeloma of recent diagnosis is being tested in the IMROZ study. The combinations Isa-Pd and Isa-Kd are approved and recommend for use in multiple myeloma relapsed or refractory.

REFERENCES

1. Dhillon S. Isatuximab: First approval. Drugs 2020; 80 (9):905-912.

2. Moreau P, van de Donk N, San Miguel J, Lokhorst H, NahiH, Ben-Yehuda, D, et al. Practical considerations for the useof daratumumab, a novel CD38 monoclonal antibody, inmyeloma. Drugs 2016; 76 (8): 853-867.

3. Laubach JP, van de Donk N, Davies FE, Mikhael J. Practicalconsiderations for antibodies in myeloma. American Societyof Clinical Oncology Educational Book. American Societyof Clinical Oncology Meeting 2018; 38 (38): 667-674.

4. van de Donk N, Richardson PG, Malavasi F. CD38 antibodiesin multiple myeloma: back to the future. Blood 2018;131(1): 13-29.

5. Martin T. G, Corzo K, Chiron M, Velde H. van de, AbbadessaG, Campana F, et al. Therapeutic opportunities withpharmacological inhibition of CD38 with isatuximab. Cells2019; 8 (12): 1522.

6. Kennedy BE, Sadek M, Elnenaei M. O, Reiman A, Gujar S.A. Targeting NAD+ synthesis to potentiate CD38-basedimmunotherapy of multiple myeloma. Trends Cancer2020; 6 (1): 9-12.

7. Deckert J, Wetzel M-C, Bartle L, Skaletskaya A, GoldmacherS, Vallée F, et al. SAR650984, a novel humanizedCD38-targeting antibody, demonstrates potent antitumoractivity in models of multiple myeloma and other CD38+hematologic malignancies. Clin Cancer Res 2014; 20 (17):4574-4583.

8. Moreno L, Perez C, Zabaleta A, Manrique I, Alignani D,Ajona D, et al. The mechanism of action of the anti-CD38monoclonal antibody isatuximab in multiple myeloma. ClinCancer Res 2019; 25 (10): 3176-3187.

9. Horenstein A. L, Chillemi A, Quarona V, Zito A, Roato I,Morandi F, et al. NAD+-metabolizing ectoenzymes in remodelingtumor-host interactions: The human myelomamodel. Cells 2015; 4 (3): 520-537.

10. van de Donk N, Usmani SZ. CD38 antibodies in multiplemyeloma: Mechanisms of action and modes of resistance.Front Immunol 2018; 9: 2134.

11. Konen JM, Fradette JJ, Gibbons DL. The good, the bad andthe unknown of CD38 in the metabolic microenvironmentand immune cell functionality of solid tumors. Cells 2019;9 (1): 52.

12. Richter J, Sanchez L, Thibaud S. Therapeutic potential ofisatuximab in the treatment of multiple myeloma: Evidenceto date. Semin Oncol 2020; 47 (2-3): 155-164.

13. Mellor JD, Brown MP, Irving HR, Zalcberg JR, Dobrovic A. Acritical review of the role of Fc gamma receptor polymorphismsin the response to monoclonal antibodies in cancer.J Hematol Oncol 2013; 6 (1): 1.

14. Taylor RP, Lindorfer MA. Cytotoxic mechanisms of immunotherapy:Harnessing complement in the action ofanti-tumor monoclonal antibodies. Semin Immunol 2016;28 (3): 309-316.

15. Jiang H, Acharya C, An G, Zhong M, Feng X, Wang L, et al.SAR650984 directly induces multiple myeloma cell deathvia lysosomal-associated and apoptotic pathways, whichis further enhanced by pomalidomide. Leukemia 2016;30 (2): 399-408.

16. Lammerts van Bueren J, Jakobs D, Kaldenhoven N, Roza M,Hiddingh S, Meesters J, et al. Direct in vitro comparison ofdaratumumab with surrogate analogs of CD38 antibodiesMOR03087, SAR650984 and Ab79. Blood 2014; 124 (21):3474-3474.

17. Tai Y-T, Anderson KC. Targeting CD38 alleviates tumorinducedimmunosuppression. Oncotarget 2017; 8 (68):112166-112167.

18. Mikhael J. Treatment options for triple-class refractorymultiple myeloma. Clin Lymph Myeloma Leukemia 2020;20 (1): 1-7.

19. Hill E, Morrison C, Kazandjian D. Daratumumab: A reviewof current indications and future directions. Semin Oncol

20. 2022.20. Dimopoulos MA, Moreau P, Terpos E, Mateos MV, ZweegmanS, Cook G, et al. Multiple myeloma: Eha-ESMO clinicalpractice guidelines for diagnosis, treatment and follow-up.Annals of Oncology. 2021;32(3):309–22.

21. Attal M, Richardson PG, Rajkumar SV, San-Miguel J,Beksac M, Spicka I, et al. Isatuximab plus pomalidomideand low-dose dexamethasone versus pomalidomide andlow-dose dexamethasone in patients with relapsed andrefractory multiple myeloma (ICARIA-MM): A randomised,multicentre, open-label, phase 3 study. Lancet 2019; 394(10214): 2096-107.

22. Moreau P, Dimopoulos M-A, Mikhael J, Yong K, Capra M,Facon T, et al. Isatuximab, carfilzomib, and dexamethasonein relapsed multiple myeloma (IKEMA): A multicentre,open-label, randomised phase 3 trial. Lancet 2021; 397(10292): 2361-71.

23. Dimopoulos M, Bringhen S, Anttila P, Capra M, Cavo M,Cole C, et al. Isatuximab as monotherapy and combinedwith dexamethasone in patients with relapsed/refractorymultiple myeloma. Blood 2021; 137 (9): 1154-65.

24. Mikhael J, Belhadj-Merzoug K, Hulin C, Vincent L, MoreauP, Gasparetto C, et al. A phase 2 study of isatuximabmonotherapy in patients with multiple myeloma who arerefractory to daratumumab. Blood Cancer J 2021; 11 (5).

25. Orlowski RZ, Goldschmidt H, Cavo M, Martin TG, Paux G,Oprea C, et al. Phase III (IMROZ) study design: Isatuximabplus bortezomib (V), lenalidomide (R), and dexamethasone(d) VS vrd in transplant-ineligible patients (PTS) with newlydiagnosed multiple myeloma (NDMM). J Clin Oncol 2018; 36.