Jess Hatfield

Introduction. Multiple myeloma (MM) is a cancer of terminally differentiated plasma cells in the bone marrow and peripheral blood, and accounts for 10% of all hematological malignancies.¹ MM symptoms occur when abnormal plasma cells secrete monoclonal proteins, or M proteins, in the bone and kidneys.¹ In the MM microenvironment, myeloid-derived suppressor cells (MDSCs) are pathologically activated myeloid cells that suppress immune responses, allowing tumor progression.² Methods. MM cells were taken from various cohorts of patients, and underwent flow cytometry,³, were treated with gemcitabine,⁴ and were treated with daratumumab.⁵ MDSCs were additionally cultured with T cells under various conditions.⁶ Daratumumab was given to patients in various clinical trials.^7-14 Results. MDSCs from MM patients are characterized by flow cytometry as dysregulated mature neutrophils with a CD11b+CD13+CD16+ marker, and are associated with decreased MM survival.³ These MDSCs suppress the immune system in the MM microenvironment by increasing the levels of regulatory T cells and regulatory B cells, thus decreasing CD8+ T cell response. The ultimate effect of MDSC accumulation is to inhibit CD8+ T cells, IFN-γ, and IL-2; this T cell inhibition is induced by IL-18.⁶ Daratumumab is a monoclonal antibody that inhibits MDSCs, regulatory T cells, and regulatory B cells in MM cells.⁵ Two early clinical trials in which heavily pretreated/refractory MM patients were treated with 16 mg/kg daratumumab showed overall rates of 36%¹⁰ and 29%¹¹. In recent clinical trials, daratumumab increased survival in relapsed/refractory MM patients when combined with bortezomib/dexamethasone (HR 0.39, 95% CI 0.28-0.53),¹⁴ lenalidomide/dexamethasone (HR 0.37, 95% CI 0.27-0.52),⁸ and carfilzomib/dexamethasone (HR 0.63, 95% CI 0.48-0.85).⁷ Additionally, daratumumab increased survival in untreated MM patients when combined with bortezomib/thalidomide/dexamethasome ((HR 0.47, 95% CI 0.33-0.67),¹³ lenalidomide/dexamethasome (HR 0.56, 95% CI 0.43-0.73),⁹ and bortezomib/melphalan/prednisone (HR 0.42, 95% CI 0.34-0.51).¹⁵ Conclusions. Multiple studies have found that MDSCs suppress the CD8+ T cell response, and that the monoclonal antibody daratumumab inhibits this pathway. Daratumumab has been highly successful in recent clinical trials, is FDA approved, and is now being used as a frontline treatment for MM patients.¹⁶ More investigation into the mechanism of tumor microenvironment’s effect on immunosuppression on MM is warranted, and may uncover more therapeutic targets. In general, more investigation into the field of the effect of the tumor microenvironment effect on cancer progression will lead to more targeted therapy options in all cancers.

1. Kumar SK, Rajkumar V, Kyle RA, et al. Multiple myeloma. Nat Rev Dis Primers. Jul 20 2017;3:17046. doi:10.1038/nrdp.2017.46
2. Veglia F, Perego M, Gabrilovich D. Myeloid-derived suppressor cells coming of age. Nat Immunol. Feb 2018;19(2):108-119. doi:10.1038/s41590-017-0022-x
3. Perez C, Botta C, Zabaleta A, et al. Immunogenomic identification and characterization of granulocytic myeloid-derived suppressor cells in multiple myeloma. Blood. Jul 9 2020;136(2):199-209. doi:10.1182/blood.2019004537
4. Xu X, Zhang C, Trotter TN, et al. Runx2 Deficiency in Osteoblasts Promotes Myeloma Progression by Altering the Bone Microenvironment at New Bone Sites. Cancer Res. Mar 1 2020;80(5):1036-1048. doi:10.1158/0008-5472.Can-19-0284
5. Krejcik J, Casneuf T, Nijhof IS, et al. Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. Blood. Jul 21 2016;128(3):384-94. doi:10.1182/blood-2015-12-687749
6. Nakamura K, Kassem S, Cleynen A, et al. Dysregulated IL-18 Is a Key Driver of Immunosuppression and a Possible Therapeutic Target in the Multiple Myeloma Microenvironment. Cancer Cell. Apr 9 2018;33(4):634-648.e5. doi:10.1016/j.ccell.2018.02.007
7. Dimopoulos M, Quach H, Mateos MV, et al. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): results from a randomised, multicentre, open-label, phase 3 study. Lancet. Jul 18 2020;396(10245):186-197. doi:10.1016/s0140-6736(20)30734-0
8. Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med. Oct 6 2016;375(14):1319-1331. doi:10.1056/NEJMoa1607751
9. Facon T, Kumar S, Plesner T, et al. Daratumumab plus Lenalidomide and Dexamethasone for Untreated Myeloma. N Engl J Med. May 30 2019;380(22):2104-2115. doi:10.1056/NEJMoa1817249
10. Lokhorst HM, Plesner T, Laubach JP, et al. Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma. N Engl J Med. Sep 24 2015;373(13):1207-19. doi:10.1056/NEJMoa1506348
11. Lonial S, Weiss BM, Usmani SZ, et al. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet. Apr 9 2016;387(10027):1551-1560. doi:10.1016/s0140-6736(15)01120-4
12. Mateos MV, Cavo M, Blade J, et al. Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial. Lancet. Jan 11 2020;395(10218):132-141. doi:10.1016/s0140-6736(19)32956-3
13. Moreau P, Attal M, Hulin C, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet. Jul 6 2019;394(10192):29-38. doi:10.1016/s0140-6736(19)31240-1
14. Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma. N Engl J Med. Aug 25 2016;375(8):754-66. doi:10.1056/NEJMoa1606038
15. Mateos MV, Dimopoulos MA, Cavo M, et al. Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma. N Engl J Med. Feb 8 2018;378(6):518-528. doi:10.1056/NEJMoa1714678
16. Hosoya H, Sidana S. Antibody-Based Treatment Approaches in Multiple Myeloma. Curr Hematol Malig Rep. Apr 2021;16(2):183-191. doi:10.1007/s11899-021-00624-6