DARATUMUMAB FOR THE TREATMENT OF MULTIPLE MYELOMA
Keywords:
daratumumab, multiple myeloma, therapy, prognosis
Abstract
Daratumumab is the first approved monoclonal antibody that targets the CD38 protein on the surface of myeloma cells. Historically, a well-established anti-myeloma protocol included oral melphalan and prednisolone as the standard of care. Apart from this, in a bit longer than two decades the high dose of melphalan followed by autologous stem cell transplantation became the standard for young and fit myeloma patients. Simultaneously, the prophylactic treatment of frequent and devastating skeletal complications was improved using intravenous bisphosphonate. In the following years, there came an era of significant improvements in anti-myeloma treatment that had an impact on survival rate of elderly and/or frail myeloma patients. The treatment included immunomodulatory drug thalidomide followed by the development of a less toxic and more effective analogue lenalidomide. At the same time, bortezomib, a first-in-class proteasome inhibitor, was introduced in the therapeutic protocols. Despite these improvements in survival, the prognosis remained poor for patients relapsing after treatment with bortezomib and lenalidomide with a median overall survival of only 9 months. After the initial dose escalation studies daratumumab resulted in a prolonged survival in the absence of significant killing of tumor cells through modulation of the immune system or the bone marrow microenvironment. The emerging picture showed that the addition of daratumumab alone or in combination improved the outcome in all myeloma patients without adding significantly to toxicity. Owing to this approach, myeloma patients live longer and have a better quality of life and there are further efforts to cure them which represents the main therapeutic goal.
References
1. Alexanian R, Haut A, Khan AU, Lane M, McKelvey EM, Migliore PJ, et al. Treatment for multiple myeloma. Combination chemotherapy with different melphalan dose regimens. JAMA. 1969 Jun 2;208(9):1680-5. doi: 10.1001/jama.208.9.1680.
2. Attal M, Harousseau JL, Stoppa AM, Sotto JJ, Fuzibet JG, Rossi JF, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Français du Myélome. N Engl J Med. 1996 Jul 11;335(2):91-7. doi: 10.1056/NEJM199607113350204.
3. Berenson JR, Lichtenstein A, Porter L, Dimopoulos MA, Bordoni R, George S, et al. Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. Myeloma Aredia Study Group. N Engl J Med. 1996 Feb 22;334(8):488-93. doi: 10.1056/NEJM199602223340802.
4. Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med. 1999 Nov 18;341(21):1565-71. doi: 10.1056/NEJM199911183412102.
5. Richardson PG, Schlossman RL, Weller E, Hideshima T, Mitsiades C, Davies F, et al. Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood. 2002 Nov 1;100(9):3063-7. doi: 10.1182/blood-2002-03-0996.
6. Orlowski RZ, Stinchcombe TE, Mitchell BS, Shea TC, Baldwin AS, Stahl S, et al. Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin Oncol. 2002 Nov 15;20(22):4420-7. doi: 10.1200/JCO.2002.01.133.
7. Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003 Jun 26;348(26):2609-17. doi: 10.1056/NEJMoa030288.
8. Kumar SK, Lee JH, Lahuerta JJ, Morgan G, Richardson PG, Crowley J, et al; International Myeloma Working Group. Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study. Leukemia. 2012 Jan;26(1):149-57. doi: 10.1038/leu.2011.196.
9. Lin P, Owens R, Tricot G, Wilson CS. Flow cytometric immunophenotypic analysis of 306 cases of multiple myeloma. Am J Clin Pathol. 2004 Apr;121(4):482-8. doi: 10.1309/74R4-TB90-BUWH-27JX.
10. Nijhof IS, Groen RW, Noort WA, van Kessel B, de Jong-Korlaar R, Bakker J, et al. Preclinical evidence for the therapeutic potential of CD38-targeted immuno-chemotherapy in multiple myeloma patients refractory to lenalidomide and bortezomib. Clin Cancer Res. 2015 Jun 15;21(12):2802-10. doi: 10.1158/1078-0432.CCR-14-1813.
11. Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD, et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med. 2006 Sep 7;355(10):1018-28. doi: 10.1056/NEJMoa063842.
12. Lokhorst HM, Plesner T, Laubach JP, Nahi H, Gimsing P, Hansson M, et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma. N Engl J Med. 2015 Sep 24;373(13):1207-19. doi: 10.1056/NEJMoa1506348.
13. Lonial S, Weiss BM, Usmani SZ, Singhal S, Chari A, Bahlis NJ, et al. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet. 2016 Apr 9;387(10027):1551-60. doi: 10.1016/S0140-6736(15)01120-4.
14. Usmani SZ, Weiss BM, Plesner T, Bahlis NJ, Belch A, Lonial S, et al. Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma. Blood. 2016 Jul 7;128(1):37-44. doi: 10.1182/blood-2016-03-705210.
15. Mateos MV, Cavo M, Blade J, Dimopoulos MA, Suzuki K, Jakubowiak A, et al. Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial. Lancet. 2020 Jan 11;395(10218):132-41. doi: 10.1016/S0140-6736(19)32956-3.
16. Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, Bahlis NJ, Usmani SZ, et al. Overall survival with daratumumab, lenalidomide, and dexamethasone in previously treated multiple myeloma (POLLUX): A randomized, open-label, phase III trial. J Clin Oncol. 2023 Mar 10;41(8):1590-9. doi: 10.1200/JCO.22.00940.
17. Sonneveld P, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M, et al. Overall survival with daratumumab, bortezomib, and dexamethasone in previously treated multiple myeloma (CASTOR): A randomized, open-label, phase III trial. J Clin Oncol. 2023 Mar 10;41(8):1600-9. doi: 10.1200/JCO.21.02734.
18. Facon T, Kumar SK, Plesner T, Orlowski RZ, Moreau P, Bahlis N, et al. Daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone alone in newly diagnosed multiple myeloma (MAIA): overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Nov;22(11):1582-96. doi: 10.1016/S1470-2045(21)00466-6.
19. Facon T, Kumar S, Plesner T, Orlowski RZ, Moreau P, Bahlis N, et al; MAIA Trial Investigators. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019 May 30;380(22):2104-15. doi: 10.1056/NEJMoa1817249.
20. Moreau P, Attal M, Hulin C, Arnulf B, Belhadj K, Benboubker L, 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. 2019 Jul 6;394(10192):29-38. doi: 10.1016/S0140-6736(19)31240-1.
21. Perrot A, Facon T, Plesner T, Usmani SZ, Kumar S, Bahlis NJ, et al. Health-related quality of life in transplant-ineligible patients with newly diagnosed multiple myeloma: findings from the phase III MAIA trial. J Clin Oncol. 2021 Jan 20;39(3):227-37. doi: 10.1200/JCO.20.01370.
22. Nijhof IS, Casneuf T, van Velzen J, van Kessel B, Axel AE, Syed K, et al. CD38 expression and complement inhibitors affect response and resistance to daratumumab therapy in myeloma. Blood. 2016 Aug 18;128(7):959-70. doi: 10.1182/blood-2016-03-703439.
23. Overdijk MB, Verploegen S, Bögels M, van Egmond M, Lammerts van Bueren JJ, Mutis T, et al. Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma. MAbs. 2015;7(2):311-21. doi: 10.1080/19420862.2015.1007813.
24. Horenstein AL, Bracci C, Morandi F, Malavasi F. CD38 in adenosinergic pathways and metabolic re-programming in human multiple myeloma cells: in-tandem insights from basic science to therapy. Front Immunol. 2019 Apr 24;10:760. doi: 10.3389/fimmu.2019.00760.
25. Ghose J, Viola D, Terrazas C, Caserta E, Troadec E, Khalife J, et al. Daratumumab induces CD38 internalization and impairs myeloma cell adhesion. Oncoimmunology. 2018 Jul 23;7(10):e1486948. doi: 10.1080/2162402X.2018.1486948.
26. Marlein CR, Piddock RE, Mistry JJ, Zaitseva L, Hellmich C, Horton RH, et al. CD38-driven mitochondrial trafficking promotes bioenergetic plasticity in multiple myeloma. Cancer Res. 2019 May 1;79(9):2285-97. doi: 10.1158/0008-5472.CAN-18-0773.
27. Krejcik J, Casneuf T, Nijhof IS, Verbist B, Bald J, Plesner T, et al. Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. Blood. 2016 Jul 21;128(3):384-94. doi: 10.1182/blood-2015-12-687749.
2. Attal M, Harousseau JL, Stoppa AM, Sotto JJ, Fuzibet JG, Rossi JF, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Français du Myélome. N Engl J Med. 1996 Jul 11;335(2):91-7. doi: 10.1056/NEJM199607113350204.
3. Berenson JR, Lichtenstein A, Porter L, Dimopoulos MA, Bordoni R, George S, et al. Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. Myeloma Aredia Study Group. N Engl J Med. 1996 Feb 22;334(8):488-93. doi: 10.1056/NEJM199602223340802.
4. Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med. 1999 Nov 18;341(21):1565-71. doi: 10.1056/NEJM199911183412102.
5. Richardson PG, Schlossman RL, Weller E, Hideshima T, Mitsiades C, Davies F, et al. Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood. 2002 Nov 1;100(9):3063-7. doi: 10.1182/blood-2002-03-0996.
6. Orlowski RZ, Stinchcombe TE, Mitchell BS, Shea TC, Baldwin AS, Stahl S, et al. Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin Oncol. 2002 Nov 15;20(22):4420-7. doi: 10.1200/JCO.2002.01.133.
7. Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003 Jun 26;348(26):2609-17. doi: 10.1056/NEJMoa030288.
8. Kumar SK, Lee JH, Lahuerta JJ, Morgan G, Richardson PG, Crowley J, et al; International Myeloma Working Group. Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study. Leukemia. 2012 Jan;26(1):149-57. doi: 10.1038/leu.2011.196.
9. Lin P, Owens R, Tricot G, Wilson CS. Flow cytometric immunophenotypic analysis of 306 cases of multiple myeloma. Am J Clin Pathol. 2004 Apr;121(4):482-8. doi: 10.1309/74R4-TB90-BUWH-27JX.
10. Nijhof IS, Groen RW, Noort WA, van Kessel B, de Jong-Korlaar R, Bakker J, et al. Preclinical evidence for the therapeutic potential of CD38-targeted immuno-chemotherapy in multiple myeloma patients refractory to lenalidomide and bortezomib. Clin Cancer Res. 2015 Jun 15;21(12):2802-10. doi: 10.1158/1078-0432.CCR-14-1813.
11. Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD, et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med. 2006 Sep 7;355(10):1018-28. doi: 10.1056/NEJMoa063842.
12. Lokhorst HM, Plesner T, Laubach JP, Nahi H, Gimsing P, Hansson M, et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma. N Engl J Med. 2015 Sep 24;373(13):1207-19. doi: 10.1056/NEJMoa1506348.
13. Lonial S, Weiss BM, Usmani SZ, Singhal S, Chari A, Bahlis NJ, et al. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet. 2016 Apr 9;387(10027):1551-60. doi: 10.1016/S0140-6736(15)01120-4.
14. Usmani SZ, Weiss BM, Plesner T, Bahlis NJ, Belch A, Lonial S, et al. Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma. Blood. 2016 Jul 7;128(1):37-44. doi: 10.1182/blood-2016-03-705210.
15. Mateos MV, Cavo M, Blade J, Dimopoulos MA, Suzuki K, Jakubowiak A, et al. Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial. Lancet. 2020 Jan 11;395(10218):132-41. doi: 10.1016/S0140-6736(19)32956-3.
16. Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, Bahlis NJ, Usmani SZ, et al. Overall survival with daratumumab, lenalidomide, and dexamethasone in previously treated multiple myeloma (POLLUX): A randomized, open-label, phase III trial. J Clin Oncol. 2023 Mar 10;41(8):1590-9. doi: 10.1200/JCO.22.00940.
17. Sonneveld P, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M, et al. Overall survival with daratumumab, bortezomib, and dexamethasone in previously treated multiple myeloma (CASTOR): A randomized, open-label, phase III trial. J Clin Oncol. 2023 Mar 10;41(8):1600-9. doi: 10.1200/JCO.21.02734.
18. Facon T, Kumar SK, Plesner T, Orlowski RZ, Moreau P, Bahlis N, et al. Daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone alone in newly diagnosed multiple myeloma (MAIA): overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Nov;22(11):1582-96. doi: 10.1016/S1470-2045(21)00466-6.
19. Facon T, Kumar S, Plesner T, Orlowski RZ, Moreau P, Bahlis N, et al; MAIA Trial Investigators. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019 May 30;380(22):2104-15. doi: 10.1056/NEJMoa1817249.
20. Moreau P, Attal M, Hulin C, Arnulf B, Belhadj K, Benboubker L, 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. 2019 Jul 6;394(10192):29-38. doi: 10.1016/S0140-6736(19)31240-1.
21. Perrot A, Facon T, Plesner T, Usmani SZ, Kumar S, Bahlis NJ, et al. Health-related quality of life in transplant-ineligible patients with newly diagnosed multiple myeloma: findings from the phase III MAIA trial. J Clin Oncol. 2021 Jan 20;39(3):227-37. doi: 10.1200/JCO.20.01370.
22. Nijhof IS, Casneuf T, van Velzen J, van Kessel B, Axel AE, Syed K, et al. CD38 expression and complement inhibitors affect response and resistance to daratumumab therapy in myeloma. Blood. 2016 Aug 18;128(7):959-70. doi: 10.1182/blood-2016-03-703439.
23. Overdijk MB, Verploegen S, Bögels M, van Egmond M, Lammerts van Bueren JJ, Mutis T, et al. Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma. MAbs. 2015;7(2):311-21. doi: 10.1080/19420862.2015.1007813.
24. Horenstein AL, Bracci C, Morandi F, Malavasi F. CD38 in adenosinergic pathways and metabolic re-programming in human multiple myeloma cells: in-tandem insights from basic science to therapy. Front Immunol. 2019 Apr 24;10:760. doi: 10.3389/fimmu.2019.00760.
25. Ghose J, Viola D, Terrazas C, Caserta E, Troadec E, Khalife J, et al. Daratumumab induces CD38 internalization and impairs myeloma cell adhesion. Oncoimmunology. 2018 Jul 23;7(10):e1486948. doi: 10.1080/2162402X.2018.1486948.
26. Marlein CR, Piddock RE, Mistry JJ, Zaitseva L, Hellmich C, Horton RH, et al. CD38-driven mitochondrial trafficking promotes bioenergetic plasticity in multiple myeloma. Cancer Res. 2019 May 1;79(9):2285-97. doi: 10.1158/0008-5472.CAN-18-0773.
27. Krejcik J, Casneuf T, Nijhof IS, Verbist B, Bald J, Plesner T, et al. Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. Blood. 2016 Jul 21;128(3):384-94. doi: 10.1182/blood-2015-12-687749.
Published
2023/12/29
Section
Invited paper