Pomalidomide for Treatment of Relapsed and Refractory Multiple Myeloma

Pomalidomide is a third-generation immunomodulatory drug recommended for patients with multiple myeloma refractory to lenalidomide and bortezomib. The safety profile is optimized for application in patients with intensive and continuous anti-tumor treatment. Pomalidomide was approved by the Food and Drug Administration (FDA) and by the European Medicines Agency (EMA) in 2013 for use in patients with relapsed and refractory MM who have received at least two prior therapies, including lenalidomide and bortezomib, and have demonstrated disease progression on their last therapy or within 60 days after completion of the last therapy. Registration of pomalidomide for similar indications in Russia is pending in 2015. Pomalidomide has a similar mechanism of action with the other immunomodulators. The drug produces a direct cytostatic effect and causes an indirect effect by affecting the bone marrow microenvironment and T/NK-cells immunity. The recommended starting dose of pomalidomide is 4 mg daily (1–21/28) combined with low-dose dexamethasone 40 mg weekly for young patients or 20 mg for patients older than 75 years. The treatment should be performed till disease progression or unacceptable toxicity. This review summarizes current recommendations for dose adjustment depending on tolerance and prevention of thrombotic complications. The article presents author’s own clinical experience of successful application of pomalidomide for the management of a patient at high cytogenetic risk with «double» refractoriness to lenalidomide and bortezomib and preceding intensive anti-tumor treatment. The life expectancy was about 16 months after initiation of pomalidomide; this fact is consistent with literature data.

• Sergei Vyacheslavovich Semochkin N.I. Pirogov Russian National Research Medical University under the Ministry of Health of the Russian Federation, 1 Ostrovityanova str., Moscow, Russian Federation, 117997 ; ГБОУ ВПО «Российский национальный медицинский исследовательский университет им. Н.И. Пирогова» Минздрава России, ул. Островитянова, д. 1, Москва, Российская Федерация, 117997

1. Менделеева Л.П., Вотякова О.М., Покровская О.М. и др. Национальные клинические рекомендации по диагностике и лечению множественной миеломы. Гематология и трансфузиология. 2014;1(приложение 3):2–24.
2. [Mendeleeva LP, Votyakova OM, Pokrovskaya OM, et al. National clinical guidelines for diagnosis and treatment of multiple myeloma. Gematologiya i transfuziologiya. 2014;1(Suppl. 3):2–24. (In Russ)]
3. Бессмельцев С.С. Множественная миелома (лечение рецидивов и рефрактерных форм): обзор литературы и собственные данные. Часть III. Клиническая онкогематология. 2014;7(2):137–74.
4. [Bessmel’tsev SS. Multiple myeloma (treatment of relapsed and refractory forms): literature review and own data. Part III. Klinicheskaya onkogematologiya. 2014;7(2):137–74. (In Russ)]
5. Rajkumar SV. Multiple myeloma: 2014 Update on diagnosis, risk-stratification, and management. Am J Hematol. 2014;89(10):999–1009. doi: 10.1002/ajh.23810. DOI: https://doi.org/10.1002/ajh.23810
6. Kumar SK, Lee JH, Lahuerta JJ, et al. Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study. Leukemia. 2012;26(1):149–57. doi: 10.1038/leu.2012.15. DOI: https://doi.org/10.1038/leu.2012.15
7. Kumar A, Porwal M, Verma A, Mishra AK. Impact of pomalidomide therapy in multiple myeloma: a recent survey. J Chemother. 2014;26(6):321–7. doi: 10.1179/1973947814y.0000000201. DOI: https://doi.org/10.1179/1973947814Y.0000000201
8. Семочкин С.В. Биологические основы применения иммуномодулирующих препаратов в лечении множественной миеломы. Онкогематология. 2010;1:21–31.
9. [Semochkin SV. Biological fundamentals of application of immunomodulatory agents in treatment of multiple myeloma. Onkogematologiya 2010;1:21–31. (In Russ)]
10. Lopez-Girona A, Mendy D, Ito T, et al. Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide. Leukemia. 2012;26(11):2326–35. doi: 10.1038/leu.2012.119. DOI: https://doi.org/10.1038/leu.2012.119
11. Zhu YX, Braggio E, Shi CX, et al. Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide. Blood. 2011;118(18):4771–9. doi: 10.1182/blood-2011-05-356063. DOI: https://doi.org/10.1182/blood-2011-05-356063
12. Heintel D, Rocci A, Ludwig H, et al. High expression of cereblon (CRBN) is associated with improved clinical response in patients with multiple myeloma treated with lenalidomide and dexamethasone. Br J Haematol. 2013;161(5):695–700. doi: 10.1111/bjh.12338. DOI: https://doi.org/10.1111/bjh.12338
13. Schuster SR, Kortuem KM, Zhu YX, et al. The clinical significance of cereblon expression in multiple myeloma. Leuk Res. 2014;38(1):23–8. doi: 10.1016/j.leukres.2013.08.015. DOI: https://doi.org/10.1016/j.leukres.2013.08.015
14. Chamberlain PP, Lopez-Girona A, Miller K, et al. Structure of the human Cereblon-DDB1-lenalidomide complex reveals basis for responsiveness to thalidomide analogs. Nat Struct Mol Biol. 2014;21(9):803–9. doi: 10.1038/nsmb.2874. DOI: https://doi.org/10.1038/nsmb.2874
15. Lu G, Middleton RE, Sun H, et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science. 2014;343(6168):305–9. doi: 10.1126/science.1244917. DOI: https://doi.org/10.1126/science.1244917
16. Gandhi AK, Kang J, Havens CG, et al. Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4 (CRBN). Br J Haematol. 2014;164(6):811–21. doi: 10.1111/bjh.12708. DOI: https://doi.org/10.1111/bjh.12708
17. Kronke J, Udeshi ND, Narla A, et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science. 2014;343(6168):301–5. doi: 10.1126/science.124485. DOI: https://doi.org/10.1126/science.1244851
18. Shi ChX, Zhu YuX, Jedlowski P, et al. Ikaros Degradation Efficiency Correlates with Response of Multiple Myeloma (MM) Cells to IMiD Therapy and Is Blocked By Proteasome Inhibitors. Blood (ASH Annual Meeting Abstracts). 2014;124(21): Abstract 2247. DOI: https://doi.org/10.1182/blood.V124.21.2247.2247
19. Mitsiades N, Mitsiades CS, Poulaki V, et al. Biologic sequelae of nuclear factor-kappaB blockade in multiple myeloma: therapeutic applications. Blood. 2002;99(11):4079–86. doi: 10.1182/blood.v99.11.4079. DOI: https://doi.org/10.1182/blood.V99.11.4079
20. Zhu YX, Kortuem KM, Stewart AK. Molecular mechanism of action of immune-modulatory drugs thalidomide, lenalidomide and pomalidomide in multiple myeloma. Leuk Lymphoma. 2013;54(4):683–7. doi: 10.3109/10428194.2012.728597. DOI: https://doi.org/10.3109/10428194.2012.728597
21. Li S, Pal R, Monaghan SA, et al. IMiD immunomodulatory compounds block C/EBPb translation through eIF4E down-regulation resulting in inhibition of MM. Blood. 2011;117(19):5157–65. doi: 10.1182/blood-2010-10-314278. DOI: https://doi.org/10.1182/blood-2010-10-314278
22. Huang X, Di Liberto M, Jayabalan D, et al. Prolonged early G(1) arrest by selective CDK4/CDK6 inhibition sensitizes myeloma cells to cytotoxic killing through cell cycle-coupled loss of IRF4. Blood. 2012;120(5):1095–106. doi: 10.1182/blood-2012-03-415984. DOI: https://doi.org/10.1182/blood-2012-03-415984
23. Corral LG, Haslett PA, Muller GW, et al. Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-alpha. J Immunol. 1999;163(1):380–6. DOI: https://doi.org/10.4049/jimmunol.163.1.380
24. Anderson G, Gries M, Kurihara N, et al. Thalidomide derivative CC-4047 inhibits osteoclast formation by down-regulation of PU.1. Blood. 2006;107(8):3098–105. doi: 10.1182/blood-2005-08-3450. DOI: https://doi.org/10.1182/blood-2005-08-3450
25. Haslett PA, Corral LG, Albert M, Kaplan G. Thalidomide costimulates primary human T lymphocytes, preferentially inducing proliferation, cytokine production, and cytotoxic responses in the CD8+ subset. J Exp Med. 1998;187(11):1885–92. doi: 10.1084/jem.187.11.1885. DOI: https://doi.org/10.1084/jem.187.11.1885
26. Davies FE, Raje N, Hideshima T, et al. Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma. Blood. 2001;98(1):210–6. doi: 10.1182/blood.V98.1.210. DOI: https://doi.org/10.1182/blood.V98.1.210
27. Galustian C, Meyer B, Labarthe MC, et al. The anti-cancer agents lenalidomide and pomalidomide inhibit the proliferation and function of T regulatory cells. Cancer Immunol. Immunother. 2009;58(7):1033–45. doi: 10.1007/s00262-008-0620-4. DOI: https://doi.org/10.1007/s00262-008-0620-4
28. Schey SA, Fields P, Bartlett JB, et al. Phase I study of an immunomodulatory thalidomide analog, CC-4047, in relapsed or refractory multiple myeloma. J Clin Oncol. 2004;22(16):3269–76. doi: 10.1200/jco.2004.10.052. DOI: https://doi.org/10.1200/JCO.2004.10.052
29. Streetly MJ, Gyertson K, Daniel Y, et al. Alternate day pomalidomide retains anti-myeloma effect with reduced adverse events and evidence of in vivo immunomodulation. Br J Haematol. 2008;141(1):41–51. doi: 10.1111/j.1365-2141.2008.07013.x DOI: https://doi.org/10.1111/j.1365-2141.2008.07013.x
30. Richardson PG, Siegel D, Baz R, et al. Phase 1 study of pomalidomide MTD, safety, and efficacy in patients with refractory multiple myeloma who have received lenalidomide and bortezomib. Blood. 2013;121(11):1961–7. doi: 10.1182/blood-2012-08-450742. DOI: https://doi.org/10.1182/blood-2012-08-450742
31. Leleu X, Attal M, Arnulf B, et al. Pomalidomide plus low-dose dexamethasone is active and well tolerated in bortezomib and lenalidomide-refractory multiple myeloma: intergroupe Francophone du Myelome 2009-02. Blood. 2013;121(11):1968–75. doi: 10.1182/blood-2012-09-452375. DOI: https://doi.org/10.1182/blood-2012-09-452375
32. Pegourie B, Petillon MO, Karlin L, et al. Long-Term Exposure to Pomalidomide-Dexamethasone in Pts with Refractory Myeloma. Blood (ASH Annual Meeting Abstracts). 2014;124(21): Abstract 3466. DOI: https://doi.org/10.1182/blood.V124.21.3466.3466
33. Lacy MQ, Allred JB, Gertz MA, et al. Pomalidomide plus low-dose dexamethasone in myeloma refractory to both bortezomib and lenalidomide: comparison of 2 dosing strategies in dual-refractory disease. Blood. 2011;118(11):2970–5. doi: 10.1182/blood-2011-04-348896. DOI: https://doi.org/10.1182/blood-2011-04-348896
34. Richardson PG, Siegel DS, Vij R, et al. Pomalidomide alone or in combination with low-dose dexamethasone in relapsed and refractory multiple myeloma: a randomized phase II study. Blood. 2014;123(12):1826–32. doi: 10.1182/blood-2014-04-566661. DOI: https://doi.org/10.1182/blood-2014-04-566661
35. San Miguel J, Weisel K, Moreau P, et al. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, Phase III trial. Lancet Oncol. 2013;14(11):1055–66. doi: 10.1016/s1470-2045(13)70380-2. DOI: https://doi.org/10.1016/S1470-2045(13)70380-2
36. Dimopoulos M, Palumbo A, Weisel K, et al. Safety and Efficacy in the Stratus (MM-010) Trial, a Single-Arm Phase 3b Study Evaluating Pomalidomide + Low-Dose Dexamethasone in Patients with Refractory or Relapsed and Refractory Multiple Myeloma. Blood (ASH Annual Meeting Abstracts). 2014;124(21): Abstract 80. DOI: https://doi.org/10.1182/blood.V124.21.80.80
37. Richardson P, Hofmeister CC, Siegel D, et al. MM-005: A phase I trial of pomalidomide, bortezomib, and low-dose dexamethasone (PVD) in relapsed and/or refractory multiple myeloma (RRMM). ASCO Meet Abstr. 2013;31:8584. DOI: https://doi.org/10.1200/jco.2013.31.15_suppl.8584
38. Shah JJ, Edward A, Stadtmauer EA, et al. Phase I/II Dose Expansion Of a Multi-Center Trial Of Carfilzomib and Pomalidomide With Dexamethasone (Car-Pom-d) In Patients With Relapsed/Refractory Multiple Myeloma. Blood. 2013;122:690. DOI: https://doi.org/10.1182/blood.V122.21.690.690
39. Dimopoulos MA, Leleu X, Palumbo A, et al. Expert panel consensus statement on the optimal use of pomalidomide in relapsed and refractory multiple myeloma. Leukemia. 2014;28(8):1573–9. doi: 10.1038/leu.2014.60. DOI: https://doi.org/10.1038/leu.2014.60
40. Palumbo A, Palladino C. Venous and arterial thrombotic risks with thalidomide: evidence and practical guidance. Ther Adv Drug Saf. 2012;3(5):255–66. doi: 10.1177/2042098612452291. DOI: https://doi.org/10.1177/2042098612452291
41. Palumbo A, Cavo M, Bringhen S, et al. Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol. 2011;29(8):986–93. doi: 10.1200/jco.2010.31.6844. DOI: https://doi.org/10.1200/JCO.2010.31.6844
42. Kasserra C, Assaf M, Hoffmann M, et al. Pomalidomide: evaluation of cytochrome P450 and transporter-mediated drug-drug interaction potential in vitro and in healthy subjects. J Clin Pharmacol. 2015;55(2):168–78. doi: 10.1002/jcph.384. DOI: https://doi.org/10.1002/jcph.384
43. Khalafallah A, Maiwald M, Cox A, et al. Effect of immunoglobulin therapy on the rate of infections in multiple myeloma patients undergoing autologous stem cell transplantation or treated with immunomodulatory agents. Mediterr J Hematol Infect Dis. 2010;2(1):e2010005. doi: 10.4084/mjhid.2010.005. DOI: https://doi.org/10.4084/mjhid.2010.005
44. Palumbo A, Dimopoulos MA, Weisel K, et al. Outcomes for Older Patients in Stratus (MM-010), a Single-Arm, and Phase 3b Study of Pomalidomide + Low-Dose Dexamethasone in Refractory or Relapsed and Refractory Multiple Myeloma. Blood (ASH Annual Meeting Abstracts). 2014;124(21): Abstract 4770. DOI: https://doi.org/10.1182/blood.V124.21.4770.4770
45. Weisel K, Dimopoulos MA, Cavo M, et al. Pomalidomide + Low-Dose Dexamethasone in Patients with Refractory or Relapsed and Refractory Multiple Myeloma and Renal Impairment: Analysis of Patients from the Phase 3b Stratus Trial (MM-010). Blood (ASH Annual Meeting Abstracts). 2014;124(21): Abstract 4755. DOI: https://doi.org/10.1182/blood.V124.21.4755.4755
46. Rossi CA, Aneja E, Boyer A, et al. Effect of Renal and Hepatic Function on Pomalidomide Dose in Patients with Relapsed/Refractory Multiple Myeloma. Blood (ASH Annual Meeting Abstracts). 2014;124(21): Abstract 4754. DOI: https://doi.org/10.1182/blood.V124.21.4754.4754
47. Short KD, Rajkumar SV, Larson D, et al. Incidence of extramedullary disease in patients with multiple myeloma in the era of novel therapy, and the activity of pomalidomide on extramedullary myeloma. Leukemia. 2011;25(6):906–8. doi: 10.1038/leu.2011.29. DOI: https://doi.org/10.1038/leu.2011.29
48. Leleu X, Karlin L, Macro M, et al. Pomalidomide plus low-dose dexamethasone in relapsed or refractory multiple myeloma (RRMM) with deletion (del)17p and/or translocation t(4;14). Blood (ASH Annual Meeting Abstracts). 2013;122(21): Abstract 689. DOI: https://doi.org/10.1182/blood.V122.21.689.689
49. Leleu X, Karlin L, Macro M, et al. Pomalidomide plus low-dose dexamethasone in multiple myeloma with deletion 17p and/or translocation (4;14): IFM 2010-02 trial results. Blood. 2015;125(9):1411–7. doi: 10.1182/blood-2014-11-612069. DOI: https://doi.org/10.1182/blood-2014-11-612069
50. Hanaizi Z, Flores B, Hemmings R, et al. The European Medicines Agency Review of Pomalidomide in Combination with Low-Dose Dexamethasone for the Treatment of Adult Patients with Multiple Myeloma: Summary of the Scientific Assessment of the Committee for Medicinal Products for Human Use. The Oncologist. 2015;20(3):329–34. doi: 10.1634/theoncologist.2014-0073. DOI: https://doi.org/10.1634/theoncologist.2014-0073