Pomalidomide in the management of relapsed/refractory multiple myeloma: A review

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Abstract

Pomalidomide is a third-generation immunomodulatory drug (IMiD) that has taken an important place in the management of relapsed/refractory multiple myeloma (RRMM) including in patients with resistance to lenalidomide (R). Synergism of antitumor activity was obtained by combining pomalidomide with dexamethasone (Pd), proteasome inhibitors (PIs), and monoclonal antibodies directed against CD38 and SLAMF7 receptors. The dose-limiting toxicity of pomalidomide is neutropenia (48–60% grade ≥3 for a dose of 4 mg/day). Overcoming resistance to lenalidomide is seen as a key benefit of pomalidomide in the development of triplets that can be used in 2nd and subsequent lines of RRMM treatment. In OPTIMISMM study (phase III), 70% of patients were lenalidomide resistant. Randomization was performed on VPd (bortezomib-Pd) and Vd (bortezomib, dexamethasone) therapy. Vd as control was implemented in two related phases III trials ENDEAVOR (carfilzomib, dexamethasone) and CASTOR (daratumumab-Vd). For patients with resistance to lenalidomide, the median progression-free survival (PFS) was 9.5 mon for VPd in OPTIMISMM; 9.3 mon in CASTOR (resistant to R 21%) for DVd, and 9.3 mon in ENDEAVOR (21%) for Kd - 8.6 mon. The ICARIA-MM study (phase 3; resistance to R – 94%) demonstrated the benefit of incorporating isutaximab into the triplet (median PFS 11.1 and 5.9 mon for Isa-Pd and Pd respectively; p<0.0001). Similar data were obtained in the ELOQUENT-3 study (phase II; resistance to R - 90%) for elotuzumab (10.3 and 4.7 mon for EPd and Pd respectively; p=0.008). In the APOLLO study (phase III; resistance - 80%), the efficacy of the triplet with daratumumab was confirmed (12.4 and 6.9 mon for DPd and Pd respectively; p = 0.0018). In the present review, the focus is on the consideration of treatment regimens that are of relevance to Russian clinical practice.

About the authors

Sergej Semochkin

Hertsen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Centre; Pirogov Russian National Research Medical University

Author for correspondence.
Email: kapelovich@hpmp.ru
ORCID iD: 0000-0002-8129-8114

D. Sci. (Med.), Prof., Hertsen Moscow Oncology Research Institute, Professor of the Department of Oncology, Hematology and Radiation Therapy, Pediatric Faculty

Russian Federation, Moscow; Moscow

References

  1. Бессмельцев С.С. Множественная миелома: диагностика и терапия (часть 2). Вестник гематологии. 2022;18(3):4-31 [Bessmeltsev SS. Multiple myeloma: diagnosis and therapy (part 2). Bulletin of Hematology. 2022;18(3):4-31 (in Russian)].
  2. Лучинин А.С., Семочкин С.В., Минаева Н.В., и др. Эпидемиология множественной миеломы по данным популяционного регистра Кировской области. Онкогематология. 2017;12(3):50-6 [Luchinin AS, Semochkin SV, Minaeva NV, et al. Epidemiology of multiple myeloma according to the Кirov region population registers. Oncohematology. 2017;12(3):50-6 (in Russian)]. doi: 10.17650/1818-8346-2017-12-3-50-56
  3. Соловьев М.В., Менделеева Л.П., Покровская О.С., и др. Множественная миелома: поддерживающая терапия после трансплантации аутологичных гемопоэтических стволовых клеток в зависимости от минимальной остаточной болезни. Терапевтический архив. 2017;89(7):25-31 [Solovyev MV, Mendeleeva LP, Pokrovskaya OS, et al. Multiple myeloma: Maintenance therapy after autologous hematopoietic stem cell transplantation, depending on minimal residual disease. Terapevticheskii Arkhiv (Ter. Arkh.). 2017;89(7):25-31 (in Russian)]. doi: 10.17116/terarkh201789725-31
  4. Misund K, Hofste Op Bruinink D, Coward E, et al. Clonal evolution after treatment pressure in multiple myeloma: heterogenous genomic aberrations and transcriptomic convergence. Leukemia. 2022;36(7):1887-97. doi: 10.1038/s41375-022-01597-y
  5. Kastritis E, Roussou M, Gavriatopoulou M, et al. Impact of last lenalidomide dose, duration, and IMiD-free interval in patients with myeloma treated with pomalidomide/dexamethasone. Blood Adv. 2019;3(23):4095-103. doi: 10.1182/bloodadvances.2019000539
  6. Семочкин С.В. Механизмы действия противоопухолевых иммуномодуляторов – от тератогенности к терапии множественной миеломы. Гематология и трансфузиология. 2022;67(2):240-60 [Semochkin SV. Mechanisms of action of immunomodulatory drugs — from teratogenicity to treatment of multiple myeloma. Russian Journal of Hematology and Transfusiology. 2022;67(2):240-60 (in Russian)]. doi: 10.35754/0234-5730-2022-67-2-240-260
  7. Heim C, Pliatsika D, Mousavizadeh F, et al. De-Novo Design of Cereblon (CRBN) Effectors Guided by Natural Hydrolysis Products of Thalidomide Derivatives. J Med Chem. 2019;62(14):6615-29. doi: 10.1021/acs.jmedchem.9b00454
  8. Krönke 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.1244851
  9. 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
  10. Read KA, Jones DM, Freud AG, Oestreich KJ. Established and emergent roles for Ikaros transcription factors in lymphoid cell development and function. Immunol Rev. 2021;300(1):82-99. doi: 10.1111/imr.12936
  11. Bjorklund CC, Lu L, Kang J, et al. Rate of CRL4(CRBN) substrate Ikaros and Aiolos degradation underlies differential activity of lenalidomide and pomalidomide in multiple myeloma cells by regulation of c-Myc and IRF4. Blood Cancer J. 2015;5(10):e354. doi: 10.1038/bcj.2015.66
  12. Harada T, Ozaki S, Oda A, et al. Association of Th1 and Th2 cytokines with transient inflammatory reaction during lenalidomide plus dexamethasone therapy in multiple myeloma. Int J Hematol. 2013;97(6):743-8. doi: 10.1007/s12185-013-1321-0
  13. 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
  14. Lagrue K, Carisey A, Morgan DJ, et al. Lenalidomide augments actin remodeling and lowers NK-cell activation thresholds. Blood. 2015;126(1):50-60. doi: 10.1182/blood-2015-01-625004
  15. 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
  16. 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
  17. Borsi E, Martello M, Santacroce B, et al. Treatment optimization for multiple myeloma: schedule-dependent synergistic cytotoxicity of pomalidomide and carfilzomib in in vitro and ex vivo models. Haematologica. 2018;103(12):e602-6. doi: 10.3324/haematol.2017.186924
  18. Miguel JS, 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 3 trial. Lancet Oncol. 2013;14(11):1055-66. doi: 10.1016/S1470-2045(13)70380-2
  19. Rychak E, Mendy D, Shi T, et al. Pomalidomide in combination with dexamethasone results in synergistic anti-tumour responses in pre-clinical models of lenalidomide-resistant multiple myeloma. Br J Haematol. 2016;172(6):889-901. doi: 10.1111/bjh.13905
  20. 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
  21. Chiu H, Trisal P, Bjorklund C, et al. Combination lenalidomide-rituximab immunotherapy activates anti-tumour immunity and induces tumour cell death by complementary mechanisms of action in follicular lymphoma. Br J Haematol. 2019;185(2):240-53. doi: 10.1111/bjh.15797
  22. Lacy MQ, Hayman SR, Gertz MA, et al. Pomalidomide (CC4047) plus low-dose dexamethasone as therapy for relapsed multiple myeloma. J Clin Oncol. 2009;27(30):5008-14. doi: 10.1200/JCO.2009.23.6802
  23. Lacy MQ, Hayman SR, Gertz MA, et al. Pomalidomide (CC4047) plus low dose dexamethasone (Pom/dex) is active and well tolerated in lenalidomide refractory multiple myeloma (MM). Leukemia. 2010;24(11):1934-9. doi: 10.1038/leu.2010.190
  24. 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
  25. 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
  26. 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 2 study. Blood. 2014;123(12):1826-32. doi: 10.1182/blood-2013-11-538835
  27. Hoffmann M, Kasserra C, Reyes J, et al. Absorption, metabolism and excretion of [14C]pomalidomide in humans following oral administration. Cancer Chemother Pharmacol. 2013;71(2):489-501. doi: 10.1007/s00280-012-2040-6
  28. Li Y, Wang X, O’Mara E, et al. Population pharmacokinetics of pomalidomide in patients with relapsed or refractory multiple myeloma with various degrees of impaired renal function. Clin Pharmacol. 2017;9:133-45. doi: 10.2147/CPAA.S144606
  29. Li Y, Kassir N, Wang X, et al. Population Pharmacokinetics and Exposure Response Analysis of Pomalidomide in Subjects With Relapsed or Refractory Multiple Myeloma From the Novel Combination Treatment of Pomalidomide, Bortezomib, and Low-Dose Dexamethasone. J Clin Pharmacol. 2020;60(8):1061-75. doi: 10.1002/jcph.1602
  30. Li Y, Xu Y, Liu L, et al. Population pharmacokinetics of pomalidomide. J Clin Pharmacol. 2015;55(5):563-72. doi: 10.1002/jcph.455
  31. San Miguel JF, Weisel KC, Song KW, et al. Impact of prior treatment and depth of response on survival in MM-003, a randomized phase 3 study comparing pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone in relapsed/refractory multiple myeloma. Haematologica. 2015;100(10):1334-9. doi: 10.3324/haematol.2015.125864
  32. Dimopoulos MA, Palumbo A, Corradini P, et al. Safety and efficacy of pomalidomide plus low-dose dexamethasone in STRATUS (MM-010): a phase 3b study in refractory multiple myeloma. Blood. 2016;128(4):497-503. doi: 10.1182/blood-2016-02-700872
  33. Dechow T, Aldaoud A, Behlendorf T, et al. Pomalidomide plus dexamethasone for patients with relapsed or refractory multiple myeloma: Final results of the non-interventional study POSEIDON and comparison with the pivotal phase 3 clinical trials. Eur J Haematol. 2022;108(2):133-44. doi: 10.1111/ejh.13719
  34. Потапенко В.Г., Баумерт Е.В., Боброва А.А., и др. Применение помалидомида у пациентов c рефрактерным и рецидивирующим течением множественной миеломы: многоцентровое ретроспективное исследование. Онкогематология. 2022;17(3):48-61 [Potapenko VG, Baumert EV, Bobrova AA, et al. Pomalidomide in relapsed and refractory multiple myeloma: multicenter retrospective study. Oncohematology. 2022;17(3):48-61 (in Russian)]. doi: 10.17650/1818-8346-2022-17-3-48-61
  35. 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 Myélome 2009-02. Blood. 2013;121(11):1968-75. doi: 10.1182/blood-2012-09-452375
  36. Sehgal K, Das R, Zhang L, et al. Clinical and pharmacodynamic analysis of pomalidomide dosing strategies in myeloma: impact of immune activation and cereblon targets. Blood. 2015;125(26):4042-51. doi: 10.1182/blood-2014-11-611426
  37. 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
  38. Oka S, Ono K, Nohgawa M. Successful treatment with pomalidomide and intrathecal injections for central nervous system plasmacytoma in a patient under haemodialysis. J Clin Pharm Ther. 2020;45(1):221-5. doi: 10.1111/jcpt.13054
  39. 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
  40. Ganesan S, Palani HK, Balasundaram N, et al. Combination Lenalidomide/Bortezomib Treatment Synergistically Induces Calpain-Dependent Ikaros Cleavage and Apoptosis in Myeloma Cells. Mol Cancer Res. 2020;18(4):529-36. doi: 10.1158/1541-7786.MCR-19-0431
  41. Richardson PG, Oriol A, Beksac M, et al. Pomalidomide, bortezomib, and dexamethasone for patients with relapsed or refractory multiple myeloma previously treated with lenalidomide (OPTIMISMM): a randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20(6):781-94. doi: 10.1016/S1470-2045(19)30152-4
  42. Richardson PG, Schjesvold F, Weisel K, et al. Pomalidomide, bortezomib, and dexamethasone at first relapse in lenalidomide-pretreated myeloma: A subanalysis of OPTIMISMM by clinical characteristics. Eur J Haematol. 2022;108(1):73-83. doi: 10.1111/ejh.13706
  43. Moreau P, Joshua D, Chng WJ, et al. Impact of prior treatment on patients with relapsed multiple myeloma treated with carfilzomib and dexamethasone vs bortezomib and dexamethasone in the phase 3 ENDEAVOR study. Leukemia. 2017;31(1):115-22. doi: 10.1038/leu.2016.186
  44. Spencer A, Lentzsch S, Weisel K, et al. Daratumumab plus bortezomib and dexamethasone versus bortezomib and dexamethasone in relapsed or refractory multiple myeloma: updated analysis of CASTOR. Haematologica. 2018;103(12):2079-87. doi: 10.3324/haematol.2018.194118
  45. Семочкин С.В. Новые ингибиторы протеасомы в терапии множественной миеломы. Онкогематология. 2019;14(2):29-40 [Semochkin SV. New proteasome inhibitors in the management of multiple myeloma. Oncohematology. 2019;14(2):29-40 (in Russian)]. doi: 10.17650/1818-8346-2019-14-2-29-40
  46. Sonneveld P, Zweegman S, Cavo M, et al. Carfilzomib, Pomalidomide, and Dexamethasone As Second-line Therapy for Lenalidomide-refractory Multiple Myeloma. Hemasphere. 2022;6(10):e786. doi: 10.1097/HS9.0000000000000786
  47. Cohen YC, Shragai T, Lavi N, et al. A Phase II Multicenter Clinical Trial Assessing the Safety and Efficacy of Ixazomib Pomalidomide Dexamethasone Combination As Second or Third-Line Treatment for Patients with Triple Exposed Relapsed and Refractory Multiple Myeloma: Prespecified Interim Analysis (IPoD-790 trial). Blood. 2022;140(S1):10131-2. doi: 10.1182/blood-2022-164722
  48. Семочкин С.В. Терапия рецидивирующей и рефрактерной множественной миеломы, отягощенной двойной рефрактерностью (обзор литературы). Онкогематология. 2021;16(3):58-73 [Semochkin SV. Treatment of double-refractory multiple myeloma. Oncohematology. 2021;16(3):58-73 (in Russian)]. doi: 10.17650/1818-8346-2021-16-3-58-73
  49. Richardson PG, Perrot A, San-Miguel J, et al. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): follow-up analysis of a randomised, phase 3 study. Lancet Oncol. 2022;23(3):416-427. doi: 10.1016/S1470-2045(22)00019-5.
  50. Richardson PG, Perrot A, San-Miguel J, et al. Isatuximab Plus Pomalidomide/Low-Dose Dexamethasone Versus Pomalidomide/Low-Dose Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma (ICARIA-MM): Characterization of Subsequent Antimyeloma Therapies. Blood. 2022;140 (Suppl. 1):608-10. doi: 10.1182/blood-2022-159710
  51. Dimopoulos MA, Dytfeld D, Grosicki S, et al. Elotuzumab plus Pomalidomide and Dexamethasone for Multiple Myeloma. N Engl J Med. 2018;379(19):1811-22. doi: 10.1056/NEJMoa1805762
  52. Dimopoulos MA, Dytfeld D, Grosicki S, et al. Elotuzumab Plus Pomalidomide and Dexamethasone for Relapsed/Refractory Multiple Myeloma: Final Overall Survival Analysis From the Randomized Phase II ELOQUENT-3 Trial. J Clin Oncol. 2022;JCO2102815. doi: 10.1200/JCO.21.02815
  53. Chari A, Suvannasankha A, Fay JW, et al. Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. Blood. 2017;130(8):974-81. doi: 10.1182/blood-2017-05-785246
  54. Dimopoulos MA, Terpos E, Boccadoro M, et al. Daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone alone in previously treated multiple myeloma (APOLLO): an open-label, randomised, phase 3 trial. Lancet Oncol. 2021;22(6):801-12. doi: 10.1016/S1470-2045(21)00128-5
  55. Dimopoulos MA, Terpos E, Boccadoro M, et al. Subcutaneous daratumumab plus pomalidomide and dexamethasone (D-Pd) versus pomalidomide and dexamethasone (Pd) alone in patients with relapsed or refractory multiple myeloma (RRMM): overall survival results from the phase 3 APOLLO study. Blood. 2022;140 (Suppl. 1):7272-4. doi: 10.1182/blood-2022-163483
  56. Менделеева Л.П., Вотякова О.М., Рехтина И.Г., и др. Множественная миелома. Клинические рекомендации. Современная Онкология. 2020;22(4):6-28 [Mendeleeva LP, Votiakova OM, Rekhtina IG, et al. Multiple myeloma. Journal of Modern Oncology. 2020;22(4):6-28 (in Russian)]. doi: 10.26442/18151434.2020.4.200457.

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2. Fig. 1. IMiDs induces a reversible myeloid maturation arrest while bendamustine induces an irreversible neutrophil cytotoxicity: a – inhibition of CD34+ colony formation by bone marrow cells of healthy donors with bendamustine (red bars); b – schematic diagram of the cell series with flow cytometry data on CD33 and CD11b expression demonstrates 10 stages of myeloid differentiation from hematopoietic stem cell to mature neutrophil; c – the effect of culturing with IMiDs in an in vitro experiment. Adapted from [21].

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3. Fig. 2. Dose-time pomalidomide concentration in healthy volunteers and in patients with relapsed/refractory multiple myeloma (RRMM) [30]: a – individual dose-normalized concentration; b – pomalidomide concentration in plasma; c – in peripheral tissues and organs.

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4. Fig. 3. Correlation between pomalidomide exposure in the peripheral compartment and disease stage of patients with RRMM (box-and-whisker plot; quoted by [30]).

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5. molecular compound

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