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Review

Targeting Ikaros and Aiolos: reviewing novel protein degraders for the treatment of multiple myeloma, with a focus on iberdomide and mezigdomide

, , ORCID Icon, ORCID Icon, ORCID Icon, ORCID Icon, , , , , & ORCID Icon show all
Pages 445-465 | Received 21 Mar 2024, Accepted 17 Jul 2024, Published online: 27 Jul 2024

References

  • Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–249. doi: 10.3322/caac.21660
  • Siegel RL, Miller KD, Wagle NS, et al. Cancer statistics, 2023. CA Cancer J Clin. 2023;73(1):17–48. doi: 10.3322/caac.21763
  • Dyba T, Randi G, Bray F, et al. The European cancer burden in 2020: incidence and mortality estimates for 40 countries and 25 major cancers. Eur J Cancer. 2021;157:308–347. doi: 10.1016/j.ejca.2021.07.039
  • NIH National Cancer Institute Surveillance E and end results program. Cancer stat facts: myeloma. [cited 2023 Aug 22]. Available from: https://seer.cancer.gov/statfacts/html/mulmy.html
  • van de Donk N, Pawlyn C, Yong KL. Multiple myeloma. Lancet. 2021;397(10272):410–427. doi: 10.1016/S0140-6736(21)00135-5
  • Leone P, Solimando AG, Malerba E, et al. Actors on the scene: immune cells in the myeloma niche. Front Oncol. 2020;10:599098. doi: 10.3389/fonc.2020.599098
  • Joseph NS, Kaufman JL, Dhodapkar MV, et al. Long-term follow-up results of lenalidomide, bortezomib, and dexamethasone induction therapy and risk-adapted maintenance approach in newly diagnosed multiple myeloma. J Clin Oncol. 2020;38(17):1928–1937. doi: 10.1200/JCO.19.02515
  • Raje N, Mateos MV, Iida S, et al. Clinical evidence for immune-based strategies in early-line multiple myeloma: current challenges in decision-making for subsequent therapy. Blood Cancer J. 2023;13(1):41. doi: 10.1038/s41408-023-00804-y
  • Richardson PG, San Miguel JF, Moreau P, et al. Interpreting clinical trial data in multiple myeloma: translating findings to the real-world setting. Blood Cancer J. 2018;8(11):109. doi: 10.1038/s41408-018-0141-0
  • Gandolfi S, Vekstein C, Laubach JP, et al. The evolving role of transplantation in multiple myeloma: the need for a heterogeneous approach to a heterogeneous disease. Clin Adv Hematol Oncol. 2018;16(8):564–574.
  • Kumar SK, Callander NS, Adekola K, et al. Multiple myeloma, version 2.2024, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2023;21(12):1281–1301. doi: 10.6004/jnccn.2023.0061
  • Sonneveld P, Dimopoulos MA, Boccadoro M, et al. Daratumumab, Bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2024;390(3):301–313. doi: 10.1056/NEJMoa2312054
  • Dimopoulos MA, Moreau P, Terpos E, et al. Multiple myeloma: EHA-ESMO clinical practice guidelines for diagnosis, treatment and follow-up(dagger). Ann Oncol. 2021;32(3):309–322. doi: 10.1016/j.annonc.2020.11.014
  • Rajkumar SV. Multiple myeloma: 2022 update on diagnosis, risk stratification, and management. Am J Hematol. 2022;97(8):1086–1107. doi: 10.1002/ajh.26590
  • Stalker ME, Mark TM. Clinical management of triple-class refractory multiple myeloma: a review of current strategies and emerging therapies. Curr Oncol. 2022;29(7):4464–4477. doi: 10.3390/curroncol29070355
  • Mo CC, Yee AJ, Midha S, et al. Selinexor: targeting a novel pathway in multiple myeloma. EJHaem. 2023;4(3):792–810. doi: 10.1002/jha2.709
  • More S, Offidani M, Corvatta L, et al. Belantamab Mafodotin: from clinical trials data to real-life experiences. Cancers (Basel). 2023;15(11):2948. doi: 10.3390/cancers15112948
  • Nadeem O, Mateos MV, Efebera YA, et al. Melphalan flufenamide for relapsed/refractory multiple myeloma. Drugs Today (Barc). 2022;58(8):407–423. doi: 10.1358/dot.2022.58.8.3367680
  • Parikh RH, Lonial S. Chimeric antigen receptor T-cell therapy in multiple myeloma: a comprehensive review of current data and implications for clinical practice. CA Cancer J Clin. 2023;73(3):275–285. doi: 10.3322/caac.21771
  • Cho SF, Yeh TJ, Anderson KC, et al. Bispecific antibodies in multiple myeloma treatment: a journey in progress. Front Oncol. 2022;12:1032775. doi: 10.3389/fonc.2022.1032775
  • Gengenbach L, Graziani G, Reinhardt H, et al. Choosing the right therapy for patients with relapsed/refractory multiple myeloma (RRMM) in consideration of patient-, disease- and treatment-related factors. Cancers (Basel). 2021;13(17):4320. doi: 10.3390/cancers13174320
  • Ramasamy K, Gay F, Weisel K, et al. Improving outcomes for patients with relapsed multiple myeloma: challenges and considerations of current and emerging treatment options. Blood Rev. 2021;49:100808. doi: 10.1016/j.blre.2021.100808
  • Snowden JA, Greenfield DM, Bird JM, et al. Guidelines for screening and management of late and long-term consequences of myeloma and its treatment. Br J Haematol. 2017;176(6):888–907. doi: 10.1111/bjh.14514
  • Marriott JB, Clarke IA, Dredge K, et al. Thalidomide and its analogues have distinct and opposing effects on TNF-alpha and TNFR2 during co-stimulation of both CD4(+) and CD8(+) T cells. Clin Exp Immunol. 2002;130(1):75–84. doi: 10.1046/j.1365-2249.2002.01954.x
  • Hansen JD, Correa M, Nagy MA, et al. Discovery of CRBN E3 ligase modulator CC-92480 for the treatment of relapsed and refractory multiple myeloma. J Med Chem. 2020;63(13):6648–6676. doi: 10.1021/acs.jmedchem.9b01928
  • Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med. 1999;341(21):1565–1571. doi: 10.1056/NEJM199911183412102
  • Rajkumar SV, Hayman S, Gertz MA, et al. Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma. J Clin Oncol. 2002;20(21):4319–4323. doi: 10.1200/JCO.2002.02.116
  • Richardson PG, Schlossman RL, Weller E, et al. Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood. 2002;100(9):3063–3067. doi: 10.1182/blood-2002-03-0996
  • Rajkumar SV, Hayman SR, Lacy MQ, et al. Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood. 2005;106(13):4050–4053. doi: 10.1182/blood-2005-07-2817
  • 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):3269–3276. doi: 10.1200/JCO.2004.10.052
  • 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):5008–5014. doi: 10.1200/JCO.2009.23.6802
  • Lonial S, Popat R, Hulin C, et al. Iberdomide plus dexamethasone in heavily pretreated late-line relapsed or refractory multiple myeloma (CC-220-MM-001): a multicentre, multicohort, open-label, phase 1/2 trial. Lancet Haematol. 2022;9(11):e822–e32. doi: 10.1016/S2352-3026(22)00290-3
  • Richardson PG, Trudel S, Popat R, et al. Mezigdomide plus dexamethasone in relapsed and refractory multiple myeloma. N Engl J Med. 2023;389(11):1009–1022. doi: 10.1056/NEJMoa2303194
  • Jan M, Sperling AS, Ebert BL. Cancer therapies based on targeted protein degradation - lessons learned with lenalidomide. Nat Rev Clin Oncol. 2021;18(7):401–417. doi: 10.1038/s41571-021-00479-z
  • Zhu YX, Braggio E, Shi CX, et al. Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide. Blood. 2011;118(18):4771–4779. doi: 10.1182/blood-2011-05-356063
  • Zhu YX, Braggio E, Shi CX, et al. Identification of cereblon-binding proteins and relationship with response and survival after IMiDs in multiple myeloma. Blood. 2014;124(4):536–545. doi: 10.1182/blood-2014-02-557819
  • Ito T, Ando H, Handa H. Discovery of the target for immunomodulatory drugs (IMiDs). Rinsho Ketsueki. 2016;57(5):556–562. doi: 10.11406/rinketsu.57.556
  • Kronke J, Udeshi ND, Narla A, et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science. 2014;343(6168):301–305. doi: 10.1126/science.1244851
  • Lu G, Middleton RE, Sun H, et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of ikaros proteins. Science. 2014;343(6168):305–309. doi: 10.1126/science.1244917
  • Kronke J, Hurst SN, Ebert BL. Lenalidomide induces degradation of IKZF1 and IKZF3. Oncoimmunology. 2014;3(7):e941742. doi: 10.4161/21624011.2014.941742
  • Matyskiela ME, Zhang W, Man HW, et al. A cereblon modulator (CC-220) with improved degradation of ikaros and Aiolos. J Med Chem. 2018;61(2):535–542. doi: 10.1021/acs.jmedchem.6b01921
  • Rasco DW, Papadopoulos KP, Pourdehnad M, et al. A first-in-human study of novel cereblon modulator avadomide (CC-122) in advanced malignancies. Clin Cancer Res. 2019;25(1):90–98. doi: 10.1158/1078-0432.CCR-18-1203
  • Costacurta M, He J, Thompson PE, et al. Molecular mechanisms of Cereblon-interacting small molecules in multiple myeloma therapy. J Pers Med. 2021;11(11):1185. doi: 10.3390/jpm11111185
  • Sperling AS, Burgess M, Keshishian H, et al. Patterns of substrate affinity, competition, and degradation kinetics underlie biological activity of thalidomide analogs. Blood. 2019;134(2):160–170. doi: 10.1182/blood.2019000789
  • Michot J-N, Chavez JC, Carpio C, et al. Clinical activity of CC-99282, a novel, oral small molecule cereblon E3 ligase modulator (CELMoD) agent, in patients (pts) with relapsed or refractory non-hodgkin lymphoma (R/R NHL) - first results from a phase 1, open-label study. Blood. 2021;138(Supplement 1):3574. doi: 10.1182/blood-2021-147333
  • Surka C, Jin L, Mbong N, et al. CC-90009, a novel cereblon E3 ligase modulator, targets acute myeloid leukemia blasts and leukemia stem cells. Blood. 2021;137(5):661–677. doi: 10.1182/blood.2020008676
  • Xia R, Cheng Y, Han X, et al. Ikaros proteins in tumor: Current perspectives and new developments. Front Mol Biosci. 2021;8:788440. doi: 10.3389/fmolb.2021.788440
  • Affar M, Bottardi S, Quansah N, et al. IKAROS: from chromatin organization to transcriptional elongation control. Cell Death Differ. 2023. doi: 10.1038/s41418-023-01212-2
  • John LB, Ward AC. The ikaros gene family: transcriptional regulators of hematopoiesis and immunity. Mol Immunol. 2011;48(9–10):1272–1278. doi: 10.1016/j.molimm.2011.03.006
  • 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
  • Cippitelli M, Stabile H, Kosta A, et al. Role of Aiolos and ikaros in the antitumor and immunomodulatory activity of IMiDs in multiple myeloma: better to lose than to find them. Int J Mol Sci. 2021;22(3):1103. doi: 10.3390/ijms22031103
  • Marke R, van Leeuwen FN, Scheijen B. The many faces of IKZF1 in B-cell precursor acute lymphoblastic leukemia. Haematologica. 2018;103(4):565–574. doi: 10.3324/haematol.2017.185603
  • Song C, Gowda C, Pan X, et al. Targeting casein kinase II restores ikaros tumor suppressor activity and demonstrates therapeutic efficacy in high-risk leukemia. Blood. 2015;126(15):1813–1822. doi: 10.1182/blood-2015-06-651505
  • Zhang J, Ding L, Holmfeldt L, et al. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature. 2012;481(7380):157–163. doi: 10.1038/nature10725
  • Conserva MR, Redavid I, Anelli L, et al. IKAROS in acute leukemia: a positive influencer or a mean hater? Int J Mol Sci. 2023;24(4):3282. doi: 10.3390/ijms24043282
  • Bourgeois W, Cutler JA, Aubrey BJ, et al. Mezigdomide is effective alone and in combination with Menin inhibition in pre-clinical models of KMT2A-r and NPM1c AML. Blood. 2024;143(15):1513–1527. doi: 10.1182/blood.2023021105
  • Mulet-Lazaro R, Delwel R. From genotype to Phenotype: how enhancers control gene expression and cell identity in hematopoiesis. Hemasphere. 2023;7(11):e969. doi: 10.1097/HS9.0000000000000969
  • Geng CL, Chen JY, Song TY, et al. Lenalidomide bypasses CD28 co-stimulation to reinstate PD-1 immunotherapy by activating notch signaling. Cell Chem Biol. 2022;29(8):1260–72 e8. doi: 10.1016/j.chembiol.2022.05.012
  • Kirstetter P, Thomas M, Dierich A, et al. Ikaros is critical for B cell differentiation and function. Eur J Immunol. 2002;32(3):720–730. doi: 10.1002/1521-4141(200203)32:3<720:AID-IMMU720>3.0.CO;2-P
  • Powell MD, Read KA, Sreekumar BK, et al. Ikaros zinc finger transcription factors: regulators of cytokine signaling pathways and CD4(+) T helper cell differentiation. Front Immunol. 2019;10:1299. doi: 10.3389/fimmu.2019.01299
  • Dumortier A, Kirstetter P, Kastner P, et al. Ikaros regulates neutrophil differentiation. Blood. 2003;101(6):2219–2226. doi: 10.1182/blood-2002-05-1336
  • Hung KH, Su ST, Chen CY, et al. Aiolos collaborates with blimp-1 to regulate the survival of multiple myeloma cells. Cell Death Differ. 2016;23(7):1175–1184. doi: 10.1038/cdd.2015.167
  • Murakami Y, Kimura-Masuda K, Oda T, et al. MYC causes multiple myeloma progression via attenuating TP53-induced MicroRNA-34 expression. Genes (Basel). 2022;14(1):100. doi: 10.3390/genes14010100
  • Fedele PL, Willis SN, Liao Y, et al. IMiDs prime myeloma cells for daratumumab-mediated cytotoxicity through loss of Ikaros and Aiolos. Blood. 2018;132(20):2166–2178. doi: 10.1182/blood-2018-05-850727
  • 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):811–821. doi: 10.1111/bjh.12708
  • Fionda C, Abruzzese MP, Zingoni A, et al. The IMiDs targets IKZF-1/3 and IRF4 as novel negative regulators of NK cell-activating ligands expression in multiple myeloma. Oncotarget. 2015;6(27):23609–23630. doi: 10.18632/oncotarget.4603
  • Shaffer AL, Emre NC, Lamy L, et al. IRF4 addiction in multiple myeloma. Nature. 2008;454(7201):226–231. doi: 10.1038/nature07064
  • Lopez-Girona A, Heintel D, Zhang LH, et al. Lenalidomide downregulates the cell survival factor, interferon regulatory factor-4, providing a potential mechanistic link for predicting response. Br J Haematol. 2011;154(3):325–336. doi: 10.1111/j.1365-2141.2011.08689.x
  • Hideshima T, Ogiya D, Liu J, et al. Immunomodulatory drugs activate NK cells via both zap-70 and cereblon-dependent pathways. Leukemia. 2021;35(1):177–188. doi: 10.1038/s41375-020-0809-x
  • Richardson PG, Mateos MV, Vangsted AJ, et al. The role of E3 ubiquitin ligase in multiple myeloma: potential for cereblon E3 ligase modulators in the treatment of relapsed/refractory disease. Expert Rev Proteomics. 2022;19(4–6):235–246. doi: 10.1080/14789450.2022.2142564
  • Errico A. Haematological cancer: ikaros–not a myth for myeloma. Nat Rev Clin Oncol. 2014;11(2):65. doi: 10.1038/nrclinonc.2013.237
  • 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):803–809. doi: 10.1038/nsmb.2874
  • Fischer ES, Bohm K, Lydeard JR, et al. Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide. Nature. 2014;512(7512):49–53. doi: 10.1038/nature13527
  • Shortt J, Phimister EG. Mezigdomide and multiple myeloma. N Engl J Med. 2023;389(11):1046–1050. doi: 10.1056/NEJMe2307370
  • Pourabdollah M, Bahmanyar M, Atenafu EG, et al. High IKZF1/3 protein expression is a favorable prognostic factor for survival of relapsed/refractory multiple myeloma patients treated with lenalidomide. J Hematol Oncol. 2016;9(1):123. doi: 10.1186/s13045-016-0354-2
  • Borsi E, Mazzocchetti G, Dico AF, et al. High levels of CRBN isoform lacking IMiDs binding domain predicts for a worse response to IMiDs-based upfront therapy in newly diagnosed myeloma patients. Clin Exp Med. 2023;23(8):5227–5239. doi: 10.1007/s10238-023-01205-y
  • Bolomsky A, Hubl W, Spada S, et al. IKAROS expression in distinct bone marrow cell populations as a candidate biomarker for outcome with lenalidomide-dexamethasone therapy in multiple myeloma. Am J Hematol. 2017;92(3):269–278. doi: 10.1002/ajh.24634
  • Dimopoulos K, Fibiger Munch-Petersen H, Winther Eskelund C, et al. Expression of CRBN, IKZF1, and IKZF3 does not predict lenalidomide sensitivity and mutations in the cereblon pathway are infrequent in multiple myeloma. Leuk Lymphoma. 2019;60(1):180–188. doi: 10.1080/10428194.2018.1466290
  • Ng YLD, Ramberger E, Bohl SR, et al. Proteomic profiling reveals CDK6 upregulation as a targetable resistance mechanism for lenalidomide in multiple myeloma. Nat Commun. 2022;13(1):1009. doi: 10.1038/s41467-022-28515-1
  • Tachita T, Kinoshita S, Ri M, et al. Expression, mutation, and methylation of cereblon-pathway genes at pre- and post-lenalidomide treatment in multiple myeloma. Cancer Sci. 2020;111(4):1333–1343. doi: 10.1111/cas.14352
  • Kronke J, Kuchenbauer F, Kull M, et al. IKZF1 expression is a prognostic marker in newly diagnosed standard-risk multiple myeloma treated with lenalidomide and intensive chemotherapy: a study of the German myeloma study group (DSMM). Leukemia. 2017;31(6):1363–1367. doi: 10.1038/leu.2016.384
  • Kronke J, Knop S, Langer C. Prognostic impact of ikaros expression in lenalidomide-treated multiple myeloma. Oncotarget. 2017;8(63):106163–106164. doi: 10.18632/oncotarget.22572
  • Misiewicz-Krzeminska I, de Ramon C, Corchete LA, et al. Quantitative expression of ikaros, IRF4, and PSMD10 proteins predicts survival in VRD-treated patients with multiple myeloma. Blood Adv. 2020;4(23):6023–6033. doi: 10.1182/bloodadvances.2020002711
  • Kriegsmann K, Baertsch MA, Awwad MHS, et al. Cereblon-binding proteins expression levels correlate with hyperdiploidy in newly diagnosed multiple myeloma patients. Blood Cancer J. 2019;9(2):13. doi: 10.1038/s41408-019-0174-z
  • Chretien ML, Corre J, Lauwers-Cances V, et al. Understanding the role of hyperdiploidy in myeloma prognosis: which trisomies really matter? Blood. 2015;126(25):2713–2719. doi: 10.1182/blood-2015-06-650242
  • Watson ER, Novick S, Matyskiela ME, et al. Molecular glue CELMoD compounds are regulators of cereblon conformation. Science. 2022;378(6619):549–553. doi: 10.1126/science.add7574
  • Sperling AS, Guerra VA, Kennedy JA, et al. Lenalidomide promotes the development of TP53-mutated therapy-related myeloid neoplasms. Blood. 2022;140(16):1753–1763. doi: 10.1182/blood.2021014956
  • D’Souza C, Prince HM, Neeson PJ. Understanding the role of T-Cells in the antimyeloma effect of immunomodulatory drugs. Front Immunol. 2021;12:632399. doi: 10.3389/fimmu.2021.632399
  • Thakurta A, Pierceall WE, Amatangelo MD, et al. Developing next generation immunomodulatory drugs and their combinations in multiple myeloma. Oncotarget. 2021;12(15):1555–1563. doi: 10.18632/oncotarget.27973
  • Quach H, Ritchie D, Stewart AK, et al. Mechanism of action of immunomodulatory drugs (IMiDS) in multiple myeloma. Leukemia. 2010;24(1):22–32. doi: 10.1038/leu.2009.236
  • Hayashi T, Hideshima T, Akiyama M, et al. Molecular mechanisms whereby immunomodulatory drugs activate natural killer cells: clinical application. Br J Haematol. 2005;128(2):192–203. doi: 10.1111/j.1365-2141.2004.05286.x
  • 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):1033–1045. doi: 10.1007/s00262-008-0620-4
  • Mougiakakos D, Bach C, Bottcher M, et al. The IKZF1-IRF4/IRF5 axis controls polarization of myeloma-associated macrophages. Cancer Immunol Res. 2021;9(3):265–278. doi: 10.1158/2326-6066.CIR-20-0555
  • Costa F, Vescovini R, Bolzoni M, et al. Lenalidomide increases human dendritic cell maturation in multiple myeloma patients targeting monocyte differentiation and modulating mesenchymal stromal cell inhibitory properties. Oncotarget. 2017;8(32):53053–53067. doi: 10.18632/oncotarget.18085
  • Jian Y, Gao W, Geng C, et al. Arsenic trioxide potentiates sensitivity of multiple myeloma cells to lenalidomide by upregulating cereblon expression levels. Oncol Lett. 2017;14(3):3243–3248. doi: 10.3892/ol.2017.6502
  • Lopez-Girona A, Havens CG, Lu G, et al. CC-92480 is a novel cereblon E3 ligase modulator with enhanced tumoricidal and immunomodulatory activity against sensitive and resistant multiple myeloma cells. Blood. 2019;134(Supplement_1):1812. doi: 10.1182/blood-2019-124338
  • Bjorklund CC, Kang J, Amatangelo M, et al. Iberdomide (CC-220) is a potent cereblon E3 ligase modulator with antitumor and immunostimulatory activities in lenalidomide- and pomalidomide-resistant multiple myeloma cells with dysregulated CRBN. Leukemia. 2020;34(4):1197–1201. doi: 10.1038/s41375-019-0620-8
  • Amatangelo M, Bjorklund CC, Hagner P, et al. P-230: preclinical and translational biomarker analysis to support further clinical development and dose optimization of mezigdomide (MEZI; CC-92480) in combination with either bortezomib or carfilzomib. Clin Lymphoma Myeloma Leukemia. 2022;22(Supplement):S161–S2. doi: 10.1016/S2152-2650(22)00560-2
  • Van Oekelen O, Amatangelo M, Guo M, et al. Large-scale mass cytometry reveals significant activation of innate and adaptive immunity in bone marrow tumor microenvironment of iberdomide-treated myeloma patients. Blood. 2021;138(Supplement 1):730. doi: 10.1182/blood-2021-151542
  • Ye Y, Gaudy A, Schafer P, et al. First-in-human, single- and multiple-ascending-dose studies in healthy subjects to assess pharmacokinetics, pharmacodynamics, and safety/tolerability of iberdomide, a novel cereblon E3 ligase modulator. Clin Pharmacol Drug Dev. 2021;10(5):471–485. doi: 10.1002/cpdd.869
  • Chen LY, Van Oekelen O, Amatangelo M, et al. Mezigdomide treatment in relapsed-refractory myeloma patients shifts bone marrow NK and T cell populations from exhaustion to activation. Blood. 2023;142(Supplement 1):4686. doi: 10.1182/blood-2023-187748
  • Chiu H, Zhao J, Ortiz Estevez M, et al. Mezigdomide reverses T-Cell exhaustion through degradation of aiolos/ikaros and reinvigoration of cytokine production pathways. Blood. 2023;142(Supplement 1):335. doi: 10.1182/blood-2023-189445
  • Gaffney B, Shi Y, de Jong P, et al. Mezigdomide (CC-92480), a novel cereblon E3 ligase modulator, induces vulnerability of multiple myeloma cells to T-Cell-mediated killing. Blood. 2022;140(Supplement 1):7108–7109. doi: 10.1182/blood-2022-157939
  • Wong L, Krishna Narla R, Leisten J, et al. CC-92480, a novel cereblon E3 ligase modulator, is synergistic with dexamethasone, bortezomib, and daratumumab in multiple myeloma. Blood. 2019;134(Supplement_1):1815. doi: 10.1182/blood-2019-124345
  • Chow TT, Amatangelo M, Ma P, et al. Preclinical and translational biomarker analyses to inform clinical development of mezigdomide (CC-92480) in combination with dexamethasone and daratumumab in multiple myeloma. Blood. 2023;142(Supplement 1):3318. doi: 10.1182/blood-2023-178881
  • Ma P, Sridharan V, Wollerman K, et al. Iberdomide enhances dara mediated cytotoxicity through upregulation of CDC activity and elevated NK cell mediated ADCC. Blood. 2023;142(Supplement 1):3289. doi: 10.1182/blood-2023-189423
  • Paiva B, Gaffney B, Burnett K, et al. Synergistic antitumor activity of alnuctamab (ALNUC; BMS-986349; CC-93269), a BCMA 2+1 T cell engager (TCE), and celmod agents in multiple myeloma (MM) preclinical models. Blood. 2022;140(Supplement 1):7054–7055. doi: 10.1182/blood-2022-157987
  • Eckmann J, Hage C, Stefanie L, et al. Early intervention with Celmods, but not imids, prevents relapse to forimtamig driven by GPRC5D-Negative myeloma cells. Blood. 2023;142(Supplement 1):4659. doi: 10.1182/blood-2023-174253
  • Aleman A, Kogan‑Zajdman A, Upadhyaya B, et al. Improving anti‑BCMA CAR‑T functionality with novel immunomodulatory agent iberdomide (CC220) in multiple myeloma. Clin Lymphoma Myeloma Leukemia. 2023;23(Supplement 2):S131–S2. doi: 10.1016/S2152-2650(23)01793-7
  • Bjorklund CC, Amatangelo M, Chiu H, et al. Pre-clinical and clinical immunomodulatory effects of pomalidomide or CC-92480 in combination with bortezomib in multiple myeloma. Blood. 2021;138(Supplement 1):1613. doi: 10.1182/blood-2021-153994
  • Bjorklund CC, Amatangelo M, Kang J, et al. CC-92480 enhances cell-autonomous cytotoxicity through blockade of G 2/M transition when combined with bortezomib/dexamethasone in pre-clinical multiple myeloma. Blood. 2021;138(Supplement 1):2669. doi: 10.1182/blood-2021-153907
  • Jeyaraju DV, Alapa M, O’Donohue A, et al. Suppression of myeloid cell-derived proinflammatory cytokines with celmod agents: implications for CRS with T-Cell engagers (TCEs). Blood. 2022;140(Supplement 1):7070–7071. doi: 10.1182/blood-2022-157927
  • Henderson JA, Eron SJ, Good A, et al. Abstract ND13: the discovery and characterization of CFT7455: a potent and selective degrader of IKZF1/3 for the treatment of relapsed/refractory multiple myeloma. Cancer Res. 2022;82(12_Supplement):ND13. doi: 10.1158/1538-7445.AM2022-ND13
  • Lonial S, Richard S, Matous JV, et al. Pharmacokinetic (PK) profile of a novel IKZF1/3 degrader, CFT7455, enables significant potency advantage over other IKZF1/3 degraders in models of multiple myeloma (MM) and the results of the initial treatment cohort from a first-in-human (FIH) phase 1/2 study of CFT7455 in MM. Cancer Res. 2022;82(12_Supplement):CT186. doi: 10.1158/1538-7445.AM2022-CT186
  • Arp CJ, Reynders M, Sreekanth V, et al. Photoswitchable molecular glues enable optical control of transcription factor degradation. bioRxiv. 2023. doi: 10.1101/2023.04.09.536172
  • Koduri V, Duplaquet L, Lampson BL, et al. Targeting oncoproteins with a positive selection assay for protein degraders. Sci Adv. 2021;7(6):eabd6263. doi: 10.1126/sciadv.abd6263
  • Liu XP, He L, Zhang QP, et al. Baicalein inhibits proliferation of myeloma U266 cells by downregulating IKZF1 and IKZF3. Med Sci Monit. 2018;24:2809–2817. doi: 10.12659/MSM.907058
  • Meng F, Xu C, Park KS, et al. Discovery of a first-in-class degrader for nuclear receptor binding SET domain protein 2 (NSD2) and ikaros/aiolos. J Med Chem. 2022;65(15):10611–10625. doi: 10.1021/acs.jmedchem.2c00807
  • Bird S, Pawlyn C. IMiD resistance in multiple myeloma: current understanding of the underpinning biology and clinical impact. Blood. 2023;142(2):131–140. doi: 10.1182/blood.2023019637
  • Gooding S, Ansari-Pour N, Kazeroun M, et al. Loss of COP9 signalosome genes at 2q37 is associated with IMiD resistance in multiple myeloma. Blood. 2022;140(16):1816–1821. doi: 10.1182/blood.2022015909
  • Bird S, Xu Y, Sialana F, et al. P-179 altered lipid metabolism in IMiD/CELMoD resistant multiple myeloma confers novel and targetable vulnerabilities. Clin Lymphoma Myeloma Leukemia. 2023;23(Supplement 2):S134. doi: 10.1016/S2152-2650(23)01797-4
  • Gooding S, Ansari-Pour N, Towfic F, et al. Multiple cereblon genetic changes are associated with acquired resistance to lenalidomide or pomalidomide in multiple myeloma. Blood. 2021;137(2):232–237. doi: 10.1182/blood.2020007081
  • Tilmont R, Maity R, Leblay N, et al. CRBN structural changes, copy number changes and COP9 signalosome subunits gene expression mediate sensitivity to new celmod compound CC-92480 in multiple myeloma patients. Blood. 2022;140(Supplement 1):9964–9965. doi: 10.1182/blood-2022-169550
  • Chrisochoidou Y, LeBihan Y-V, Morales S, et al. Investigating the functional impact of CRBN mutations on response to IMiD/Celmod agents in myeloma. Blood. 2023;142(Supplement 1):753. doi: 10.1182/blood-2023-179986
  • Barrio S, Munawar U, Zhu YX, et al. IKZF1/3 and CRL4(CRBN) E3 ubiquitin ligase mutations and resistance to immunomodulatory drugs in multiple myeloma. Haematologica. 2020;105(5):e237–e41. doi: 10.3324/haematol.2019.217943
  • Zhou N, Gutierrez-Uzquiza A, Zheng XY, et al. RUNX proteins desensitize multiple myeloma to lenalidomide via protecting IKZFs from degradation. Leukemia. 2019;33(8):2006–2021. doi: 10.1038/s41375-019-0403-2
  • Nguyen TV. USP15 antagonizes CRL4(CRBN)-mediated ubiquitylation of glutamine synthetase and neosubstrates. Proc Natl Acad Sci USA. 2021;118(40):e2111391118. doi: 10.1073/pnas.2111391118
  • Li Y, Barber A, Martin S, et al. EZH2 inhibition overcomes immunomodulatory drug (IMiD) resistance in multiple myeloma cell lines in a cereblon pathway dependent manner. Blood. 2023;142(Supplement 1):4187. doi: 10.1182/blood-2023-186614
  • Osada N, Kikuchi J, Iha H, et al. c-FOS is an integral component of the IKZF1 transactivator complex and mediates lenalidomide resistance in multiple myeloma. Clin Transl Med. 2023;13(8):e1364. doi: 10.1002/ctm2.1364
  • Barwick BG, Neri P, Bahlis NJ, et al. Multiple myeloma immunoglobulin lambda translocations portend poor prognosis. Nat Commun. 2019;10(1):1911. doi: 10.1038/s41467-019-09555-6
  • Durie BGM, Hoering A, Sexton R, et al. Longer term follow-up of the randomized phase III trial SWOG S0777: bortezomib, lenalidomide and dexamethasone vs. lenalidomide and dexamethasone in patients (pts) with previously untreated multiple myeloma without an intent for immediate autologous stem cell transplant (ASCT). Blood Cancer J. 2020;10(5):53. doi: 10.1038/s41408-020-0311-8
  • Richardson PG, Jacobus SJ, Weller EA, et al. Triplet therapy, transplantation, and maintenance until progression in myeloma. N Engl J Med. 2022;387(2):132–147. doi: 10.1056/NEJMoa2204925
  • Voorhees PM, Sborov DW, Laubach J, et al. Addition of daratumumab to lenalidomide, bortezomib, and dexamethasone for transplantation-eligible patients with newly diagnosed multiple myeloma (GRIFFIN): final analysis of an open-label, randomised, phase 2 trial. Lancet Haematol. 2023;10(10):e825–e37. doi: 10.1016/S2352-3026(23)00217-X
  • Facon T, Kumar SK, Plesner T, 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;22(11):1582–1596. doi: 10.1016/S1470-2045(21)00466-6
  • 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):1055–1066. doi: 10.1016/S1470-2045(13)70380-2
  • 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):781–794. doi: 10.1016/S1470-2045(19)30152-4
  • Dimopoulos MA, Terpos E, Boccadoro M, et al. Subcutaneous daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma (APOLLO): extended follow up of an open-label, randomised, multicentre, phase 3 trial. Lancet Haematol. 2023;10(10):e813–e24. doi: 10.1016/S2352-3026(23)00218-1
  • 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
  • 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):801–812. doi: 10.1016/S1470-2045(21)00128-5
  • Attal M, Richardson PG, Rajkumar SV, 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): a randomised, multicentre, open-label, phase 3 study. Lancet. 2019;394(10214):2096–2107. doi: 10.1016/S0140-6736(19)32556-5
  • van de Donk NWCJ, Touzeau C, Terpos E, et al. Iberdomide maintenance after autologous stem-cell transplantation in newly diagnosed MM: first results of the phase 2 EMN26 study. Blood. 2023;142(Supplement 1):abstract 208. doi: 10.1182/blood-2023-177564
  • Biran N, Vesole DH, Parmar H, et al. A phase 1/2 study of carfilzomib, Iberdomide and dexamethasone (KID) in patients with newly diagnosed transplant-eligible multiple myeloma. Blood. 2023;142(Supplement 1):abstract 2022. doi: 10.1182/blood-2023-1899072022-2022
  • Lonial S, Abdallah A-O, Anwer F, et al. Iberdomide (IBER) in combination with dexamethasone (DEX) in relapsed/refractory multiple myeloma (RRMM): results from the anti-B-Cell maturation antigen (BCMA)-exposed cohort of the CC-220-MM-001 trial. Blood. 2022;140(Supplement 1):4398–4400. doi: 10.1182/blood-2022-158180
  • Lonial S, Richardson PG, Popat R, et al. Iberdomide in combination with dexamethasone and daratumumab, bortezomib, or carfilzomib in patients with relapsed/refractory multiple myeloma. Hemasphere. 2021;5(suppl 2):S187. doi: 10.1097/HS9.0000000000000566
  • Oriol A, Sandhu I, Raab M, et al. OA-49 mezigdomide (MEZI) plus dexamethasone (DEX) and bortezomib (BORT) or carfilzomib (CFZ) in patients (pts) with relapsed/refractory multiple myeloma (RRMM): results from the CC-92480-MM-002 trial. Clin Lymphoma Myeloma Leukemia. 2023;23(Supplement 2):S31. doi: 10.1016/S2152-2650(23)01616-6
  • Richardson PG, Sandhu I, Hofmeister CC, et al. Mezigdomide (MEZI) plus dexamethasone (DEX) and Daratumumab (DARA) or elotuzumab (ELO) in patients (pts) with relapsed/refractory multiple myeloma (RRMM): results from the CC-92480-MM-002 trial. Blood. 2023;142(Supplement 1):1013. doi: 10.1182/blood-2023-174443
  • Goldsmith S, Oriol A, Anttila P, et al. P-265 mezigdomide (MEZI) monotherapy in relapsed/refractory multiple myeloma (RRMM): results from the CC-92480-MM-001 trial. Clin Lymphoma Myeloma Leukemia. 2023;23(Supplement 2):S181–S2. doi: 10.1016/S2152-2650(23)01883-9
  • White D, Lipe B, Gironella Mesa M, et al. Iberdomide, bortezomib, and dexamethasone (IberVd) in transplant‑ineligible newly diagnosed multiple myeloma (NDMM): results from the CC‑220‑MM‑001 trial. Clin Lymphoma Myeloma Leukemia. 2023;23(Supplement 2):S25. doi: 10.1016/S2152-2650(23)01608-7
  • Wong L, Lamba M, Jiménez Nuñez MD, et al. Dose- and schedule-dependent immunomodulatory effects of the novel celmod agent CC-92480 in patients with relapsed/refractory multiple myeloma. Blood. 2020;136(Supplement 1):47–48. doi: 10.1182/blood-2020-137161
  • Prabhala R, Pierceall WE, Samur M, et al. Immunomodulation of NK, NKT and B/T cell subtypes in relapsed/refractory multiple myeloma patients treated with pomalidomide along with velcade and dexamethasone and its association with improved progression-free survival. Front Oncol. 2023;13:1271807. doi: 10.3389/fonc.2023.1271807
  • Dimopoulos MA, Chen C, Spencer A, et al. Long-term follow-up on overall survival from the MM-009 and MM-010 phase III trials of lenalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma. Leukemia. 2009;23(11):2147–2152. doi: 10.1038/leu.2009.147
  • Dimopoulos MA, Swern AS, Li JS, et al. Efficacy and safety of long-term treatment with lenalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma. Blood Cancer J. 2014;4(11):e257. doi: 10.1038/bcj.2014.77
  • van de Donk N, White D, Lipe B, et al. Iberdomide (IBER) plus dexamethasone (DEX) in patients with relapsed/refractory multiple myeloma (RRMM): a safety analysis from the CC‑220‑MM‑001 trial. Clin Lymphoma Myeloma Leukemia. 2023;23(Supplement 2):S214–S5. doi: 10.1016/S2152-2650(23)01938-9
  • Pal R, Monaghan SA, Hassett AC, et al. Immunomodulatory derivatives induce PU.1 down-regulation, myeloid maturation arrest, and neutropenia. Blood. 2010;115(3):605–614. doi: 10.1182/blood-2009-05-221077
  • Liu A, Li S, Donnenberg V, et al. Immunomodulatory drugs downregulate IKZF1 leading to expansion of hematopoietic progenitors with concomitant block of megakaryocytic maturation. Haematologica. 2018;103(10):1688–1697. doi: 10.3324/haematol.2018.188227
  • Kumar SK, Callander NS, Alsina M, et al. NCCN guidelines insights: multiple myeloma, version 3.2018. J Natl Compr Canc Netw. 2018;16(1):11–20. doi: 10.6004/jnccn.2018.0002
  • Dytfeld D, Wrobel T, Jamroziak K, et al. Carfilzomib, lenalidomide, and dexamethasone or lenalidomide alone as maintenance therapy after autologous stem-cell transplantation in patients with multiple myeloma (ATLAS): interim analysis of a randomised, open-label, phase 3 trial. Lancet Oncol. 2023;24(2):139–150. doi: 10.1016/S1470-2045(22)00738-0
  • Nooka AK, Kaufman JL, Muppidi S, et al. Consolidation and maintenance therapy with lenalidomide, bortezomib and dexamethasone (RVD) in high-risk myeloma patients. Leukemia. 2014;28(3):690–693. doi: 10.1038/leu.2013.335
  • Leypoldt LB, Tichy D, Besemer B, et al. Isatuximab, carfilzomib, Lenalidomide, and dexamethasone for the treatment of high-risk newly diagnosed multiple myeloma. J Clin Oncol. 2024;42(1):26–37. doi: 10.1200/JCO.23.01696
  • Ravi G, Bal S, Joiner L, et al. Subsequent therapy and outcomes in patients with newly diagnosed multiple myeloma experiencing disease progression after quadruplet combinations. Br J Haematol. 2024;204(4):1300–1306. doi: 10.1111/bjh.19303
  • Gay F, Dimopoulos M, Huang X, et al. A phase 3, two‑stage, randomized study of iberdomide maintenance versus lenalidomide maintenance post autologous stem cell transplantation in newly diagnosed multiple myeloma: EXCALIBER‑maintenance. Clin Lymphoma Myeloma Leukemia. 2023;23(Supplement 2):S111. doi: 10.1016/S2152-2650(23)01755-X
  • Lonial S, Quach H, Dimopoulos MA, et al. EXCALIBER-RRMM: a phase 3, two-stage study of iberdomide, daratumumab, and dexamethasone (IberDd) versus daratumumab, bortezomib, and dexamethasone (DVd) in patients (pts) with relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2023;41(16_suppl):TPS8069. doi: 10.1200/JCO.2023.41.16_suppl.TPS8069
  • Richardson PG, Badelita SN, Besemer B, et al. MM-372 a phase III, two-stage, randomized study of mezigdomide, bortezomib, and dexamethasone (MeziVd) versus pomalidomide, bortezomib, and dexamethasone (PVd) in relapsed/refractory multiple myeloma (RRMM): SUCCESSOR-1. Clin Lymphoma Myeloma Leukemia. 2023;23(Supplement 1):S495–S6. doi: 10.1016/S2152-2650(23)01446-5
  • Richardson P, Amatangelo M, Berenson J, et al. A phase 3, two-stage, randomized study of mezigdomide, carfilzomib, and dexamethasone (MeziKd) versus carfilzomib and dexamethasone (kd) in relapsed/refractory multiple myeloma (RRMM): SUCCESSOR-2. J Clin Oncol. 2023;42(Supplement):TPS8070. doi: 10.1200/JCO.2023.41.16_suppl.TPS8070