Moduladores da ligase E3 cereblon (CELMoDs)
Os moduladores da cereblon, como os medicamentos experimentais iberdomida e CC-92480, ligam-se à cereblon com maior afinidade que a lenalidomida ou a pomalidomida e degradam as Ikaros (IKZF1) e Aiolos (IKZF3) em pacientes refratários à pomalidomida.[183]Matyskiela ME, Zhang W, Man HW, et al. A cereblon modulator (CC-220) with improved degradation of Ikaros and Aiolos. J Med Chem. 2018 Jan 25;61(2):535-42.
http://www.ncbi.nlm.nih.gov/pubmed/28425720?tool=bestpractice.com
A iberdomida está sendo avaliada como monoterapia em pacientes com mieloma múltiplo recidivante ou refratário (MMRR), e em combinação com os tratamentos padrão em pacientes com MM recém-diagnosticado ou MMRR.[184]ClinicalTrials.gov. A study to determine dose, safety, tolerability, drug levels, and efficacy of CC-220 monotherapy, and in combination with other treatments in participants with multiple myeloma. NCT02773030. Aug 2023 [internet publication].
https://www.clinicaltrials.gov/ct2/show/NCT02773030
[185]ClinicalTrials.gov. Open-label study comparing iberdomide, daratumumab and dexamethasone (IberDd) versus daratumumab, bortezomib, and dexamethasone (DVd) in participants with relapsed or refractory multiple myeloma (RRMM) (EXCALIBER-RRMM). NCT04975997. Jul 2023 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT04975997
Também há ensaios clínicos em andamento para avaliar a iberdomida como terapia de manutenção em pacientes com MM pós-transplante.[186]ClinicalTrials.gov. Iberdomide maintenance therapy in patients with multiple myeloma. NCT05177536. Jun 2023 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT05177536
[187]ClinicalTrials.gov. Iberdomide (Cc220) maintenance after Asct in newly diagnosed MM patients. NCT04564703. Aug 2022 [internet publication].
https://www.clinicaltrials.gov/ct2/show/NCT04564703
O CC-92480 está sendo avaliado em combinação com a dexametasona em pacientes com MMRR, e em combinação com tratamentos padrão em pacientes com MM recém-diagnosticado ou MMRR.[188]ClinicalTrials.gov. A safety, PK and efficacy study of CC-92480 monotherapy and in combination with dexamethasone in subjects with relapsed and refractory multiple myeloma (RRMM). NCT03374085. Aug 2023 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT03374085
[189]ClinicalTrials.gov. A study to determine the recommended dose and regimen and to evaluate the safety and preliminary efficacy of CC-92480 in combination with standard treatments in participants with relapsed or refractory multiple myeloma (RRMM) and newly diagnosed multiple myeloma (NDMM). NCT03989414. Jun 2023 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT03989414
Ixazomibe associado a pomalidomida e dexametasona (para MM refratário)
Em um estudo de fase 1/2 de pacientes com MM refratário à lenalidomida e a inibidor de proteassoma, um esquema triplo oral compreendendo ixazomibe associado a pomalidomida e dexametasona demonstrou uma taxa de resposta global de 51.7%.[190]Voorhees PM, Suman VJ, Tuchman SA, et al. A phase I/II study of ixazomib, pomalidomide, and dexamethasone for lenalidomide and proteasome inhibitor refractory multiple myeloma (Alliance A061202). Am J Hematol. 2021 Dec 1;96(12):1595-603.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8713771
http://www.ncbi.nlm.nih.gov/pubmed/34559902?tool=bestpractice.com
A duração mediana da resposta foi de 16.8 meses, a mediana da sobrevida livre de progressão foi de 4.4 meses e a mediana da sobrevida global foi de 34.3 meses.[190]Voorhees PM, Suman VJ, Tuchman SA, et al. A phase I/II study of ixazomib, pomalidomide, and dexamethasone for lenalidomide and proteasome inhibitor refractory multiple myeloma (Alliance A061202). Am J Hematol. 2021 Dec 1;96(12):1595-603.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8713771
http://www.ncbi.nlm.nih.gov/pubmed/34559902?tool=bestpractice.com
Inibidores de proteossomos de nova geração
Os inibidores de proteassoma de última geração experimentais incluem o marizomibe (um inibidor de todas as três subunidades do proteassoma 20S [beta5, beta1 e beta2]) e o oprozomibe.[191]Chauhan D, Catley L, Li G, et al. A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from bortezomib. Cancer Cell. 2005 Nov;8(5):407-19.
http://www.ncbi.nlm.nih.gov/pubmed/16286248?tool=bestpractice.com
[192]Kumar SK, Bensinger WI, Zimmerman TM, et al. Phase 1 study of weekly dosing with the investigational oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma. Blood. 2014 Aug 14;124(7):1047-55.
https://ashpublications.org/blood/article/124/7/1047/33652/Phase-1-study-of-weekly-dosing-with-the
http://www.ncbi.nlm.nih.gov/pubmed/24904120?tool=bestpractice.com
[193]Richardson PG, Baz R, Wang M, et al. Phase 1 study of twice-weekly ixazomib, an oral proteasome inhibitor, in relapsed/refractory multiple myeloma patients. Blood. 2014 Aug 14;124(7):1038-46.
https://ashpublications.org/blood/article/124/7/1038/33629/Phase-1-study-of-twice-weekly-ixazomib-an-oral
http://www.ncbi.nlm.nih.gov/pubmed/24920586?tool=bestpractice.com
Em um ensaio clínico fase 1 de escalonamento da dose, pacientes com MMRR responderam ao agente único marizomibe com efeitos adversos mínimos.[194]Richardson PG, Zimmerman TM, Hofmeister CC, et al. Phase 1 study of marizomib in relapsed or relapsed and refractory multiple myeloma: NPI-0052-101 Part 1. Blood. 2016 Jun 2;127(22):2693-700.
https://ashpublications.org/blood/article/127/22/2693/35152/Phase-1-study-of-marizomib-in-relapsed-or-relapsed
http://www.ncbi.nlm.nih.gov/pubmed/27009059?tool=bestpractice.com
O marizomibe recebeu designação de medicamento órfão para MM da Food and Drug Administration (FDA) e da European Medicines Agency (EMA).
Terapias direcionadas ao antígeno de maturação das células B (BCMA)
O BCMA é uma proteína de superfície das células expressa em células B selecionadas e nos plasmócitos maduros. A ligação do BCMA aos seus ligandos APRIL e BAFF promove a proliferação e a diferenciação das células B.[195]Tai YT, Anderson KC. Targeting B-cell maturation antigen in multiple myeloma. Immunotherapy. 2015;7(11):1187-99.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4976846
http://www.ncbi.nlm.nih.gov/pubmed/26370838?tool=bestpractice.com
Os anticorpos bioespecíficos direcionados a BCMA/envolvedores de células T (BITEs) experimentais incluem o PF-06863135 e o CC-93269. Os conjugados anticorpo-medicamento direcionados ao BCMA incluem o AMG-224 e o SEA-BCMA.[196]Usmani SZ, Garfall AL, van de Donk NWCJ, et al. Teclistamab, a B-cell maturation antigen × CD3 bispecific antibody, in patients with relapsed or refractory multiple myeloma (MajesTEC-1): a multicentre, open-label, single-arm, phase 1 study. Lancet. 2021 Aug 21;398(10301):665-74.
http://www.ncbi.nlm.nih.gov/pubmed/34388396?tool=bestpractice.com
[197]ClinicalTrials.gov. PF-06863135 as single agent and in combination with immunomodulatory agents in relapse/refractory multiple myeloma. NCT03269136. Apr 2023 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT03269136
[198]ClinicalTrials.gov. Study of CC-93269, a BCMA x CD3 T cell engaging antibody, in participants with relapsed and refractory multiple myeloma. NCT03486067. Jul 2023 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT03486067
[199]Lee HC, Raje NS, Landgren O, et al. Phase 1 study of the anti-BCMA antibody-drug conjugate AMG 224 in patients with relapsed/refractory multiple myeloma. Leukemia. 2021 Jan;35(1):255-8.
http://www.ncbi.nlm.nih.gov/pubmed/32317775?tool=bestpractice.com
[200]ClinicalTrials.gov. A safety study of SEA-BCMA in patients with multiple myeloma. NCT03582033. Apr 2023 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT03582033
Inibidores de leucemia de células mieloides 1 (LCM-1)
A proteína induzida Mcl-1 de diferenciação celular da leucemia mieloide, codificada pelo gene MCL-1 é uma membra da família BCL-2 (linfoma de células B-2) de proteínas multidomínio que regulam a apoptose.[201]Adams JM, Cory S. Bcl-2-regulated apoptosis: mechanism and therapeutic potential. Curr Opin Immunol. 2007 Oct;19(5):488-96.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2754308
http://www.ncbi.nlm.nih.gov/pubmed/17629468?tool=bestpractice.com
A MCL-1 promove a sobrevivência das células MM.[202]Peperzak V, Vikström I, Walker J, et al. Mcl-1 is essential for the survival of plasma cells. Nat Immunol. 2013 Mar;14(3):290-7.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4041127
http://www.ncbi.nlm.nih.gov/pubmed/23377201?tool=bestpractice.com
Os inibidores de MCL-1 investigacionais que estão sendo avaliados em pacientes com MM incluem o MIK665 (também chamado de S64315), o AMG 397, o AZD5991 e o AMG 176.
Inibidores de BCL-2
A BCL-2 é uma membra da família BCL-2 de proteínas pró-apoptóticas e antiapoptóticas, que funcionam para regular a apoptose.[203]Tsujimoto Y. Role of Bcl-2 family proteins in apoptosis: apoptosomes or mitochondria? Genes Cells. 1998 Nov;3(11):697-707.
https://onlinelibrary.wiley.com/doi/full/10.1046/j.1365-2443.1998.00223.x
http://www.ncbi.nlm.nih.gov/pubmed/9990505?tool=bestpractice.com
Ensaios clínicos com o venetoclax (um inibidor oral de BCL-2) em pacientes com MMRR foram temporariamente suspensos após relatos de aumento do risco de morte entre pacientes que receberam venetoclax (combinado com bortezomibe e dexametasona [VD]) em comparação com o grupo-controle.[204]Kumar SK, Harrison SJ, Cavo M, et al. Venetoclax or placebo in combination with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma (BELLINI): a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2020 Dec;21(12):1630-42.
http://www.ncbi.nlm.nih.gov/pubmed/33129376?tool=bestpractice.com
Uma análise da sobrevida global do ensaio clínico indicou que os pacientes que mais se beneficiaram do venetoclax associado a VD foram aqueles com t(11;14) ou com células tumorais com alta expressão de BCL-2.[205]Kumar S, Harrison SJ, Cavo M, et al. Final overall survival results from BELLINI, a phase 3 study of venetoclax or placebo in combination with bortezomib and dexamethasone in relapsed/refractory multiple myeloma. Paper presented at: 63rd ASH Annual Meeting. Dec 11-14, 2021. Atlanta, GA/online. 653: myeloma and plasma cell dyscrasias - clinical-prospective therapeutic trials. Oral abstracts. Blood. 2021 Nov 23;138(suppl 1):84.
https://ashpublications.org/blood/article/138/Supplement%201/84/477532/Final-Overall-Survival-Results-from-BELLINI-a
Inibidores de BRAF e MEK
O uso de terapia combinada com um inibidor de BRAF (por exemplo, encorafenibe, vemurafenibe) e um inibidor de MEK (por exemplo, cobimetinibe, binimetinibe) tem sido relatado em pacientes com MMRR positivo para mutação BRAF V600.[206]Otieno SB, Nasir S, Weir A, et al. Rapid response in a patient with relapsed/refractory multiple myeloma treated with BRAF/MEK inhibitors. Case Rep Hematol. 2020 Dec 11;2020:8821415.
https://www.hindawi.com/journals/crihem/2020/8821415
http://www.ncbi.nlm.nih.gov/pubmed/33381330?tool=bestpractice.com
[207]Mey UJM, Renner C, von Moos R. Vemurafenib in combination with cobimetinib in relapsed and refractory extramedullary multiple myeloma harboring the BRAF V600E mutation. Hematol Oncol. 2017 Dec;35(4):890-3.
http://www.ncbi.nlm.nih.gov/pubmed/27641727?tool=bestpractice.com
[208]Raab MS, Giesen N, Schneid C, et al. Safety and preliminary efficacy results from a phase II study evaluating combined BRAF and MEK inhibition in relapsed/refractory multiple myeloma (rrMM) patients with activating BRAF V600E mutations: the GMMG-Birma trial. Paper presented at: 62nd ASH Annual Meeting. Dec 5-8, 2020. Online. 653: myeloma/amyloidosis: therapy, excluding transplantation. Oral abstracts. Blood. 2020 Nov 5;136(suppl 1):44-5.
https://ashpublications.org/blood/article/136/Supplement%201/44/470151/Safety-and-Preliminary-Efficacy-Results-from-a
Pesquisas estão em andamento.
Transplante autólogo de medula óssea seguido de transplante alogênico
O transplante autólogo de células-tronco seguido de transplante alogênico não mieloablativo melhorou a sobrevida, em comparação com o transplante autólogo duplo durante um acompanhamento médio de 45 meses.[209]Bruno B, Rotta M, Patriarca F, et al. A comparison of allografting with autografting for newly diagnosed myeloma. N Engl J Med. 2007 Mar 15;356(11):1110-20.
https://www.nejm.org/doi/full/10.1056/NEJMoa065464
http://www.ncbi.nlm.nih.gov/pubmed/17360989?tool=bestpractice.com
Os regimes não-mieloablativos que preservam a imunidade alogênica do enxerto contra o mieloma podem ajudar a reduzir a toxicidade.[106]Lokhorst H, Einsele H, Vesole D, et al; International Myeloma Working Group. International Myeloma Working Group consensus statement regarding the current status of allogeneic stem-cell transplantation for multiple myeloma. J Clin Oncol. 2010 Oct 10;28(29):4521-30.
http://www.ncbi.nlm.nih.gov/pubmed/20697091?tool=bestpractice.com
[210]Krishnan A, Pasquini MC, Logan B, et al. Autologous haemopoietic stem-cell transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a phase 3 biological assignment trial. Lancet Oncol. 2011 Dec;12(13):1195-203.
http://www.ncbi.nlm.nih.gov/pubmed/21962393?tool=bestpractice.com
O transplante alogênico deve ser feito apenas em centros especializados ou em ensaios clínicos.
Melfalano flufenamida
Em fevereiro de 2024, a FDA anunciou sua decisão final de suspender a aprovação do melfalano flufenamida nos EUA devido aos resultados do estudo confirmatório de fase 3 e seu perfil de segurança e eficácia.[211]U.S. Food & Drug Administration. FDA issues final decision to withdraw approval of Pepaxto (melphalan flufenamide). 2024 [internet publication]
https://www.fda.gov/drugs/drug-safety-and-availability/fda-issues-final-decision-withdraw-approval-pepaxto-melphalan-flufenamide
O melfalano flufenamida está aprovado em outros países (incluindo Europa) para pacientes com MMRR (as indicações específicas podem ser diferentes).