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Avanços na terapêutica do mieloma múltiplo
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O mieloma múltiplo (MM) é a segunda doença oncológica hematológica com maior
prevalência, logo após o Linfoma de Não Hodgkin. Esta neoplasia caracteriza-se pela expansão
monoclonal de plasmócitos na medula óssea que secretam imunoglobulina, também designada
de proteína M, passível de ser detetada no sangue e/ou urina e cuja sua acumulação se traduz
em sintomas conhecidos como CRAB (hipercalcemia, insuficiência renal, anemia e lesões
ósseas).
Nas últimas décadas, as investigações levadas a cabo nesta área tem melhorado o
conhecimento acerca da fisiopatologia do MM, levaram à identificação das alterações
citogenéticas desencadeadoras da doença e expandiram as opções terapêuticas, desde
imunomodeladores, inibidores do proteossoma, inibidores da histona desacetilase e anticorpos
monoclonais, para além do autotransplante de células percursoras hematopoiéticas, corticoides
e agentes alquilantes como o melfalano.
Posteriormente ao diagnóstico e estadiamento da doença, é investigada a possibilidade de
realização de autotransplante de células percursoras hematopoiéticas, segundo critérios
individuais dos doentes, tais como a idade. O tratamento é dividido em várias fases sequenciais:
indução; autotransplante; consolidação; manutenção. Os esquemas terapêuticos são
habitualmente tripletos que incluem um corticoide e dois fármacos com ação antitumoral. O
esquema inicial preferencial descrito na guideline da National Comprehensive Cancer Network
(NCCN) é composto pelos fármacos bortezomib - lenalidomida - dexametasona (VRd).
Apesar de os tratamentos atuais terem melhorado significativamente a sobrevivência global
(OS) dos doentes, o mieloma múltiplo permanece até aos dias de hoje uma condição incurável
e os doentes tornam-se inevitavelmente refratários à terapêutica, acabando por falecer da
doença.
Doentes refratários às terapêuticas standard apresentem fracos “outcomes”, daí a
necessidade da introdução de novos agentes terapêuticos capazes de aumentar a sobrevivência
e a qualidade de vida destes doentes. Torna-se imprescindível a procura de novos alvos
terapêuticos expressos nas células tumorais, tais como o antigénio de maturação das células B
(BCMA) para o qual se desenvolveram três modalidades distintas de tratamento: conjugados
fármaco-anticorpo (ADC), BITEs (bispecific T cell engagers) e CAR-T. Já se encontram
disponíveis no mercado moléculas anti-BCMA, tais como Belantamab mafodotina e muitas
outras são alvo de ensaios clínicos onde se tem evidenciado resultados bastantes promissores
em doentes já anteriormente submetidos a várias terapêuticas.
Multiple myeloma (MM) is the second most prevalent hematological oncological disease, after non-Hodgkin's Lymphoma. This cancer is characterized by the monoclonal expansion of plasmocytes in the bone marrow that secrete immunoglobulin, also called M protein, which can be detected in the blood and/or urine and whose accumulation consists into symptoms known as CRAB (hypercalcemia, renal, anemia and bone lesions). In the last decades, investigation into this area have upgrade knowledge about the pathophysiology of MM, led to the identification of the cytogenic alterations that trigger the disease and increased therapeutic options, from immunomodulators, proteasosome inhibitors, histone deacetylase inhibitors and monoclonal antibodies, in addition to stem cell autotransplantation, corticoids and alkylating agents such as melphalan. After the diagnosis and staging of the disease, the possibility of performing an autologous stem cell transplant is investigated, according to individual patient criteria, such as age. Treatment is divided into several sequential phases: induction; autotransplantation; consolidation; maintenance. Therapeutic regimens are usually triplets that include a corticoid and two drugs with antitumor action. The preferred initial regimen described in the National Comprehensive Cancer Network (NCCN) guideline is bortezomib - lenalidomide - dexamethasone (VRd). Although current treatments have significantly improved overall survival (OS) of patients, multiple myeloma remains an incurable condition and patients inevitably become refractory to therapy, eventually dying from the disease. Patients refractory to standard therapies have poor outcomes, hence the need to introduce new therapeutic agents capable of increasing the survival and quality of life of these patients. It is essential to search for new therapeutic targets expressed in tumor cells, such as the B cell maturation antigen (BCMA) for which three different treatment modalities have been developed: drug-antibody conjugates (ADC), bispecific T cell engagers (BITEs) and CAR-T. Anti-BCMA molecules such as Belantamab mafodotin and many others are already available on the market and are the subject of clinical trials where very promising results have been shown in patients who have previously undergone various therapies.
Multiple myeloma (MM) is the second most prevalent hematological oncological disease, after non-Hodgkin's Lymphoma. This cancer is characterized by the monoclonal expansion of plasmocytes in the bone marrow that secrete immunoglobulin, also called M protein, which can be detected in the blood and/or urine and whose accumulation consists into symptoms known as CRAB (hypercalcemia, renal, anemia and bone lesions). In the last decades, investigation into this area have upgrade knowledge about the pathophysiology of MM, led to the identification of the cytogenic alterations that trigger the disease and increased therapeutic options, from immunomodulators, proteasosome inhibitors, histone deacetylase inhibitors and monoclonal antibodies, in addition to stem cell autotransplantation, corticoids and alkylating agents such as melphalan. After the diagnosis and staging of the disease, the possibility of performing an autologous stem cell transplant is investigated, according to individual patient criteria, such as age. Treatment is divided into several sequential phases: induction; autotransplantation; consolidation; maintenance. Therapeutic regimens are usually triplets that include a corticoid and two drugs with antitumor action. The preferred initial regimen described in the National Comprehensive Cancer Network (NCCN) guideline is bortezomib - lenalidomide - dexamethasone (VRd). Although current treatments have significantly improved overall survival (OS) of patients, multiple myeloma remains an incurable condition and patients inevitably become refractory to therapy, eventually dying from the disease. Patients refractory to standard therapies have poor outcomes, hence the need to introduce new therapeutic agents capable of increasing the survival and quality of life of these patients. It is essential to search for new therapeutic targets expressed in tumor cells, such as the B cell maturation antigen (BCMA) for which three different treatment modalities have been developed: drug-antibody conjugates (ADC), bispecific T cell engagers (BITEs) and CAR-T. Anti-BCMA molecules such as Belantamab mafodotin and many others are already available on the market and are the subject of clinical trials where very promising results have been shown in patients who have previously undergone various therapies.
Descrição
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2023, Universidade de Lisboa, Faculdade de Farmácia.
Palavras-chave
Mieloma múltiplo Autotransplante de células percursoras hematopoiéticas CAR-T Anticorpos bi-específicos Doença residual mínima Mestrado Integrado - 2023