RESUMO
This phase II study evaluated time-limited (24 cycles) treatment with ibrutinib and ixazomib in newly diagnosed (NDWM; n = 9) and relapsed/refractory (RRWM; n = 12) Waldenström macroglobulinaemia (WM). The overall response rate (ORR) was 76.2% (n = 16) in 21 evaluable patients with no patient achieving a complete response (CR). The median duration of treatment was 15.6 months, and after a median follow-up time of 25.7 months, the median progression-free survival (PFS) was 22.9 months. While the primary end-point was not met (CR rate at any time) and 28.5% discontinued treatment due to toxicity, ibrutinib plus ixazomib led to a clinically meaningful ORR and PFS. Combined Bruton's tyrosine kinase (BTK) and proteasome inhibition merits further evaluation in WM.
Assuntos
Adenina , Protocolos de Quimioterapia Combinada Antineoplásica , Compostos de Boro , Glicina , Piperidinas , Macroglobulinemia de Waldenstrom , Humanos , Compostos de Boro/uso terapêutico , Compostos de Boro/administração & dosagem , Compostos de Boro/efeitos adversos , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Glicina/análogos & derivados , Glicina/administração & dosagem , Glicina/efeitos adversos , Glicina/uso terapêutico , Adenina/análogos & derivados , Masculino , Idoso , Pessoa de Meia-Idade , Feminino , Piperidinas/uso terapêutico , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Idoso de 80 Anos ou mais , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Pirimidinas/administração & dosagem , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Pirazóis/administração & dosagem , Adulto , Resultado do TratamentoRESUMO
Therapeutic strategies that target novel pathways are urgently needed for patients with relapsed/refractory multiple myeloma (RRMM). Ibrutinib is an oral covalent inhibitor of Bruton tyrosine kinase, which is overexpressed in MM cells. This phase 1 dose-escalation study examined various doses of ibrutinib in combination with standard doses of lenalidomide (25 mg) and dexamethasone (40 mg) using a standard 3 + 3 design in RRMM patients. The primary objective was to determine the maximum tolerated dose (MTD) of ibrutinib in combination with lenalidomide and dexamethasone. Patients (n = 15) had received a median of 4 prior regimens, 53% were triple-class exposed, 33% were penta-exposed, and 54% were lenalidomide-refractory. The MTD of ibrutinib was 840 mg (n = 6) and only 1 dose-limiting toxicity; a grade 3 rash possibly related to ibrutinib was noted. The most common ≥ grade 3 adverse events were rash in 2 (13%), lymphopenia in 2 (13%), leukopenia, neutropenia, thrombocytopenia, and anemia all occurring in 3 (20%) patients each. One patient achieved a partial response for an overall response rate of 7%. The clinical benefit rate was 80%. The median time to progression was 3.8 months. Ibrutinib, lenalidomide and dexamethasone appears to be a safe and well-tolerated regimen with reasonable efficacy in heavily pretreated RRMM patients.