RESUMO
The phase 1b 16-BCNI-001/CTRIAL-IE 16-02 CyBorD-DARA trial investigated the combination of Daratumumab with cyclophosphamide, bortezomib and dexamethasone in patients with newly diagnosed multiple myeloma (NDMM), followed by autologous stem cell transplantation and Daratumumab maintenance. CR/sCR rates were 50% after transplant and 62.5% at end of treatment. The overall percentage of patients achieving complete response or better was 77.8%. Progression-free survival rate at end of maintenance was 81.3% and estimated 2-year overall survival was 88.9%. 37.5% of patients demonstrated sustained MRD negativity to a level of 10-5 from transplant to analysis at EOT. In this phase 1b study, we have shown CyBorD-DARA to be an effective and well-tolerated immunomodulatory agent-free regiment in transplant-eligible NDMM.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Mieloma Múltiplo , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bortezomib/uso terapêutico , Ciclofosfamida/uso terapêutico , Dexametasona/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Mieloma Múltiplo/tratamento farmacológico , Transplante Autólogo , Resultado do TratamentoRESUMO
Daratumumab (DARA) has shown impressive activity in combination with other agents for the treatment of multiple myeloma (MM). We conducted a phase 1b study to assess the safety and preliminary efficacy, as well as potential mechanisms of action, of DARA (16 mg/kg) in combination with a weekly schedule of subcutaneous bortezomib (1.3-1.5 mg/m2), cyclophosphamide (150-300 mg/m2), and dexamethasone (40 mg) (CyBorD DARA) as initial induction before autologous stem cell transplantation (ASCT). Eligible patients were ≤70 years of age with untreated MM requiring treatment and who lacked significant comorbidities. A total of 18 patients were enrolled. Their median age was 56 years (range, 32-66 years), and all patients had Eastern Cooperative Oncology Group performance status ≤1. The International Staging System stages were I, II, and III in 78%, 17%, and 6% of patients, respectively; 28% of patients had high-risk genetic features. There was no dose-limiting toxicity, and the incidence of grade 3 or 4 infection or neutropenia was <10%. On an intention-to-treat basis, 94% achieved ≥very good partial response with ≥complete response in 44% of patients. Among 14 of 15 patients who underwent ASCT and were evaluable for response, all 14 achieved at least very good partial response, with 8 (57%) of 14 achieving complete response. After ASCT, 10 (83%) of 12 patients in whom minimal residual disease analysis was possible were negative at a sensitivity of 10-5 (56% on intention-to-treat/whole study population) according to next-generation sequencing. Flow cytometry analysis of patient samples indicated CyBorD DARA induced activation of macrophage-mediated antibody-dependent cellular phagocytosis. This trial was registered at www.clinicaltrials.gov as #NCT02955810.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacologia , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/uso terapêutico , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica , Bortezomib/administração & dosagem , Bortezomib/uso terapêutico , Ciclofosfamida/administração & dosagem , Ciclofosfamida/uso terapêutico , Dexametasona/administração & dosagem , Dexametasona/uso terapêutico , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Incidência , Infecções/induzido quimicamente , Infecções/epidemiologia , Injeções Subcutâneas , Irlanda/epidemiologia , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Neutropenia/epidemiologia , Inibidores de Proteassoma/administração & dosagem , Inibidores de Proteassoma/uso terapêutico , Transplante Autólogo , Resultado do TratamentoRESUMO
Multiple myeloma (MM) is characterized by the clonal expansion and metastatic spread of malignant plasma cells to multiple sites in the bone marrow (BM). Recently, we implicated the sialyltransferase ST3Gal-6, an enzyme critical to the generation of E-selectin ligands, in MM BM homing and resistance to therapy. Since E-selectin is constitutively expressed in the BM microvasculature, we wished to establish the contribution of E-selectin ligands to MM biology. We report that functional E-selectin ligands are restricted to a minor subpopulation of MM cell lines which, upon expansion, demonstrate specific and robust interaction with recombinant E-selectin in vitro. Moreover, an increase in the mRNA levels of genes involved in the generation of E-selectin ligands was associated with inferior progression-free survival in the CoMMpass study. In vivo, E-selectin ligand-enriched cells induced a more aggressive disease and were completely insensitive to Bortezomib. Importantly, this resistance could be reverted by co-administration of GMI-1271, a specific glycomimetic antagonist of E-selectin. Finally, we report that E-selectin ligand-bearing cells are present in primary MM samples from BM and peripheral blood with a higher proportion seen in relapsed patients. This study provides a rationale for targeting E-selectin receptor/ligand interactions to overcome MM metastasis and chemoresistance.