ABSTRACT
In previous observational studies, we have separately characterized patients with multiple myeloma (MM) both from Latin America (LA) and from Asia. Here, we analyze these two datasets jointly, in order to assess the overall survival (OS) in these two world regions. Data were available from 3664 patients (1968 from LA and 1696 from Asia); all of whom diagnosed between 1998 and 2007. Approximately, 26% of patients in both world regions underwent transplantation. OS (from diagnosis of MM) was explored with Kaplan-Meier analyses and Cox proportional hazards models. Patients from LA were significantly younger and had hypercalcemia more often than Asian patients, who in turn had higher proportions of anemia and International Staging System (ISS) stage III disease. The median OS was 56 months in LA, and 47 months in Asia (hazard ratio [HR] = 0.83; 95% confidence interval [CI], 0.76 to 0.91; P < 0.001). In multivariable analysis, age, ISS stage III, anemia, hypercalcemia, and world region remained significantly associated with OS (P < 0.001 for all covariates). These results were largely driven by patients not undergoing transplantation, as no difference in OS emerged between the two world regions in univariable or multivariable analysis for transplanted patients. Despite adverse prognostic features differentially favoring each region, and adjusting for such differences, we found an OS advantage for patients from LA, in comparison with contemporaneous patients from Asia. Whether this is due to different biological features, differences in access to novel agents (especially thalidomide in earlier periods of the study), unmeasured confounders, or the play of chance, remain unknown.
Subject(s)
Multiple Myeloma/mortality , Multiple Myeloma/therapy , Registries , Aged , Asia/epidemiology , Disease-Free Survival , Female , Humans , Latin America/epidemiology , Male , Middle Aged , Neoplasm Staging , Survival RateABSTRACT
Despite the advantage observed with novel drugs such as bortezomib, thalidomide, or lenalidomide, multiple myeloma (MM) remains incurable and there is a clear need for new drugs or combinations based on the pathogenetic mechanism of MM. One of the proposed mechanisms in MM pathogenesis is the involvement of kinase molecules in the growth and survival of myelomatous cells. In this study, we have explored the optimal combination for dasatinib, a tyrosine kinase inhibitor, in MM cells. A clear synergistic effect was observed with the triple combination of dasatinib with bortezomib and dexamethasone which was evident even in the presence of bone marrow microenvironment. Experiments performed on freshly isolated patients' cells also demonstrated potentiation of response in the triple as compared with the agents alone or in double combinations. Gene expression profiling experiments provided some clues on the transcriptional rationale underlying this potentiation, as the triple combination led to significant deregulation of genes involved in cell death, cell growth, proliferation, DNA replication, repair and recombination, and cell-cell signaling. Some of these results were further confirmed by apoptosis and cell cycle experiments and also by Western blot and PCR. These data provide the rationale for the use of this novel combination in MM patients.
