RESUMEN
The success of the autologous stem cell transplantation is strictly related to an adequate hematopoietic stem cell mobilization and collection. The minimum threshold for a successful mobilization is currently defined as 2 × 106/kg CD34+ cells. However, the optimal stem cell mobilization strategy is still controversial. The availability of plerixafor, a selective and reversible CXCR4 inhibitor, has been associated with an higher use of chemo-free protocols by many centres. In the near future, it is conceivable that artificial intelligence may became more accurate and comprehensive, possibly guiding clinicians in choosing the optimal mobilisation treatment for the various patients undergoing hematopoietic stem cell transplantation. Machine learning-based scoring models may be the basis for the development of "intelligent" mobilisation algorithms.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Compuestos Heterocíclicos , Mieloma Múltiple , Humanos , Movilización de Célula Madre Hematopoyética/métodos , Trasplante de Células Madre Hematopoyéticas/métodos , Inteligencia Artificial , Antígenos CD34/metabolismo , Trasplante Autólogo , Compuestos Heterocíclicos/farmacología , Células Madre Hematopoyéticas/metabolismo , Factor Estimulante de Colonias de Granulocitos/farmacología , Mieloma Múltiple/terapiaRESUMEN
Hyperactivation of the Hedgehog (Hh) pathway, which controls refueling of multiple myeloma (MM) clones, might be critical to disease recurrence. Although several studies suggest the Hh pathway is activated in CD138- immature cells, differentiated CD138+ plasma cells might also be able to self-renew by producing themselves the Hh ligands. We studied the gene expression profiles of 126 newly diagnosed MM patients analyzed in both the CD138+ plasma cell fraction and CD138-CD19+ B-cell compartment. Results demonstrated that an Hh-gene signature was able to cluster patients in two subgroups characterized by the opposite Hh pathway expression in mature plasma cells and their precursors. Strikingly, patients characterized by Hh hyperactivation in plasma cells, but not in their B cells, displayed high genomic instability and an unfavorable outcome in terms of shorter progression-free survival (hazard ratio: 1.92; 95% confidence interval: 1.19-3.07) and overall survival (hazard ratio: 2.61; 95% confidence interval: 1.26-5.38). These results suggest that the mechanisms triggered by the Hh pathway ultimately led to identify a more indolent vs a more aggressive biological and clinical subtype of MM. Therefore, patient stratification according to their molecular background might help the fine-tuning of future clinical and therapeutic studies.
Asunto(s)
Linfocitos B/patología , Proteínas Hedgehog/metabolismo , Mieloma Múltiple/diagnóstico , Células Plasmáticas/patología , Animales , Antígenos CD19 , Linfocitos B/inmunología , Linfocitos B/metabolismo , Línea Celular Tumoral , Xenoinjertos , Humanos , Ratones SCID , Mieloma Múltiple/inmunología , Mieloma Múltiple/metabolismo , Células Plasmáticas/inmunología , Células Plasmáticas/metabolismo , Pronóstico , Transducción de Señal , Sindecano-1 , Células Tumorales CultivadasRESUMEN
Despite significant improvement in outcomes have been observed for multiple myeloma (MM) patients over the past 10-15 years, mainly due to the introduction of novel agents targeting the tumor clone and the bone marrow microenvironment, treatment of refractory and/or relapsed (RR) disease remains a challenge, particularly for patients who have failed prior bortezomib- and lenalidomide-based therapies. More recently, new drugs with different mechanisms of action, including second generation proteasome inhibitors, third generation immunomodulatory drugs, histone deacetylase inhibitors and monoclonal antibodies, have been developed and are under investigation, further increasing treatment options for RRMM patients. Overall, novel agent-based triplet combinations demonstrated superior response rates and prolonged disease control when compared with two-drug regimens in several randomized clinical trials, without adding any relevant additional toxicity. Salvage triplet therapies are likely to play a key role in overcoming drug-resistance and hold promise to further improve long-term outcomes of RRMM patients.
Asunto(s)
Antineoplásicos/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Anticuerpos Monoclonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bortezomib/uso terapéutico , Inhibidores de Histona Desacetilasas/uso terapéutico , Humanos , Factores Inmunológicos/uso terapéutico , Lenalidomida , Mieloma Múltiple/patología , Mieloma Múltiple/terapia , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/terapia , Inhibidores de Proteasoma/uso terapéutico , Terapia Recuperativa , Talidomida/análogos & derivados , Talidomida/uso terapéuticoRESUMEN
Incorporation of novel agents into auto-SCT for patients with multiple myeloma has led to improvement in their outcomes. However, the effects of new drugs, either single or combined, on PBSC mobilization have not been fully evaluated, particularly in phase 3 clinical studies. We analyzed the impact of two novel agent-based induction treatments in patients enrolled in the GIMEMA MMY-3006 study comparing bortezomib, thalidomide and dexamethasone (VTD) versus thalidomide and dexamethasone (TD) in preparation for double auto-SCT. Results showed that a short-term induction therapy with VTD did not adversely affect CD34(+) cell yields as compared with TD (9.75 vs 10.76 × 10(6) CD34(+) cells/kg, P=0.220). For poor mobilizers (<4 × 10(6) CD34(+) cells/kg), 5-year rates of time to progression (TTP), progression-free survival (PFS) and overall survival (OS) were significantly shorter than for successful mobilizers (TTP:17 vs 48%, P<0.0001; PFS: 16 vs 46%, P<0.0001; OS: 50 vs 80%, P<0.0001). These differences were retained across patients randomized to the TD arm; conversely, no differences in outcomes were seen in patients treated with VTD, irrespective of the number of harvested CD34(+) cells. The number of collected PBSCs predicted better outcomes after auto-SCT and VTD overcame the negative impact of a poor stem cell mobilization.
Asunto(s)
Bortezomib/administración & dosificación , Dexametasona/administración & dosificación , Movilización de Célula Madre Hematopoyética/métodos , Mieloma Múltiple/terapia , Trasplante de Células Madre de Sangre Periférica , Talidomida/administración & dosificación , Autoinjertos , Femenino , Humanos , Quimioterapia de Inducción/métodos , Masculino , Persona de Mediana EdadRESUMEN
The role of high-dose therapy and autologous stem-cell transplantation (ASCT) in the treatment of multiple myeloma (MM) has continued to evolve in recent years. The novel agents thalidomide, bortezomib, and lenalidomide have been successfully incorporated into induction therapy in preparation for ASCT and are currently being investigated also as post-ASCT consolidation and maintenance therapy. Consolidation treatment is generally short term and aims to increase the frequency and depth of response obtained with the previous treatment phases, including novel agent-based induction therapy and ASCT. This review will focus on recent trials of novel agents as post-ASCT consolidation therapy, offering an overview of pros and cons of this new treatment strategy in the ASCT sequence for MM patients.