RESUMEN
Deeper responses are associated with improved survival in patients being treated for myeloma. However, the sensitivity of the current blood-based assays is limited. Historical studies suggested that normalisation of the serum free light chain (FLC) ratio in patients who were negative by immunofixation electrophoresis (IFE) was associated with improved outcomes. However, recently this has been called into question. Mass spectrometry (MS)-based FLC assessments may offer a superior methodology for the detection of monoclonal FLC due to greater sensitivity. To test this hypothesis, all available samples from patients who were IFE negative after treatment with carfilzomib and lenalidomide-based induction and autologous stem cell transplantation (ASCT) in the Myeloma XI trial underwent FLC-MS testing. FLC-MS response assessments from post-induction, day+100 post-ASCT and six months post-maintenance randomisation were compared to serum FLC assay results. Almost 40% of patients had discordant results and 28.7% of patients with a normal FLC ratio had residual monoclonal FLC detectable by FLC-MS. FLC-MS positivity was associated with reduced progression-free survival (PFS) but an abnormal FLC ratio was not. This study demonstrates that FLC-MS provides a superior methodology for the detection of residual monoclonal FLC with FLC-MS positivity identifying IFE-negative patients who are at higher risk of early progression.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Mieloma Múltiple , Humanos , Cadenas Ligeras de Inmunoglobulina , Espectrometría de Masas , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/terapia , Supervivencia sin Progresión , Trasplante Autólogo , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Robust establishment of survival in multiple myeloma (MM) and its relationship to recurrent genetic aberrations is required as outcomes are variable despite apparent similar staging. We assayed copy number alterations (CNA) and translocations in 1036 patients from the NCRI Myeloma XI trial and linked these to overall survival (OS) and progression-free survival. Through a meta-anlysis of these data with data from MRC Myeloma IX trial, totalling 1905 newly diagnosed MM patients (NDMM), we confirm the association of t(4;14), t(14;16), t(14;20), del(17p) and gain(1q21) with poor prognosis with hazard ratios (HRs) for OS of 1.60 (P=4.77 × 10-7), 1.74 (P=0.0005), 1.90 (P=0.0089), 2.10 (P=8.86 × 10-14) and 1.68 (P=2.18 × 10-14), respectively. Patients with 'double-hit' defined by co-occurrence of at least two adverse lesions have an especially poor prognosis with HRs for OS of 2.67 (P=8.13 × 10-27) for all patients and 3.19 (P=1.23 × 10-18) for intensively treated patients. Using comprehensive CNA and translocation profiling in Myeloma XI we also demonstrate a strong association between t(4;14) and BIRC2/BIRC3 deletion (P=8.7 × 10-15), including homozygous deletion. Finally, we define distinct sub-groups of hyperdiploid MM, with either gain(1q21) and CCND2 overexpression (P<0.0001) or gain(11q25) and CCND1 overexpression (P<0.0001). Profiling multiple genetic lesions can identify MM patients likely to relapse early allowing stratification of treatment.
Asunto(s)
Mieloma Múltiple/diagnóstico , Mieloma Múltiple/patología , Adulto , Anciano , Anciano de 80 o más Años , Aberraciones Cromosómicas , Deleción Cromosómica , Ensayos Clínicos Fase III como Asunto , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/genética , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Pronóstico , Modelos de Riesgos Proporcionales , Translocación Genética/genética , Trasplante Autólogo/métodosRESUMEN
Myeloma is heterogeneous at the molecular level with subgroups of patients characterised by features of epigenetic dysregulation. Outcomes for myeloma patients have improved over the past few decades except for molecularly defined high-risk patients who continue to do badly. Novel therapeutic approaches are, therefore, required. A growing number of epigenetic inhibitors are now available including EZH2 inhibitors that are in early-stage clinical trials for treatment of haematological and other cancers with EZH2 mutations or in which overexpression has been correlated with poor outcomes. For the first time, we have identified and validated a robust and independent deleterious effect of high EZH2 expression on outcomes in myeloma patients. Using two chemically distinct small-molecule inhibitors, we demonstrate a reduction in myeloma cell proliferation with EZH2 inhibition, which leads to cell cycle arrest followed by apoptosis. This is mediated via upregulation of cyclin-dependent kinase inhibitors associated with removal of the inhibitory H3K27me3 mark at their gene loci. Our results suggest that EZH2 inhibition may be a potential therapeutic strategy for the treatment of myeloma and should be investigated in clinical studies.
Asunto(s)
Puntos de Control del Ciclo Celular/genética , Proteína Potenciadora del Homólogo Zeste 2/genética , Expresión Génica , Mieloma Múltiple/genética , Mieloma Múltiple/mortalidad , Apoptosis/genética , Biomarcadores , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/genética , Proteína Potenciadora del Homólogo Zeste 2/antagonistas & inhibidores , Epigénesis Genética , Perfilación de la Expresión Génica , Histonas/metabolismo , Humanos , Estimación de Kaplan-Meier , Células Madre Mesenquimatosas/metabolismo , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/terapia , Fenotipo , Pronóstico , Modelos de Riesgos Proporcionales , ARN Mensajero/genéticaRESUMEN
INTRODUCTION: Pomalidomide, a derivative of thalidomide and member of the immunomodulatory drugs is licenced for use in relapsed and refractory multiple myeloma (RRMM) in Europe, USA, Canada and Japan. AREAS COVERED: This review details all published trials in which pomalidomide has been used in the treatment of myeloma including phase I, II and III studies via PubMed searches for randomised control trials, observational cohort, case reports, meta-analysis and reviews. In addition abstract searches from the 2015 IMW and ASH conferences have been included. Drug safety has been a main focus with additional detail outlining the current clinical experience and treatment efficacy. Drug related toxicities and management of such events are covered in detail. EXPERT OPINION: Pomalidomide is well tolerated and has been demonstrated to prolong progression free survival and overall survival in RRMM patients in comparison to other agents commonly used later in the disease. Treatment related toxicities are usually easily managed using treatment interruption, dose modification, prophylactic therapies and blood/platelet transfusions. There is scope for the drug to be used in combination with newer agents at disease presentation, relapse and as a long-term maintenance option. At present trials assessing its use in early disease and maintenance are lacking.
Asunto(s)
Factores Inmunológicos/efectos adversos , Factores Inmunológicos/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Talidomida/análogos & derivados , Ensayos Clínicos como Asunto , Estudios de Cohortes , Humanos , Metaanálisis como Asunto , Estudios Observacionales como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Seguridad , Talidomida/efectos adversos , Talidomida/uso terapéuticoAsunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Biomarcadores de Tumor/genética , Resistencia a Antineoplásicos , Agentes Inmunomoduladores/uso terapéutico , Mieloma Múltiple/patología , Mutación , Ubiquitina-Proteína Ligasas/genética , Humanos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/genéticaRESUMEN
We have carried out the largest randomised trial to date of newly diagnosed myeloma patients, in which lenalidomide has been used as an induction and maintenance treatment option and here report its impact on second primary malignancy (SPM) incidence and pathology. After review, 104 SPMs were confirmed in 96 of 2732 trial patients. The cumulative incidence of SPM was 0.7% (95% confidence interval (CI) 0.4-1.0%), 2.3% (95% CI 1.6-2.7%) and 3.8% (95% CI 2.9-4.6%) at 1, 2 and 3 years, respectively. Patients receiving maintenance lenalidomide had a significantly higher SPM incidence overall (P=0.011). Age is a risk factor with the highest SPM incidence observed in transplant non-eligible patients aged >74 years receiving lenalidomide maintenance. The 3-year cumulative incidence in this group was 17.3% (95% CI 8.2-26.4%), compared with 6.5% (95% CI 0.2-12.9%) in observation only patients (P=0.049). There was a low overall incidence of haematological SPM (0.5%). The higher SPM incidence in patients receiving lenalidomide maintenance therapy, especially in advanced age, warrants ongoing monitoring although the benefit on survival is likely to outweigh risk.