Prognostic utility of serum free light chain ratios and heavy-light chain ratios in multiple myeloma in three PETHEMA/GEM phase III clinical trials

We investigated the prognostic impact and clinical utility of serum free light chains (sFLC) and serum heavy-light chains (sHLC) in patients with multiple myeloma treated according to the GEM2005MENOS65, GEM2005MAS65, and GEM2010MAS65 PETHEMA/GEM phase III clinical trials. Serum samples collected at diagnosis were retrospectively analyzed for sFLC (n = 623) and sHLC (n = 183). After induction or autologous transplantation, 309 and 89 samples respectively were available for sFLC and sHLC assays. At diagnosis, a highly abnormal (HA) sFLC ratio (sFLCr) (32) was not associated with higher risk of progression. After therapy, persistence of involved-sFLC levels >100 mg/L implied worse survival (overall survival [OS], P = 0.03; progression-free survival [PFS], P = 0.007). Among patients that achieved a complete response, sFLCr normalization did not necessarily indicate a higher quality response. We conducted sHLC investigations for IgG and IgA MM. Absolute sHLC values were correlated with monoclonal protein levels measured with serum protein electrophoresis. At diagnosis, HA-sHLCrs (73) showed a higher risk of progression (P = 0.006). Additionally, involved-sHLC levels >5 g/L after treatment were associated with shorter survival (OS, P = 0.001; PFS, P = 0.018). The HA-sHLCr could have prognostic value at diagnosis; absolute values of involved-sFLC >100 mg/L and involved-sHLC >5 g/L could have prognostic value after treatment

Prognostic value of antigen expression in multiple myeloma: a PETHEMA/GEM study on 1,265 patients enrolled in four consecutive clinical trials

Persistence of minimal residual disease (MRD) after treatment for myeloma predicts inferior outcomes, but within MRD-positive patients there is great heterogeneity with both early and very late relapses. Among different MRD techniques, flow cytometry provides additional information about antigen expression on tumor cells, which could potentially contribute to stratify MRD-positive patients. We investigated the prognostic value of those antigens required to monitor MRD in 1265 newly diagnosed patients enrolled in the GEM2000, GEM2005MENOS65, GEM2005MAS65 and GEM2010MAS65 protocols. Overall, CD19pos, CD27neg, CD38lo, CD45pos, CD81pos, CD117neg and CD138lo expression predicted inferior outcomes. Through principal component analysis, we found that simultaneous CD38lowCD81posCD117neg expression emerged as the most powerful combination with independent prognostic value for progression-free survival (HR:1.69; P=0.002). This unique phenotypic profile retained prognostic value among MRD-positive patients. We then used next-generation flow to determine antigen stability throughout the course of the disease, and found that the expression of antigens required to monitor MRD is mostly stable from diagnosis to MRD stages, except for CD81 whose expression progressively increased from baseline to chemoresistant tumor cells (14 vs 28%). Altogether, we showed that the phenotypic profile of tumor cells provides additional prognostic information, and could be used to further predict risk of relapse among MRD-positive patients

Depth of Response in Multiple Myeloma: A Pooled Analysis of Three PETHEMA/GEM Clinical Trials

Purpose To perform a critical analysis on the impact of depth of response in newly diagnosed multiple myeloma (MM). Patients and Methods Data were analyzed from 609 patients who were enrolled in the GEM (Grupo Español de Mieloma) 2000 and GEM2005MENOS65 studies for transplant-eligible MM and the GEM2010MAS65 clinical trial for elderly patients with MM who had minimal residual disease (MRD) assessments 9 months after study enrollment. Median follow-up of the series was 71 months. Results Achievement of complete remission (CR) in the absence of MRD negativity was not associated with prolonged progression-free survival (PFS) and overall survival (OS) compared with near-CR or partial response (median PFS, 27, 27, and 29 months, respectively; median OS, 59, 64, and 65 months, respectively). MRD-negative status was strongly associated with prolonged PFS (median, 63 months; P , .001) and OS (median not reached; P , .001) overall and in subgroups defined by prior transplantation, disease stage, and cytogenetics, with prognostic superiority of MRD negativity versus CR particularly evident in patients with high-risk cytogenetics. Accordingly, Harrell C statistics showed higher discrimination for both PFS and OS in Cox models that included MRD (as opposed to CR) for response assessment. Superior MRD-negative rates after different induction regimens anticipated prolonged PFS. Among 34 MRD-negative patients withMMand a phenotypic pattern of bone marrow involvement similar to monoclonal gammopathy of undetermined significance at diagnosis, the probability of “operational cure” was high; median PFS was 12 years, and the 10-year OS rate was 94%. Conclusion Our results demonstrate that MRD-negative status surpasses the prognostic value of CR achievement for PFS and OS across the disease spectrum, regardless of the type of treatment or patient risk group. MRD negativity should be considered as one of the most relevant end points for transplant-eligible and elderly fit patients with MM

Predicting long-term disease control in transplant-ineligible patients with multiple myeloma: impact of an MGUS-like signature

Disease control at 5 years would be a desirable endpoint for elderly multiple myeloma (MM) patients, but biomarkers predicting this are not defined. Therefore, to gain further insights in this endpoint, a population of 498 newly diagnosed transplant-ineligible patients enrolled in two Spanish trials (GEM2005MAS65 and GEM2010MAS65), has been analyzed. Among the 435 patients included in this post-hoc study, 18.6% remained alive and progression free after 5 years of treatment initiation. In these patients, overall survival (OS) rate at 10 years was 60.8% as compared with 11.8% for those progressing within the first 5 years. Hemoglobin (Hb) >= 12 g/dl (OR 2.74, p = 0.001) and MGUS-like profile (OR 4.18, p = 0.005) were the two baseline variables associated with long-term disease-free survival. Upon including depth of response (and MRD), Hb >= 12 g/dl (OR 2.27) and MGUS-like signature (OR 7.48) retained their predictive value along with MRD negativity (OR 5.18). This study shows that despite the use of novel agents, the probability of disease control at 5 years is still restricted to a small fraction (18.6%) of elderly MM patients. Since this endpoint is associated with higher rates of OS, this study provides important information about diagnostic and post-treatment biomarkers helpful in predicting the likelihood of disease control at 5 years

Minimal residual disease monitoring and immune profiling using second generation flow cytometry in elderly multiple myeloma

The value of minimal residual disease (MRD) in multiple myeloma (MM) has been more frequently investigated in transplant-eligible than elderly patients. Since an optimal balance between treatment efficacy and toxicity is of utmost importance in elderly MM, sensitive MRD monitoring might be particularly valuable in this patient population. Here, we used 2nd generation 8-color multiparameter-flow-cytometry (MFC) to monitor MRD in 162 transplant-ineligible MM patients enrolled in the PETHEMA/GEM2010MAS65 study, The transition from 1st to 2nd generation MFC resulted in increased sensitivity, and allowed to identify three patient groups according to MRD levels: MRD-negative (75-years (HR:4.8; P<.001), and those with high-risk cytogenetics (HR:12.6; P=.01). Using 2nd generation MFC, immune profiling concomitant to MRD monitoring also contributed to identify patients with poor, intermediate and favorable outcome (25%, 61% and 100% OS at 3-years; P=.01); the later patients being characterized by an increased compartment of mature B-cells. Our results show that similarly to transplant-candidates, MRD monitoring is one of the most relevant prognostic factors in elderly MM, irrespectively of patients’ age and cytogenetic risk

Immune status of high-risk smoldering multiple myeloma patients and its therapeutic modulation under LenDex: a longitudinal analysis

Persistence of chemoresistant minimal residual disease (MRD) plasma cells (PCs) is associated with inferior survival in multiple myeloma (MM). Thus, characterization of the minor MRD subclone may represent a unique model to understand chemoresistance, but to our knowledge, the phenotypic and genetic features of the MRD subclone have never been investigated. Here, we compared the antigenic profile of MRD vs diagnostic clonal PCs in 40 elderly MM patients enrolled in the GEM2010MAS65 study and showed that the MRD subclone is enriched in cells overexpressing integrins (CD11a/CD11c/CD29/CD49d/CD49e), chemokine receptors (CXCR4), and adhesion molecules (CD44/CD54). Genetic profiling of MRD vs diagnostic PCs was performed in 12 patients; 3 of them showed identical copy number alterations (CNAs), in another 3 cases, MRD clonal PCs displayed all genetic alterations detected at diagnosis plus additional CNAs that emerged at the MRD stage, whereas in the remaining 6 patients, there were CNAs present at diagnosis that were undetectable in MRD clonal PCs, but also a selected number of genetic alterations that became apparent only at the MRD stage. The MRD subclone showed significant downregulation of genes related to protein processing in endoplasmic reticulum, as well as novel deregulated genes such as ALCAM that is prognostically relevant in MM and may identify chemoresistant PCs in vitro. Altogether, our results suggest that therapy-induced clonal selection could be already present at the MRD stage, where chemoresistant PCs show a singular phenotypic signature that may result from the persistence of clones with different genetic and gene expression profiles. This trial was registered at www.clinicaltrials.gov as #NCT01237249

Effect of different doses of equine chorionic gonadotropin on ovary response and in vitro mouse embryo development

The aim of this study was to evaluate the effect of different doses of equine gonatotropin hormone (eCG) (5, 7.5 or 10 IU) on the ovary response and in vitro embryo development in Balb C mice. The ovary weight and diameter increased for 7.5 and 10 IU of eCG compared to control group (P0.05). In vitro, the differentiation was not modified by the dose level. The hatching rate at 96 h was higher for embryos from 7.5 IU compared to 10 IU (82.22 vs 64.39, P<0.05). We concluded that, the percentage of normal oocytes and morulae and the differentiation rate are not dependent of the dose of eCG, however, the hatching in vitro is dose eCG dependent.Fil: Teruel, M.T. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Área de Ciencias Morfológicas. Buenos Aires, ArgentinaFil: Teruel, M.T. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Área de Reproducción. Buenos Aires, ArgentinaFil: Catalano, R.C. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Área de Reproducción. Buenos Aires, ArgentinaFil: Callejas, S.S. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Área de Reproducción. Buenos Aires, ArgentinaFil: Cabodevila, J.A. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Área de Reproducción. Buenos Aires, ArgentinaFil: Gómez, S. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Área de Ciencias Morfológicas. Buenos Aires, ArgentinaEl objetivo del trabajo fue evaluar el efecto de diferentes dosis de gonadotrofina coriónica equina (eCG) (5, 7,5 o 10 UI) sobre parámetros ováricos y desarrollo in vitro de embriones de hembras ratón Balb C. El peso y diámetro ovárico fueron superiores en animales tratados con 7,5 y 10 UI de eCG que en animales controles (P<0,05). La dosis de 10 UI produjo más ovocitos que aquella de 5 UI (30,8 ± 12,4 vs. 18,9 ± 6,8 respectivamente, P<0,05). El número total de mórulas no difirió entre grupos. Los porcentajes de ovocitos y mórulas morfológicamente normales resultaron independientes de la dosis de eCG (73,8 ± 22,7; 63,8 ± 24,8; 70,6 ± 16,1 y 53,3 ± 36,0; 80,7 ± 16,0; 69,2 ± 25,5 para 5, 7,5 o 10 UI de eCG respectivamente). La formación de blastocistos no fue modificada por la dosis de eCG. A las 96 horas de cultivo, el porcentaje de hatching del grupo 7,5 UI fue superior al del grupo estimulado con 10 UI de eCG (82,22 vs 64,39, P<0,05). Se concluye que la morfología de ovocitos y mórulas y la diferenciación in vitro, son independientes de la dosis de eCG, no obstante, el hatching resulta modificado por el nivel de eCG

Interface homem-máquina para controle de processos de resfriamento com ar forçado visando à economia de energia Man-machine interface for the control of cooling processes with forced-air aimed at energy savings

Apresenta-se o desenvolvimento de um equipamento microprocessado, com saída de corrente, para controle da velocidade de rotação do motor do ventilador de sistemas de ar forçado, usando inversor de freqüência. Através de programação (software IHM.EXE), o usuário pode definir a massa a ser resfriada em quilogramas de produto. O equipamento calcula, através de um polinômio previamente estabelecido e programável, a freqüência de operação do inversor, que corresponde a uma vazão de ar específica, dentro dos limites estabelecidos no projeto. O equipamento foi instalado num sistema de resfriamento com ar forçado, estimando-se, pelo cálculo da variação da potência útil mecânica, uma economia de energia da ordem de 82%, com uma rotação equivalente a 56% da nominal do ventilador, proporcionando, desta forma, uma economia significativa no custo de operação do sistema.<br>The development of micro processed equipment is presented, with current exit for control of the speed of rotation of the fan motor of the system of forced air, using investing of the frequency. Through programming (software IHM.EXE), the user can define the mass to be cooled, in kilograms of the product. The equipment calculates through a programmable polynomial previously defined, the frequency of operation of the investor which corresponds to air specific flux, within the limits of the project. The equipment was installed in a forced-air cooling system, being considered by the calculation in useful mechanical power, the energy savings is estimated at around 82% with a rotation equivalent to 56% of the fan nominal, thus providing significant savings in system operating costs