RESUMO
Despite the advances in the management of hemoglobinopathies, further insight into disease pathophysiology is necessary to improve our therapeutic approach. Activin-A has emerged as a regulator of erythropoiesis and bone turnover in malignant disorders; however, clinical data in hemoglobinopathies are currently scarce. Thus, we aimed to investigate the role of activin-A among hemoglobinopathy patients and evaluate the rationale of its targeting. Circulating levels of activin-A were measured in patients (n = 227) with beta-thalassemia major (TM) (n = 58), beta-thalassemia intermedia (TI) (n = 43), double heterozygous sickle cell/beta-thalassemia (HbS/beta-thal) (n = 109), or homozygous sickle cell disease (n = 17), and we explored possible correlations with clinical and laboratory data. Seventeen age- and gender-matched, healthy individuals served as controls. Bone marrow density (BMD) was determined using dual-energy X-ray absorptiometry. TM and HbS/beta-thal patients had elevated activin-A compared to controls (p = 0.041 and p = 0.038, respectively). In TM patients, high circulating activin-A showed strong correlations with hemolysis markers, namely reticulocyte count (p = 0.011) and high lactate dehydrogenase (LDH; p = 0.024). Similarly, in HbS/beta-thal patients, activin-A showed positive correlations with indirect bilirubin (p < 0.001), ferritin (p = 0.005), and LDH (p = 0.044). High activin-A correlated with low Z-score of both lumbar spine BMD in TI patients (p < 0.01) and femoral neck BMD in TM patients (p < 0.01). Serum activin-A is elevated in patients with TM and HbS/beta-thal and correlates with markers of hemolysis and low BMD. These data support a role of activin-A in the biology of these disorders and provide further rationale for the broader clinical development of activin-A inhibitors in this setting.
Assuntos
Ativinas/sangue , Anemia Falciforme , Densidade Óssea , Hemólise , Heterozigoto , Talassemia beta , Ativinas/genética , Adulto , Idoso , Anemia Falciforme/sangue , Anemia Falciforme/genética , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Contagem de Reticulócitos , Talassemia beta/sangue , Talassemia beta/genéticaRESUMO
In patients with myelodysplastic syndrome (MDS), the prognostic significance of chromosome 17 abnormalities has not yet been fully elucidated, except for isochromosome 17q that has been characterized as an intermediate risk abnormality in the Revised International Prognostic Scoring System (IPSS-R). To further characterize the prognostic significance of chromosome 17 abnormalities we analyzed the hematologic and prognostic characteristics of 548 adult patients with MDS treated with 5-azacytidine through the Hellenic 5-azacytidine registry and found 32 patients with a chromosome 17 abnormality (6 with i[17q], 15 with -17, 3 with add[17p] and the rest with other rarer abnormalities, mostly translocations). The presence of a chromosome 17 abnormality was correlated with poor prognostic features (high IPSS, IPSS-R, and WPSS scores) and a low overall survival rate (15.7 vs 36.4 months for patients without chromosome 17 abnormalities, Kaplan-Meier, Log Rank P < 0.00001), but these results were confounded by the fact that most (92.3%) of the cases with a chromosome 17 abnormality (with the exception of i(17q) that was found in all cases as an isolated abnormality) were found in the context of a complex karyotype. Nevertheless, one should not ignore the contribution of chromosome 17 abnormalities to the prognostic significance of a complex karyotype since 33.8% of complex karyotypes encompassed a chromosome 17 abnormality.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Azacitidina/uso terapêutico , Cromossomos Humanos Par 17 , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
There is limited data regarding the efficacy and safety of lenalidomide, adriamycin and dexamethasone (RAD) combination on newly diagnosed multiple myeloma (NDMM) patients. There is also scarce information about the effect of lenalidomide on bone metabolism and angiogenesis in NDMM. Thus, we conducted a Phase 2 study to evaluate the efficacy and safety of RAD regimen as induction in transplant-eligible NDMM patients and we studied the effects on bone metabolism and angiogenesis. A total of 45 patients were enrolled. Following four cycles of RAD, the overall response rate was 66.7% and after a median follow up of 29.1 months (range 21.0-34.9), the median survival outcomes have not been reached yet. RAD had a favorable toxicity profile and did not impair stem cell collection. RAD significantly reduced bone resorption markers CTX (p = 0.03) and TRACP-5b (p < 0.01). Interestingly, RAD also increased bone formation markers bone-specific alkaline phosphatase (p = 0.036), procollagen type 1 amino-terminal propeptide (p = 0.028) and osteocalcin (p = 0.026), which has not been described before with lenalidomide-containing regimens in the absence of bortezomib coadministration. Furthermore, the angiogenic cytokines VEGF (p = 0.01), angiogenin (p = 0.02) and bFGF (p < 0.01) were significantly reduced post-RAD induction. Our results suggest that RAD is an effective induction regimen before autologous stem cell transplantation with beneficial effects on bone metabolism and angiogenesis.
Assuntos
Proteínas Angiogênicas/metabolismo , Reabsorção Óssea/tratamento farmacológico , Dexametasona/administração & dosagem , Doxorrubicina/administração & dosagem , Lenalidomida/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Adulto , Idoso , Fosfatase Alcalina/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Reabsorção Óssea/metabolismo , Dexametasona/farmacologia , Doxorrubicina/farmacologia , Quimioterapia Combinada , Feminino , Fator 2 de Crescimento de Fibroblastos/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Quimioterapia de Indução , Lenalidomida/farmacologia , Masculino , Pessoa de Meia-Idade , Osteocalcina/metabolismo , Fragmentos de Peptídeos/metabolismo , Pró-Colágeno/metabolismo , Ribonuclease Pancreático/metabolismo , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Optimizing consolidation treatment in transplant-eligible newly diagnosed multiple myeloma patients in order to improve efficacy and bone-related outcomes is intriguing. We conducted an open-label, prospective study evaluating the efficacy and safety of bortezomib and lenalidomide (VR) consolidation after ASCT, in the absence of dexamethasone and bisphosphonates. Fifty-nine patients, who received bortezomib-based induction, were given 4 cycles of VR starting on day 100 post-ASCT. After ASCT, 58% of patients improved their response status, while following VR consolidation 39% further deepened their response; stringent complete response rates increased to 51% after VR from 24% post-ASCT. VR consolidation resulted in a significant reduction of soluble receptor activator of nuclear factor-κB ligand/osteoprotegerin ratio and sclerostin circulating levels, which was more pronounced among patients achieving very good partial response or better. After a median follow-up of 62 months, no skeletal-related events (SREs) were observed, despite the lack of bisphosphonates administration. The median TTP after ASCT was 37 months, while median overall survival (OS) has not been reached yet; the probability of 4- and 5-year OS was 81% and 64%, respectively. In conclusion, VR consolidation is an effective, dexamethasone- and bisphosphonate-free approach, which offers long OS with improvements on bone metabolism and no SREs.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Doenças Ósseas , Quimioterapia de Consolidação , Mieloma Múltiplo , Transplante de Células-Tronco , Adulto , Idoso , Autoenxertos , Doenças Ósseas/metabolismo , Doenças Ósseas/mortalidade , Doenças Ósseas/patologia , Doenças Ósseas/terapia , Bortezomib/administração & dosagem , Bortezomib/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Difosfonatos/administração & dosagem , Difosfonatos/efeitos adversos , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Lenalidomida/administração & dosagem , Lenalidomida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Mieloma Múltiplo/terapia , Estudos Prospectivos , Taxa de SobrevidaRESUMO
Chemotherapy associated osteoporosis is a severe problem in patients with malignant diseases as it increases the risk for fractures and deteriorates quality of life. There are very limited data in the literature for the effect of chemotherapy on bone metabolism of adult patients with Non-Hodgkin Lymphoma (NHL). We prospectively evaluated bone remodeling pre- and post-chemotherapy in 61 patients with newly diagnosed NHL. First-line chemotherapy resulted in high bone turnover, which led to increased bone loss and reduced bone mineral density (BMD) of lumbar spine (L1-L4) and femur neck (FN). The reduction of L1-L4 and FN BMD post-chemo was more profound in males and in older patients (>55 years). Patients who received 8 cycles of chemotherapy had a greater reduction of L1-L4 and FN BMD as compared to 6 cycles. The administration of chemotherapy also resulted in a dramatic increase of bone resorption markers (CTX and TRACP-5b), bone formation markers, (bALP and Osteocalcin) and of osteoblast regulator Dickkopf-1. During study period, one patient had a pathological fracture in his right FN.
RESUMO
Denosumab (DNM) is a fully human monoclonal antibody against the receptor activator of nuclear factor kappa-B ligand (RANKL) that has been licensed for the treatment of different types of osteoporosis. However, the prospective data for the evaluation of DNM efficacy on transfusion-dependent thalassemia (TDT)-induced osteoporosis are rather limited. Thus, we conducted a randomized, placebo-controlled, double-blind, phase 2b clinical trial to evaluate DNM in TDT osteoporosis. Patients were assigned to receive either 60 mg DNM (n = 32) or placebo (n = 31) subcutaneously on day 0 and 180 during a total of 12 months of follow-up. The percentage increase of L1-L4 bone mineral density was higher in the DNM group than the placebo group (5.92% ± 5.25% vs 2.92% ± 5.56%, respectively; P = .043), whereas the advantage of DNM regarding wrist bone mineral density was much higher compared with placebo (-0.26% ± 5.31% vs -3.92% ± 8.71%, respectively; P = .035). No grade 3 or 4 toxicity was observed. DNM reduced pain scores that remained unaltered in the placebo group. DNM showed a significant reduction of soluble RANKL (sRANKL), sRANKL/osteoprotegerin ratio, C-telopeptide of collagen type I, tartrate-resistant acid phosphatase isoform-5b, and bone-specific alkaline phosphatase between baseline and the 12th month (P < .01 for all comparisons) without changes in dickkopf-1, sclerostin, and osteocalcin. On the contrary, placebo patients showed an increase in sRANKL, osteoprotegerin, dickkopf-1, sclerostin, C-telopeptide of collagen type I, tartrate-resistant acid phosphatase isoform-5b, and bone-specific alkaline phosphatase during the study period (P < .01 for all comparisons). In conclusion, DNM increased lumbar spine and wrist bone mineral density and reduced pain and bone remodeling markers, and thus it is another valuable option for the management of TDT-induced osteoporosis. This trial was registered at www.clinicaltrials.gov as #NCT02559648.
Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Denosumab/uso terapêutico , Osteoporose/tratamento farmacológico , Talassemia/complicações , Adulto , Idoso , Densidade Óssea , Conservadores da Densidade Óssea/efeitos adversos , Remodelação Óssea , Colágeno Tipo I/metabolismo , Denosumab/efeitos adversos , Método Duplo-Cego , Esquema de Medicação , Feminino , Cefaleia/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Osteoporose/etiologia , Osteoprotegerina/metabolismo , Peptídeos/metabolismo , Efeito Placebo , Ligante RANK/metabolismo , Resultado do TratamentoRESUMO
Multiple myeloma (MM) is characterized by bone destruction due to increased bone resorption and decreased bone formation. Semaphorin 4D (CD100, Sema4D) is expressed by osteoclasts, binds to its receptor Plexin-B1, and acts as a mediator of osteoclast-osteoblast interaction that ultimately inhibits osteoblastic bone formation. Preclinical data suggest that Sema4D/Plexin-B1 pathway is implicated in MM-induced bone disease. However, there is no information on the role of Sema4D in MM patients. Thus, we evaluated Sema4D and Plexin-B1 in six myeloma cells lines in vitro; in the bone marrow plasma (BMP) and serum of 72 newly diagnosed symptomatic MM (NDMM) patients and in 25 healthy controls. Only one myeloma cell line produced high Sema4D. BMP and circulating Sema4D and Plexin-B1 levels were significantly higher in MM patients compared to controls (p < 0.01). Sema4D correlated with serum calcium levels (p < 0.001), increased bone resorption (as assessed by CTX; p < 0.01), and ISS (p < 0.001). There was a trend for higher Sema4D levels in patients with osteolysis (p = 0.07), while patients with diffuse MRI pattern had higher BMP Sema4D levels (p = 0.02). Our data suggest that Sema4D is elevated in MM patients and correlate with adverse myeloma features and increased bone resorption, providing a possible target for novel therapeutic approaches in MM.
Assuntos
Antígenos CD/sangue , Hipercalcemia/etiologia , Mieloma Múltiplo/sangue , Mieloma Múltiplo/complicações , Osteólise/etiologia , Semaforinas/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/genética , Biomarcadores , Feminino , Humanos , Hipercalcemia/diagnóstico , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico por imagem , Mieloma Múltiplo/patologia , Estadiamento de Neoplasias , Proteínas do Tecido Nervoso/sangue , Osteólise/diagnóstico , Receptores de Superfície Celular/sangue , Semaforinas/genéticaRESUMO
BACKGROUND: Serum receptor activator of nuclear factor κB ligand (sRANKL) and chemokine (C-C) motif ligand 3 (CCL-3) have been reported to be elevated in Waldenström macroglobulinemia (WM) patients. However, there are no published data regarding the prognostic value of these molecules in WM regarding progression-free and overall survival. METHODS: To evaluate the effect of these markers of bone remodeling on survival parameters, we prospectively evaluated serum cytokines and biological markers in 55 patients with symptomatic WM before they received any kind of treatment. Serum levels of CCL-3 and bone remodeling markers were also evaluated in asymptomatic WM and IgM monoclonal gammopathy of undetermined significance. Furthermore, we assessed bone marrow biopsy samples from newly diagnosed WM patients for CCL-3 and RANKL expression. RESULTS: High circulating sRANKL values predicted shorter median overall survival (46 months vs. not reached, P = .025). High serum levels of CCL-3 predicted shorter median progression-free survival (27 months vs. not reached, P = .048). At bone marrow biopsy evaluation, the whole number of the neoplastic cells revealed strong cytoplasmic positivity for CCL-3, while the neoplastic clone did not express RANKL. CONCLUSION: We conclude that WM cells produce CCL-3 and possibly enhance the production of RANKL in the bone microenvironment. The correlation of sRANKL and CCL-3 with survival reveals the importance of these cytokines in disease biology and highlights the significance of the interactions between WM and stromal cells for the development of WM. Finally, these findings provide the rationale for the use of anti-RANKL and anti-CCL-3 drugs in animal models of WM before their clinical evaluation.
Assuntos
Biomarcadores Tumorais/sangue , Quimiocina CCL3/sangue , Ligante RANK/sangue , Macroglobulinemia de Waldenstrom/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Assintomáticas , Biomarcadores Tumorais/metabolismo , Biópsia , Medula Óssea/patologia , Quimiocina CCL3/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Gamopatia Monoclonal de Significância Indeterminada/sangue , Prognóstico , Intervalo Livre de Progressão , Estudos Prospectivos , Ligante RANK/metabolismo , Análise de Sobrevida , Macroglobulinemia de Waldenstrom/sangue , Macroglobulinemia de Waldenstrom/patologiaRESUMO
We have studied the efficacy and the prognostic impact of novel agents in 50 primary plasma cell leukemia (pPCL) patients registered in our database. Eighty percent of patients were treated upfront with novel agent-based combinations; 40% underwent autologous stem cell transplantation (ASCT). Objective response rate was 76; 38% achieved at least very good partial response (≥vgPR) and this correlated significantly with bortezomib-based therapy plus ASCT. At the time of evaluation, 40 patients had died. Early mortality rate (≤1 month) was 6%. Median progression-free survival (PFS) and overall survival (OS) were 12 months and 18 months respectively, both significantly longer in patients treated with bortezomib-based therapy + ASCT vs. others (PFS: 18 vs. 9 months; p = 0.004, OS: 48 vs. 14 months; p = 0.007). Bortezomib-based therapy + ASCT predicted for OS in univariate analysis. In multivariate analysis, achievement of ≥vgPR and LDH ≥ 300 U/L were significant predictors for OS. These real-world data, based on one of the largest reported national multicenter series of pPCL patients treated mostly with novel agents support that, among the currently approved induction therapies, bortezomib-based regimens are highly effective and reduce the rate of early mortality whereas in combination with ASCT consolidation they prolong OS.
Assuntos
Bortezomib/administração & dosagem , Leucemia Plasmocitária/mortalidade , Leucemia Plasmocitária/terapia , Transplante de Células-Tronco , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoenxertos , Intervalo Livre de Doença , Feminino , Grécia/epidemiologia , Humanos , Leucemia Plasmocitária/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Myeloma bone disease (MBD) is the most common complication of multiple myeloma (MM), resulting in skeleton-related events (SREs) such as severe bone pain, pathologic fractures, vertebral collapse, hypercalcemia, and spinal cord compression that cause significant morbidity and mortality. It is due to an increased activity of osteoclasts coupled to the suppressed bone formation by osteoblasts. Novel molecules and pathways that are implicated in osteoclast activation and osteoblast inhibition have recently been described, including the receptor activator of nuclear factor-kB ligand/osteoprotegerin pathway, activin-A and the wingless-type signaling inhibitors, dickkopf-1 (DKK-1) and sclerostin. These molecules interfere with tumor growth and survival, providing possible targets for the development of novel drugs for the management of lytic disease in myeloma but also for the treatment of MM itself. Currently, bisphosphonates are the mainstay of the treatment of myeloma bone disease although several novel agents such as denosumab and sotatercept appear promising. This review focuses on recent advances in MBD pathophysiology and treatment, in addition to the established therapeutic guidelines.
Assuntos
Doenças Ósseas/etiologia , Doenças Ósseas/terapia , Mieloma Múltiplo/complicações , Mieloma Múltiplo/terapia , Animais , Conservadores da Densidade Óssea/uso terapêutico , Doenças Ósseas/fisiopatologia , Remodelação Óssea , Difosfonatos/uso terapêutico , Humanos , Mieloma Múltiplo/fisiopatologiaRESUMO
PURPOSE: The role of Protein Z (PZ) in conditions, such as thrombosis, inflammation or cancer, is under investigation. Plasminogen Activator Inhibitor-1 (PAI-1) is an acute phase reactant that promotes thrombosis and tumorigenesis. Subject of this work was to study PZ and PAI-1 in patients with Hodgkin Lymphoma (HL), a malignancy with inflammatory background and relatively low incidence of thrombosis. METHODS: Newly diagnosed patients were enrolled in the study. Healthy individuals were used as controls. RESULTS: PZ levels were higher in patients compared to controls (not significantly), while PAI-1 levels were significantly higher in patients. Both PZ and PAI-1 concentrations did not correlate with most of patients' characteristics. Lower PZ levels at diagnosis were associated with presence of B symptoms and positive final positron emission tomography (PET) and higher baseline PAI-1 levels with positive final PET, too. PZ had a declining trend, but PAI-1 increased initially and decreased thereafter, during the treatment period. CONCLUSIONS: Conclusively, PAI-1, but not PZ, seems to be an acute phase protein in HL. Lower PZ and higher PAI-1 levels at diagnosis may be indicative of aggressive disease. These results need further verification.
Assuntos
Proteínas Sanguíneas/metabolismo , Doença de Hodgkin/sangue , Doença de Hodgkin/metabolismo , Inibidor 1 de Ativador de Plasminogênio/sangue , Proteínas de Fase Aguda/metabolismo , Adulto , Idoso , Feminino , Humanos , Inflamação/sangue , Inflamação/metabolismo , Masculino , Pessoa de Meia-Idade , Trombose/sangue , Trombose/metabolismo , Adulto JovemRESUMO
The aim of the study was to assess the value of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in patients with newly diagnosed multiple myeloma (MM) who were treated with novel anti-myeloma agents. We studied 60 previously untreated MM patients at diagnosis, 14 with smoldering MM (SMM) and 5 with MGUS. All patients underwent MRI of the thoracolumbar spine and pelvis before the administration of any kind of therapy, and DCE-MRI was performed. The MRI perfusion parameters evaluated were wash-in (WIN), washout (WOUT), time-to-peak (TTPK), time-to-maximum slope (TMSP), and the WIN/TMSP ratio. The following serum levels of angiogenic cytokines were measured on the day of MRI: VEGF, angiogenin (Ang), angiopoietin-1 (Angp-1), and -2 (Angp-2). Symptomatic MM patients had increased WIN compared to SMM (p < 0.05) and MGUS patients (p = 0.001). TTPK was decreased, and WIN/TMSP was increased in both symptomatic and SMM patients compared to MGUS patients (p < 0.05). Symptomatic MM patients had decreased TMSP compared to MGUS patients. The Angp-1/Angp-2 ratio was reduced in symptomatic MM compared to SMM (p = 0.017) and MGUS patients (p < 0.001). TTPK correlated with Angp-1/Angp-2 ratio and importantly with R-ISS. Patients with R-ISS-3 had lower TTPK median value (23 s, range 18-29 s) compared to patients with R-ISS-2 (48 s, range 27-68 s) and patients with R-ISS-1 MM (54 s, range 42-76 s; p ANOVA = 0.01). A subset of patients with low TTPK (lower quartile) had shorter time to progression compared to all other patients. These data suggest that certain DCE-MRI parameters correlate with R-ISS and adverse prognostic features of angiogenesis, such as the ratio of Angp-1/Angp-2.
Assuntos
Angiopoietina-1/sangue , Angiopoietina-2/sangue , Imageamento por Ressonância Magnética , Mieloma Múltiplo , Proteínas de Neoplasias/sangue , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/diagnóstico por imagem , Mieloma Múltiplo/terapia , Pelve/diagnóstico por imagem , Coluna Vertebral/diagnóstico por imagemRESUMO
Purpose To evaluate the apparent diffusion coefficients (ADCs) of magnetic resonance (MR) imaging patterns in the bone marrow of patients with multiple myeloma (MM) and to determine a threshold ADC that may help distinguish a diffuse from a normal pattern with high accuracy. Materials and Methods This prospective study was approved by the ethics review board, and informed consent was obtained. Ninety-nine patients with newly diagnosed, untreated MM and 16 healthy control subjects underwent spinal MR imaging including diffusion-weighted imaging, and bone marrow ADCs were calculated. Pattern assignment was based on visual assessment of conventional MR images. The Kruskal-Wallis H test, the Mann-Whitney test, and the one-way analysis of variance were used to compare ADCs between patient subsets and control subjects, and a receiver operating characteristic analysis was performed. Results Mean ADCs ± standard deviation in patients with MM for the normal, focal, and diffuse MR imaging patterns were 0.360 × 10-3 mm2/sec ± 0.110, 1.046 × 10-3 mm2/sec ± 0.232, and 0.770 × 10-3 mm2/sec ± 0.135, respectively. There were significant differences in ADCs between diffuse and normal (P < .001), diffuse and focal (P < .001), and focal and normal (P < .001) patterns. Patients with a diffuse pattern had more features of advanced disease, higher international staging system score, increased incidence of high-risk cytogenetics, and higher revised international staging system score. ADCs greater than 0.548 × 10-3 mm2/sec showed 100% sensitivity (26 of 26) and 98% specificity (48 of 49) for the diagnosis of a diffuse (vs normal) MR imaging pattern, whereas an ADC greater than 0.597 × 10-3 mm2/sec showed 96% sensitivity (25 of 26) and 100% specificity (49 of 49). Conclusion ADCs of MR imaging patterns in patients with MM differ significantly. A diffuse MR imaging pattern can be distinguished more objectively from a normal MR imaging pattern by adding quantitative diffusion-weighted imaging to standard MR imaging protocols. © RSNA, 2016 Online supplemental material is available for this article.
Assuntos
Medula Óssea/diagnóstico por imagem , Medula Óssea/patologia , Imagem de Difusão por Ressonância Magnética/métodos , Mieloma Múltiplo/diagnóstico por imagem , Mieloma Múltiplo/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
To compare the outcomes of patients with relapsed or refractory multiple myeloma (RRMM) who were treated with lenalidomide combined with high versus low dose of dexamethasone. One hundred forty consecutive relapsed or refractory multiple myeloma (RRMM) patients who received lenalidomide with dexamethasone, in two consecutive time periods, were divided into two groups: group RD (70 consecutive patients in the first period) who received lenalidomide with intermediate doses of dexamethasone and group Rd (70 consecutive patients in the more recent period) who received lenalidomide with low-dose dexamethasone. 62% and 73% of patients who received RD and Rd (p = 0.148) achieved at least a partial response, accordingly. The median OS was 20 and 41 months for the RD and the Rd group, accordingly. In the multivariate analysis, Rd was associated with improved PFS. More patients treated with RD developed grade 3&4 neutropenia and fatigue. It seems that Rd is at least as effective as RD.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Dexametasona/farmacologia , Mieloma Múltiplo/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Talidomida/análogos & derivados , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dexametasona/uso terapêutico , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Fadiga/induzido quimicamente , Humanos , Lenalidomida , Mieloma Múltiplo/mortalidade , Recidiva Local de Neoplasia/mortalidade , Neutropenia/induzido quimicamente , Estudos Retrospectivos , Talidomida/farmacologia , Talidomida/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: Renal impairment is a common complication of patients with multiple myeloma (MM). We aimed to evaluate the clinical significance of 2 newly discovered biomarkers of renal injury, cystatin C (CysC), a protein reflecting glomerular filtration rate, and neutrophil gelatinase-associated lipocalin (NGAL), a protein reflecting tubular injuries. PATIENTS AND METHODS: We studied 64 patients with newly diagnosed myeloma: 16 with asymptomatic (smoldering) MM and 48 with symptomatic myeloma; 8 patients with monoclonal gammopathy of undetermined significance (MGUS); and 20 healthy control subjects. Along with common blood and urine chemistry determinations, measurements of CysC, NGAL, ß2-microglobulin, high-sensitivity C-reactive protein, and interleukin 6 were performed. RESULTS: We found that only patients with symptomatic MM had increased levels of CysC compared to controls (P < .01); that serum NGAL levels were elevated in all patients compared to controls P < .001; that NGAL strongly correlated with both estimation of glomerular filtration rate (eGFR) (CysC) and eGFR (Modification of Diet in Renal Disease [MDRD] formula) (r = 0.616, P < .0001; and r = -0.371, P < .01, respectively); that CysC showed strong correlation with eGFR (r = -0.782, P < .001) and with the International Scoring System (ISS) (more pronounced in patients with ISS-3); and that receiver operating characteristic curve analysis showed that NGAL values of > 50.5 µg/L have a 80.8% sensitivity and 86.4% specificity for eGFR < 60 mL/min (area under the curve = 0.764). CONCLUSION: These findings suggest that both NGAL and CysC are very sensitive markers that reflect renal impairment in newly diagnosed patients with MM. The high levels of NGAL in asymptomatic patients and in MGUS patients support the hypothesis of the presence of renal damage in these patients early in the course of their disease and may reveal NGAL to be an early marker that predicts the presence of renal impairment in MM.
Assuntos
Cistatina C/sangue , Taxa de Filtração Glomerular , Lipocalinas/sangue , Mieloma Múltiplo/complicações , Proteínas Proto-Oncogênicas/sangue , Insuficiência Renal/sangue , Proteínas de Fase Aguda/urina , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Biomarcadores/urina , Cistatina C/urina , Feminino , Humanos , Lipocalina-2 , Lipocalinas/urina , Masculino , Pessoa de Meia-Idade , Gamopatia Monoclonal de Significância Indeterminada/sangue , Gamopatia Monoclonal de Significância Indeterminada/urina , Mieloma Múltiplo/sangue , Mieloma Múltiplo/urina , Proteínas Proto-Oncogênicas/urina , Curva ROC , Insuficiência Renal/etiologia , Sensibilidade e EspecificidadeRESUMO
Involvement of the central nervous system (CNS) is a rare complication of multiple myeloma (MM). Herein, we have described the incidence, characteristics, prognostic factors for post CNS-MM survival, and outcome of CNS-MM and explored the efficacy of novel agents (NA) (thalidomide, bortezomib, lenalidomide) in this setting. Between 2000 and 2013, 31 (0.9 %) out of 3408 newly diagnosed symptomatic MM patients, consecutively diagnosed and treated during the same period in 12 Greek centers, developed CNS-MM (M/F 15/16, median age 59 years, range 20-96 years; newly diagnosed/relapsed-refractory 2/29; median time to CNS-MM diagnosis 29 months). Clinical and laboratory characteristics were retrospectively recorded. Twenty-six percent of patients had circulating plasma cells (PCs) or plasma cell leukemia (PCL) at CNS-MM and 39 % had skull-derived plasmacytomas, suggesting hematological and contiguous spread. Treatment for CNS-MM was offered in 29/31 patients and 11/29 responded (NA 18/29, additional radiotherapy 9/28, intrathecal chemotherapy 13/29). The median post CNS-MM survival was 3 months (95 % CI 1.9-4.1) and did not differ between patients treated with NA and/or radiotherapy vs. others. In the multivariate analysis, prior treatment of MM with NA, extramedullary disease (EMD) during MM course (i.e., plasmacytomas, circulating PCs, or documented PCL) and abnormally high LDH at MM diagnosis were independent prognostic factors, whereas treatment of CNS-MM with NA did not predict for post CNS-MM survival. Despite the relatively limited number of patients due to the rarity of CNS-MM, our results suggest that NA do not seem to improve post CNS-MM survival. Patients with EMD display shortened post CNS-MM survival and should be followed thoroughly.
Assuntos
Neoplasias do Sistema Nervoso Central/mortalidade , Neoplasias do Sistema Nervoso Central/terapia , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Grécia/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de SobrevidaRESUMO
Solitary plasmacytoma (SP) is a rare plasma cell dyscrasia characterized by the presence of bone or extramedullary plasma cell tumors. The treatment of choice is local radiotherapy (R/T) ± surgical excision. The role of adjuvant chemotherapy (C/T) or novel agents (NA) is uncertain. Data related to prognostic factors are inconclusive. Herein, we describe the clinical features, survival and prognosis of 97 consecutive patients, 65 with bone SP (SBP), and 32 with extramedullary SP (SEP), diagnosed and treated in 12 Greek Myeloma Centers. Objective response rate (≥PR) and complete response (CR) was 91.8% and 61.9%, respectively, and did not differ between the 2 groups. Overall, 38 patients relapsed or progressed to multiple myeloma (MM). After a median follow-up of 60 months, 5 and 10-year overall survival (OS) probability was 92% and 89% in SEP and 86% and 69% in SBP, respectively (P = 0.2). The 5- and 10-year MM-free survival (MMFS) probability was 90% and 70% for patients with SEP vs. 59% and 50% for patients with SBP, respectively (P = 0.054). Overall, the 5- and 10-year OS probability, plasmacytoma relapse-free survival (PRFS), progression-free survival and MMFS was 84% and 78%, 72% and 58%, 58% and 43%, and 70% and 59%, respectively. In the multivariate analysis, prolonged PRFS and young age were positive predictors of OS. Achievement of CR was the only positive predictor of PRFS. Immunoparesis was the only negative predictor of progression to MM. The addition of C/T or NA-based treatment increased toxicity without offering any survival advantage over R/T.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Ósseas/tratamento farmacológico , Mieloma Múltiplo/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Plasmocitoma/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antraciclinas/administração & dosagem , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/patologia , Ácidos Borônicos/administração & dosagem , Bortezomib , Quimioterapia Adjuvante , Dexametasona/administração & dosagem , Progressão da Doença , Feminino , Grécia , Humanos , Masculino , Melfalan/administração & dosagem , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Análise Multivariada , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Plasmocitoma/diagnóstico , Plasmocitoma/mortalidade , Plasmocitoma/patologia , Prognóstico , Pirazinas/administração & dosagem , Indução de Remissão , Estudos Retrospectivos , Análise de Sobrevida , Resultado do TratamentoRESUMO
Plasma cell leukemia (PCL) is a rare and aggressive plasma cell disorder, with poor outcome. Bortezomib-based regimens (BBR) are highly effective in myeloma, but there is limited information about their efficacy and safety in PCL. Thus, we retrospectively collected data from 42 consecutive PCL patients (25 with primary PCL-pPCL and 17 with secondary PCL-sPCL) to explore the role of BBR in this entity. BBR were administered in 29 of 42 patients, while 6 of 25 patients with pPCL underwent autologous transplantation. Objective response (≥partial response) was significantly higher in patients treated with BBR versus conventional therapies (69% vs. 30.8%, P = 0.04); 27.5% of patients treated with BBR achieved at least very good partial response (vgPR). The highest ORR was observed in pPCL patients treated with BBR (88.9%; ≥vgPR: 33.3%). In BBR-group, grade 3 of 4 hematological, neurological and renal toxicity and neutropenic infections were observed in 41.4%, 7%, 3.4%, and 31%, respectively. With a median follow-up of 51 months, median overall survival (OS) for patients treated with BBR versus conventional therapies was 13 versus 2 months (P < 0.007). Median OS of patients with pPCL and sPCL treated with BBR was 18 and 7 months, respectively (P < 0.001). In the multivariate analysis normal PLTs, treatment with BBR and high quality response were the only powerful predictors for survival. Our study carrying the longest reported median follow-up, demonstrated that treatment of PCL with BBR induces high response rates and prolongs survival over conventional therapies, regardless of additional autologous transplantation rescue or established high risk features, with manageable toxicity.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Plasmocitária/tratamento farmacológico , Leucemia Plasmocitária/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ácidos Borônicos/administração & dosagem , Bortezomib , Feminino , Humanos , Leucemia Plasmocitária/diagnóstico , Leucemia Plasmocitária/etiologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Pirazinas/administração & dosagem , Estudos Retrospectivos , Resultado do TratamentoRESUMO
The combination of lenalidomide plus dexamethasone (RD) is very effective for patients with relapsed/ refractory myeloma. However, the effect of RD on bone metabolism has not been previously evaluated in these patients. To address this issue, we initially performed a retrospective study in 106 consecutive patients with relapsed or refractory myeloma who received RD. We measured the following bone indices on Cycle 1/Day 1 and then on Cycles 3 and 6/Day 28: dickkopf-1 (Dkk-1), sRANKL, osteoprotegerin (OPG), bone resorption markers (C-telopeptide of collagen type-I, CTX and TRACP-5b) and bone formation markers (bone-specific alkaline phosphatase-bALP and osteocalcin). RD produced a reduction of CTX only in responders, with no effect on bone formation. To validate these results, we then evaluated prospectively 99 patients who received either RD (n550) or VRD (bortezomib + RD, n549). RD reduced CTX, mainly in responders but showed no effect on bone formation, confirming the result of the retrospective study. However, the addition of bortezomib to RD (VRD arm) reduced Dkk-1, sRANKL/OPG, and CTX, while it increased bALP and OC after six cycles of therapy. These changes were irrespective of treatment response, which was similar between treatment arms. No skeletal-related events were observed in the VRD arm while two, nonresponding patients treated with RD developed a vertebral fracture. We conclude that RD reduces bone resorption only in responding patients with relapsed/refractory myeloma but has no effect on bone formation. Combination with bortezomib, which enhances bone formation, seems to be preferred for the management of myeloma patients with osteolytic disease.