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OBJECTIVE: To assess associations between bone marrow infiltration patterns and localization in magnetic resonance imaging (MRI) and baseline clinical/prognostic parameters in multiple myeloma (MM). METHODS: We compared baseline MM parameters, MRI patterns and localization of focal lesions to the mineralized bone in 206 newly diagnosed MM patients. RESULTS: A high tumour mass (represented by International Staging System stage III) was significantly associated with severe diffuse infiltration (p = 0.015) and a higher number of focal lesions (p = 0.006). Elevated creatinine (p = 0.003), anaemia (p < 0.001) and high LDH (p = 0.001) correlated with severe diffuse infiltration. A salt and pepper diffuse pattern had a favourable prognosis. A higher degree of destruction of mineralized bone (assessed by X-ray or computed tomography) was associated with an increasing number of focal lesions on MRI (p < 0.001). Adverse cytogenetics (del17p/gain1q21/t(4;14)) were associated with diffuse infiltration (p = 0.008). The presence of intraosseous focal lesions exceeding the mineralized bone had a borderline significant impact on prognosis. CONCLUSIONS: Diffuse bone marrow infiltration on MRI correlates with adverse cytogenetics, lowered haemoglobin values and high tumour burden in newly diagnosed MM whereas an increasing number of focal lesions correlates with a higher degree of bone destruction. Focal lesions exceeding the cortical bone did not adversely affect the prognosis. KEY POINTS: ⢠Diffuse MRI correlates with adverse cytogenetics, lowered haemoglobin and high tumour burden. ⢠Higher numbers of MRI focal lesions correlate with increasing degree of bone destruction. ⢠Focal lesions exceeding the cortical bone borderline significantly influence survival. ⢠Moderate/severe diffuse infiltration and more than 23 focal lesions adversely affect survival.
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Neoplasias da Medula Óssea/diagnóstico por imagem , Neoplasias da Medula Óssea/patologia , Imageamento por Ressonância Magnética , Mieloma Múltiplo/diagnóstico por imagem , Mieloma Múltiplo/patologia , Idoso , Medula Óssea/diagnóstico por imagem , Medula Óssea/patologia , Humanos , Masculino , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: High-dose therapy (HDT) with autologous stem cell transplantation (ASCT) is considered the standard of care for multiple myeloma (MM) patients <65 years. Safety and outcome of ASCT for patients >65 years is currently uncertain, especially since the introduction of novel agents for induction and maintenance therapy. Furthermore, there are no conclusive data available on risk assessment in elderly patients treated with HDT. PATIENTS AND METHODS: We retrospectively analyzed 202 patients ≥60 years with newly diagnosed MM who underwent ASCT at our institution. Patients were stratified by age into three groups (60-64, 65-69 and 70-75 years). For safety assessment, we compared data about hospitalization, hematopoetic reconstitution and early mortality. Remission before and after ASCT was analyzed according to age and application of novel agents. Event-free (EFS) and overall survival (OS) were analyzed to identify impact of age, remission before/after ASCT and maintenance therapy as well as ISS score and cytogenetic aberrations on outcome in elderly patients. RESULTS: The assessment of safety, remission before/after ASCT as well as EFS and OS showed no significant differences between the three groups (median EFS: 60-64 years: 27 months; 65-69 years: 23 months; 70-75 years: 23 months; median OS: not reached). Patients receiving novel agents as part of induction therapy achieved significantly higher nCR + CR rates than patients treated without novel agents. In Cox regression analysis, ISS and cytogenetics as well as remission after ASCT had the highest prognostic impact on EFS and OS. Maintenance therapy was associated with longer EFS in uni- and multivariate analyses. CONCLUSION: ASCT is feasible for selected patients >65 and >70 years without increased mortality. Age at transplantation has no prognostic significance on outcome after ASCT. Novel agents during induction therapy and maintenance therapy improves outcome of older patients eligible for ASCT. ISS and cytogenetic analysis should be carried out routinely for risk assessment.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/terapia , Transplante de Células-Tronco , Idoso , Autoenxertos , Ciclofosfamida/administração & dosagem , Dexametasona/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Humanos , Quimioterapia de Indução , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/mortalidade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Teclistamab, a B-cell maturation antigen (BCMA) × CD3 directed bispecific antibody, has shown high response rates and durable remissions in the MAJESTEC-1 trial in patients with relapsed and refractory multiple myeloma (RRMM). We retrospectively assessed efficacy and tolerability in 123 patients treated at 18 different German centers to determine whether outcome is comparable in the real-world setting. Most patients had triple-class (93%) or penta-drug (60%) refractory disease, 37% of patients had received BCMA-directed pretreatment including idecabtagene vicleucel (ide-cel) CAR-T cell therapy (21/123, 17.1%). With a follow-up of 5.5 months, we observed an overall response rate (ORR) of 59.3% and a median progression-free survival (PFS) of 8.7 months. In subgroup analyses, we found significantly lower ORR and median PFS in patients with extramedullary disease (37%/2.1 months), and/or an ISS of 3 (37%/1.3 months), and ide-cel pretreated patients (33%/1.8 months). Nonetheless, the duration of response in ide-cel pretreated patients was comparable to that of anti-BCMA naive patients. Infections and grade ≥3 cytopenias were the most frequent adverse events. In summary, we found that teclistamab exhibited a comparable efficacy and safety profile in the real-world setting as in the pivotal trial.
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Anticorpos Biespecíficos , Antineoplásicos , Mieloma Múltiplo , Neoplasias de Plasmócitos , Humanos , Mieloma Múltiplo/tratamento farmacológico , Antígeno de Maturação de Linfócitos B , Estudos Retrospectivos , Alemanha , Imunoterapia AdotivaRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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PURPOSE: The 7th Heidelberg Myeloma Workshop was held on April 5th and 6th, 2019 at the University Hospital Heidelberg. METHODS AND RESULTS: Main topics of the meeting were (1) diagnostics and prognostic factors, (2) role of immunotherapy in multiple myeloma (MM), (3) current therapy of MM, (4) biology and genomics of MM as well as (5) novel treatment concepts. A debate on the status of minimal residual disease (MRD) driven therapy was held. CONCLUSION: Diagnostics and treatment of newly diagnosed and relapsed MM are continuously evolving. While advances in the field of (single cell) genetic analysis now allow for characterization of the disease at an unprecedented resolution, immunotherapeutic approaches and MRD testing are at the forefront of the current clinical trial landscape.
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Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/terapia , Gerenciamento Clínico , Humanos , Mieloma Múltiplo/etiologia , Mieloma Múltiplo/mortalidadeRESUMO
In a phase III randomized, multicenter study, the German-speaking Myeloma-Multicenter Group (GMMG) and the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON) group investigated the influence of thalidomide (Thal) on the outcome of peripheral blood stem cell (PBSC) collection in multiple myeloma (MM) before peripheral autologous blood stem cell transplantation (ABSCT). We analyzed the data of 398 myeloma patients after induction with Thal, doxorubicin and dexamethasone (TAD) in comparison with vincristine, doxorubicin and dexamethasone (VAD) followed by mobilization with cyclophosphamide, doxorubicin, dexamethasone (CAD) and PBSC collection. Within both the study groups, patients treated with TAD showed to collect significantly fewer CD34(+) cells compared with VAD (GMMG, TAD: median 9.8 x 10(6)/kg; range 2.0-33.6; VAD: median 10.9 x 10(6)/kg range 3.0-36.0; P=0.02) (HOVON, TAD: median 7.4 x 10(6)/kg; range 2.0-33.0; VAD: median 9.4 x 10(6)/kg; range 0.0-48.7; P=0.009). However, engraftment after peripheral autologous stem cell transplantation showed no difference between Thal and VAD groups. We conclude that Thal as a part of induction regimen is associated with better response rates (GMMG-HD3: CR/PR 79%, VAD: CR/PR 58%; HOVON-50: TAD: CR/PR 81%, VAD: CR/PR 61%), but significantly affects the yield of PBSC collection. Nevertheless, the number of total CD34(+) cells collected was sufficient for double autologous transplantation in 82% of the Thal patients, with at least 2.5 x 10(6)/kg CD34(+) cells.
Assuntos
Mieloma Múltiplo/terapia , Transplante de Células-Tronco de Sangue Periférico/métodos , Talidomida/efeitos adversos , Coleta de Tecidos e Órgãos/normas , Adulto , Idoso , Antígenos CD34/análise , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Mobilização de Células-Tronco Hematopoéticas/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Transplante de Células-Tronco de Sangue Periférico/normas , Indução de Remissão/métodos , Transplante AutólogoRESUMO
The Dutch-Belgian Cooperative Trial Group for Hematology Oncology Group-65/German-speaking Myeloma Multicenter Group-HD4 (HOVON-65/GMMG-HD4) phase III trial compared bortezomib (BTZ) before and after high-dose melphalan and autologous stem cell transplantation (HDM, PAD arm) compared with classical cytotoxic agents prior and thalidomide after HDM (VAD arm) in multiple myeloma (MM) patients aged 18-65 years. Here, the long-term follow-up and data on second primary malignancies (SPM) are presented. After a median follow-up of 96 months, progression-free survival (censored at allogeneic transplantation, PFS) remained significantly prolonged in the PAD versus VAD arm (hazard ratio (HR)=0.76, 95% confidence interval (95% CI) of 0.65-0.89, P=0.001). Overall survival (OS) was similar in the PAD versus VAD arm (HR=0.89, 95% CI: 0.74-1.08, P=0.24). The incidence of SPM were similar between the two arms (7% each, P=0.73). The negative prognostic effects of the cytogenetic aberration deletion 17p13 (clone size ⩾10%) and renal impairment at baseline (serum creatinine >2 mg dl-1) on PFS and OS remained abrogated in the PAD but not VAD arm. OS from first relapse/progression was similar between the study arms (HR=1.02, P=0.85). In conclusion, the survival benefit with BTZ induction/maintenance compared with classical cytotoxic agents and thalidomide maintenance is maintained without an increased risk of SPM.
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Bortezomib/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Adolescente , Adulto , Idoso , Aberrações Cromossômicas/efeitos dos fármacos , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Masculino , Melfalan/uso terapêutico , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Prognóstico , Intervalo Livre de Progressão , Talidomida/uso terapêutico , Transplante Autólogo/métodos , Adulto JovemRESUMO
Thalidomide, lenalidomide and bortezomib have been approved for the treatment of relapsed or refractory multiple myeloma in the recent years. These agents are now being increasingly integrated into therapeutic regimens for newly diagnosed patients. First data are available on the promising activity of these novel agents in induction therapy, as well as maintenance treatment to improve outcome after stem cell transplantation. Whether these early results will lead to prolonged overall survival and thereby ultimately redefine the role of stem cell transplantation in first-line treatment of multiple myeloma will be one of the most important questions to be answered in the coming years. Bone Marrow Transplantation (2007) 40, 1129-1137; doi:10.1038/sj.bmt.1705829; published online 3 September 2007.
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Antineoplásicos/uso terapêutico , Sistemas de Liberação de Medicamentos/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Mieloma Múltiplo/terapia , Ácidos Borônicos , Bortezomib , Sistemas de Liberação de Medicamentos/tendências , Humanos , Lenalidomida , Pirazinas , Talidomida/análogos & derivados , Resultado do TratamentoRESUMO
Lack of CD56 expression was reported to be associated with a poor prognosis in multiple myeloma (MM) patients treated with conventional chemotherapy. Aim of our retrospective study was to analyse whether CD56 expression on MM cells reveals as a prognostic factor in patients treated with high-dose chemotherapy. MM cells of 99 patients prior to treatment with high-dose chemotherapy were analysed for CD56 expression by flow cytometry. Multivariable analysis of event-free survival in these patients showed no statistically significant difference between the CD56(-) (n=28) and the CD56(+) (n=71) group. The lack of CD56 expression on MM cells of these patients correlated significantly with the presence of translocation (11;14) (t(11;14)) (estimated correlation coefficient=0.655 95%, confidence interval (0.481; 0.779)). In summary, our results indicate that lack of CD56 expression on MM cells is not a prognostic marker in patients treated with high-dose chemotherapy, but is associated with t(11;14).
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Antígeno CD56/metabolismo , Melfalan/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Agonistas Mieloablativos/administração & dosagem , Adulto , Idoso , Biomarcadores , Antígeno CD56/genética , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 17/genética , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Estudos Retrospectivos , Translocação Genética/genética , Transplante AutólogoRESUMO
Multiple myeloma (MM) is a plasma cell malignancy that is still considered to be incurable in most cases. A dominant mutation cluster has been identified in RAS/RAF genes, emphasizing the potential significance of RAS/RAF/MEK/ERK signaling as a therapeutic target. As yet, however, the clinical relevance of this finding is unclear as clinical responses to MEK inhibition in RAS-mutant MM have been mixed. We therefore assessed RAS/RAF mutation status and MEK/ERK pathway activation by both targeted sequencing and phospho-ERK immunohistochemistry in 180 tissue biopsies from 103 patients with newly diagnosed MM (NDMM) and 77 patients with relapsed/refractory MM (rrMM). We found a significant enrichment of RAS/BRAF mutations in rrMM compared to NDMM (P=0.011), which was mainly due to an increase of NRAS mutations (P=0.010). As expected, BRAF mutations were significantly associated with activated downstream signaling. However, only KRAS and not NRAS mutations were associated with pathway activation compared to RAS/BRAFwt (P=0.030). More specifically, only KRASG12D and BRAFV600E were consistently associated with ERK activation (P<0.001 and P=0.006, respectively). Taken together, these results suggest the need for a more specific stratification strategy consisting of both confirmation of protein-level pathway activation as well as detailed RAS/RAF mutation status to allow for a more precise and more effective application of targeted therapies, for example, with BRAF/MEK inhibitors in MM.
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Multiple myeloma (MM) is characterized by the clonal expansion and metastatic spread of malignant plasma cells to multiple sites in the bone marrow (BM). Recently, we implicated the sialyltransferase ST3Gal-6, an enzyme critical to the generation of E-selectin ligands, in MM BM homing and resistance to therapy. Since E-selectin is constitutively expressed in the BM microvasculature, we wished to establish the contribution of E-selectin ligands to MM biology. We report that functional E-selectin ligands are restricted to a minor subpopulation of MM cell lines which, upon expansion, demonstrate specific and robust interaction with recombinant E-selectin in vitro. Moreover, an increase in the mRNA levels of genes involved in the generation of E-selectin ligands was associated with inferior progression-free survival in the CoMMpass study. In vivo, E-selectin ligand-enriched cells induced a more aggressive disease and were completely insensitive to Bortezomib. Importantly, this resistance could be reverted by co-administration of GMI-1271, a specific glycomimetic antagonist of E-selectin. Finally, we report that E-selectin ligand-bearing cells are present in primary MM samples from BM and peripheral blood with a higher proportion seen in relapsed patients. This study provides a rationale for targeting E-selectin receptor/ligand interactions to overcome MM metastasis and chemoresistance.
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Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Selectina E/antagonistas & inibidores , Selectina E/metabolismo , Mieloma Múltiplo/metabolismo , Animais , Bortezomib/farmacologia , Adesão Celular , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Ligantes , Camundongos , Mieloma Múltiplo/genética , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Prognóstico , Ligação Proteica , Recidiva , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
We report two types of modifications to the natural product griseofulvin as strategies to improve solubility and metabolic stability: the conversion of aryl methyl ethers into aryl difluoromethyl ethers at metabolic hotspots and the conversion of the C-ring ketone into polar oximes. The syntheses of the analogues are described together with their solubility, metabolic half-life in vitro and antiproliferative effect in two cancer cell lines. We conclude that on balance, the formation of polar oximes is the most promising strategy for improving the properties of the analogues.
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Antineoplásicos/química , Antineoplásicos/metabolismo , Griseofulvina/química , Griseofulvina/metabolismo , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Estabilidade de Medicamentos , Griseofulvina/síntese química , Griseofulvina/farmacologia , Células HeLa , Humanos , Masculino , Camundongos , Microssomos/metabolismo , Oxirredução , Ratos , Solubilidade , Relação Estrutura-Atividade , TermodinâmicaRESUMO
Multiple myeloma (MM) is a plasma cell malignancy that remains incurable. Novel treatment strategies to improve survival are urgently required. The Pims are a small family of serine/threonine kinases with increased expression across the hematological malignancies. Pim-2 shows highest expression in MM and constitutes a promising therapeutic target. It is upregulated by the bone marrow microenvironment to mediate proliferation and promote MM survival. Pim-2 also has a key role in the bone destruction typically seen in MM. Additional putative roles of the Pim kinases in MM include trafficking of malignant cells, promoting oncogenic signaling in the hypoxic bone marrow microenvironment and mediating resistance to therapy. A number of Pim inhibitors are now under development with lead compounds entering the clinic. The ATP-competitive Pim inhibitor LGH447 has recently been reported to have single agent activity in MM. It is anticipated that Pim inhibition will be of clinical benefit in combination with standard treatments and/or with novel drugs targeting other survival pathways in MM.
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Antineoplásicos/farmacologia , Mieloma Múltiplo/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Animais , Antineoplásicos/uso terapêutico , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Humanos , Terapia de Alvo Molecular , Mieloma Múltiplo/enzimologia , Mieloma Múltiplo/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-pim-1/metabolismo , Transdução de Sinais , Regulação para CimaRESUMO
We aimed at demonstrating non-inferiority of bortezomib/cyclophosphamide/dexamethasone (VCD) compared to bortezomib/doxorubicin/dexamethasone (PAd) induction therapy with respect to very good partial response rates or better (⩾VGPR) in 504 newly diagnosed, transplant-eligible multiple myeloma patients. VCD was found to be non-inferior to PAd with respect to ⩾VGPR rates (37.0 versus 34.3%, P=0.001). The rates of progressive disease (PD) were 0.4% (VCD) versus 4.8% (PAd; P=0.003). In the PAd arm, 11 of 12 patients with PD had either renal impairment (creatinine ⩾2 mg/dl) at diagnosis or the cytogenetic abnormality gain 1q21, whereas no PD was observed in these subgroups in the VCD arm. Leukocytopenia/neutropenia (⩾3°) occurred more frequently in the VCD arm (35.2% versus 11.3%, P<0.001). Neuropathy rates (⩾2°) were higher in the PAd group (14.9 versus 8.4%, P=0.03). Serious adverse events, both overall and those related to thromboembolic events, were higher in the PAd group (32.7 versus 24.0%, P=0.04 and 2.8 versus 0.4%, P=0.04). Stem cell collection was not impeded by VCD. VCD is as effective as PAd in terms of achieving ⩾VGPR rates with fewer PD and has a favorable toxicity profile. Therefore, VCD is preferable to PAd as induction therapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Adulto , Idoso , Ácidos Borônicos/administração & dosagem , Bortezomib , Ciclofosfamida/administração & dosagem , Dexametasona/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Seguimentos , Mobilização de Células-Tronco Hematopoéticas , Humanos , Quimioterapia de Indução , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Pirazinas/administração & dosagem , Indução de Remissão , Taxa de SobrevidaRESUMO
Multiple myeloma is a mostly incurable malignancy characterized by the expansion of a malignant plasma cell (PC) clone in the human bone marrow (BM). Myeloma cells closely interact with the BM stroma, which secretes soluble factors that foster myeloma progression and therapy resistance. Growth arrest-specific gene 6 (Gas6) is produced by BM-derived stroma cells and can promote malignancy. However, the role of Gas6 and its receptors Axl, Tyro3 and Mer (TAM receptors) in myeloma is unknown. We therefore investigated their expression in myeloma cell lines and in the BM of myeloma patients and healthy donors. Gas6 showed increased expression in sorted BMPCs of myeloma patients compared with healthy controls. The fraction of Mer(+) BMPCs was increased in myeloma patients in comparison with healthy controls whereas Axl and Tyro3 were not expressed by BMPCs in the majority of patients. Downregulation of Gas6 and Mer inhibited the proliferation of different myeloma cell lines, whereas knocking down Axl or Tyro3 had no effect. Inhibition of the Gas6 receptor Mer or therapeutic targeting of Gas6 by warfarin reduced myeloma burden and improved survival in a systemic model of myeloma. Thus, the Gas6-Mer axis represents a novel candidate for therapeutic intervention in this incurable malignancy.
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Regulação Neoplásica da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intercelular/genética , Mieloma Múltiplo/genética , Plasmócitos/metabolismo , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Animais , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Estudos de Casos e Controles , Linhagem Celular Tumoral , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Mieloma Múltiplo/terapia , Transplante de Neoplasias , Plasmócitos/patologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/metabolismo , Transdução de Sinais , Células Estromais/metabolismo , Células Estromais/patologia , Análise de Sobrevida , Varfarina/farmacologia , c-Mer Tirosina Quinase , Receptor Tirosina Quinase AxlRESUMO
Patients with multiple myeloma and dialysis-dependent renal failure have dismal outcomes. In this retrospective analysis of a case series, we evaluated 27 consecutive patients, all of whom required haemodialysis at the time of first-line induction therapy with either bortezomib or a standard regimen followed by high-dose chemotherapy and auto-SCT. The overall response rate was significantly better after bortezomib-based induction before auto-SCT (83% vs 36%, P=0.02) and at day +100 post auto-SCT (100% vs 58%, P=0.01). Bortezomib also prolonged EFS and furthermore, a trend towards a shorter time on haemodialysis was observed in the bortezomib group at a median of 6.1 months (0.2-68.2 months) vs 17.1 months (0.7-94.3 months, P=0.38) in patients who had received vincristine, adriamycin, dexamethasone or vincristine, adriamycin, dexamethasone-like induction regimens. These data demonstrate the superior efficacy of bortezomib-based induction therapy in transplant-eligible patients with end-stage renal failure.
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Antineoplásicos/administração & dosagem , Ácidos Borônicos/administração & dosagem , Falência Renal Crônica , Mieloma Múltiplo , Pirazinas/administração & dosagem , Transplante de Células-Tronco , Condicionamento Pré-Transplante , Adulto , Idoso , Autoenxertos , Bortezomib , Intervalo Livre de Doença , Humanos , Falência Renal Crônica/mortalidade , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/terapia , Diálise Renal , Estudos RetrospectivosRESUMO
Previous studies demonstrated the relevance of focal lesions (FL) in whole-body magnetic resonance imaging (wb-MRI) at the initial workup of patients with smoldering multiple myeloma (SMM). The aim of this study was to assess the effects of longitudinal wb-MRIs on progression into multiple myeloma (MM). Sixty-three patients with SMM were analyzed who received at least two wb-MRIs for follow-up before progression into MM. Radiological progressive disease (MRI-PD) was defined as detection of new FL or increase in diameter of existing FL and a novel or progressive diffuse infiltration. Radiological stable disease (MRI-SD) was defined by no change compared with the prior MRI. Patients were followed-up every 3-6 months, including a serological and clinical evaluation. One Hundred and eighty-two wb-MRIs were analyzed. MRI-PD occurred in 31 patients (49%), and 25 (40%) patients developed MM. MRI-PD was highly significantly associated with progression into MM, regardless of findings at the initial MRI. In multivariate analysis, MRI-PD remained a risk factor, independent of relevant baseline parameters like serum monoclonal protein or ⩾95% aberrant plasma cells in the bone marrow. Patients with MRI-SD had no higher risk of progression, even when FL were present at the initial MRI. Therefore, MRI is suitable for the follow-up of patients with SMM.
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Imageamento por Ressonância Magnética/métodos , Mieloma Múltiplo/patologia , Adulto , Idoso , Humanos , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Estudos RetrospectivosRESUMO
Osteolytic bone disease in multiple myeloma (MM) is caused by enhanced osteoclast (OCL) activation and inhibition of osteoblast function. Lenalidomide and bortezomib have shown promising response rates in relapsed and newly diagnosed MM, and bortezomib has recently been reported to inhibit OCLs. We here investigated the effect of lenalidomide on OCL formation and osteoclastogenesis in comparison with bortezomib. Both drugs decreased alpha V beta 3-integrin, tartrate-resistant acid phosphatase-positive cells and bone resorption on dentin disks. In addition, both agents decreased receptor activator of nuclear factor-kappaB ligand (RANKL) secretion of bone marrow stromal cells (BMSCs) derived from MM patients. We identified PU.1 and pERK as major targets of lenalidomide, and nuclear factor of activated T cells of bortezomib, resulting in inhibition of osteoclastogenesis. Furthermore, downregulation of cathepsin K, essential for resorption of the bone collagen matrix, was observed. We demonstrated a significant decrease of growth and survival factors including macrophage inflammatory protein-alpha, B-cell activating factor and a proliferation-inducing ligand. Importantly, in serum from MM patients treated with lenalidomide, the essential bone-remodeling factor RANKL, as well as the RANKL/OPG ratio, were significantly reduced, whereas osteoprotegerin (OPG) was increased. We conclude that both agents specifically target key factors in osteoclastogenesis, and could directly affect the MM-OCL-BMSCs activation loop in osteolytic bone disease.
Assuntos
Antineoplásicos/farmacologia , Remodelação Óssea/efeitos dos fármacos , Mieloma Múltiplo/tratamento farmacológico , Osteoclastos/efeitos dos fármacos , Talidomida/análogos & derivados , Fator Ativador de Células B/metabolismo , Reabsorção Óssea/prevenção & controle , Ácidos Borônicos/farmacologia , Bortezomib , Catepsina K , Catepsinas/análise , Células Cultivadas , Quimiocina CCL3/metabolismo , Humanos , Integrina alfaVbeta3/análise , Lenalidomida , Osteoclastos/fisiologia , Osteoprotegerina/sangue , Proteínas Proto-Oncogênicas/fisiologia , Pirazinas/farmacologia , Ligante RANK/metabolismo , Talidomida/farmacologia , Transativadores/fisiologia , Fator de Transcrição AP-1/fisiologia , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismoRESUMO
BACKGROUND: Non-myeloablative allogeneic stem cell transplantation followed by immunomodulatory therapies is considered a potentially curative approach in the treatment of multiple myeloma and most effective in a minimal residual disease setting. PATIENTS AND METHODS: The aim of this study was to find the most sensitive real-time PCR assay (TaqMan), based on the IGH rearrangement, to quantify the tumour load of 11 patients with multiple myeloma after non-myeloablative allogeneic transplantation. Patient-allele specific primers (ASO) and the TaqMan probe were derived from CDR2 and CDR3 hypervariable regions of IGH, while consensus primers were located within the FR3 and FR4/JH regions. Four different approaches of primer combinations were tested. RESULTS: ASO-forward and -reverse primers together with the clone-specific TaqMan probe were the most sensitive approach compared with the JH (P=0.071) or the FR3 consensus primer (P <0.001). The detection limit amounted to 1/10(4)-1/10(5) cells. Consecutively, 120 samples from 11 patients prior and post allogeneic transplantation were analysed. Three patients reached complete clinical remission accompanied by molecular remission. Disease progression or relapse was seen in six patients. In five, molecular progressive disease was detected prior to the clinical diagnosis of progression or relapse. CONCLUSION: Patient-specific real-time IGH-PCR provides the opportunity for earlier treatment intervention.
Assuntos
Mieloma Múltiplo/patologia , Mieloma Múltiplo/terapia , Transplante de Células-Tronco/métodos , Carga Tumoral , Adulto , Progressão da Doença , Humanos , Pessoa de Meia-Idade , Monitorização Imunológica/métodos , Mieloma Múltiplo/imunologia , Valor Preditivo dos Testes , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Transplante Homólogo , Carga Tumoral/imunologiaRESUMO
In order to better understand the feasibility and limitations of the autogen (White 1980), a computer simulation based on the fluctuating clay environment was used to test whether autocatalytic growth would occur under various conditions. The results suggest that overall accuracies of replication and translation in the range of 90% and 10%, and protoenzyme turnover numbers of 10--120 monomers/protoenzyme/day are adequate for exponential growth. Nucleation of the components of the autogen from random background oligomers would be extremely rapid if oligomers lengths 2--6 were adequately functional, whereas oligomer lengths much greater than 10 are prohibited. The autogen would most likely nucleate and grow to dominance either rapidly (10--100 cycles of roughly 1 day each) or not at all.