RESUMO
Stem cell transplantation (SCT), an effective therapy for amyloid light chain (AL) amyloidosis patients, is associated with low treatment-related mortality (TRM) with appropriate patient selection and risk-adapted dosing of melphalan (RA-SCT). Consolidation after SCT increases hematologic complete response (CR) rates and may improve overall survival (OS) for patients with Assuntos
Amiloidose/tratamento farmacológico
, Amiloidose/mortalidade
, Melfalan/administração & dosagem
, Amiloidose/terapia
, Bortezomib/uso terapêutico
, Quimioterapia de Consolidação/métodos
, Intervalo Livre de Doença
, Seguimentos
, Humanos
, Cadeias Leves de Imunoglobulina
, Pessoa de Meia-Idade
, Indução de Remissão
, Estudos Retrospectivos
, Risco Ajustado
, Transplante de Células-Tronco
, Taxa de Sobrevida
RESUMO
Background: Therapeutic advancements following the introduction of autologous stem cell transplantation and 'novel' agents have significantly improved clinical outcomes for patients with multiple myeloma (MM). Increased life expectancy, however, has led to renewed concerns about the long-term risk of second primary malignancies (SPMs). This review outlines the most up-to-date knowledge of possible host-, disease-, and treatment-related risk factors for the development of SPMs in patients with MM, and provides practical recommendations to assist physicians. Design: A Panel of International Myeloma Working Group members reviewed the most relevant data published in the literature as full papers, or presented at meetings of the American Society of Clinical Oncology, American Society of Hematology, European Hematology Association, or International Myeloma Workshops, up to June 2016. Here, we present the recommendations of the Panel, based on this literature review. Results: Overall, the risk of SPMs in MM is low, multifactorial, and partially related to the length of patients' survival and MM intrinsic susceptibility. Studies suggest a significantly increased incidence of SPMs when lenalidomide is administered either following, or concurrently with, oral melphalan. Increased SPM incidence has also been reported with lenalidomide maintenance following high-dose melphalan, albeit to a lesser degree. In both cases, the risk of death from MM was significantly higher than the risk of death from SPMs, with lenalidomide possibly providing a survival benefit. No increase in SPM incidence was reported with lenalidomide plus dexamethasone (without melphalan), or with bortezomib plus oral melphalan, dexamethasone, or thalidomide. Conclusion: In general, the risk of SPMs should not alter the current therapeutic decision-making process in MM. However, regimens such as lenalidomide plus dexamethasone should be preferred to prolonged exposure to lenalidomide plus oral melphalan. SPM risk should be carefully discussed with the patient in the context of benefits and risks of different treatment options.
Assuntos
Mieloma Múltiplo/terapia , Segunda Neoplasia Primária/etiologia , Humanos , Incidência , Mieloma Múltiplo/epidemiologia , Mieloma Múltiplo/patologia , Segunda Neoplasia Primária/epidemiologia , Fatores de RiscoRESUMO
Treatment of light chain (LC) deposition diseases both nonfibrillar and fibrillar is aimed at eliminating LC production but success is limited. We report on the testing of an small interfering RNA pool targeting the κ LC constant region mRNA (si[IGKC]) designed for use against all κ plasma cell clones. To test for changes in κ LC message and protein production we used real-time PCR, immunoblot, intracellular mean fluorescence intensity and κ LC secretion by enzyme-linked immunosorbent assay. In vitro we employed 4 human cell lines that make κ LCs and 20 specimens of CD138-selected marrow plasma cells from patients with κ plasma cell diseases. In vivo, we used a murine flank plasmacytoma xenograft model. In vitro and in vivo, there were significant reductions in message and protein production by all modalities in all cell types despite diversity in variable region sequence. In addition, in clones producing intact immunoglobulin, caspase 3/7 activity with si[IGKC] was significantly increased compared with clones producing κ LC only, consistent with the triggering of a terminal unfolded protein response by excess unpaired heavy chains. In conclusion, si[IGKC] can significantly reduce κ LC production by κ plasma cells. Further preclinical development is needed to optimize delivery.
Assuntos
Cadeias Leves de Imunoglobulina/genética , Cadeias kappa de Imunoglobulina/genética , Paraproteinemias/terapia , Terapêutica com RNAi/métodos , Animais , Células da Medula Óssea/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Células Cultivadas , Feminino , Humanos , Cadeias Leves de Imunoglobulina/metabolismo , Cadeias kappa de Imunoglobulina/metabolismo , CamundongosRESUMO
Amyloid light-chain (LC) amyloidosis (AL amyloidosis) is a rare and fatal disease for which there are no approved therapies. In patients with AL amyloidosis, LC aggregates progressively accumulate in organs, resulting in organ failure that is particularly lethal when the heart is involved. A significant obstacle in the development of treatments for patients with AL amyloidosis, as well as for those with any disease that is rare, severe and heterogeneous, has been satisfying traditional clinical trial end points (for example, overall survival or progression-free survival). It is for this reason that many organizations, including the United States Food and Drug Administration through its Safety and Innovation Act Accelerated Approval pathway, have recognized the need for biomarkers as surrogate end points. The international AL amyloidosis expert community is in agreement that the N-terminal fragment of the pro-brain natriuretic peptide (NT-proBNP) is analytically validated and clinically qualified as a biomarker for use as a surrogate end point for survival in patients with AL amyloidosis. Underlying this consensus is the demonstration that NT-proBNP is an indicator of cardiac response in all interventional studies in which it has been assessed, despite differences in patient population, treatment type and treatment schedule. Furthermore, NT-proBNP expression is directly modulated by amyloidogenic LC-elicited signal transduction pathways in cardiomyocytes. The use of NT-proBNP will greatly facilitate the development of targeted therapies for AL amyloidosis. Here, we review the data supporting the use of NT-proBNP, a biomarker that is analytically validated, clinically qualified, directly modulated by LC and universally accepted by AL amyloidosis specialists, as a surrogate end point for survival.
Assuntos
Amiloidose/diagnóstico , Amiloidose/mortalidade , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Biomarcadores , Ensaios Clínicos como Assunto , Humanos , Cadeias Leves de Imunoglobulina/metabolismo , Análise de SobrevidaAssuntos
Amiloidose/tratamento farmacológico , Amiloidose/terapia , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas/métodos , Compostos Heterocíclicos/administração & dosagem , Idoso , Benzilaminas , Ciclamos , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina , Pessoa de Meia-IdadeRESUMO
Treatment in medical oncology is gradually shifting from the use of nonspecific chemotherapeutic agents toward an era of novel targeted therapy in which drugs and their combinations target specific aspects of the biology of tumor cells. Multiple myeloma (MM) has become one of the best examples in this regard, reflected in the identification of new pathogenic mechanisms, together with the development of novel drugs that are being explored from the preclinical setting to the early phases of clinical development. We review the biological rationale for the use of the most important new agents for treating MM and summarize their clinical activity in an increasingly busy field. First, we discuss data from already approved and active agents (including second- and third-generation proteasome inhibitors (PIs), immunomodulatory agents and alkylators). Next, we focus on agents with novel mechanisms of action, such as monoclonal antibodies (MoAbs), cell cycle-specific drugs, deacetylase inhibitors, agents acting on the unfolded protein response, signaling transduction pathway inhibitors and kinase inhibitors. Among this plethora of new agents or mechanisms, some are specially promising: anti-CD38 MoAb, such as daratumumab, are the first antibodies with clinical activity as single agents in MM. Moreover, the kinesin spindle protein inhibitor Arry-520 is effective in monotherapy as well as in combination with dexamethasone in heavily pretreated patients. Immunotherapy against MM is also being explored, and probably the most attractive example of this approach is the combination of the anti-CS1 MoAb elotuzumab with lenalidomide and dexamethasone, which has produced exciting results in the relapsed/refractory setting.
Assuntos
Antineoplásicos/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , HumanosRESUMO
Thalidomide, lenalidomide and bortezomib have increasingly been incorporated in first-line induction therapies for multiple myeloma. Concerns regarding the impact of these agents, especially lenalidomide, on stem cell mobilization prompted us to re-evaluate the risk factors that impact mobilization, including exposure to novel induction regimens. Among 317 patients who proceeded to stem cell collection after induction therapy between 2000 and 2009, the rate of mobilization failure, defined as the inability to collect 5 × 10(6) CD34+ cells/kg following the first collection attempt, was 13%. By multivariate analysis, independent risk factors associated with mobilization failure included older age (P=0.04), lower platelet count (P=0.002) and use of single-agent G-CSF for mobilization (P<0.0001). When considering for outcome measurement stem cell collection efficiency measured by the number of CD34+ cells yielded per pheresis performed during first collection attempt, lower platelet count, use of single-agent G-CSF and older age were also associated with lower efficiency. In this population mobilized mostly with cyclophosphamide and G-CSF, the use of lenalidomide during induction was not associated with a lower stem cell collection efficiency by multivariate analysis. The data support the current International Multiple Myeloma Working Group guidelines recommending the use of cyclophosphamide and G-CSF based mobilization for patients previously exposed to lenalidomide.
Assuntos
Mobilização de Células-Tronco Hematopoéticas/métodos , Mieloma Múltiplo/terapia , Adulto , Fatores Etários , Idoso , Ciclofosfamida/administração & dosagem , Coleta de Dados , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas/normas , Humanos , Lenalidomida , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/cirurgia , Análise Multivariada , Guias de Prática Clínica como Assunto , Estudos Retrospectivos , Talidomida/administração & dosagem , Talidomida/análogos & derivados , Falha de Tratamento , Resultado do TratamentoRESUMO
Plasma cell leukemia (PCL) is a rare and aggressive variant of myeloma characterized by the presence of circulating plasma cells. It is classified as either primary PCL occurring at diagnosis or as secondary PCL in patients with relapsed/refractory myeloma. Primary PCL is a distinct clinic-pathological entity with different cytogenetic and molecular findings. The clinical course is aggressive with short remissions and survival duration. The diagnosis is based upon the percentage (≥ 20%) and absolute number (≥ 2 × 10(9)/l) of plasma cells in the peripheral blood. It is proposed that the thresholds for diagnosis be re-examined and consensus recommendations are made for diagnosis, as well as, response and progression criteria. Induction therapy needs to begin promptly and have high clinical activity leading to rapid disease control in an effort to minimize the risk of early death. Intensive chemotherapy regimens and bortezomib-based regimens are recommended followed by high-dose therapy with autologous stem cell transplantation if feasible. Allogeneic transplantation can be considered in younger patients. Prospective multicenter studies are required to provide revised definitions and better understanding of the pathogenesis of PCL.
Assuntos
Leucemia Plasmocitária/diagnóstico , Leucemia Plasmocitária/terapia , Progressão da Doença , Feminino , Humanos , Leucemia Plasmocitária/patologia , Masculino , Pessoa de Meia-IdadeRESUMO
To improve the efficacy of risk-adapted melphalan (MEL) in patients with amyloidosis (AL), we conducted a phase II trial using bortezomib and dexamethasone (BD) as consolidation. Forty untreated patients with renal (70%), cardiac (65%), liver/gastrointestinal (15%) or nervous system (13%) AL were assigned MEL 100, 140 or 200 mg/m(2) based on age, renal function and cardiac involvement. Hematological response was assessed at 3 months post stem cell transplant (SCT); patients with less than complete hematological response (CR) received BD consolidation. Four patients with advanced cardiac AL died within 100 days of SCT (10% treatment-related mortality). Survival at 12 and 24 months post treatment start was 88 and 82% overall and was 81 and 72% in patients with cardiac AL. At 3 months post SCT, 45% had ≥ partial response (PR) including 27% CR. Twenty-three patients received consolidation and in 86% response improved; all patients responded in one cycle. At 12 and 24 months, 79 and 60% had ≥ PR, 58 and 40% CR. Organ responses occurred in 55 and 70% at 12 and 24 months. Eight patients relapsed/progressed. One patient with serologic progression had organ impairment at time of progression. In newly diagnosed AL, BD following SCT rapidly and effectively improves responses resulting in high CR rates and maintained organ improvement.
Assuntos
Amiloidose/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ácidos Borônicos/administração & dosagem , Bortezomib , Dexametasona/administração & dosagem , Feminino , Humanos , Masculino , Melfalan/administração & dosagem , Pessoa de Meia-Idade , Pirazinas/administração & dosagemRESUMO
Light-chain amyloidosis (AL) is a plasma cell dyscrasia closely related to multiple myeloma. In multiple myeloma, the cancer-testis antigens (CTAs) CT7 (MAGE-C1), CT10 (MAGE-C2) and MAGE-A CTAs are expressed in up to 80% of cases. In this study, we investigated the expression and immunogenicity of several CTAs in patients with AL amyloidosis in a total of 38 bone marrow specimens by employing standard immunohistochemistry techniques on paraffin-embedded archival tissues. Plasma samples from 35 patients (27 with matched bone marrow samples) were also analyzed by ELISA for sero reactivity to a group of full-length CTA proteins. CT7 was present in 25/38 (66%) while CT10 was demonstrated in 3/38 and GAGE in 1/38 AL amyloid cases. The expression pattern was mostly focal. There were no significant differences with regard to organ involvement, response to treatment, or prognosis in CTA positive compared to negative cases. None of the specimens showed spontaneous humoral immunity to CT7, but sero reactivity was observed in individual patients to other CTAs. This study identifies CT7 as the prevalent CTA in plasma cells of patients with AL amyloidosis. Further analyses determining the biology of CTAs in AL amyloidosis and their value as potential targets for immunotherapy are warranted.
RESUMO
This manuscript summarizes the recommendations that emerged from the first Roundtable on Clinical Research in Immunoglobulin Light-chain Amyloidosis (AL), a meeting sponsored by the Amyloidosis Foundation (Clarkston, MI, USA) to develop a consensus of experts on a modern framework for clinical trial design and drug development in AL. Recent diagnostic and technical advances in AL, and updated consensus guidelines for assessing hematologic and organ responses, enable us to define study populations, appropriate end points, and other criteria for all phases of clinical research. This manuscript provides a framework for the design and conduct of systematic collaborative clinical research in AL to encourage more rapid testing of therapies and to expedite new drug development and approval.
Assuntos
Amiloidose/terapia , Ensaios Clínicos como Assunto , Guias de Prática Clínica como Assunto , Determinação de Ponto Final , HumanosRESUMO
Amyloid diseases in man are caused by as many as 23 different pre-cursor proteins already described. Cardiologists predominantly encounter three main types of amyloidosis that affect the heart: light chain (AL) amyloidosis, senile systemic amyloidosis (SSA) and hereditary amyloidosis, most commonly caused by a mutant form of transthyretin. In the third world, secondary amyloid (AA) is more prevalent, due to chronic infections and inadequately treated inflammatory conditions. Much less common, are the non-transthyretin variants, including mutations of fibrinogen, the apolipoproteins apoA1 and apoA2 and gelsolin. These rarer types do not usually cause significant cardiac compromise. Occurring worldwide, later in life and of less clinical significance, isolated atrial amyloid (IAA) also involves the heart. Heart involvement by amyloid often has devastating consequences. Clinical outcome depends on amyloid type, the extent of systemic involvement and the treatment options available. An exact determination of amyloid type is critical to appropriate therapy. In this review we describe the different approaches required to treat this spectrum of amyloid cardiomyopathies.
Assuntos
Amiloidose/terapia , Cardiomiopatias/terapia , Amiloidose/diagnóstico , Amiloidose/etiologia , Biomarcadores/metabolismo , Cardiomiopatias/diagnóstico , Cardiomiopatias/etiologia , Progressão da Doença , Transplante de Coração , HumanosRESUMO
Peripheral neuropathy (PN) is one of the most important complications of multiple myeloma (MM) treatment. PN can be caused by MM itself, either by the effects of the monoclonal protein or in the form of radiculopathy from direct compression, and particularly by certain therapies, including bortezomib, thalidomide, vinca alkaloids and cisplatin. Clinical evaluation has shown that up to 20% of MM patients have PN at diagnosis and as many as 75% may experience treatment-emergent PN during therapy. The incidence, symptoms, reversibility, predisposing factors and etiology of treatment-emergent PN vary among MM therapies, with PN incidence also affected by the dose, schedule and combinations of potentially neurotoxic agents. Effective management of treatment-emergent PN is critical to minimize the incidence and severity of this complication, while maintaining therapeutic efficacy. Herein, the state of knowledge regarding treatment-emergent PN in MM patients and current management practices are outlined, and recommendations regarding optimal strategies for PN management during MM treatment are provided. These strategies include early and regular monitoring with neurological evaluation, with dose modification and treatment discontinuation as indicated. Areas requiring further research include the development of MM-specific, patient-focused assessment tools, pharmacogenomic analysis of patient DNA, and trials to assess the efficacy of pharmacological interventions.
Assuntos
Mieloma Múltiplo/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Ácidos Borônicos/efeitos adversos , Bortezomib , Diagnóstico Precoce , Humanos , Fatores Imunológicos/efeitos adversos , Incidência , Mieloma Múltiplo/complicações , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/diagnóstico , Doenças do Sistema Nervoso Periférico/epidemiologia , Inibidores de Proteassoma , Pirazinas/efeitos adversos , Talidomida/efeitos adversosAssuntos
Ácidos Borônicos/uso terapêutico , Dexametasona/uso terapêutico , Melfalan/uso terapêutico , Pirazinas/uso terapêutico , Transplante de Células-Tronco , Ácidos Borônicos/administração & dosagem , Bortezomib , Terapia Combinada , Dexametasona/administração & dosagem , Humanos , Melfalan/administração & dosagem , Pirazinas/administração & dosagemRESUMO
BACKGROUND: Bortezomib is approved for the treatment of multiple myeloma and a role has been suggested in the treatment of systemic AL amyloidosis (AL). METHODS: In this phase 1 dose-escalation portion of the first prospective study of single-agent bortezomib in AL, 31 patients with relapsed disease, including 14 (45%) with cardiac involvement, received bortezomib in seven dose cohorts on once-weekly (0.7, 1.0, 1.3, 1.6 mg/m(2)) and twice-weekly (0.7, 1.0, 1.3 mg/m(2)) schedules. Electrocardiographic, Holter and echocardiographic studies were evaluated in all patients to determine safety and response. RESULTS: During therapy (median treatment period 210 days), no patient developed significant ventricular or supraventricular rhythm disturbance on 24-h Holter monitoring; however, no patient satisfied study criteria for cardiac response using echocardiographic assessment or New York Heart Association classification. Seven patients (23%) had a ≥ 10% fall in left ventricular ejection fraction, but only one met criteria for cardiac deterioration. The predominant cardiac adverse events were peripheral edema (23%), orthostatic hypotension (13%) and hypotension (10%). Two patients developed grade 3 congestive heart failure, which resolved following treatment interruption. In this Phase 1 portion, the maximum tolerated dose of bortezomib on either schedule was not reached. Hematologic responses occurred in 14 patients (45%), including seven (23%) complete responses. In non-responders mean left ventricular wall thickness increased during the course of treatment. CONCLUSION: AL is frequently rapidly progressive; in these patients who had relapsed or progressed following previous conventional therapies, these results suggest that bortezomib may slow the progression of cardiac amyloid with limited toxicity.
Assuntos
Amiloidose/tratamento farmacológico , Antineoplásicos/administração & dosagem , Ácidos Borônicos/administração & dosagem , Cardiopatias/tratamento farmacológico , Pirazinas/administração & dosagem , Idoso , Amiloidose/complicações , Bortezomib , Progressão da Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Eletrocardiografia , Feminino , Cardiopatias/etiologia , Humanos , Nefropatias/tratamento farmacológico , Nefropatias/etiologia , Hepatopatias/tratamento farmacológico , Hepatopatias/etiologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Paraproteinemias/complicações , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/etiologia , Estudos Prospectivos , Resultado do TratamentoRESUMO
The high doses of chemotherapy used for the preparatory regimens before autologous blood or marrow stem cell transplantation leave patients at risk for neutropenic complications. The administration of filgrastim post transplant reduces the time to neutrophil recovery and therefore has become a standard practice at many institutions. In 2006, we implemented a practice change from filgrastim to pegfilgrastim. We present data on 164 consecutive patients (82 patients who received filgrastim compared with 82 patients who received pegfilgrastim) who received an auto-SCT between January 2006 and November 2007. Patients who received pegfilgrastim had faster engraftment (9.6 days compared with 10.9 days, P<0.0001), a lower incidence of febrile neutropenia (59% compared with 78%, P=0.015), as well as shorter hospital stay, fewer days of treatment with i.v. antibiotics (6.3 days compared with 9.6 days, P=0.006), and fewer radiographic tests, which translated to an estimated total cost savings of over $8000 per patient. Overall, there were no differences in toxicity with these two agents. We conclude that a single dose of pegfilgrastim is a safe and efficacious alternative to daily injections of filgrastim and can be a cost-effective approach in auto-SCT patients.
Assuntos
Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Fármacos Hematológicos/uso terapêutico , Neutropenia/tratamento farmacológico , Neutropenia/epidemiologia , Transplante de Células-Tronco , Adulto , Idoso , Antibacterianos/economia , Antibacterianos/uso terapêutico , Estudos de Coortes , Feminino , Febre/epidemiologia , Filgrastim , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Fator Estimulador de Colônias de Granulócitos/economia , Custos de Cuidados de Saúde , Fármacos Hematológicos/efeitos adversos , Fármacos Hematológicos/economia , Neoplasias Hematológicas/terapia , Humanos , Incidência , Tempo de Internação/economia , Tempo de Internação/estatística & dados numéricos , Leucopoese/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Neutropenia/sangue , Neutropenia/economia , Polietilenoglicóis , Proteínas Recombinantes , Estudos Retrospectivos , Transplante Autólogo , Adulto JovemRESUMO
In 2005, the first guidelines were published on the management of patients with multiple myeloma (MM). An expert panel reviewed the currently available literature as the basis for a set of revised and updated consensus guidelines for the diagnosis and management of patients with MM who are not eligible for autologous stem cell transplantation. Here we present recommendations on the diagnosis, treatment of newly diagnosed non-transplant-eligible patients and the management of complications occurring during induction therapy among these patients. These guidelines will aid the physician in daily clinical practice and will ensure optimal care for patients with MM.
Assuntos
Antineoplásicos/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/terapia , Humanos , Transplante AutólogoRESUMO
Multiple myeloma is the most common indication for high-dose chemotherapy with autologous stem cell support (ASCT) in North America today. Stem cell procurement for ASCT has most commonly been performed with stem cell mobilization using colony-stimulating factors with or without prior chemotherapy. The target CD34+ cell dose to be collected as well as the number of apheresis performed varies throughout the country, but a minimum of 2 million CD34+ cells/kg has been traditionally used for the support of one cycle of high-dose therapy. With the advent of plerixafor (AMD3100) (a novel stem cell mobilization agent), it is pertinent to review the current status of stem cell mobilization for myeloma as well as the role of autologous stem cell transplantation in this disease. On June 1, 2008, a panel of experts was convened by the International Myeloma Foundation to address issues regarding stem cell mobilization and autologous transplantation in myeloma in the context of new therapies. The panel was asked to discuss a variety of issues regarding stem cell collection and transplantation in myeloma especially with the arrival of plerixafor. Herein, is a summary of their deliberations and conclusions.