RESUMEN
This multicenter, phase II study of the Australasian Lymphoma and Leukemia Group and the Asian Myeloma Network investigated fixed-duration (18-month) treatment with carfilzomib (K), thalidomide (T), and dexamethasone (d) (KTd) in patients with relapsed and/or refractory multiple myeloma who had received one to three prior lines of therapy. Patients received induction with up to 12 28-day cycles of carfilzomib (20 mg/m2 intravenously in cycle 1 on days 1 and 2, then 56 mg/m2 [36 mg/m2 for patients ≥75 years] from day 8 onwards), thalidomide 100 mg orally in the evening and weekly dexamethasone 40 mg (20 mg for patients ≥75 years). During maintenance, thalidomide was omitted, while carfilzomib was continued on days 1, 2, 15, and 16 with fortnightly dexamethasone. The primary endpoint was progression-free survival. Secondary endpoints were overall response rate, overall survival, duration of response, safety, and tolerability. Ninety-three patients (median age 66.3 years [range, 41.9-84.5]) were enrolled and followed up for a median of 26.4 months (range, 1.6-54.6). The median progression-free survival was 22.3 months (95% confidence interval: 15.7-25.6) and the 2-year progression-free survival was 46.3% (95% confidence interval: 35.1-52.8). The median overall survival was not reached and the 2-year overall survival was 73.8% (95% confidence interval: 62.9-81.9). The overall response rate was 88% (73% had a very good partial response or better). There was no difference in the depth of response, progression-free survival or overall survival comparing Asian and non-Asian cohorts (P=0.61). The safety profile of KTd was consistent with that of each individual drug. KTd is well tolerated and effective in patients with relapsed and/or refractory multiple myeloma irrespective of Asian or non-Asian ethnicity and provides an alternative treatment option, particularly in circumstances in which the use of carfilzomib, lenalidomide, and dexamethasone (KRd) is limited by access, cost, or renal impairment.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Dexametasona , Mieloma Múltiple , Oligopéptidos , Talidomida , Humanos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/mortalidad , Dexametasona/administración & dosificación , Dexametasona/uso terapéutico , Dexametasona/efectos adversos , Anciano , Oligopéptidos/administración & dosificación , Oligopéptidos/uso terapéutico , Oligopéptidos/efectos adversos , Femenino , Persona de Mediana Edad , Masculino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Talidomida/administración & dosificación , Talidomida/uso terapéutico , Anciano de 80 o más Años , Adulto , Resultado del Tratamiento , Resistencia a Antineoplásicos/efectos de los fármacos , RecurrenciaRESUMEN
BACKGROUND: Cardiac amyloidosis has a very poor prognosis, but it is the nature of the involved precursor protein that ultimately dictates treatment and survival. AIM: Definitively characterise the amyloid subtype by mass spectrometry (MS) in an Australian cohort of patients with cardiac amyloidosis. METHODS: We report the clinical characteristics and survival of 47 cardiac amyloid patients across two Australian centres including 39 patients evaluated for definitive amyloid subtype utilising laser microdissection and tandem mass spectrometry. RESULTS: A quarter (n = 12) of patients were classified as wild-type transthyretin amyloidosis (ATTRwt), 33 patients as light or heavy chain amyloidosis (AL or AH) and two as hereditary mutant transthyretin amyloidosis. Greater left ventricular hypertrophy (interventricular septum 22 vs 15 mm; P = 0.005) and history of cardiac arrhythmia (75% vs 31%; P = 0.016) were significantly associated with ATTRwt patients compared with AL/AH patients. AL patients demonstrated significantly shorter median survival compared with ATTRwt patients (3.5 vs 37 months; P = 0.007). New York Heart Association class III-IV symptoms or plasma cells ≥10% at diagnosis, were the only independent predictors of worse survival in AL patients on multivariate analysis. CONCLUSIONS: AL amyloidosis accounted for 68% of our cohort of patients with cardiac amyloidosis while ATTR accounted for 26%. In the era of novel therapies for both AL amyloid and ATTR, identification of the correct amyloid subtype is essential in making therapeutic decisions and providing accurate prognostic information to patients. Laser microdissection and tandem mass spectrometry plays an important role in identifying amyloid subtype, particularly in complex cases.
Asunto(s)
Neuropatías Amiloides Familiares , Proteómica , Neuropatías Amiloides Familiares/diagnóstico , Australia/epidemiología , Humanos , Espectrometría de Masas , PronósticoRESUMEN
Imaging modalities for multiple myeloma (MM) have evolved to enable earlier detection of disease. Furthermore, the diagnosis of MM requiring therapy has recently changed to include disease prior to bone destruction, specifically the detection of focal bone lesions. Focal lesions are early, abnormal areas in the bone marrow, which may signal the development of subsequent lytic lesions that typically occur within the next 18-24 months. Cross-sectional imaging modalities are more sensitive for the detection and monitoring of bone and bone marrow disease and are now included in the International Myeloma Working Group current consensus criteria for initial diagnosis and treatment response assessment. The aim of this consensus practice statement is to review the evidence supporting these modalities. A more detailed Position Statement can be found on the Myeloma Australia website.
Asunto(s)
Mieloma Múltiple , Paraproteinemias , Consenso , Diagnóstico por Imagen , Humanos , Mieloma Múltiple/diagnóstico por imagen , Mieloma Múltiple/terapia , Células PlasmáticasAsunto(s)
ADN Tumoral Circulante , Mieloma Múltiple , Humanos , Médula Ósea , Mieloma Múltiple/terapia , Neoplasia ResidualRESUMEN
Daratumumab, a CD38 human monoclonal antibody, demonstrated significant clinical activity in combination with bortezomib and dexamethasone versus bortezomib and dexamethasone alone in the primary analysis of CASTOR, a phase 3 study in relapsed and/or refractory multiple myeloma. A post hoc analysis based on treatment history and longer follow up is presented. After 19.4 (range: 0-27.7) months of median follow up, daratumumab plus bortezomib and dexamethasone prolonged progression-free survival (median: 16.7 versus 7.1 months; hazard ratio, 0.31; 95% confidence interval, 0.24-0.39; P<0.0001) and improved the overall response rate (83.8% versus 63.2%; P<0.0001) compared with bortezomib and dexamethasone alone. The progression-free survival benefit of daratumumab plus bortezomib and dexamethasone was most apparent in patients with 1 prior line of therapy (median: not reached versus 7.9 months; hazard ratio, 0.19; 95% con fidence interval, 0.12-0.29; P<0.0001). Daratumumab plus bortezomib and dexamethasone was also superior to bortezomib and dexamethasone alone in subgroups based on prior treatment exposure (bortezomib, thalidomide, or lenalidomide), lenalidomide-refractory status, time since last therapy (≤12, >12, ≤6, or >6 months), or cytogenetic risk. Minimal residual disease-negative rates were >2.5-fold higher with daratumumab across subgroups. The safety profile of daratumumab plus bortezomib and dexamethasone remained consistent with longer follow up. Daratumumab plus bortezomib and dexamethasone demonstrated significant clinical activity across clinically relevant subgroups and provided the greatest benefit to patients treated at first relapse. Trial registration: clinicaltrials.gov identifier: 02136134.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Neoplasia Residual/diagnóstico , Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/administración & dosificación , Bortezomib/administración & dosificación , Dexametasona/administración & dosificación , Resistencia a Antineoplásicos , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mieloma Múltiple/patología , Recurrencia Local de Neoplasia , Evaluación de Resultado en la Atención de Salud/métodosRESUMEN
Multiple myeloma (MM) is a haematological malignancy characterised by the clonal proliferation of plasma cells in the bone marrow. More than 80% of patients with MM display evidence of myeloma bone disease (MBD), characterised by the formation of osteolytic lesions throughout the axial and appendicular skeleton. MBD significantly increases the risk of skeletal-related events such as pathologic fracture, spinal cord compression and hypercalcaemia. MBD is the result of MM plasma cells-mediated activation of osteoclast activity and suppression of osteoblast activity. Bisphosphonates (BP), pyrophosphate analogues with high bone affinity, are the only pharmacological agents currently recommended for the treatment and prevention of MBD and remain the standard of care. Pamidronate and zoledronic acid are the most commonly used BP to treat MBD. Although generally safe, frequent high doses of BP are associated with adverse events such as renal toxicity and osteonecrosis of the jaw. As such, optimal duration and dosing of BP therapy is required in order to minimise BP-associated adverse events. The following guidelines provide currently available evidence for the adoption of a tailored approach when using BP for the management of MBD.
Asunto(s)
Conservadores de la Densidad Ósea/efectos adversos , Neoplasias Óseas/tratamiento farmacológico , Difosfonatos/efectos adversos , Mieloma Múltiple/tratamiento farmacológico , Guías de Práctica Clínica como Asunto , Osteonecrosis de los Maxilares Asociada a Difosfonatos/etiología , Conservadores de la Densidad Ósea/administración & dosificación , Neoplasias Óseas/complicaciones , Neoplasias Óseas/prevención & control , Huesos , Difosfonatos/administración & dosificación , Medicina Basada en la Evidencia , Humanos , Enfermedades Renales/etiología , Mieloma Múltiple/complicaciones , Mieloma Múltiple/prevención & control , Radiografía , Factores de RiesgoRESUMEN
Waldenström macroglobulinaemia (WM) is an indolent B-cell malignancy characterised by the presence of immunoglobulin M (IgM) paraprotein and bone marrow infiltration by clonal small B lymphocytes, plasmacytoid lymphocytes and plasma cells. The symptoms of WM are protean, often follow an asymptomatic phase and may include complications related to the paraneoplastic effects of IgM paraprotein. The revised 2016 World Health Organization classification includes the MYD88 L265P mutation, which is seen in >90% of cases, within the diagnostic criteria for WM. While treatment of WM has often been considered together with other indolent B cell lymphomas, there are unique aspects of WM management that require specific care. These include the unreliability of IgM and paraprotein measurements in monitoring patients prior to and after treatment, the lack of correlation between disease burden and symptoms and rituximab-induced IgM flare. Moreover, while bendamustine and rituximab has recently been approved for reimbursed frontline use in WM in Australia, other regimens, including ibrutinib- and bortezomib-based treatments, are not funded, requiring tailoring of treatment to the regional regulatory environment. The Medical and Scientific Advisory Group of the Myeloma Foundation Australia has therefore developed clinical practice guidelines with specific recommendations for the work-up and therapy of WM to assist Australian clinicians in the management of this disease.
Asunto(s)
Antineoplásicos/uso terapéutico , Inmunoglobulina M/sangre , Macroglobulinemia de Waldenström/tratamiento farmacológico , Adenina/análogos & derivados , Comités Consultivos , Australia , Clorhidrato de Bendamustina/uso terapéutico , Médula Ósea/patología , Bortezomib/uso terapéutico , Humanos , Mutación , Factor 88 de Diferenciación Mieloide/genética , Piperidinas , Células Plasmáticas/patología , Guías de Práctica Clínica como Asunto , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Rituximab/uso terapéutico , Sociedades Médicas , Macroglobulinemia de Waldenström/diagnósticoRESUMEN
BACKGROUND: Previous results from an interim analysis of an open-label, randomized, phase 3 study demonstrated that bortezomib combined with pegylated liposomal doxorubicin (PLD) was superior to bortezomib monotherapy in patients with relapsed/refractory multiple myeloma who had previously received one or more lines of therapy. Protocol-defined final survival data from that study are provided here. METHODS: Patients were randomized (1:1) to receive either bortezomib alone (1.3 mg/m(2) intravenously on days 1, 4, 8, and 11 of every 21-day cycle) or bortezomib-PLD (bortezomib plus PLD 30 mg/m(2) intravenously on day 4). The primary endpoint was the time to progression. Secondary efficacy endpoints included overall survival (OS), progression-free survival, and the overall response rate. RESULTS: In total, 646 patients (bortezomib-PLD, n = 324; bortezomib alone, n = 322) were randomized between December, 2004, and March, 2006. On the clinical cutoff date (May 16, 2014) for the final survival analysis, at a median follow-up of 103 months, 79% of patients had died (bortezomib-PLD group: 253 of 324 patients; 78%; bortezomib alone group: 257 of 322 patients; 80%). The median OS in the bortezomib-PLD group was 33 months (95% confidence interval [CI], 28.9-37.1) versus 30.8 months (95% CI, 25.2-36.5) in the bortezomib alone group (hazard ratio, 1.047; 95% CI, 0.879-1.246; P = .6068). Salvage therapies included conventional and novel drugs, which were well balanced between the two treatment groups. CONCLUSIONS: Despite inducing a superior time to progression, long-term follow-up revealed that PLD-bortezomib did not improve OS compared with bortezomib alone in patients with relapsed/refractory multiple myeloma. The inability to sustain the early observed survival advantage may have been caused by the effects of subsequent lines of therapy, and underscores the need for long-term follow-up of phase 3 trials while recognizing the challenge of having adequate power to detect long-term differences in OS. Cancer 2016;122:2050-6. © 2016 American Cancer Society.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Bortezomib/administración & dosificación , Doxorrubicina/análogos & derivados , Mieloma Múltiple/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Administración Intravenosa , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bortezomib/uso terapéutico , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Doxorrubicina/uso terapéutico , Esquema de Medicación , Femenino , Humanos , Masculino , Mieloma Múltiple/mortalidad , Polietilenglicoles/administración & dosificación , Polietilenglicoles/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND: Plasma cell dyscrasias (PCD) are a spectrum of disorders resulting from the clonal expansion of plasma cells, ranging from the pre-malignant condition monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM). MM generates a significant burden of disease on the community and it is predicted that it will increase in both incidence and prevalence owing to an ageing population and longer survival secondary to new therapeutic options. Robust and comprehensive clinical data are currently lacking but are required to define current diagnostic, investigational and management patterns in Australia and New Zealand (ANZ) for comparison to both local and international guidelines for standards of care. A clinical registry can provide this information and subsequently support development of strategies to address any differences, including providing a platform for clinical trials. The Myeloma and Related Diseases Registry (MRDR) was developed to monitor and explore variations in practices, processes and outcomes in ANZ and provide benchmark outcomes nationally and internationally for PCD. This paper describes the MRDR aims, development and implementation and discusses challenges encountered in the process. METHODS: The MRDR was established in 2012 as an online database for a multi-centre collaboration across ANZ, collecting prospective data on patients with a diagnosis of MGUS, MM, solitary plasmacytoma or plasma cell leukaemia. Development of the MRDR required multi-disciplinary team participation, IT and biostatistical support as well as financial resources. RESULTS: More than 1250 patients have been enrolled at 23 sites to date. Here we describe how database development, data entry and securing ethics approval have been major challenges for participating sites and the coordinating centre, and our approaches to resolving them. Now established, the MRDR will provide clinically relevant and credible monitoring, therapy and 'real world' outcome data, to support the conduction of high quality studies. In addition, the Myeloma 1000 sub-study is establishing a repository of paired peripheral blood specimens from registry patients to study mechanisms underlying disease progression. CONCLUSION: Establishment of the MRDR has been challenging, but it is a valuable investment that will provide a platform for coordinated national and international collaboration for clinical research in PCD in ANZ.
Asunto(s)
Bases de Datos Factuales/estadística & datos numéricos , Mieloma Múltiple/epidemiología , Paraproteinemias/epidemiología , Sistema de Registros/estadística & datos numéricos , Australia/epidemiología , Progresión de la Enfermedad , Humanos , Incidencia , Informática Médica/métodos , Informática Médica/estadística & datos numéricos , Nueva Zelanda/epidemiología , PrevalenciaRESUMEN
Increasing dose intensity (DI) of chemotherapy for patients with aggressive non-Hodgkin lymphoma (NHL) may improve outcomes at the cost of increased toxicity. This issue was addressed in a randomized trial aiming to double the DI of myelosuppressive drugs. Between 1994 and 1999, 250 patients with previously untreated aggressive NHL were randomized to treatment with six cycles of 3-weekly standard (s) or intensive (i) chemotherapy: s-CEOP-cyclophosphamide 750, epirubicin 75, vincristine 1.4 mg/m(2) all on day 1, and prednisolone 100 mg days 1-5; i-CEOP-cyclophosphamide 1,500, epirubicin 150, vincristine 1.4 mg/m(2) all on day 1, and prednisolone 100 mg days 1-5. Primary endpoint was 5-year overall survival (OS). Relative to s-CEOP patients, i-CEOP patients achieved a 78% increase in the DI of cyclophosphamide and epirubicin. Despite this, there was no significant difference in any outcome: 5-year OS (56.7% i-CEOP; 55.1% s-CEOP; P = 0.80), 5-year progression free survival (PFS; 41% i-CEOP; 43% s-CEOP; P = 0.73), 5-year time to progression (TTP; 44% i-CEOP; 47% s-CEOP; P = 0.72), or complete remission (CR) + unconfirmed CR (CRu) rates (53% i-CEOP; 59% s-CEOP; P = 0.64). Long-term follow up at 10 years also showed no significant differences in OS, PFS, or TTP. The i-CEOP arm had higher rates of febrile neutropenia (70 vs. 26%), hospitalisations, blood product utilisation, haematological and gastrointestinal toxicities, and lower quality of life scores during treatment, although without significant differences 6-month later. In the treatment of aggressive NHL in the prerituximab era, increasing DI did not result in improved outcomes, while at the same time lead to increased toxicity.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma no Hodgkin/tratamiento farmacológico , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Epirrubicina/administración & dosificación , Epirrubicina/efectos adversos , Femenino , Filgrastim , Estudios de Seguimiento , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Factor Estimulante de Colonias de Granulocitos/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Prednisona/administración & dosificación , Prednisona/efectos adversos , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Vincristina/administración & dosificación , Vincristina/efectos adversos , Adulto JovenRESUMEN
BACKGROUND AND PURPOSE: Renal impairment (RI) confers adverse prognosis in myeloma; its reversal and avoidance of dialysis are crucial. We investigated whether serum free light chain (SFLC) measurements can predict renal outcome, to enable change in therapy to optimize prognosis and avoid dialysis. PATIENTS AND METHODS: We investigated 36 myeloma patients (17 newly diagnosed [ND]; 19 relapsed refractory [RR]; with median of 5 prior lines) with eGFR 15-40 ml/min treated with carfilzomib (Cfz)-dexamethasone to determine whether SFLC kinetics can predict renal outcomes, and assess efficacy and tolerability. RESULTS: The change in involved SFLC at Cycle 2 Day 1 was significantly correlated with renal function; for every one log10 reduction in involved SFLC, eGFR increased by 9.0-15.0 mL/min at cycles 2-4, with SFLC reduction of 54%-78%. At a median follow-up of 30.6 months, renal outcomes were favorable-CRrenal 25%, MRrenal 36%. Disease responses (ND 100%, RR 75%), progression-free survival (ND 32.2 months, RR 11.1 months) and overall survival (ND not reached, RR 42.0 months) were comparable to patients without RI. There was significant toxicity, including Cfz-related cardiac impairment of 20% within a cohort with high co-morbidity, and a high incidence of infections. CONCLUSION: We propose that one log10 reduction in involved SFLC at Cycle 2 Day 1 is an appropriate target for reducing the risk of dialysis in myeloma patients with RI; below this threshold patients may benefit from a change in therapy. While Cfz-dexamethasone achieved favorable renal and disease outcomes, toxicity can be significant in this vulnerable cohort.
Asunto(s)
Dexametasona , Cadenas Ligeras de Inmunoglobulina , Mieloma Múltiple , Oligopéptidos , Humanos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/complicaciones , Dexametasona/uso terapéutico , Dexametasona/farmacología , Dexametasona/administración & dosificación , Masculino , Femenino , Anciano , Persona de Mediana Edad , Oligopéptidos/farmacología , Oligopéptidos/uso terapéutico , Oligopéptidos/administración & dosificación , Cadenas Ligeras de Inmunoglobulina/sangre , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Insuficiencia Renal/etiología , Insuficiencia Renal/complicaciones , Anciano de 80 o más Años , Adulto , PronósticoRESUMEN
ABSTRACT: In newly diagnosed transplant-ineligible patients with myeloma, daratumumab has improved outcomes when added to the standard-of-care regimens. In a randomized trial, we tested whether similar improvements would be observed when daratumumab was added to the bortezomib, cyclophosphamide, and dexamethasone (VCD) regimen. Transplant-ineligible patients with untreated myeloma were randomized to receive VCD or VCD plus daratumumab (VCDD). A total of 121 patients were randomized: 57 in the VCD arm and 64 in the VCDD arm. Baseline characteristics were balanced between the 2 arms. The median progression-free survival (PFS) was 16.8 months (95% confidence interval [CI], 15.3-21.7) and 25.8 months (95% CI, 19.9-33.5) in the VCD and VCDD arms, respectively (hazard ratio, 0.67; log-rank test P = .066). In a preplanned analysis, it was demonstrated that the daratumumab-containing arm showed a significant improvement in PFS from 18 months onward, based on estimates at fixed time points after randomization. The proportions of patients who were progression-free at the following time points were: 18 months, 48% vs 68% (P = .0002); 24 months, 36% vs 52% (P = .0001); and 30 months, 27% vs 41% (P < .0001) in the VCD and VCDD arms, respectively. The best overall response and very good partial response rate were significantly higher in the daratumumab arm compared with the VCD and VCDD arms, respectively (65% vs 86%, P = .007; and 28% vs 52%, P = .009). Seventy-two percent of the VCDD patients completed the 9 cycles of induction therapy with no grade 3 or 4 peripheral neuropathy adverse events. This study supports VCDD as an option for the initial treatment of transplant-ineligible patients with myeloma. This trial was registered at the Australian New Zealand Clinical Trials Registry (ACTRN12617000202369).
Asunto(s)
Anticuerpos Monoclonales , Protocolos de Quimioterapia Combinada Antineoplásica , Bortezomib , Ciclofosfamida , Dexametasona , Mieloma Múltiple , Humanos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/mortalidad , Bortezomib/uso terapéutico , Bortezomib/administración & dosificación , Ciclofosfamida/uso terapéutico , Ciclofosfamida/administración & dosificación , Dexametasona/uso terapéutico , Dexametasona/administración & dosificación , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Femenino , Anciano , Masculino , Persona de Mediana Edad , Anciano de 80 o más Años , Resultado del TratamientoRESUMEN
BACKGROUND: Lenalidomide is commonly used for treatment of multiple myeloma (MM) as well as other hematological disorders. Cutaneous adverse reactions occur frequently and withholding lenalidomide treatment may have implications for prognosis. OBJECTIVE: To evaluate the role of lenalidomide desensitization in patients with cutaneous adverse reactions. METHODS: A retrospective review of patients referred for lenalidomide desensitization between May 2019 and May 2022 at a tertiary hospital. All patients underwent a 6-week outpatient desensitization with premedication. RESULTS: There were 12 patients: 10 males and 2 females with a median age of 65 years. All had MM with autologous stem cell transplantation and lenalidomide 10 mg daily added for maintenance therapy. Most patients (n = 8) had a generalized maculopapular exanthem with or without pruritus. All patients had delayed cutaneous reactions; the median time to onset was 14 days (range 2-28 d). Six patients tolerated desensitization: 5 on the first attempt and 1 after 3 attempts and supplementary oral prednisolone. Four patients underwent multiple (≤3) attempts at desensitization owing to breakthrough symptoms. In patients who failed desensitization, recurrence of symptoms occurred variably, either early (within days), within weeks, or delayed by more than 1 month. CONCLUSIONS: Lenalidomide desensitization is worthwhile and allows continuation of treatment. In our MM cohort, lenalidomide desensitization was successful in only 50% of cases, including some cases in whom ongoing symptoms were mitigated by cotreatment with antihistamine.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Mieloma Múltiple , Masculino , Femenino , Humanos , Anciano , Lenalidomida/uso terapéutico , Lenalidomida/efectos adversos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante Autólogo , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/etiología , PielRESUMEN
BACKGROUND: Multiple myeloma, a malignancy of the antibody-secreting plasma cells, remains incurable by current therapy. However, the proteasome inhibitor bortezomib and other new drugs are revolutionizing its treatment. It remains unclear why myelomas are peculiarly sensitive to bortezomib, or what causes primary or acquired resistance. The 'unfolded protein response' is necessary for folding and assembly of immunoglobulin chains in both normal and malignant plasma cells, as well as for the disposal of incorrectly folded or unpaired chains via the ubiquitin-proteasome pathway. We tested the hypothesis that levels of transcription factor XBP-1, a major regulator of the unfolded protein response, predict response to bortezomib. DESIGN AND METHODS: Expression of XBP-1 and other regulators of the unfolded protein response were measured in myeloma and other cancer cell lines and two cohorts of patients with refractory myeloma and correlated with sensitivity/response to bortezomib. Bortezomib-resistant myeloma cell lines were derived and the effects on expression of unfolded protein response regulators, immunoglobulin secretion, proteasome activity and cross-resistance to cytotoxic drugs and tunicamycin determined. The consequences of manipulation of XBP-1 levels for sensitivity to bortezomib were tested. RESULTS: Low XBP-1 levels predicted poor response to bortezomib, both in vitro and in myeloma patients. Moreover, myeloma cell lines selected for resistance to bortezomib had down-regulated XBP-1 and immunoglobulin secretion. Expression of ATF6, another regulator of the unfolded protein response, also correlated with bortezomib sensitivity. Direct manipulation of XBP-1 levels had only modest effects on sensitivity to bortezomib, suggesting it is a surrogate marker of response to bortezomib rather than a target itself. CONCLUSIONS: The unfolded protein response may be a relevant target pathway for proteasome inhibitors in the treatment of myeloma and its regulator XBP-1 is a potential response marker. (The BIR study was registered with Australian Clinical Trial Registry Number 12605000770662).
Asunto(s)
Antineoplásicos , Ácidos Borónicos/uso terapéutico , Proteínas de Unión al ADN/genética , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/genética , Inhibidores de Proteasoma , Pirazinas/uso terapéutico , Factores de Transcripción/genética , Factor de Transcripción Activador 6/metabolismo , Adulto , Anciano , Bortezomib , Proteínas de Unión al ADN/metabolismo , Resistencia a Antineoplásicos/genética , Femenino , Células HEK293 , Células HeLa , Humanos , Inmunoglobulinas/biosíntesis , Células Jurkat , Masculino , Persona de Mediana Edad , Empalme del ARN , ARN Mensajero/genética , Factores de Transcripción del Factor Regulador X , Factores de Transcripción/metabolismo , Resultado del Tratamiento , Respuesta de Proteína Desplegada/efectos de los fármacos , Respuesta de Proteína Desplegada/genética , Proteína 1 de Unión a la X-BoxRESUMEN
BACKGROUND: Initial therapy for patients with acute promyelocytic leukemia most often involves the combination of all-trans-retinoic acid with anthracycline-based chemotherapy. The role of non-anthracycline drugs in induction and consolidation is less well-established and varies widely between different cooperative group protocols. DESIGN AND METHODS: In an attempt to minimize relapse and maximize survival for patients with newly diagnosed acute promyelocytic leukemia, the Australasian Leukaemia and Lymphoma Group utilized all-trans-retinoic acid and idarubicin as anti-leukemic therapy for both induction and consolidation. The protocol (known as APML3) was subsequently amended to incorporate maintenance with all-trans-retinoic acid, methotrexate and 6-mercaptopurine. RESULTS: Eight (8%) of 101 patients died within 30 days, and 91 (90%) achieved complete remission. With a median estimated potential follow-up of 4.6 years, 4-year overall survival was 84%, and 71% of the patients remained in remission at 4 years. The cumulative incidence of all relapses was 28.1%, with 15 of the 25 relapses initially identified as an isolated molecular relapse. Both FLT3 mutations (internal tandem duplications and codon 835/836 kinase domain mutations) and increased white cell count at diagnosis were associated with inferior overall survival, but in multivariate analyses only FLT3 mutations remained significant (hazard ratio 6.647, P=0.005). Maintenance therapy was significantly associated with improved remission duration (hazard ratio 0.281, P<0.001) and disease-free survival (hazard ratio 0.290, P<0.001). CONCLUSIONS: The combination of all-trans-retinoic acid and just two cycles of idarubicin followed by triple maintenance produced durable remissions in most patients, but patients with high-risk disease, especially those with FLT3 mutations, require additional agents or alternative treatment approaches. The significant reduction in relapse seen after the addition of maintenance to the protocol supports a role for maintenance in the context of relatively low chemotherapy exposure during consolidation. (actr.org.au identifier: ACTRN12607000410459).
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Quimioterapia de Consolidación/métodos , Quimioterapia de Inducción/métodos , Leucemia Promielocítica Aguda/tratamiento farmacológico , Leucemia Promielocítica Aguda/mortalidad , Adulto , Anciano , Femenino , Estudios de Seguimiento , Humanos , Idarrubicina/administración & dosificación , Masculino , Mercaptopurina/administración & dosificación , Persona de Mediana Edad , Tasa de Supervivencia , Tretinoina/administración & dosificación , Adulto JovenRESUMEN
PURPOSE: Multiple myeloma is an incurable disease with heterogeneous clinical behavior. Bortezomib has offered some patients with relapsed and refractory disease an opportunity for prolonged survival. However, there remains a paucity of data in patients treated with bortezomib that accurately delineates and identifies such patients. This information is crucial to guide management. EXPERIMENTAL DESIGN: In this study, we aimed to identify the patients most likely to respond to bortezomib salvage therapy. We analyzed the baseline clinical variables and profiled the baseline expression of a broad range of immunohistochemical markers of cell cycle activity, apoptosis, and angiogenesis in a large cohort of multiply relapsed myeloma patients recruited to one of two prospective multicentre trials assessing the efficacy of bortezomib salvage therapy. RESULTS: Using the European Group for Bone Marrow Transplantation criteria, response (complete or partial) to bortezomib salvage therapy was associated with a previous history of complete response to alternative antimyeloma treatment. Patients who expressed cyclin D1 were more likely to achieve a response. In contrast, patients who expressed p16(INK4A), cytoplasmic p53, and the highest intensity of Bcl-2 staining had a poor response. Patients who achieved a response to bortezomib and those patients who expressed cyclin D1 at baseline showed a significant survival advantage. Patients who expressed FGFR3, a poor prognostic marker, responded equally well and had similar outcomes with bortezomib compared with FGFR3-negative patients. CONCLUSIONS: Baseline clinical variables and selective immunohistochemical markers expressed by patients may be used effectively to identify patients that are most likely to achieve a meaningful clinical response to bortezomib salvage therapy.
Asunto(s)
Antineoplásicos/uso terapéutico , Ácidos Borónicos/uso terapéutico , Inmunohistoquímica/métodos , Mieloma Múltiple/tratamiento farmacológico , Pirazinas/uso terapéutico , Adulto , Anciano , Bortezomib , Ciclo Celular , Estudios de Cohortes , Ciclina D1/biosíntesis , Inhibidor p16 de la Quinasa Dependiente de Ciclina/biosíntesis , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Proteínas Proto-Oncogénicas c-bcl-2/biosíntesis , Resultado del Tratamiento , Proteína p53 Supresora de Tumor/biosíntesisRESUMEN
BACKGROUND: Multiple myeloma (MM) patients with high cytogenetic risk have poor outcomes. In CASTOR, daratumumab plus bortezomib/dexamethasone (D-Vd) prolonged progression-free survival (PFS) versus bortezomib/dexamethasone (Vd) alone and exhibited tolerability in patients with relapsed or refractory MM (RRMM). METHODS: This subgroup analysis evaluated D-Vd versus Vd in CASTOR based on cytogenetic risk, determined using fluorescence in situ hybridization and/or karyotype testing performed locally. High-risk patients had t(4;14), t(14;16), and/or del17p abnormalities. Minimal residual disease (MRD; 10-5 sensitivity threshold) was assessed via the clonoSEQ® assay V2.0. Of the 498 patients randomized, 40 (16%) in the D-Vd group and 35 (14%) in the Vd group were categorized as high risk. RESULTS: After a median follow-up of 40.0 months, D-Vd prolonged median PFS versus Vd in patients with standard (16.6 vs 6.6 months; HR, 0.26; 95% CI, 0.19-0.37; P < 0.0001) and high (12.6 vs 6.2 months; HR, 0.41; 95% CI, 0.21-0.83; P = 0.0106) cytogenetic risk. D-Vd achieved deep responses, including higher rates of MRD negativity and sustained MRD negativity versus Vd, regardless of cytogenetic risk. The safety profile was consistent with the overall population of CASTOR. CONCLUSION: These updated data reinforce the effectiveness and tolerability of daratumumab-based regimens for RRMM, regardless of cytogenetic risk status. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02136134 . Registered 12 May 2014.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Cariotipo Anormal , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/administración & dosificación , Bortezomib/administración & dosificación , Dexametasona/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Hibridación Fluorescente in Situ , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mieloma Múltiple/genética , Mieloma Múltiple/patología , Neoplasia Residual , Supervivencia sin Progresión , Recurrencia , RiesgoRESUMEN
RANKL is a key mediator of osteoclast differentiation, activation, and survival. Preclinical data suggest that aberrant production and activation of osteoclasts may influence proliferation of multiple myeloma (MM) cells in the bone marrow. Reports have also shown that inhibiting RANKL may have a direct effect on RANK-expressing myeloma cells and a therapeutic role in treating the disease. In mouse myeloma models, inhibition of RANKL led to reduced serum paraprotein levels and tumor burden. Based on this hypothesis, this proof-of-concept, single-arm study investigated whether RANKL inhibition with denosumab could reduce serum M-protein levels in relapsed or plateau-phase myeloma subjects. All subjects received denosumab monthly, with loading doses on days 8 and 15 of month one, until disease progression or subject discontinuation. Results of this ongoing study demonstrated that no subjects in either cohort met the protocol-defined objective response criteria of complete response (CR) or partial response (PR), but that denosumab effectively inhibited the RANKL pathway regardless of previous exposure to bisphosphonates, as evidenced by suppressed levels of the bone turnover marker, serum C-terminal telopeptide of type 1 collagen (sCTx). Eleven (21%) subjects who relapsed within 3 months before study entry maintained stable disease for up to 16.5 months. Nineteen (46%) subjects with plateau-phase myeloma maintained stable disease for up to 18.3 months. The adverse event (AE) profile for denosumab and its dosing schedule in these populations was consistent with that for advanced cancer patients receiving systemic therapy. Additional controlled clinical studies of denosumab in subjects with both relapsed and plateau-phase MM are warranted.