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BACKGROUND: Belantamab mafodotin had single-agent activity in patients with relapsed or refractory multiple myeloma, a finding that supports further evaluation of the agent in combination with standard-care therapies. METHODS: In this phase 3, open-label, randomized trial, we evaluated belantamab mafodotin, bortezomib, and dexamethasone (BVd), as compared with daratumumab, bortezomib, and dexamethasone (DVd), in patients who had progression of multiple myeloma after at least one line of therapy. The primary end point was progression-free survival. Key secondary end points were overall survival, response duration, and minimal residual disease (MRD)-negative status. RESULTS: In total, 494 patients were randomly assigned to receive BVd (243 patients) or DVd (251 patients). At a median follow-up of 28.2 months (range, 0.1 to 40.0), median progression-free survival was 36.6 months (95% confidence interval [CI], 28.4 to not reached) in the BVd group and 13.4 months (95% CI, 11.1 to 17.5) in the DVd group (hazard ratio for disease progression or death, 0.41; 95% CI, 0.31 to 0.53; P<0.001). Overall survival at 18 months was 84% in the BVd group and 73% in the DVd group. An analysis of the restricted mean response duration favored BVd over DVd (P<0.001). A complete response or better plus MRD-negative status occurred in 25% of the patients in the BVd group and 10% of those in the DVd group. Grade 3 or higher adverse events occurred in 95% of the patients in the BVd group and 78% of those in the DVd group. Ocular events were more common in the BVd group than in the DVd group (79% vs. 29%); such events were managed with dose modifications, and events of worsening visual acuity mostly resolved. CONCLUSIONS: As compared with DVd therapy, BVd therapy conferred a significant benefit with respect to progression-free survival among patients who had relapsed or refractory multiple myeloma after at least one line of therapy. Most patients had grade 3 or higher adverse events. (Funded by GSK; DREAMM-7 ClinicalTrials.gov number, NCT04246047; EudraCT number, 2018-003993-29.).
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Protocolos de Quimioterapia Combinada Antineoplásica , Bortezomib , Dexametasona , Mieloma Múltiple , Supervivencia sin Progresión , Humanos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/mortalidad , Bortezomib/efectos adversos , Bortezomib/administración & dosificación , Bortezomib/uso terapéutico , Dexametasona/efectos adversos , Dexametasona/uso terapéutico , Dexametasona/administración & dosificación , Masculino , Femenino , Persona de Mediana Edad , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Adulto , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/administración & dosificación , Neoplasia Residual , Estimación de Kaplan-Meier , Análisis de SupervivenciaRESUMEN
In this issue, the British Society for Haematology presents guidelines for the diagnosis and management of patients with smouldering multiple myeloma (SMM). The authors provide a practical, evidence-based approach to managing these patients. Key questions remain yet unsolved. Commentary on: Hughes et al. Diagnosis and management of smouldering myeloma: A British Society for Haematology Good Practice Paper. Br J Haematol 2024;204:1193-1206.
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Gammopatía Monoclonal de Relevancia Indeterminada , Mieloma Múltiple , Mieloma Múltiple Quiescente , Humanos , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/terapia , Gammopatía Monoclonal de Relevancia Indeterminada/diagnóstico , Mieloma Múltiple Quiescente/terapia , Progresión de la EnfermedadRESUMEN
BACKGROUND: Systemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38+ plasma cells. Daratumumab, a human CD38-targeting antibody, may improve outcomes for this disease. METHODS: We randomly assigned patients with newly diagnosed AL amyloidosis to receive six cycles of bortezomib, cyclophosphamide, and dexamethasone either alone (control group) or with subcutaneous daratumumab followed by single-agent daratumumab every 4 weeks for up to 24 cycles (daratumumab group). The primary end point was a hematologic complete response. RESULTS: A total of 388 patients underwent randomization. The median follow-up was 11.4 months. The percentage of patients who had a hematologic complete response was significantly higher in the daratumumab group than in the control group (53.3% vs. 18.1%) (relative risk ratio, 2.9; 95% confidence interval [CI], 2.1 to 4.1; P<0.001). Survival free from major organ deterioration or hematologic progression favored the daratumumab group (hazard ratio for major organ deterioration, hematologic progression, or death, 0.58; 95% CI, 0.36 to 0.93; P = 0.02). At 6 months, more cardiac and renal responses occurred in the daratumumab group than in the control group (41.5% vs. 22.2% and 53.0% vs. 23.9%, respectively). The four most common grade 3 or 4 adverse events were lymphopenia (13.0% in the daratumumab group and 10.1% in the control group), pneumonia (7.8% and 4.3%, respectively), cardiac failure (6.2% and 4.8%), and diarrhea (5.7% and 3.7%). Systemic administration-related reactions to daratumumab occurred in 7.3% of the patients. A total of 56 patients died (27 in the daratumumab group and 29 in the control group), most due to amyloidosis-related cardiomyopathy. CONCLUSIONS: Among patients with newly diagnosed AL amyloidosis, the addition of daratumumab to bortezomib, cyclophosphamide, and dexamethasone was associated with higher frequencies of hematologic complete response and survival free from major organ deterioration or hematologic progression. (Funded by Janssen Research and Development; ANDROMEDA ClinicalTrials.gov number, NCT03201965.).
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Anticuerpos Monoclonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bortezomib/administración & dosificación , Ciclofosfamida/administración & dosificación , Dexametasona/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Humanos , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/mortalidad , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
Systemic light chain amyloidosis (AL) is a clonal plasma cell disorder characterized by the deposition of misfolded immunoglobulin light chains (LC) as insoluble fibrils in organs. The lack of suitable models has hindered the investigation of the disease mechanisms. Our aim was to establish AL LC-producing plasma cell lines and use them to investigate the biology of the amyloidogenic clone. We used lentiviral vectors to generate cell lines expressing LC from patients suffering from AL amyloidosis. The AL LC-producing cell lines showed a significant decrease in proliferation, cell cycle arrest, and an increase in apoptosis and autophagy as compared with the multiple myeloma LC-producing cells. According to the results of RNA sequencing the AL LC-producing lines showed higher mitochondrial oxidative stress, and decreased activity of the Myc and cholesterol pathways. The neoplastic behavior of plasma cells is altered by the constitutive expression of amyloidogenic LC causing intracellular toxicity. This observation may explain the disparity in the malignant behavior of the amyloid clone compared to the myeloma clone. These findings should enable future in vitro studies and help delineate the unique cellular pathways of AL, thus expediting the development of specific treatments for patients with this disorder.
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Amiloidosis , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas , Mieloma Múltiple , Humanos , Células Plasmáticas/patología , Supervivencia Celular , Amiloidosis/genética , Amiloidosis/metabolismo , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/genética , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/patología , Amiloide/metabolismo , Cadenas Ligeras de Inmunoglobulina/genética , Cadenas Ligeras de Inmunoglobulina/metabolismo , Mieloma Múltiple/patologíaRESUMEN
Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CAR T) therapy shows remarkable efficacy in patients with relapsed and/or refractory (R/R) multiple myeloma (MM). HBI0101, a novel second generation optimized anti- BCMA CAR T-cell therapy, was developed in an academic setting. We conducted a phase I dose-escalation study of HBI0101 (cohort 1: 150x106 CAR T cells, n=6; cohort 2: 450x106 CAR T cells, n=7; cohort 3: 800x106 CAR T cells, n=7) in 20 heavily pre-treated R/R MM patients. Grade 1-2 cytokine release syndrome (CRS) was reported in 18 patients (90%). Neither grade 3-4 CRS nor neurotoxicity of any grade were observed. No dose-limiting toxicities were observed in any cohort. The overall response rate (ORR), (stringent) complete response (CR/sCR), and very good partial response rates were 75%, 50%, and 25%, respectively. Response rates were dose-dependent with 85% ORR, 71% CR, and 57% minimal residual disease negativity in the high-dose cohort 3. Across all cohorts, the median overall survival (OS) was 308 days (range 25-466+), with an estimated OS of 55% as of June 27th (data cut-off). The median progression-free survival was 160 days, with 6 subjects remaining progression free at the time of data cut-off. Our findings demonstrate the manageable safety profile and efficacy of HBI0101. These encouraging data support the decentralization of CAR T production in an academic setting, ensuring sufficient CAR T supply to satisfy the increasing local demand. Clinicaltrials.gov NCT04720313.
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Mieloma Múltiple , Receptores Quiméricos de Antígenos , Humanos , Mieloma Múltiple/tratamiento farmacológico , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Linfocitos T , AnticuerposRESUMEN
INTRODUCTION AND OBJECTIVES: Lenalidomide is considered a standard of care in multiple myeloma (MM) Some MM patients will develop delayed hypersensitivity to lenalidomide, which can lead to treatment discontinuation. Desensitization to lenalidomide can help these patients to complete treatment courses. Here, we aimed to review lenalidomide-treated MM patients who developed delayed hypersensitivity-induced rash and were treated with desensitization. METHODS: A retrospective analysis of medical files of MM patients, who were desensitized to lenalidomide due to delayed hypersensitivity rash. Patients were treated between 2018 and 2022 at Hadassah Medical Center, Jerusalem, Israel. RESULTS: Search of patients yielded 16 patients that underwent desensitization to lenalidomide within the study period. The desensitization protocol consisted of a slow, 3-week-long protocol with lenalidomide's target doses of 10, 15, and 25 mg/day. Of the 16 patients, 10 (62.5%) succeeded to complete the protocol and thus were able to complete lenalidomide treatment cycles. One patient with unsuccessful desensitization was subsequently treated with first-generation IMiD thalidomide, with no rash appearing. None of the patients that were treated with desensitization had severe immune-mediated or non-dermatological adverse reactions. CONCLUSIONS: Desensitization to lenalidomide is safe and effective. Discontinuation of lenalidomide in MM patients with delayed hypersensitivity and no contraindication to desensitization should be discouraged. Collaboration between hematologists and allergists is needed.
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Exantema , Hipersensibilidad Tardía , Mieloma Múltiple , Humanos , Lenalidomida/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Estudios Retrospectivos , Exantema/inducido químicamente , Exantema/terapia , Hipersensibilidad Tardía/inducido químicamente , Hipersensibilidad Tardía/terapiaRESUMEN
Chimeric antigen receptor (CAR) T-cell based immunotherapy has become a promising treatment mainly for hematological malignancies. Following the major success of CD19-targeted CAR, new potential targets for other malignancies are required. As such, B-cell maturation antigen (BCMA) is an attractive tumor-associated antigen to be targeted in multiple myeloma (MM). Herein, we aimed at assessing the function and optimal configuration of different BCMA-specific CAR, based on the same targeting moiety but with a different hinge and co-stimulatory domain. We compared their function to that of a previously characterized BCMA-CAR used in clinical trials. All constructs were expressed at high levels by primary human T cells and could trigger cytokine production and cytotoxicity upon co-culture with multiple myeloma targets. Nonetheless, critical differences were observed in off-target activation, exhaustion, and activation marker expression and in vivo antitumoral activity mediated by these different constructs. Interestingly, we noted that CD8-based hinge, combined with a 4-1BB intracellular domain, proved superior compared to IgG4-connecting regions, and/or a CD28-signaling moiety respectively. Overall, this study emphasizes the influence of CAR primary structure on its function and led to the identification of a highly efficient BCMA-specific CAR, namely H8BB, which displayed superior anti-tumoral activity both in vitro and long-term in vivo efficacy.
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Mieloma Múltiple , Receptores Quiméricos de Antígenos , Antígeno de Maduración de Linfocitos B/metabolismo , Antígenos CD28 , Citocinas , Humanos , Inmunoglobulina G , Inmunoterapia Adoptiva , Mieloma Múltiple/patologíaRESUMEN
INTRODUCTION: Mutated RUNX1 is considered a poor prognostic factor and usually is mutually exclusive with NPM1 mutations. Monitoring of molecular markers for minimal residual disease provides a powerful tool to assess remission and guide clinical decisions. METHODS: Newly diagnosed RUNX1-mutated AML patients, designated to intensive chemotherapy-based treatment or nonintensive regimens, were monitored for mutated RUNX1 transcript levels by qPCR with patient-specific primers. Samples were obtained along the treatment course and follow-up. RESULTS: A clear correlation was observed between mutated RUNX1 levels and response to treatment as observed by flow cytometry and STR-based assessment. CONCLUSION: We demonstrate the feasibility of RUNX1-based MRD to correlate with the clinicopathological status of leukemia. We further suggest how RUNX1 qPCR monitoring can influence clinical decision-making and contribute to improved personalized patient care.
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Subunidad alfa 2 del Factor de Unión al Sitio Principal , Leucemia Mieloide Aguda , Humanos , Neoplasia Residual/diagnóstico , Neoplasia Residual/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Citometría de Flujo , Reacción en Cadena en Tiempo Real de la Polimerasa , Pronóstico , MutaciónRESUMEN
BACKGROUND: Selinexor combined with dexamethasone has shown activity in patients with heavily pre-treated multiple myeloma. In a phase 1b/2 study, the combination of oral selinexor with bortezomib (a proteasome inhibitor) and dexamethasone induced high response rates with low rates of peripheral neuropathy, the main dose-limiting toxicity of bortezomib. We aimed to evaluate the clinical benefit of weekly selinexor, bortezomib, and dexamethasone versus standard bortezomib and dexamethasone in patients with previously treated multiple myeloma. METHODS: This phase 3, randomised, open-label trial was done at 123 sites in 21 countries. Patients aged 18 years or older, who had multiple myeloma, and who had previously been treated with one to three lines of therapy, including proteasome inhibitors, were randomly allocated (1:1) to receive selinexor (100 mg once per week), bortezomib (1·3 mg/m2 once per week), and dexamethasone (20 mg twice per week), or bortezomib (1·3 mg/m2 twice per week for the first 24 weeks and once per week thereafter) and dexamethasone (20 mg four times per week for the first 24 weeks and twice per week thereafter). Randomisation was done using interactive response technology and stratified by previous proteasome inhibitor therapy, lines of treatment, and multiple myeloma stage. The primary endpoint was progression-free survival in the intention-to-treat population. Patients who received at least one dose of study treatment were included in the safety population. This trial is registered at ClinicalTrials.gov, NCT03110562. The trial is ongoing, with 55 patients remaining on randomised therapy as of Feb 20, 2020. FINDINGS: Of 457 patients screened for eligibility, 402 were randomly allocated-195 (49%) to the selinexor, bortezomib, and dexamethasone group and 207 (51%) to the bortezomib and dexamethasone group-and the first dose of study medication was given between June 6, 2017, and Feb 5, 2019. Median follow-up durations were 13·2 months [IQR 6·2-19·8] for the selinexor, bortezomib, and dexamethasone group and 16·5 months [9·4-19·8] for the bortezomib and dexamethasone group. Median progression-free survival was 13·93 months (95% CI 11·73-not evaluable) with selinexor, bortezomib, and dexamethasone and 9·46 months (8·11-10·78) with bortezomib and dexamethasone (hazard ratio 0·70 [95% CI 0·53-0·93], p=0·0075). The most frequent grade 3-4 adverse events were thrombocytopenia (77 [39%] of 195 patients in the selinexor, bortezomib, and dexamethasone group vs 35 [17%] of 204 in the bortezomib and dexamethasone group), fatigue (26 [13%] vs two [1%]), anaemia (31 [16%] vs 20 [10%]), and pneumonia (22 [11%] vs 22 [11%]). Peripheral neuropathy of grade 2 or above was less frequent with selinexor, bortezomib, and dexamethasone (41 [21%] patients) than with bortezomib and dexamethasone (70 [34%] patients; odds ratio 0·50 [95% CI 0·32-0·79], p=0·0013). 47 (24%) patients in the selinexor, bortezomib, and dexamethasone group and 62 (30%) in the bortezomib and dexamethasone group died. INTERPRETATION: A once-per-week regimen of selinexor, bortezomib, and dexamethasone is a novel, effective, and convenient treatment option for patients with multiple myeloma who have received one to three previous lines of therapy. FUNDING: Karyopharm Therapeutics.
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Antineoplásicos/administración & dosificación , Bortezomib/administración & dosificación , Dexametasona/administración & dosificación , Hidrazinas/administración & dosificación , Mieloma Múltiple/tratamiento farmacológico , Triazoles/administración & dosificación , Adolescente , Adulto , Anciano , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bortezomib/efectos adversos , Dexametasona/efectos adversos , Esquema de Medicación , Femenino , Humanos , Hidrazinas/efectos adversos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Supervivencia sin Progresión , Triazoles/efectos adversosRESUMEN
BACKGROUND: Lymphoma of the nervous system is rare and usually involves the brain, spinal cord, or peripheral nerves. Hence, it has varied clinical presentations, and correct diagnosis is often challenging. Incorrect diagnosis delays the appropriate treatment and affects prognosis. We report 5 patients with delayed diagnosis of lymphoma involving the central and/or peripheral nervous system, initially evaluated for other neurological diagnoses. We also discuss the challenge of diagnosis and appropriate testing. METHODS: Retrospective review of 2011-2019 records of patients with confirmed nervous system lymphoma diagnosed in a tertiary care medical center. RESULTS: We present 5 adult patients initially evaluated for inflammatory myelopathy, inflammatory lumbosacral plexopathy, atypical parkinsonism, and demyelinating disease of the CNS. Final diagnosis of the nervous system lymphoma was delayed by 4 to 18 months and was based on tissue biopsy in 4, and on CSF and bone marrow examination in 1 patient. CONCLUSIONS: Lymphoma may imitate various central and peripheral nervous system disorders. We suggest several red flags that indicate the need to consider lymphoma, including subacute but progressive symptomatic evolution, painful neurological deficit, unclear clinical diagnosis, and transient steroid responsiveness. Correct diagnosis often requires a combination of diagnostic tests, while pathology testing is crucial for early diagnosis and is strongly recommended in the appropriate clinical setting.
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Linfoma , Adulto , Encéfalo , Errores Diagnósticos , Humanos , Linfoma/diagnóstico , Estudios Retrospectivos , Médula EspinalRESUMEN
Ixazomib, the first oral proteasome inhibitor (PI), has been approved for the treatment of relapsed refractory multiple myeloma (RRMM) in combination with lenalidomide and dexamethasone, based on the TOURMALINE-MM1 phase 3 trial, which demonstrated the efficacy and safety of this all-oral triplet, compared with lenalidomide-dexamethasone. However, clinical trial outcomes do not always translate into real-world outcomes. The aim of this study was to assess the outcomes of ixazomib-based combination for treatment of patients with RRMM in a real-world setting. All consecutive RRMM patients who received at least one cycle of ixazomib-based treatment combination between June 2013 and June 2018 were identified. Data was extracted from medical charts focusing on demographics, disease characteristics, prior treatment, and responses. Primary endpoint was progression-free survival (PFS); secondary endpoints included overall response rate (ORR), overall survival (OS), safety, and tolerability. A total of 78 patients across 7 sites were retrospectively included. Median follow-up was 22 months. Median age was 68 (range 38-90). Sixty-four percent received ixazomib in 2nd line, 19% in 3rd line. Overall, 89% of patients had been exposed to PIs (bortezomib 87%) prior to IRd, 41% to IMiDs. Twenty-nine (48%, of 60 available) had high (t(4:14), t(14:16), del17p) or intermediate (+1q21) risk aberrations. Most patients (82%) received ixazomib in combination with lenalidomide and dexamethasone. An exploratory assessment for disease aggressiveness at diagnosis was classified by a treating physician as indolent (rapid control to protect from target organ damage not required) vs aggressive (imminent target organ damage) in 63% vs 37%, respectively. Treatment was well tolerated, with a low discontinuation rate (11%). Median PFS on ixazomib therapy was 24 months (95% CI 17-30). PFS was 77% and 47% at 12 and 24 months, respectively. Median OS was not reached; OS was 91% and 80% at 12 and 24 months, respectively. Higher LDH, older age, and worse clinical aggressiveness were associated with worse PFS, whereas a deeper response to ixazomib (≥ VGPR) and a longer response to first-line bortezomib (≥ 24 m) were associated with an improved PFS on ixazomib. No effect on PFS was found for cytogenetic risk by FISH, ISS/rISS, and prior anti-myeloma treatment. Ixazomib-based combinations are efficacious and safe regimens in RRMM patients in the real-world setting, regardless to cytogenetic risk, with a PFS of 24 months comparable with clinical trial data. This regimen had most favorable outcomes among patients who remained progression-free more than 24 months after a bortezomib induction and for those who have a more indolent disease phenotype.
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Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Compuestos de Boro/administración & dosificación , Glicina/análogos & derivados , Mieloma Múltiple/tratamiento farmacológico , Ensayos Clínicos Pragmáticos como Asunto/métodos , Sistema de Registros , Adulto , Anciano , Anciano de 80 o más Años , Análisis de Datos , Femenino , Estudios de Seguimiento , Glicina/administración & dosificación , Humanos , Israel/epidemiología , Masculino , Persona de Mediana Edad , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/epidemiología , Ensayos Clínicos Pragmáticos como Asunto/estadística & datos numéricos , Recurrencia , Resultado del TratamientoRESUMEN
Overt central nervous system (CNS) involvement in aggressive non-Hodgkin's lymphoma (NHL) is rare at diagnosis. Much effort is put to identify risk factors for occult CNS involvement, and the risk assessment of CNS relapse. Prophylactic treatment carries risk of adverse events and its efficacy is not clear. Detection of cerebrospinal fluid molecular gene rearrangement (GRR) as a method to detect occult disease has been studied in acute leukemia and primary CNS lymphoma. To date, the capacity of a positive GRR in newly diagnosed NHL patients to predict CNS relapse has not been addressed. We retrospectively studied the prognostic value of GRR in cerebrospinal fluid samples of 148 newly diagnosed patients with high grade NHL. We demonstrate that positive GRR at diagnosis does not affect PFS or OS and did not predict CNS relapse. However, although numbers were small, repeated positive samples (≥ 2) correlated with a higher risk for CNS relapse (p = 0.048), possibly stressing the need for an aggressive preventive approach.
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Neoplasias del Sistema Nervioso Central , Reordenamiento Génico , Linfoma no Hodgkin , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias del Sistema Nervioso Central/diagnóstico , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/patología , Femenino , Humanos , Linfoma no Hodgkin/diagnóstico , Linfoma no Hodgkin/genética , Linfoma no Hodgkin/patología , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
BACKGROUND: The treatment of relapsed/refractory (R/R) peripheral T cell lymphoma (PTCL) is limited to a few agents. Romidepsin, a histone deacetylase inhibitor, was approved for PTCL treatment as a single agent in the R/R setting, yet with partial efficacy. Several attempts to combine romidepsin with other chemotherapy regimens have been reported, however, with significant toxicity. OBJECTIVES: To study the romidepsin-bendamustine combination in PTCL in an attempt to maximize efficacy while minimizing toxicity. METHODS: We report on a series of 7 heavily pretreated PTCL patients (2-5 previous lines of therapy) treated with a romidepsin-bendamustine combination. RESULTS: Four patients were not previously exposed to either drug. Of these, 2 achieved complete remission. Interestingly, 1 patient continued treatment with a prolonged progression-free survival of more than 4 years. Toxicity was minimal and no treatment-related deaths or discontinuation were noted. Significant nausea and vomiting were reported in over 50% of patients. Hematological toxicity was mild and lower than that reported for other romidepsin-chemotherapy combinations and was correlated with bone marrow involvement by lymphoma. CONCLUSIONS: Although reporting a small number of patients, our data suggest that the combination of romidepsin and bendamustine may be a feasible therapeutic option in R/R PTCL patients and merits further study.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Linfoma de Células T/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Clorhidrato de Bendamustina/administración & dosificación , Clorhidrato de Bendamustina/efectos adversos , Depsipéptidos/administración & dosificación , Depsipéptidos/efectos adversos , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Linfoma de Células T/mortalidad , Linfoma de Células T/patología , Masculino , Persona de Mediana Edad , Recurrencia , Tasa de SupervivenciaRESUMEN
The discrimination between benign and malignant forms of plasma cell dyscrasia (PCD) is often difficult. Free light chain monomer-dimer pattern analysis (FLC-MDPA) may assist in solving this dilemma and distinguish between AL amyloidosis and benign PCD. Serum samples of patients with AL amyloidosis and benign PCD were analysed in a blinded manner. Quantitative Western blotting was performed to estimate dimerization and clonality indices, and thereby determine the source of the tested samples, as derived either from benign or malignant PCD. The findings obtained by the FLC-MDPA were compared with the actual diagnosis. Of 37 samples from patients with active AL amyloidosis, 34 (91·9%) fulfilled dimerization criteria for diagnosis of AL amyloidosis. Of the 45 samples from patients with benign PCD, 10 (21·2%) tested falsely positive or gave an inconclusive result. Thus, the sensitivity of the analysis was 92·5% with a remarkable negative predictive value of 91·9%. In addition, of 20 patients who were in complete or very good partial remission, only one tested positive. By multivariate analysis, FLC-MDPA was the best independent marker predicting AL amyloidosis (odds ratio of 84). The FLC-MDPA offers a highly effective tool in the diagnostic assessment of patients with PCD.
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Cadenas Ligeras de Inmunoglobulina/sangre , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/diagnóstico , Paraproteinemias/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Algoritmos , Biomarcadores/sangre , Biomarcadores/química , Western Blotting , Diagnóstico Diferencial , Dimerización , Reacciones Falso Positivas , Femenino , Humanos , Cadenas Ligeras de Inmunoglobulina/química , Masculino , Persona de Mediana Edad , Gammopatía Monoclonal de Relevancia Indeterminada/diagnóstico , Sensibilidad y Especificidad , Método Simple CiegoRESUMEN
OBJECTIVE: Daratumumab is a promising new antimyeloma agent. We report a single center "real-world" series of multiple myeloma (MM) and amyloidosis (AL) patients treated with daratumumab. METHODS: Forty-one patients were included: 7 second-line MM, 30 heavily pretreated (median number of therapies of 5) advanced MM, and 4 with AL. RESULTS: Second-line patients and advanced AL showed high rate of durable overall responses. However, advanced MM patients had a dismal prognosis with an overall response rate (ORR) of 36%, and a short median progression-free and overall survival of 2.3 and 6.6 months, respectively. Responses were particularly poor in patients with extramedullary plasmacytomas. Neither the addition of another agent to daratumumab nor changing to the next line of therapy produced significant durable responses in this patient population. Flow cytometry analysis demonstrated that CD38 expression level was not predictive of response. We show that CD38 expression dynamics by a commercially available anti-CD38 antibody after daratumumab administration was hindered by competitive binding of daratumumab. CONCLUSIONS: Responses to daratumumab and combinations in patients with advanced MM, particularly with extramedullary disease, are low and short-lived, stressing the administration of this agent should be early in the course of the disease.
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ADP-Ribosil Ciclasa 1/metabolismo , Amiloidosis/tratamiento farmacológico , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/metabolismo , Anciano , Amiloidosis/etiología , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Resistencia a Antineoplásicos , Femenino , Humanos , Inmunoglobulinas/metabolismo , Masculino , Persona de Mediana Edad , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/mortalidad , Estadificación de Neoplasias , Pronóstico , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Del17p is a genomic imbalance occurring in â¼7%-10% of myeloma at diagnosis newly diagnosed myeloma patients (NDMM) and comprises a poor prognostic factor. The goal of this study is to analyze real world data and outcomes among NDMM patients carrying 17p deletion. We report an observational, retrospective, multicenter study. Sixty consecutive patients diagnosed with multiple myeloma in the 8 participating centers diagnosed between 1/2008 and 1/2016 proven to carry 17p deletion by means of fluorescence in situ hybridization (FISH) were identified. Most received a bortezomib-based induction, over half underwent autologous hematopoietic cell transplantation (HCT); 30% of the patients gained early access to new novel agents via clinical trials, access programs or private insurance. Overall response rate (ORR) after induction was 85%; 94% for transplant eligible (TE); and 75% for transplant ineligible (NTE), and declined in subsequent treatment lines, 64% achieved ≥ VGPR. Median overall survival (OS) was 43 months; median progression free survival (PFS) was 11 months, 19 months for TE and 7 for NTE. In multivariate analysis: higher M-Spike, presence of extramedullary disease, and >50% of cells baring del17p were associated with adverse PFS; Autologous HCT and higher hemoglobin were associated with longer PFS; OS was 59 months for patients with early access to newer agents. Older age and higher M-Spike levels were associated with adverse OS, Autologous HCT was associated with favorable OS, 59.7 vs 28.7 months for NTE patients. Despite the improvement achieved with autologous HCT and new novel agents, the prognosis of patients with 17p deletion is still inferior, emphasizing the need for novel approaches.
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Cromosomas Humanos Par 17/genética , Eliminación de Gen , Mieloma Múltiple/genética , Mieloma Múltiple/terapia , Adulto , Anciano , Femenino , Trasplante de Células Madre Hematopoyéticas , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/mortalidad , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Análisis de Supervivencia , Trasplante Autólogo , Resultado del TratamientoRESUMEN
The treatment of relapsed/refractory acute lymphoblastic leukemia (RR-ALL) presents a true clinical challenge. In 2012, a protocol combining bortezomib, dexamethasone, asparaginase, doxorubicin, and vincristine administered to children with RR-ALL was published with encouraging results. Over the past 5 years, we have implemented this protocol in the adult RR-ALL population (> 18 years) and addressed its feasibility in terms of remission rate and toxicity. Here, we present the results of our experience in 9 patients, all of whom received multiple previous chemotherapy protocols, two of them relapsing after an allogeneic bone marrow transplantation. All of the five B-ALL patients, and two of the four T-ALL achieved complete remission. Of the seven patients achieving complete remission, two patients were referred for allogeneic bone marrow transplantation, two patients were subsequently given blinatumomab, and one patient subsequently received donor lymphocyte infusion followed by blinatumomab. Thus, five out of nine patients treated (55%) were able to proceed to best available therapy in a complete remission. We observed minimal adverse effects, mainly hematological toxicity. We conclude that the bortezomib-based protocol should be evaluated as an effective and well-tolerated treatment option for adult patients either unfit for or failing standard salvage chemotherapy, as a bridge to immunotherapy or allogeneic bone marrow transplantation.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bortezomib/administración & dosificación , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anticuerpos Biespecíficos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Trasplante de Médula Ósea , Bortezomib/efectos adversos , Neutropenia Febril/etiología , Humanos , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Recurrencia , Inducción de Remisión , Estudios RetrospectivosRESUMEN
Multiple myeloma (MM) and primary systemic light chain amyloidosis (AL) are both chronic plasma cell dyscrasias with different clinical expression but limited treatment options for relapsed refractory disease. We report the effect of the addition of clarithromycin on 31 MM and 17 AL with relapsed or refractory disease who had an insufficient response or disease progression while on an IMiD based therapy. In this high risk population, hematological response was reported in 48% of MM patients and 94% of AL patients. Responses were reported early in both groups (median 35 days) and were more sustained in AL patients. Adverse events were common and included mostly grade 1-2 fatigue, infections and abdominal discomfort. Cytopenias were common and cardiac complications were rare in both MM and AL patients. Clarithromycin-IMiD combination therapy appears to be both effective and safe in progressive MM and primarily in AL patients, although a prospective clinical trial is warranted to validate these results. Am. J. Hematol. 92:131-135, 2017. © 2016 Wiley Periodicals, Inc.
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Amiloidosis/tratamiento farmacológico , Claritromicina/farmacología , Mieloma Múltiple/tratamiento farmacológico , Terapia Recuperativa/métodos , Adulto , Anciano , Amiloidosis/complicaciones , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Claritromicina/administración & dosificación , Progresión de la Enfermedad , Fatiga/inducido químicamente , Femenino , Humanos , Cadenas Ligeras de Inmunoglobulina , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas , Infecciones/inducido químicamente , Masculino , Persona de Mediana Edad , Mieloma Múltiple/complicaciones , Inhibidores de la Síntesis de la Proteína/uso terapéutico , Recurrencia , Terapia Recuperativa/efectos adversos , Resultado del TratamientoRESUMEN
Carfilzomib has been established in previous years as a treatment for patients with relapsed and/or refractory multiple myeloma (RR-MM). A retrospective multicentre study to evaluate the clinical use of carfilzomib for RR-MM outside of a clinical trial setting was conducted by our group. One hundred and thirty-five patients were included. All patients had been previously exposed to bortezomib and 93% had also been treated with lenalidomide. The vast majority of patients received carfilzomib as part of a two- or three-drug combination. The overall response rate was 47·2%. Multivariate analysis revealed bortezomib resistance, lenalidomide resistance and albumin <35 g/l to negatively impact the likelihood of achieving response. The median duration of response was 8·4 months, and was significantly higher in patients receiving three-drug combination and patients presenting without extramedullary disease. The median progression-free survival and overall survival for the entire cohort was 4·9 months (95% confidence interval [CI] 3·8-6·4) and 12·2 months (95% CI 9-not reached), respectively. Toxicity was manageable, although treatment-related death was seen in 5% of patients. In the setting of progressive multiple myeloma, carfilzomib in a combination regimens yields effective results with a manageable toxicity.