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1.
Int J Mol Sci ; 25(14)2024 Jul 16.
Artículo en Inglés | MEDLINE | ID: mdl-39063038

RESUMEN

This study investigates the association between circulating microRNA (miRNA) expression and cardiovascular adverse events (CVAE) in multiple myeloma (MM) patients treated with a carfilzomib (CFZ)-based regimen. A cohort of 60 MM patients from the Prospective Observation of Cardiac Safety with Proteasome Inhibitor (PROTECT) study was analyzed. Among these, 31 patients (51.6%) developed CVAE post-CFZ treatment. The Taqman OpenArray Human microRNA panels were used for miRNA profiling. We identified 13 differentially expressed miRNAs at baseline, with higher expressions of miR-125a-5p, miR-15a-5p, miR-18a-3p, and miR-152-3p and lower expression of miR-140-3p in patients who later developed CVAE compared to those free of CVAE, adjusting for age, gender, race, and higher B-type natriuretic peptide levels. We also identified three miRNAs, including miR-150-5p, that were differentially expressed in patients with and without CVAE post-treatment. Additionally, five miRNAs responded differently to CFZ treatment in CVAE vs. non-CVAE patients, including significantly elevated post-treatment expression of miR-140-3p and lower expressions of miR-598, miR-152, miR-21, and miR-323a in CVAE patients. Pathway enrichment analysis highlighted the involvement of these miRNAs in cardiovascular diseases and vascular processes. These findings suggest that specific miRNAs could serve as predictive biomarkers for CVAE and provide insights into the underlying mechanisms of CFZ-CVAE. Further investigation is warranted before these findings can be applied in clinical settings.


Asunto(s)
Enfermedades Cardiovasculares , MicroARN Circulante , Mieloma Múltiple , Oligopéptidos , Humanos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/genética , Mieloma Múltiple/sangre , Masculino , Femenino , Oligopéptidos/efectos adversos , Anciano , Persona de Mediana Edad , MicroARN Circulante/sangre , MicroARN Circulante/genética , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/inducido químicamente , Enfermedades Cardiovasculares/sangre , MicroARNs/genética , MicroARNs/sangre , Estudios Prospectivos , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos
2.
N Engl J Med ; 381(8): 727-738, 2019 08 22.
Artículo en Inglés | MEDLINE | ID: mdl-31433920

RESUMEN

BACKGROUND: Selinexor, a selective inhibitor of nuclear export compound that blocks exportin 1 (XPO1) and forces nuclear accumulation and activation of tumor suppressor proteins, inhibits nuclear factor κB, and reduces oncoprotein messenger RNA translation, is a potential novel treatment for myeloma that is refractory to current therapeutic options. METHODS: We administered oral selinexor (80 mg) plus dexamethasone (20 mg) twice weekly to patients with myeloma who had previous exposure to bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, and an alkylating agent and had disease refractory to at least one proteasome inhibitor, one immunomodulatory agent, and daratumumab (triple-class refractory). The primary end point was overall response, defined as a partial response or better, with response assessed by an independent review committee. Clinical benefit, defined as a minimal response or better, was a secondary end point. RESULTS: A total of 122 patients in the United States and Europe were included in the modified intention-to-treat population (primary analysis), and 123 were included in the safety population. The median age was 65 years, and the median number of previous regimens was 7; a total of 53% of the patients had high-risk cytogenetic abnormalities. A partial response or better was observed in 26% of patients (95% confidence interval, 19 to 35), including two stringent complete responses; 39% of patients had a minimal response or better. The median duration of response was 4.4 months, median progression-free survival was 3.7 months, and median overall survival was 8.6 months. Fatigue, nausea, and decreased appetite were common and were typically grade 1 or 2 (grade 3 events were noted in up to 25% of patients, and no grade 4 events were reported). Thrombocytopenia occurred in 73% of the patients (grade 3 in 25% and grade 4 in 33%). Thrombocytopenia led to bleeding events of grade 3 or higher in 6 patients. CONCLUSIONS: Selinexor-dexamethasone resulted in objective treatment responses in patients with myeloma refractory to currently available therapies. (Funded by Karyopharm Therapeutics; STORM ClinicalTrials.gov number, NCT02336815.).


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Dexametasona/administración & dosificación , Hidrazinas/administración & dosificación , Carioferinas/antagonistas & inhibidores , Mieloma Múltiple/tratamiento farmacológico , Receptores Citoplasmáticos y Nucleares/antagonistas & inhibidores , Triazoles/administración & dosificación , Administración Oral , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores de Tumor/sangre , Dexametasona/efectos adversos , Esquema de Medicación , Resistencia a Antineoplásicos , Femenino , Humanos , Hidrazinas/efectos adversos , Análisis de Intención de Tratar , Masculino , Persona de Mediana Edad , Análisis de Supervivencia , Trombocitopenia/inducido químicamente , Triazoles/efectos adversos , Adulto Joven , Proteína Exportina 1
3.
Am J Hematol ; 97(9): 1170-1177, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35731911

RESUMEN

The incremental impact of autologous hematopoietic cell transplantation (AHCT) on disease burden with quadruplet induction in newly diagnosed multiple myeloma (NDDM) can be reappraised with the serial assessment of minimal residual disease (MRD). We describe the impact of AHCT on MM burden assessed by next-generation sequencing (NGS) for patients enrolled in a clinical trial utilizing quadruplet induction, AHCT, followed by MRD-adapted consolidation. We describe quantitative changes in MRD burden with AHCT and explore patient and disease features influencing the magnitude of MRD reduction with AHCT. Among 123 included patients, 109 underwent AHCT and had MRD assessment pre and post AHCT. Forty percent achieved MRD < 10-5 post-induction, increasing to 70% after AHCT. Of the 65 patients (60%) who remained MRD positive post-induction, 54 (83%) had a reduction in MRD burden with AHCT. The median reduction in MRD with AHCT was 1.10 log10 (range, -1.26 to 3.41). Patients with high-risk cytogenetic abnormalities (HRCA) had greater reduction in MRD burden (p = .02) after AHCT. Median relative reduction was 0.91 log10 (range, -0.75 to 2.14), 1.26 log10 (range, -0.21 to 3.26) and 1.34 log10 (range, -1.28 to 3.41) for patients with 0, 1 and 2+ HRCA, respectively. The presence of HRCA was the only factor associated with greater than 1 log10 reduction in MRD burden with AHCT. Serial NGS MRD demonstrates the incremental effect of AHCT in MM marrow burden in the context of quadruplet induction, particularly in high-risk MM.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Mieloma Múltiple , Costo de Enfermedad , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/genética , Mieloma Múltiple/terapia , Neoplasia Residual/diagnóstico , Trasplante Autólogo
4.
Br J Haematol ; 190(4): 555-561, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32314352

RESUMEN

Immunomodulatory drugs (IMiDs) have improved survival of patients with multiple myeloma (MM) and comprise the therapeutic backbone at all phases of therapy. Although well-tolerated, IMiDs increase rates of venous thromboembolism (VTE). In this phase IV, single-arm pilot study, fifty patients with MM on IMiDs received apixaban 2·5 mg orally twice daily for primary prevention of VTE and were prospectively monitored for six months. The primary safety outcomes were rates of major haemorrhage and clinically relevant non-major haemorrhage over six months. The primary efficacy outcome was the rate of symptomatic VTE over six months. IMiDs used were lenalidomide (58%) or pomalidomide (42%). During the six-month evaluation period, no patients experienced major haemorrhage or VTE. Three patients experienced clinically relevant, non-major haemorrhage which was managed medically, and all were able to resume apixaban. One patient stopped therapy shortly after initiation due to an allergic reaction to apixaban. No patients experienced stroke, myocardial infarction, or death. In this pilot study, low-dose apixaban was safe and well-tolerated as a primary prevention therapy of VTE for patients with MM receiving IMiDs. Further studies are needed to validate low-dose apixaban as a standard primary prevention anti-thrombotic strategy for patients with MM receiving IMiDs.


Asunto(s)
Inhibidores del Factor Xa/uso terapéutico , Factores Inmunológicos/efectos adversos , Mieloma Múltiple/tratamiento farmacológico , Pirazoles/uso terapéutico , Piridonas/uso terapéutico , Trombofilia/tratamiento farmacológico , Tromboembolia Venosa/prevención & control , Anciano , Comorbilidad , Quimioterapia de Consolidación , Inhibidores del Factor Xa/efectos adversos , Femenino , Hemorragia/epidemiología , Hemorragia/etiología , Humanos , Factores Inmunológicos/uso terapéutico , Lenalidomida/efectos adversos , Lenalidomida/uso terapéutico , Quimioterapia de Mantención , Masculino , Persona de Mediana Edad , Mieloma Múltiple/sangre , Infarto del Miocardio/epidemiología , Infarto del Miocardio/prevención & control , Proyectos Piloto , Prueba de Estudio Conceptual , Estudios Prospectivos , Embolia Pulmonar/epidemiología , Embolia Pulmonar/etiología , Embolia Pulmonar/prevención & control , Pirazoles/efectos adversos , Piridonas/efectos adversos , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/prevención & control , Talidomida/efectos adversos , Talidomida/análogos & derivados , Talidomida/uso terapéutico , Trombofilia/etiología , Trombosis de la Vena/epidemiología , Trombosis de la Vena/etiología , Trombosis de la Vena/prevención & control
5.
Hematol Oncol ; 38(3): 353-362, 2020 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-32053229

RESUMEN

Patients with multiple myeloma (MM) inevitably relapse on initial treatment regimens, and novel combination therapies are needed. Ibrutinib is a first-in-class, once-daily inhibitor of Bruton's tyrosine kinase, an enzyme implicated in growth and survival of MM cells. Preclinical data suggest supra-additivity or synergy between ibrutinib and proteasome inhibitors (PIs) against MM. This phase 1/2b study evaluated the efficacy and safety of ibrutinib plus the PI carfilzomib and dexamethasone in patients with relapsed/refractory MM (RRMM). In this final analysis, we report results in patients who received the recommended phase 2 dose (RP2D; ibrutinib 840 mg and carfilzomib 36 mg/m2 with dexamethasone), which was determined in phase 1. The primary efficacy endpoint was overall response rate (ORR). Fifty-nine patients with RRMM received the RP2D (18 in phase 1 and 41 in phase 2b). These patients had received a median of three prior lines of therapy; 69% were refractory to bortezomib, and 90% were refractory to their last treatment. ORR in the RP2D population was 71% (stringent complete response and complete response: 3% each). Median duration of clinical benefit and median duration of response were both 6.5 months. Median progression-free survival (PFS) was 7.4 months, and median overall survival (OS) was 35.9 months. High-risk patients had comparable ORR and median PFS (67% and 7.7 months, respectively) to non-high-risk patients, whose ORR was 73% and median PFS was 6.9 months, whereas median OS in high-risk patients was 13.9 months and not reached in non-high-risk patients. The most common grade ≥3 hematologic treatment-emergent adverse events (TEAEs) were anemia and thrombocytopenia (17% each); the most common grade ≥3 non-hematologic TEAE was hypertension (19%). In patients with RRMM treated with multiple previous lines of therapy, ibrutinib plus carfilzomib demonstrated anticancer activity within the expected efficacy range. No new safety signals were identified and the combination was well-tolerated.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Mieloma Múltiple/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adenina/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Dexametasona/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/patología , Recurrencia Local de Neoplasia/patología , Oligopéptidos/administración & dosificación , Piperidinas , Pronóstico , Pirazoles/administración & dosificación , Pirimidinas/administración & dosificación , Terapia Recuperativa , Tasa de Supervivencia
6.
Br J Haematol ; 186(6): 807-819, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31364160

RESUMEN

Treatment response assessment in multiple myeloma (MM) relies on the detection of paraprotein in serum and/or urine, bone marrow morphology and immunohistochemistry. With remarkable advances in therapy, particularly in the newly diagnosed setting, achievement of complete remission became frequent, creating the need to identify smaller amounts of residual disease and understand their prognostic and therapeutic implications. Measurable residual disease (MRD) can be assessed primarily by flow cytometry and next generation sequencing and state-of-the-art assays have sensitivity approaching 1 in 106 cells. This review discusses the existing challenges in utilizing MRD to inform management of MM and highlights open research questions and opportunities as MRD is more routinely incorporated into clinical practice for patients with MM.


Asunto(s)
Citometría de Flujo , Secuenciación de Nucleótidos de Alto Rendimiento , Mieloma Múltiple , Humanos , Mieloma Múltiple/sangre , Mieloma Múltiple/genética , Mieloma Múltiple/terapia , Neoplasia Residual
7.
J Natl Compr Canc Netw ; 17(10): 1154-1165, 2019 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-31590151

RESUMEN

The NCCN Guidelines for Multiple Myeloma provide recommendations for diagnosis, workup, treatment, follow-up, and supportive care for patients with monoclonal gammopathy of renal significance, solitary plasmacytoma, smoldering myeloma, and multiple myeloma. These NCCN Guidelines Insights highlight some of the important updates and changes in the 1.2020 version of the NCCN Guidelines for Multiple Myeloma.


Asunto(s)
Mieloma Múltiple , Humanos
8.
Curr Oncol Rep ; 21(4): 29, 2019 03 05.
Artículo en Inglés | MEDLINE | ID: mdl-30834998

RESUMEN

PURPOSE OF REVIEW: Multiple myeloma is a common hematologic malignancy characterized by recurrent relapsing disease course requiring use of various therapies. Over the past few decades, significant advancements in the treatment of myeloma have occurred including routine use of proteasome inhibitors and immunomodulatory drugs. These have effectively improved survival; however, some also have increased risk of cardiovascular toxicity. Here, we will review the incidence, pathophysiology, and management of cardiovascular complications associated with antimyeloma agents. RECENT FINDINGS: Cardiovascular complications associated with myeloma treatment are common. These cardiovascular complications include accelerated hypertension, ischemic heart disease, congestive heart failure, arrhythmia, pulmonary hypertension, venous thromboembolism, and arterial thromboembolism. Thromboprophylactic strategies during treatment with immunomodulatory agents and screening strategies to detect changes in myocardial function prior to the development of overt heart failure have occurred. Cardiovascular complications associated with proteasome inhibitors and immunomodulatory drugs are an important component in supportive care of patients with myeloma. The incidence of cardiotoxicity is high, and, as such, early intervention and collaborative efforts between cardiologists and oncologists to mitigate and effectively manage these complications are imperative. Additional studies are needed to clarify the underlying pathophysiology and evaluate effective strategies for prevention and treatment.


Asunto(s)
Antineoplásicos/efectos adversos , Cardiotoxicidad/prevención & control , Cardiopatías/prevención & control , Factores Inmunológicos/efectos adversos , Mieloma Múltiple/tratamiento farmacológico , Inhibidores de Proteasoma/efectos adversos , Cardiotoxicidad/epidemiología , Cardiotoxicidad/etiología , Cardiotoxicidad/fisiopatología , Manejo de la Enfermedad , Cardiopatías/inducido químicamente , Cardiopatías/epidemiología , Cardiopatías/fisiopatología , Humanos , Incidencia , Mieloma Múltiple/patología , Estados Unidos/epidemiología
9.
Biol Blood Marrow Transplant ; 24(12): 2443-2449, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30142419

RESUMEN

The Revised International Staging System (R-ISS) and the International Myeloma Working Group 2014 (IMWG 2014) are newer staging systems used to prognosticate multiple myeloma (MM) outcomes. We hypothesized that these would provide better prognostic differentiation for newly diagnosed multiple myeloma (MM) compared with ISS. We analyzed the Center for International Blood and Marrow Transplant Research database from 2008 to 2014 to compare the 3 systems (N = 628) among newly diagnosed MM patients undergoing upfront autologous hematopoietic cell transplantation (AHCT). The median follow-up of survivors was 48 (range, 3 to 99) months. The R-ISS provided the greatest differentiation between survival curves for each stage (for overall survival [OS], the differentiation was 1.74 using the R-ISS, 1.58 using ISS, and 1.60 using the IMWG 2014) . Univariate analyses at 3 years for OS showed R-ISS I at 88% (95% confidence interval [CI], 83% to 93%), II at 75% (95% CI, 70% to 80%), and III at 56% (95% CI, 3% to 69%; P < .001). An integrated Brier score function demonstrated the R-ISS had the best prediction for PFS, though all systems had similar prediction for OS. Among available systems, the R-ISS is the most optimal among available prognostic tools for newly diagnosed MM undergoing AHCT. We recommend that serum lactate dehydrogenase and cytogenetic data be performed on every MM patient at diagnosis to allow accurate prognostication.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Mieloma Múltiple/diagnóstico , Trasplante Autólogo/métodos , Adulto , Anciano , Diferenciación Celular , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/patología , Estadificación de Neoplasias , Estudios Prospectivos
10.
Br J Haematol ; 180(2): 271-275, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-29048105

RESUMEN

Patients with multiple myeloma (MM) have improved treatment options, including immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs). Despite their efficacy, increased rates of cardiovascular (CV) complications occur in patients exposed to some of these therapies. While previous research has focused on identifying the toxicities inherent to each specific agent, the CV side effects may be potentiated by the combination of PIs and IMiDs plus dexamethasone. We present a patient with MM with recurrent cardiotoxicity only when exposed to combination PI and IMiD-based therapy. We also review the literature in this context, and propose a potential algorithm for cardiotoxicity prevention in this population.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Cardiopatías/etiología , Mieloma Múltiple/complicaciones , Adulto , Antineoplásicos Inmunológicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cardiotoxicidad , Electrocardiografía , Femenino , Cardiopatías/diagnóstico , Humanos , Imagen por Resonancia Magnética/métodos , Mieloma Múltiple/tratamiento farmacológico , Inhibidores de Proteasoma/administración & dosificación
11.
Lancet Oncol ; 18(2): 241-250, 2017 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-27956157

RESUMEN

BACKGROUND: In the era of widespread rituximab use for Waldenström's macroglobulinaemia, new treatment options for patients with rituximab-refractory disease are an important clinical need. Ibrutinib has induced durable responses in previously treated patients with Waldenström's macroglobulinaemia. We assessed the efficacy and safety of ibrutinib in a population with rituximab-refractory disease. METHODS: This multicentre, open-label substudy was done at 19 sites in seven countries in adults aged 18 years and older with confirmed Waldenström's macroglobulinaemia, refractory to rituximab and requiring treatment. Disease refractory to the last rituximab-containing therapy was defined as either relapse less than 12 months since last dose of rituximab or failure to achieve at least a minor response. Key exclusion criteria included: CNS involvement, a stroke or intracranial haemorrhage less than 12 months before enrolment, clinically significant cardiovascular disease, hepatitis B or hepatitis C viral infection, and a known bleeding disorder. Patients received oral ibrutinib 420 mg once daily until progression or unacceptable toxicity. The substudy was not prospectively powered for statistical comparisons, and as such, all the analyses are descriptive in nature. This study objectives were the proportion of patients with an overall response, progression-free survival, overall survival, haematological improvement measured by haemoglobin, time to next treatment, and patient-reported outcomes according to the Functional Assessment of Cancer Therapy-Anemia (FACT-An) and the Euro Qol 5 Dimension Questionnaire (EQ-5D-5L). All analyses were per protocol. The study is registered at ClinicalTrials.gov, number NCT02165397, and follow-up is ongoing but enrolment is complete. FINDINGS: Between Aug 18, 2014, and Feb 18, 2015, 31 patients were enrolled. Median age was 67 years (IQR 58-74); 13 (42%) of 31 patients had high-risk disease per the International Prognostic Scoring System Waldenström Macroglobulinaemia, median number of previous therapies was four (IQR 2-6), and all were rituximab-refractory. At a median follow-up of 18·1 months (IQR 17·5-18·9), the proportion of patients with an overall response was 28 [90%] of 31 (22 [71%] of patients had a major response), the estimated 18 month progression-free survival rate was 86% (95% CI 66-94), and the estimated 18 month overall survival rate was 97% (95% CI 79-100). Baseline median haemoglobin of 10·3 g/dL (IQR 9·3-11·7) increased to 11·4 g/dL (10·9-12·4) after 4 weeks of ibrutinib treatment and reached 12·7 g/dL (11·8-13·4) at week 49. A clinically meaningful improvement from baseline in FACT-An score, anaemia subscale score, and the EQ-5D-5L were reported at all post-baseline visits. Time to next treatment will be presented at a later date. Common grade 3 or worse adverse events included neutropenia in four patients (13%), hypertension in three patients (10%), and anaemia, thrombocytopenia, and diarrhoea in two patients each (6%). Serious adverse events occurred in ten patients (32%) and were most often infections. Five (16%) patients discontinued ibrutinib: three due to progression and two due to adverse events, while the remaining 26 [84%] of patients are continuing ibrutinib at the time of this report. INTERPRETATION: The sustained responses and median progression-free survival time, combined with a manageable toxicity profile observed with single-agent ibrutinib indicate that this chemotherapy-free approach is a potential new treatment choice for patients who had heavily pretreated, rituximab-refractory Waldenström's macroglobulinaemia. FUNDING: Pharmacyclics LLC, an AbbVie Company.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Terapia Recuperativa , Macroglobulinemia de Waldenström/tratamiento farmacológico , Adenina/análogos & derivados , Adulto , Anciano , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Piperidinas , Pronóstico , Pirazoles/administración & dosificación , Pirimidinas/administración & dosificación , Rituximab/administración & dosificación , Tasa de Supervivencia , Macroglobulinemia de Waldenström/patología
12.
Biol Blood Marrow Transplant ; 23(3): 529-532, 2017 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-28013014

RESUMEN

New-onset post-transplantation diabetes mellitus (PTDM) occurs commonly after allogeneic hematopoietic cell transplantation (HCT) and is associated with inferior survival. We hypothesize that PTDM and nonrelapse mortality (NRM) are related to IL-33/suppression of tumorigenicity 2 (ST2) signaling and that soluble ST2 (sST2) levels will predict PTDM diagnosis. sST2 was measured at engraftment and day +30 in 36 euglycemic HCT recipients followed prospectively for PTDM (cohort 1). Results were confirmed in a validation cohort of 26 patients without pre-existing diabetes analyzed retrospectively for PTDM (cohort 2). Twelve patients with established diabetes before HCT were analyzed in cohort 3. When compared with recipients without PTDM, patients developing PTDM (n = 24) from cohort 1 had elevated sST2 levels at engraftment (P = .02) and at day +30 (P < .01). Cohort 2 confirmed this finding at engraftment (P = .01). Cohort 3 patients with pretransplantation diabetes had higher sST2 at engraftment than patients maintaining euglycemia after HCT from cohort 2 (P = .03). Multivariate analysis of cohorts 1 and 2 showed high engraftment sST2 predicted increased PTDM and NRM risk, independent of conditioning and grades 3 to 4 acute graft-versus-host-disease. sST2 was elevated in PTDM, indicating a relationship between glucose homeostasis and the IL-33/ST2 axis after transplantation. Correction of metabolic complications may decrease sST2 and improve NRM.


Asunto(s)
Diabetes Mellitus/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Proteína 1 Similar al Receptor de Interleucina-1/metabolismo , Interleucina-33/metabolismo , Transducción de Señal , Adulto , Anciano , Glucemia/metabolismo , Femenino , Humanos , Proteína 1 Similar al Receptor de Interleucina-1/sangre , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Trasplante Homólogo , Adulto Joven
13.
Biol Blood Marrow Transplant ; 23(1): 60-66, 2017 01.
Artículo en Inglés | MEDLINE | ID: mdl-27789362

RESUMEN

Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) is characterized by lymphoplasmacytic proliferation, lymph node and spleen enlargement, bone marrow involvement, and IgM production. Treatment varies based on the extent and biology of disease. In some patients, the use of allogeneic hematopoietic cell transplantation (alloHCT) may have curative potential. We evaluated long-term outcomes of 144 patients who received adult alloHCT for WM/LPL. Data were obtained from the Center for International Blood and Marrow Transplant Research database (2001 to 2013). Patients received myeloablative(n = 67) or reduced-intensity conditioning (RIC; n = 67). Median age at alloHCT was 53 years, and median time from diagnosis to transplantation was 41 months. Thirteen percent (n = 18) failed prior autologous HCT. About half (n = 82, 57%) had chemosensitive disease at the time of transplantation, whereas 22% had progressive disease. Rates of progression-free survival, overall survival, relapse, and nonrelapse mortality at 5 years were 46%, 52%, 24%, and 30%, respectively. Patients with chemosensitive disease and better pretransplant disease status experienced significantly superior overall survival. There were no significant differences in progression-free survival based on conditioning (myeloablative, 50%, versus RIC, 41%) or graft source. Conditioning intensity did not impact treatment-related mortality or relapse. The most common causes of death were primary disease and graft-versus-host disease (GVHD). AlloHCT yielded durable survival in select patients with WM/LPL. Strategies to reduce mortality from GVHD and post-transplant relapse are necessary to improve this approach.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Linfoma/terapia , Macroglobulinemia de Waldenström/terapia , Adulto , Anciano , Bases de Datos Factuales , Enfermedad Injerto contra Huésped/mortalidad , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Linfoma/mortalidad , Persona de Mediana Edad , Recurrencia , Análisis de Supervivencia , Tiempo de Tratamiento , Acondicionamiento Pretrasplante/métodos , Acondicionamiento Pretrasplante/mortalidad , Trasplante Homólogo , Resultado del Tratamiento , Macroglobulinemia de Waldenström/mortalidad , Adulto Joven
14.
Biol Blood Marrow Transplant ; 23(2): 269-277, 2017 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-27864161

RESUMEN

Bortezomib (V), lenalidomide (R), cyclophosphamide (C), and dexamethasone (D) are components of the most commonly used modern doublet (RD, VD) or triplet (VRD, CVD) initial induction regimens before autologous hematopoietic cell transplantation (AHCT) for multiple myeloma (MM) in the United States. In this study we evaluated 693 patients receiving "upfront" AHCT after initial induction therapy with modern doublet or triplet regimens using data reported to the Center for International Blood and Marrow Transplant Research from 2008 to 2013. Analysis was limited to those receiving a single AHCT after 1 line of induction therapy within 12 months from treatment initiation for MM. In multivariate analysis, progression-free survival (PFS) and overall survival were similar irrespective of induction regimen. However, high-risk cytogenetics and nonreceipt of post-transplant maintenance/consolidation therapy were associated with higher risk of relapse. Patients receiving post-transplant therapy had significantly improved 3-year PFS versus no post-transplant therapy (55% versus 39%, P = .0001). This benefit was most evident in patients not achieving at least a complete response post-AHCT (P = .005). In patients receiving upfront AHCT, the choice of induction regimen (doublet or triplet therapies) appears to be of lower impact than use of post-transplant therapy.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Mieloma Múltiple/tratamiento farmacológico , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Causas de Muerte , Terapia Combinada , Bases de Datos Factuales , Supervivencia sin Enfermedad , Femenino , Humanos , Factores Inmunológicos/administración & dosificación , Hibridación Fluorescente in Situ , Estimación de Kaplan-Meier , Quimioterapia de Mantención , Masculino , Persona de Mediana Edad , Mieloma Múltiple/genética , Mieloma Múltiple/terapia , Neoplasias Primarias Secundarias/mortalidad , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Inhibidores de Proteasoma/administración & dosificación , Inducción de Remisión , Estudios Retrospectivos , Trasplante Autólogo , Resultado del Tratamiento , Adulto Joven
15.
Heart Fail Clin ; 13(2): 409-416, 2017 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-28279425

RESUMEN

Cardiac amyloidosis is a complex and vexing clinical condition that requires a high degree of suspicion for the diagnosis with a substantial amount of discipline to discern the extent of disease and the best available therapy. There is a complex interplay between multiple organ systems, and the clinical presentation may involve a myriad of confusing clinical symptoms. The diagnosis of cardiac amyloidosis can be confirmed with a combination of physical findings, cardiac biomarkers, noninvasive testing, and, if necessary, myocardial biopsy. Genetic testing is critical to establish the type of amyloidosis.


Asunto(s)
Amiloidosis/diagnóstico , Cardiopatías/diagnóstico , Amiloidosis/genética , Amiloidosis/metabolismo , Amiloidosis/terapia , Manejo de la Enfermedad , Diagnóstico Precoz , Cardiopatías/genética , Cardiopatías/metabolismo , Cardiopatías/terapia , Humanos
16.
J Card Fail ; 22(6): 465-71, 2016 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-27038642

RESUMEN

There is an increasing awareness and clinical interest in cardiac safety during cancer therapy as well as in optimally addressing cardiac issues in cancer survivors. Although there is an emerging expertise in this area, known as cardio-oncology, there is a lack of organization in the essential components of contemporary training. This proposal, an international consensus statement organized by the International Cardioncology Society and the Canadian Cardiac Oncology Network, attempts to marshal the important ongoing efforts for training the next generation of cardio-oncologists. The necessary elements are outlined, including the expectations for exposure necessary to develop adequate training. There should also be a commitment to local, regional, and international education and research in cardio-oncology as a requirement for advancement in the field.


Asunto(s)
Cardiología/educación , Enfermedades Cardiovasculares/terapia , Consenso , Educación de Postgrado en Medicina/métodos , Oncología Médica/educación , Sociedades Médicas , Canadá , Humanos , Relaciones Interprofesionales
17.
Am J Hematol ; 91(10): 1044-51, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27415608

RESUMEN

Although upfront treatment of multiple myeloma has become more effective, relapses are the norm, often driven by the emergence of a genetically divergent clone selected by the initial therapy. Recent trials have demonstrated the safety and efficacy of combination therapy also in the relapsed and refractory setting and supported the regulatory approval of several new agents including new proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies. We provide a detailed summary of recent practice-changing trials in relapsed and refractory MM and share a practical approach to assimilate disease and patient-features into treatment decision. Am. J. Hematol. 91:1044-1051, 2016. © 2016 Wiley Periodicals, Inc.


Asunto(s)
Mieloma Múltiple/terapia , Terapia Recuperativa/métodos , Manejo de la Enfermedad , Humanos , Terapia Recuperativa/tendencias
18.
Clin Transl Sci ; 17(5): e13828, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38783568

RESUMEN

As a treatment for relapsed or refractory multiple myeloma (MM), carfilzomib has been associated with a significant risk of cardiovascular adverse events (CVAE). The goals of our study were to evaluate the metabolomic profile of MM patients to identify those at high risk prior to carfilzomib treatment and to explore the mechanisms of carfilzomib-CVAE to inform potential strategies to protect patients from this cardiotoxicity. Global metabolomic profiling was performed on the baseline and post-baseline plasma samples of 60 MM patients treated with carfilzomib-based therapy, including 31 who experienced CVAE, in a prospective cohort study. Baseline metabolites and post-baseline/baseline metabolite ratios that differ between the CVAE and no-CVAE patients were identified using unadjusted and adjusted methods. A baseline metabolomic risk score was created to stratify patients. We observed a lower abundance of tauroursodeoxycholic acid (T-UDCA) in CVAE patients at baseline (odds ratio [OR] = 0.47, 95% confidence interval [CI] = 0.21-0.94, p = 0.044) compared with the no-CVAE patients. A metabolite risk score was able to stratify patients into three risk groups. The area under the receiver-operating curve of the model with clinical predictors and metabolite risk score was 0.93. Glycochenodeoxycholic acid (OR = 0.56, 95% CI = 0.31-0.87, p = 0.023) was significantly lower in post-baseline/baseline ratios of CVAE patients compared with no-CVAE patients. Following metabolomic analysis, we created a baseline metabolite risk score that can stratify MM patients into different risk groups. The result also provided intriguing clues about the mechanism of carfilzomib-CVAE and potential cardioprotective strategies.


Asunto(s)
Cardiotoxicidad , Metabolómica , Mieloma Múltiple , Oligopéptidos , Humanos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/sangre , Oligopéptidos/efectos adversos , Masculino , Femenino , Anciano , Persona de Mediana Edad , Cardiotoxicidad/etiología , Cardiotoxicidad/sangre , Cardiotoxicidad/diagnóstico , Metabolómica/métodos , Estudios Prospectivos , Metaboloma/efectos de los fármacos , Anciano de 80 o más Años , Factores de Riesgo
19.
Front Cardiovasc Med ; 10: 1181806, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37408649

RESUMEN

Background: Proteasome inhibitor Carfilzomib (CFZ) is effective in treating patients with refractory or relapsed multiple myeloma (MM) but has been associated with cardiovascular adverse events (CVAE) such as hypertension, cardiomyopathy, and heart failure. This study aimed to investigate the contribution of germline genetic variants in protein-coding genes in CFZ-CVAE among MM patients using whole-exome sequencing (WES) analysis. Methods: Exome-wide single-variant association analysis, gene-based analysis, and rare variant analyses were performed on 603,920 variants in 247 patients with MM who have been treated with CFZ and enrolled in the Oncology Research Information Exchange Network (ORIEN) at the Moffitt Cancer Center. Separate analyses were performed in European Americans and African Americans followed by a trans-ethnic meta-analysis. Results: The most significant variant in the exome-wide single variant analysis was a missense variant rs7148 in the thymosin beta-10/TraB Domain Containing 2A (TMSB10/TRABD2A) locus. The effect allele of rs7148 was associated with a higher risk of CVAE [odds ratio (OR) = 9.3 with a 95% confidence interval of 3.9-22.3, p = 5.42*10-7]. MM patients with rs7148 AG or AA genotype had a higher risk of CVAE (50%) than those with GG genotype (10%). rs7148 is an expression quantitative trait locus (eQTL) for TRABD2A and TMSB10. The gene-based analysis also showed TRABD2A as the most significant gene associated with CFZ-CVAE (p = 1.06*10-6). Conclusions: We identified a missense SNP rs7148 in the TMSB10/TRABD2A as associated with CFZ-CVAE in MM patients. More investigation is needed to understand the underlying mechanisms of these associations.

20.
EJHaem ; 4(3): 775-778, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37601885

RESUMEN

Quadruplet induction, autologous hematopoietic cell transplant (AHCT), and measurable residual disease (MRD) response-adapted consolidation yield an unprecedented depth of response in newly diagnosed multiple myeloma. Patients treated on MASTER (NCT03224507) ceased therapy and entered active surveillance (MRD-SURE) after achieving MRD negativity. This study characterizes quantitative changes in the immunoglobulin (Ig) gene repertoire by next-generation sequencing and serum gamma globulin levels. Quadruplet therapy leads to profound hypogammaglobulinemia and reduction in the Ig gene repertoire. Immune reconstitution (IR) is delayed in patients who received post-AHCT consolidation compared to those who do not. Eighteen months after treatment cessation, there was no statistically significant difference between the groups.

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