Real-World Outcomes of Belantamab Mafodotin for Relapsed/Refractory Multiple Myeloma (RRMM): Preliminary Results of a Spanish Expanded Access Program (EAP).

INTRODUCTION: Belantamab mafodotin (BM) is a new anti-BCMA antibody-drug conjugate, recently approved for triple-class relapsed and refractory multiple myeloma (RRMM). We assessed real-world outcomes with BM in patients under the Spanish Expanded Access Program (EAP). METHODS: We conducted an observational, retrospective, multicenter study including RRMM patients who received ≥ 1 dose of BM (Nov 2019 to Jun 2021). The primary endpoint was overall response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and incidence of treatment-emergent adverse events (TEAEs). RESULTS: Thirty-three patients were included with a median of 70 years of age (range, 46-79 years). Median time from diagnosis was 71 months (range, 10-858 months). Median prior lines was 5 (range, 3-8 lines); 90% of patients were triple-/quad-/penta-refractory; 48% showed high-risk cytogenetics. Median BM doses was 3 (range 1-16 doses), with a median follow-up of 11 months (6-15 months). ORR was 42.2% (≥ VGPR, 18.2%). Median PFS was 3 months (95% CI 0.92-5.08) in the overall population, and 11 months (HR 0.26; 95% CI 0.10-0.68) for patients who achieved ≥ PR. PFS was not significantly different according to age, cytogenetic risk, and prior therapy lines. OS was 424 days (95% CI 107-740). Non-hematological TEAEs (57.6% of patients; 30.3% ≥ G3) included keratopathy (51.5%; 21.2% ≥ G3) and patient-reported vision-related symptoms (45.5%). Keratopathy was resolved in 70.6% of patients. G3 hematological TEAEs was 18.2%, thrombocytopenia (21.2%). Dose reductions due to TEAEs: 30.3%; delays: 36.4%. Treatment discontinuation causes: progression (54.5%), toxicity (non-ocular; 6%/ocular; 6% /ocular + non-ocular toxicity; 3%), death (6%), and patient's decision (3%). CONCLUSIONS: BM showed relevant anti-myeloma activity in RRMM with a manageable safety profile. These results corroborate those observed in the BM pivotal trial.

Phase I study of plitidepsin in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma.

Previous studies showed antitumor activity for plitidepsin plus dexamethasone (DXM) in relapsed/refractory multiple myeloma (r/r MM), and in vitro synergism with bortezomib (BTZ) or DXM against MM cells. This phase I trial evaluated plitidepsin (3-h intravenous infusion Day 1 and 15), BTZ (subcutaneous bolus Day 1, 4, 8, and 11), and DXM (orally Day 1, 8, 15, and 22), every 4 weeks in 36 r/r MM patients. Twenty-two patients were treated using a standard dose escalation design (10 at the recommended dose [RD] cohort), and 14 additional patients were treated to expand the RD cohort. No dose-limiting toxicities (DLTs) occurred during dose escalation. The highest dose level evaluated (plitidepsin 5.0 mg/m2 , BTZ 1.3 mg/m2 , DXM 40.0 mg) was the RD for phase II studies. Results shown herein are focused on this RD. Two patients had DLTs (grade 3 diarrhea, and grade 3 nausea/vomiting refractory to antiemetic therapy). Grade ≥ 3 hematological toxicity (thrombocytopenia 46%, anemia 33%, and neutropenia 17%) was manageable and did not result in treatment discontinuation. Transient and manageable grade 3 ALT increase (26%) was the most common biochemical abnormality. At the RD cohort, overall response rate was 22.2% (95%CI, 6.4%-47.6%), including one stringent complete response, one very good partial response, and two partial responses in r/r patients to BTZ and/or lenalidomide. The clinical benefit rate was 77.8% (95%CI, 52.4-93.6%). No major pharmacokinetic drug-drug interaction was found. In conclusion, the triple combination of plitidepsin, BTZ, and DXM showed an acceptable safety profile and had moderate activity in adult patients with r/r MM.

Circulating Tumor and Immune Cells for Minimally Invasive Risk Stratification of Smoldering Multiple Myeloma.

PURPOSE: Early intervention in smoldering multiple myeloma (SMM) requires optimal risk stratification to avoid under- and overtreatment. We hypothesized that replacing bone marrow (BM) plasma cells (PC) for circulating tumor cells (CTC), and adding immune biomarkers in peripheral blood (PB) for the identification of patients at risk of progression due to lost immune surveillance, could improve the International Myeloma Working Group 20/2/20 model. EXPERIMENTAL DESIGN: We report the outcomes of 150 patients with SMM enrolled in the iMMunocell study, in which serial assessment of tumor and immune cells in PB was performed every 6 months for a period of 3 years since enrollment. RESULTS: Patients with >0.015% versus ≤0.015% CTCs at baseline had a median time-to-progression of 17 months versus not reached (HR, 4.9; P < 0.001). Presence of >20% BM PCs had no prognostic value in a multivariate analysis that included serum free light-chain ratio >20, >2 g/dL M-protein, and >0.015% CTCs. The 20/2/20 and 20/2/0.015 models yielded similar risk stratification (C-index of 0.76 and 0.78). The combination of the 20/2/0.015 model with an immune risk score based on the percentages of SLAN+ and SLAN- nonclassical monocytes, CD69+HLADR+ cytotoxic NK cells, and CD4+CXCR3+ stem central memory T cells, allowed patient' stratification into low, intermediate-low, intermediate-high, and high-risk disease with 0%, 20%, 39%, and 73% rates of progression at 2 years. CONCLUSIONS: This study showed that CTCs outperform BM PCs for assessing tumor burden. Additional analysis in larger series are needed to define a consensus cutoff of CTCs for minimally invasive stratification of SMM.

Urgencias psiquiátricas infanto-juveniles: 7 años de seguimiento / A 7-year follow-up study of Child and Adolescent Mental Health Emergencies

INTRODUCCIÓN: A pesar de la mayor demanda de urgencias psiquiátricas infanto-juveniles, las características de este colectivo no han sido definidas con precisión. OBJETIVOS: Analizar variables clínicas y sociodemográficas de los menores de 17 años evaluados en Urgencias Psiquiátricas de un hospital general. Estudiar la adherencia terapéutica y la estabilidad diagnóstica tras la atención urgente. MÉTODO: Estudio retrospectivo en una muestra de 218 atenciones psiquiátricas infanto-juveniles durante 7 años (2010-2017). RESULTADOS: Edad media 13,60 años (DE: 2,36). Sexo: 54% mujeres, 46% varones. El número de atenciones psiquiátricas infanto-juveniles aumentó desde 11,6% en 2010 hasta 23,3% en 2016. Motivo de consulta más frecuente: alteraciones conductuales en varones y autolesiones en mujeres. Antecedentes de intento autolítico mujeres: 46,4%, varones: 14%. La mayoría de los pacientes presentaban antecedentes psiquiátricos personales y familiares. Antecedentes somáticos (17,1%), la enfermedad más prevalente fue la epilepsia (9,7%). El 11,5% consumían tóxicos (droga más frecuente: THC), el abuso de alcohol era más prevalente entre las mujeres. Tasa de hospitalización (14,7%), los pacientes más jóvenes precisaban ingreso con mayor frecuencia. En Urgencias se prescribieron psicofármacos en el 62,3% de los casos (grupo más recetado: antipsicóticos 38,9%). Derivación para seguimiento ambulatorio (72,5%), asistencia a la primera consulta (81%), retirada de prescripciones farmacológicas (58%). Estabilidad diagnostica: 77,8%. CONCLUSIONES: Existen importantes diferencias de género en las urgencias psiquiátricas infanto-juveniles. Se trata de un colectivo vulnerable, la mayoría de los pacientes tienen antecedentes psiquiátricos personales y familiares, con perfil socio-demográfico desfavorable. Es necesario mejorar la adherencia terapéutica tras la atención urgente

INTRODUCTION: Despite the upward trend in child and adolescent psychiatric emergencies, the characteristics of this population have not been accurately described. OBJECTIVES: To underpin the clinical and sociodemographic variables associated with minors assessed in the Emergency Department (ED) due to mental health concerns. To analyze the therapeutic compliance and diagnostic stability upon ED discharge. METHOD: A retrospective study was undertaken on a sample composed of 218 patients aged under 17 years old over a 7-year period (2010-2017). RESULTS: Mean age 13,60 years (SD: 2.36). 54% females, 46% males. An upward trend in ED visits was noted, increasing from 11,6% in 2010 to 23,3% in 2016. Most common causes for assessment: behavioral disturbances in males and self-harm in females. 46,4% of females and 14% of males had a history of suicide attempt. Somatic history was recorded in 17,1% of cases: epilepsy (9,7%), coeliac disease (4,6%), diabetes (4,1%). In the overall sample, 11,5% of patients presented with substance misuse (cannabis was the most prevalent drug of abuse). Females had a higher prevalence of alcohol misuse. 62,3% of cases received pharmacological treatment upon discharge from ED (antipsychotics 38,9%, benzodiazepines 34,3%). 81% of patients attended the first follow-up outpatient appointment whilst only 58% followed the prescribed treatment accurately. Inpatient admission rate: 14,7%. Diagnostic stability: 77,8%. CONCLUSIONS: Relevant gender differences are noted in child and adolescent mental health emergencies. Patients assessed in ED due to psychiatric crises represent a vulnerable population with an unfavorable sociodemographic profile and high prevalence of somatic and psychiatric history

Bendamustine, bortezomib and prednisone for the treatment of patients with newly diagnosed multiple myeloma: results of a prospective phase 2 Spanish/PETHEMA trial.

Bendamustine is a bifunctional alkylating agent with proven activity in myeloma. In this study 60 newly diagnosed myeloma patients were given bendamustine plus bortezomib and prednisone in a regimen consisting of one cycle of bortezomib twice weekly for 6 weeks (1.3 mg/m(2) on days 1, 4, 8, 11, 22, 25, 29, and 32), plus bendamustine (90 mg/m(2) on days 1 and 4) and prednisone. The following cycles included bortezomib once weekly. Patients who were transplant candidates proceeded to stem cell collection after four cycles and the transplant was performed after six cycles. Patients who were not candidates for transplantation received up to nine cycles. Forty-two patients were transplant candidates and after six cycles, 50% achieved at least a very good partial response, with 24% having complete responses; 35 proceeded to a transplant, and the complete response rate was 54%. Seventeen patients continued up to nine cycles, and 57% achieved at least a very good partial response, including 26% with complete responses. The 2-year progression-free survival and overall survival rates were 62% and 86%, respectively. The safety profile was manageable, but stem cell mobilization was compromised in 35% of patients. In summary, this combination is effective in untreated patients, with an acceptable toxicity profile, but given the introduction of second-generation novel agents and monoclonal antibodies, the combination will probably be better reserved for relapsing patients, in whom stem cell collection is not needed, while cost-effective combinations with non-cross-resistant drugs continue to represent a medical need. This trial was registered with ClinicalTrials.gov, number NCT01376401.

ST proteins, a new family of plant tandem repeat proteins with a DUF2775 domain mainly found in Fabaceae and Asteraceae.

BACKGROUND: Many proteins with tandem repeats in their sequence have been described and classified according to the length of the repeats: I) Repeats of short oligopeptides (from 2 to 20 amino acids), including structural cell wall proteins and arabinogalactan proteins. II) Repeats that range in length from 20 to 40 residues, including proteins with a well-established three-dimensional structure often involved in mediating protein-protein interactions. (III) Longer repeats in the order of 100 amino acids that constitute structurally and functionally independent units. Here we analyse ShooT specific (ST) proteins, a family of proteins with tandem repeats of unknown function that were first found in Leguminosae, and their possible similarities to other proteins with tandem repeats. RESULTS: ST protein sequences were only found in dicotyledonous plants, limited to several plant families, mainly the Fabaceae and the Asteraceae. ST mRNAs accumulate mainly in the roots and under biotic interactions. Most ST proteins have one or several Domain(s) of Unknown Function 2775 (DUF2775). All deduced ST proteins have a signal peptide, indicating that these proteins enter the secretory pathway, and the mature proteins have tandem repeat oligopeptides that share a hexapeptide (E/D)FEPRP followed by 4 partially conserved amino acids, which could determine a putative N-glycosylation signal, and a fully conserved tyrosine. In a phylogenetic tree, the sequences clade according to taxonomic group. A possible involvement in symbiosis and abiotic stress as well as in plant cell elongation is suggested, although different STs could play different roles in plant development. CONCLUSIONS: We describe a new family of proteins called ST whose presence is limited to the plant kingdom, specifically to a few families of dicotyledonous plants. They present 20 to 40 amino acid tandem repeat sequences with different characteristics (signal peptide, DUF2775 domain, conservative repeat regions) from the described group of 20 to 40 amino acid tandem repeat proteins and also from known cell wall proteins with repeat sequences. Several putative roles in plant physiology can be inferred from the characteristics found.

[Prostatic lymphoma and review of the literature]. / Linfoma prostático y revisión de la literatura.

Prostatic lymphoma is an exceptional pathology, that usually is diagnosed because its prostatic symthomatology or as consequence of its invasion by an extraprostatic lymphoma. We present a case of a patient affected by a prostatic lymphoma and we perform a review of the literature in order to establish the diagnostic and therapeutic steps.

Linfoma prostático y revisión de la literatura / Prostatic Lymphoma and review of the literature

El linfoma prostático es una patología excepcional que suele diagnosticarse como consecuencia de su sintomatomatología prostática o como consecuencia de su invasión por un linfoma extraprostático. Presentamos un caso de un paciente afecto por un linfoma prostático y realizamos una revisión de la literatura, para establecer las pautas diagnósticas y terapéuticas (AU)

Prostatic Lymphoma is an exceptional pathology, that usually is diagnosed because its prostatic symthomatology or as consequence of its invasion by an extraprostatic lymphoma. We present a case of a patient affected by a prostatic lymphoma and we perform a review of the literature in order to establish the diagnostic and therapeutic steps (AU)

[Decreased transfusion requirements in acquired severe bleeding with recombinant activated factor VII]. / Reducción de las necesidades transfusionales en hemorragias adquiridas graves mediante factor VII activo recombinante.

BACKGROUND AND OBJECTIVE: Patients with severe and persistent bleeding have high mortality rates despite standard therapy, including blood transfusion support. The aim of the study was to evaluate the role of rFVIIa in the management of severe bleeding, refractory to other treatments. PATIENTS AND METHODS: All cases with severe bleeding and failure of previous treatments who received rFVIIa (n = 21) at one single center were retrospectively included in the study. RESULTS: A response after the administration of rFVIIa was reported in 16 of 21 patients (76.2%). Hemorrhage was completely halted in 14 cases, and 12 patients (57.1%) were alive 30 days after treatment. The use of rFVIIa was associated with a normalization of coagulation tests, especially the prothrombin time (p = 0.001). A marked reduction in blood requirements, red cell units (p = 0.003), fresh frozen plasma (p = 0.009) and platelets (p = 0.017) was also observed. CONCLUSIONS: rFVIIa may have an important role in the achievement of an adequate hemostasis and reduces blood requirements in patients with severe bleeding, emerging as an alternative to blood transfusion.

Reducción de las necesidades transfusionales en hemorragias adquiridas graves mediante factor VII activo recombinante / Decreased transfusion requirements in acquired severe bleeding with recombinant activated factor VII

Fundamento y objetivo: Los pacientes con hemorragias graves y persistentes presentan una elevada mortalidad pese a los tratamientos convencionales, entre ellos el soporte transfusional. El objetivo del estudio ha sido evaluar el papel del factor VII activo recombinante (rFVIIa) en el tratamiento de hemorragias graves, refractarias a otros tratamientos. Pacientes y métodos: En el estudio se incluyeron retrospectivamente todos los casos (n = 21) tratados en un único centro con rFVIIa debido a hemorragias graves, en las que previamente habían fracasado otras medidas terapéuticas. Resultados: La tasa de respuesta al tratamiento fue del 76,2%, cediendo completamente la hemorragia en 14 pacientes. La supervivencia a los 30 días tras la administración del fármaco fue del 57,1% (12 de 21 pacientes). La utilización de rFVIIa se asoció con una mejoría de los parámetros de la coagulación, especialmente del tiempo de protrombina (p = 0,001), así como con una marcada reducción de los requerimientos transfusionales, concentrados de hematíes (p = 0,003), plasma fresco (p = 0,009) y plaquetas (p = 0,017). Conclusiones: El rFVIIa consigue una adecuada hemostasia y disminución de requerimientos de hemoderivados en hemorragias graves, por lo que representa una alternativa a la transfusión en estos pacientes

Background and objective: Patients with severe and persistent bleeding have high mortality rates despite standard therapy, including blood transfusion support. The aim of the study was to evaluate the role of rFVIIa in the management of severe bleeding, refractory to other treatments. Patients and methods: All cases with severe bleeding and failure of previous treatments who received rFVIIa (n = 21) at one single center were retrospectively included in the study. Results: A response after the administration of rFVIIa was reported in 16 of 21 patients (76.2%). Hemorrhage was completely halted in 14 cases, and 12 patients (57.1%) were alive 30 days after treatment. The use of rFVIIa was associated with a normalization of coagulation tests, especially the prothrombin time (p = 0.001). A marked reduction in blood requirements, red cell units (p = 0.003), fresh frozen plasma (p = 0.009) and platelets (p = 0.017) was also observed. Conclusions: rFVIIa may have an important role in the achievement of an adequate hemostasis and reduces blood requirements in patients with severe bleeding, emerging as an alternative to blood transfusion