Ide-cel or standard regimens in relapsed and refractory multiple myeloma

BACKGROUND: Survival is poor among patients with triple-class-exposed relapsed and refractory multiple myeloma. Idecabtagene vicleucel (ide-cel), a B-cell maturation antigen-directed chimeric antigen receptor (CAR) T-cell therapy, previously led to deep, durable responses in patients with heavily pretreated relapsed and refractory multiple myeloma. METHODS: In this international, open-label, phase 3 trial involving adults with relapsed and refractory multiple myeloma who had received two to four regimens previously (including immunomodulatory agents, proteasome inhibitors, and daratumumab) and who had disease refractory to the last regimen, we randomly assigned patients in a 2:1 ratio to receive either ide-cel (dose range, 150×10 RESULTS: A total of 386 patients underwent randomization: 254 to ide-cel and 132 to a standard regimen. A total of 66% of the patients had triple-class-refractory disease, and 95% had daratumumab-refractory disease. At a median follow-up of 18.6 months, the median progression-free survival was 13.3 months in the ide-cel group, as compared with 4.4 months in the standard-regimen group (hazard ratio for disease progression or death, 0.49; 95% confidence interval, 0.38 to 0.65; P\u3c0.001). A response occurred in 71% of the patients in the ide-cel group and in 42% of those in the standard-regimen group (P\u3c0.001); a complete response occurred in 39% and 5%, respectively. Data on overall survival were immature. Adverse events of grade 3 or 4 occurred in 93% of the patients in the ide-cel group and in 75% of those in the standard-regimen group. Among the 225 patients who received ide-cel, cytokine release syndrome occurred in 88%, with 5% having an event of grade 3 or higher, and investigator-identified neurotoxic effects occurred in 15%, with 3% having an event of grade 3 or higher. CONCLUSIONS: Ide-cel therapy significantly prolonged progression-free survival and improved response as compared with standard regimens in patients with triple-class-exposed relapsed and refractory multiple myeloma who had received two to four regimens previously. The toxicity of ide-cel was consistent with previous reports. (Funded by 2seventy bio and Celgene, a Bristol-Myers Squibb company; KarMMa-3 ClinicalTrials.gov number, NCT03651128.)

Roadmap to cure multiple myeloma

Despite significant advances in the treatment of multiple myeloma which had led to unprecedented rates of response and survival, patients still relapse, and cure remains elusive. We propose in this review a roadmap to achieve the dream of cure for multiple myeloma based on five complementary strategies. First, to increase knowledge about disease pathogenesis with a focus on the biology of circulating tumor cells, responsible for dissemination and extramedullary disease, and minimal residual disease clones who represent the reservoir of clonal evolution and disease recurrence. Second, to consider undetectable measurable residual disease (MRD), defined by high-sensitive techniques, as the new endpoint of therapy. Third, to treat disease causation instead of symptomatology through early detection and intervention. Thereby, by treating high-risk smoldering myeloma patients early, we may not only contribute to delay disease progression into active disease but also to increase the cure rates. Fourth, to use the most active scheme in standard-risk patients if the cure is in the horizon. Fifth, to investigate experimental therapies in newly diagnosed patients with high-risk MM, implementing early rescue intervention strategies with the goal of eradicating all tumor clones, and achieving minimal residual disease negativity

Difficult-to-treat patients with relapsed/refractory multiple myeloma:A review of clinical trial results

Overall outcomes for multiple myeloma have improved due to the availability of new therapies, but patients with relapsed/refractory multiple myeloma harbouring certain factors continue to pose a therapeutic challenge. These challenging features include high-risk cytogenetics, renal impairment, patient characteristics such as age and frailty, and extramedullary disease. Prior refractory status and number of prior lines add further complexity to the treatment of these patients. While newer regimens are available and have suggested efficacy in these patient populations through subgroup analyses, differences in trial definitions and cut-offs make meaningful comparisons difficult. This review aims to examine the available clinical trial data for patients with high-risk cytogenetics, renal impairment, age and frailty and extramedullary disease.</p

Prognostic Value of Serum Paraprotein Response Kinetics in Patients With Newly Diagnosed Multiple Myeloma

Mieloma recién diagnosticado; Marcador pronósticoNewly diagnosed myeloma; Prognostic markerMieloma recent diagnosticat; Marcador pronòsticIntroduction Response kinetics is a well-established prognostic marker in acute lymphoblastic leukemia. The situation is not clear in multiple myeloma (MM) despite having a biomarker for response monitoring (monoclonal component [MC]). Materials and Methods We developed a mathematical model to assess the prognostic value of serum MC response kinetics during 6 induction cycles, in 373 NDMM transplanted patients treated in the GEM2012Menos65 clinical trial. The model calculated a “resistance” parameter that reflects the stagnation in the response after an initial descent. Results Two patient subgroups were defined based on low and high resistance, that respectively captured sensitive and refractory kinetics, with progression-free survival (PFS) at 5 years of 72% and 59% (HR 0.64, 95% CI 0.44-0.93; P = .02). Resistance significantly correlated with depth of response measured after consolidation (80.9% CR and 68.4% minimal residual disease negativity in patients with sensitive vs. 31% and 20% in those with refractory kinetics). Furthermore, it modulated the impact of reaching CR after consolidation; thus, within CR patients those with refractory kinetics had significantly shorter PFS than those with sensitive kinetics (median 54 months vs. NR; P = .02). Minimal residual disease negativity abrogated this effect. Our study also questions the benefit of rapid responders compared to late responders (5-year PFS 59.7% vs. 76.5%, respectively [P < .002]). Of note, 85% of patients considered as late responders were classified as having sensitive kinetics. Conclusion This semi-mechanistic modeling of M-component kinetics could be of great value to identify patients at risk of early treatment failure, who may benefit from early rescue intervention strategies

Seaweed-derived proteins and peptides: promising marine bioactives

Seaweeds are a typical food of East-Asian cuisine, to which are alleged several beneficial health effects have been attributed. Their availability and their nutritional and chemical composition have favored the increase in its consumption worldwide, as well as a focus of research due to their bioactive properties. In this regard, seaweed proteins are nutritionally valuable and comprise several specific enzymes, glycoproteins, cell wall-attached proteins, red algae phycobiliproteins, lectins, peptides, or mycosporine-like amino acids. This great extent of molecules has been reported to exert significant antioxidant, antimicrobial, anti-inflammatory, antihypertensive, antidiabetic, or antitumoral properties. Hence, knowledge on algae proteins and derived compounds have gained special interest for the potential nutraceutical, cosmetic or pharmaceutical industries based on these bioactivities. Although several molecular mechanisms of action on how these proteins and peptides exert biological activities have been described, many gaps in knowledge still need to be filled. Updating the current knowledge related to seaweed proteins and peptides is of interest to further asses their potential health benefits. This review addresses the characteristics of seaweed protein and protein-derived molecules, their natural occurrence, their studied bioactive properties, and their described potential mechanisms of action.The research leading to these results was supported by MICINN supporting the Ramón y Cajal grant for M.A. Prieto (RYC-2017-22891), to Xunta de Galicia for the pre-doctoral grant of P. Garcia-Oliveira (ED481A-2019/295), the program Grupos de Referencia Competitiva (GRUPO AA1-GRC 2018) that supports the work of J. Echave, to the Bio Based Industries Joint Undertaking (JU) under grant agreement No 888003 UP4HEALTH Project (H2020-BBI-JTI-2019) that supports the work of P. Otero. The JU receives support from the European Union’s Horizon 2020 research and innovation program and the Bio Based Industries Consortium. P.E.S. Munekata, M. Pateriro, and J.M. Lorenzo acknowledge GAIN (Axencia Galega de Innovación) for supporting this study (grant number IN607A2019/01).info:eu-repo/semantics/publishedVersio

Single-institution experience in clinical trials during the COVID-19 pandemic in Spain: Not so bad after all?

The impact of the COVID-19 outbreak in Spain during March-April 2020 has been unbalanced throughout the different regions of the country. The alarm status defined by the government on March 14, and still in place at the time of this writing, has transformed the country in different perspectives, including care of patients with cancer.1 In many centers, clinical trial activity was suspended, because it was not considered a priority under the health care challenge of the COVID-19 pandemic.2 Nevertheless, experimental therapy is the only and/or best therapeutic option for many patients with cancer

Desarrollo de un Manual de Calidad Radiológica para las Ips de Imágenes Diagnosticas en Rayos X que Busquen Mejorar la Calidad de su Servicio

Correcciones, tipo y tamaño de fuente en todo el documento, los títulos de primer nivel centrados y en negrita, interlineado, sangrías, las referencias bibliográficas no contienen las palabras obtenido, recuperado, formato de las tablas.Desde la experiencia laboral y educativa del grupo investigador se identificó que algunas IPS de la ciudad tenía falencias en los procesos y procedimientos para la toma de imágenes diagnósticas, evidenciando la carencia de un manual de calidad radiológica, condición que generaba problemas en la aceptación de dichos estudios, comprometiendo la calidad de las instituciones, sobre exposición de los pacientes entre otras problemáticas asociadas a la prestación del servicio. El proyecto tiene como fin la elaboración de un manual de calidad Radiológica, describiendo el paso a paso desde el reconocimiento de la problemática a nivel local en el cual se identificó la necesidad de mejorar la calidad del diagnóstico por imágenes de rayos X, el proyecto recolecto información de referentes teóricos que han trabajado sobre el objetivo de estandarizar los procesos de la toma de imágenes diagnósticas, a partir de estos y con apoyo del manual de Bontrager, se realizó una estructuración de los estudios más comunes que pueden trabajar las IPS de la ciudad, las cuales podrán tener aspectos para evaluar la calidad de la imagen, estableciendo ejes transversales como la radio protección, el posicionamiento y el Principio ALARA. El manual de Calidad Radiológica sigue lineamientos para la definición de requisitos y características del servicio a ofertar según la norma ISO 9001 la cual busca alcanzar estándares de calidad, que da una referencia teórica a este proyecto permitiendo crear una guía clara, de fácil aplicabilidad a la institución que necesite adherir este proceso.From the work and educational experience of the research group, it was identified that some IPS in the city had shortcomings in the processes and procedures for taking diagnostic images, evidencing the lack of a radiological quality manual, a condition that generated problems in the acceptance of such documents. studies, compromising the quality of the institutions, on patient exposure among other problems associated with the provision of the service. The purpose of the project is the elaboration of a Radiological quality manual, describing the step by step from the recognition of the problem at the local level in which the need to improve the quality of diagnosis by X-ray images was identified, the project collected information from theoretical references that have worked on the objective of standardizing the processes of taking diagnostic images, based on these and with the support of the Bontrager manual, a structuring of the most common studies that the IPS of the city, which may have aspects to evaluate the quality of the image, establishing transversal axes such as radio protection, positioning and the ALARA Principle. The Radiological Quality manual follows guidelines for the definition of requirements and characteristics of the product to be carried out according to the ISO 9001 standard, which seeks to achieve quality standards, which, when applied to this project, allowed the creation of a clear guide that is easily applicable to the institution that needs it. adhere to this process

CAR T-Cells in Multiple Myeloma Are Ready for Prime Time

The survival of patients with multiple myeloma (MM) has been dramatically improved in the last decade thanks to the incorporation of second-generation proteasome inhibitors (PI), immunomodulatory drugs (IMID), and, more recently, anti-CD38 monoclonal antibodies (MoAb). Nevertheless, still, a major proportion of MM patients will relapse, underscoring the need for new therapies in this disease. Moreover, survival in patients failing the current standard of care regimens (including PI, IMIDs, and anti-CD38 MoAb), which is now defined as triple-class refractory, remains dismal, and new drugs with different mechanism of action are needed. B-cell maturation antigen (BCMA)-targeted therapies and in particular chimeric antigen receptor T cell (CAR T-cell) treatment have emerged as promising platforms to overcome refractoriness to conventional drugs. In this manuscript, we review the current available data regarding CAR T-cell therapy for MM, with a special focus on target selection, clinical results, limitations, and future strategies

11C-Methionine-PET in multiple myeloma: a combined study from two different institutions

$^{11}$C-methionine (MET) has recently emerged as an accurate marker of tumor burden and disease activity in patients with multiple myeloma (MM). This dual-center study aimed at further corroboration of the superiority of MET as positron emission tomography (PET) tracer for staging and re-staging MM, as compared to $^{18}$F-2`-deoxy-2`-fluoro-D-glucose (FDG). 78 patients with a history of solitary plasmacytoma (n=4), smoldering MM (SMM, n=5), and symptomatic MM (n=69) underwent both MET- and FDG-PET/computed tomography (CT) at the University Centers of Würzburg, Germany and Navarra, Spain. Scans were compared on a patient and on a lesion basis. Inter-reader agreement was also evaluated. In 2 patients, tumor biopsies for verification of discordant imaging results were available. MET-PET detected focal lesions (FL) in 59/78 subjects (75.6%), whereas FDG-PET/CT showed lesions in only 47 patients (60.3%; p<0.01), accordingly disease activity would have been missed in 12 patients. Directed biopsies of discordant results confirmed MET-PET/CT results in both cases. MET depicted more FL in 44 patients (56.4%; p<0.01), whereas in two patients (2/78), FDG proved superior. In the remainder (41.0%, 32/78), both tracers yielded comparable results. Inter-reader agreement for MET was higher than for FDG (κ = 0.82 vs κ = 0.72). This study demonstrates higher sensitivity of MET in comparison to standard FDG to detect intra- and extramedullary MM including histologic evidence of FDG-negative, viable disease exclusively detectable by MET-PET/CT. MET holds the potential to replace FDG as functional imaging standard for staging and re-staging of MM