Towards Molecular Profiling in Multiple Myeloma: A Literature Review and Early Indications of Its Efficacy for Informing Treatment Strategies.

Multiple myeloma (MM), the second most common hematologic malignancy, is characterized by the clonal expansion of plasma cells. Despite dramatic improvements in patients' survival over the past decade due to advances in therapy exploiting novel molecular targets (immunomodulatory drugs, proteasome inhibitors and monoclonal antibodies), the treatment of relapsed and refractory disease remains challenging. Recent studies confirmed complex, dynamic, and heterogeneous genomic alterations without unifying gene mutations in MM patients. In the current review, we survey recent therapeutic strategies, as well as molecular profiling data on MM, with emphasis on relapsed and refractory cases. A critical appraisal of novel findings and of their potential therapeutic implications will be discussed in detail, along with the author's own experiences/views

Analysis of the frequency of polymorphic repetitive motives in the PAX-7 promotor region in schizophrenic and healthy populations

PAX 7 ist ein Gen mit, neben anderen Funktionen, ausgeprägter neuroentwicklungsgeschichtlicher Bedeutung. Schizophrenie wird heute als primär genetisch bedingte Neuroentwicklungstörung aufgefaßt (I.1.2, Abbildung 2). Im Rahmen dieser Dissertation wurde die Assoziation zwischen den drei repetitiven Trinukleotidpolymorphismen vom (CCT)n Typ und ihren fünf korrespondierenden Genotypen in der regulatorischen Sequenz der PAX 7 Promotorregion, die bekannterweise die Expressionshöhe des PAX 7 Genproduktes beeinflussen und einer Prädisposition zur Entwicklung einer Schizophrenie oder einer Ihrer Subkategorien nach DSM-IV3 (paranoid, nicht-paranoid, schizoaffektiv) mittels eines Polymerasekettenreaktions-basierten Assays in Proben von 280 an Schizophrenie erkrankten Patienten und 229 Kontrollproben gesunder Blutspender untersucht. Weder auf der genotypischen noch auf der allelischen Ebene konnte eine statistisch signifikante Korrelation nachgewiesen werden. Die PAX 7 Promotor Polymorphismen stellen also keine nützlichen Biomarker einer schizophren Polymorphismen Prädisposition dar. Die Rolle dieser Polymorphismen in anderen PAX 7 abhängigen Mechanismen bedarf weiterer Aufklärung, während polygen orientierte „Komplettgenom“ Techniken (z.B. genexpression profiling) besser geeignet sein könnten um das multifaktorielle Netz der Schizophrenie-Entwicklung aufzuklären.Pax 7 is a gene of , among other features, enormous neurodevelopmental importance. Schizophrenia is today considered to be a primarily genetic based neurodevelopmental disease (I.1.2, figure 2). In this thesis the association between the three repetitive trinucleotide polymorphisms of the (CCT)n type and their five existing genotypic expressions, known to affect expression levels of Pax 7, in the regulative sequence of the Pax 7 promotor and the predisposition towards development of schizophrenia or its subcategories according to DSM-IV3 (paranoid, not-paranoid, schizoaffective) was analyzed by means of an polymerase chain reaction based assay in the DNA of 280 pts. afflicted by this condition and 229 control samples from healthy blood donors. No statistical association was found neither on the genotypic nor the allelic level. Thus Pax 7 promotor polymorphisms are no usefull biomarkers of a predisposition towards a development of schizophrenic manifestations. The role this polymorphisms in other Pax 7 related mechanisms should be further elucidated, while polygenic oriented whole genome techniques (e.g. genexpression profiling) seem to be candidates to entangle the multifactorial web of schizophrenic predisposition

Real-World Use of 3rd Line Therapy for Multiple Myeloma in Austria: An Austrian Myeloma Registry (AMR) Analysis of the Therapeutic Landscape and Clinical Outcomes prior to the Use of Next Generation Myeloma Therapeutics

Objective: Clinical trials demonstrate improving survival in patients with multiple myeloma (MM) after treatment. However, it is unclear whether increased survival translates to a similar benefit in a real world setting. Methods: We analyzed the overall survival of 347 multiple myeloma patients in Austria by means of a national registry (AMR), focused on results from 3rd and later lines of therapy. This benchmark was chosen to define a baseline prior to the broad application of upcoming 2nd generation drugs (carfilzomib, pomalidomide). Results: Projected 10 years survival for patients with MM in Austria is estimated to be 56% in patients diagnosed in between the years 2011–2014, 21% in patients with a diagnosis made between 2000–2005, and 39% in those with a diagnosis made between 2006–2010). For the same intervals a significant increase in the use of both bortezomib, lenalidomide and thalidomide—so called IMiDs (from 2005 onwards) and their simultaneous use in combination therapies (from 2010 onwards) could be shown. The use of autologous transplantation (ASCT) remained more or less constant at ~ 35% of patients in the 1st line setting over the whole period, comparing well to international practice patterns, while the use of 2nd line ASCT increased from 5.5% to 18.7% of patients. Patients in 3rd or later line treatment (n = 105), showed that even in relapsed and refractory disease median survival was 27 months with a considerable proportion of long-term survivors (~20%). Conclusion & Perspective With the expected emergence of additional active anti-myeloma compounds, we aim to assess survival in patients with relapsed and refractory MM

Patients and treatment lines.

<p>illustrates the distribution of treatment lines and patients (pts.) documented in the Austrian Myeloma Registry (AMR). Patients who had received at least 3 lines of therapy were included in the analysis (yellow boxes).</p

Patient disposition in patients receiving or not receiving 3^rd line therapy for Multiple myeloma in Austria.

<p>Patient disposition in patients receiving or not receiving 3^rd line therapy for Multiple myeloma in Austria.</p

Survival of Multiple Myeloma patients in Austria overtime and extrapolated Weibull model survival estimates.

<p>The upper part (Fig 2A) illustrates the survival of Myeloma patients in Austria respective to the date of their first diagnosis in between 2000–2005 (blue line), 2006–2010 (red line), and 2011–2014 (green line). The x-axis represents time in years, and the y-axis represents the proportion of patients surviving. The dotted lines give the respective Weibull extrapolation of the patients’ 10 years survival. The lower part (Fig 2B) illustrates the survival of Myeloma patients in Austria respective to the date of their first diagnosis in between 2000–2005 (blue line), 2006–2010 (red line), and 2011–2014 (green line). The x-axis represents time in years, and the y-axis represents the proportion of patients surviving. The dotted lines give the respective Weibull extrapolation of the patients’ 10 years survival.</p