Beyond the marrow: insights from comprehensive next-generation sequencing of extramedullary multiple myeloma tumors.

Extramedullary multiple myeloma (EMM) is an aggressive form of multiple myeloma (MM). This study represents the most comprehensive next-generation sequencing analysis of EMM tumors (N = 14) to date, uncovering key molecular features and describing the tumor microenvironment. We observed the co-occurrence of 1q21 gain/amplification and MAPK pathway mutations in 79% of EMM samples, suggesting that these are crucial mutational events in EMM development. We also demonstrated that patients with mutated KRAS and 1q21 gain/amplification at the time of diagnosis have a significantly higher risk of EMM development (HR = 2.4, p = 0.011) using data from a large CoMMpass dataset. We identified downregulation of CXCR4 and enhanced cell proliferation, along with reduced expression of therapeutic targets (CD38, SLAMF7, GPRC5D, FCRH5), potentially explaining diminished efficacy of immunotherapy. Conversely, we identified significantly upregulated EZH2 and CD70 as potential future therapeutic options. For the first time, we report on the tumor microenvironment of EMM, revealing CD8+ T cells and NK cells as predominant immune effector cells using single-cell sequencing. Finally, this is the first longitudinal study in EMM revealing the molecular changes from the time of diagnosis to EMM relapse.

[Thalidomide in the treatment of multiple myeloma: focus on combination with bortezomib]. / Thalidomid v lécbe mnohocetného myelomu se zamerením na kombinaci s bortezomibem.

Thalidomide, the first clinically available immunomodulatory drug, reaches monotherapy treatment response in about 1/ 3 of significantly pretreated patients with multiple myeloma, and in combination with glucocorticoids approximately 50% response rate. After addition of conventional cytostatic into the triple combination, therapeutic response is achieved in 80% of untreated patients or about 60% of pretreated patients. Therapeutic response is achieved even in 1/3 of patients with refractory multiple myeloma resistant to other available treatment. With regard to the frequency of adverse effects, particularly peripheral polyneuropathy, its use as maintenance therapy was nearly abandoned. The combination of thalidomide and bortezomib has a high therapeutic potential that was accompanied by a high frequency of peripheral polyneuropathy in entry studies. After optimizing bortezomib schedule and route of administration, which lead to significant reduction in the frequency of polyneuropathy, this combination is currently a very interesting therapeutic alternative for clinical practice. This is one of the most economically available treatment regimens combining the benefits of two major drug classes in the treatment of multiple myeloma -  proteasome inhibitor and imunumodulatory drugs. There is also a renewed interest in thalidomide following sharp decline in its use in recent years in the Czech Republic. Comprehensive work is focused on summarizing the longterm experience with thalidomide, with special reference to combination with bortezomib.

[Pre-operative care for cardiac surgery patients with cold antibody disorder, cryoglobulinaemia and cryofibrinogenemia]. / Péce a pacienty s nemocí chladovych protilátek, kryoglobulinemií a kryofibrinogenemií pred kardiochirurgickými zákroky.

We present an example of a patient with confirmed cold agglutinin disease who underwent cardiac surgery in hypothermia to illustrate a known fact that, when exposed to cold, cold agglutinins induce haemolysis of erythrocytes and that cryoglobulins and cryofibrinogens may, upon exposition to cold during a surgery under hypothermia, precipitate or gelify and thus increase plasma viscosity and damage microcirculation. Detailed immunological and haematological investigations in all patients awaiting cardiac surgery with a risk of developing hypothermia is not advantageous considering the low number of patients with clinical and laboratory signs of cold agglutinin disease, autoimmune haemolytic anaemia or paroxysmal cold haemoglobinuria and considering that these investigations, in addition, might not detect cryoglobulinaemia and cryofibrinogenemia. Identification of in-risk patients from the warning signs in the medical history, physical or basal laboratory testing who would subsequently undergo confirmatory investigations to verify the presence of these entities and define them accurately might be a potential solution to this clinical issue. Cardiac surgery strategy and peri-operative care should be tailored to the results of these investigations. Well-structured, practiced and functional cooperation between clinicians and laboratory personnel is a prerequisite for success in these circumstances.