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Le myélome multiple (MM) est le second cancer hématologique le plus répandu après les lymphomes. Malgré une amélioration de sa prise en charge au cours des 20 dernières années, les traitements actuels ne permettent pas d’éviter les rechutes répétitives associées au développement de mécanismes de résistance. Les résistances aux traitements sont notamment expliquées par la forte hétérogénéité de la maladie qui rend nécessaire le développement de prises en charges adaptées aux profils moléculaires des patients. L’avènement des technologies de séquençage haut-débit permet d’accéder à des niveaux de plus en plus détaillés de l’hétérogénéité moléculaire tumorale, ce qui permettra de proposer des solutions plus performantes dans l’optique de développer une médecine personnalisée. Dans cet objectif, nous avons analysé l’exome, le transcriptome et l’épigénome de cellules primaires de patients et de lignées cellulaires de MM. Sur la base de ces analyses, nous avons non seulement mis en évidence de nouveaux mécanismes impliqués dans la physiopathologie du MM mais également de nouvelles cibles thérapeutiques potentielles, des biomarqueurs pronostiques ainsi que des signatures d’orientation thérapeutiques. Les données et résultats de nos études constituent une ressource d’intérêt pour la communauté scientifique et permettront d’améliorer la prise en charge thérapeutique des patients atteints de MM. / Multiple myeloma (MM) is the second most common hematological malignancy after lymphoma. Recent advances in treatment have led to an overall survival of intensively-treated patients of 6-7 years. However, patients invariably relapse after multiple lines of treatment, with shortened intervals between relapses, and finally become resistant to all treatments, resulting in loss of clinical control over the disease in association with drug resistance. Treatment improvements will come from a better comprehension of tumorigenesis and detailed molecular analyses to develop individualized therapies taking into account the molecular heterogeneity and subclonal evolution. In this purpose, we analyzed the exome, transcriptome and epigenome of primary MM cells from patients and human MM cell lines. Our results have highlighted new mechanisms involved in the pathophysiology of MM as well as potential new therapeutic targets, prognostic signatures and theranostic biomarkers. The data and results of our studies represent an important resource to understand the mechanisms of tumor progression and drug resistance and develop new ways to diagnose and treat patients.

Résumé confidentiel / Confidential abstract

Orientador: Maria Aparecida Custodio Domingues / Resumo: Mieloma Múltiplo é uma neoplasia maligna de células plasmocitárias, cujas repercussões clínicas de interação da célula tumoral com seu microambiente e com o hospedeiro podem causar danos irreversíveis e progressivos ao doente. Estratégias terapeuticas têm tentado reunir antídotos às várias linhas de atuação da célula tumoral. Objetivou-se avaliar características clíncas e possíveis interações com o microambiente da medula óssea. Foram colhidos dados clínicos, reavaliado material histológico e confeccionado bloco de TMA com grupos de pacientes ao diagnóstico, na primeira recaída e após transplante autólogo de medula óssea. A análise estatística compreendeu descrição dos dados de distribuições de frequência para as variáveis qualitativas e calculadas as médias, desvios padrão, valores mínimo e máximo e mediana para as variáveis quantitativas. O teste de Qui-quadrado de Pearson foi empregado para variáveis qualitativas. Gráficos do tipo mosaico apresentaram os cruzamentos das variáveis discretas e técnica FAMD para verificação da contribuição das variáveis qualitativas e quantitativas simultaneamente. As curvas de sobrevida foram obtidas usando a metodologia de Kaplan & Meier e a estatística de Breslow foi empregada para testar a diferença entre as curvas observadas. Os intervalos de confiança para as curvas e testes foram feitos com nível de significância de 5%. As análises e figuras foram elaboradas com o software R (R Core Team, 2017). Concluímos que pacientes com condições c... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Multiple Myeloma is a malignant neoplasm of plasma cells whose clinical repercussions of tumor cell interaction with its microenvironment and host may cause irreversible and progressive damage to the patient. Therapeutic strategies have attempted to gather antidotes to the various lines of action of the tumor cell. This study aimed to evaluate clinical characteristics and possible interactions with the bone marrow microenvironment. Clinical data were collected, histological material was reevaluated and an AMT block was made with patient groups at diagnosis, in the first relapse and after autologous bone marrow transplantation. Statistical analysis included description of frequency distribution data for qualitative variables and calculated means, standard deviations, minimum and maximum values and median for quantitative variables. Pearson's chi-square test was used for qualitative variables. Mosaic graphs showed the intersections of discrete variables and FAMD technique to verify the contribution of qualitative and quantitative variables simultaneously. Survival curves were obtained using the Kaplan & Meier methodology and the Breslow statistic was employed to test the difference between the observed curves. Confidence intervals for curves and tests were made at a significance level of 5%. The analyzes and figures were elaborated with the R software (R Core Team, 2017).We conclude that patients with clinical conditions for more aggressive initial therapies may impact their su... (Complete abstract click electronic access below) / Doutor

Multiple myeloma is characterized by the malignant proliferation of clonal plasma cells producing monoclonal paraproteins, leading to multi-organ damage. On the other hand monoclonal B-cell lymphocytosis (MBCL) is characterized by the malignant proliferation of clonal B-lymphocytes, with potential to develop into chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). CLL/SLL can result in visceromegaly, anemia, thrombocytopenia, fevers, night sweats and unintentional weight loss. Literature review demonstrates these two malignant clonal bone marrow disorders are most frequently seen independently in patients; however, we report one rare diagnostic challenge where both clonal disorders were identified in a single patient concurrently. A 64-year-old man initially presented with worsening back pain. Thoracic spine x-ray revealed a T11 compression fracture, confirmed by magnetic resonance imaging. Complete blood count revealed a white blood cell count of 7.3 K/uL with 54% lymphocyte predominance and peripheral smear demonstrated a population of small lymphocytes with round nuclei and an atypical chromatin pattern suggestive of CLL/MBCL. Flow cytometry revealed a monoclonal B-cell CD5 positive, CD23 positive, CD10 negative population with an absolute count of 1.6 K/uL. Due to the instability and pain associated with the spinal fracture, patient had kyphoplasty performed and intraoperative bone biopsies were taken from both T11 and T12 vertebrae. Interestingly each bone biopsy revealed involvement by both a kappa-light chain restricted plasma cell neoplasm, ranging from 15% to 30% cellularity, as well as a CD5-positive B-cell lymphocyte population. It suggested two concurrent but pathologically distinct pathologies including plasma cell myeloma and a separate B-cell lymphoproliferative disorder with immunophenotypic features suggestive of CLL/MBCL. Bone marrow biopsy was performed for definitive evaluation and confirmed multiple myeloma with 15-20% kappa-restricted plasma cells identified, and also confirmed concurrent MBCL with CD5 and CD23-positive, kappa-restricted B-cells identified on bone marrow flow cytometry. Adding an additional layer of complexity, bone marrow molecular genetics revealed presence of a MYD88 mutation, raising concern for possible lymphoplasmacytic lymphoma (LPL). However, secondary pathologic review ruled out LPL, as the immunophenotypic pattern of the clonal B-cells was not consistent with that of LPL, and although the MYD88 mutation is predominantly seen in LPL, it has also been seen in a small percentage of CLL/SLL cases and exceedingly rarely described in MM as well. Serum protein electrophoresis with immunofixation, serum quantitative immunoglobulins and serum quantitative free light chain assay revealed findings consistent with IgG kappa multiple myeloma and systemic CT imaging was negative for any lymphadenopathy, confirming MBCL. Patient was started on first-line multiple myeloma systemic therapy for transplant eligible patients and has demonstrated an excellent response to treatment thus far. This patient case serves to demonstrate the importance of maintaining a broad differential when approaching hematological problems; It also underlines the necessity for a complete diagnostic evaluation to identify rare clinical conundrums such as with our patient, allowing for proper and timely treatment. While we use “Occam’s razor” to explain multiple problems with a single unifying diagnosis the rare possibility of divergent diagnosis is to be always entertained.

Thalidomid ist eine in der Therapie des fortgeschrittenen refraktären oder rezidivierten multiplen Myeloms (MM) wirksame Substanz, obwohl dosislimitierende Toxizitäten (DLT) ihren Einsatz beschränken können. In der vorliegenden Phase-I-Studie mit 28 Patienten mit rezidiviertem oder refraktärem MM nach konventioneller Chemotherapie oder Hochdosis (HD)-Chemotherapie mit Stammzelltransplantation (SCT) konnte gezeigt werden, dass eine Kombination von niedrig dosiertem Thalidomid mit Bendamustin und Prednisolon (BPT) die Wirksamkeit beibehält oder erhöht und gleichzeitig keine DLT auftritt. Die BPT-Therapie umfasste eine Dosis von Bendamustin (60mg/m2) Tag 1, 8 und 15 und Prednisolon (100mg) Tag 1, 8, 15 und 22, und eine eskalierende tägliche Dosis Thalidomid (50, 100, 200mg). Die Behandlungszyklen wurden alle 28 Tage bis zum Auftreten des maximalen Ansprechens, DLT oder Fortschreiten der Erkrankung wiederholt. 24 Patienten sprachen nach mindestens zwei Zyklen auf die Therapie an (vier komplette, sechs sehr gute partielle und 14 partielle Remissionen). Das mediane progressionsfreie Überleben und Gesamtüberleben für alle Patienten betrug 11 und 19 Monate. Nur leichte oder mittelschwere nicht-hämatologische Nebenwirkungen wurden beobachtet und kein Patient entwickelte dosislimitierende Hämatotoxizitäten. Die BPT-Therapie weist bei Patienten mit rezidiviertem oder refraktärem MM eine gute Verträglichkeit mit einem Ansprechen von über 80% auf. Die maximal tolerierte Dosis von Thalidomid wurde in dieser Studie nicht erreicht.

Background: Individuals with metastatic bone disease (MBD) and multiple myeloma (MM) are commonly excluded from exercise oncology research due to safety concerns regarding potential skeletal complications including the incidence of pain, impaired mobility, pathological fracture, and spinal cord compression. However, over the past decade research has demonstrated that exercise is not only safe for this population but may offer other therapeutic benefits. To our knowledge, the specific perspectives and needs of individuals with MBD related to physical activity and exercise have not yet been explored. The objective of this study was to identify the attitudes towards and needs related to physical activity and exercise among individuals with MBD and MM. Methods: A phenomenological qualitative study utilizing a pragmatic approach to thematic analysis within a patient-oriented research framework was utilized. Semi-structured interview questions and various questionnaires were utilized to gather this descriptive information. Thematic analysis was completed using the 7-stage Framework Method, including transcription, familiarization, coding, analytical framework, and interpreting the data. Results: Of the 20 volunteer participants (90% male), four were living with MM (20%), and 16 had MBD diagnosed within 2-66 months of the study. Half of the participants did not report feeling any bone pain, with none experiencing severe bone pain, and eight (40%) experienced pain specifically with movement. Most participants engaged in a variety of physical activities and at various intensities, although 25% were found to be sedentary/insufficiently active. Five major themes emerged from the interviews including “meaning of physical activity”, “cancer care ‘exercise is medicine’ support (or lack thereof)”, “motivators to engage in physical activity”, “barriers causing a reduction in physical activity post diagnosis”, and “physical activity program preferences”. These themes encompassed a total of 32 categories and 44 subcategories, creating the overall thematic framework. Discussion: Individuals with MBD and MM do engage in regular physical activity, although differences in the frequency and intensity of exercise exist. Exercise has a recognized and valued role in their lives and health, including bone health. These patients are genuinely interested in some form of exercise program as part of their cancer care. Movement or activity modifications may be required for some based on bony lesions and fracture prevention. Differences may also be related to comorbidities, preferences, and/or abilities. While there is no “one size fits all” approach to oncology-based exercise prescription and implementation among this population, the findings of this study demonstrate that there is a strong patient-identified need to support those living with MBD and MM to engage in regular exercise in order to obtain its physical and psychological benefits. / Graduate / 2023-03-03

Neisseria meningitidis infection in humans usually manifests as meningitis and septicemia with skin manifestations. Infections of the respiratory tract with N meningitidis have been documented in the past, but often this organism is not routinely considered in the differential diagnosis of pneumonia. The pathogenic role of N meningitidis in lower respiratory tract infections may be underestimated because its isolation is difficult, particularly when oropharyngeal flora are present. We profile 2 elderly patients with primary meningococcal pneumonia to show the importance of Gram stain and culture in early diagnosis. These modalities helped guide treatment and prophylactic measures.

Chest pain is an extremely common presenting symptom that is usually related to a cardiac cause. This case illustrates an unusual presentation of multiple myeloma as a cause of atypical chest pain. This case presentation shows the importance of having a broad differential diagnosis while evaluating patients with atypical chest pain. It also illustrates the potential role of Tc-99m sestamibi imaging as a diagnostic modality in patients with multiple myeloma.

Indiana University-Purdue University Indianapolis (IUPUI) / Multiple myeloma (MM) is the most frequent cancer to involve the skeleton, with over 80% of myeloma patients developing lytic bone disease (MMBD). Importantly, MM-associated bone lesions rarely heal even when patients are in complete remission. Bone marrow stromal cells (BMSCs) isolated from MM patients have a distinct genetic profile and an impaired osteoblast (OB) differentiation capacity when compared to BMSCs from healthy donors. Utilizing an in vivo model of MMBD and patient samples, we showed that BMSCs from tumor-bearing bones failed to differentiate into OBs weeks after removal of MM cells. Both Runx2 and Osterix, the master transcription factors for OB differentiation, remained suppressed in these BMSCs. However, the molecular mechanisms for MM-induced long-term OB suppression are poorly understood. We characterized both Runx2 and Osterix promoters in murine pre-osteoblast MC4 cells by chromatin immunoprecipitation (ChIP). The transcriptional start sites (TSSs) of Runx2 and Osterix in untreated MC4 cells were co-occupied by transcriptionally active histone 3 lysine 4 tri-methylation (H3K4me3) and transcriptionally repressive histone 3 lysine 27 tri-methylation (H3K27me3), termed the “bivalent domain”. These bivalent domains became transcriptionally silent with increasing H3K27me3 levels when MC4 cells were co-cultured with MM cells or treated with TNF-α, an inflammatory cytokine increased in MM bone marrow microenvironment. The increasing H3K27me3 levels induced by MM cells or TNF-α were associated with the downregulation of the H3K27 demethylase JMJD3 in MC4 cells and murine BMSCs. Knockdown of JMJD3 in MC4 cells was sufficient to inhibit OB differentiation. Further, ectopic overexpression of JMJD3 in MC4 cells partially rescued the suppression of osteoblast differentiation induced by TNFa. We also found that pre-incubation of MC4 cells with the NF-kB inhibitor quinazoline (QNZ) before TNF-a treatment prevented the downregulation of JMJD3. In agreement with our in vitro findings, BMSCs from MM patients had persistently decreased JMJD3 expression compared to healthy BMSCs. Our findings together demonstrate that decreased JMJD3 expression in BMSCs contributes to the long-term OB suppression in MMBD by remodeling histone landscapes at the Runx2 and Osterix TSSs. Thus, developing strategies to restore JMJD3 expression in BMSCs should increase bone formation and possibly decrease tumor burden in MM.