Osteolytic bone disease is present in about 80% of patients with multiple myeloma at the time of diagnosis. Managing bone disease in patients with multiple myeloma is a challenge and requires a ...multi-faceted treatment approach with medication, surgery, and radiation. The established treatments with intravenous or subcutaneous antiresorptives can cause debilitating adverse events for patients, mainly osteonecrosis of the jaw, which, traditionally, has been difficult to manage. Now, oral surgery is recommended and proven successful in 60-85% of patients. Patients with spinal involvement may benefit from surgery in the form of vertebroplasty and kyphoplasty for pain relief, improved mobility, and reestablished sagittal balance, as well as the restoration of vertebral height. These procedures are considered safe, but the full therapeutic impact needs to be investigated further. Ixazomib, the first oral proteasome inhibitor, increases osteoblast differentiation, and recently published preliminary results in patients treated with Ixazomib maintenance have promisingly shown increased trabecular volume caused by prolonged bone formation activity. Other novel potential treatment strategies are discussed as well.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Purpose of Review
We discuss current topics on the definition of plasma cell leukemia and the distinction between plasma cell leukemia and multiple myeloma. Moreover, we review the latest literature ...on how to treat plasma cell leukemia.
Recent Findings
Plasma cell leukemia is clinically and genetically distinct from multiple myeloma. Plasma cell leukemia is defined by the observation in blood of more than 20% clonal plasma cells by differential count of the leucocytes or by counting more than 2 × 10
9
per liter circulating clonal plasma cells. However, patients with lower levels of circulating plasma cells have the same adverse prognosis, which challenges the disease definition. Survival has improved after implementation of high-dose chemotherapy with stem-cell support, bortezomib, and lenalidomide in the treatment; yet, the prognosis remains poor. The results of allo-transplants have been disappointing.
Summary
The diagnostic criteria of PCL are currently discussed in the international myeloma community. Despite some improvement in survival, the prognosis remains adverse. New, more targeted treatment modalities, including immunotherapies, will hopefully improve the outcome in the near future.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
To examine the perspectives of patients and healthcare professionals of self-administration of subcutaneous (SC) injection of Bortezomib in the homes of patients with Multiple Myeloma (MM), and to ...assess organizational aspects.
A prospective, clinical, parallel mixed-method design with a qualitative core and a quantitative supplementary component was conducted at a single hematological centre in Denmark. Qualitative data were obtained from individual, semi-structured interviews with patients (n = 10) and a focus group interview with healthcare professionals (n = 5); data were analyzed using a hermeneutic approach. Quantitative data were acquired from time registrations performed by patients and nurses and descriptively analyzed applying a micro-costing approach, using cost data per individual.
In general, patients and healthcare professionals were pleased with self-administration as patient empowerment increased. Qualitative findings yielded three themes: “Home is best”, “Everyone is different”, and “Safety first”. Quantitative data were confirmative and revealed self-administration to be time saving for patients and nurses. In a Danish context, delivery of the medicine to the patient's home was slightly more expensive than administration at the hospital.
Self-administration of SC Bortezomib in the homes of patients with MM is advantageous for patients and healthcare professionals. It is feasible, safe, and timesaving. These advantages come with a negligible increase in expenses.
•Self-administration of SC Bortezomib at home is advantageous for both patients with MM and healthcare professionals.•Self-administration is timesaving for patients and healthcare professionals.•Treatment relocation is feasible and safe.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Multiple Myeloma (MM) progresses from monoclonal gammopathy of undetermined significance (MGUS) and/or smoldering MM (SMM). Despite similar primary genetic events as MM, MGUS and SMM PCs are non- or ...low-proliferative. Since oncogene activation and DNA damage drive senescence growth arrest to promote immune clearance of potentially malignant cells, we hypothesized that MGUS and SMM pre-malignant PCs exhibit senescence features. To test this, we performed gene set enrichment analysis (GSEA) of a published human PC gene array dataset (GSE5900) comparing normal, MGUS, and SMM PCs for custom senescence phenotyping gene sets (Senescence Up, SenUp; Senescent Cell Anti-Apoptosis Pathways, SCAPs; Senescence Growth Arrest, SenGA; Inflammatory Senescence Associated Secretory Phenotype, iSASP; Interferon SASP, IFN-SASP) versus biological aging gene sets (SenMayo; CellAge). MGUS and SMM PCs exhibited significant enrichment (NES>1.5, q<0.05) for senescence gene sets SenUp, SenGA, and SCAPs compared to normal PCs, with no enrichment for aging gene sets. MGUS PCs were also enriched for iSASP (NES=1.4, q=0.11), whereas SMM PCs were enriched for IFN-SASP (NES=2.3, q<0.05), characteristic of late-senescence. Thus, both MGUS and SMM PCs show enrichment of senescence gene sets compared to normal PCs with differential SASP profiles. Next, we evaluated MGUS, SMM, and MM patient PCs isolated by magnetic sorting for histological senescence features. PCs were immunostained for LMNB1 and HMGB1, and fluorescent in situ hybridized for α-satellite. Cellular senescence was defined as loss of ≥50% nuclear membrane LMNB1, loss of HMGB1, and ≥2 senescence-associated distensions of satellite (SADS) per nuclei. PCs from MGUS patients (N=12) exhibited increased percentage of senescent PCs (26.9±4.1%, Mean±SEM, p<0.0001) compared to SMM (11.0±1.9%, N=19, p<0.0001) and MM (11.6±1.5%, N=11, p<0.001). A subset analysis of SMM patients for which disease stability was known (≥2 years, N=6-8) showed no differences. These results demonstrate that the percentage of senescent PCs is increased in MGUS but not SMM PCs compared to proliferative disease. To assess PC senescence in the native bone marrow microenvironment (BMME), we evaluated trephine bone biopsies from MGUS and SMM patients that progressed or not to MM ≤10 years, as well as newly diagnosed MM. Biopsies were immunostained for CD138, LMNB1, and HMGB1. Whole biopsy images were analyzed using the artificial intelligence-based software HALO. Cells were classified as senescent if they were double negative and non-senescent if they were double positive for LMNB1 and HMGB1. The percentage of non-senescent PCs increased with progression to MM and positively correlated with total PC burden (R=0.52, p<0.0001), reflective of proliferative disease. Senescent PCs correlated with total senescent BMME (R=0.87, p<0.0001), consistent with a role for senescent cells to drive paracrine senescence. We performed proximity analysis to evaluate the cellular composition within 25um of senescent and non-senescent PCs. As expected, non-senescent PCs exhibited a significantly greater percentage of proximate non-senescent BMME in all groups (p<0.0001). In contrast, senescent PCs in stable MGUS (N=16) and SMM (N=14) were equally surrounded by senescent and non-senescent BMME. In progressing MGUS (N=21) and SMM (N=20), as well as MM (N=18), senescent PCs exhibited significantly reduced senescent BMME in their proximate environment (p<0.05). This suggests that senescent PCs in progressive disease, in contrast to stable disease, fail to drive local paracrine senescence responses. These data demonstrate that PCs from stable MGUS and SMM patients exhibit senescence features, with isolated PCs from stable MGUS showing increased senescence gene expression and histologic features. While stable SMM also exhibits senescence gene expression, they lose morphological features of senescence and show a preferential IFN SASP. Within the bone compartment, senescent PCs in stable MGUS and SMM exhibit the expected proximity to senescent BMME. In contrast, progressing MGUS and SMM, as well as NDMM, show a loss of proximate senescent BMME. Given the role of senescence to drive inflammation to clear potentially tumorigenic cells, these data support that failure to drive paracrine senescence may be key to the immune escape of pre-malignant cells in MGUS and SMM.
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IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZRSKP
To test if Patient Reported Outcomes (PRO) data can replace physical on-site consultation in determining if patients with multiple myeloma, AL amyloidosis, or plasma cell leukemia are ready for their ...next bortezomib treatment without dose reduction.
We developed an online questionnaire addressing common side effects to bortezomib and an algorithm stratifying patients according to their responses and asked them to complete the questionnaire the day before attending the clinic. Applying a mixed-method study design of PRO data, time registrations, and interviews with patients and healthcare professionals, we tested the usability of electronic PRO data forming the basis of decision-making on whether patients are physically fit for the next treatment with an unchanged dose.
The questionnaire and the associated algorithm were able to identify patients who were physically fit for treatment without need for further consultation, with a positive predictive value of 98 %. The method proved to be feasible for all groups of patients regardless of age and educational level. Patients and healthcare professionals found the online questionnaire to be advantageous and flexible.
The use of PRO data to evaluate patients prior to bortezomib treatment is safe and feasible. Patients prefer to report their side effects themselves as it provides them with more freedom during their treatment.
•PRO data is useable to decide if patients are physically fit for chemotherapy.•We developed a questionnaire and a stratifying algorithm with a PPV of 98 %.•Electronic PRO-guided chemotherapy is suitable for older patients too.•Self-reporting of side-effects made patients feel empowered and independent.•Healthcare professionals considered the algorithm as a good and valid working tool.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Multiple Myeloma (MM) is the second most common hematological malignancy and is characterized by clonal expansion of malignant plasma cells in the bone marrow. In spite of recent advances in the ...field of MM, the disease has remained incurable. MM is preceded by a premalignant state known as monoclonal gammopathy of undetermined significance (MGUS), with a risk of progression to MM of 1% per year. Establishing a scalable approach that refines the identification of MGUS patients at high risk of progression to MM can transform the clinical management of the disease, improve the patient's quality of life, and will have significant socioeconomic implications. Here, we provide evidence that changes in the bone marrow adipose tissue (BMAT) provide an early sign for progression from MGUS to MM. We employed AI-assisted histological analysis of unstained bone marrow biopsies from MGUS subjects with or without progression to MM within 10 years (
= 24,
= 17 respectively). Although the BMAT fraction was not different between the two groups, bone marrow adipocyte (BMAd) density was decreased in MGUS patients who developed MM, compared to non-progressing MGUS patients. Importantly, the distribution profile for BMAd size and roundness was significantly different between the two groups, indicating a shift toward increased BMAd size and roundness in MGUS patients who developed MM. These early changes in the BMAT could serve as valuable early indicators for the transition from MGUS to MM, potentially enabling timely interventions and personalized treatment strategies. Finally, the AI-based approach for histological characterization of unstained bone marrow biopsies is cost-effective and fast, rendering its clinical implementation feasible.
The tyrosine kinase receptor c-Met has been suggested to be involved in crucial parts of glioma biology like tumor stemness, growth and invasion. The aim of this study was to investigate the ...prognostic value of c-Met in a population-based glioma patient cohort. Tissue samples from 238 patients with WHO grade I, II, III and IV tumors were analyzed using immunohistochemical staining and advanced image analysis. Strong c-Met expression was found in tumor cells, blood vessels, and peri-necrotic areas. At the subcellular level, c-Met was identified in the cytoplasm and in the cell membrane. Measurements of high c-Met intensity correlated with high WHO grade (p = 0.006) but no association with survival was observed in patients with WHO grade II (p = 0.09) or III (p = 0.17) tumors. High expression of c-Met was associated with shorter overall survival in patients with glioblastoma multiforme (p = 0.03). However the prognostic effect of c-Met in glioblastomas was time-dependent and only observed in patients who survived more than 8.5 months, and not within the first 8.5 months after diagnosis. This was significant in multivariate analysis (HR 1.99, 95 % CI 1.29–3.08, p = 0.002) adjusted for treatment and the clinical variables age (HR 1.01, 95 % CI 0.99–1.03, p = 0.30), performance status (HR 1.34, 95 % CI 1.17–1.53, p < 0.001), and tumor crossing midline (HR 1.28, 95 % CI 0.79–2.07, p = 0.29). In conclusion, this study showed that high levels of c-Met holds unfavorable prognostic value in glioblastomas.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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