Thalidomide-dexamethasone as induction therapy before autologous stem cell transplantation in patients with newly diagnosed multiple myeloma and renal insufficiency.

The aim of this study was to evaluate the efficacy and the toxicity of thalidomide-dexamethasone (Thal-Dex) as induction therapy before autologous peripheral blood stem cell (PBSC) transplantation in patients with newly diagnosed multiple myeloma (MM) with renal insufficiency. The study included 31 patients with a baseline creatinine clearance value ≤50 mL/min, 7 of whom required chronic hemodialysis. Patients received 4 months of Thal-Dex, followed by PBSC collection and subsequent transplantation. After induction, a partial response (PR) or greater was obtained in 23 patients (74%), including 8 (26%) who achieved a very good PR. Renal function improved more frequently in patients achieving a PR or greater (82%, vs 37% in patients achieving less than a PR; P = .04). Twenty-six patients underwent PBSC mobilization; in 17 of these patients (65%), >4 × 10 6 CD34 + cells/kg were collected. Double autologous transplantation was performed in 15 patients, and a single autologous transplantation was performed in 7 patients. After a median of 32 months of follow-up, median event-free survival was 30 months, and median survival was not determined. According to our data, Thal-Dex is effective and safe in patients with newly diagnosed MM and renal insufficiency. Given the relationship between recovery of renal function and response to induction treatment, more intensive Thal + bortezomib regimens could be explored to rescue higher numbers of patients

Early Light Chains Removal and Albumin Levels with a Double Filter-Based Extracorporeal Treatment for Acute Myeloma Kidney

Renal impairment in Multiple Myeloma (MM) represents one of the most important factors that influences patient survival. In fact, before the introduction of modern chemotherapy, less than 25% of patients with acute kidney injury (AKI) and MM who required dialysis recovered sufficient renal function to become independent from dialysis, with a median overall survival of less than 1 year. There are many other factors involved in determining patient survival. In this study we aimed to investigate the role of double filter-based extracorporeal treatment for removal of serum free light chains (sFLC) in acute myeloma kidney (AKI for MM) and to evaluate patient overall survival. All patients received Bortezomib-based chemotherapy and extracorporeal treatment for sFLC removal. For each session 2 dialyzers of the same kind were used. The dialytic dose was not related to the degree of renal function but to the removal of sFLC. The factors that have been found to be significantly associated with lower mortality were reduction of sFLC at day 12 and day 30, >50% reduction of sFLC at day 30, number of sessions and independence from dialysis. Among baseline characteristics, albumin level was statistically associated with the patients' outcome. Our analysis highlights the importance of the early treatment for removal of sFLC in AKI for MM. These results indicate that the early removal of sFLC can improve patient's outcome

11C-choline vs. 18F-FDG PET/CT in assessing bone involvement in patients with multiple myeloma

<p>Abstract</p> <p>Background</p> <p>Multiple Myeloma (MM) is a B cell neoplasm causing lytic or osteopenic bone abnormalities. Whole body skeletal survey (WBSS), Magnetic resonance (MR) and ¹⁸F-FDG PET/CT are imaging techniques routinely used for the evaluation of bone involvement in MM patients.</p> <p>Aim</p> <p>As MM bone lesions may present low ¹⁸F-FDG uptake; the aim of this study was to assess the possible added value and limitations of ¹¹C-Choline to that of ¹⁸F-FDG PET/CT in patients affected with MM.</p> <p>Methods</p> <p>Ten patients affected with MM underwent a standard ¹¹C-Choline PET/CT and an ¹⁸F-FDG PET/CT within one week. The results of the two scans were compared in terms of number, sites and SUV_maxof lesions.</p> <p>Results</p> <p>Four patients (40%) had a negative concordant ¹¹C-Choline and ¹⁸F-FDG PET/CT scans. Two patients (20%) had a positive ¹¹C-Choline and ¹⁸F-FDG PET/CT scans that identified the same number and sites of bone lesions. The remaining four patients (40%) had a positive ¹¹C-Choline and ¹⁸F-FDG PET/CT scan, but the two exams identified different number of lesions. Choline showed a mean SUV_maxof 5 while FDG showed a mean SUV_maxof 3.8 (P = 0.042). Overall, ¹¹C-Choline PET/CT scans detected 37 bone lesions and ¹⁸F-FDG PET/CT scans detected 22 bone lesions but the difference was not significant (P = 0.8).</p> <p>Conclusion</p> <p>According to these preliminary data, ¹¹C-Choline PET/CT appears to be more sensitive than ¹⁸F-FDG PET/CT for the detection of bony myelomatous lesions. If these data are confirmed in larger series of patients, ¹¹C-Choline may be considered a more appropriate functional imaging in association with MRI for MM bone staging.</p

The ALLgorithMM: How to define the hemodilution of bone marrow samples in lymphoproliferative diseases

IntroductionMinimal residual disease (MRD) is commonly assessed in bone marrow (BM) aspirate. However, sample quality can impair the MRD measurement, leading to underestimated residual cells and to false negative results. To define a reliable and reproducible method for the assessment of BM hemodilution, several flow cytometry (FC) strategies for hemodilution evaluation have been compared. MethodsFor each BM sample, cells populations with a well-known distribution in BM and peripheral blood - e.g., mast cells (MC), immature (IG) and mature granulocytes (N) - have been studied by FC and quantified alongside the BM differential count. ResultsThe frequencies of cells' populations were correlated to the IG/N ratio, highlighting a mild correlation with MCs and erythroblasts (R=0.25 and R=0.38 respectively, with p-value=0.0006 and 0.0000052), whereas no significant correlation was found with B or T-cells. The mild correlation between IG/N, erythroblasts and MCs supported the combined use of these parameters to evaluate BM hemodilution, hence the optimization of the ALLgorithMM. Once validated, the ALLgorithMM was employed to evaluate the dilution status of BM samples in the context of MRD assessment. Overall, we found that 32% of FC and 52% of Next Generation Sequencing (NGS) analyses were MRD negative in samples resulted hemodiluted (HD) or at least mildly hemodiluted (mHD). ConclusionsThe high frequency of MRD-negative results in both HD and mHD samples implies the presence of possible false negative MRD measurements, impairing the correct assessment of patients' response to therapy and highlighs the importance to evaluate BM hemodilution

The ocular albinism type 1 protein, an intracellular G protein-coupled receptor, regulates melanosome transport in pigment cells

The protein product of the ocular albinism type 1 gene, named OA1, is a pigment cell-specific G protein-coupled receptor exclusively localized to intracellular organelles, namely lysosomes and melanosomes. Loss of OA1 function leads to the formation of macromelanosomes, suggesting that this receptor is implicated in organelle biogenesis, however the mechanism involved in the pathogenesis of the disease remains obscure. We report here the identification of an unexpected abnormality in melanosome distribution both in retinal pigment epithelium (RPE) and skin melanocytes of Oa1-knock-out (KO) mice, consisting in a displacement of the organelles from the central cytoplasm towards the cell periphery. Despite their depletion from the microtubule (MT)-enriched perinuclear region, Oa1-KO melanosomes were able to aggregate at the centrosome upon disruption of the actin cytoskeleton or expression of a dominant-negative construct of myosin Va. Consistently, quantification of organelle transport in living cells revealed that Oa1-KO melanosomes displayed a severe reduction in MT-based motility; however, this defect was rescued to normal following inhibition of actin-dependent capture at the cell periphery. Together, these data point to a defective regulation of organelle transport in the absence of OA1 and imply that the cytoskeleton might represent a downstream effector of this receptor. Furthermore, our results enlighten a novel function for OA1 in pigment cells and suggest that ocular albinism type 1 might result from a different pathogenetic mechanism than previously thought, based on an organelle-autonomous signalling pathway implicated in the regulation of both membrane traffic and transport

Imaging in multiple myeloma: Which? When?

Bone disease is the most frequent feature of multiple myeloma (MM) and represents a marker of end-organ damage, used to establish the diagnosis and to dictate the immediate need of therapy. For this reason, imaging plays a significant role in the management of MM patients. Although conventional radiography has traditionally been the standard imaging modality, its low sensitivity in detecting osteolytic lesions and inability to evaluate response to therapy has called for the use of more sophisticated techniques, such as whole body low dose computed tomography (WBLDCT), whole body magnetic resonance imaging (WBMRI), and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET/CT). In this review, the advantages, indications of use, and applications of the three different techniques in the management of patients with MM in different settings will be discussed. The European Myeloma Network (EMN) and the European Society for Medical Oncology (ESMO) guidelines have recommended whole body low-dose CT (WBLDCT) as the imaging modality of choice for the initial assessment of MM-related lytic bone lesions. MRI is the gold-standard imaging modality for detection of bone marrow involvement, while PET/CT provides valuable prognostic data and is to date the preferred technique in assessment of response to therapy. Standardization of most of the techniques is on-going

Role of Imaging in the Evaluation of Minimal Residual Disease in Multiple Myeloma Patients

The International Myeloma Working Group (IMWG) recently introduced the evaluation of minimal residual disease (MRD) within the multiple myeloma (MM) response criteria, and MRD negativity assessed inside and outside the bone marrow is currently considered the most powerful predictor of favorable long-term outcomes. However, MRD evaluation has thus far relied on flow-cytometry or molecular-based methods, despite the limitations associated with the patchy infiltration of bone marrow (BM) plasma cells and the presence of extra-medullary (EMD). On the contrary, imaging-based sensitive response assessment through the use of functional rather than morphological whole-body (WB) imaging techniques, such as positron emission tomography with computed tomography (PET/CT) and magnetic resonance imaging (MRI), likely is a promising strategy to overcome these limitations in evaluating response to therapy and in the assessment of the MRD status in MM patients. However, despite the significant advances in the development and availability of novel functional imaging techniques for MRD evaluation, a worldwide standardization of imaging criteria for acquisition, interpretation, and reporting is yet to be determined and will be object of future investigations