Publications by authors named "Daniele Derudas"

14 Publications

  • Page 1 of 1

How I manage frontline transplant-ineligible multiple myeloma.

Hematol Rep 2020 Sep 21;12(Suppl 1):8956. Epub 2020 Sep 21.

Hematology Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola (FC), Italy.

The Multiple Myeloma (MM) is a plasma cells hematological malignancy with a median age of 69 years at diagnosis. The autologous stem cell transplantation is the standard of care for this disease but less than half of newly diagnosed patients are assessed for this treatment due to comorbidities or complications of disease. The management of transplant ineligible MM patients is based on the balance safety and efficacy of the new available regimen and a careful assessment of the frailty status is mandatory to define the goals. In this review we discuss of the clinical dilemmas in the management and define how to manage them based on the evidence from clinical trials and "real life" experience.
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http://dx.doi.org/10.4081/hr.2020.8956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520858PMC
September 2020

Old and new generation immunomodulatory drugs in multiple myeloma.

Panminerva Med 2020 Dec 21;62(4):207-219. Epub 2020 Sep 21.

Unit of Hematology, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, Forlì-Cesena, Italy.

Introduction: Over the last two decades, the outcomes of patients with multiple myeloma (MM), a malignant plasma cells dyscrasia, have dramatically improved. The development and the introduction of the immunomodulatory drugs (IMiDs) which include thalidomide, lenalidomide, and pomalidomide, have contributed significantly to these improvements.

Evidence Acquisition: The IMiDs have been shown a multitude of mechanisms of action, including antiangiogenic, cytotoxic and immunomodulatory. The more recent discoveries that the IMiDs bind to cereblon and thus regulate the ubiquitination of key transcription factors including IKZF1 and IKZF3, have provided new insight about their activities.

Evidence Synthesis: The IMIDs are widely used in the treatment of the different setting of MM patients and particularly lenalidomide represents the backbone in the therapy of newly diagnosed transplant eligible and transplant ineligible patients, in the maintenance setting post-transplant and in the relapsed/refractory setting, while pomalidomide is currently utilized in the relapsed/refractory setting.

Conclusions: Here the mechanisms of action, the clinical efficacy and the management of side effects are reviewed as well as the new classes of cereblon E3 ligase modulator (CELMoD) and their promising clinical data are described.
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http://dx.doi.org/10.23736/S0031-0808.20.04125-7DOI Listing
December 2020

Homotypic and Heterotypic Activation of the Notch Pathway in Multiple Myeloma-Enhanced Angiogenesis: A Novel Therapeutic Target?

Neoplasia 2019 01 5;21(1):93-105. Epub 2018 Dec 5.

Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy.

Interactions of multiple myeloma (MM) cells with endothelial cells (ECs) enhance angiogenesis and MM progression. Here, we investigated the role of Notch signaling in the cross talk between ECs and MM cells enabling angiogenesis. MMECs showed higher expression of Jagged1/2 ligands, of activated Notch1/2 receptors, and of Hes1/Hey1 Notch target genes than ECs from monoclonal gammopathy of undetermined significance patients, suggesting that homotypic activation of Notch pathway occurs in MM. MM cells co-cultured with MMECs triggered Notch activation in these cells through a cell-to-cell contact-dependent way via Jagged1/2, resulting in Hes1/Hey1 overexpression. The angiogenic effect of Notch pathway was analyzed through Notch1/2·siRNAs and the γ-secretase inhibitor MK-0752 by in vitro (adhesion, migration, chemotaxis, angiogenesis) and in vivo (Vk12598/C57B/6 J mouse model) studies. Activated Notch1/2 pathway was associated with the overangiogenic MMEC phenotype: Notch1/2 knockdown or MK-0752 treatment reduced Hes1/Hey1 expression, impairing in vitro angiogenesis of both MMECs alone and co-cultured with MM cells. MM cells were unable to restore angiogenic abilities of treated MMECs, proving that MMEC angiogenic activities closely rely on Notch pathway. Furthermore, Notch1/2 knockdown affected VEGF/VEGFR2 axis, indicating that the Notch pathway interferes with VEGF-mediated control on angiogenesis. MK-0752 reduced secretion of proangiogenic/proinflammatory cytokines in conditioned media, thus inhibiting blood vessel formation in the CAM assay. In the Vk12598/C57B/6 J mouse, MK-0752 treatment restrained angiogenesis by reducing microvessel density. Overall, homotypic and heterotypic Jagged1/2-mediated Notch activation enhances MMECs angiogenesis. Notch axis inhibition blocked angiogenesis in vitro and in vivo, suggesting that the Notch pathway may represent a novel therapeutic target in MM.
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http://dx.doi.org/10.1016/j.neo.2018.10.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282459PMC
January 2019

Systemic Immunoglobulin Light Chain Amyloidosis-Associated Myopathy: Presentation, Diagnostic Pitfalls, and Outcome.

Mayo Clin Proc 2016 Oct;91(10):1354-1361

Division of Hematology, Mayo Clinic, Rochester, MN. Electronic address:

Objective: To characterize the natural history of immunoglobulin light chain amyloidosis-associated myopathy and to provide guidelines for recognition.

Patients And Methods: Fifty-one patients with systemic immunoglobulin light chain amyloidosis and biopsy-confirmed muscle amyloid deposition diagnosed between January 1, 1995, and December 31, 2015, were included in this study.

Results: Common presenting symptoms were muscle weakness in 49 patients (96%), dysphagia in 23 (45%), myalgia in 17 (33%), macroglossia in 17 (33%), jaw claudication in 13 (25%), and hoarseness in 9 (18%). The median time from the onset of symptoms to diagnosis was almost 2 years. Less than two-thirds of the patients with an outside muscle biopsy (16 of 27) had an established pathologic confirmation of amyloidosis due to failure to routinely incorporate Congo red staining. Moreover, 12 patients were incorrectly treated before diagnosis of amyloid myopathy. More than half of the patients had normal creatine kinase levels at diagnosis. Cardiac troponin T levels were elevated above the reference range in 5 of 12 patients who lacked evidence of cardiac involvement. Median overall survival was 32 months. Factors associated with inferior survival were involvement of more than 2 organs (median survival, 13 months), cardiac involvement (median survival, 15 months), and absence of stem cell transplant (median survival, 18 months). With the exclusion of patients treated with stem cell transplant, no improvement in survival was seen over the 1995-2004 and 2005-2015 decades.

Conclusion: Immunoglobulin light chain amyloidosis-associated myopathy is rare. Delay in diagnosis is common, and there is a high rate of pathologic and clinical misdiagnosis. Awareness of elevation of cardiac troponin T levels in the absence of cardiac disease may be a clue to diagnosis.
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http://dx.doi.org/10.1016/j.mayocp.2016.06.027DOI Listing
October 2016

Treosulfan-fludarabine-thiotepa conditioning before allogeneic haemopoietic stem cell transplantation for patients with advanced lympho-proliferative disease. A single centre study.

Hematol Oncol 2016 Mar 28;34(1):17-21. Epub 2015 Jan 28.

Unità Operativa Ematologia e Centro Trapianti, Ospedale Oncologico di Riferimento Regionale 'Armando Businco', Cagliari, Italy.

In recent years, with the aim of reducing transplant-related mortality, new conditioning regimens have been explored in patients not eligible for conventional haemopoietic stem cell transplantation. In this setting, we investigated safety and feasibility of the treosulfan-fludarabine-thiotepa combination prior to allogeneic haemopoietic stem cell transplantation in patients with advanced lympho-proliferative diseases and at high transplant risk. Twenty-seven consecutive patients, median age 43 years (range 19-60), entered this study. All of them were affected by lympho-proliferative disease in advanced phase and have been heavily pre-treated. The median haemopoietic stem cell transplant co-morbidity index was 1 (range 0-3). Twenty-five patients had regular engraftment, while the remaining two patients were not evaluable for early deaths. Non-haematological toxicity was limited. No patient developed veno-occlusive disease. The estimated probability of overall survival and progression-free survival with a median follow-up of 40 months was 52% (95% confidence interval 33-73) and 50% (95% confidence interval 30-70) respectively. Six patients have relapsed; all of them were not in remission before transplantation. The treosulfan-fludarabine-thiotepa combination is a reduced toxicity but myeloablative regimen that can be proposed to patients not fitting criteria for conventional myeloablative transplant regimens. Longer follow-up and prospective randomized studies are necessary to evaluate this regimen.
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http://dx.doi.org/10.1002/hon.2187DOI Listing
March 2016

HIF-1α of bone marrow endothelial cells implies relapse and drug resistance in patients with multiple myeloma and may act as a therapeutic target.

Clin Cancer Res 2014 Feb 2;20(4):847-58. Epub 2013 Dec 2.

Authors' Affiliations: Section of Internal Medicine, Department of Biomedical Sciences and Human Oncology; Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy, National Cancer Institute "Giovanni Paolo II", Bari, Italy; Department of Human Anatomy, Histology and Embryology, and Pathological Anatomy, University of Bari Medical School; Hematology Unit, Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Oncologic Hospital; Laboratory of Preclinical and Translational Research, IRCCS Basilicata Cancer Reference Centre, Potenza; Department of Clinical and Experimental Medicine, University of Foggia Medical School, Foggia; Hematology Unit, Ospedale Di Venere, Carbonara di Bari, Bari; and Department of Haematology, Businco Hospital, Cagliari, Italy.

Purpose: To investigate the role of hypoxia-inducible factor-1α (HIF-1α) in angiogenesis and drug resistance of bone marrow endothelial cells of patients with multiple myeloma.

Experimental Design: HIF-1α mRNA and protein were evaluated in patients with multiple myeloma endothelial cells (MMEC) at diagnosis, at relapse after bortezomib- or lenalidomide-based therapies or on refractory phase to these drugs, at remission; in endothelial cells of patients with monoclonal gammapathies of undetermined significance (MGUS; MGECs), and of those with benign anemia (controls). The effects of HIF-1α inhibition by siRNA or panobinostat (an indirect HIF-1α inhibitor) on the expression of HIF-1α proangiogenic targets, on MMEC angiogenic activities in vitro and in vivo, and on overcoming MMEC resistance to bortezomib and lenalidomide were studied. The overall survival of the patients was also observed.

Results: Compared with the other endothelial cell types, only MMECs from 45% of relapsed/refractory patients showed a normoxic HIF-1α protein stabilization and activation that were induced by reactive oxygen species (ROS). The HIF-1α protein correlated with the expression of its proangiogenic targets. The HIF-1α inhibition by either siRNA or panobinostat impaired the MMECs angiogenesis-related functions both in vitro and in vivo and restored MMEC sensitivity to bortezomib and lenalidomide. Patients with MMECs expressing the HIF-1α protein had shorter overall survival.

Conclusions: The HIF-1α protein in MMECs may induce angiogenesis and resistance to bortezomib and lenalidomide and may be a plausible target for the antiangiogenic management of patients with well-defined relapsed/refractory multiple myeloma. It may also have prognostic significance.
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http://dx.doi.org/10.1158/1078-0432.CCR-13-1950DOI Listing
February 2014

Pentraxin 3 (PTX3) inhibits plasma cell/stromal cell cross-talk in the bone marrow of multiple myeloma patients.

J Pathol 2013 Jan 1;229(1):87-98. Epub 2012 Oct 1.

Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy.

Pentraxin 3 (PTX3) is a soluble pattern recognition receptor that binds with high affinity and selectivity to fibroblast growth factor-2 (FGF2), thus inhibiting its pro-angiogenic activity. Here we investigated the effects of PTX3 on monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) patient-derived bone marrow (BM) plasma cells (PCs), endothelial cells (ECs), and fibroblasts (FBs), and assessed whether PTX3 can modulate the cross-talk between PCs and those microenvironment cells. PTX3 and FGF2 expression was evaluated by ELISA. Functional studies, including cell viability, wound healing, chemotaxis, and Matrigel(®) assays, were performed on MGUS and MM ECs and FBs upon the PTX3 treatment. Through western blot PTX3-induced modulation in FGF2/FGF receptor signalling pathways was evaluated in MGUS and MM ECs and FBs through western blot. Co-cultures between MM ECs/FBs and human PC lines were used to evaluate possible PTX3 indirect effects on MM PCs. Adhesion molecules were studied by flow cytometry. PTX3 provides a direct time- and dose-dependent apoptotic effect on MM ECs and FBs, but not on either MM primary PCs or human PC lines. PTX3 inhibits migration of MM ECs and FBs in a dose-dependent manner, and impacts in vitro and in vivo FGF2-mediated MM angiogenesis. Co-cultures of PCs and ECs/FBs show that PTX3 treatment indirectly impairs PC viability and adhesion. We conclude that PTX3 is an anti-angiogenic factor in MM and behaves as a cytotoxic molecule on MM cells by inhibiting the cross-talk between PCs and ECs/FBs.
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http://dx.doi.org/10.1002/path.4081DOI Listing
January 2013

Bortezomib-thalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma.

Blood 2012 Jul 12;120(1):9-19. Epub 2012 Apr 12.

Istituto di Ematologia Seràgnoli, Università degli Studi di Bologna, Policlinico S. Orsola-Malpighi, Bologna, Italy.

In a randomized, phase 3 study, superior complete/near-complete response (CR/nCR) rates and extended progression-free survival were demonstrated with bortezomib-thalidomide-dexamethasone (VTD) versus thalidomide-dexamethasone (TD) as induction therapy before, and consolidation after, double autologous stem cell transplantation for newly diagnosed myeloma patients (intention-to-treat analysis; VTD, n = 236; TD, n = 238). This per-protocol analysis (VTD, n = 160; TD, n = 161) specifically assessed the efficacy and safety of consolidation with VTD or TD. Before starting consolidation, CR/nCR rates were not significantly different in the VTD (63.1%) and TD arms (54.7%). After consolidation, CR (60.6% vs 46.6%) and CR/nCR (73.1% vs 60.9%) rates were significantly higher for VTD-treated versus TD-treated patients. VTD consolidation significantly increased CR and CR/nCR rates, but TD did not (McNemar test). With a median follow-up of 30.4 months from start of consolidation, 3-year progression-free survival was significantly longer for the VTD group (60% vs 48% for TD). Grade 2 or 3 peripheral neuropathy (8.1% vs 2.4%) was more frequent with VTD (grade 3, 0.6%) versus TD consolidation. The superior efficacy of VTD versus TD as induction was retained despite readministration as consolidation therapy after double autologous transplantation. VTD consolidation therapy significantly contributed to improved clinical outcomes observed for patients randomly assigned to the VTD arm of the study. The study is registered at www.clinicaltrials.gov as #NCT01134484.
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http://dx.doi.org/10.1182/blood-2012-02-408898DOI Listing
July 2012

Myocardial iron overload assessment by T2* magnetic resonance imaging in adult transfusion dependent patients with acquired anemias.

Haematologica 2008 Sep 4;93(9):1385-8. Epub 2008 Jul 4.

U.O. Ematologia, Ospedale Oncologico "A. Businco", via Edward Jenner, 09121 Cagliari, Italy.

Only limited data are available regarding myocardial iron overload in adult patients with transfusion dependent acquired anemias. To address this topic using MRI T2* we studied 27 consecutive chronic transfusion dependent patients with acquired anemias: (22 myelodysplastic syndrome, 5 primary myelofibrosis). Cardiac MRI T2* values obtained ranged from 5.6 to 58.7 (median value 39.8) milliseconds. Of the 24 analyzable patients, cardiac T2* correlated with transfusion burden (p=0.0002). No patient who had received less than 290 mL/kg of packed red blood cells (101 units=20 grams of iron) had a pathological cardiac T2* value (< 20 ms). All patients who had received at least 24 PRBC units showed MRI T2* detectable hepatic iron (liver T2* value
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http://dx.doi.org/10.3324/haematol.12759DOI Listing
September 2008

Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: updated results of a randomized controlled trial.

Blood 2008 Oct 27;112(8):3107-14. Epub 2008 May 27.

Divisione di Ematologia dell'Università di Torino, Azienda Ospedaliera S. Giovanni Battista, Torino, Italy.

The initial analysis of the oral combination melphalan, prednisone, and thalidomide (MPT) in newly diagnosed patients with myeloma showed significantly higher response rate and longer progression-free survival (PFS) than did the standard melphalan and prednisone (MP) combination and suggested a survival advantage. In this updated analysis, efficacy and safety end points were updated. Patients were randomly assigned to receive oral MPT or MP alone. Updated analysis was by intention to treat and included PFS, overall survival (OS), and survival after progression. After a median follow-up of 38.1 months, the median PFS was 21.8 months for MPT and 14.5 months for MP (P = .004). The median OS was 45.0 months for MPT and 47.6 months for MP (P = .79). In different patient subgroups, MPT improved PFS irrespective of age, serum concentrations of beta(2)-microglobulin, or high International Staging System. Thalidomide or bortezomib administration as salvage regimens significantly improved survival after progression in the MP group (P = .002) but not in the MPT group (P = .34). These data confirm activity of MPT for PFS but failed to show any survival advantage. New agents in the management of relapsed disease could explain this finding. The study is registered at www.clinicaltrials.gov as #NCT00232934.
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http://dx.doi.org/10.1182/blood-2008-04-149427DOI Listing
October 2008

T-cell receptor repertoire in healthy Sardinian subjects.

Hum Immunol 2003 Jul;64(7):689-95

Institute of Hematology, University of Sassari, Sassari, Italy.

The T-cell receptor (TCR) Vbeta gene usage of CD4+ and CD8+ T-cell subpopulations was evaluated by flow cytometric analysis and by CDR3 spectratyping in healthy subjects belonging to Sardinian population, which is ethnically homogeneous and genetically distant from all other Italian and Caucasoid groups. As described in healthy Caucasian subjects, we found a nonrandom Vbeta gene usage and in some Vbeta families a significant skewed reactivity toward CD4+ T cells. Moreover, different subjects showed expansions in some Vbeta subfamilies, mainly in the CD8+ T cells. By CDR3 spectratyping analysis we found a significantly higher degree of skewness in the TCR Vbeta repertoire of CD8+ than in that of CD4+ T cells. The similarity found in the TCR Vbeta gene usage between the population examined and other Caucasoid groups suggest that the shape of the TCR repertoire is more influenced by rearrangement processes than ethnic background. However, genetic polymorphisms may condition the expression levels of some Vbetas, determining the variability of the TCR repertoire between different populations. Finally, the profound perturbations evidenced in the CD8+ T cell subpopulation could be related to a different response to the antigenic stimulation between CD8+ and CD4+ T lymphocytes.
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http://dx.doi.org/10.1016/s0198-8859(03)00086-7DOI Listing
July 2003