Publications by authors named "Paola Tacchetti"

61 Publications

Type I SMA "new natural history": long-term data in nusinersen-treated patients.

Ann Clin Transl Neurol 2021 Feb 6. Epub 2021 Feb 6.

Paediatric Neurology, Catholic University, Rome, Italy.

Objective: The aim of this paper was to report the 2-year follow-up in type I patients treated with Nusinersen and to assess whether possible changes in motor function are related to the subtype, age, or SMN2 copy number.

Methods: Sixty-eight patients, with ages ranging from 0.20 to 15.92 years (mean: 3.96; standard deviation: +3.90) were enrolled in the study. All patients were assessed using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and the developmental section of the Hammersmith Infant Neurological Examination (HINE-2) at the time they started treatment and 12 and 24 months after that.

Results: For both CHOP and HINE-2 repeated measures analysis of variance showed a significant difference (P < 0.001) between baseline and 12 months, 12 months and 24 months, and baseline and 24-month scores for the whole group. When age subgroups (<210 days, <2 years, 2-4 years, 5-11 years, 12-18 years) were considered, on the CHOP INTEND the difference was significant between baseline and 24 months in all age subgroups. On the HINE-2, the difference between baseline and 24 months was significant in all the subgroups before the age of 4 years. Age was predictive of changes on both scales (P < 0.05), whereas SMN2 copy number and decimal classification were not.

Interpretation: Our results suggest that some improvement of motor function can be observed even after the first year of treatment. This is more obvious in the infants treated in the first 2 years but some improvement can also be found in older children.
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http://dx.doi.org/10.1002/acn3.51276DOI Listing
February 2021

Bortezomib, thalidomide, and dexamethasone followed by double autologous haematopoietic stem-cell transplantation for newly diagnosed multiple myeloma (GIMEMA-MMY-3006): long-term follow-up analysis of a randomised phase 3, open-label study.

Lancet Haematol 2020 Dec;7(12):e861-e873

Istituto di Ematologia "Seràgnoli", Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Azienda Ospedaliero-Universitaria di Bologna, Università di Bologna, Bologna, Italy. Electronic address:

Background: The phase 3 GIMEMA-MMY-3006 trial, which compared bortezomib, thalidomide, and dexamethasone (VTD) combination therapy with thalidomide and dexamethasone (TD) as induction therapy before and consolidation therapy after double autologous haematopoietic stem-cell transplantation (HSCT) for newly diagnosed multiple myeloma, showed the superiority of the triplet regimen over the doublet in terms of increased complete response rate and improved progression-free survival. We report the results from the final analysis of the study.

Methods: In this randomised, open-label, phase 3 study, patients aged 18-65 years with previously untreated symptomatic multiple myeloma and a Karnofsky Performance Status of 60% or higher were enrolled at 73 centres in Italy. Patients were randomised (1:1) by a web-based system to receive three 21-day cycles of thalidomide (100 mg daily orally for the first 14 days and 200 mg daily thereafter) plus dexamethasone (total 320 mg per cycle; 40 mg on days 1-2, 4-5, 8-9, and 11-12 in the VTD regimen, and 40 mg on days 1-4 and 9-12 in the TD regimen), either alone (TD group) or with bortezomib (1·3 mg/m intravenously on days 1, 4, 8, and 11; VTD group). After double autologous HSCT, patients received two 35-day cycles of either the VTD or TD regimen, according to random assignment, as consolidation therapy. The primary outcome was the rate of complete response and near complete response after induction (already reported). In this updated analysis we assessed long-term progression-free survival and overall survival (secondary endpoints of the study) with an extended 10-year median follow-up, and analysed the variables influencing survival. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, NCT01134484.

Findings: Between May 10, 2006, and April 30, 2008, 480 patients were enrolled and randomly assigned to receive VTD (241 patients) or TD (239 patients). Six patients withdrew consent before start of treatment. 236 (99 [42%] women) in the VTD group and 238 (102 [43%] women) in the TD group were included in the intention-to-treat analysis. The data cutoff date for this analysis was May 31, 2018. Median follow-up for surviving patients was 124·1 months (IQR 117·2-131·7). The 10-year progression-free survival estimate for patients in the VTD group was 34% (95% CI 28-41) compared with 17% (13-23) for the TD group (hazard ratio [HR] 0·62 [95% CI 0·50-0·77]; p<0·0001). 60% (95% CI 54-67) of patients in the VTD group were alive at 10 years versus 46% (40-54) of patients in the TD group (HR 0·68 [95% CI 0·51-0·90]; p=0·0068). VTD was an independent predictor of improved progression-free survival (HR 0·60 [95% CI 0·48-0·76]; p<0·0001) and overall survival (HR 0·68 [0·50-0·91]; p=0·010). The incidence of second primary malignancies per 100 person-years was 0·87 (95% CI 0·49-1·44) in the VTD group compared with 1·41 (0·88-2·13) in the TD group.

Interpretation: Incorporation of VTD into double autologous HSCT resulted in clinically meaningful improvements in long-term progression-free survival and overall survival, confirming that a regimen including bortezomib and an immunomodulatory drug is the gold standard treatment for patients with newly diagnosed myeloma who are fit for high-dose chemotherapy.

Funding: Seràgnoli Institute of Haematology, University of Bologna, and BolognAIL.
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http://dx.doi.org/10.1016/S2352-3026(20)30323-9DOI Listing
December 2020

Standardization of F-FDG-PET/CT According to Deauville Criteria for Metabolic Complete Response Definition in Newly Diagnosed Multiple Myeloma.

J Clin Oncol 2021 Jan 5;39(2):116-125. Epub 2020 Nov 5.

Nuclear Medicine Department, Nantes University Hospital, CRCINA INSERM, CNRS, Université d'Angers, Université de Nantes, Nantes, France.

Purpose: F-Fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) is currently the standard technique to define minimal residual disease (MRD) status outside the bone marrow (BM) in patients with multiple myeloma (MM). This study aimed to define criteria for PET complete metabolic response after therapy, jointly analyzing a subgroup of newly diagnosed transplantation-eligible patients with MM enrolled in two independent European randomized phase III trials (IFM/DFCI2009 and EMN02/HO95).

Patients And Methods: Two hundred twenty-eight patients were observed for a median of 62.9 months. By study design, PET/CT scans were performed at baseline and before starting maintenance (premaintenance [PM]). The five-point Deauville scale (DS) was applied to describe BM (BM score [BMS]) and focal lesion (FL; FL score [FS]) uptake and tested a posteriori in uni- and multivariable analyses for their impact on clinical outcomes.

Results: At baseline, 78% of patients had FLs (11% extramedullary), 80% with an FS ≥ 4. All patients had BM diffuse uptake (35.5% with BMS ≥ 4). At PM, 31% of patients had visually detectable FLs (2% extramedullary), 24% and 67.7% of them with an FS of 3 and ≥ 4, respectively. At PM, 98% of patients retained residual BM diffuse uptake, which was significantly lower than at baseline (mainly between BMS 2 and 3, BMS was ≥ 4 in only 8.7% of patients). By both uni- and multivariable analysis, FS and BMS < 4 were associated with prolonged progression-free survival (PFS) and overall survival (OS) at PM (OS: hazard ratio [HR], 0.6 and 0.47, respectively; PFS: HR, 0.36 and 0.24, respectively).

Conclusion: FL and BM FDG uptake lower than the liver background after therapy was an independent predictor for improved PFS and OS and can be proposed as the standardized criterion of PET complete metabolic response, confirming the value of the DS for patients with MM.
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http://dx.doi.org/10.1200/JCO.20.00386DOI Listing
January 2021

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

J Clin Med 2020 Oct 31;9(11). Epub 2020 Oct 31.

Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Istituto di Ematologia "Seràgnoli", Università degli Studi, Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy.

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.
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http://dx.doi.org/10.3390/jcm9113519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692446PMC
October 2020

A real-world efficacy and safety analysis of combined carfilzomib, lenalidomide, and dexamethasone (KRd) in relapsed/refractory multiple myeloma.

Hematol Oncol 2021 Feb 1;39(1):41-50. Epub 2020 Nov 1.

Azienda Ospedaliero-Universitaria di Bologna, Italia - Istituto di Ematologia "Seràgnoli", Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale - Università degli Studi, Bologna, Italy.

Carfilzomib-lenalidomide-dexamethasone (KRd) has been approved for the treatment of relapsed/refractory multiple myeloma (RRMM). We conducted a retrospective analysis of 197 RRMM patients (pts) between January 2016 and March 2018 in six Italian hematologic centers, with the aim to evaluate efficacy and safety of KRd in real-life. At KRd initiation 27% carried high risk cytogenetic abnormalities (HRCA) [del17p and/or t(4;14) and/or t(14;16)], median number of prior lines of therapy was 2 (1-8), nearly all pts (96%) received prior bortezomib (18% refractory) while 45% were exposed to lenalidomide (R; 22% refractory). At the median of 12.5 months, 52% of the pts had discontinued treatment, mainly (66%) for progression. Main grade 3-4 adverse events were neutropenia (21%), infections (11%), and hypertension (6%). Overall, the response rate was 88%. The median progression-free survival (PFS) was 19.8 months and 1-year overall survival (OS) rate was 80.6%. By subgroup analysis, extended PFS and OS were observed for pts who received ≤2 prior lines of therapy (HR = 0.42, p < 0.001 and HR = 0.35, p = 0.001, respectively), not refractory to prior R (HR = 0.37, p < 0.001, and HR = 0.47, p = 0.024), without HRCA (HR = 0.33, p = 0.005 and HR = 0.26, p = 0.016) and achieving ≥ very good partial response (VGPR; HR = 0.17, p < 0.001 and HR = 0.18, p < 0.001). In conclusion, KRd demonstrated to be effective in RRMM pts treated in real-world setting, without new safety concerns. Better survival outcomes emerged for pts with ≤2 prior lines of therapy, achieving at least a VGPR, and without HRCA.
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http://dx.doi.org/10.1002/hon.2820DOI Listing
February 2021

Genetic modifiers of respiratory function in Duchenne muscular dystrophy.

Ann Clin Transl Neurol 2020 05 28;7(5):786-798. Epub 2020 Apr 28.

Department of Neurosciences DNS, University of Padova, Padova, Italy.

Objective: Respiratory insufficiency is a major complication of Duchenne muscular dystrophy (DMD). Its progression shows considerable interindividual variability, which has been less thoroughly characterized and understood than in skeletal muscle. We collected pulmonary function testing (PFT) data from a large retrospective cohort followed at Centers collaborating in the Italian DMD Network. Furthermore, we analyzed PFT associations with different DMD mutation types, and with genetic variants in SPP1, LTBP4, CD40, and ACTN3, known to modify skeletal muscle weakness in DMD. Genetic association findings were independently validated in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG-DNHS).

Methods And Results: Generalized estimating equation analysis of 1852 PFTs from 327 Italian DMD patients, over an average follow-up time of 4.5 years, estimated that forced vital capacity (FVC) declined yearly by -4.2%, forced expiratory volume in 1 sec by -5.0%, and peak expiratory flow (PEF) by -2.9%. Glucocorticoid (GC) treatment was associated with higher values of all PFT measures (approximately + 15% across disease stages). Mutations situated 3' of DMD intron 44, thus predicted to alter the expression of short dystrophin isoforms, were associated with lower (approximately -6%) PFT values, a finding independently validated in the CINRG-DNHS. Deletions amenable to skipping of exon 51 and 53 were independently associated with worse PFT outcomes. A meta-analysis of the two cohorts identified detrimental effects of SPP1 rs28357094 and CD40 rs1883832 minor alleles on both FVC and PEF.

Interpretation: These findings support GC efficacy in delaying respiratory insufficiency, and will be useful for the design and interpretation of clinical trials focused on respiratory endpoints in DMD.
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http://dx.doi.org/10.1002/acn3.51046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261745PMC
May 2020

Maintenance therapy with bortezomib and dexamethasone after autotransplantation for high-risk multiple myeloma.

Bone Marrow Transplant 2020 09 26;55(9):1865-1867. Epub 2020 Feb 26.

Seràgnoli Institute of Hematology, Department of Experimental, Diagnostic and Specialty Medicine, Bologna University School of Medicine, S. Orsola Malpighi Hospital, Bologna, Italy.

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http://dx.doi.org/10.1038/s41409-020-0844-2DOI Listing
September 2020

The timing of plerixafor addition to G-Csf and chemotherapy affects immunological recovery after autologous stem cell transplant in multiple myeloma.

Bone Marrow Transplant 2020 05 25;55(5):946-954. Epub 2019 Nov 25.

Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Genoa, Italy.

Plerixafor inhibits CXCR4, thus inducing the mobilization of hematopoietic stem/progenitor cells in lymphoma and multiple myeloma (MM) patients eligible for autologous stem cell transplantation (ASCT). However, the kinetics of plerixafor-induced mobilization of lymphocyte subsets is poorly known. Here, we evaluated the graft content, the engraftment, and the immunological reconstitution of MM patients receiving plerixafor. Thirty-seven patients undergoing one or tandem ASCT were enrolled. After mobilization with cyclophosphamide plus G-CSF, plerixafor was added at hematological recovery regardless of CD34 cell count. We evaluated the number of CD34, CD34/CD38, CD3, CD4, CD8, CD19, CD56/CD3, CD4/CD25/FOXP3, and CD138/CD38 cells on each apheresis. Hematological and immunological recovery were determined at 30 days, 3, 6, 9, and 12 months after ASCT. Overall, 34/37 patients mobilized a median of 10.1 × 10 CD34 cells/Kg (IQ 7.7-13.4). Patients with <20/µL CD34 cells at plerixafor administration (18/33) had a significantly higher CD34 cell fold increase, but not a higher absolute number, than 16/33 patients with ≥20/µL CD34 cells. A similar CD34 and immune graft composition was reported. A higher number of CD3 and CD8 cells/µL was observed at 3 months after first ASCT (p < 0.05) in the group with ≥20 CD34 cells/µL. Thus, in MM patients, the timing of plerixafor administration influences immunological recovery.
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http://dx.doi.org/10.1038/s41409-019-0756-1DOI Listing
May 2020

Nusinersen in type 1 spinal muscular atrophy: Twelve-month real-world data.

Ann Neurol 2019 09 8;86(3):443-451. Epub 2019 Jul 8.

Paediatric Neurology and Neuromuscular Omnicentre Clinical Center, Agostino Gemelli University Polyclinic Foundation, Scientific Institute for Research and Health Care, Rome.

Objective: The aim of the study was to report 12-month changes after treatment with nusinersen in a cohort of 85 type I spinal muscular atrophy patients of ages ranging from 2 months to 15 years and 11 months.

Methods: All patients were assessed using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and the Hammersmith Infant Neurological Examination-Section 2 (HINE-2).

Results: Two of the 85 patients had 1 SMN2 copy, 61 had 2 copies, and 18 had 3 copies. In 4 patients the SMN2 copy number was not available. At baseline, the mean CHOP INTEND scores ranged between 0 and 52 (mean = 15.66, standard deviation [SD] = ±13.48), and the mean HINE-2 score was between 0 and 5 (mean = 0.69, SD = ±1.23). There was a difference between baseline and the 12-month scores on both the CHOP INTEND and the HINE-2 for the whole group (p < 0.001), the subgroups with 2 SMN2 copies (p < 0.001), and those with 3 SMN2 copies (p < 0.001). The difference was found not only in patients younger than 210 days at baseline (p < 0.001) but also in those younger than 5 years on the CHOP INTEND and younger than 2 years on the HINE-2.

Interpretation: Our results, expanding the age range and the severity of type I patients treated with nusinersen over 1 year, provide additional data on the range of efficacy of the drug that will be helpful in making an informed decision on whether to start treatment in patients of different ages and severity. ANN NEUROL 2019;86:443-451.
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http://dx.doi.org/10.1002/ana.25533DOI Listing
September 2019

Imaging in multiple myeloma: How? When?

Blood 2019 02 26;133(7):644-651. Epub 2018 Dec 26.

"Seràgnoli" Institute of Hematology, Bologna University School of Medicine, Bologna, Italy.

Bone disease is the most frequent feature of multiple myeloma (MM) and represents a marker of end-organ damage; it is used to establish the diagnosis and to dictate the immediate need for 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, and F-fluorodeoxyglucose-positron emission tomography/computed tomography (PET/CT). In this review, the advantages, indications of use, and applications of the 3 techniques in the management of patients with MM in different settings will be discussed. The European Myeloma Network and the European Society for Medical Oncology guidelines have recommended WBLDCT as the imaging modality of choice for the initial assessment of MM-related lytic bone lesions. Magnetic resonance imaging is the gold-standard imaging modality for detection of bone marrow involvement, whereas PET/CT provides valuable prognostic data and is the preferred technique for assessment of response to therapy. Standardization of most of the techniques is ongoing.
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http://dx.doi.org/10.1182/blood-2018-08-825356DOI Listing
February 2019

Treatment optimization for multiple myeloma: schedule-dependent synergistic cytotoxicity of pomalidomide and carfilzomib in and models.

Haematologica 2018 12 19;103(12):e602-e606. Epub 2018 Jul 19.

"L. & A. Seràgnoli" Institute of Haematology, Department of Experimental Diagnostic and Specialty Medicine (DIMES), Bologna University School of Medicine, Italy.

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http://dx.doi.org/10.3324/haematol.2017.186924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269297PMC
December 2018

Tele-monitoring in paediatric and young home-ventilated neuromuscular patients: A multicentre case-control trial.

J Telemed Telecare 2019 Aug 4;25(7):414-424. Epub 2018 Jun 4.

1 Paediatric Neurology and Muscle Disease Unit, Istituto Giannina Gaslini, Genoa, Italy.

Introduction: Tele-monitoring (TM) has proved effective in the home management of adult ventilator-dependent neuromuscular disease (NMD) patients. We aimed to evaluate a 2-year longitudinal multicentre TM trial designed for young ventilated NMD patients in terms of feasibility, home management of exacerbations and caregivers' burden.

Methods: The TM trial protocol included patients' weekly scheduled overnight home-recording of SpO, heart rate and ventilation and their transmission to each TM centre the following morning. Overnight data were reviewed by non-physicians and calls to families made to assess clinical condition. If clinical conditions (assessed by a scoring system) or overnight parameters worsened, either unscheduled transmissions or calls were activated and managed by non-physicians or medical team according to severity. Hospitalisations were compared with those of TM patients prior to TM start and with those of age-disease-severity-matched controls. Scores from the Caregiver Burden Inventory (CBI) questionnaire pre- and post-TM were compared.

Results: Forty-eight patients were enrolled, 30 males, median age 16.4 years (interquartile range (IQR) 8.9-22.1), median ventilation/day 10.5 h (IQR 8-16). Exacerbations in TM patients did not differ (59 versus 53; = 0.15) from controls. Hospitalisations were significantly reduced in TM patients when compared with those prior to TM (11 versus 24,  = 0.04) and to controls (11 versus 21,  = 0.03). Median hospitalisation length was significantly lower in TM patients than controls (6 versus 7 days,  = 0.03. Caregivers satisfaction was excellent whereas no significant changes in CBI were seen (32.5 versus 35.5,  = 0.06).

Discussion: TM was effective in improving the home management of respiratory exacerbations in young ventilated NMD patients and overall well tolerated.
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http://dx.doi.org/10.1177/1357633X18778479DOI Listing
August 2019

Maintenance in myeloma patients achieving complete response after upfront therapy: a pooled analysis.

J Cancer Res Clin Oncol 2018 Jul 19;144(7):1357-1366. Epub 2018 Apr 19.

Myeloma Unit, Division of Hematology, University of Torino, Azienda-Ospedaliero Universitaria Città della Salute e della Scienza di Torino, via Genova 3, 10126, Torino, Italy.

Purpose: Maintenance demonstrated to improve survival in newly diagnosed multiple myeloma (NDMM) patients and the achievement of complete response (CR) is a strong predictor of survival. Nevertheless, the role of maintenance according to response after induction/consolidation has not been investigated so far. To evaluate the impact of maintenance according to response, we pooled together and retrospectively analyzed data from 955 NDMM patients enrolled in two trials (GIMEMA-MM-03-05 and RV-MM-PI-209).

Methods: Primary endpoints were progression-free survival (PFS)1, PFS2 and overall survival (OS) of CR patients randomized to maintenance and no maintenance. Secondary endpoints were PFS1, PFS2 and OS in very good partial response/partial response (VGPR/PR) patients.

Results: Overall, 213 patients obtained CR after induction/consolidation, 118 received maintenance and 95 no maintenance. In patients achieving CR, maintenance significantly improved PFS1 (HR 0.50, P < 0.001), PFS2 (HR 0.58, P 0.02) and OS (HR 0.51, P 0.02) compared with no maintenance; the advantage was maintained across all the analyzed subgroups according to age, International Staging System (ISS) stage, cytogenetic profile and treatment. Similar features were seen in VGPR/PR patients.

Conclusion: Maintenance prolonged survival in CR and in VGPR/PR patients. The benefit in CR patients suggests the importance of continuing treatment in patients with chemo-sensitive disease.

Trial Registration: The two source studies are registered at ClinicalTrials.gov: identification numbers NCT01063179 and NCT00551928.
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http://dx.doi.org/10.1007/s00432-018-2641-5DOI Listing
July 2018

Safety and efficacy of daratumumab in dialysis-dependent renal failure secondary to multiple myeloma.

Haematologica 2018 06 5;103(6):e277-e278. Epub 2018 Apr 5.

"Seràgnoli" Institute of Hematology, Bologna University School of Medicine, Italy.

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http://dx.doi.org/10.3324/haematol.2018.191122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6058770PMC
June 2018

Anti-CD38 and anti-SLAMF7: the future of myeloma immunotherapy.

Expert Rev Hematol 2018 05 27;11(5):423-435. Epub 2018 Mar 27.

a "Seràgnoli" Institute of Hematology , Bologna University School of Medicine , Bologna , Italy.

Introduction: the high expression of a number of surface antigens on malignant plasma cells, the bone marrow micro-environment and immune effector T cells, makes these appealing targets for immune therapy with monoclonal antibodies (mAbs). Areas covered: Two mAbs, anti-CD38 daratumumab (Dara) and anti-SLAMF7 elotuzumab (Elo), have achieved recent regulatory approval for relapsed or refractory MM (RRMM) and are currently being explored as possible treatment options in novel combinations and different settings. This review discusses the current landscape and possible development of anti-CD38 and anti-SLAMF7 mAbs. Expert commentary: Three phase III trials demonstrated a significant advantage in terms of response and PFS when Dara or Elo are combined with lenalidomide-dexamethsone (Rd) or bortezomib-dexamethsone (Vd), in comparison to doublet regimens, for patients with RRMM. Treatment algorithms including Dara- or Elo-based triplets may be defined on the basis of disease and patients' characteristics, as well as of their prior exposure to different classes of novel agents. Evaluation of these agents in new combination regimens, including second and third generation PIs and IMiDs, are under investigation. Moreover, use of mAbs in phases of the disease where the immune system is less compromised, such as newly diagnosed MM or even high-risk smoldering myeloma, appears logical.
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http://dx.doi.org/10.1080/17474086.2018.1456331DOI Listing
May 2018

Detection of early nocturnal hypoventilation in neuromuscular disorders.

J Int Med Res 2018 Mar 6;46(3):1153-1161. Epub 2017 Dec 6.

1 Unit of Pediatric Neurology and Muscle Disease, 18572 Istituto Giannina Gaslini , Genova, Italy.

Objective Nocturnal hypoventilation (NH) is a complication of respiratory involvement in neuromuscular disorders (NMD) that can evolve into symptomatic daytime hypercapnia if not treated proactively with non-invasive ventilation. This study aimed to assess whether NH can be detected in the absence of other signs of nocturnal altered gas exchange. Methods We performed nocturnal transcutaneous coupled (tc) pCO/SpO monitoring in 46 consecutive cases of paediatric-onset NMD with a restrictive respiratory defect (forced vital capacity < 60%). Nocturnal hypoventilation was defined as tcPCO > 50 mmHg for > 25% of recorded time, and hypoxemia as tcSpO < 88% for > 5 minutes. Daytime symptoms and bicarbonate were recorded after overnight monitoring. Results Twenty-nine of 46 consecutive patients showed NH. Twenty-three patients did not have nocturnal hypoxemia and 18 were clinically asymptomatic. In 20 patients, PaCO in daytime blood samples was normal. Finally, 13/29 patients with NH had isolated nocturnal hypercapnia without nocturnal hypoxia, clinical NH symptoms, or daytime hypercapnia. Conclusions Paediatric patients with NMD can develop NH in the absence of clinical symptoms or significant nocturnal desaturation. Therefore, monitoring of NH should be included among nocturnal respiratory assessments of these patients as an additional tool to determine when to commence non-invasive ventilation.
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http://dx.doi.org/10.1177/0300060517728857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5972237PMC
March 2018

Extramedullary metastatic plasmacytoma in multiple myeloma.

G Ital Dermatol Venereol 2018 Oct 16;153(5):741-743. Epub 2017 Nov 16.

Unit of Dermatology, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.

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http://dx.doi.org/10.23736/S0392-0488.17.05687-5DOI Listing
October 2018

Novel agent-based salvage autologous stem cell transplantation for relapsed multiple myeloma.

Ann Hematol 2017 Dec 24;96(12):2071-2078. Epub 2017 Oct 24.

"Seràgnoli" Institute of Hematology, Sant'Orsola-Malpighi University Hospital, Bologna, Italy.

High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is a standard frontline therapy for multiple myeloma (MM). Therapeutic options for patients with relapsed MM after ASCT include novel agents in different combos, salvage ASCT (sASCT), and allogeneic transplant, with no unique standard of care. We retrospectively analyzed 66 MM patients who relapsed after up-front single or double ASCT(s) and received novel agent-based sASCT at five Italian centers. Median event-free survival from up-front ASCT(s) to first relapse (EFS1) was 44 months. Seventy-three percent of patients received sASCT at first disease progression. Re-induction regimens were bortezomib based in 87% of patients. Response to re-induction therapy included complete response (CR) 18%, ≥ very good partial response (VGPR) 48%, and overall response rate (ORR) 83%. Response to sASCT included CR 44%, ≥ VGPR 77%, and ORR 94%. With a median follow-up of 24 months after sASCT, 39 patients experienced disease progression. Median EFS from sASCT (EFS2) was 17 months. Median overall survival from ASCT (OS1) and sASCT (OS2) was 166 and 43 months, respectively. EFS2 and OS2 were significantly shorter in patients with EFS1 ≤ 24 months, in patients who did not receive sASCT at first disease progression and in patients with extramedullary disease (EMD). In multivariate analysis, EFS1 ≤ 24 months was associated with shorter EFS2 and OS2, EMD was associated with shorter EFS2, and < CR after sASCT was associated with shorter OS2. Novel agent-based sASCT is a safe and effective procedure for relapsed MM.
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http://dx.doi.org/10.1007/s00277-017-3140-5DOI Listing
December 2017

Respiratory pattern in a FSDH paediatric population.

Respir Med 2017 05 29;126:132. Epub 2017 Mar 29.

Pediatric Neurology and Muscle Disease Unit, Istituto Giannina Gaslini, Genova, Italy; Department of Pediatrics, University of Genova, Italy.

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http://dx.doi.org/10.1016/j.rmed.2017.03.023DOI Listing
May 2017

Dermoscopy of cutaneous involvement by multiple myeloma.

J Am Acad Dermatol 2017 Feb;76(2S1):S71-S72

Section of Dermatology, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.

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http://dx.doi.org/10.1016/j.jaad.2016.08.003DOI Listing
February 2017

Role of serum free light chain assay in the detection of early relapse and prediction of prognosis after relapse in multiple myeloma patients treated upfront with novel agents.

Haematologica 2017 03 1;102(3):e104-e107. Epub 2016 Dec 1.

"Seràgnoli" Institute of Hematology, Department of Experimental, Diagnostic and Specialty Medicine, Bologna University School of Medicine, Italy

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http://dx.doi.org/10.3324/haematol.2016.154070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5394964PMC
March 2017

Respiratory pattern in a FSHD pediatric population.

Respir Med 2016 10 22;119:78-80. Epub 2016 Aug 22.

Pediatric Neurology and Muscle Disease Unit, Istituto Giannina Gaslini, Genova, Italy; Department of Pediatrics, University of Genova, Italy.

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant inherited disorder characterized by selective weakness of face and upper arms and girdle. Respiratory involvement in FSHD has been described mainly in the most severely affected patients. In this work we tested the respiratory function by spirometry in 12 patients affected by FSHD with onset before 18 years. Spirometry results were correlated with motor involvement and compared to aged matched group of Becker patients. Of note FSHD patients present a peculiar pattern characterized by a flat shape in flow-volume loop. Respiratory volumes correlate with clinical severity and expiratory phase is specifically affected in comparison to other muscular dystrophies.
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http://dx.doi.org/10.1016/j.rmed.2016.08.014DOI Listing
October 2016

Prognostic impact of serial measurements of serum-free light chain assay throughout the course of newly diagnosed multiple myeloma treated with bortezomib-based regimens.

Leuk Lymphoma 2016 09 14;57(9):2058-64. Epub 2016 Jan 14.

a Department of Experimental, Diagnostic and Specialty Medicine, "Seràgnoli" Institute of Hematology , Bologna University School of Medicine , Bologna , Italy.

We retrospectively investigated the role of serial serum-free light chain (sFLC) evaluations in 150 multiple myeloma (MM) patients treated with first-line bortezomib-based regimens. Baseline sFLC ratio (sFLCR) identified three groups of patients - normal, lightly abnormal (<100), and highly abnormal (≥100) - with different progression-free survival (PFS: 3-year estimate 72% versus 61% versus 44%, respectively, p = 0.03). Moreover, the achievement of a normal sFLCR correlated with extended PFS (49 versus 17 months, p < 0.0001) and overall survival (75 versus 43 months, p < 0.0001) as compared with abnormal sFLCR, a gain maintained in a multivariate analysis for PFS. At relapse, a high sFLCR was associated with earlier start of salvage therapy compared with sFLCR <100 (3-month probability: 89% versus 64%, p = 0.0426). In 20% of patients, sFLC escape preceded the conventional relapse by a median of 3.8 months. Our results highlight the role of sFLC assay in the prognosis and follow-up of MM.
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http://dx.doi.org/10.3109/10428194.2015.1124994DOI Listing
September 2016

The genetic and genomic background of multiple myeloma patients achieving complete response after induction therapy with bortezomib, thalidomide and dexamethasone (VTD).

Oncotarget 2016 Mar;7(9):9666-79

"Seràgnoli" Institute of Hematology, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Bologna University School of Medicine, Bologna, Italy.

The prime focus of the current therapeutic strategy for Multiple Myeloma (MM) is to obtain an early and deep tumour burden reduction, up to the level of complete response (CR). To date, no description of the characteristics of the plasma cells (PC) prone to achieve CR has been reported. This study aimed at the molecular characterization of PC obtained at baseline from MM patients in CR after bortezomib-thalidomide-dexamethasone (VTD) first line therapy.One hundred and eighteen MM primary tumours obtained from homogeneously treated patients were profiled both for gene expression and for single nucleotide polymorphism genotype. Genomic results were used to obtain a predictor of sensitivity to VTD induction therapy, as well as to describe both the transcription and the genomic profile of PC derived from MM with subsequent optimal response to primary induction therapy.By analysing the gene profiles of CR patients, we identified a 5-gene signature predicting CR with an overall median accuracy of 75% (range: 72%-85%). In addition, we highlighted the differential expression of a series of genes, whose deregulation might explain patients' sensitivity to VTD therapy. We also showed that a small copy number loss, covering 606Kb on chromosome 1p22.1 was the most significantly associated with CR patients.
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http://dx.doi.org/10.18632/oncotarget.5718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891075PMC
March 2016

PET/CT Improves the Definition of Complete Response and Allows to Detect Otherwise Unidentifiable Skeletal Progression in Multiple Myeloma.

Clin Cancer Res 2015 Oct 15;21(19):4384-90. Epub 2015 Jun 15.

"Seràgnoli" Institute of Hematology, Bologna University School of Medicine, Bologna, Italy.

Purpose: To evaluate the role of 18F-FDG PET/CT in 282 symptomatic multiple myeloma patients treated up-front between 2002 and 2012.

Experimental Design: All patients were studied by PET/CT at baseline, during posttreatment follow-up, and at the time of relapse. Their median duration of follow-up was 67 months.

Results: Forty-two percent of the patients at diagnosis had >3 focal lesions, and in 50% SUVmax was >4.2; extramedullary disease was present in 5%. On multivariate analysis, ISS stage 3, SUVmax >4.2, and failure to achieve best complete response (CR) were the leading factors independently associated with shorter progression-free survival (PFS) and overall survival (OS). These 3 variables were used to construct a prognostic scoring system based on the number of risk factors. After treatment, PET/CT negativity (PET-neg) was observed in 70% of patients, whereas conventionally defined CR was achieved in 53%. Attainment of PET-neg favorably influenced PFS and OS. PET-neg was an independent predictor of prolonged PFS and OS for patients with conventionally defined CR. Sixty-three percent of patients experienced relapse or progression; in 12%, skeletal progression was exclusively detected by systematic PET/CT performed during follow-up. A multivariate analysis revealed that persistence of SUVmax >4.2 following first-line treatment was independently associated with exclusive PET/CT progression.

Conclusions: PET/CT combined with ISS stage and achievement or not of CR on first-line therapy sorted patients into different prognostic groups. PET/CT led to a more careful evaluation of CR. Finally, in patients with persistent high glucose metabolism after first-line treatment, PET/CT can be recommended during follow-up, to screen for otherwise unidentifiable progression.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-0396DOI Listing
October 2015

Predicting poor peripheral blood stem cell collection in patients with multiple myeloma receiving pre-transplant induction therapy with novel agents and mobilized with cyclophosphamide plus granulocyte-colony stimulating factor: results from a Gruppo Italiano Malattie EMatologiche dell'Adulto Multiple Myeloma Working Party study.

Stem Cell Res Ther 2015 Apr 17;6:64. Epub 2015 Apr 17.

Myeloma Unit, AOU Città della Salute e della Scienza, Turin, Italy.

Introduction: A still not well defined proportion of patients with multiple myeloma (MM) and eligible for autologous stem cell transplantation (AuSCT) fails to mobilize CD34+ peripheral blood stem cells (PBSC) at all or to collect an adequate number for a safe procedure or sufficient for multiple transplants. These so-called "poor-mobilizers" are difficult to be predicted, due to marked difference across previous heterogeneous studies.

Methods: We aimed to develop a method based on simple clinical parameters for predicting unsuccessful (<2×10(6)/kg) or sub-optimal (<5×10(6)/kg) collections of CD34+ PBSC in newly diagnosed MM patients eligible for AuSCT, treated with novel agents and receiving an homogeneous mobilizing therapy with cyclophosphamide and granulocyte-colony stimulating factor (G-CSF). To this purpose, 1,348 patients enrolled in five consecutive Italian clinical trials were retrospectively analysed. Age, baseline low peripheral blood cell counts, use of lenalidomide, and haematological toxicity developed during induction were taken into account as possible factors associated with poor mobilization.

Results: Overall, 280 patients (20.8%) showed either sub-optimal (167 patients, 12.4%) or unsuccessful (113 patients, 8.4%) collections. All analysed parameters negatively influenced the procedure, but only age and haematological toxicity during induction maintained their significance at multivariate analysis. Based on ordinal logistic regression model, we constructed a risk heat-map where the four parameters were pooled and weighted according to their relevance as single or combined variables. This model was predictive for different probabilities of failure, suboptimal or optimal outcomes.

Conclusions: We found that about one fifth of newly diagnosed MM fails to collect an adequate number of PBSC. Our model, based on a large group of patients treated frontline with novel agents and receiving the most popular mobilizing approach currently employed in Europe, is applicable in individual subjects and may contribute to the early identification of "poor mobilizer" phenotypes.
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http://dx.doi.org/10.1186/s13287-015-0033-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4425876PMC
April 2015

Bortezomib-based therapy combined with high cut-off hemodialysis is highly effective in newly diagnosed multiple myeloma patients with severe renal impairment.

Am J Hematol 2015 Jul;90(7):647-52

"Seràgnoli" Institute of Hematology, Department of Experimental, Diagnostic and Specialty Medicine Bologna, University School of Medicine, Sant'Orsola-Malpighi University Hospital, Bologna, Italy.

Multiple myeloma (MM) is often associated with renal insufficiency (RI) which adversely influences the prognosis. Several studies demonstrated that bortezomib can improve both renal function and outcome. We prospectively evaluated 21 newly diagnosed MM patients with severe renal impairment secondary to tubular-interstitial damage, most of them due to myeloma kidney, who were primarily treated with bortezomib-based therapy combined with high cut-off hemodialysis (HCOD). The median serum creatinine level at baseline was 6.44 mg dL(-1) and calculated median estimated glomerular filtration rate (eGFR), according to Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation, was 8 mL/min/1.73 m(2) . Serum free light chain (sFLC) median concentration was 6,040 mg L(-1) . Post induction and best stringent complete response rates were 19 and 38%, respectively. Responses were fast, occurring within a median of 1.4 months. The combination of bortezomib and HCOD led to a prompt and remarkable (>90%) decrease in sFLC levels. Sixteen patients (76%) became dialysis independent within a median of 32 days. With a median follow up of 17.2 months, the 3-year PFS and OS were 76 and 67%, respectively. No early deaths were observed. This study demonstrates that incorporation of bortezomib into induction therapy combined with HCOD is a highly effective strategy in rescuing renal function and improving outcomes in patients with MM and RI.
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http://dx.doi.org/10.1002/ajh.24035DOI Listing
July 2015

Therapeutic targeting of hypoxia and hypoxia-inducible factor 1 alpha in multiple myeloma.

Transl Res 2015 Jun 11;165(6):641-50. Epub 2014 Dec 11.

Department of Experimental Diagnostic and Specialty Medicine (DIMES), Institute of Hematology, "L. & A. Seràgnoli," Bologna University, S. Orsola's University Hospital, Bologna, Italy. Electronic address:

Multiple myeloma (MM) is a clonal B-cell malignancy characterized by accumulation of malignant plasma cells (PCs) within the bone marrow (BM). The PCs are in close contact with stromal cells, which secrete growth factors and cytokines, promoting tumor cell growth and survival. Despite the availability of new drugs with immunomodulatory properties targeting the neoplastic clone and its microenvironment, MM is still an incurable disease, with patients experiencing subsequent phases of remission and relapse, eventually leading to disease resistance and patient death. It is now well established that the MM BM microenvironment is hypoxic, a condition required for the activation of the hypoxia-inducible factor 1 alpha (HIF-1α). It has been shown that HIF-1α is constitutively expressed in MM even in normoxic conditions, suggesting that HIF-1α suppression might be part of a therapeutic strategy. Constitutively activated HIF-1α enhances neovascularization, increases glucose metabolism, and induces the expression of antiapoptotic proteins. HIF-1α is thought to be one of the most important molecular targets in the treatment of cancer, and a variety of chemical inhibitors for HIF-1α have been developed to date. This review examines the role of HIF-1α in MM and recent developments in harnessing the therapeutic potential of HIF-1α inhibition in MM.
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http://dx.doi.org/10.1016/j.trsl.2014.12.001DOI Listing
June 2015

HIF-1α inhibition blocks the cross talk between multiple myeloma plasma cells and tumor microenvironment.

Exp Cell Res 2014 Nov 26;328(2):444-55. Epub 2014 Sep 26.

Department of Experimental Diagnostic and Specialty Medicine (DIMES), "L. & A. Seràgnoli", Bologna University School of Medicine, S. Orsola׳s University Hospital, Italy.

Multiple myeloma (MM) is a malignant disorder of post-germinal center B cells, characterized by the clonal proliferation of malignant plasma cells (PCs) within the bone marrow (BM). The reciprocal and complex interactions that take place between the different compartments of BM and the MM cells result in tumor growth, angiogenesis, bone disease, and drug resistance. Given the importance of the BM microenvironment in MM pathogenesis, we investigated the possible involvement of Hypoxia-Inducible transcription Factor-1 alpha (HIF-1α) in the PCs-bone marrow stromal cells interplay. To test this hypothesis, we used EZN-2968, a 3rd generation antisense oligonucleotide against HIF-1α, to inhibit HIF-1α functions. Herein, we provide evidence that the interaction between MM cells and BM stromal cells is drastically reduced upon HIF-1α down-modulation. Notably, we showed that upon exposure to HIF-1α inhibitor, neither the incubation with IL-6 nor the co-culture with BM stromal cells were able to revert the anti-proliferative effect induced by EZN-2968. Moreover, we observed a down-modulation of cytokine-induced signaling cascades and a reduction of MM cells adhesion capability to the extracellular matrix proteins in EZN-2968-treated samples. Taken together, these results strongly support the concept that HIF-1α plays a critical role in the interactions between bone BM cells and PCs in Multiple Myeloma.
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http://dx.doi.org/10.1016/j.yexcr.2014.09.018DOI Listing
November 2014

Bortezomib- and thalidomide-induced peripheral neuropathy in multiple myeloma: clinical and molecular analyses of a phase 3 study.

Am J Hematol 2014 Dec 17;89(12):1085-91. Epub 2014 Sep 17.

"Seràgnoli" Institute of Hematology, Department of Experimental, Diagnostic and Specialty Medicine, Bologna University School of Medicine, Bologna, Italy.

A subanalysis of the GIMEMA-MMY-3006 trial was performed to characterize treatment-emergent peripheral neuropathy (PN) in patients randomized to thalidomide-dexamethasone (TD) or bortezomib-TD (VTD) before and after double autologous transplantation (ASCT) for multiple myeloma (MM). A total of 236 patients randomized to VTD and 238 to TD were stratified according to the emergence of grade ≥2 PN. Gene expression profiles (GEP) of CD138+ plasma cells were analyzed in 120 VTD-treated patients. The incidence of grade ≥2 PN was 35% in the VTD arm and 10% in the TD arm (P < 0.001). PN resolved in 88 and 95% of patients in VTD and TD groups, respectively. Rates of complete/near complete response, progression-free and overall survival were not adversely affected by emergence of grade ≥2 PN. Baseline characteristics were not risk factors for PN, while GEP analysis revealed the deregulated expression of genes implicated in cytoskeleton rearrangement, neurogenesis, and axonal guidance. In conclusion, in comparison with TD, incorporation of VTD into ASCT was associated with a higher incidence of PN which, however, was reversible in most of the patients and did not adversely affect their outcomes nor their ability to subsequently receive ASCT. GEP analysis suggests an interaction between myeloma genetic profiles and development of VTD-induced PN.
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http://dx.doi.org/10.1002/ajh.23835DOI Listing
December 2014