Gay F.,Myeloma Unit
Leukemia | Year: 2017
In newly diagnosed myeloma patients, upfront autologous transplant (ASCT) prolongs progression-free survival 1 (PFS1) compared with chemotherapy plus lenalidomide (CC+R). Salvage ASCT at first relapse may still effectively rescue patients who did not receive upfront ASCT. To evaluate the long-term benefit of upfront ASCT vs CC+R and the impact of salvage ASCT in patients who received upfront CC+R, we conducted a pooled analysis of 2 phase III trials (RV-MM-209 and EMN-441). Primary endpoints were PFS1, progression-free survival 2 (PFS2), overall survival (OS). A total of 268 patients were randomized to 2 courses of melphalan 200 mg/m2 and ASCT (MEL200-ASCT) and 261 to CC+R. Median follow-up was 46 months. MEL200-ASCT significantly improved PFS1 (median: 42 vs 24 months, HR 0.53; P<0.001), PFS2 (4 years: 71 vs 54%, HR 0.53, P<0.001) and OS (4 years: 84 vs 70%, HR 0.51, P<0.001) compared with CC+R. The advantage was noticed in good and bad prognosis patients. Only 53% of patients relapsing from CC+R received ASCT at first relapse. Upfront ASCT significantly reduced the risk of death (HR 0.51; P=0.007) in comparison with salvage ASCT. In conclusion, these data confirm the role of upfront ASCT as the standard approach for all young myeloma patients.Leukemia advance online publication, 24 January 2017; doi:10.1038/leu.2016.381. © 2017 Macmillan Publishers Limited, part of Springer Nature.
Offidani M.,Clinica di Ematologia |
Polloni C.,Clinica di Ematologia |
Cavallo F.,Myeloma Unit |
Marina Liberati A.,Unita Oncoematologia Autotrapianto |
And 9 more authors.
Leukemia and Lymphoma | Year: 2012
The combination of melphalan, prednisone and thalidomide (MPT) has demonstrated efficacy and acceptable toxicity in newly diagnosed and relapsed/refractory patients with multiple myeloma (MM). Panobinostat is a potent oral pan-deacetylase inhibitor (pan-DACi). In preclinical and clinical studies, panobinostat showed good anti-myeloma activity in combination with several agents. This phase II study evaluated the combination of a fixed dose of MPT with escalating doses of panobinostat (three times weekly for 3 weeks, followed by a 9-day rest period) in relapsed/refractory MM. We used a two-stage design to determine whether the combination was safe and effective. At least a partial response was observed in 38.5% of patients. The maximum tolerated dose of panobinostat in combination with MPT could not be determined due to the high rate of dose-limiting toxicities experienced with panobinostat at doses of 10 and 15 mg. The most common grade 3/4 adverse events were neutropenia (71%) and thrombocytopenia (35.5%). In conclusion, MPT in combination with panobinostat three times weekly for 3 weeks followed by a 9-day rest period is not well tolerated in patients with relapsed/refractory MM. Future studies should evaluate alternative dose schedules of panobinostat. © 2012 Informa UK, Ltd.
Bringhen S.,Myeloma Unit |
Petrucci M.T.,University of Rome La Sapienza |
Larocca A.,Myeloma Unit |
Conticello C.,Ospedale Ferrarotto |
And 16 more authors.
Blood | Year: 2014
This multicenter, open-label phase 2 trial determined the safety and efficacy of carfilzomib, a novel and irreversible proteasome inhibitor, in combination with cyclophosphamide and dexamethasone (CCyd) in patients with newly diagnosed multiple myeloma (NDMM) ≥65 years of age or who were ineligible for autologous stem cell transplantation. Patients (N 5 58) received CCyd for up to 9 28-day cycles, followed by maintenance with carfilzomib until progression or intolerance. After a median of 9 CCyd induction cycles (range 1-9), 95% of patients achieved at least a partial response, 71% achieved at least a very good partial response, 49% achieved at least a near complete response, and 20% achieved stringent complete response. After a median follow-up of 18 months, the 2-year progression-free survival and overall survival rates were 76% and 87%, respectively. The most frequent grade 3 to 5 toxicities were neutropenia (20%), anemia (11%), and cardiopulmonary adverse events (7%). Peripheral neuropathy was limited to grades 1 and 2 (9%). Fourteen percent of patients discontinued treatment because of adverse events, and 21% of patients required carfilzomib dose reductions. In summary, results showed high complete response rates and a good safety profile. This trial was registered at clinicaltrials.gov as #NCT01346787. © 2014 by The American Society of Hematology.
Palumbo A.,Myeloma Unit |
Bringhen S.,Myeloma Unit |
Mateos M.-V.,University of Salamanca |
Larocca A.,Myeloma Unit |
And 23 more authors.
Blood | Year: 2015
We conducted a pooled analysis of 869 individual newly diagnosed elderly patient data from 3 prospective trials. At diagnosis, a geriatric assessment had been performed. An additive scoring system (range 0-5), based on age, comorbidities, and cognitive and physical conditions, was developed to identify 3 groups: fit (score = 0, 39%), intermediate fitness (score = 1,31%), and frail (score ≥2, 30%). The 3-year overall survivalwas 84%in fit, 76% in intermediate-fitness (hazard ratio [HR], 1.61; P = .042), and 57% in frail (HR, 3.57; P < .001) patients. Thecumulative incidence of grade ≥3 nonhematologic adverse events at 12 months was 22.2%in fit, 26.4%in intermediate-fitness (HR, 1.23; P = .217), and 34.0%in frail (HR, 1.74; P < .001) patients. The cumulative incidence of treatment discontinuation at 12months was 16.5%in fit, 20.8%in intermediate-fitness (HR, 1.41; P = .052), and 31.2% in frail (HR, 2.21; P < .001) patients. Our frailty score predicts mortality and the risk of toxicity in elderly myeloma patients. The International Myeloma Working group proposes this score for the measurement of frailty in designing future clinical trials. These trials are registered at www.clinicaltrials.gov as #NCT01093136 (EMN01), #NCT01190787 (26866138MMY2069), and #NCT01346787 (IST-CAR-506).
PubMed | Barwon Health, AO S.Maria di Terni, Clinica di Ematologia, University of Bari and 13 more.
Type: | Journal: Leukemia | Year: 2016
In newly diagnosed myeloma patients, upfront autologous transplant (ASCT) prolongs progression-free survival-1 (PFS1) compared with chemotherapy plus lenalidomide (CC+R). Salvage ASCT at first relapse may still effectively rescue patients who did not receive upfront ASCT. To evaluate the long-term benefit of upfront ASCT vs CC+R and the impact of salvage ASCT in patients who received upfront CC+R, we conducted a pooled analysis of 2 phase III trials (RV-MM-209 and EMN-441). Primary endpoints were PFS1, progression-free survival-2 (PFS2), overall survival (OS). A total of 268 patients were randomized to 2 courses of melphalan 200mg/m
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 dellAdulto Multiple Myeloma Working Party study
PubMed | S Carlo Hospital, Haematology Unit, Clinica di Ematologia, Centro Oncologico Fiorentino and 7 more.
Type: | Journal: Stem cell research & therapy | Year: 2015
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.We aimed to develop a method based on simple clinical parameters for predicting unsuccessful (<210(6)/kg) or sub-optimal (<510(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.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.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.
Tacchetti P.,University of Bologna |
Terragna C.,University of Bologna |
Galli M.,Ospedali Riuniti |
Zamagni E.,University of Bologna |
And 16 more authors.
American Journal of Hematology | Year: 2014
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. © 2014 Wiley Periodicals, Inc.
PubMed | Instituto Giannina Gaslini, University of Parma, Instituto Of Ricovero E Cura A Carattere Scientifico, U.O. di Anatomia Patologica and 4 more.
Type: Journal Article | Journal: Blood | Year: 2016
The importance of glutamine (Gln) metabolism in multiple myeloma (MM) cells and its potential role as a therapeutic target are still unknown, although it has been reported that human myeloma cell lines (HMCLs) are highly sensitive to Gln depletion. In this study, we found that both HMCLs and primary bone marrow (BM) CD138(+) cells produced large amounts of ammonium in the presence of Gln. MM patients have lower BM plasma Gln with higher ammonium and glutamate than patients with indolent monoclonal gammopathies. Interestingly, HMCLs expressed glutaminase (GLS1) and were sensitive to its inhibition, whereas they exhibited negligible expression of glutamine synthetase (GS). High GLS1 and low GS expression were also observed in primary CD138(+) cells. Gln-free incubation or treatment with the glutaminolytic enzyme l-asparaginase depleted the cell contents of Gln, glutamate, and the anaplerotic substrate 2-oxoglutarate, inhibiting MM cell growth. Consistent with the dependence of MM cells on extracellular Gln, a gene expression profile analysis, on both proprietary and published datasets, showed an increased expression of the Gln transporters SNAT1, ASCT2, and LAT1 by CD138(+) cells across the progression of monoclonal gammopathies. Among these transporters, only ASCT2 inhibition in HMCLs caused a marked decrease in Gln uptake and a significant fall in cell growth. Consistently, stable ASCT2 downregulation by a lentiviral approach inhibited HMCL growth in vitro and in a murine model. In conclusion, MM cells strictly depend on extracellular Gln and show features of Gln addiction. Therefore, the inhibition of Gln uptake is a new attractive therapeutic strategy for MM.
Guglielmelli T.,S Luigi Gonzaga Hospital |
Palumbo A.,Myeloma Unit
Current Hematologic Malignancy Reports | Year: 2013
In recent years, the treatment of multiple myeloma has undergone significant changes. The availability of novel agents bortezomib, thalidomide and lenalidomide considerably improved the outcome of patients. The advantages related to the use of novel agents have been shown in various studies in patients eligible and ineligible for transplant. In elderly patients, novel agents have also revolutionized the treatment paradigm and have replaced the traditional melphalan-prednisone regimen. A sequential approach consisting of an induction regimen associated with a high rate of complete response, followed by consolidation/maintenance therapy, induces a profound cytoreduction and delays relapse, thus improving survival. Patients older than 75 years or who are otherwise vulnerable are more susceptible to adverse events. In this setting, less toxic regimens and appropriate dose-reductions should be adopted. This article provides an overview of the main trials for transplant-ineligible multiple myeloma patients. Recommendations on how to manage unfit patients and treatment-related toxicities are also provided. © 2013 Springer Science+Business Media New York.
Belloni D.,Myeloma Unit |
Veschini L.,Myeloma Unit |
Foglieni C.,IRCCS H San Raffaele |
Dell'Antonio G.,IRCCS H San Raffaele |
And 4 more authors.
Experimental Cell Research | Year: 2010
The proteasome inhibitor Bortezomib has been approved for the treatment of relapsed/refractory multiple myeloma (MM), thanks to its ability to induce MM cell apoptosis. Moreover, Bortezomib has antiangiogenic properties. We report that endothelial cells (EC) exposed to Bortezomib undergo death to an extent that depends strictly on their activation state. Indeed, while quiescent EC are resistant to Bortezomib, the drug results maximally toxic in EC switched toward angiogenesis with FGF, and exerts a moderate effect on subconfluent HUVEC. Moreover, EC activation state deeply influences the death pathway elicited by Bortezomib: after treatment, angiogenesis-triggered EC display typical features of apoptosis. Conversely, death of subconfluent EC is preceded by ROS generation and signs typical of autophagy, including intense cytoplasmic vacuolization with evidence of autophagosomes at electron microscopy, and conversion of the cytosolic MAP LC3 I form toward the autophagosome-associated LC3 II form. Treatment with the specific autophagy inhibitor 3-MA prevents both LC3 I/LC3 II conversion and HUVEC cell death. Finally, early removal of Bortezomib is accompanied by the recovery of cell shape and viability. These findings strongly suggest that Bortezomib induces either apoptosis or autophagy in EC; interfering with the autophagic response may potentiate the antiangiogenic effect of the drug. © 2009 Elsevier Inc. All rights reserved.