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In: American Journal of Hematology, Wiley, Vol. 90, No. 7 ( 2015-07), p. 647-652

Abstract: 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. Am. J. Hematol. 90:647–652, 2015. © 2015 Wiley Periodicals, Inc.

Type of Medium: Online Resource

ISSN: 0361-8609 , 1096-8652

URL: Issue

URL: Article

DOI: 10.1002/ajh.v90.7

DOI: 10.1002/ajh.24035

Language: English

Publisher: Wiley

Publication Date: 2015

detail.hit.zdb_id: 1492749-4

In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 24-24

Abstract: INTRODUCTION In newly diagnosed Multiple Myeloma (MM) patients (pts), Copy Number (CN) losses of chromosome 17p13, carrying the TP53 tumor-suppressor gene, are strong predictors of poor outcomes. On the contrary, the prognostic relevance of TP53 mutations at the onset of the disease is less clear, due to the very limited frequency of clonal lesions, as revealed by Sanger sequencing. To address this poorly investigated issue, we used an ultra-deep sequencing (UDS) approach to characterize the TP53 structural architecture in both newly diagnosed and relapsed MM pts and to assess the prognostic role and evolution over time of small TP53 mutated sub-clones. SAMPLES AND METHODS A cohort of 99 newly diagnosed MM pts treated up-front with bortezomib-based regimens and autologous stem cell transplantation, was included in this molecular study. In 29 cases, samples were collected both at diagnosis and at relapse(s). DNA was obtained from CD138+ highly purified plasma cells. TP53 gene mutational status was analysed by using an amplicon-targeted UDS approach (GSJ, 454 Roche Life Sciences). In order to discriminate between low frequency sub-clonal TP53 variants and sequencing errors, sequencing raw data were filtered according to cut-off values based on different ranges of sequences' coverage depth. Additional filters were also applied, based on both quality and biological cut-offs, to obtain a final confident list of variants. Analysis of CN alterations (CNAs) was performed by SNPs array and results analysed with ChAS software. RESULTS With a median coverage of 1386X, a list of 129 correctly called TP53 variants (either missense, or nonsense or splice ones), including 20 INDELs, was detected. Only deleterious and N/A variants (according to SIFT classification) were included in the list. Most newly diagnosed MM pts (55%) carried at least one TP53 sub-clonal variant (on average 1.08 variants per pts), with 45/99 (45%) carrying non-mutated TP53. Pts carrying TP53 sub-clonal variants bared also TP53 CN hemizygous losses (20%), CKS1B gains (56%) and cdkn2c losses (14%). According to TP53 sub-clonal mutational load, pts were stratified in two sub-groups, including 28 pts with ≥2 (high load) and 71 with 〈 2 variants (low load), respectively. Eleven out of 129 variants were recurrent (RVs), as being detected in at least 3% of pts, with Variants Allele Frequencies (VAFs) ranging from 0.24 to 70.1% (median 0,53%); RVs were observed in 29 pts. The clinical impact of the TP53 sub-clonal mutational load, as well as of variants recurrence, was evaluated in 90/99 MM (median follow up = 70 months). Results of statistical analysis are summarized in Table 1. Pts carrying either high TP53 sub-clonal mutational load or RVs had significantly shorter OS and OS after relapse, as compared to the others, while no difference between these two groups was seen regarding PFS and TTP. Multivariate analysis showed that high TP53 mutational load, as well as the presence of TP53 RVs, both resulted independent factors adversely affecting OS and OS after relapse (Table 2). Of note, none of the detected genomic aberrations significantly influenced the response to front-line induction therapy. The distribution of both TP53 sub-clonal variants and genomic CNAs was overall modified in samples collected at relapse(s): 90% of relapsed pts carried at least one sub-clonal variant (on average 1.63 variants per pts) with 3/29 (10%) relapsed MM carrying non-mutated TP53. Moreover, 5 different sub-clonal lesions proved a linear increment of both TP53 VAFs (from 29.4% to 54.6%; from 7.8% to 12.4%; from 0.5% to 4.3%) and TP53 CN loss smooth signal (from 7% to 89% and from 50% to 100%), as evaluated in longitudinally collected samples. CONCLUSIONS The UDS analysis of TP53 coding sequence in newly diagnosed MM highlighted for the first time a high rate of variants, recurring with a wide range of frequencies among samples. The increased number of TP53 sub-clonal variants per pts in samples collected at relapse(s), compared to that seen at the onset of the disease, suggests a sub-clonal dynamics over time. This finding might explain the adverse impact of high TP53 sub-clonal mutational load and TP53 RVs on OS, due to a shorter OS after relapse. Acknowledgments: Roche Diagnostics for applicationsupport in the realization of this project. Disclosures Zamagni: Celgene Corporation: Honoraria, Speakers Bureau; Janssen Pharmaceuticals: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Martinelli:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Ariad: Consultancy; AMGEN: Consultancy; ROCHE: Consultancy; Pfizer: Consultancy; MSD: Consultancy. Cavo:Janssen-Cilag, Celgene, Amgen, BMS: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.24.24

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 3997-3997

Abstract: Venous thromboembolism (VTE) has emerged as a major adverse event of primary induction therapy with thalidomide (thal) and dexamethasone (dex) for newly diagnosed multiple myeloma (MM). Aim of the present study was to investigate the relationship between thrombophilic alterations and the risk of VTE in 266 patients who received four months of therapy with thal (200 mg/d) and pulsed high-dose dex in preparation for double autologous transplantation. The rate of VTE in the whole group of patients was 11.6%. The risk of VTE was 26.3% (86.2% patient-years) among the first 19 patients who entered the study and did not received any prophylaxis against thrombosis. The corresponding value among the remaining 247 patients who received thromboprophylaxis with fixed low-dose (1.25 mg/d) warfarin during the four months of thal-dex therapy was 10.6% (35.5% patient-years) (P=0.04). Episodes of VTE occurred at a median of 53 days from the start of thal therapy and, with the exception of 3 patients, were observed after at least a partial response to thal-dex was documented. No VTE events were recorded during the first two months after the end of the induction phase. After VTE occurrence, the majority of patients went on with thal treatment plus full anticoagulation, without evidence of progression of thrombosis. One hundred and ninety patients were evaluated for the presence of thrombophilic alterations at baseline and at the end of thal-dex therapy. The prevalence of factor V Leiden (3.2%) or g20210A prothrombin (2.1%) polymorphism in patients with MM was similar to that observed in 183 healthy controls (3.3%, P= 0.81; 3.8%, P= 0.50, respectively). The relative risk of VTE for patients carrying one of these thrombophilic alterations was 20% compared with 9.4% for patients who lacked both of them (P= 0.58). Reduced protein C and S activities or acquired activated protein C resistance (aAPCR) were recorded at baseline in 11% and 7.4% of MM patients, respectively. Abnormal values at baseline normalized almost completely at the end of treatment. Carriers of aAPCR and/or of reduced levels of natural anticoagulants at baseline did not have a significantly higher risk of VTE compared with normal patients (15.2% vs 9.3%; P=0.49). In conclusion, no significant relationship was found between baseline thrombophilic alterations, including aAPCR, and the risk of thal-related VTE. Prophylaxis with fixed low-dose warfarin was associated with an apparent decrease in the rate of VTE in comparison with a subgroup of patients who did not receive any thromboprophylaxis. A prospective phase III study comparing low molecular weight heparin with fixed low-dose warfarin with aspirin is currently ongoing in Italy to evaluate the best prophylaxis against the risk of thal-related VTE for patients with newly diagnosed MM.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V110.11.3997.3997

Language: English

Publisher: American Society of Hematology

Publication Date: 2007

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 3562-3562

Abstract: Abstract 3562 Aim of the present study was to evaluate the clinical outcome of a large series of younger patients with symptomatic multiple myeloma (MM) who were enrolled in two subsequent clinical trials of thalidomide-dexamethasone (thal-dex) incorporated into double autologous stem-cell transplantation (ASCT) to support high-dose melphalan (200 mg/m2). In both studies, thal (100 mg/day for the first 14 days and then 200 mg/day) and pulsed dex (between 480 and 160 mg per cycle), were administered from the onset until the second ASCT. The analysis was performed on an intention-to-treat basis on a total of 593 patients who were followed for a median of 36 months. The best VGPR and CR rates were 69% and 35%, respectively. The median duration of CR was 66 months. Median TTP and PFS were 53 and 44 months, respectively. The 5-year projected rates of TTP and PFS were 46% and 38%, respectively, while the corresponding value for OS was 67%. More than 80% of the patients were screened at diagnosis for the presence of cytogenetic abnormalities by FISH analysis. Forty-five percent of patients had del(13q), while t(4;14) and del(17p) were found in 16 % and 7 % of patients, respectively. The presence of del(17p) and/or t(4;14) was associated with a significantly shorter 5-year projected TTP, PFS and OS in comparison with the absence of these abnormalities, indifferently from the presence or absence of del(13q) (TTP: 30% vs 53%, respectively P=0.0000; PFS: 28% vs 45%, respectively, P=0.0000; OS: 53% vs 69%, respectively, P=0.0000). OS and PFS curves of patients carrying del(13q) alone were almost superimposable to those of patients without cytogenetic abnormalities, while TTP was significantly shorter for patients with del(13q) alone (5-year projected rates: 40% vs 53%, respectively, P=0.04). Patients carrying del(17p) in the absence of t(4;14) had similar 5-year projected TTP and PFS as compared with t(4;14) positive but del(17p) negative patients. However, OS was significantly shorter for the subgroup with del(17p) and absence of t(4;14) in comparison with that of patients carrying t(4;14) without del(17p) (5 year projected rates: 18% vs 70%, respectively, P=0.03). In a multivariate analysis, presence of del(17p) and high beta2-m at baseline were the most important variables adversely influencing TTP (HR: 2.3, P=0.001 and HR: 1.8, P=0.002, respectively), PFS (HR: 2.0, P=0.001 and HR: 1.9, P=0.001, respectively), and OS (HR: 3.9, P=0.000 and HR: 2.0, P=0.005, respectively). Additional variables predicting for shorter TTP and PFS were the presence of t(4;14) (HR: 1.8, P=0.004) and of del(13q) (HR: 1.6, P= 0.009). Also the quality of best response to the overall treatment program influenced clinical outcomes. In particular, patients achieving CR had a significantly longer PFS and OS than those achieving a VGPR (PFS: median 68 vs 40 months, respectively, P=0.007; 5-year projected OS rates: 84% vs 70%, respectively, P=0.01). In conclusion, incorporation of thal-dex into double autotransplantation failed to overcome the poor prognosis conferred by del(13 q), t(4;14) and del(17p). In a multivariate Cox regression analysis, del(17p) and high levels of serum beta2-m at diagnosis were the strongest variables adversely influencing PFS and OS. In comparison with the presence of t(4;14) but absence of del(17p), patients carrying del(17p) without t(4;14) had a significantly shorter OS, possibly due to their worst outcome after relapse. Presence of del(13q) alone conferred a significantly shorter TTP, but did not have an adverse impact on OS due to the favorable role of effective salvage therapies incorporating either bortezomib or lenalidomide. Disclosures: Off Label Use: use of first line thalidomide in preparation for ASCT. Cavo:Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, no; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, no; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, no.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V116.21.3562.3562

Language: English

Publisher: American Society of Hematology

Publication Date: 2010

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 120, No. 1 ( 2012-07-05), p. 9-19

Abstract: 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.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2012-02-408898

Language: English

Publisher: American Society of Hematology

Publication Date: 2012

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 73-73

Abstract: In May 2006, the Italian Myeloma Network GIMEMA initiated a multicenter, randomized phase III study comparing VTD (arm A) with TD (arm B) incorporated into ASCT for newly diagnosed MM. Both VTD and TD were planned to be administered before (induction) and after (consolidation) double ASCT with melphalan 200 mg/m2 (MEL-200). In both arms, induction therapy consisted of three 21-d courses [63 days (d)]. The VTD regimen included Vel, 1.3 mg/m2 on d 1, 4, 8, and 11, plus Dex, 40 mg on each day of and after Vel administration; Thal was given at 200 mg/d from d 1 to 63. Patients randomized to TD received Thal as in arm A and Dex 40 mg/d on d 1–4 and 9–12 of every 21-d cycle. Primary study end point was complete response [either immunofixation negative (CR) or immunofixation positive (nCR)] to induction therapy. Secondary study end points included CR+nCR to consolidation therapy, time to progression, event-free survival, overall survival and toxicity. An interim analysis was planned to be performed after one year from study initiation to assess efficacy and toxicity of induction therapy. As of May 30, 2007, 234 patients entered the study and 187 were evaluated for response to induction therapy and adverse events (AEs). Of these patients, 92 were randomly assigned to receive VTD and 95 to receive TD. Efficacy and toxicity analyses were performed on an intention-to-treat basis. The rate of CR+nCR to VTD was 38% vs 7% to TD (P 〈 0.001); 60% of patients in VTD arm and 25% of patients in the control group attained at least a very good partial response (P 〈 0.001). Patients who failed at least a partial response to VTD were significantly less than those who failed on TD (7% vs 21%, respectively; P=0.004). Grade ≥ 2 and grade ≥ 3 AEs were similar in both arms, with the exception of grade ≥ 3 skin rash (6.5% in VTD arm vs 1% in TD arm; P=0.04). Grade 3 peripheral neuropathy was reported in 8% of patients randomly assigned to VTD and in 2% of patients treated with TD (P=0.07). All patients received acyclovir prophylaxis against reactivation of varicella zoster virus (VZV). VZV infection occurred in 2% of patients in VTD arm and in 1% of patients in the control group. Treatment discontinuation due to AEs was required in a single patient in each of the two treatment arms. No patient died for any cause during the induction phase. In a subgroup of patients with longer follow-up response to first ASCT was also evaluated. The rate of CR or CR+nCR to MEL-200 was significantly higher in VTD arm than in the control group (P=0.02 for CR comparison and P=0.05 for CR+nCR comparison between the two treatment arms). Preliminary analysis of this study provides demonstration that VTD is a highly active and well tolerated induction regimen, resulting in a significantly higher CR or CR+nCR rate compared to TD both before ASCT and after the first autologous transplantation with MEL-200.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V110.11.73.73

Language: English

Publisher: American Society of Hematology

Publication Date: 2007

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 992-992

Abstract: F-18-fluorodeoxyglucose positron emission tomography integrated with computed tomography (FDG-PET/CT) enables to detect with relatively high sensitivity and specificity myeloma bone disease and extramedullary sites of metabolically active clonal plasma cells. FDG-PET/CT has also been used to assess and monitor the metabolic response to therapy and to predict the prognosis. One of the major limitation of PET/CT is the lack of standardized image criteria and of inter-observer reproducibility in interpreting the results. Aim of the present sub-study was to prospectively evaluate FDG-PET/CT at diagnosis, after 4 cycles of induction therapy and prior to maintenance therapy in a sub-group of patients enrolled into EMN02/HO95 MM international phase III trial. In particular, the two primary end-points were firstly to assess the prognostic significance of PET/CT at diagnosis and after therapy and secondly to standardize PET/CT evaluation by centralized imaging and revision and definition of criteria for interpretation. Seven hundred and 18 patients with newly diagnosed transplant-eligible symptomatic MM have been prospectively randomized in Italy from February 2011 through April 2014 to receive 4 cycles of bortezomib-melphalan-prednisone (VMP) vs high-dose melphalan and single or double autologous stem cell transplantation (ASCT) as intensification following induction with bortezomib-cyclophosphamide-dexamethasone (VCD). Consolidation therapy with bortezomib-lenalidomide-dexamethasone vs no consolidation was planned after VMP or ASCT(s), followed by lenalidomide maintenance until progression or toxicity. One hundred and three patients were included in the PET/CT imaging sub-study, and followed for a median of 24 months. By study design, PET/CT was performed and analysed in each of the 8 participating centres at baseline, after induction therapy and prior to the start of maintenance (EOT). Each PET scan was a posteriori re-interpreted in a blinded independent central review process, managed by WIDEN®, by a panel of 5 expert nuclear medicine physicians. They described the following characteristics: bone marrow metabolic state (BM), number (Fx) and score (Fs) of focal PET positive lesions, osteolysis (Lx), presence and site of extramedullary disease (EM), and fractures(Fr), according to the IMPeTUs criteria (Nanni et al, EJNM 2015). Moreover, a global score (GS), from 1 to 5, was given to each patient, considering the highest score among BM, Fx, Fs and EM. Concordance among reviewers on different metrics was calculated using Krippendorf's alpha (AK) coefficient Baseline characteristics of the patients were the following: median age 58 years, ISS and R-ISS stage III 15% and 10%, high-risk cytogenetics (t(4;14) ± del(17p) ±del (1p)±1q gain detected by FISH) 42%. At baseline, 78% of the patients had FLs, with a median SUVmax of 6.0. The percentages of PET positive patients for the different characteristics are summarized in table 1. The agreement among reviewer was good for BM (AK=0.49), Fx (AK=0.65), Fs (AK=0.62), Lx (AK=0.62) and EM (AK=0.40). Of all parameters, only Fx ≥ 4 was associated with worse PFS and OS (P = 0.06) Following 4 cycles of VCD, PET/CT remained positive in 59% of the patients, with a median SUVmax of 3.7. Of all parameters, only Fs ≥ 4 was predictive of worse OS (P= 0.05). Prior to maintenance therapy, PET/CT remained positive in 34% of the patients, with a median SUVmax of 3.4. Normal PET/CT findings before maintenance (66%) were associated with a significant improvement in PFS, in particular the following: presence of FLs (P=0.03), Fx ≥ 4 (P=0.001), Fs ≥2 (P=0.03), 3 (P=0.03) and 4 (P=0.006) and SUVmax ≥ 3.4 (p=0.002). GS was also predictive for PFS if ≥ 3 (P=0.033), 4 (P=0.0001) and 5 (P=0.004). The same parameters were also predictive for OS. The prognostic relevance of pre-maintenance PET/CT was retained across the randomization arm (VMP or ASCT), in terms of PFS and OS. In conclusion, PET/CT was confirmed to be a reliable predictor of outcome in newly diagnosed transplant eligible MM patients, whatever the treatment. Normalization of PET/CT before maintenance was associated with a significant improvement for PFS and OS. FDG-PET/CT is by now the preferred imaging technique for evaluating and monitoring response to therapy. Acknowledgments: this study was partially supported by a grant to Elena Zamagni from Fondazione del Monte di Bologna e Ravenna Table 1 Table 1. Disclosures Gay: Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Membership on an entity's Board of Directors or advisory committees. Larocca:Bristol-Myers Squibb: Honoraria; Janssen-Cilag: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Sonneveld:Celgene: Other: Advisory board, Research Funding; Onyx: Other: Advisory board, Research Funding; Millennium: Other: Advisory board, Research Funding; Janssen-Cilag: Other: Advisory board, Research Funding. Cavo:Amgen: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.992.992

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 351-351

Abstract: Abstract 351 Introduction A phase III study of melphalan (200 mg/m2)-based double autologous stem-cell transplantation (ASCT) incorporating thalidomide (T) and dexamethasone (D) with or without the addition of bortezomib (V) as first-line therapy for younger (≤65 years) patients (pts) with newly diagnosed multiple myeloma (MM) is currently being conducted by the Italian Myeloma Network GIMEMA. Patients and Methods By study design, pts were random assigned to receive three 21-d cycles of either bortezomib-thalidomide-dexamethasone (VTD) (V, 1.3 mg/m2 twice-weekly; T, 200 mg/d through d 1 to 63; D, 320 mg/cycle) or thalidomide-dexamethasone (TD) (both drugs at the same dose and schedule than in VTD) as induction therapy in preparation for ASCTs. Two 35-d cycles of either VTD or TD were given as consolidation therapy following ASCTs (V, 1.3 mg/m2 once-weekly; T, 100 mg/d through d 1 to 70; D, 320 mg/cycle). Primary study end point was the rate of high-quality responses [immunofixation negative complete response (CR) and ≥very good partial response (VGPR)] to induction therapy. Secondary study end points included response to, and toxicity of, subsequent treatment phases (including first and second ASCTs, and consolidation therapy), progression-free survival (PFS) and overall survival (OS). Analyses were intent to treat. All the 474 pts were evaluated for response to, and toxicity of, induction therapy. Responses reported by study investigators were centrally reassessed to confirm CR and VGPR; pts reported as complete responders but in whom bone marrow aspirate was not evaluable or not performed were reassessed as in VGPR. The VGPR category included the subcategories of near CR and VGPR. Results The study was closed to pts accrual after a total of 480 pts were enrolled; of these, 6 failed inclusion criteria and the remaining 474 were randomized to the VTD (n=236) or TD (n=238) arm. The mean total dose of V received in induction therapy was 14.7 mg (or 94% of that planned). Grade 3 peripheral neuropathy (PN) and skin rash (SR) were reported more frequently with VTD induction therapy than with TD (PN: 9.7% vs 2.1%, respectively; P 〈 0.001) (SR: 10% vs 1.7%, respectively; P 〈 0.001). In the VTD arm, resolution or reduction to at least grade 2 of PN was observed within a median of 26 days. Remarkably, once-weekly standard dose administration of V and reduction of T dose in VTD as consolidation therapy resulted in a dramatic decrease in the frequency of grade ≥3 PN (2%) and SR (1%). Reported rates of herpes zoster infection with VTD as both induction and consolidation therapy were 0.4% and 1%, respectively. Overall, the CR (≥VGPR) rate with VTD induction therapy was 19% (62%) vs 5% (31%) with TD (P 〈 0.001 for both CR and ≥VGPR comparisons); no pt had disease progression while on VTD, as compared to 5% of pts treated with TD (P 〈 0.001) who discontinued therapy and went off study. Progression through the subsequent treatment phases was associated with an increase in the frequency of CR and ≥VGPR up to a final value of 44% and 80%, respectively, in the VTD arm; the corresponding rates in the TD arm were 32% (p=0.02) and 65% (p=0.001), respectively. On an intention to treat basis, best responses in the VTD vs TD arm were the following: CR, 55% vs 38%, respectively (P 〈 0.001); ≥VGPR: 87% vs 69%, respectively (P 〈 0.001). Superiority of the VTD vs TD arm in terms of CR rate was confirmed in pts with high-risk cytogenetics, as defined by the presence of t(4;14) and/or del(17p) (58% vs 33%, respectively; p=0.004). Two year-projected PFS was 85% in the VTD arm as compared to 75% in TD (p=0.008). Improved PFS with VTD vs TD, both added to double ASCT, was consistent across subgroup analyses of pts with poor prognosis, including those with high-risk cytogenetic profiles (p=0.03; HR=0.42, 95% CI: 0.18 to 0.96). PFS curves for pts in the VTD arm who carried or not high-risk cytogenetics were similar (p=0.19). No difference in OS was seen between the two treatment groups, but longer follow up is required. Conclusions Incorporation of VTD into double ASCT for newly diagnosed MM resulted in a significant improvement in clinical outcomes (CR, ≥VGPR, PFS) in comparison with TD and double autotransplantation. Superior benefit with VTD and double ASCT in comparison with the control group was maintained in pts at high risk of progression or death, including those with t(4;14) and/or del(17p). Disclosures: Cavo: Celgene: Honoraria; Ortho Biotech, Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau; Millennium Pharmaceuticals: Honoraria; Novartis: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V114.22.351.351

Language: English

Publisher: American Society of Hematology

Publication Date: 2009

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 4728-4728

Abstract: Magnetic resonance imaging (MRI) of the spine has demonstrated to be a useful tool for correct staging of multiple myeloma (MM), as it is more sensitive than plain x-rays in detecting vertebral lesions. Furthermore, different patterns of bone marrow involvement (focal, diffuse or normal) can be depicted, and this could contribute to better define the prognosis in newly diagnosed patients. In the present study we prospectively evaluated the clinical and prognostic role of spinal MRI in 120 newly diagnosed MM patients (68M, 52F, median age = 56yrs) that subsequently received high-dose chemotherapy and autologous stem cell transplantion, either single (n=28) or double (n=92). Pattern of marrow involvement was focal in 72 cases (60%), diffuse in 29 (24%) and negative in 19 (16%). Patients with a diffuse pattern showed a significantly higher bone marrow plasma cell infiltration (p=0.05) and beta2 microglobulin values (p= 0.04) as compared to patients with a focal pattern; stage III disease according to ISS was observed in 29%, 8% and 1% of patients with a diffuse, focal or negative pattern, respectively. Response rate to treatment program was similar in the three groups of patients, with a stringently defined CR obtained in 34% of patients with a focal pattern, 29% in those with a diffuse pattern and 35% in patients with a negative MRI. Median progression-free survival showed a trend in favor of patients with a negative MRI (54 months) as compared to those with a focal or diffuse pattern (42 and 38 months, respectively). A focal pattern of bone marrow involvement was associated with a significantly higher probability of experiencing an overt vertebral lesion (73% vs 48% in patients with diffuse pattern, p=0.03), including either a compression fracture or a vertebral mass. Consistently with this finding, also extra-spinal bone lesions were more common in patients with a focal pattern (66%) as compared to patients with a diffuse or negative pattern (42% and 6% respectively) (p=0.05). Serum crosslaps were significantly increased in patients with a focal pattern (7032 pmol/L±635SE vs 5431pmol/L±812SE in those with a diffuse pattern, p=0.04). According to our data, a diffuse pattern of bone marrow involvement could be predictive of a more aggressive disease, even though these data needs to be confirmed in a larger series of patients. A focal pattern of bone marrow involvement at diagnosis could help to identify MM patients more prone to develop skeletal complications, so that a careful monitoring and bisphosphonate therapy should be recommended.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V110.11.4728.4728

Language: English

Publisher: American Society of Hematology

Publication Date: 2007

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 124-124

Abstract: Introduction: Conflicting results from two recently reported randomized studies comparing double vs single autotransplantation (ASCT) for newly diagnosed multiple myeloma (MM) patients (pts) [(Cavo M et al, Blood 2017;130(1); Stadtmauer EA et al, Blood 2016;128(22)] are likely to reflect differences in the design of the trials. To address this controversial issue, we performed a long-term follow-up analysis of pt-level data from three phase 3 trials of bortezomib-thalidomide-dexamethasone (VTD) (Cavo M et al, Lancet 376; 2075-85, 2010; Rosinol L et al, Blood 120; 1589-96, 2012) or bortezomib-doxorubicin-dexamethasone (PAD) (Sonneveld P et al, J Clin Oncol 30; 2946-55, 2012) as induction therapy before ASCT, followed by post-ASCT bortezomib-based consolidation and/or maintenance treatment. According to study design, patients were assigned to receive either a single or double ASCT (ASCT-1 or ASCT-2), thus allowing a comparison between these treatments. Methods: The intent-to-treat population included 909 pts who were randomized to either VTD or PAD arms of the studies and for whom ASCT-1 (n=501) or ASCT-2 (n=408) were planned at study entry. Median age was 58 yrs in both groups; the rate of ISS stage III was 20% and 17%, respectively, while 18% and 23% of pts in ASCT-1 and ASCT-2 groups were positive for t(4;14) and/or del(17p) (cut-off levels ≥10% and ≥20%, respectively) by FISH analysis. Results: With a median follow up of 117 mos (IQR 91-126), assignment to ASCT-2 resulted in superior PFS (median: 47 vs 38 mos; HR 0.76, 95%CI=0.65-0.89, p=0.0008) and OS (estimated 10-yr probability: 58% vs 47%; HR 0.69, CI 0.56-0.84, p=0.0002) in comparison with ASCT-1 (Figure 1). PFS benefit with ASCT-2 was retained across prespecified subgroups, including pts with both standard-risk (median: 53 vs 43 mos; HR 0.74, CI 0.61-0.91, p=0.005) and high-risk cytogenetics (cyto) (median: 36 vs 20 mos; HR 0.67, CI 0.46-0.97, p=0.032). The 10-yr OS rates were 72% with ASCT-2 vs 60% with ASCT-1 (HR 0.68, CI 0.52-0.88, p=0.004) for pts with standard-risk and 51% vs 34% (HR 0.54, CI 0.36-0.83, p=0.004) for those with high-risk cyto. In a multivariate Cox regression analysis, independent predictors for prolonged PFS included ASCT-2 (HR 0.81, CI 0.66-0.99, p=0.048), platelet (PLT) count 〉 150.000/mmc (HR 0.74, CI 0.54-0.99, p=0.049), ISS stage I+II (HR 0.62, CI 0.48-0.80, p 〈 0.001), absence of t(4;14) and/or del(17p) (HR 0.57, CI 0.45-0.73, p 〈 0.001), and complete response (CR) recorded at any time throughout treatment (best CR) (HR 0.53, CI 0.43-0.64, p 〈 0.001). These variables were also significantly related to longer OS (ASCT-2: HR 0.75, CI 0.57-0.98, p=0.036; PLTs: HR 0.55, CI 0.38-0.78, p=0.001; ISS stage: HR 0.66, CI 0.48-0.91, p=0.010; cyto: HR 0.55, CI 0.41-0.73, p 〈 0.001; best CR: HR 0.55, CI 0.43-0.72, p 〈 0.001). HR estimates of the leading, not including therapy, predictors of outcomes (ISS stage II+III, high-risk cyto and failure to achieve best CR) were used to build a score index that stratified patients into 3 subgroups at low-risk (20%, none of the 3 adverse variables), intermediate-risk (42%, 1 adverse variable) and high-risk (38%, 2 or 3 adverse variables). Median PFS for these subgroups was 87, 53 and 27 mos (p 〈 0.001), while the corresponding 10-yr OS rates were 78%, 53% and 32% (p 〈 0.001) (Figure 2). There was a trend to improved PFS, but not OS, with ASCT-2 vs ASCT-1 in the low-risk subgroup (53% vs 28% at 10 yrs; HR 0.66, CI 0.66-0.41, p=0.093). Conversely, in the high-risk subgroup assignment to ASCT-2 significantly prolonged both PFS (median: 32 vs 20 mos, HR 0.71, CI 0.54-0.93, p=0.012) and OS (43% vs 20% at 10 yrs; HR 0.58, CI 0.42-0.80; p=0.001) in comparison with ASCT-1. Notably, the greatest benefit from ASCT-2 was observed in the ultra high-risk subset of pts with 3 adverse variables who enjoyed a two-fold increased PFS (median: 35 vs 14 mos; HR 0.45, CI 0.21-0.79; p=0.008) and 56% reduction in the risk of death (26% vs 6% estimated 10-yr OS probability; HR 0.44, CI 0.21-0.90; p=0.025) compared with ASCT-1. Conclusions: Results of this pooled analysis of phase 3 studies incorporating bortezomib-based triplets into ASCT confirmed the superiority of ASCT-2 over ASCT-1 in terms of extended PFS and OS. The subgroup of pts at high-risk mostly benefited from ASCT-2, in particular those who had advanced ISS stage, adverse cyto and failed to achieve CR. Disclosures Cavo: GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Goldschmidt:Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Research Funding; Adaptive Biotechnology: Consultancy; Sanofi: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Chugai: Honoraria, Research Funding; Mundipharma: Research Funding; Novartis: Honoraria, Research Funding; ArtTempi: Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Rosinol:Janssen, Celgene, Amgen, Takeda: Honoraria. Zweegman:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corp.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Salwender:Novartis: Honoraria, Other: travel suppport, Research Funding; Amgen: Honoraria, Other: travel suppport, Research Funding; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria, Other: travel suppport, Research Funding; Janssen: Honoraria, Other: travel support, Research Funding; Celgene: Honoraria, Other: travel suppport, Research Funding. Lahuerta:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Petrucci:Bristol-Myers Squibb: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; Amgen: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board; Janssen-Cilag: Honoraria, Other: Advisory Board. Oriol:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Weisel:Amgen, Celgene, Janssen, and Sanofi: Research Funding; Amgen, BMS, Celgene, Janssen, and Takeda: Honoraria; Amgen, BMS, Celgene, Janssen, Juno, Sanofi, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rios:Amgen, Celgene, Janssen, and Takeda: Consultancy. Patriarca:Celgene: Other: Advisory Role; Travel, accommodations, expenses; Medac: Other: Travel, accommodations, expenses; Jazz: Other: Travel, accommodations, expenses; Janssen: Other: Advisory role; MSD Italy: Other: Advisory Role. Mateos:GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Galli:Sigma-Tau: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria. San-Miguel:Novartis: Honoraria; Sanofi: Honoraria; Roche: Honoraria; BMS: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Boccadoro:Novartis: Honoraria, Research Funding; AbbVie: Honoraria; Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Mundipharma: Research Funding; Sanofi: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Blade:Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Sonneveld:Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; BMS: Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-112899

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7