Kooperativer Bibliotheksverbund

In: The Lancet, Elsevier BV, Vol. 376, No. 9758 ( 2010-12), p. 2075-2085

Type of Medium: Online Resource

ISSN: 0140-6736

URL: Article

DOI: 10.1016/S0140-6736(10)61424-9

Language: English

Publisher: Elsevier BV

Publication Date: 2010

detail.hit.zdb_id: 2067452-1

detail.hit.zdb_id: 3306-6

detail.hit.zdb_id: 1476593-7

SSG: 5,21

In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 2395-2395

Abstract: CIK cells are a unique population of CD3+CD56+ immune effector cells capable of lysing a broad variety of tumor cells targeted through a perforin based mechanism mediated by NKG2D. We started a pilot clinical trial in patients with refractory lymphoma and solid tumors according to GMP guidelines that is currently ongoing. Methods: CIK cells were generated from PBMNC and incubated in LifeCell culture bags in the presence of IFN-γ followed by IL-1β, OKT3 and IL-2. Expansion was assessed between day 21 and 28 and flow cytometric analysis was performed every week. Patients were monitored before and after treatment. Unpaired t-test was used to analyze for statistical significance. A p-value & lt;0.05 was considered statistically significant. Results: At present 10 patients are enrolled: 6 advanced lymphomas, 3 metastatic kidney carcinoma and 1 hepatocellular carcinoma. The median number of transferred cells per patient was 19 x109 (6–37 x109) and the absolute number of CD3+CD56+ cells infused ranged from 1 to 16 x109 (median value 5 x107/Kg). Patients affected by solid tumors received in association low doses of rhIL-2 or α-interferon. Protocol adherence was excellent and the toxicity profile was favourable. Only 2 patients developed low-grade fever during the first cycle of infusion (5%) but promptly resolved without antibiotic treatment. After CIK cell infusion, in patient’s peripheral blood the absolute median count of PBLs, CD3+, CD8+ and CD3+CD56+ cells significantly increased with a p-value of 0.034, 0.025, 0.034 and 0.038, respectively. Clinical outcome appeared promising: 2 patients had complete response (1 metastatic kidney carcinoma and 1 hepatocellular carcinoma) and 2 patients had stabilization of disease (1 metastatic kidney carcinoma and 1 NHL) with a median follow-up of 12 months (range 4–14). Conclusions: These preliminary data showed that adoptive immunotherapy with CIK cells is a safe therapy with some suggestion of efficacy that significantly enhances immune functions increasing absolute numbers of effector cells without side effects. If confirmed in larger scale studies, these promising results may have a favourable impact on conventional treatment strategy of malignancies.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V106.11.2395.2395

Language: English

Publisher: American Society of Hematology

Publication Date: 2005

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. 8002-8002

Abstract: 8002 Background: High and comparable rates of MRD negativity were seen in NDMM pts after 4 28-day induction cycles with KRd followed by ASCT and 4 KRd consolidation (KRd_ASCT_KRd) and after 12 KRd cycles (KRd12), showing the superiority of both regimens over KCd induction-ASCT-KCd consolidation (KCd-ASCT-KCd) (Gay F ASH 2018). Here we evaluated the benefit of KRd_ASCT_KRd vs KRd12 in specific subgroups of pts. Methods: 474 NDMM pts ≤65 years were randomized to KRd_ASCT_KRd or KRd12 or KCd_ASCT_KCd. We compared rate of ≥VGPR, ≥CR, sCR, MRD negativity (centralized, second generation flow cytometry, sensitivity 10 -5 ) after consolidation with KRd_ASCT_KRd vs KRd12 in patients with R-ISS 1 and R-ISS 2/3. Since high-risk pts may sometimes respond rapidly, but then relapse early, we also analyzed the rate of early relapse ( 〈 18 months from randomization). We performed a multivariate logistic regression analysis to evaluate factors predictive of early relapse. Results: Median follow-up was 25 months. Rates of ≥VGPR, ≥CR, sCR, MRD negativity were comparable between KRd_ASCT_KRd and KRd12 overall, in pts with R-ISS Stage 1 and with R-ISS Stage 2/3 (Table). A significantly lower number of pts experienced early relapse with KRd_ASCT_KRd vs KRd12 (12 pts [8%] vs 26 pts [17%] ; P=0.015). This difference was mainly related to a significantly lower rate of early relapse in R-ISS Stage 2/3 pts receiving KRd_ASCT_KRd vs KRd12 (11 pts [12%] vs 22 pts [23%] ; P=0.05); no difference was seen in R-ISS 1 (0 vs 2 pts). In multivariate regression analysis, KRd_ASCT_KRd vs KRd12 reduced the risk of early progression (OR 0.42; P=0.021); R-ISS Stage 2 (OR 3.6; P=0.001) and R-ISS Stage 3 (OR 4.85; P=0.003) increased the risk compared with R-ISS 1. Conclusions: KRd-ASCT-KRd and KRd12 were equally effective in inducing high-quality responses, with about 50% of high-risk pts achieving MRD negativity. In high-risk pts ASCT reduced the risk of early relapse. Clinical trial information: NCT02203643. [Table: see text]

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/JCO.2019.37.15_suppl.8002

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2019

detail.hit.zdb_id: 2005181-5

In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 158-158

Abstract: Over the last few years, Thalidomide-Dexamethsone (TD) has been one of the most commonly used induction regimens for the treatment of newly diagnosed multiple myeloma (MM). In a phase III study conducted by the Italian Myeloma Network GIMEMA, TD was compared with Velcade-Thalidomide-Dexamethasone (VTD) as induction therapy in preparation for, and as consolidation after, melphalan (200 mg/m2)-based double autologous stem-cell transplantation (ASCT) in pts aged ≤65 years with symptomatic MM. Up-front VTD comprised Velcade, 1.3 mg/m2 on d 1, 4, 8, and 11; Dexamethasone, 40 mg on each day of and after Velcade administration; Thalidomide, 200 mg/d through d 1 to 63. Pts randomized to TD received Thalidomide as in VTD and Dexamethasone, 40 mg/d on d 1–4 and 9–12 of every cycle. Primary study end point was the rate of complete response (CR)/near CR (nCR) following three 21-d cycles of induction therapy. The study was started in May 2006 and was closed to accrual in April 2008, after a total of 480 pts were enrolled. Of these, 399 pts (199 randomized to VTD and 200 to TD) could be evaluated for primary study end point and toxicity of induction regimens (secondary end point). All analyses were intent to treat. In comparison with TD, VTD effected significantly higher rates of response (≥partial response: 78.5% vs 92%, P & lt;0.001), including CR (6% vs 21%, P & lt;0.001), CR+nCR (12% vs 33%, P & lt;0.001) and ≥very good partial response (VGPR) (30% vs 61%, P & lt;0.001). Remarkably, no pt treated on VTD had disease progression, as compared to 4.5% of pts on TD (P=0.002). Serious adverse events were recorded in 13.5% of pts randomized to VTD vs 12.5% of those assigned to TD. Although grade ≥3 peripheral neuropathy (PN) and skin rash (SR) were more frequent with VTD than TD (PN: 9% vs 2.5% of pts, P=0.005) (SR: 7.5% vs 1% of pts, P=0.001), only 4 pts in the VTD arm (2 in each of the two toxicity sub-groups) necessitated early treatment discontinuation. Overall, discontinuation of primary therapy due to treatment-related adverse events was required in 4.5% of pts on VTD vs 5% of those on TD, including a single pt in VTD and 2 pts in TD who died early. Eight additional pts randomized to TD discontinued induction therapy and went off study due to disease progression. Peripheral blood stem-cell (PBSC) harvest and response to first ASCT (secondary study end points) could be assessed in 297 pts (145 randomized to VTD and 152 to TD) for whom data were available at the time of analysis. Pts who achieved the minimum threshold dose of CD34+ cells to safely perform double ASCT (≥4×106/kg) were 91% in the VTD arm vs 87% in TD; median yields were 9.3 and 10.6 (×106 CD34+ cells/Kg), respectively. Pts who actually received the first ASCT were 89% (129/145) in VTD and 80% (121/152) in TD. On an intention-to-treat basis, the rates of high-quality responses in the VTD arm were significantly higher than in TD, including CR (41% vs 20%, P & lt;0.001), CR+nCR (54% vs 29%, P & lt;0.001) and ≥VGPR (75% vs 53%, P & lt;0.001). After a median follow-up of 15 months, progression-free survival (PFS) was significantly superior with VTD as compared to TD (20-month estimate: 93% vs 86%, P=0.04), while the 20-month overall survival rate was 93% for both treatment groups. We conclude that, in comparison with TD, three 21-d cycles of VTD as primary therapy for newly diagnosed MM significantly increased the CR+nCR rates, up to values previously seen with one or two autotransplants preceded by conventional chemotherapy. Importantly, response benefit with up-front VTD vs TD translated into significantly higher CR+nCR rates after ASCT and significantly improved PFS. Effective combinations of novel induction agents, such as VTD, can, thus, have a remarkable impact on both pre and post-ASCT clinical outcome. Updated results, including response to second ASCT and consolidation therapy, will be presented at the meeting.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V112.11.158.158

Language: English

Publisher: American Society of Hematology

Publication Date: 2008

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 1871-1871

Abstract: Abstract 1871 Introduction: In a randomized phase 3 study, the use of VTD as induction therapy prior to and consolidation therapy following double ASCT increased the rate of complete or near complete response (CR/nCR) and extended PFS in comparison with TD given as induction and post-ASCT consolidation therapy in 474 newly diagnosed MM patients (Cavo et al, Lancet 2010). However, the specific impact of VTD consolidation on improved clinical outcomes was not defined. Methods: To address this issue, we performed a per-protocol analysis of 321 patients who received the entire treatment program, including the two pre-planned cycles of consolidation therapy with either VTD (160 of 236 patients, 68%) or TD (161 of 238 patients, 68%). By study design, two 35-d cycles of VTD (V 1.3 mg/m2 on days 1, 8, 15, and 22; T 100 mg/d on days 1–35; D 40 mg on the days of and after each V administration) or TD (at the same doses as in VTD) were given as consolidation therapy to patients randomly assigned to each of the two respective induction regimens. Patient and disease characteristics at baseline were comparable in the two groups of patients. Results: The rates of CR and CR/nCR were significantly higher after consolidation therapy with VTD compared with TD (CR: 61% vs 47%; p=0.012; CR/nCR: 73% vs 61%; p=0.020). The impact of VTD consolidation on post-ASCT enhanced rates of CR and CR/nCR was confirmed by the McNemar test (CR: p=0.0009; CR/nCR: p=0.004) which conversely failed to demonstrate a significant increase in the frequencies of CR (p=0.052) and CR/nCR (p=0.110) with TD consolidation therapy. The absolute probability of upgrading from less than CR before consolidation to CR after consolidation was 31% with VTD and 17% with TD (Pearson chi-square test: p=0.03). Ninety six percent of patients who upgraded from less than CR to CR after VTD consolidation were in nCR (44%) or VGPR (52%) before starting consolidation therapy. A landmark analysis (with the landmark set as the start of consolidation therapy) was performed to compare time to progression (TTP), PFS, and overall survival (OS) between treatment groups. With a median follow-up of 30 months, the estimated 3-year probability of relapse or progression was 38% with VTD and 52% with TD (p=0.039 by Kaplan-Meier analysis) (HR: 0.68, 95% CI: 0.47–0.98, p=0.041). PFS was significantly longer for patients receiving VTD consolidation than for those treated with TD (3-year estimates: 62% vs 46%; p=0.025) (HR: 0.66, 95% CI: 0.46–0.95, p=0.027), a gain particularly evident for patients who failed to achieve CR after ASCT (3-year PFS estimates: 66% vs 43%; HR: 0.54, 95% CI: 0.32–0.91, p=0.022). Superior PFS with VTD vs TD consolidation was retained across poor prognosis subgroups, including patients with t(4;14) and/or del(17q) (HR: 0.44, p=0.004), del(13q) (HR: 0.44, p=0.002), β2-microglobulin 〉 3.5 mg/L (HR: 0.57, p=0.025), lactate dehydrogenase 〉 190 U/L (HR: 0.57, p=0.005), or ISS stage 2 and 3 (HR: 0.57, p=0.021). In a multivariate regression analysis, the most important and independent variables positively correlated with PFS were VTD consolidation therapy (p=0.002), double ASCT (p=0.001), low β2-microglobulin (p 〈 0.0001), and absence of t(4;14) and/or del(17q) (p 〈 0.0001). No OS difference was seen between the two groups. Both VTD and TD consolidation therapy were very well tolerated. The frequency of treatment-emergent grade 3–4 adverse events was comparable in the two groups (9.3% in VTD, 8.6% in TD). Of particular note, peripheral neuropathy was 0.6% with VTD, while the rates of skin rash and deep vein thrombosis were 0.6% in each of the two groups. Patients treated with VTD received 93% of planned doses of bortezomib and thalidomide. Conclusions: In comparison with TD, post-ASCT consolidation therapy with the triplet VTD regimen significantly increased the rates of CR and CR/nCR, and extended landmarked TTP and PFS. Superior PFS with VTD consolidation was maintained across poor prognosis subgroups, including those with advanced ISS stage and/or high-risk cytogenetic profiles. In a multivariate regression analysis VTD consolidation was confirmed to be an independent variable favorably affecting PFS. The superior activity seen with VTD versus TD as induction therapy before ASCT was retained despite the same triplet regimen being used as post-ASCT consolidation. Disclosures: Cavo: Millennium: 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: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria; Genzyme: Honoraria. Off Label Use: Bortezomib and Thalidomide as post autotransplantation consolidation therapy in myeloma. Patriarca:Schering-Plough: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Roche: Honoraria. Petrucci:Celgene: Honoraria; Janssen: Honoraria. Di Raimondo:Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau. Palumbo:Merck: Honoraria; Janssen: 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; Amgen: Honoraria. Offidani:Celgene: Honoraria; Janssen: Honoraria. Baccarani:Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V118.21.1871.1871

Language: English

Publisher: American Society of Hematology

Publication Date: 2011

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 4210-4210

Abstract: Abstract 4210 In a previous analysis performed with a median follow-up of 36 months (mos), superior CR/nCR rates and extended PFS were demonstrated with bortezomib-thalidomide-dexamethasone (VTD) vs thalidomide-dexamethasone (TD) as induction therapy before, and consolidation after, double autotransplantation (ASCT) for newly diagnosed myeloma (MM). Here we report an updated analysis of that study, including a detailed analysis of outcomes after relapse or progression (R/P), an important issue for patients (pts) who received up-front a triplet novel agent-based therapy incorporated into ASCT. After a median follow-up of 52 mos, continued TTP and PFS benefits with VTD vs TD were demonstrated, while no difference in OS was seen between the two arms. Median PFS for pts randomized to the VTD arm was 56 mos vs 42 mos for those assigned to TD (HR=0.64, p=0.001). Similarly to PFS, median TTP for pts in the VTD group was longer than in the TD group (57 vs 45 mos, HR=0.63, p=0.0006), reflecting a 37% reduction in the risk of R/P with VTD. The probabilities of R/P in the VTD and TD arms were 41% vs 55% (p=0.002). In comparison with the VTD-treated group, a higher percentage of pts in the TD arm required the immediate start of salvage therapy after symptomatic R/P was documented (67% vs 82.5%). By the opposite, the fraction of pts with asymptomatic R/P that did not require any antimyeloma therapy until the cut-off date for the analysis was higher in the VTD arm compared with the TD-treated group (33% vs 17.5%, p=0.016). In these pts, the median interval from the date of R/P to the cut-off date for the analysis was 7 mos for the TD-treated group vs 17 mos for the VTD-treated group. Median time to subsequent antimyelomatherapy (defined as the interval between start of induction therapy and administration of the first dose of second-line therapy) was significantly longer for pts who experienced R/P in the VTD arm in comparison with pts who progressed in the TD arm (35 vs 29 mos, p=0.018). The associated interval between last administration of front-line therapy (e.g. consolidation for pts who received the entire treatment program or every other treatment before consolidation for those who discontinued earlier) and first administration of second-line therapy (salvage therapy-free interval) was 22.5 mos for the VTD-treated group vs 15 mos for the TD-treated group (p=0.009). Both bortezomib and lenalidomide were the most frequently used agents at the time of R/P (82% of all cases), while only 18% of pts were treated with conventional cytotoxic drugs. As expected, the majority of pts in the TD arm received a second-line therapy that included bortezomib (70%), while lenalidomide-dexamethasone was received by 10% of pts. By the opposite, in the VTD arm both bortezomib- and lenalidomide-based salvage therapies were equally distributed (41% vs 39%). The probability to achieve at least a partial response after second-line therapy including bortezomib was 60% for pts with prior exposure to VTD vs 63% for those randomized to TD. No difference in post-R/P OS was demonstrated between VTD-treated and TD-treated subgroups of pts who received bortezomib-based salvage therapy after R/P (2-yr estimates: 48% vs 53%, p=0.59). In the overall population, post-R/P OS was significantly shorter for pts who received salvage therapy with conventional cytotoxic drugs (2-yr estimate: 41%) in comparison with pts treated with novel agents, including bortezomib or lenalidomide (2-yr estimates: 52% and 53%, respectively) (p=0.0001). In conclusion, front-line therapy with VTD incorporated into ASCT was superior in comparison with TD plus ASCT in terms of extended TTP, PFS, time to subsequent antimyeloma therapy and salvage therapy-free interval. VTD-treated pts had a higher probability than TD-treated pts to experience long-lasting asymptomatic R/P not requiring second-line therapy. VTD-treated and TD-treated pts who subsequently received bortezomib-based salvage therapies had similar rates of response and post-R/P OS. This finding suggests that short-term exposure to VTD, as planned in our study, did not favor the selection of bortezomib-resistant clones, thus allowing to rechallenge bortezomib as (part of) second-line therapy after symptomatic R/P. Disclosures: Cavo: Janssen, Celgene, Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria. Di Raimondo:Celgene, Janssen: Honoraria, Speakers Bureau. Offidani:Janssen, Celgene: Honoraria. Caravita:Celgene, Janssen, Novartis, Genzyme: Honoraria. Boccadoro:Celgene, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V120.21.4210.4210

Language: English

Publisher: American Society of Hematology

Publication Date: 2012

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 36, No. 15_suppl ( 2018-05-20), p. 8009-8009

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/JCO.2018.36.15_suppl.8009

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2018

detail.hit.zdb_id: 2005181-5

In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 492-492

Abstract: Abstract 492 Background. The risk of venous thromboembolism (VTE) is high in newly diagnosed myeloma (MM) patients who receive thalidomide-based regimens. Anticoagulant prophylaxis is recommended. Controversies exist on the best thromboprophylactic regimen to adopt. Aims. In this prospective, multicenter phase III trial we evaluated the safety and the efficacy of low-molecular weight heparin (LMWH) or low-dose aspirin (ASA) or low-fixed dose warfarin (WAR) as anticoagulant prophylaxis. End-points were incidence of VTE, acute cardiovascular events, sudden death, major and minor bleeding. Methods. In a GIMEMA study, 991 newly diagnosed MM patients were randomized to VTD (Velcade 1.3 mg/m2 d 1,4,8,11; Thalidomide 200 mg/d; Dexamethasone 320 mg/21 d) or TD (Thalidomide 200 mg/d; Dexamethasone 320 mg/21 d) or VMPT (Velcade 1.3 mg/m2 d 1,8,15,22; Melphalan 9 mg/m2 d 1-4; Prednisone 60 mg/m2 d 1-4; Talidomide 50 mg/d) or VMP (Velcade 1.3 mg/m2 d 1,8,15,22; Melphalan 9 mg/m2 d 1-4; Prednisone 60 mg/m2 d 1-4). In a sub-study, patients treated with VTD or TD or VMPT were randomly assigned to receive LMWH (Enoxaparin 40 mg/d, N=223) or ASA (Aspirin 100 mg/d, N=227) or WAR (Warfarin 1.25 mg/d, N=223) for the duration of the induction therapy; 61 patients were excluded from sub-study because of indication for anticoagulant/antiplatelet therapy or high-risk of bleeding. Patients treated with VMP (N=257) did not receive any prophylaxis and were used as controls. Results. Patient characteristics and distribution of major risk factors were similar in all groups. The incidence of VTE was 5% in the LMWH group, 6% in the ASA group and 8% in the WAR group (p not significant). VTEs were 2% in the VMP group. Median time to onset of VTE for patients who received LMWH or ASA or WAR were 4.7, 2.4 and 2.4 months, respectively. Patients who received higher doses of both steroids and thalidomide (VTD and TD) had a higher VTE incidence (7%) in comparison with those who received lower doses (VMPT, 3%, p=0.06). Patients treated with bortezomib (VTD and VMPT) had a lower VTE incidence (5%) in comparison with patients on TD (8%, p=0.08). The rates of cardiovascular events were 2% in the LMWH group, 1% in the ASA group and 0.5% in the WAR group. The incidence of major and minor bleeding was 2% in the LMWH group, 3% in the ASA group and 1% in the WAR group (p not significant). The incidence of combined thrombosis, bleeding and cardiovascular events was 9% in the LMWH group, 10% in the ASA group and 9% in the WAR group (p not significant). Conclusion. The overall incidence of VTE was less than 10% in all groups and was not superior to that expected during the natural course of MM. The LMWH patients had lower risk of VTE, although no statistical difference was observed. LMWH, WAR and ASA are likely to be effective thromboprophylactic regimens. The final analysis on 991 patients will be presented at the meeting. Disclosures: No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V114.22.492.492

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. 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. 136, No. Supplement 1 ( 2020-11-5), p. 44-45

Abstract: Background. In multiple myeloma (MM), the role of minimal residual disease (MRD) by multiparameter flow cytometry (MFC) and next-generation sequencing (NGS) is well established (H. Avet-Loiseau et al. IMW 2019, S. Oliva et al. EHA 2020). Aims. The aims of this analysis were the evaluation of (1) the rate of conversion from MRD-positivity (MRD-pos) to MRD-negativity (MRD-neg) with MFC and NGS during maintenance and (2) the impact on progression-free survival (PFS) and overall survival (OS) of MRD-neg with both techniques in different subgroups including different treatment arms. Methods. Newly diagnosed (ND)MM patients (pts) aged ≤65 years were randomized (R1) to receive carfilzomib (K)-lenalidomide (R)-dexamethasone (d) induction followed by autologous stem-cell transplantation (ASCT) and KRd consolidation (KRd_ASCT), 12 KRd cycles (KRd12), or K-cyclophosphamide(C)-d induction followed by ASCT and KCd consolidation (KCd_ASCT). After consolidation, pts were further randomized (R2) to KR vs R maintenance. MRD was assessed every 6 months (m) by 8-color second-generation flow cytometry (sensitivity 10-5) in pts with ≥very good partial response (VGPR). In pts achieving at least a complete response (≥CR), MRD was also assessed by NGS at the same time points (Adaptive Biotechnologies, Seattle, US-WA; sensitivity 10-5-10-6). Logistic regression analysis adjusted for International Staging System (ISS) stage (I vs II/III) and R1 was performed to evaluate the conversion rate from MRD-pos to MRD-neg during maintenance (KR vs R). PFS and OS of MRD-neg vs MRD-pos in the intention-to-treat (ITT) population were evaluated. For these analyses, MFC-pos pts included those who were positive by MRD plus those & lt;VGPR, whereas NGS-pos pts included those who were MRD-pos plus & lt;CR (excluding CR pts not evaluable by NGS). 1-year sustained MRD-neg by MFC and NGS was evaluated in pts with at least 2 samples available at least 1 year apart. Results. Rates of MRD-neg by MFC and NGS before maintenance in the 3 induction/consolidation arms have been previously presented (S. Oliva et al. EHA 2020). At R2, 65% of randomized pts were MRD-neg by MFC (equally distributed in the 2 arms); 39% (48/123) of MRD-pos pts turned MRD-neg after a median of 7.6 m (IQR 6.5-12): 46% (29/63) in KR vs 32% (19/60) in R (OR 2.27; P=0.04) arms. At R2, 72% of pts evaluable for CR were MRD-neg by NGS (equally distributed in the 2 arms); 33% of MRD-pos pts (15/45) became MRD-neg at 10-5: 39% (9/23) in KR vs 27% (6/22) in R arms (=NS). In the ITT analysis, after a median follow-up of 45 m from R1, pts who were MRD-neg before maintenance by both techniques showed a superimposable prolonged PFS and OS vs pts who were MRD-pos: 3-year PFS was 80% vs 52% (HR 0.36, 95% CI 0.26-0.49 P & lt;0.001) in MFC-neg vs MFC-pos pts and 83% vs 55% (HR 0.34, 95% CI 0.22-0.52, P & lt;0.001) in NGS-neg vs NGS-pos pts (Fig. 1A); 3-year OS was 96% vs 79% (HR 0.24, 95% CI 0.14-0.42 P & lt;0.001) in MFC-neg vs MFC-pos pts and 97% vs 82% in NGS-neg vs NGS-pos pts (HR 0.30, 95% CI 0.15-0.61, P & lt;0.001). The favorable impact of MRD-neg on PFS was confirmed in all subgroups, in particular in the high-risk setting. PFS in 1-year sustained MRD-neg was superimposable between MFC and NGS (4-year PFS 88% by MFC and 94% by NGS at 10-5). The impact of pre-maintenance MRD negativity by MFC on PFS was explored in different treatment arms: 3-year PFS was longer in KRd_ASCT vs KRd12 and in KRd_ASCT vs KCd_ASCT arms; MRD-pos pts showed a similar PFS in the 3 arms. The same trend was shown by NGS MRD negativity: 3-year PFS was longer in KRd_ASCT vs KRd12 and in KRd_ASCT vs KCd_ASCT arms. A longer PFS was observed in pre-maintenance MRD-neg pts who were randomized to KR vs R both by MFC (HR 0.51, P=0.02) and NGS (HR 0.38, P=0.03); similar features were observed in MRD-pos pts (Fig. 1B). Conclusions. KR maintenance induced a high rate of conversion from MRD-pos to MRD-neg both by MFC and NGS. The outcomes of pts who were MRD-neg by MFC and NGS at 10-5 were similar, as well as those of pts with 1-year sustained MRD-neg both by MFC and NGS. These clinical findings confirmed a high degree of concordance between these two techniques. MRD-neg pts receiving KRD_ASCT showed a longer PFS (88% at 3 years) than pts receiving KRd12 and KCd_ASCT. KR vs R significantly prolonged PFS even in pts who were MRD-neg before maintenance. Figure 1 Disclosures Oliva: Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Janssen: 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; Takeda: Membership on an entity's Board of Directors or advisory committees. Petrucci:Janssen: 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; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. D'Agostino:GSK: Membership on an entity's Board of Directors or advisory committees. Jacob:Adaptive Biotechnologies: Current Employment, Current equity holder in publicly-traded company. Gozzetti:Amgen: Honoraria; Takeda: Honoraria; Janssen: Honoraria, Research Funding. Kirsch:Adaptive Biotechnologies: Current Employment. Corradini:KiowaKirin: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Travel and accommodations paid by for; F. Hoffman-La Roche Ltd: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other; BMS: Other; Amgen: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Celgene: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Daiichi Sankyo: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Incyte: Consultancy; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations paid by for. Musto:Amgen: Honoraria; Celgene: Honoraria. Boccadoro:Sanofi: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Research Funding; AbbVie: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Zamagni:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau; Takeda: Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Gay:Celgene: 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; Janssen: 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; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Roche: 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; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: The presentation includes discussion of off-label use of a drug or drugs for the treatment of multiple myeloma (including carfilzomib, cyclophosphamide, lenalidomide and dexamethasone).

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-137351

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7