Kooperativer Bibliotheksverbund

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 121-121

Abstract: Background: Proteasome inhibitor (PI)-based induction and consolidation proved to be effective in newly diagnosed multiple myeloma (NDMM) patients (pts) eligible for melphalan 200 mg/m2-autologous stem cell transplant (MEL200-ASCT). High response rates have been reported with the second-generation PI Carfilzomib in combination with Lenalidomide-dexamethasone (KRd) or Cyclophosphamide-dexamethasone (KCd). Aims: The primary aim was to evaluate the efficacy and safety of KRd induction-ASCT-KRd consolidation (KRd-ASCT-KRd) vs 12 cycles of KRd (KRd12) vs KCd induction-ASCT-KCd consolidation (KCd-ASCT-KCd). Methods: NDMM pts ≤65 years were randomized (1:1:1; stratification ISS and age) to: KRd-ASCT-KRd: 4 28-day cycles with KRd induction (Carfilzomib 20/36 mg/m2 IV days 1,2,8,9,15,16; Lenalidomide 25 mg days 1-21; dexamethasone 20 mg days 1,2,8,9,15,16) followed by MEL200-ASCT and 4 KRd consolidation cycles; KRd12: 12 KRd cycles; KCd-ASCT-KCd: 4 28-day induction cycles with KCd (Carfilzomib 20/36 mg/m2 IV days 1,2,8,9,15,16; Cyclophosphamide 300 mg/m2 days 1,8,15; dexamethasone 20 mg days 1,2,8,9,15,16) followed by MEL200-ASCT and 4 KCd consolidation cycles. Thereafter, pts were randomized to maintenance with Lenalidomide alone or plus Carfilzomib. Centralized minimal residual disease (MRD) evaluation - 8-color second generation flow cytometry, sensitivity 10-5 - was performed in pts achieving ≥very good partial response (VGPR). Endpoints were pre-maintenance stringent complete response (sCR) and MRD negativity in intention-to-treat (ITT) analysis. Data cut-off was May 30, 2018. Results: 474 NDMM pts were randomized (KRd-ASCT-KRd, n=158; KRd12, n=157; KCd-ASCT-KCd, n=159) and analyzed. Pts characteristics were well balanced. Median follow-up was 20 months. Depth of response improved during treatment (Figure). By ITT analysis, rates of pre-maintenance sCR was similar between KRd-ASCT-KRd (41%) and KRd12 (42%), and significantly higher than with KCd-ASCT-KCd (30%; P value KRd-ASCT-KRd vs KCd-ASCT-KCd=0.047; P value KRd12 vs KCd-ASCT-KCd=0.028). Similarly, rate of ≥CR was 49% with KRd-ASCT-KRd, 52% with KRd12 and 38% with KCd-ASCT-KCd (P value KRd-ASCT-KRd vs KCd-ASCT-KCd=0.041; P value KRd12 vs KCd-ASCT-KCd=0.014) and rate of ≥CR+unconfirmed CR (missing immunofixation confirmation) raised to 60% vs 63% vs 46% in the 3 groups, respectively; rate of ≥VGPR was 88% with KRd-ASCT-KRd, 86% with KRd12 and 74% with KCd-ASCT-KCd (P value KRd-ASCT-KRd vs KCd-ASCT-KCd=0.002; P value KRd12 vs KCd-ASCT-KCd=0.008). In multivariate analysis, the main factor affecting probability of achieving ≥VGPR, ≥CR or sCR was treatment with KRd-ASCT-KRd or KRd12 vs KCd, with no significant impact of ISS Stage or FISH abnormalities. In ITT analysis (MRD missing [31/395 VGPR pts, 8%] and 〈 VGPR were considered as MRD positive), MRD negativity was again similar with KRd-ASCT-KRd (58%) and KRd12 (54%) and significantly higher than with KCd-ASCT-KCd (41%; P value KRd-ASCT-KRd vs KCd-ASCT-KCd=0.004; P value KRd12 vs KCd-ASCT-KCd=0.023); 82% vs 78% vs 88% of pts in the 3 groups, respectively, could maintain extended MRD negative status with 2 MRD negative results obtained apart ≥6 months (either pre-ASCT and post consolidation or post consolidation and during maintenance). During treatment (excluding ASCT) the most frequent grade 3-4 AEs were neutropenia (KRd-ASCT-KRd 20%, KRd12 10%, KCd-ASCT-KCd 16%), thrombocytopenia (KRd-ASCT-KRd 15%, KRd12 8%, KCd-ASCT-KCd 13%) and infections (KRd-ASCT-KRd 14%, KRd12 12%, KCd-ASCT-KCd 13%). Grade 3-4 dermatologic AEs (KRd-ASCT-KRd, 5% with KRd12 12%, KCd-ASCT-KCd 1%), increase in liver enzymes (KRd-ASCT-KRd 9%, KRd12 10%, KCd-ASCT-KCd 1%) and hypertension (KRd-ASCT-KRd 3%, KRd12 8%, KCd-ASCT-KCd 3%) were more frequent with KRd12. Rates of grade 3-4 cardiac AEs (KRd-ASCT-KRd 3%, KRd12 2%, KCd-ASCT-KCd 4%) and thrombosis (KRd-ASCT-KRd 1%, KRd12 2%, KCd-ASCT-KCd 2%) were below 5% in all arms. Discontinuation for AEs was similar in the 3 arms (KRd-ASCT-KRd 6%, KRd12 8%, KCd-ASCT-KCd 7%). Conclusions: Rates of MRD negativity, sCR, ≥CR, ≥VGPR were significantly higher with KRd-ASCT-KRd and KRd12 vs KCd. At present, no differences in MRD and overall best response (sCR, ≥CR, ≥VGPR) were noticed between KRd-ASCT-KRd and KRd12; longer follow-up is needed to evaluate survival. Treatment was well tolerated. Updated data will be presented at the meeting. Figure. Figure. Disclosures Gay: Roche: Other: Advisory Board; Seattle Genetics: Other: Advisory Board; Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Celgene: Honoraria, Other: Advisory Board; Amgen: Honoraria; Takeda: Honoraria, Other: Advisory Board. Galli:Sigma-Tau: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria. Belotti:Celgene: Other: Advisory Board; Amgen: Other: Advisory Board. Zamagni:BMS: 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; 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. Angelucci:Novartis: Honoraria, Other: Chair Steering Committee TELESTO protocol in MDS; Celgene: Honoraria, Other: Chair DMC proptocol BELIEVE 1 and BELIVE 2 in Thalassemia; Vertex Pharmaceuticals Incorporated (MA) and CRISPR Therapeutics AG (CH): Other: Chair DMC CRISPR CAS9 in Hemoglobinopathies; Jazz Pharmaceuticals Italy: Other: Local (national) advisory board on AML; Roche Italia: Other: Local (national) advisory board on biosimilars. Annibali:Celgene; Takeda; Amgen, Janssen Cilag: Honoraria. Offidani:Amgen: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board; Bristol-Myers Squibb: Honoraria, Other: Advisory Board. Palumbo:Takeda: Employment. Musto:Amgen: Honoraria; BMS: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria. 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. Boccadoro:Bristol-Myers Squibb: Honoraria, Research Funding; Mundipharma: Research Funding; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-112093

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 127, No. 9 ( 2016-03-03), p. 1102-1108

Abstract: Triplet lenalidomide-based regimens did not induce any advantage over doublet lenalidomide-based regimens in elderly myeloma patients.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2015-08-662627

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. 126, No. 23 ( 2015-12-03), p. 1760-1760

Abstract: Introduction: Multiple myeloma (MM) is still an incurable disease and patients may relapse despite achievement of complete remission (CR). Minimal residual disease (MRD) assessment by multiparameter flow cytometry (MFC) on bone marrow (BM) is a sensitive diagnostic tool to measure response and is highly predictive of outcome in MM as previously reported. The aim of this study is to evaluate the role of MRD monitoring by MFC in MM patients receiving novel agents with or without autologous stem cell transplantation (ASCT) and to investigate the efficacy of treatments by using MRD-negativity as a deeper response criteria. Methods: The RV-MM-COOP-0556 (EMN02/HO95 MM) study is a phase III, randomized, trial including newly diagnosed MM patients ≤ 65 years. All subjects received 4 cycles of Bortezomib-Cyclophosphamide-Dexamethasone (VCD) induction, followed by Cyclophosphamide chemotherapy and subsequent stem cell mobilization and collection. Afterward, patients were randomized to receive 4 cycles of Bortezomib-Melphalan-Prednisone (VMP) vs one or two cycles of High-Dose-Melphalan (HDM) followed by ASCT. After intensification patients were secondly randomized to receive two cycles of consolidation with Bortezomib-Lenalidomide-Dexamethasone (VRD) vs no consolidation, followed by Lenalidomide maintenance in both arms. Patients who achieved CR/sCR according to IMWG criteria (Rajkumar et al. Blood 2011) after intensification/consolidation treatment, were eligible for the MRD sub-study. MRD analysis by MFC was performed on BM samples after intensification/consolidation, after 6 courses of maintenance, and thereafter every 6 months until progression, to detect monoclonal plasma cells (PCs). Here, we used a double antibody combination (CD138Fitc/CD20PerCp-Cy5.5/CD117APC/CD45APC-H7/CD38PE-Cy7; cyKappaFitc/cyLambdaPE/CD19PerCp-Cy5.5/CD56APC/CD45APC-H7/CD38 PE-Cy7): one tube was employed to obtain PCs quantification, the other one to validate PCs clonality. MRD-negativity was defined when 〈 20 clonal PCs were detected among ≥2.000.000 leukocytes ( 〈 0.001%). Results: One hundred-eleven Italian patients (58 male/53 female) with a median age of 56 years (IQR 52-62) entered MRD sub-study. Sixteen (14%) were ISS stage III, 24 (22%) had high-risk cytogenetic profile and 10 (9%) had LDH levels higher than the upper normal limit. Forty-five patients (40%) received VMP as intensification and 66 (60%) underwent ASCT, thereafter 65 (58%) received VRD consolidation, 24 after VMP and 41 after ASCT. The median follow-up were 28.7 and 17 months from starting treatment and from MRD enrollment, respectively. After intensification/consolidation, 4 patients were not evaluable for MRD due to unsuitable samples, MRD negativity rate was 79% (85 out of 107 evaluable patients) and was independent from the intensification therapy: actually 50/63 patients who received ASCT and 35/44 patients who received VMP achieved MRD negativity. Within MRD-negative patients, 48/85 (56%) received VRD consolidation without major differences between VMP and ASCT. With the limitation related to the shorter follow-up, depth of response further improved during maintenance: 11/22 (50%) of MRD-positive patients became MRD-negative, independently from previous intensification therapy. Conclusions: MRD detection by MFC is a feasible technique in MM and allows to detect residual tumor cells among CR and sCR patients. Preliminary MRD results show that, in patients achieving CR, intensification with VMP or ASCT induced comparable rates of MRD-negativity and maintenance with Lenalidomide further improved depth of response in both arms. Longer follow-up is needed to correlate MRD status to prognosis and clinical outcome and to evaluate the role of maintenance therapy in increasing the quality of response. Disclosures Off Label Use: Use off-label of drugs for the dose and/or schedule and/or association . Gay:Sanofi: 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-Cilag: Honoraria. Larocca:Janssen-Cilag, Celgene: Honoraria. Caravita:Celgene: Honoraria. Gamberi:Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. Rossi:Celgene: Research Funding. Offidani:Janssen-Cilag, Celgene, Sanofi, Amgen, Mundipharma: Honoraria. Boccadoro:Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sonneveld:Janssen-Cilag, Celgene, Onyx, Karyopharm: Honoraria, Research Funding; novartis: Honoraria. Palumbo:Novartis, Sanofi Aventis: Honoraria; Celgene, Millennium Pharmaceuticals, Amgen, Bristol-Myers Squibb, Genmab, Janssen-Cilag, Onyx Pharmaceuticals: Consultancy, Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.1760.1760

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. 122, No. 21 ( 2013-11-15), p. 2077-2077

Abstract: The extensive use of new drugs in multiple myeloma (MM) allowed the achievement of unprecedented levels of cytoreduction and major advantages in survival rates, though almost all patients still relapse after a successful treatment. PCR-based minimal residual disease (MRD) studies are powerful prognostic tools, able to indentify patients at high risk of relapse. Thus, there is a growing interest in MRD to modulate therapy also in MM, as already happens in other lymphoid neoplasms. However available reports have a too short follow-up to be conclusive. In particular some points need to be addressed: 1) which is the long-term outcome of patients achieving molecular remission (MR) in the absence of further treatment? 2) What is the prognostic impact of MR loss? 3) How long is the window between MR loss and clinical relapse? These issues have been addressed based on the mature results of the GIMEMA VEL-03-096 trial [EudraCT Number 2004-000531-28], which currently has a median follow-up (mFU) of 93 months. Patients and methods Inclusion criteria and treatment schedule have been already reported [Ladetto et al., J Clin Oncol 2010]. MRD was assessed on bone marrow at diagnosis, study entry, after two VTD courses, at the end of treatment and then every six months up to clinical relapse. Patients underwent MRD detection using both qualitative nested PCR and Real Time Quantitative (RQ)-PCR, employing immunoglobulin heavy chain-derived patient specific primers, as described [Voena et al., Leukemia 1997; Ladetto et al., Biol Bone Marrow Transpl 2000; van der Velden et al., Leukemia 2007] . MR was defined as negative MRD results by nested-PCR or less than 1EE-04 by RQ-PCR. Loss of MR was defined as an increase of MRD levels of at least one log in consecutive samples at whenever timepoint. For survival analysis duration of response (DOR), progression-free survival (PFS), time to next treatment (TNT) and overall survival (OS) rates were used, as detailed in IMWG criteria [Rajkumar et al., Blood 2011]. Results Thirty-nine patients were enrolled. So far 27 serological progressions, 22 clinical relapses needing salvage treatment and 12 deaths (two non-MM-related) were observed. Median PFS was 60 months, median TNT 67 months and OS at mFU was 64%. 270 of the planned samples for MRD monitoring (86%) were actually received by the centralized lab. Currently, 26 MR and 11 MR losses have been registered. The achievement of MR was strongly associated with a better outcome, in terms of median DOR (62 vs 9 months, p 〈 0.001), PFS (67 vs 22 months, p 〈 0.001), TNT (108 vs 30 months, p 〈 0.001) and resulted significant for OS, too (72% vs 48% at mFU, p=0.04, Figure 1A-B). Moreover, patients with ongoing MR, MR loss or not achieving MR at all showed increasing risk of relapse, respectively (DOR not reached vs 38 vs 9 months, PFS 92 vs 63 vs 22 months, TNT not reached vs 72 vs 30 months, each p 〈 0.001, Figure 2). Interestingly, the time lag between MR loss and clinical relapse for patients achieving and then loosing MR was comparable to that between end of consolidation and clinical relapse for patients never obtaining MR (TNT 19 vs 11 months p=0.34). Finally, analyzing the relationship between MR achievement, MR loss and need for a salvage treatment, of the 26 patients who obtained MR only 11 (42%) received a retreatment at a median time of 42 months (range: 22-87 months). Of these 11 clinical relapses, 7 were anticipated by a molecular relapse (64%), occurring at a median time of 9 months (range: 2-39 months). The 4 relapses not anticipated by MR loss occurred in cases with inadequate follow-up sampling or at least two years after the end of the planned molecular follow-up. Conclusions Besides confirming the strong prognostic value of PCR-based MRD monitoring in MM, our long-term results indicate the following: 1) the 42 months TNT of patients achieving MR underlines the excellent disease control of MM patients once obtained MR; 2) the occurrence of MR loss heralds relapse, with a TNT from MR loss comparable to TNT of patients not achieving MR; 3) there is a 9 months lag between MR loss and need for salvage treatment. These observations will have increasing relevance considering that ongoing methodological developments will allow effective MRD monitoring in the vast majority of MM patients. Disclosures: Off Label Use: Bortezomib and thalidomide as post-transplant consolidation during first-line treatment of multiple myeloma. Ladetto:Celgene: Research Funding, Speakers Bureau; Jannsen Cilag: Research Funding, Speakers Bureau; Mundipharma: Research Funding, Speakers Bureau; Roche: Research Funding, Speakers Bureau; Amgen: Research Funding, Speakers Bureau. Cavallo:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Jannsen Cilag: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Caravita:Celgene: Honoraria, Research Funding; Jannsen Cilag: Honoraria. Guglielmelli:Celgene: Research Funding. Boccadoro:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Jannsen Cilag: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Palumbo:Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria; Amgen: Consultancy, Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V122.21.2077.2077

Language: English

Publisher: American Society of Hematology

Publication Date: 2013

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 3316-3316

Abstract: Background. Several trials have shown the superiority of high-dose melphalan (usually 200 mg/m2, MEL200) versus standard therapy in myeloma patients. Intermediate-dose melphalan (100 mg/m2, MEL100) was also superior to the standard dose, but MEL100 has not been clinically compared with MEL200 in a randomized study. In this prospective, randomized, phase III trial, we compared the efficacy and toxicity of MEL200 and MEL100. Aims. The primary end points were complete remission (CR) rate, event-free survival (EFS) and incidence of gastrointestinal toxicity, infections and treatment-related mortality (TRM). Methods. Inclusion criteria were previously untreated myeloma, aged ≤ 65 and Durie and Salmon stage II or III. Exclusion criteria were abnormal pulmonar, cardiac, liver and renal function, HBV, HCV, or HIV positivity, concomitant cancer or psychiatric disease. The institutional review board approved the protocol and written informed consent was obtained from all patients. All patients received 2 cycles of 28-day-dexamethasone- doxorubicin-vincristine (doxorubicin 50 mg/m2 day 1, vincristine 1 mg day 1, dexamethasone 40 mg days 1–4) and 2 cycles of cyclophosphamide (4 g/m2, day 1) followed by stem cell harvest. MEL200 patients was conditioned with 2 cycles of melphalan 200 mg/m2 and MEL100 patients with 2 courses of melphalan 100 mg/m2. All MEL courses were followed by stem cell reinfusion. Results. Two-hundred and ninety-eight patients (median age 57) were randomly assigned either to MEL200 (149 patients) or to MEL100 (149 patients). All patients were evaluated for response, EFS and OS in intention-to-treat analysis. Patient characteristics were similar in both groups with the exception of chromosomal 13 deletion, present in 69% of MEL200 and 45% of MEL100 patients (p=0.02). Ninety-six patients completed tandem MEL200; 103 tandem MEL100. The very good partial response rate was higher in MEL200 group (37% versus 21%, p=0.003), but CR was 15% in the MEL200 group and 8% in the MEL100 group (p=0.07). The median follow-up for censored patients was 40.5 months. The 4-years EFS was 44.5% in the MEL200 and 18.3% in the MEL100 group (HR=0.71, 95% CI 0.53–0.95, p=0.02). The 5-years overall survival (OS) was 59.2% in the MEL200 and 44.7% in the MEL100 group (HR=0.78, 95% CI 0.52–1.16, p=0.22). Duration of grade 4 neutropenia and thrombocytopenia was comparable, but a higher proportion of MEL200 patients required platelet transfusions (p=0.002). Grade 3–4 non-hematologic adverse events were reported in 38% of MEL200 patients and in 19% of MEL100 patients (p 〈 0.0001). The incidence of grade 3–4 mucositis was 16% after MEL200 and 3% after MEL100 (p 〈 0.0001). The incidence of severe gastrointestinal toxicity was 19% after MEL200 and 2% after MEL100 (p 〈 0.0001). The incidence of grade 3–4 infections and of TRM was similar in both groups. Conclusions. In conclusion, MEL200 resulted in a significantly higher very good partial response rate. This translated in a superior EFS, but not OS. Mel200 was associated with less gastrointestinal toxicity, including mucositis.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V112.11.3316.3316

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. 126, No. 23 ( 2015-12-03), p. 392-392

Abstract: Introduction. High-dose melphalan plus autologous stem-cell transplantation (ASCT) is the standard approach in newly diagnosed, transplant-eligible myeloma patients. We compared consolidation with high-dose melphalan plus ASCT versus cyclophosphamide-lenalidomide-dexamethasone (CRD), and maintenance with lenalidomide-prednisone (RP) versus lenalidomide alone (R). Methods. This is an open-label, randomized, phase 3 study. We enrolled newly diagnosed, transplant-eligible myeloma patients aged ≤65 years. Using a 2-by-2 factorial design, we randomized patients to consolidation with melphalan 200 mg/m2 (MEL200) followed by ASCT or CRD (cyclophosphamide 300 mg/m2 days 1, 8, 15; dexamethasone 40 mg days 1, 8, 15, 22; lenalidomide 25 mg days 1-21); and to maintenance with RP (lenalidomide 10 mg days 1-21; prednisone 50 mg every other day) or R alone. The primary endpoint was progression-free survival (PFS). Results. 389 patients were enrolled between July 6, 2009 and May 6, 2011. Median follow-up was 54.5 months. MEL200 significantly increased PFS (median PFS from the start of consolidation: 43.3 versus 28.6 months; HR 0.40, P 〈 0.001) and overall survival (OS; 4-year: 86% versus 73%; HR 0.42, P=0.004) compared with CRD. Median PFS from the start of maintenance was 37.5 months with RP versus 28.5 months with R maintenance (HR 0.84, P=0.336); 3-year OS was 83% with RP versus 88% with R maintenance (HR 1.53, P=0.210). Grade 3-4 hematologic toxicities (84% versus 26%, P 〈 0.001), gastrointestinal toxicities (20% versus 5%, P 〈 0.001) and infections (19% versus 6%, P=0.002) were higher with MEL200 than with CRD. No significant difference in adverse events (AEs) between RP and R was noticed. The most frequent grade 3-4 hematologic AEs were neutropenia (8% with RP versus 13% with R; P=0.193), infections (8% with RP versus 5% with R; P=0.417), systemic AEs (6% vs 2%; P=0.174) and vascular AEs (4% with RP versus 2% with R; P=0.449). In the RP arm, lenalidomide dose-reduction for AEs was required in 9% of patients; prednisone dose-reduction was required in 36% of patients (median time to prednisone dose-reduction: 4 months); 5% discontinued treatment for toxicity and 3% stopped treatment after developing a second primary malignancy (SPM). In the R arm, lenalidomide dose-reduction was required in 21% of patients; 8% discontinued lenalidomide for toxicity; 2% stopped treatment after developing a SPM. The median duration of lenalidomide treatment was comparable in the 2 groups. Conclusions. MEL200 significantly prolonged PFS and OS compared with CRD, regardless of maintenance. RP maintenance did not significantly improve PFS and OS compared with R alone. Disclosures Gay: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria; Sanofi: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Use off-label of drugs for the dose and/or schedule and/or association. Petrucci:Celgene: Honoraria; Janssen-Cilag: Honoraria; Sanofi: Honoraria; Bristol-Myers Squibb: Honoraria. Di Raimondo:Janssen-Cilag, Celgene: Honoraria. Caravita:Celgene: Honoraria. Ria:Italfarmaco: Honoraria; Novartis: Honoraria; Janssen-Cilag: Honoraria; Celgene: Honoraria. Offidani:Janssen-Cilag, Celgene, Sanofi, Amgen, Mundipharma: Honoraria. Bringhen:Merck Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag, Celgene, Novartis: Honoraria; Onyx: Consultancy. Patriarca:Janssen-Cilag, Celgene, Merck Sharp & Dohme: Honoraria. Spencer:Celgene: Honoraria. Hajek:Merck Sharp & Dohme: Consultancy, Honoraria; Janssen-Cilag: Honoraria; Celgene: Consultancy, Honoraria. Boccadoro:Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees. Palumbo:Novartis, Sanofi Aventis: Honoraria; Celgene, Millennium Pharmaceuticals, Amgen, Bristol-Myers Squibb, Genmab, Janssen-Cilag, Onyx Pharmaceuticals: Consultancy, Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.392.392

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. 115, No. 10 ( 2010-03-11), p. 1873-1879

Abstract: High-dose (200 mg/m2, MEL200) and intermediate-dose melphalan (100 mg/m2, MEL100) showed significant activity in myeloma. In a phase 3 study, 298 patients were randomly assigned to receive 2 autologous transplantations after conditioning with MEL200 or MEL100. Ninety-six of 149 (64%) completed MEL200 and 103 of 149 (69%) MEL100. Best response to MEL200 was: complete remission 22 of 149 (15%); partial remission 95 of 149 (64%), for an overall response rate of 79%. Best response to MEL100 was: complete remission 12 of 149 (8%); partial remission 95 of 149 (64%), for an overall response rate of 72%. Overall survival did not differ (P = .13); median progression-free survival (31.4 vs 26.2 months, P = .01), median time to progression (34.4 vs 27.0 months, P = .014) were longer in the MEL200. Treatment-related mortality was 3.1% in the MEL200 and 2.9% in the MEL100 group. Severe neutropenia and infections were marginally superior, whereas severe thrombocytopenia, mucositis, gastrointestinal adverse events, and the overall occurrence of at least 1 nonhematologic grade 3 or 4 adverse event were significantly higher in the MEL200 cohort. We conclude that MEL200 leads to longer remission duration and should be considered the standard conditioning regimen for autologous transplantation. This study was registered at www.clinicaltrials.gov as #NCT00950768.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2009-09-241737

Language: English

Publisher: American Society of Hematology

Publication Date: 2010

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. 200-200

Abstract: Abstract 200 Background: In a multicenter phase 3 randomized trial, VMPT-VT was superior to VMP for response rates, progression-free survival and time to next treatment (Palumbo A, et al. J Clin Oncol 2010). Here we report an updated analysis on survival after 4 years of follow-up. Methods: Patients (N=511) were randomly assigned to receive nine 6-week cycles of VMPT-VT (induction: bortezomib 1.3 mg/m2, d 1, 4, 8, 11, 22, 25, 29, 32, cycles 1–4, d 1, 8, 22, 29, cycles 5–9; melphalan 9 mg/m2 d 1–4, prednisone 60 mg/m2, d 1–4, thalidomide 50 mg d 1–42; maintenance: bortezomib 1.3 mg/m2 every 14 days and thalidomide 50 mg/day up to 2 years) or VMP alone. After the inclusion of 139 patients, the protocol was amended: both VMPT-VT and VMP induction schedules were changed to nine 5-week cycles and bortezomib schedule was modified to weekly administration (1.3 mg/m2 d 1,8,15,22, all cycles). Results: After a median follow-up of 47.2 months, median OS was not reached in the VMPT-VT arm and was 58.2 months in the VMP arm; 5-year OS rates were 59.3% and 45.9%, respectively (HR 0.74, p=0.04), with 26% reduced risk of death for patients receiving VMPT-VT (Figure-panel A). This benefit was more evident in patients younger than 75 years (5-year rates 67.8% for VMPT-VT vs 49.9% for VMP, HR 0.63, p=0.01, Figure-panel B) and in patients in complete response (CR) after induction (5-year rates 81.4% for VMPT-VT vs 48.2% for VMP, HR 0.38, p=0.006, Figure-panel C) while no significant differences were evident in patients with standard- or high-risk features detected by FISH (HR 0.99, p=0.99). A 1-year landmark analysis for patients completing induction was performed: the 4-year OS was 64.6% in the VMPT-VT group and 49.7% in the VMP group, with 33% reduced the risk of death for patients receiving VT maintenance (HR 0.67, p=0.02). Forty-nine percent of VMPT-VT and 70% of VMP patients relapsed and received subsequent salvage therapies; there was no difference in survival from relapse in the two groups (2-year OS rates 40.7% vs 50.2%,HR 1.11, p=0.54). The median duration of VT maintenance was 23.8 months. During VT maintenance 7% of patients experienced grade 3–4 peripheral neuropathy, 5% grade 3–4 hematological toxicity, 3% grade 3–4 infection and 12% discontinued due to adverse events. Second primary malignancies were reported in 7/254 patients in the VMPT-VT group and 7/257 patients in the VMP group. These corresponded to incidence rates of 0.9 and 1.05 per 100 patient-years, respectively, and were consistent with background incidence rates in the general population (aged 65–74 years 1.9, aged ≥ 75 years 2.3, SEER database). Conclusions: VMPT-VT significantly prolonged OS compared with VMP, especially in patients younger than 75 years and in patients achieving CR after induction. In patients 67–75 years of age, VMPT-VT reduced the risk of death by 37% and it should be considered a new standard of care. Disclosures: Palumbo: Celgene: Advisory Board, Advisory Board Other, Consultancy, Honoraria; Janssen: Advisory Board Other, Consultancy, Honoraria. Bringhen:Janssen: Honoraria; Celgene: Honoraria. Gentilini:Janssen: Honoraria; Celgene: Honoraria. Patriarca:Janssen: Honoraria. Guglielmelli:Janssen: Honoraria; Celgene: Honoraria. Musto:Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Petrucci:Janssen: Honoraria; Celgene: Honoraria. Boccadoro:Janssen: Consultancy, Research Funding, Scientific Advisory Board Other; Celgene: Consultancy, Research Funding, Scientific Advisory Board, Scientific Advisory Board Other.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V120.21.200.200

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. 132, No. Supplement 1 ( 2018-11-29), p. 305-305

Abstract: INTRODUCTION: Elderly patients with newly diagnosed multiple myeloma (NDMM) are highly heterogeneous and their outcome is influenced by many factors: beside age, also comorbidities, general physical fitness, and cognitive function play a crucial role. The IMWG frailty score combines age, functional status, and comorbidities, and it identifies fit, intermediate-fit and frail patients, with different risk of toxicity, treatment discontinuation, and mortality (Palumbo A et al. Blood 2015). Until now, evidence-based tailored treatments according to patients' frailty are still lacking. Therefore, this phase III study investigated the efficacy and feasibility of dose/schedule-adjusted lenalidomide-dexamethasone therapy followed by lenalidomide maintenance (Rd-R) versus continuous lenalidomide-dexamethasone (Rd) in elderly, intermediate-fit NDMM patients. METHODS: Intermediate-fit NDMM patients, with a total frailty score (age, Charlson Index, ADL and IADL) of 1 (http://www.myelomafrailtyscorecalculator.net/), were enrolled and randomized to receive Rd-R or continuous Rd. To better approximate a real-world older population, patients usually excluded from clinical trials or with abnormal laboratory values could be included in the trial. Rd-R treatment consisted of nine 28-day cycles of lenalidomide 25 mg/day for 21 days and dexamethasone 20 mg on days 1,8,15,22, followed by lenalidomide maintenance 10 mg/day for 21 days, until disease progression. Continuous Rd consisted of lenalidomide 25 mg/day for 21 days and dexamethasone 20 mg on days 1,8,15,22, until disease progression. The dose and schedule of continuous Rd was the one adopted in patients 〉 75 years in the FIRST trial (Hulin C et al. JCO 2016). The primary endpoint was event-free survival (EFS), defined as progression or death for any cause or discontinuation of lenalidomide or occurrence of any hematological grade 4 or non-hematological grade 3-4 adverse events (AEs), including Secondary Primary Malignancies (SPMs), whichever came first. RESULTS: 199 patients (98 in Rd-R arm and 101 in continuous Rd arm) could be evaluated. Patients characteristics were well balanced between the 2 arms. Median age was 75 and 76 years (p=0.06); 47% in Rd-R vs 57% in continuous Rd were defined intermediate-fit for age (≥76 years), 53% vs 43% due to an impairment in Charlson Index, ADL or IADL (p=ns). In intention-to-treat analysis, after a median follow-up of 25 months, EFS was 9.3 vs 6.6 months (HR 0.72, 95% CI 0.52-0.99, p=0.04), in Rd-R versus continuous Rd, respectively (Figure 1). Best response rates were not significantly different between the 2 groups: ≥PR rates were 73% vs 63%, and ≥VGPR rates were 43% vs 35% in the Rd-R vs Rd continuous group, respectively (p=ns). No difference in progression-free survival (PFS) and overall survival (OS) was observed. Median PFS was 18.3 vs 15.5 months (HR 0.93, 95% CI 0.64-1.34, p=ns) (Figure 1), 18 month-OS was 85% versus 81% (HR 0.73, 95% CI 0.40-1.33, p=ns). Adverse events accounting for EFS (any hematologic grade 4, non-hematologic grade 3-4) were less frequent in the Rd-R group (30% vs 39%) than in the continuous Rd group (p=ns). The most frequent adverse events were neutropenia, infection and skin reactions (less than 10% in each arm). After 9 treatment cycles, these adverse events were less frequent in Rd-R vs continuous Rd group (3% vs 7%, p=ns). Lenalidomide dose reduction after 9 treatment cycles was required in 1% of Rd-R patients and 21% of continuous Rd patients (p =0.06). Dexamethasone dose reduction was required in 17% vs 29% of patients, respectively (p=0.06). CONCLUSION: This is the first prospective randomized phase III trial specifically designed for real-life intermediate-fit NDMM patients. A dose/schedule-adjusted Rd-R treatment was more feasible compared to full dose continuous Rd treatment in elderly intermediate-fit NDMM patients, with no negative impact but rather a comparable outcome. These results confirm the need for an appropriate definition of patient frailty, and pave the way to a frailty-adjusted treatment approach to better balance efficacy and safety in elderly NDMM patients. Figure 1. Figure 1. Disclosures Larocca: Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Janssen-Cilag: Honoraria; Amgen: Honoraria. De Paoli:Amgen: Other: Advisory Board; Janssen: Other: Advisory Board; Celgene: Other: Advisory Board; Gilead: Other: Advisory Board. Galli:Celgene: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Sigma-Tau: Honoraria. Montefusco:Janssen: Other: Advisory Board; Amgen: Other: Advisory Board; Celgene: Other: Advisory Board. Caravita di Toritto:Johnson & Johnson: Other: Advisory Board, Travel and Accomodation EHA; Amgen: Other: Advisory Board; Bristol-Myers Squibb: Honoraria, Other: Travel and Accomodation EMN; Takeda: Other: Advisory Board; Celgene: Other: Advisory Board, Travel and Accomodation ASH, Research Funding. Giuliani:Celgene Italy: Other: Avisory Board, Research Funding; Takeda Pharmaceutical Co: Research Funding; Janssen Pharmaceutica: Other: Avisory Board, Research Funding. Patriarca:Jazz: Other: Travel, accommodations, expenses; Janssen: Other: Advisory role; Celgene: Other: Advisory Role; Travel, accommodations, expenses; Medac: Other: Travel, accommodations, expenses; MSD Italy: Other: Advisory Role. Offidani:Takeda: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board; Amgen: Honoraria, Other: Advisory Board; Bristol-Myers Squibb: Honoraria, Other: Advisory Board. 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; 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; Adaptive Biotechnologies: 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, Research Funding, Speakers Bureau; Bristol-Myers Squibb: 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. Palumbo:Takeda: Employment. Boccadoro:Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Mundipharma: Research Funding. Bringhen:Janssen: Honoraria, Other: Advisory Board; Celgene: Honoraria; Amgen: Honoraria, Other: Advisory Board; Takeda: Consultancy; Bristol-Myers Squibb: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-111796

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Clinical Lymphoma Myeloma and Leukemia, Elsevier BV, Vol. 17, No. 1 ( 2017-02), p. e9-

Type of Medium: Online Resource

ISSN: 2152-2650

URL: Article

DOI: 10.1016/j.clml.2017.03.015

Language: English

Publisher: Elsevier BV

Publication Date: 2017

detail.hit.zdb_id: 2540998-0

detail.hit.zdb_id: 2193618-3