Kooperativer Bibliotheksverbund

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 2138-2138

Abstract: Introduction: CD38 is highly and uniformly expressed on myeloma cells (1). Daratumumab is a human anti-CD38 IgG1κ monoclonal antibody that has previously shown a favourable safety profile as a single agent in patients with relapsed and refractory (RR) multiple myeloma (MM) (2). This study further assesses the efficacy of Daratumumab in combination with Dexamethasone in heavily pre-treated myeloma patients that are refractory to Lenalidomide, Pomalidomide, and Bortezomib. Methods: This study is an ongoing, open-label phase II study of Daratumumab in combination with Dexamethasone (NCT02626481). Sixty-four, heavily pretreated Patients were recruited in thirty centres in France and Belgium from November 2015, to receive Daratumumab and Dexamethasone. Daratumumab 16 mg/kg was administered weekly during the first two 28-day cycles, every other week during Cycles three through six, and monthly in Cycle seven and beyond until disease progression or unacceptable toxicity. Patients were all refractory to Lenalidomide (Len), Pomalidomide (Pom) (defined by a progression within 60 days from last drug dosing) and Bortezomib (Bz) (defined by a progression within 6 months from last drug dosing). The primary objective was overall response rate as per the International Myeloma Working Group criteria. A planned safety and efficacy interim analysis was performed after the first 19 patients were enrolled. The last patient was enrolled on the 1stof August 2016. Results: Sixty-four patients were recruited onto the study. The median age (range) at screening was 61 (30-80). The median number (range) of prior lines of therapy was 6 (2-9). Sixty-seven percent of patient had previously received an autologous stem-cell transplant. At the time of screening, 20% of patients (n=13) had a t(4;14) and 12.5% (n=8) a del(17p). Planned interim analysis after the first 19 patients were enrolled did not find any unexpected toxicity. Safety and efficacy results (data cut May 15, 2016) of Daratumumab 16 mg/kg are presented here. No patient discontinued treatment due to Treatment Emergent Adverse Event such as infusion related reactions. Ten (15%) patients discontinued treatment due to disease progression after a median of one-cycle. The most common non-haematological TEAEs included infusion related (IRR, n=5, 8%), and fatigue (n=6, 9.3%). All patients with IRRs recovered and continued to receive treatment. Only six (9.5%) patients experienced hyperthermia. Thrombocytopenia and neutropenia were the most frequently reported grade 3 or 4 TEAE (11 and 5% respectively). Planned interim efficacy assessment showed a response rate (defined as a Partial Response (PR) or greater) in 3/19 patients at the end of the first cycle and 4/19 at the end of the second cycle, and a clinically relevant response (Stable Disease (SD) or greater) at the end of the second cycle for 11 of 19 patients, thus meeting the planed futility criteria and enabling the trial to go forward. As per the 15thof May, among the 40 evaluable patients (that had received at least 2 treatment cycles or progressed within the first) the overall response rate (3) was 25%, with eight (20%) partial responses (PR) and two (5%) very good partial responses (VGPRs) after a median of two cycles (range 1-5). An additional seven patients (17.5%) obtained a Minimal Response (MR) according to the EBMT criteria (4). This is consistent with prior results. Updated results will be presented at the time of ASH. Conclusions: Daratumumab in combination with Dexamethasone is a safe treatment option with a favourable benefit/risk profile for the treatment of triple relapsed or refractory (Len, Pom and Bz) myeloma patients. 1. Stevenson GT. CD38 as a Therapeutic Target. Mol Med. 2006;12(11-12):345-6. 2. Lokhorst HM, Plesner T, Laubach JP, Nahi H, Gimsing P, Hansson M, et al. Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma. N Engl J Med. 2015 Sep 24;373(13):1207-19. 3. Kyle R, Rajkumar S. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leuk Off J Leuk Soc Am Leuk Res Fund UK. 2009 Jan;23(1):3-9. 4. Bladé J,et al. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. Br J Haematol. 1998 Sep;102(5):1115-23. Disclosures Boyle: Novartis: Honoraria; Pfizer: Honoraria; Takeda: Honoraria; Janssen: Honoraria. Leleu:Novartis: Honoraria; LeoPharma: Honoraria; Pierre Fabre: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria; TEVA: Membership on an entity's Board of Directors or advisory committees. Hulin:Amgen: Honoraria; Janssen: Honoraria; Bristol: Honoraria; celgene: Honoraria; takeda: Honoraria. Moreau:Takeda: Honoraria; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria. Fohrer:amgen: Consultancy; celgne: Consultancy. Decaux:SIEMENS: Honoraria, Other: supply of free light chain assays , Research Funding; The Binding Site: Other: supply of free light chain assays , Research Funding. Avet-Loiseau:celgene: Consultancy; amgen: Consultancy; janssen: Consultancy; sanofi: Consultancy. Attal:celgene: Consultancy, Research Funding; amgen: Consultancy, Research Funding; janssen: Consultancy, Research Funding; sanofi: Consultancy. Facon:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: travel and expense, Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.2138.2138

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Haematologica, Ferrata Storti Foundation (Haematologica), Vol. 108, No. 10 ( 2023-04-20), p. 2774-2782

Abstract: Belantamab mafodotin (BM) is an anti-BCMA antibody-drug conjugate (GSK2857916) that represents an alternative option in multiple myeloma. We sought to assess the efficacy and safety of BM in a real-world setting in patients who benefited from an early access program. We conducted an observational, retrospective, multicenter study. Eligibility criteria were treatment of relapsed or refractory multiple myeloma (RRMM) in monotherapy in adult patients who have received at least three lines of therapy previously, including at least one immunomodulatory agent (IMiD), a proteasome inhibitor (PI) and an anti-CD38 monoclonal antibody, and whose disease progressed during the last treatment period. The primary endpoint of the study is to assess the overall survival (OS). Between November 2019 and December 2020, 106 patients were treated with BM; 97 were eligible for the efficacy evaluation and 104 for safety. The median age was 66 (range, 37–82) years. High-risk cytogenetics were identified in 40.9% of patients. Fifty-five (56.7%) patients were triple-class refractory and 11 (11.3%) were penta-class refractory. The median number of prior lines of treatment was five (range, 3–12). The median number of BM cycles administered was three (range, 1–22). The overall response rate at best response was 38.1% (37/97). The median OS was 9.3 months (95% confidence interval [CI]: 5.9-15.3), and median progression-free survival was 3.5 months (95% CI: 1.9-4.7). The median duration of response was 9 months (range, 4.65-10.4). Treatment was delayed for 55 (52.9%) patients including 36.5% for treatment-related toxicity. Ophthalmic adverse events, mainly grade ≤2, were the most common toxicity (48%). The occurrence of keratopathy was 37.5%. Overall, our data are concordant with the results from DREAMM-2 in terms of efficacy and safety on a non-biased population.

Type of Medium: Online Resource

ISSN: 1592-8721 , 0390-6078

URL: Article

DOI: 10.3324/haematol.2022.281772

Language: Unknown

Publisher: Ferrata Storti Foundation (Haematologica)

Publication Date: 2023

detail.hit.zdb_id: 2186022-1

detail.hit.zdb_id: 2030158-3

detail.hit.zdb_id: 2805244-4

In: Leukemia, Springer Science and Business Media LLC, Vol. 37, No. 1 ( 2023-01), p. 91-101

Type of Medium: Online Resource

ISSN: 0887-6924 , 1476-5551

URL: Article

DOI: 10.1038/s41375-022-01742-7

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2023

detail.hit.zdb_id: 2008023-2

In: Blood, American Society of Hematology, Vol. 139, No. 18 ( 2022-05-5), p. 2747-2757

Abstract: High-dose melphalan (HDM) and transplantation are recommended for eligible patients with multiple myeloma. No other conditioning regimen has proven to be more effective and/or safer. We previously reported in a phase 2 study that bortezomib can safely and effectively be combined with HDM (Bor-HDM), with a 32% complete response (CR) rate after transplantation. These data supported a randomized phase 3 trial. Randomization was stratified according to risk and response to induction: 300 patients were enrolled, and 154 were allocated to the experimental arm (ie, arm A) with bortezomib (1 mg/m2 intravenously [IV]) on days −6, –3, +1, and +4 and melphalan (200 mg/m2 IV) on day –2. The control arm (ie, arm B) consisted of HDM alone (200 mg/m2 IV). There were no differences in stringent CR + CR rates at day 60 posttransplant (primary end point): 22.1% in arm A vs 20.5% in arm B (P = .844). There were also no differences in undetectable minimum residual disease rates: 41.3% vs 39.4% (P = .864). Median progression-free survival was 34.0 months for arm A vs 29.6 months for arm B (adjusted HR, 0.82; 95% CI, 0.61-1.13; P = .244). The estimated 3-year overall survival was 89.5% in both arms (hazard ratio, 1.28; 95% CI, 0.62-2.64; P = .374). Sixty-nine serious adverse events occurred in 18.7% of Bor-HDM–treated patients (vs 13.1% in HDM-treated patients). The proportion of grade 3/4 AEs was similar within the 2 groups (72.0% vs 73.1%), mainly (as expected) blood and gastrointestinal disorders; 4% of patients reported grade 3/4 or painful peripheral neuropathy in arm A (vs 1.5% in arm B). In this randomized phase 3 study, a conditioning regimen with Bor-HDM did not improve efficacy end points or outcomes compared with HDM alone. The original trial was registered at www.clinicaltrials.gov as #NCT02197221.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.2021014635

Language: English

Publisher: American Society of Hematology

Publication Date: 2022

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 8996-8998

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2022-159125

Language: English

Publisher: American Society of Hematology

Publication Date: 2022

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 35, No. 15_suppl ( 2017-05-20), p. 8004-8004

Abstract: 8004 Background: Melphalan-prednisone-bortezomib (MPV) is a standard of care upfront for newly diagnosed elderly myeloma (eNDMM). Despite significant improvements on MPV’s safety profile, toxicity issues remain. Carfilzomib (K) is a novel generation proteasome inhibitor with a different safety profile from Bortezomib. Carmysap phase I/II study (twice a week Carfilzomib+MP) demonstrated K at 36mg/m² safe and active in eNDMM. We thought to study the K weekly-MP combination in eNDMM. Methods: IFM2012-03 is a multicenter phase I/II study in eNDMM (65 and older) aimed to determine the maximum tolerated dose (MTD) of K weekly. 4 cohorts of 6 patients each were recruited at K 36, 45, 56 and 70 mg/m 2 on days 1, 8, 15, 22 IV of 35-days cycles, with oral Melphalan and Prednisone from days 1 to 4 at usual doses. Patients received a 9-cycles induction followed by a K monotherapy maintenance at 36 mg/m 2 IV every 2 weeks for 1 year. 3 dose-limiting toxicities (DLTs) defined MTD at the lower N-1 dose. Results: 24 patients were included at K 36, 45, 56 and 70 mg/m². One DLT occurred at 36 mg/m² (grade 4 lymphopenia), one at 45 mg/m² (tumor lysis syndrome with grade 4 renal insufficiency), two at 56 mg/m² (grade 3 cardiac insufficiency and grade 3 febrile neutropenia) and two at 70 mg/m² (grade 3 nausea/vomiting and grade 3 hepatic cytolysis). One patient died from cardiac dysfunction considered related to K at 56 mg/m². 3 patients stopped therapy and 3 others required dose reduction of K. Following DSMB’s request a second 6-patients cohort was recruited at 70 mg/m², with increased attention around hyperhydration and monitoring HTA. We observed no DLT and no grade 3/4 adverse event in this cohort. Median age was 75 years, 56% patients were R-ISS 2 or 3. For the whole cohort (N=30), the overall response rate was 87% including 67% very good partial responses and 44% complete responses. Conclusions: The MTD of weekly K in the KMP combination is 70 mg/m² upfront for eNDMM, but it seems reasonable to recommend 56mg/m² after 75 years-old for safety reasons. KMP offers high response rates and possibly greater CR rate. However, since the CLARION study (VMP vs KMP) will not allow KMP’s approval in eNDMM in Europe, IFM decided to stop IFM2012-03 after phase I without performing phase II. Clinical trial information: NCT02302495.

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/JCO.2017.35.15_suppl.8004

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2017

detail.hit.zdb_id: 2005181-5

In: Blood, American Society of Hematology, Vol. 139, No. 17 ( 2022-04-28), p. 2666-2672

Abstract: Primary plasma cell leukemia (pPCL) is an aggressive form of multiple myeloma (MM) that has not benefited from recent therapeutic advances in the field. Because it is very rare and heterogeneous, it remains poorly understood at the molecular level. To address this issue, we performed DNA and RNA sequencing of sorted plasma cells from a large cohort of 90 newly diagnosed pPCL and compared with MM. We observed that pPCL presents a specific genomic landscape with a high prevalence of t(11;14) (about half) and high-risk genomic features such as del(17p), gain 1q, and del(1p32). In addition, pPCL displays a specific transcriptome when compared with MM. We then wanted to characterize specifically pPCL with t(11;14). We observed that this subentity displayed significantly fewer adverse cytogenetic abnormalities. This translated into better overall survival when compared with pPCL without t(11;14) (39.2 months vs 17.9 months, P = .002). Finally, pPCL with t(11;14) displayed a specific transcriptome, including differential expression of BCL2 family members. This study is the largest series of patients with pPCL reported so far.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.2021014968

Language: English

Publisher: American Society of Hematology

Publication Date: 2022

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. 4245-4245

Abstract: Background. Thalidomide is one of the most prescribed regimens upfront in eNDMM, e.g. elderly myeloma, essentially as melphalan-prednisone-Thalidomide (MPT). Several options are offered at 1st and 2nd relapse to patients initially exposed to Thalidomide with either bortezomib or lenalidomide-based therapy. On the other hand, the second most prescribed drug in elderly myeloma upfront is Bortezomib, primarily as Bortezomib-melphalan-prednisone (VMP), the 2nd standard of care upfront in Multiple Myeloma (MM) ineligible for transplantation. Interestingly, lenalidomide is the drug of choice at first relapse in the vast majority of cases in most countries where lenalidomide is approved at first relapse and beyond. In this situation, it is likely that the patients would not receive thalidomide throughout the disease course of myeloma. We sought to analyse whether patients not exposed to thalidomide upfront, and that were solely exposed to the 2 drugs, bortezomib-based regimen and lenalidomide-based therapy would have a lower survival than patients exposed to all 3 drugs, e.g. thalidomide, lenaldiomide and bortezomib. Method. A total of 145 patients were recruited in this multicentric study, 46,2% were in the thalidomide upfront exposed arm and 53,8% had never been exposed to thalidomide. Patients were required to be aged ≥65 years, NDMM treated with either thalidomide upfront or never been exposed to thalidomide upfront or later in the myeloma disease course. If not exposed to thalidomide, the patients were to have received bortezomib upfront and lenalidomide first relapse or vice versa. In the thalidomide group, all patients had MPT initially for a median of 8 cycles (range 3 - 12), at a median dose of thalidomide of 100mg/day (50-200), with 11% dose reduction. In the non-exposed thalidomide group, all patients had bortezomib upfront, patients received Vd, VCd or VMP upfront; lenalidomide was then given at first relapse to all patients. The median dose administered of bortezomib was 1.3mg/m², for a median of 5 cycles (2-9). Results. Overall, the median age was 73 years (range, 65 - 85), with 35% aged 〉 75. The M/F ratio was 1.1, 38% were ISS 3, the median b2m was 5.5mg/L, 26% had an ECOG score ≥ 2, 42% had renal insufficiency, 11% had elevated LDH, 8% presence of plasmacytoma, and 14% had adverse FISH (del17p, t(4;14) and or t(14;16)). There was no difference in patients' characteristics across studied groups, according to exposure or not to thalidomide. With a median follow-up of 5 years, 60% have died overall; 69% in the thalidomide exposed group versus 52% in the thalidomide non-exposed group (p=0.027). The median OS of thalidomide exposed patients was 55.7 months (46;65) versus 44 months (35;53) in the thalidomide non exposed patients (p=0.079). In the thalidomide exposed group, the median PFS of the thalidomide, bortezomib then lenalidomide lines were 27 months (24;30), 11 months (8;13) and 13 months (10;15). In the thalidomide non-exposed group, the median PFS of bortezomib then lenalidomide lines were 17 months (13;21) and 13 months (6;20). We then studied the survival of patients from onset of first relapse in the thalidomide exposed group, e.g. upon treatment with bortezomib, followed by lenalidomide at subsequent relapse, 22.5 months (10;34) compared to patients in the thalidomide non-exposed group that received bortezomib upfront and lenalidomide at first relapse, 44 months (35;53), p=0.005. Conclusion. Overall, thalidomide exposed versus non exposed groups had similar OS, while OS was significantly lower in the thalidomide exposed patients at first relapse onset versus in the thalidomide non exposed patients from diagnosis. This data seems to recommend use of bortezomib- and lenalidomide-based regimens as early as possible in the myeloma disease course, but not to abandon thalidomide. Study of the impact of thalidomide in the post bortezomib, lenalidomide and pomalidomide era might thus be important to study and optimize. Disclosures Karlin: Amgen: Honoraria; BMS: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees. Legros:BMS: Speakers Bureau; ARIAD: Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Garderet:Bristol-Myers Squibb: Consultancy. Hulin:Celgene Corporation: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Bristol Myers Squibb: Honoraria. Stoppa:Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria. Moreau:Janssen: Other: Adboard; Novartis: Other: Adboard; Takeda: Other: Adboard; Amgen: Other: Adboard; Celgene: Honoraria, Other: Adboard. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Pierre Fabre: Membership on an entity's Board of Directors or advisory committees. Zweegman:Janssen: 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: Membership on an entity's Board of Directors or advisory committees, Research Funding. MACRO:celgene: Membership on an entity's Board of Directors or advisory committees; jansen: Membership on an entity's Board of Directors or advisory committees; millenium: Membership on an entity's Board of Directors or advisory committees. Terpos:Janssen: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Amgen: Honoraria, Research Funding. Leleu:LeoPharma: Honoraria; Pierre Fabre: Honoraria; BMS: Honoraria; Novartis: Honoraria; TEVA: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Chugai: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.4245.4245

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. 126, No. 23 ( 2015-12-03), p. 3028-3028

Abstract: Background. New standards with increasing efficacy that are also characterized with improving the quality of life are needed for elderly myeloma patients. Although MPT and MPV regimens are remarkable in terms of efficacy, quality of life while on treatment with these 2 regimens remain an issue. The Carmysap twice weekly carfilzomib-based phase 2 study has demonstrated that Carfilzomib at the MTD of 36mg/m² might challenge bortezomib in the VMP standard. However, it has become routine practice to use bortezomib on a weekly schedule, with maintained efficacy and an improved safety profile. We sought to demonstrate that Carfilzomib Weekly plus Melphalan and Prednisone will prove strongly efficacious with acceptable safety profile and quality of life to newly diagnosed elderly multiple myeloma (eNDMM). Methods . IFM2012-03 (also called carmysap weekly) is a phase 1/2 multicenter open label single arm study to determine MTD during the phase 1 part and VGPR+CR rate during the phase 2 part of the study. The inclusion/exclusion criteria of interest were eNDMM (65 and older), with symptomatic and measurable disease, with absolute neutrophils ≥1 G/L, untransfused platelet count ≥75 G/L, hemoglobine ≥8.5 g/dL and clairance creatinine ≥ 30ml/min. We report herein the phase 1 part of the study which last cohort was completed at ASH abstract deadline. For the phase 1 part of the study, each cohort was 6 patients based, and started at 36mg/m² of carfilzomib on days 1, 8, 15, 22 using IV, 30 minutes infusion, route followed by a 13-day rest period per 35-days cycles, melphalan given at 0.25mg/kg/j and oral prednisone 60mg/m², both on days 1 to 4. The subsequent cohorts' doses for carfilzomib were 45, then 56 and finally 70mg/m². 9 cycles were planned as induction followed by a maintenance phase of weekly carfilzomib monotherapy given at 36mg/m² weekly for one year. The MTD was determined when ˃2 DLTs were observed. DLTs were considered during cycle 1 if any hematologic toxicity of grade 4 intensity or preventing administration of 2 or more of the 4 carfilzomib doses of the first treatment cycle, grade ≥3 febrile neutropenia, grade ≥3 gastrointestinal toxicities, any other grade ≥3 nonhematologic toxicity considered related to CMP by the principal investigator, grade ≥ 3 peripheral neuropathy persisting for more than 3 weeks after discontinuation of study drugs. Results. 26 NDMM patients recruited, 24 treated in the study, 6 per cohort at 36 mg/m² carfilzomib +MP, then 45 then 56, and finally at 70mg/m² which cohort cycle 1 is up and running. The median age was 74 with 10 patients older than 75 and sex ratio M/F 65. There was a DLT at 36 mg/m² carfilzomib (grade 4 lymphopenia), one at 45 (lysis syndrome complicated with grade 4 renal insufficiency, two at 56 (cardiac insufficiency grade 3 and febrile neutropenia grade 3). At ASH deadline, all patients from cohort 36 of carfilzomib have completed induction and maintenance up to cycle 6, 5/6 of cohort 45 have completed induction and started the maintenance phase, 5/6 of cohort 56 have completed cycle 6 of induction and pursue within the induction phase, and finally all patients from cohort 70 of carfilzomib are undergoing cycle 1. There are 22 SAE reported for a total of 171 cycles administered of carfilzomib +MP. So far, 3 patients (out of 24) have stopped treatment, including the 2 patients with DLTs, lysis syndrome and cardiac failure, and one patient that presented with pulmonary hypertension later in the disease course on cycle 5 of the 56mg/m² carfilzomib +MP cohort. And, an extra 3 patients have had Carfilzomib dose reduction, 2 patients at 36 from 45 and one at 45 from 56, for neutropenia grade 4, thrombocytopenia grade 4, and Dyspnea grade 3, respectively. Conclusion. The MTD of weekly carfilzomib in the combination to Melphalan and Prednisone could be determined at 70mg/m² in elderly NDMM, demonstrating the good safety profile of carfilzomib in this regimen and fragile population. The complete dataset of the entire study will be updated at ASH with response rate, survival and safety profile. Disclosures Leleu: Chugai: Honoraria; LeoPharma: Honoraria; Pierre Fabre: Honoraria; BMS: Honoraria; Novartis: Honoraria; TEVA: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Karlin:Janssen: Honoraria; BMS: Honoraria; Amgen: Honoraria; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria. Fitoussi:Sandoz: Membership on an entity's Board of Directors or advisory committees. Moreau:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: 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-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: 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.V126.23.3028.3028

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. 128, No. 22 ( 2016-12-02), p. 2128-2128

Abstract: Background. Melphalan plus prednisone and bortezomib combination is the most frequent standard of care used upfront for newly diagnosed elderly myeloma (eNDMM). Despite significant improvements with bortezomib sub-cutaneous administration and weekly schedule, safety profile issues remain with MPV, that only can be resolved with lowering the doses, albeit of the potential loss of efficacy. Carfilzomib (K), a novel generation proteasome inhibitor, has different safety profile with absence of neuropathy. Carmysap, a phase I/II trial of twice weekly Carfilzomib plus MP in eNDMM, demonstrated carfilzomib MTD at 36mg/m2. The safety profile appeared otherwise good for this frail population. We hypothesized that Carfilzomib can be used on a weekly schedule allowing to increase the dose of Carfilzomib given its positive safety profile. Methods. IFM2012-03 (carmysap weekly) is a phase 1/2 multicenter symptomatic eNDMM (65 and older) study to determine MTD during the phase 1 part and VGPR+CR rate (IMWG criteria) during the phase 2 part of KMP (Carfilzomib Weekly Plus Melphalan and Prednisone) regimen. Inclusion criteria required absolute neutrophils ≥1G/L, untransfused platelet count ≥75G/L, hemoglobine ≥8.5g/dL and clairance creatinine ≥30ml/min. Induction comprised nine 5 weeks cycles. K is given 36, 45, 56 and 70 mg/m2 on days 1, 8, 15, 22 IV route in combination to oral Melphalan 0.25mg/kg/j and oral prednisone 60mg/m2, both on days 1 to 4. Maintenance. Carfilzomib. 36 mg/m2 weekly, every two weeks IV route for 1 year. Melphalan and Prednisone is not pursued at maintenance. Analysis is done on ITT. Recruitment was 6 patients per cohort, 3 DLTs defined MTD at the lower N-1 dose. We will report at ASH the results of the phase 1 and 2. Results. 32 NDMM recruited, 30 treated in the study, 6 per cohort at K 36 mg/m², 45, 56, and 70 twice per DSMB request. The median age was 76 with 2/3rd older than 75, sex ratio M/F 1.2, R-ISS 2 and 3 in 80%.There was one DLT at K 36 (grade 4 lymphopenia), one at 45 (lysis syndrome complicated with grade 4 renal insufficiency, two at 56 (cardiac insufficiency grade 3 and febrile neutropenia grade 3) and 2 at 70 (vomiting grade 3 and liver cholestase enzyme grade 3) across the 2 70 cohorts. As a whole for the study, the ORR is 87.5%, with 45.7% at least in CR. At data cut-off, with a median follow-up at 15 months, one patient had progressed and 2 had died of whom one of cardiac dysfunction considered K related at 56. The safery profile appeared well tolerated, however, 22 SAE were reported for a total of greater than 200 cycles administered of KMP. Of particular interest, 19 SAEs were reported across the K 56 and 70 cohorts, 6 of which were cardiovascular origin. Conclusion. IFM2012-03, KMP weekly, Carfilzomib plus Melphalan and Prednisone in elderly NDMM has reached RP2D at 70mg/m2 of K. The SAE signal at the highest dose of K 70 raise concerns on using K 70 in patients older than 75-80 years old, and the DSMB may recommend for these patients to limit the RP2D at 56mg/m2 of K. Updated data for phase 1 and 2 portions will be presented at ASH for the first time. Disclosures Leleu: TEVA: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; LeoPharma: Honoraria; Pierre Fabre: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Karlin:celgene: Consultancy, Honoraria; Bristol: Consultancy; takeda: Consultancy; janssen-cilag: Consultancy, Honoraria; amgen: Consultancy, Honoraria. Meuleman:Celgene: Consultancy; Bristol-Myers-Squibb: Consultancy; Takeda: Consultancy; Amgen: Consultancy. Roussel:AMGEN: Consultancy, Other: lecture fees, Research Funding; sanofi: Other: lecture fees; celgene: Consultancy, Other: lecture fees, Research Funding; janssen: Consultancy, Other: lecture fees; BMS: Other: lecture fees. Decaux:The Binding Site: Other: supply of free light chain assays , Research Funding; SIEMENS: Honoraria, Other: supply of free light chain assays , Research Funding. Hulin:celgene: Honoraria; Bristol: Honoraria; Janssen: Honoraria; Amgen: Honoraria; takeda: Honoraria. Attal:amgen: Consultancy, Research Funding; sanofi: Consultancy; celgene: Consultancy, Research Funding; janssen: Consultancy, Research Funding. Moreau:Celgene: Honoraria; Takeda: Honoraria; Janssen: Honoraria, Speakers Bureau; Amgen: Honoraria; Novartis: Honoraria; Bristol-Myers Squibb: Honoraria. Facon:Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Bristol: Consultancy; Janssen: Consultancy, Speakers Bureau; Karyopharm: Consultancy; Novartis: Consultancy; Millenium/Takeda: Consultancy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.2128.2128

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7