bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical responses and pharmacokinetics of fully human BCMA targeting CAR T-cell therapy in relapsed/refractory multiple myeloma.
Authors: li chunrui , Zhou Jianfeng , Wang Jue , Hu Guang , Du Aihua , Zhou Xiaoxi , Meng Li , Hong Zhenya , Chen Liting , Mao Xia 
Published: March 2020

8013 Background: Previous studies indicate patients with relapsed/refractory multiple myeloma (RRMM) who receive high-dose BCMA-targeting CAR-T cells may achieve better remission but have worse adverse events. Moreover, once the disease progresses again, the re-infusion of CAR-T cells is not effective. To solve this dilemma, we have developed a novel BCMA-targeting CAR-T (CT103A) with a lentiviral vector containing a CAR structure with a fully human scFv, CD8a hinger and transmembrane, 4-1BB co-stimulatory and CD3z activation domains. Methods: ChiCTR1800018137 is a single-center and single-arm trial of CT103A in patients with RRMM. The primary objectives are to characterize the safety and tolerability in patients with R/R MM. The secondary objectives include evaluation of anti-myeloma activity, cytokines, CAR-T cell persistence, and pharmacokinetics. Between September 21, 2018, and January 21, 2019, nine patients (including 3 patients having relapsed after being given a murine BCMA CAR-T) received CT103A in 3+3 dose-escalation trial (three doses at 1, 3, 6 ×106/kg) after a conditioning chemotherapy regimen of cyclophosphamide and fludarabine. All Patients had received a median of 4 prior lines (range 3 - 5) of MM therapy. Results: At the time of the February 4, 2019 data analysis, the overall response rate was 100% (Table), and all patients had a rapid response within 14 days, with 67% (2/3) reaching CR/sCR at the lowest dose. The pharmacokinetics of CT103A were assessed by a digital polymerase chain reaction. Robust expansions were seen even at the lowest dosage level. In addition, Cmax and AUC0-28 reached levels comparable to reported CD19 CAR-T. In the first two dose groups, the grade of cytokine release syndrome (CRS) was 0 - 2. In the 6 ×106 /kg dose group, DLT had been observed in one patient. Conclusions: Data from this early-stage clinical study showed the unparalleled safety and efficacy of CT103A. Major AEs were transient, manageable, and reversible. three patients who relapsed the murine BCMA CAR-T were treated with CT103A, two patients achieved CR, and one patient achieved VGPR. 100% ORR and a rapid response within 2 weeks, suggests CT103A could be developed as a competitive therapeutic to treat patients with RRMM. Treatment Response (Case 1,5 and 7 are patients who relapsed the murine BCMA CAR-T). Clinical trial information: ChiCTR1800018137. [Table: see text]
Efficacy of daratumumab (DARA) + bortezomib/thalidomide/dexamethasone (D-VTd) in transplant-eligible newly diagnosed multiple myeloma (TE NDMM) based on minimal residual disease (MRD) status: Analysis of the CASSIOPEIA trial.
Authors: Avet-Loiseau Herve , Moreau Philippe , Attal Michel , Hulin Cyrille , Arnulf Bertrand , Corre Jill , Garderet Laurent , Karlin Lionel , Lambert Jérôme , Macro Margaret , Perrot Aurore , Sonneveld Pieter , Levin Mark-David , Klein Saskia , Chiu Christopher , Pei Lixia , De Boer Carla , Kampfenkel Tobias , Wuilleme Soraya , Béné Marie-Christine ,   on behalf of IFM and HOVON
Published: March 2020

8017 Background: In TE NDMM patients (pts), the CD38 monoclonal antibody DARA significantly reduced the risk of progression/death and improved stringent CR, ≥CR, and MRD-negative rates when added to VTd in the phase 3 CASSIOPEIA study. MRD status and its association with progression-free survival (PFS) was evaluated in TE NDMM pts receiving D-VTd vs VTd as pre-transplant induction/post-transplant consolidation in Part 1 of CASSIOPEIA. Methods: In Part 1, TE NDMM pts were randomized 1:1 to 4 cycles of pre-ASCT induction and 2 cycles of post-ASCT consolidation with DARA + VTd or VTd. Landmark analyses of MRD were performed on bone marrow aspirates after induction by multiparametric flow cytometry (MFC; 10–5 sensitivity threshold) and after consolidation (at Day 100 post-ASCT) by MFC (10–5) and next-generation sequencing (NGS; 10–6) for all pts, regardless of response. Results: A cohort of 1085 pts was randomized (D-VTd, n = 543; VTd, n = 542). Post-induction and post-consolidation MRD-negative rates were significantly higher for D-VTd vs VTd (Table). Post-consolidation MRD-negative rates (MFC) were consistent across pt subgroups, including ISS stage III or high-risk cytogenetics. Multivariate analyses accounting for treatment arm and MRD negativity (MFC) showed a PFS benefit in pts reaching MRD negativity (HR, 0.31; 95% CI, 0.20-0.50; P <0.0001). Based on these analyses, D-VTd showed additional PFS benefit vs VTd (HR, 0.48; 95% CI, 0.30-0.78; P = 0.0028). Analysis of MRD based on response (per IMWG criteria) will be presented. Conclusions: Adding DARA to VTd induction and consolidation deepened responses, as demonstrated by significant increases in MRD-negative rates. MRD negativity was associated with a PFS benefit regardless of treatment group. However, deepened responses with D-VTd led to improved outcomes, with MRD negativity associated with prolonged PFS, versus VTd in pts with TE NDMM. Clinical trial information: NCT02541383. [Table: see text]
Phase 1 study of elotuzumab in combination with autologous stem cell transplantation and lenalidomide maintenance for multiple myeloma.
Authors: Osman Keren , Cho Hearn J. , Chari Ajai , Parekh Samir S. 
Published: March 2020

8021 Background: Elotuzumab is a humanized monoclonal antibody directed against SLAMF7 that is approved for use in relapsed multiple myeloma. We initiated a single-center, open label, phase 1 trial based on the hypothesis that the addition of elotuzumab and autologous peripheral blood mononuclear cell (PBMC) reconstitution to standard-of-care autologous hematopoietic stem cell transplantation (auto-SCT) and lenalidomide maintenance for consolidation therapy in myeloma patients will be safe and feasible. Methods: This is a Phase 1b, open-label, trial investigating elotuzumab and autologous PBMC reconstitution with auto-SCT consolidation therapy and lenalidomide maintenance. The primary objective of this study is to assess the safety and tolerability of elotuzumab and autologous PBMC reconstitution in the setting of auto-SCT and lenalidomide maintenance. The secondary objectives are to assess myeloma disease status and progression-free survival (PFS) after one year of treatment. Subjects must be eligible for auto-SCT, and meet inclusion/exclusion criteria. Fifteen subjects participated in this study. The treatment plan is: In addition to PBSC harvest, subjects undergo steady-state leukopheresis for PBMC collection. Subjects receive standard melphalan (day -1) and autologous stem cell rescue (day 0). Autologous PBMC are reinfused on day +3 and cycle 1 of elotuzumab 20 mg/kg IV is given on day +4. Subjects receive elotuzumab every 28 days up to cycle 12. Lenalidomide maintenance at 10 mg orally daily begins with cycle 4 of elotuzumab. The evaluable population constitutes all subjects who received at least four of the first five planned doses of elotuzumab. Results: 15 subjects have been enrolled in the study. All of these subjects are included in the safety population, having received at least 1 dose of elotuzumab. Nine of 15 subjects have completed 4 of the first 5 planned elotuzumab infusions.. The majority of adverse events, including infusion reactions attributable to elotuzumab, have been grade 2 or lower. There were no delays in hematopoietic reconstitution. No AEs were attributed to PBMC reconstitution. Conclusions: The combination of elotuzumab and PBMC reconstitution with standard auto-SCT and lenalidomide maintenance for consolidation therapy appears to be safe and feasible. The trial is ongoing and has completed accrual. The clinical results will be updated for presentation.
Maintenance with weekly carfilzomib in elderly newly diagnosed multiple myeloma (IFM 2012-03).
Authors: Bobin Arthur , Fouquet Guillemette , Duhamel Alain , Manier Salomon , Karlin Lionel , Kolb Brigitte , Tiab Mourad , Araujo Carla , Meuleman Nathalie , Malfuson Jean-Valère , Bourquard Pascal , Lenain Pascal , Jaccard Arnaud , Belhadj Karim , Attal Michel , Moreau Philippe , Avet-Loiseau Herve , Hulin Cyrille , Facon Thierry , Leleu Xavier 
Published: March 2020

8029 Background: Prolonged treatments have significantly improved survival in newly diagnosed multiple myeloma (NDMM). Lenalidomide (IMiDs), is currently approved in this indication, but remains a daily treatment, although oral, and may favor side effects in the long run. Furthermore, the use of a proteasome inhibitor (PI) is warranted in certain type of MM, such as high-risk. Carfilzomib, a second generation PI, has proved active combined with an acceptable security profile but its added benefit when given continuously is unknown. We thought to study maintenance Carfilzomib for elderly NDMM (eNDMM). Methods: The IFM 2012-03 multicenter phase I KMP (Carfilzomib, Melphalan, Prednisone) weekly study for eNDMM (≥ 65 years old) determined the maximal tolerated dose of weekly Carfilzomib at 70mg/m². We focus herein on the second part of the study with IV Carfilzomib monotherapy given at 36mg/m² for 13 cycles maintenance on an every 2 weeks schedule. Results: Thirty eNDMM were recruited in IFM 2012-03. Median age is 75, with 56% R-ISS 2 or 3 and 11% high-risk cytogenetic. With K weekly from 36 to 70mg/m², OS is reported at 93.3%, including 46.7% ≥CR; median PFS is 35.8 months and median OS was not reached. Twenty-two (73%) patients started K maintenance and 16 (73%) completed it. Four patients progressed and 2 stopped for AEs (renal amylosis, sensory neuropahty) during the maintenance phase. At maintenance completion, 50% were ≥CR. From the start of maintenance, in landmark analysis, median PFS is 28.1 months and the estimated 36-months OS approximately 70%. Conclusions: Carfilzomib monotherapy can be used safely in maintenance for 1 year in eNDMM, including for patients above 75 years. K maintenance may lead to deep response rate, certainly a most relevant prognostic factor for prolonged survival. Therefore, Carfilzomib maintenance, characterized with a simple administration modality, might be considered as an alternative to Lenalidomide and integrate the armamentarium of prolonged therapy in eNDMM. Clinical trial information: NCT02302495.
Biomodulatory therapy approach with lenalidomide in combination with pioglitazone, dexamethasone, and metronomic low-dose chemotherapy with treosulfan in patients with relapsed/refractory multiple myeloma > second-line.
Authors: Heudobler Daniel , Elger Tanja , Mayer Stephanie , Hart Christina , Vogelhuber Martin , Grube Matthias , Hahn Joachim , Lüke Florian , Ditz Diana , Günther Andreas , Gramatzki Martin , Schmidt Burkhard , Ferenczy Peter , Herr Wolfgang , Rechenmacher Michael , Reichle Albrecht 
Published: March 2020

8037 Background: Nowadays, therapy for relapsed or refractory multiple myeloma (rrMM) usually consists of multi-targeted combination regimens for achieving complete remission. In this context, resistance resembles a therapeutic challenge that may be overcome by novel biomodulatory therapies communicatively reprogramming dysregulated cellular and intercellular homeostasis in neoplasia. Methods: The present, prospective phase II, one-arm, one-stage multi-center, open label trial, following phase I, focused on reprogramming myeloma and adjacent stroma cells in order to control rrMM beyond > 2nd-line treatment and following lenalidomide resistance in prior line. Adults with rrMM were eligible for receiving continuously, oral, daily dexamethasone 1mg, pioglitazone 45mg, low-dose treosulfan as metronomic chemotherapy ( 250mg bid) and lenalidomide 15mg, respectively, until disease progression. Results: Thirty-nine patients (mean time since diagnosis, 5.7 years; 66.7% with age > 60 years) had received a median of 5.5 (range 2 to 10) prior treatments. 89.5% of the patients were refractory to last therapy (all IMiD resistant), and 48.7% had received autologous stem-cell transplants. The overall response rate (CR, VGPR) was 17.9%. Eighteen patients (46.2%) had partial response or better; ten patients (25.6%) had stable disease. The disease control rate (DCR) was 71.8%. Time-to-progression was not significantly different between IMiD refractory patients and those relapsing following prior IMiD therapy or between high-risk versus non-high-risk cytogenetics. The median progression-free survival (PFS) and overall survival was 5.6 months (95% confidence interval [CI], 3.8 to 8.5) and 17.6 months (95% [CI], 14.9 to 39.2), respectively. The major AE (NCI-CTCAE grade) with grade ≥ 3 and relation to study drugs was hematologic toxicity (N = 31, 67.4%). Due to scheduled dose reductions, this was associated with only 7 (15.2%) grade ≥ 3 infections. Conclusions: The favorable safety profile, encouraging efficacy and equivalent median PFS between biomodulatory and modern targeted therapy in a historic comparison reveal a proof of concept of combined biomodulatory therapy in patients with heavily pretreated and IMiD-resistant rrMM, which should be further evaluated. Clinical trial information: NCT001010243.
Continued improvement in survival in multiple myeloma (MM) including high-risk patients.
Authors: Nandakumar Bharat , Binder Moritz , Dispenzieri Angela , Kapoor Prashant , Buadi Francis , Gertz Morie A. , Lacy Martha , Dingli David , Hwa Lisa , Leung Nelson , Hayman Suzanne R. , Gonsalves Wilson I. , Kourelis Taxiarchis , Muchtar Eli , Warsame Rahma M. , Go Ronald S. , Hobbs Miriam A. , Kyle Robert A. , Rajkumar S. Vincent , Kumar Shaji 
Published: March 2020

8039 Background: Treatment of MM has evolved significantly over the past decade, with increasing use of multi-drug combinations for initial therapy. In addition, supportive care approaches have also improved. We examined how these improvements have translated to survival outcomes in patients with newly diagnosed MM. Methods: Patients (n=3449) with a diagnosis of MM made between 2004 and 2017 and seen at Mayo Clinic within six months of the diagnosis, were included in this analysis. Patients were divided into three groups based on the year of diagnosis; group 1- 2004-07 (n=831), group 2-2008-12 (n=1161), and group 3-2013-17 (n=1457). Survival of the groups were estimated using Kaplan-Meier method, and compared using log rank test. Results: The median age was 64 years (22 to 96); 60% were male and 40% were female. 14% were >75 years, 33% were aged 65-75 and 53% were <65 years. The median overall survival for the whole cohort was 5.7 years (95%CI; 5.4, 6.3). The median OS for the groups 1, 2 and 3 were 3.9, 6.3 and NR, respectively; p<0.001. The 4-year survival estimates were 50%, 62%, and 75%, respectively. We then explored the improvements in patient subgroups. While all patients experienced improvements in OS over time, improvement in group 3 was most prominent for those >75 years. In patients <65 years, the 4-yr OS for groups 1, 2 and 3 were 57, 71, and 79% respectively. In patients 65-75 years of age, the 4-yr OS for groups 1, 2 and 3 were 48, 60, and 75% respectively. In patients >75 years, the 4-yr OS for groups 1, 2 and 3 were 24, 35, and 56% respectively. While patients with high-risk disease did not see as much benefit in the earlier period, substantial progress was seen in the last group. The 3-yr OS for patients with high-risk cytogenetics were 52, 55, and 73% for groups 1, 2 and 3 compared to 67, 75, and 85% for standard-risk cytogenetics respectively. 2067 patients were staged according to the International Staging System and the median OS for stages 1, 2 and 3 were 6.5, 4.6 and 2.4 in group 1; 9.2, 6.6 and 3.5 in group 2 and NR for any of the stages in group 3. Conclusions: The results confirm continued improvement in survival of newly diagnosed multiple myeloma patients, including elderly and high-risk MM.
Stem cell (SC) yield and transplantation results from transplant-eligible newly diagnosed multiple myeloma (TE NDMM) patients (pts) receiving daratumumab (DARA) + bortezomib/thalidomide/dexamethasone (D-VTd) in the phase 3 CASSIOPEIA study.
Authors: Hulin Cyrille , Moreau Philippe , Attal Michel , Belhadj Karim , Benboubker Lotfi , Caillot Denis , Facon Thierry , Garderet Laurent , Kuhnowski Frederique , Stoppa Anne-Marie , Kolb Brigitte , Tiab Mourad , Sonneveld Pieter , Jie Kon-Siong , Westerman Matthijs , Pei Lixia , Kampfenkel Tobias , De Boer Carla , Vermeulen Jessica , van de Donk Niels W.C.J. ,   on behalf of IFM and HOVON
Published: March 2020

8042 Background: High-dose therapy (HDT) followed by autologous stem-cell transplantation (ASCT) is the standard of care in TE NDMM. In the phase 3 CASSIOPEIA study, D-VTd significantly improved stringent complete response (sCR), ≥CR, and minimal residual disease (MRD)-negative rates and reduced the risk of progression/death vs VTd in TE NDMM pts. We assessed SC yield and transplantation results among pts receiving D-VTd vs VTd induction prior to HDT/ASCT in Part 1 of CASSIOPEIA. Methods: In Part 1, TE NDMM pts ages 18-65 y were randomized 1:1 to 4 pre-transplant induction and 2 post-transplant consolidation cycles of DARA + VTd or VTd alone. After induction, pts underwent SC mobilization with cyclophosphamide 3 g/m2 (recommended dose) and GCSF. Peripheral blood SCs were harvested based on response to mobilization. Plerixafor was given if SC collection failed at first attempt and in accordance with institutional practice. Melphalan 200 mg/m2 IV was given as HDT prior to ASCT. Results: A total of 1085 pts were randomized (D-VTd, 543; VTd, 542). Among pts who completed mobilization (D-VTd, 506; VTd, 492), more pts receiving D-VTd vs VTd received plerixafor during mobilization (21.7% vs 7.9%). Pts underwent a median (range) of 2 (1-6) vs 1 (1-4) days of apheresis for D-VTd vs VTd. The median number of CD34+ cells collected was lower for D-VTd vs VTd (6.3×106/kg vs 8.9×106/kg). Nevertheless, a similar percentage of ITT pts receiving D-VTd vs VTd underwent ASCT (90.1% vs 89.3%). The median number of CD34+ cells transplanted for D-VTd vs VTd was 3.3×106/kg vs 4.3×106/kg. Hematopoietic reconstitution rates were high and similar for transplanted pts receiving D-VTd vs VTd (99.8% vs 99.6%). For D-VTd vs VTd, a median (range) of 13.0 (6-54) vs 13.0 (4-43) days was required to achieve sustained ANC > 500 cells/mm3, and a median (range) of 14.0 (2-56) vs 12.0 (1-47) days was required to achieve sustained platelets > 20,000 cells/mm3 without transfusion. Conclusions: SC mobilization and collection was feasible with D-VTd induction. Adding DARA to VTd allowed successful transplantation in pts with TE NDMM. Clinical trial information: NCT02541383.
Local activator and T cell engager (LocATE) selectively blocks PD-L1 at the cytolytic synapse for deeper responses in multiple myeloma.
Authors: Leisner Christian , Borras Leonardo , Jungmichel Stephanie , Richle Philipp , Scheifele Fabian , Schleier Thomas 
Published: March 2020

8045 Background: The BCMA-targeting bispecific T-cell engager AMG420 emerged as the first bispecific that achieved responses similar to CAR-T therapies in patients with relapsed/refractory (RR) multiple myeloma (MM). Despite improved ORR, the median duration until relapse is currently limited to approximately 12 months. Persistent minimal residual disease drives relapse and is characterized by increased expression of PD-1/PD-L1. Efficacy with checkpoint inhibitors is compromised by 1) their activity not been targeted specifically to the immune synapse between T cells and cancer cells, and 2) dose-limiting broadly distributed immune-related adverse events, which has halted several clinical trials. This underscores the need for localized checkpoint inhibition within the cytolytic synapse. We developed a Local Activator and T cell Engager (LocATE) antibody that combines binding to CD3 and BCMA with selective blockade of PD-L1 at the immune synapse in just one scaffold. Selectivity is achieved via low afffinity for PD-L1 and high affinity for BCMA. Methods: Antibody mediated Cytotoxicity (LDH assay) and T cell activation (IL-2 release) was measured in vitro using MM cell lines together with isolated human CD3+ T cells. Human ex vivo T cell activity and redirection was evaluated on fresh bone marrow biopsies from MM patients with different disease stages by automated microscopy (pharmacoscopy) and image analysis. Results: The LocATE antibody showed a 5-fold increase in T cell activation and MM cell killing in vitro compared to a BCMAxCD3 BiTE. Furthermore, patient-derived MM cells showed up to a 19-fold increase in T cell activation as compared to a BCMAxCD3 BiTE or a combination of BiTE and PD-L1 inhibitor, while no activity was observed on healthy cells. Conclusions: These results suggest that T cell redirection with simultaneous checkpoint inhibition in the synapse is highly potent while minimizing off-tumor toxicity, therefore, has high therapeutic potential for patients with relapsed MM.
Veliparib (Vel) in combination with chemoradiotherapy (CRT) of carboplatin/paclitaxel (C/P) plus radiation in patients (pts) with stage III non-small cell lung cancer (NSCLC) (M14-360/AFT-07).
Authors: Kozono David E. , Stinchcombe Tom , Salama Joseph Kamel , Bogart Jeffrey , Petty William J. , Guarino Michael J. , Bazhenova Lyudmila , Larner James Mitchell , Weiss Jared , DiPetrillo Thomas A. , Feigenberg Steven J. , Hu Beibei , Nuthalapati Silpa , Luo Yan , Vokes Everett E. 
Published: March 2020

8510 Background: CRT is standard treatment (Tx) for pts with unresectable stage III NSCLC. Vel, a potent oral PARP1/2 inhibitor, interferes with repair of chemotherapy- or radiation-induced DNA damage. In a phase 2 study, Vel showed favorable efficacy vs placebo when added to C/P in stage IV NSCLC. The reported phase 1 trial assessed the safety and efficacy of Vel + C/P-based CRT in Tx of stage III NSCLC (NCT02412371). Methods: Eligible pts (≥18 yr, unresectable stage III NSCLC, no prior NSCLC therapy) received Vel + CRT of weekly C area under the curve (AUC) 2 + P 45 mg/m2 weekly + 60 Gy (2 Gy/day) RT over 6–9 weeks (wk). Vel was dose escalated from 60 mg twice daily (BID) to 240 mg BID followed by Vel 120 mg BID added to consolidation therapy (CON) once every 3 wk of C AUC 6 + P 200 mg/m2 for 2 cycles (cohort 1–5). Cohort 6 received Vel 240 mg BID + CRT followed by Vel 240 mg BID + CON. Samples for pharmacokinetic (PK) analysis were collected on wk 4 day –3. The primary endpoint was to establish the recommended phase 2 dose (RP2D) of Vel + CRT/Vel + CON. Results: As of Sep 2018, 48 pts enrolled into cohorts 1–6 at Vel 60 mg/120 mg (n = 7), 80 mg/120 mg (n = 9), 120 mg/120 mg (n = 7), 200 mg/120 mg (n = 8), 240 mg/120 mg (n = 12), and 240 mg/240 mg (n = 5) added to CRT/CON; median age 65 yr (range, 48–81). Vel PK was dose proportional; 39 (81.3%) pts completed therapy. Grade ≥3 Tx-emergent adverse events (AEs) were reported in 37 (77.1%) pts; anemia and febrile neutropenia (10.4% each) were the most common. Serious AEs were observed in 19 (39.6%) pts. Dose-limiting toxicities occurred at 200 mg/120 mg (n = 1; influenza and pneumonia), 240 mg/120 mg (n = 1; insomnia), and 240 mg/240 mg (n = 2; febrile neutropenia, neutropenia, thrombocytopenia, esophagitis, suprapubic pain, sepsis); Vel 240 mg BID + CRT/Vel 120 mg + CON was chosen as the maximum tolerated dose/RP2D. Of 41 pts evaluable for tumor assessment, 26 (63.4%) had a confirmed response. Interim median progression-free survival was 24.1 mo (range, 8.9 – not reached); updated results will be reported. Conclusions: Vel 240 + CRT/Vel 120 mg BID + CON was well tolerated with promising antitumor activity in stage III NSCLC and was determined as RP2D. Clinical trial information: NCT02412371.