ALBERT

Description: Introduction . Elderly patients (pts) with Immune thrombocytopenia (ITP) may represent a clinical challenge since comorbidities and impaired functional capacity may reduce the therapeutic landscape and drug tolerability. Aims . To report ITP characteristics at diagnosis, and type/timing of treatment strategy, including response and toxicity rates in a cohort of elderly ITP pts. Methods. An electronic database was established to retrospectively collect clinical/laboratory data on elderly (age ≥60 yrs) pts that received at least one line of therapy for ITP in 11 Italian Hematology Centers. Data cut-off was July 2018. Treatment decisions were at the physician's discretion. Diagnosis and responses were assessed according to current guidelines and terminology. Infectious, thrombotic and hemorrhagic complications were graded according to the WHO scale. Comparisons of quantitative variables between groups were carried out by Wilcoxon-Mann-Whitney rank-sum test, and association between categorical variables (2-way tables) was tested by χ2 test. Cumulative incidences of infections, bleeding, and thrombosis were calculated considering death as competing risk (Fine and Gray model). Statistical significance was set at p

Description: Background Bone marrow neovascularization is a hallmark of multiple myeloma and progression is associated with a substantial increase in pro-angiogenic factors that promote bone marrow angiogenesis, including vascular endothelial growth factor (VEGF-A) and hepatocyte growth factor (HGF). At present, anti-angiogenic agents are not part of treatment strategies in multiple myeloma, neither alone nor in combination with approved agents. MP0250 is a first-in-class, tri-specific multi-DARPin® drug candidate neutralizing VEGF-A and HGF as well as binding to human serum albumin to increase plasma half-life. This is a report on early safety and efficacy of MP0250 in combination with bortezomib plus dexamethasone (Vd) in RRMM patients that have previously been exposed to proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs). Aims To assess the efficacy and safety of MP0250 in combination with bortezomib and dexamethasone in patients with RRMM (MiRRoR, NCT03136653). Trial Design This trial is recruiting adults ≥18 years of age with RRMM who have progressed after at least two prior treatment regimens including bortezomib and an IMiD. Patients were enrolled to receive iv MP0250 on day 1 + subcutaneous bortezomib 1.3 mg/m² on days 1, 4, 8, 11, oral dexamethasone 20 mg on days 1-2, 4-5, 8-9, 11-12 of each 21-day cycle. Patients will receive treatment until there is documented disease progression or unacceptable toxicity. Methods The primary endpoint is efficacy in terms of overall response rate (ORR) per International Myeloma Working Group criteria. Secondary endpoints include safety, immunogenicity, progression-free survival (PFS) and duration of response (DOR). Exploratory endpoints include overall survival, and pharmacokinetics. Exploratory biomarkers for HGF and cMET in bone marrow biopsies are detected by IHC; MM specific markers, circulating HGF and VEGF levels are measured using patient plasma samples. Results As of 01 July 2019, 20 patients (7 ongoing) received a total of 137 doses (1-33 cycles) of MP0250 at the maximum tolerated dose of 8 mg/kg on Day 1 of each 21-day cycle in combination with Vd. Median age was 61 years (46-76), median time since diagnosis was 6.7 years. Median number of prior therapies was 4 (range, 2-9). All 20 patients had prior exposure to IMiDs and PIs and 9 patients received PI-based regimens as their immediate prior line of therapy before start of MP0250 + Vd. Importantly, 6 out of these 9 patients achieved responses ≥ Partial Response (PR). Treatment had been discontinued in 40% of patients due to PD, 15% due to Adverse Event (AE), 5% due to physician's decision and in 1 case at patient's request. The most frequent drug-related grade 3/4 AEs were hypertension in 7/1 patients, thrombocytopenia in 4/1 patients, grade 3 proteinuria in 4 patients and grade 3 anemia in 4 patients. There were no infusion-related reactions. No treatment-related deaths were reported. 20 patients received ≥ 1 dose of MP0250 + Vd and had at least 1 assessment of response and were included in the efficacy analysis. 1 patient (5%) achieved Complete Response, 4 patients achieved Very Good Partial Response (20%) and 3 patients achieved PR (15%) for an ORR of 40%. DOR at cutoff date is 6 months (range, 2-21). Pharmacokinetic data show sustained exposure over multiple cycles with a mean half-life of 11 days (range, 6-17). No indication of ADA-mediated drug clearance was observed. Summary Combining MP250 at 8 mg/kg with standard doses of bortezomib and dexamethasone was generally well tolerated with discontinuation due to AE in only 15% of patients. No unexpected toxicity was observed and AEs consistent with the toxicity profile of the individual agents. Analysis of the preliminary efficacy results showed an encouraging ORR of 40%. Recruitment to this Phase 2 study is ongoing. Disclosures Knop: Janssen, AMGEN, Bristol-Myers Squibb, Celgene: Consultancy, Honoraria. Goldschmidt:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; John-Hopkins University: Research Funding; MSD: Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Research Funding; John-Hopkins University: Research Funding; Chugai: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dietmar-Hopp-Stiftung: Research Funding; Molecular Partners: Research Funding; Mundipharma: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dürig:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Celgene: Consultancy, Other: Travel or accommodations, Speakers Bureau. Bringhen:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Bristol-Myers Squibb: Honoraria; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gamberi:Amgen: Honoraria; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees. Castellano Acosta:Molecular Partners AG: Employment. Lang:Molecular Partners AG: Employment. Lemaillet:Molecular Partners AG: Employment. Sudhir:Molecular Partners AG: Employment.

Description: Introduction: Renal impairment (RI) is common in multiple myeloma (MM), with up to 40% of the patients (pts) experiencing this complication during the course of their disease. RI increases risk of early death and affects disease management in multiple ways, as it may complicate treatment options and dosing, and render pts more susceptible to infections and prolonged hospitalizations. Therefore, there is an urgent need to restore renal function in these pts in order to improve their quality of life and prognosis. Bortezomib-based therapies are the most commonly used in pts with RI, but eventually pts may become refractory to bortezomib and other drug classes such as IMIDs. Thus, new therapeutic options are needed in order to manage pts with MM and RI who fail these drugs. Daratumumab, an IgG1κ human monoclonal antibody that targets CD38, has shown durable responses and a favorable safety profile in heavily pretreated pts with relapsed/refractory MM (RRMM) as monotherapy. Pharmacokinetic analyses suggest that there are no clinically important differences in exposure to daratumumab in pts with normal or impaired renal function, but the available data on safety and efficacy of pts with RRMM and severe RI is scarce. Methods: DARE is a prospective, open-label, multicenter, phase 2 study, which completed the enrolment of 38 adult pts with documented RRMM and severe RI, defined as either eGFR

Description: Background: 18F-FDG-PET/CT is currently the standard technique to define imaging-minimal residual disease (MRD) in multiple myeloma (MM) patients. A joint analysis of 2 prospective randomized trials in newly diagnosed transplant-eligible MM (NDTEMM) patients applied for the first time the Deauville Scores (DS) to focal lesions (FS) and bone marrow uptake (BMS) showing the liver background (DS 〈 4) as the best cut-off to define PET/CT negativity after therapy and complete metabolic response (CMR) (Zamagni et al, ASH 2018). Validation of this new standardized criteria in an independent prospective series of NDTEMM patients is highly required. Imaging-PET/CT MRD also showed to be complementary to Multiparameter Flow Cytometry (MFC) in predicting patient's outcomes (Moreau P, JCO 2017). In this analysis, we aimed at confirming the applicability and validity of DS criteria to define PET/CT CMR and showing their impact on patient's outcomes in the multicenter phase II randomized FORTE trial for NDTEMM patients. We also looked at the complementarity with BM techniques, especially MFC. Methods: NDTEMM patients ≤ 65 years were randomized to receive carfilzomib, lenalidomide, dexamethasone (KRD) induction - autologous stem cell transplantation (ASCT) intensification-KRd consolidation (arm A); KRd12 (arm B) and carfilzomib, cyclophosphamide, dexamethasone (KCd) induction-ASCT intensification-KCd consolidation (arm C). Thereafter, patients were randomized to maintenance with lenalidomide alone or plus carfilzomib. PET/CT scans were performed locally at baseline (B) and prior to the start of maintenance (PM). DS were applied both in the BM and FLs, as previously described (Zamagni E, EHA 2020). CMR was defined as DS 〈 4 both in the FLs and BM. MRD evaluation was performed by 8-color second-generation flow cytometry (sensitivity 10-5) in patients who achieved at least VGPR before maintenance (Gay F, ASCO 2019). The impact of each parameter on outcomes was evaluated by landmark analyses at PM. A multivariable Cox regression analysis was adopted to identify independent predictors for PFS and OS. Results: 182 out of the 474 global patients enrolled in the trial had a pre- and post-treatment PET/CT evaluation available and were included in this analysis. Patients' baseline characteristics were: median age 57 years, ISS and R-ISS stage III 18% and 10%, respectively, high-risk cytogenetics (t(4;14) ± del(17p) ± t(14;16), detected by FISH) 26%, reflecting baseline clinical features of the entire FORTE population. At B, 93% of patients had FLs, with a median maximum standardized uptake value (SUVmax) of 5.7 [IQR: 4.1-8.1], 7% presented extra-medullary lesions and nearly all patients had increased BM uptake, with a median SUVmax of 3.4 [IQR: 2.8-4.3]. FS and BMS ≥ 4 were present in 87% and 57% of patients, respectively. At PM, PET/CT negativity according to DS 〈 4, was present in 80% in the FLs and 85% in the BM, respectively. 63% showed CMR. 92% and 61% of patients achieved ≥ VGPR and CR as best response, respectively, while 73% of them achieved MFC MRD negativity. The achievement of a best CR significantly correlated with BMS 〈 4 at PM (P= 0.003). In univariate analysis, at Landmark time PM, FS