PURPOSE The anti–B-cell maturation antigen BiTE molecule AMG 420 was assessed in patients with relapsed/refractory multiple myeloma. PATIENTS AND METHODS In this first-in-human study, up to 10 cycles of AMG 420 were given (4-week infusions/6-week cycles). Patients had progression after ≥ 2 lines of prior therapy and no extramedullary disease. Minimal residual disease (MRD) response was defined as < 1 tumor cell/104 bone marrow cells by flow cytometry. RESULTS Forty-two patients received AMG 420 at 0.2-800 μg/d. Median age was 65 years, and median disease duration was 5.2 years. Median exposure was 1 cycle (range, 1-10 cycles) and 7 cycles (range, 1-10 cycles) for responders. Patients discontinued for disease progression (n = 25), adverse events (AEs; n = 7), death (n = 4), completion of 10 cycles (n = 3), and consent withdrawal (n = 1). Two patients remain on treatment. There were 2 nontreatment-related deaths from AEs, influenza/aspergillosis and adenovirus-related hepatitis. Serious AEs (n = 20; 48%) included infections (n = 14) and polyneuropathy (n = 2); treatment-related serious AEs included 2 grade 3 polyneuropathies and 1 grade 3 edema. There were no grade ≥ 3 CNS toxicities or anti-AMG 420 antibodies. In this study, 800 μg/d was considered to not be tolerable because of 1 instance each of grade 3 cytokine release syndrome and grade 3 polyneuropathy, both of which resolved. The overall response rate was 31% (n = 13 of 42). At the maximum tolerated dose (MTD) of 400 μg/d, the response rate was 70% (n = 7 of 10). Of these, five patients experienced MRD-negative complete responses, and 1 had a partial response, and 1 had a very good partial response; all 7 patients responded during the first cycle, and some responses lasted > 1 year. CONCLUSION In this study of AMG 420 in patients with relapsed/refractory multiple myeloma, the response rate was 70%, including 50% MRD-negative complete responses, at 400 μg/d, the MTD for this study.

Allogeneic transplantation does not improve survival in patients with standard-risk ALL and should be recommended only for patients with adverse prognostic factors.

The measurement of human cytomegalovirus (HCMV) DNA in blood is becoming the standard method for monitoring HCMV infection in immune-suppressed and unsuppressed patients. As various blood compartments can be used, we have compared the HCMV DNA measured in whole blood (WB), peripheral blood leukocytes (PBL), and plasma by real-time PCR. We tested 286 samples: HCMV DNA was extracted automatically from WB and PBL with the MagNA Pure instrument (Roche Molecular Biochemicals) and manually from plasma samples. The HCMV DNA from WB, PBL, and plasma was measured by real-time Light Cycler PCR. Primers and probe were located in the UL 83 region. HCMV DNA was detected more frequently in WB (88.5%) than in the PBL (65.7%) (P < 0.0001) or the plasma (55.2%) (P < 0.0001). There was a good correlation between the positive results in WB and in PBL (r ‫؍‬ 0.68; P < 0.0001), and 3.15 log 10 genome copies in 200,000 PBL, equivalent to the threshold value of 50 pp65-positive polymorphonuclear cells per 200,000 leukocytes, was equivalent to 3.4 log 10 genome copies in 200 l of WB. WB was shown to be suitable for automated extraction and the quantitation of HCMV DNA by real-time Light Cycler PCR by analysis of serial samples from representative patients of various populations. This system may be very useful for monitoring of immune-suppressed and unsuppressed patients.Human cytomegalovirus (HCMV) is the most important opportunistic pathogen in immune-suppressed patients, especially those who have received solid organ or bone marrow transplants. While antiviral treatment reduces the mortality and morbidity rates, the development of sensitive, specific techniques for detecting HCMV infection has now made possible preemptive treatment.A wide variety of techniques have been developed, including both nonmolecular and molecular tests. Because of its great sensitivity, qualitative PCR was the first method used (8, 18), but this method cannot differentiate between infection and disease in transplants. In contrast, quantitative PCR methods have shown that immune-suppressed patients with a high virus load are at great risk of developing HCMV disease (3,9,16,(19)(20)(21). PCR tests developed in-house and the first commercially available tests are time consuming and labor intensive because they require a post-PCR detection step. The development of automated real-time PCR instruments that can quantify DNA has led to a significant change in the routine diagnosis of CMV infection (6, 10, 17).The virus loads in several blood compartments, such as peripheral blood leukocytes (PBL) and plasma, have been compared to pp65 antigenemia (4, 13). Virus was most frequently detected in the PBL, and the virus loads were significantly higher than in the plasma (1, 2, 12). More recently, real-time quantitative PCR using the Taqman PCR or Light Cycler PCR methods have been used to measure virus DNA in various blood compartments of immune-suppressed patients, and the results were compared with pp65 antigenemia (6, 7, 10) or other PCR techniques (14). One study fou...

8007 Background: Objectives of this study included assessing safety and activity of AMG 420/BI 836909, which binds BCMA (B-Cell Maturation Antigen) on MM cells and CD3 on T cells, in relapsed and/or refractory (R/R) MM. Methods: In this FIH study, 6-week cycles of AMG 420 were given for ≤5 cycles or until disease progression (PD), toxicity, or consent withdrawal; 5 more cycles could be given for benefit. Eligible patients had progression after ≥2 lines (incl PI and IMiD). Excluded were PC leukemia, extramedullary relapse, CNS involvement, or prior allo-SCT. MRD was defined as <1 tumor cell / 104 bone marrow cells per flow cytometry. Results: As of Dec 10, 2018, 42 patients received AMG 420 (0.2-800 µg/d). Patients D/C for PD (n=24), adverse events (AE, n=7, incl 3 DLTs), death (4), completed 10 cycles (2), and consent (1). Median age was 65 y, median MM duration 5.2 y, and median # prior therapies 4. Patients were treated for a mean (SD) of 2.5 (2.6) cycles. There were 2 deaths from AEs (acute respiratory distress from flu / aspergillosis; fulminant hepatitis related to adenovirus infection); neither treatment related. Of those with serious AEs (SAEs, n=21, 50%), 18 required hospitalization. SAEs occurring in >1 patient were infections (n=12) and polyneuropathy (PN, n=2). Treatment-related SAEs included 2 grade 3 PNs and 1 edema. Grade 2-3 CRS was seen in 3 patients. No anti-AMG 420 Ab were detected. In this study, 800 µg/d was determined to not be tolerable as 2/3 patients had DLTs, 1 case of grade 3 CRS and 1 case of grade 3 PN; both required hospitalization and subsequently resolved. At 400 µg/d, there were 5 minimal residual disease (MRD)-negative sCRs, 1 VGPR, and 1 PR, for a response rate of 7/10 (70%); at Dec datacut, responses lasted for 5.6-10.4 months with 4 patients ongoing on treatment. As of Feb 2019, some responses lasted >1 year. Overall, there were 13/42 responders (6 sCRs, 3 CRs, 2 VGPRs, 2 PRs). Median time to any response was 1 month. Conclusions: In this FIH study of AMG 420, a BiTE vs BCMA, in R/R MM, there was a 70% response rate (7/10) with 5 out of 7 responders achieving a sCR at 400 µg/d, a recommended dose for further investigation. Clinical trial information: NCT02514239.

Background: BCMA, a member of the TNF receptor family, is expressed on MM and plasma cells. AMG 420, formerly BI 836909, binds BCMA on tumor cells and plasma cells and CD3 on T cells, resulting in T-cell mediated lysis of BCMA+ cells. Objectives of this study of AMG 420 in patients with R/R MM included assessing safety and tolerability and anti-tumor activity per IMWG 2006. Methods: This is a FIH phase I dose escalation study (NCT02514239) of 6-week cycles of AMG 420 (1 cycle=4 weeks continuous IV infusion, 2 weeks off). Single-patient cohorts [0.2-1.6 µg/day (d)] were followed by cohorts of 3-6 patients (3.2-800 µg/d). Eligible patients had R/R MM and progression after ≥2 prior treatment lines (including proteasome inhibitor and immunomodulators); excluded were patients with plasma cell leukemia, extramedullary relapse, known central nervous system involvement, or prior allogeneic stem cell transplant. Treatment continued for up to 5 cycles or until disease progression (PD), start of new therapy, toxicity, withdrawal of consent, or investigator decision; 5 more cycles could be given per investigator for perceived benefit. MRD response was defined for this study as <1 tumor cell / 104 normal cells in the bone marrow per FACS using antibodies to cytIgλ, cytIgκ, CD19, CD56 or CD138, CD38, and CD45. Results: As of May 22, 2018, 35 patients received AMG 420 (0.2-800 µg/d). Patients discontinued for PD (n=21), adverse events [AE, n=7, including 2 dose-limiting toxicities (DLTs)], or completed 10 cycles (n=2); 5 remain on study. Mean (SD) age was 63.8 (8.7) years, median 65 years, min-max 39-79 years, and 22 (63%) were male. Median MM disease duration was 5.4 (Q1: 3.3, Q3: 7.4) years, min-max 1.3-20 years, and median # of prior therapies was 4 (Q1: 2, Q3: 5), min-max 2-13. Patients (n=35) were treated for a mean (SD) of 2.3 (2.3) cycles and a median (min-max) of 1 (1-10) cycles; responders (n=8) were treated for a mean (SD) of 5.3 (3.3) cycles and a median (min-max) of 3.5 (2-10) cycles, including those with treatment ongoing. Regarding safety, one patient in the 50 µg/d cohort died after the first cycle from acute respiratory distress due to concurrent flu and aspergillosis not considered related to treatment. Of those with serious AEs (n=17, 49%), 12 required hospitalization and another 3 had prolonged hospitalization. Serious AEs included infections (n=10, 29%, 3 device-related, 3 pneumonias, 2 catheter site, 1 aspergillus, 1 influenza, and 1 fever/infection), cytokine release syndrome (CRS, n=3), and 1 each of peripheral polyneuropathy (PPN), cardiac failure, edema, pyrexia, biliary obstruction, and renal failure. Treatment-related serious AEs included CRS (n=3, 2 grade 1 and 1 grade 3) and 1 each of PPN (grade 3), edema (grade 3), and pyrexia (grade 1). No anti-AMG 420 antibodies were detected up to 800 μg/d and no DLTs were observed up to 400 µg/d. In this study, 800 µg/d was determined to not be tolerable as 2/3 patients experienced DLTs: 1) Grade 3 CRS within 1d of initiating treatment with fever, hypertension, tachycardia, and retrograde amnesia; symptoms resolved after stopping drug, and 2) Grade 3 PPN that required hospitalization with subsequent complete recovery; after 15d of treatment, M protein decreased by 60%. Six patients had complete responses (CRs), 1 each at 6.5, 100, and 200 µg/d, and 3 at 400 µg/d; responses are ongoing for these last 3 (≥4.6 months). There also were two partial remissions, a partial response (PR) at 50 µg/d and a very good partial response at 800 µg/d. Response duration was for up to 8 cycles (1 patient had PR cycles 3-10). All patients at 400 µg/d (3/3) had MRD negative CRs. In the dose confirmation cohort enrolled after May 22, 2 of 3 patients had PRs as of cycle 1. Thus, at the dose of 400 µg/d, the objective response rate is 5/6 (83%); all 5 are still responding on treatment. Pharmacokinetic analyses show that responders had higher free-drug exposure levels than non-responders [median (range) of 3,225 (36-108,000) vs 97 (27-1,380) pg/mL]. Conclusions: In this FIH study, AMG 420, a short half-life BiTE® targeting BCMA, showed encouraging evidence of activity in patients with R/R multiple myeloma. During dose escalation, all 3 patients dosed with 400 µg/d had MRD-negative CRs, with 2 more responders in the dose confirmation cohort to date; 3 patients at lower doses also attained CRs. No major toxicities were observed up to 400 µg/d, which is a recommended dose for further investigation; DLTs at 800 µg/d were CRS and PPN. Figure Figure. Disclosures Topp: Regeneron Pharmaceuticals, Inc.: Honoraria, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Research Funding. Zugmaier:Amgen Inc.: Consultancy, Employment, Patents & Royalties: 20170327581, 9688760, 20170122947, 9486475, 20160208001, 9192665, 20150071928, 8840888, 20140227272, 20140228316, 20130323247, 20130287774, 20130287778, 20110262440, 20100112603, 7700299, 20070037228. Moreau: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; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Facon:Takeda: 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; Amgen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Munzert:Boehringer Ingelheim: Employment, Patents & Royalties: and other intellectual property .