ALBERT

Description: Introduction: Although proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and PI+IMiD combinations have become the standard of care in multiple myeloma (MM), they are not considered curative. Most patients (pts) eventually relapse or become refractory to treatment, and outcomes are poor after treatment failure. A median overall survival (OS) of 13 mo was reported in pts with relapsed/refractory MM (RRMM) who were double-refractory to a PI and IMiD and received ≥3 prior therapies (Kumar et al, Leukemia 2017). Recently developed therapies with novel mechanisms of action (MoAs), including the monoclonal antibodies (mAbs) elotuzumab and daratumumab, are associated with prolonged progression-free survival (PFS) in clinical trials of RRMM (Dimopoulos et al, Cancer in press; NEJM 2016). However, there is little up-to-date information on real-world survival outcomes. Herein we report survival patterns across key milestone timepoints in pts with RRMM in a real-world clinical setting. Methods: PREAMBLE (NCT01838512) is an ongoing international, prospective, observational cohort study. Adults with RRMM who were not participating in a clinical trial at the time of enrollment, had ≥1 prior therapy and documented disease progression, and began treatment with a PI, IMiD, PI+IMiD combination, or newer agent (those with newer MoAs, such as mAbs, histone deacetylase inhibitors, and novel combinations) ≤90 d before to 30 d after informed consent, were included and followed for up to 3 years. During the observational period, data were collected at each healthcare visit, and vital status was assessed every 6 mo throughout the follow-up period. Clinical efficacy and patient characteristic data were collected by healthcare providers using electronic case report forms. Descriptive statistics were used to describe pt characteristics and Kaplan-Meier plots were generated for time-to-event data. Multivariate Cox regression, with stepwise variable selection to select independent variables, was used to assess the association between baseline characteristics and PFS or OS. Results: At database lock (Nov 30, 2017), 1159 pts with RRMM were enrolled from the USA (31%) and Europe (67%), and included in this analysis. After a median (IQR) follow-up of 12.4 (6.3-24.9) mo, 39% of pts were still on study and 34% had died; most deaths (67%) were due to MM progression. At enrollment, median (range) age was 69 (34-92) y; 77% of pts had relapsed disease and 21% refractory disease. Among pts with a medical history, the most common comorbidities were vascular disorders (49%), metabolism and nutrition disorders (34%), and musculoskeletal/connective tissue disorders (29%). Pts received a median of 2 prior therapies before enrollment, with 50% having received an IMiD, 61% a PI, 21% a PI+IMiD, and 2% a newer agent. At enrollment, 45% of pts were receiving an IMiD, 41% a PI, 10% a PI+IMiD, and 4% a newer agent. Since enrollment, a total of 58% of pts received an IMiD, 49% a PI, 16% a PI+IMiD, and 10% a newer agent (including regimen received at enrollment). Median (95% CI) PFS was 11.4 (10.5-12.2) mo and OS was 33.7 (28.5-37.5) mo. Survival rates at milestone timepoints are shown in Table 1. Among pts who died due to MM progression (n=266), MM-related mortality was 56% at 12 mo, 85% at 24 mo, and 97% at 36 mo. In multivariate analysis, risk of disease progression/death was lower in pts with relapsed vs refractory disease at baseline (hazard ratio [HR] 0.82; 95% CI 0.68-0.99; p=0.0425) and higher in pts who had received 2-3 (HR 1.37; 95% CI 1.15-1.64; p=0.0004) or ≥4 (HR 1.54; 95% CI 1.22-1.95; p=0.0003) vs 1 prior therapy. Multivariate analysis for OS identified younger age, female sex, non-white race, relapsed disease, early-stage disease, fewer prior therapies, and the absence of baseline cardiac or gastrointestinal disorders as independent predictors of longer OS (Table 2). Conclusions: Real-world data suggest that over the last decade, survival has improved for pts with RRMM; however, OS remained low (48%) after 3 years in this analysis and most deaths were attributed to MM. Baseline comorbidities may also increase the risk of death and should be carefully considered when selecting treatments. Newer treatment options are still needed to further extend survival in pts with RRMM. Study support: Bristol-Myers Squibb (BMS). Writing support: Janice Zhou, Caudex, funded by BMS. Disclosures Cook: Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Honoraria; Celgene Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Glycomimetics: Consultancy, Honoraria. Cella:Novartis: Consultancy, Research Funding; Janssen Global services: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Chen:Bristol-Myers Squibb: Employment. Davis:Bristol-Myers Squibb: Employment. Durie:Amgen: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Janssen: Consultancy. Goldschmidt:Novartis: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Chugai: Honoraria, Research Funding; Mundipharma: Research Funding; Sanofi: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Research Funding; Adaptive Biotechnology: Consultancy; ArtTempi: Honoraria. Moreau:Celgene: 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; Abbvie: 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. Vij:Karyopharma: 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, Research Funding; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jansson: 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, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Description: AMG 531 is a novel platelet-stimulating peptibody that stimulates the thrombopoietin (TPO) receptor, and is being studied for its ability to increase production of platelets. Here we report efficacy data in nonsplenectomized patients from a randomized, double blind, placebo-controlled Phase 3 study designed to evaluate the efficacy and safety of AMG 531 in patients with chronic ITP. Sixty-two nonsplenectomized patients were enrolled (placebo, 21; AMG 531, 41) with a median age of 52 years (range 21 to 88) and a mean baseline platelet count of 18.3x109/L. Subcutaneous AMG 531 or placebo was administered weekly for 24 weeks at a starting dose of 1μg/kg, and adjusted to maintain a target platelet count of 50-200x109/L. One patient randomized to placebo received 3 doses of AMG 531 in error and was included in the efficacy analysis as a placebo. The primary study endpoint was the incidence of a durable platelet response, defined as a platelet count ≥50x109/L for ≥6 weeks during the last 8 weeks of the 24-week treatment period in the absence of rescue medications. Starting at a low dose of AMG 531 and gradually increasing it, as well as reducing the dose of steroids in certain patients, contributed to lower platelet counts early in the study. Twenty-five of the 41 patients (61.0%) receiving AMG 531 achieved a durable platelet response compared to 1/21 (4.8%) receiving placebo (p

Description: AMG 531 is a novel thrombopoiesis-stimulating “peptibody” consisting of an Fc carrier domain linked to 4 identical peptides that bind to and activate Mpl, the human thrombopoietin receptor. It has proven efficacy in raising platelet counts of patients with chronic ITP, and is being evaluated in chemotherapy-induced thrombocytopenia and myelodysplastic syndrome. While platelets from healthy subjects receiving AMG 531 reportedly behave normally in platelet aggregation studies, the effects of this medication on protein expression profiles are not known. The platelets from 12 healthy patients without known platelet defects and 9 chronic ITP patients receiving AMG 531 were isolated and their proteins extracted. Proteins with isoelectric points between pH 3 and 7 were separated by two-dimensional gel electrophoresis and stained with Sypro protein detection reagent. These gels were scanned and compared using Progenesis SameSpots software. In this pH range, there were approximately 5000 unique spots detected, representing individual proteins, isoforms of proteins or cleavage products. On multivariate analysis, approximately 11% of these proteins were expressed at levels significantly different between healthy patients without a known platelet disorder and chronic ITP patients receiving AMG 531. Principal component analysis substantiates these differences and a protein dendrogram has been created. The most significant protein expression differences are identified by tandem mass spectrometry. It is not known if these differences in protein expression represent younger platelets, stimulation of protein synthesis by AMG 531, or altered platelet protein expression as a reflection of the ITP. There is no known clinical correlate of these protein changes.

Description: Introduction: Iron deficiency anemia (IDA) is the most common cause of anemia worldwide and is frequently untreated or undertreated (Kesselbaum et al. 2014). The association of thrombocytosis with IDA is well-recognized, with recent work elucidating its underlying physiology (Xavier-Ferrucio et al. 2018). Thrombocytosis in IDA may predispose to thrombotic complications, as described in many case reports. Given that IDA is ubiquitous, even minor increases in thrombotic risk due to thrombocytosis have dramatic public health implications. Data describing the rate, predictors, and risk of thrombotic complications are limited. This study characterizes these features of thrombocytosis in IDA. Methods: We queried a large institutional patient data repository containing comprehensive chart data for over 5.8 million patients to identify patients with IDA with and without thrombocytosis and thrombotic events over a 40-year time period (1979 to 2019). Demographic information, hematological parameters, thrombosis history, and other medical history were collected at time of peak thrombocytosis, time of IDA diagnosis, and clinical baseline (before IDA diagnosis or after resolution). The fidelity of query data was assessed by performing detailed manual chart review of 700 total patients. Clinical diagnoses of IDA were verified by confirming ferritin values

Description: AMG 531 is a novel platelet-stimulating peptibody that targets the TPO receptor, resulting in increased production of platelets. This ongoing, open-label study assessed the safety and efficacy of long-term AMG 531 dosing in ITP patients. Eligible patients have completed a previous AMG 531 study in ITP, are ≥18 years of age, have a baseline platelet count ≤50 x 109/L, with no recent significant change in medical history. The AMG 531 starting dose is 1μg/kg by SC injection with dose adjustment to an original maximum of 30μg/kg, since reduced to 15μg/kg. Patients are treated weekly unless the platelet count is 〉400x109/L. Concurrent corticosteroids can be tapered when the platelet count is ≥50x109/L. Preliminary data are available for 26 patients treated for up to 24 weeks: 17 women and 9 men; mean age, 48.4±11.6 (SD) years; mean baseline platelet count, 18.5±12.3 (SD) x109/L. Twenty-one patients (80.8%) had undergone a splenectomy before study entry; 6 (23.1%) were receiving concurrent corticosteroids for ITP. Twenty-one of 26 patients (80.8%) had a protocol-defined platelet response to AMG 531 (doubling of the baseline platelet count and ≥50x109/L). The mean AMG 531 dose at the first response was 3.7±2.7 (SD) μg/kg (at median 5 weeks); the mean dose at week 24 was 7.2±4.2 (SD) μg/kg. Twelve of 26 patients (46.2%) had a durable platelet response (doubling of the baseline count and ≥50x109/L at 6 or more of weeks 17–24). Twenty patients (76.9%) had a platelet count ≥100x109/L at least once; 7 (26.9%) had a platelet count ≥400x109/L. Of 6 patients on concurrent corticosteroids, 3 discontinued treatment and 2 had a ≥25% dose reduction. At least 1 serious adverse event was reported in 4 patients: anal fistula (unrelated to treatment), adverse drug reaction (unrelated), multiple sclerosis relapse (unrelated), bone pain (related), and diffuse reticulin formation in the bone marrow reported as myelofibrosis (related). Reticulin formation is hypothesized as due to excessive accumulation of megakaryocytes in the bone marrow. AMG 531 was discontinued, and a bone marrow 3 months later showed improvement. One patient experienced adverse events (musculoskeletal pain and headache) resulting in withdrawal from the study. No neutralizing antibodies have been detected to date. In summary, repeated exposure to AMG 531 has been generally well tolerated in this ongoing study. A total 80.8% of patients achieved a platelet response, defined as doubling of the baseline count and ≥50x109/L. Individualized weekly doses of AMG 531 may provide a therapeutic option in ITP, potentially enabling patients to taper off long-term corticosteroid therapy.

Description: Romiplostim is a thrombopoietin receptor agonist that increases platelet counts in patients with chronic immune thrombocytopenia (ITP). Thrombopoietin receptor agonists are reported to increase the risk for reticulin fiber deposition within bone marrow. This report describes bone marrow findings from romiplostim-treated rats, a retrospective analysis of reticulin observed in romiplostim ITP clinical trials, and a prospective clinical study of the effects of romiplostim on bone marrow morphology. In rats, romiplostim produced a dose-dependent increase in bone marrow fibrosis that resolved after treatment withdrawal. Of 271 ITP patients in romiplostim clinical trials, 10 were reported to have reticulin deposition; reticulin grade was increased in 4 of 5 patients with both pretreatment and on-treatment bone marrow results. Reticulin grade often decreased soon after romiplostim discontinuation. In the prospective study, reticulin grade during romiplostim treatment remained within the normal range for all patients and was increased in only 1 of 6 patients with pretreatment and on-treatment bone marrow results. This report suggests that romiplostim produces reversible, dose-dependent bone marrow changes in rats and produces modest increases in bone marrow reticulin in some ITP patients that decrease when therapy is discontinued. These studies were registered at www.clinicaltrials.gov as #NCT00102323, #NCT00102336, #NCT00861224, and #NCT00116688.

Description: Abstract 3702 Introduction: Romiplostim is a novel peptibody that increases platelet counts by a mechanism similar to endogenous thrombopoietin, and is approved for the treatment of chronic ITP. ITP is characterized by low platelet counts due to increased platelet destruction and suboptimal platelet production. The response rate to ITP therapies is variable and may be associated with substantial adverse effects. Splenectomy is commonly used as a treatment for ITP because it removes the major site of platelet destruction. A recent consensus report (Provan et al., 2010, 168–86) recommends delaying splenectomy for 6–12 months, in keeping with the new definition for chronic ITP (Rodeghiero et al., Blood 2009, 2386–93); therefore, we evaluated patients who had been diagnosed with ITP ≤1 year who participated in a recent study of romiplostim versus standard of care (SOC). Methods: A randomized, open-label study was conducted in nonsplenectomized adult patients with ITP. The co-primary study endpoints were the incidence of treatment failure and the incidence of splenectomy. Treatment failure was defined as: platelet count ≤20 × 109/L for 4 consecutive weeks at the highest recommended dose and schedule of romiplostim or SOC, or major bleeding event, or change in therapy due to intolerable side-effect or bleeding symptoms. The secondary endpoints included platelet counts and safety. Patients who discontinued treatment were considered to have met both primary endpoints. To assess the impact of study discontinuation on the primary endpoints, the actual incidence of treatment failure and splenectomy were also determined (“sensitivity analysis”). An ad hoc analysis of the study endpoints was conducted in those study patients who had been diagnosed with ITP for ≤1 year. Results: Eighty-five of 234 enrolled patients had ITP for ≤1 year; 29 received SOC and 56 received weekly subcutaneous injections of romiplostim. Patient characteristics were similar between treatment groups, as was the distribution of time since ITP diagnosis (romiplostim, 7 – 327 days; SOC 4 – 363 days). The mean (±SD) age was 53 (±20) years and 47% of the patients were male. The mean baseline platelet counts were similar in the romiplostim (26 ± 14 × 109/L) and SOC (23 ± 16 × 109/L) groups. The mean platelet count was higher in the romiplostim arm than the SOC arm at every weekly evaluation until the end of treatment (52 weeks). The incidence of treatment failure was lower in the romiplostim group (9%, 5/56) than in the SOC group (24%, 7/29) [OR, 0.34; 0.10 – 1.14; p= 0.0649]. Similarly, the incidence of splenectomy was significantly lower in the romiplostim group (7%, 4/56) than the SOC group (45%, 13/29) [OR, 0.10; 0.03 – 0.35; p20 × 109/L may have contributed to reduced differences in the rates of treatment failure per the study definition. Romiplostim was well-tolerated in this patient population, and findings were similar to those previously reported for the study population overall (Kuter et al., ASH 2009, #679). Disclosures: Boccia: Amgen Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria, Research Funding, Speakers Bureau; Acendia: Consultancy; Celgene: Equity Ownership, Honoraria, Research Funding, Speakers Bureau; Merck: Equity Ownership; Johnson & Johnson: Equity Ownership; CTI: Research Funding; Cephalon: Research Funding; Millenium: Research Funding. Kuter:Amgen Inc.: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Research Funding; ONO: Consultancy; Pfizer: Consultancy, Research Funding; Shionogi: Consultancy, Research Funding. Macik:Amgen Inc.: Research Funding; Pfizer: Research Funding; Eisai: Research Funding; Grifols: Research Funding; FDA: Consultancy; Center for Biologics Evaluation and Research: Consultancy; Hematology Consultant: Consultancy. Pabinger:Amgen Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees. Selleslag:Amgen Inc.: Consultancy, Honoraria. Rodeghiero:Amgen Inc.: Consultancy, Honoraria, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria, Speakers Bureau; Shionogi: Consultancy. Chong:CSL Australia: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Wang:Amgen Inc.: Employment, Equity Ownership. Lizambri:Amgen Inc.: Employment, Equity Ownership.