ALBERT

Description: Multicentric Castleman’s disease (MCD) is a rare, lymphoproliferative disorder with high morbidity. MCD signs and symptoms are driven by dysregulated interleukin (IL)-6 production. Preliminary data suggest efficacy of siltuximab, a chimeric mAb against human IL-6, in MCD patients (van Rhee et al. J Clin Oncol 2010;28:3701-8). We evaluated the efficacy and safety of siltuximab in patients with symptomatic, measurable, HIV- and HHV-8-negative MCD in a phase 2, randomized, double-blind, controlled, multicenter study. Patients could be newly diagnosed/pre-treated and on stable, low-dose corticosteroids. Patients were randomly assigned 2:1 to siltuximab 11 mg/kg or placebo given by 1-h IV infusion q3w. All patients also received best supportive care to manage MCD symptoms. Patients received study agent until protocol-defined treatment failure, after which patients randomized to placebo could cross over to unblinded siltuximab. Primary analysis occurred after the last treated patient completed assessments at 48 wks. Primary endpoint was durable tumor and symptomatic response defined as PR or CR (Cheson criteria) by independent review and improvement/stabilization in MCD-related symptoms for ≥18 wks. Secondary endpoints included additional predefined efficacy measures and safety. 79 patients were randomized and treated with siltuximab (n=53) or placebo (n=26) from Feb 2010 to Feb 2013. Treatment arms were well balanced. Median age was 48 yrs, 48% were Asian, 39% were white, 66% were male, 30% were on corticosteroids, and 58% had prior systemic therapy. Patients had mixed (44%), hyaline vascular (33%), or plasmacytic (23%) histologic subtypes by pre-randomization central pathology review. Baseline MCD symptoms included fatigue (86%), malaise (61%), night sweats (52%), peripheral sensory neuropathy (38%), anorexia and pruritus (37% each). Median treatment duration was 375 vs. 152 d with siltuximab vs. placebo, with 64% vs. 27% completing 48 wks of treatment. A higher percentage of durable tumor and symptomatic response was observed with siltuximab compared with placebo (34% (1 CR, 17 PR) vs. 0%; p=0.0012). Investigator-reported response provided consistent conclusions. Median duration of tumor and symptomatic response in siltuximab-treated patients of 340 d indicates prolonged disease control. Tumor response rate by central radiology review was 38% vs. 4% (p=0.0022). Median time to treatment failure was not reached vs. 134 d (p=0.0084). Median time to next treatment was not reached vs. 280 d (p=0.0013). Durable symptomatic response rate was 57% vs. 19% (p=0.0018), including complete symptom resolution in 25% vs. 0% (p=0.0037). Hb improvement by ≥15 g/L at wk 13 was seen in 61% vs. 0% anemic patients (p=0.0002). Sustained decreases in CRP (a marker of IL-6 bioactivity), ESR, and fibrinogen, and increase in albumin were seen with siltuximab. 13 of 26 patients on placebo crossed over to siltuximab. The safety profile as defined by frequencies of treatment-emergent AEs was similar between siltuximab and placebo despite the 〉2x longer treatment duration with siltuximab: gr ≥3 AEs 47% vs. 54%, SAEs 23% vs. 19%, AEs leading to discontinuation 23% vs. 38% (mostly due to PD), AEs leading to treatment interruption 28% vs. 19%. Infusion reactions with siltuximab were infrequent (8%) and low grade, except for 1 anaphylactic reaction that led to treatment discontinuation. Gr ≥3 AEs frequently reported with siltuximab were fatigue (9%); night sweats (8%); and hyperkalemia, hyperuricemia, localized edema, hyperhidrosis, neutropenia, thrombocytopenia, hypertension, and weight increased (4% each). Gr ≥3 AEs reasonably related to siltuximab reported in 〉1 patient were neutropenia and thrombocytopenia (4% each). 3 (6%) patients had SAEs reasonably related to siltuximab. 2 (4%) patients in siltuximab died due to PD after treatment discontinuation. 4 (15%) noncrossover patients in placebo died (1 AE, 3 PD). This is the first randomized study in MCD. The efficacy of siltuximab in MCD patients was demonstrated by durable tumor and symptom response, and clinical benefit was confirmed by marked improvement of time to treatment failure, MCD-related symptoms, Hb levels, and sustained reduction in inflammatory markers. In conjunction with the tolerable safety profile in this population, this study provides compelling evidence that siltuximab should be considered a new treatment of choice for MCD patients. Disclosures: Wong: Roche: Research Funding; MSD: Research Funding; Johnson & Johnson: Research Funding; Bayer: Consultancy, Research Funding; Novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Biogen-Idec: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; GlaxoSmithKline: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Baxter: Research Funding; Amgen: Research Funding; Alexion: Honoraria. Casper:St. Jude Children's Hospital and Research Center: Membership on an entity’s Board of Directors or advisory committees; Hutchinson Cancer Research Institute--Uganda: Membership on an entity’s Board of Directors or advisory committees; Up-To-Date: Royalties Patents & Royalties; National Institutes of Health: Research Funding; Janssen Research & Development: Consultancy, Research Funding. Munshi:Janssen Research & Development: Membership on an entity’s Board of Directors or advisory committees. Fosså:Janssen Research & Development: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Simpson:Janssen Research & Development: Honoraria. Goh:Gilead Sciences, Inc: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity’s Board of Directors or advisory committees; Janssen Pharmaceuticals Inc: Research Funding; Novartis Pte Ltd: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Hospira, Inc: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Cavet:Janssen Research & Development: Research Funding. Bandekar:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Rothman:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Puchalski:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Chaturvedi:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. van de Velde:Johnson & Johnson: Equity Ownership; Janssen Research & Development: Employment. Vermeulen:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. van Rhee:Janssen Research & Development: Research Funding.

Description: Introduction: Multiple myeloma (MM) evolves from precursor disorders such as monoclonal gammopathy of undetermined significance (MGUS) and SMM (Landgren O, et al. Blood 2009. 113[22]:5412-5417). Currently, there are no approved therapies for SMM, and guidelines recommend close monitoring of SMM patients (pts) and initiating treatment only upon progression to MM. However, therapeutic intervention at the SMM stage, especially in pts at higher risk of progression to MM, may yield clinical benefit and prevent the development of MM-associated complications. DARA is a CD38-targeting IgG1κ monoclonal antibody with on-tumor and immunomodulatory mechanisms of action. Based on the demonstrated efficacy and favorable safety profile of DARA monotherapy in pts with relapsed/refractory MM (RRMM; Usmani SZ, et al. Blood 2016. 128[1]:37-44), we hypothesized that DARA could delay progression from SMM to MM. A prespecified primary analysis (15.8-month median follow-up) of the phase 2 CENTAURUS study (NCT02316106) revealed that DARA monotherapy was active and well tolerated in pts with intermediate- or high-risk SMM (Hofmeister CC, et al. ASH 2017. Abstract 510). Here, we present updated data from CENTAURUS based on 10 months of additional follow-up. Methods: Eligible pts had had a confirmed diagnosis of high-risk or intermediate-risk SMM for

Description: Abstract 2972 Introduction Siltuximab is a chimeric monoclonal antibody that binds human interleukin (IL)-6 with high affinity. Formal assessments of siltuximab's effects on cardiac repolarization using triplicate electrocardiograms (ECGs) have not yet been performed in clinical studies. A phase 1 study was conducted to evaluate the effect of siltuximab, administered at the highest dose level used in clinical studies, on the QT interval in patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or indolent multiple myeloma (IMM, i.e., asymptomatic MM with ≤3 lytic bone lesions but no other end organ damage). Methods Thirty patients with MGUS, SMM, or IMM who met the following criteria on ECG at screening: pulse 45−90 bpm, QTcF and QTcB ≤500 ms, QRS

Description: Background: CNTO 328 is an anti-interleukin (IL)-6 chimeric monoclonal antibody demonstrated to have anti-myeloma activities in vitro. Because IL-6 signaling augments the anti-apoptotic heat shock protein response, a potential resistance mechanism for bortezomib, downregulation of IL-6 signaling may enhance bortezomib’s anti-myeloma activity. Pre-clinical studies have shown that this combination had an additive to synergistic effect in inducing apoptosis in IL-6-dependent and independent multiple myeloma cell lines. Methods: In this open-label, safety lead-in cohort of a pivotal phase II trial, bortezomib naïve patients with relapsed/refractory multiple myeloma received CNTO 328 at 6mg/kg IV every 2 weeks in combination with 1.3 mg/m2 bortezomib IV on days 1, 4, 8, and 11 every 3 weeks. Patients received a maximum of 4, 6-week treatment cycles, after which bortezomib was reduced to 4, once weekly doses in a 5-week maintenance cycle. Dexamethasone was added to the regimen at disease progression. Results: Twenty-one patients (median age 66, range 39–85) were treated with bortezomib + CNTO 328. The median number of prior lines of therapy was 2 (range 1–3); the median duration since diagnosis was 3.5 years (range 1–10). Eleven patients had received prior autologous stem cell transplantation; 8 patients had received prior IMiDs. Baseline β2M levels of 〉3.5mg/L were reported in 13 patients; median CRP was 2.21 mg/L (range 0.4 – 86.1). Utilizing EBMT criteria, 12 patients (57%) achieved either a complete response (CR) or partial response (PR): 3 CR, 9 PR (including 2 very good partial response [〉90% reduction] and 1 unconfirmed due to discontinuation for renal insufficiency). Thirteen of twenty-one patients discontinued treatment: 5 due to disease progression, 7 adverse events (AEs), and 1 withdrawal of consent. The other 8 remain on treatment. The median number of CNTO 328 administrations was 11 (range 2–38). Median time to disease progression/death was 280 days (range 36–540+). Grade 3 and higher hematologic toxicity was common: neutropenia (15/21); thrombocytopenia (8/21); lymphopenia (6/21); leukopenia (5/21). Grade 3 and higher hematologic AEs considered to be possibly related to CNTO 328 included neutropenia (10/21), leukopenia (3/21), lymphopenia (2/21) and thrombocytopenia (1/21). Grade 3 and higher infections were reported in 5 patients (urinary tract, bacterial, and campylobacter infection, pneumococcal sepsis, and pneumonia, 1 case each, among which the urinary tract and campylobacter infections were considered to be possibly CNTO 328-related). Other common CNTO 328-related AEs (〉15%) of any grade included diarrhea (5/21), fatigue (5/21), and hypercholesterolemia (4/21). No patients died during treatment. Dexamethasone was added to the treatment regimen for only 4/21 patients, and no conclusions regarding this treatment modification can be drawn at present. Conclusion: Treatment with CNTO 328 combined with bortezomib is a promising new regimen for the treatment of relapsed/refractory multiple myeloma. Enrollment in a larger phase 2 randomized trial with bortezomib and either CNTO 328 or placebo is now ongoing to explore its full potential.