ALBERT

Description: Background: Daratumumab is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action. The intravenous (IV) formulation of daratumumab is approved in many countries for use as monotherapy in relapsed/refractory multiple myeloma (RRMM), and in combination with standard-of-care regimens in RRMM and patients with NDMM who are transplant ineligible. A subcutaneous (SC) formulation of daratumumab is currently under investigation in several ongoing studies. In the phase 3 COLUMBA study, daratumumab SC was shown to be non-inferior to daratumumab IV, demonstrating similar efficacy and pharmacokinetics, with a significantly decreased rate of infusion-related reactions and reduced administration time. The randomized phase 2 LYNX (MMY2065) study will evaluate the efficacy and safety of retreatment with subcutaneous daratumumab in patients with RRMM who were previously exposed to daratumumab IV therapy. Study Design and Methods: In this ongoing, multicenter, open-label, randomized phase 2 study, approximately 230 patients with prior exposure to daratumumab will be randomized 1:1 to receive daratumumab plus carfilzomib and dexamethasone (D-Kd) or carfilzomib and dexamethasone (Kd) alone. Patients must have received 1 to 2 prior lines of therapy (at least one of which included daratumumab IV) with the daratumumab-based therapy completed ≥3 months prior to randomization. Eligible patients must have achieved a partial response or better (as defined by International Myeloma Working Group [IMWG] criteria) to daratumumab-based therapy, with a duration of response of ≥4 months. Patients must not have discontinued daratumumab due to a daratumumab-related adverse event or received prior treatment with carfilzomib. All patients will receive 20 mg/m2 carfilzomib IV on Day 1 of Cycle 1, escalated to 70 mg/m2 on Days 8 and 15; carfilzomib 70 mg/m2 will be administered on Days 1, 8, and 15 of each 28-day cycle thereafter. Dexamethasone 40 mg will be administered (IV or PO) QW for Cycles 1-9 and then on Days 1, 8, and 15 from Cycle 10 onwards. Patients in the D-Kd group will also receive daratumumab SC (1,800 mg co-formulated with recombinant human hyaluronidase PH20 [rHuPH20; 2,000 U/mL; ENHANZE® drug delivery technology, Halozyme, Inc.]) QW in Cycles 1-2, Q2W in Cycles 3-6, and Q4W thereafter. The primary endpoint is the rate of patients achieving a very good partial response or better. Secondary endpoints include overall response rate, rate of patients achieving complete response or better, progression-free survival, overall survival, overall MRD-negativity rate, time to next treatment, pharmacokinetics, and safety. The ClinicalTrials.gov identifier is NCT03871829. Disclosures Bahlis: Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Zonder:Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Intellia: Consultancy, Membership on an entity's Board of Directors or advisory committees; Caelum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alnylam: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wroblewski:Janssen: Employment, Equity Ownership. Qi:Janssen: Employment. Renaud:Janssen: Employment, Equity Ownership. Jackson:Janssen: Employment, Equity Ownership. Facon:Celgene: 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; Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: 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. OffLabel Disclosure: This presentation/paper includes information/discussion of a subcutaneous formulation of daratumumab, which is currently under investigation in several clinical trials, but has not yet been approved. The intravenous formulation of daratumumab is approved as monotherapy and in combination with standard-of-care regimens for the treatment of MM.

Description: Introduction Daratumumab (DARA) is a human IgGκ anti-CD38 monoclonal antibody with a direct on-tumor and immunomodulatory mechanism of action. In combination with standard of care (SOC) regimens, DARA has consistently demonstrated a doubling of complete response (CR) rates, tripling of minimal residual disease (MRD)-negative rates, and reduction in the risk of progression or death by ≥50% vs SOC alone in relapsed/refractory MM and NDMM pts. In the prespecified interim analysis of ALCYONE, a phase 3 study of D-VMP versus VMP in transplant ineligible NDMM (Mateos MV, N Engl J Med 2018. 378[6]:518-528), significant progression-free survival (PFS) benefit (median not reached [NR] vs 18.1 mo; hazard ratio [HR], 0.50; P

Description: Abstract 2410 Poster Board II-388 BACKGROUND: Eltrombopag (PROMACTA®; GlaxoSmithKline, Collegeville, PA, USA) is an oral, small molecule, thrombopoietin receptor agonist that is approved in the US for the treatment of chronic immune thrombocytopenic purpura (ITP) and is being evaluated for the treatment of thrombocytopenia of various etiologies (eg, chronic liver disease, hepatitis C, MDS, chemotherapy). The prevalence of hepatobiliary laboratory abnormalities (HBLAs) in the overall population of chronic ITP patients, specifically ALT 〉3× ULN (4.6%), has been shown to be relatively high compared with other disease populations (Bennett Haematologica 2009). OBJECTIVE: To evaluate the effects of eltrombopag on the liver by analyzing HBLAs across the ITP clinical program. METHODS: Data were collected and analyzed from patients in 3 randomized, placebo-controlled (TRA100773A, TRA100773B, RAISE) and 2 open-label (REPEAT, EXTEND) eltrombopag studies. The analysis followed an FDA draft guidance on Drug-Induced Liver Injury (DILI), taking into consideration ALT or AST ≥3× ULN, total bilirubin or alkaline phosphatase (AP) 〉1.5× ULN, and potential combinations of these HBLAs. RESULTS: In the 3 placebo-controlled studies, 7% (9/128) of placebo patients and 11% (33/299) of eltrombopag patients met at least 1 of the DILI screening criteria (Table 1). In these studies, a similar incidence of abnormalities was observed in both treatment groups with the exception of ALT ≥3× ULN (placebo 2%; eltrombopag 5%). Total bilirubin elevations were observed in 3% and 4% of patients in the placebo and eltrombopag groups, respectively. 3 patients (2%) on placebo and 4 patients (2%) on eltrombopag were withdrawn due to elevations of ALT and/or total bilirubin. In REPEAT, 5% (3/66) of patients met at least 1 of the DILI screening criteria. Results in EXTEND were similar with 24 patients (8%) meeting at least 1 of the DILI screening criteria and 5 patients (2%) being withdrawn due to an HBLA. 18 EXTEND patients met at least 1 of the DILI screening criteria in a previous eltrombopag study. Of these, 7 patients (39%) met at least 1 of the DILI screening criteria during EXTEND; 5/7 experienced the same HBLAs as in the previous study. The recurrent HBLAs were generally of a lesser magnitude than the initial ones. In studies in which fractionation was required, 17 of the 18 patients with total bilirubin 〉1.5× ULN had hyperbilirubinemia due to indirect bilirubin. Bilirubin was not fractionated in 1 patient. Of the 60 eltrombopag-treated patients with HBLAs across the program, 25 patients (42%) had their elevations resolve despite continued eltrombopag treatment. Across the program, 5 patients had ALT 〉3× ULN and bilirubin 〉1.5× ULN (Table 1). Of these 5 patients, 3 provisionally met Hy's Law criteria (ALT 3× ULN and bilirubin 〉2× ULN). Ultimately, however, none of these patients met Hy's Law criteria as 1 patient had an increase in indirect bilirubin and 2 patients had confounding factors: 1 with acute cholangitis and 1 with septicemia and right-sided congestive heart failure. None of the patients experiencing HBLAs was reported to present with clinical symptoms indicative of liver function impairment. CONCLUSION: Eltrombopag treatment can lead to an elevation of ALT or indirect bilirubin. In clinical trials, these elevations have been typically mild, reversible and not accompanied by clinical symptoms indicative of impaired liver function. Disclosures: Maddrey: GlaxoSmithKline: Consultancy. Cheng:GlaxoSmithKline: Research Funding. Wroblewski:GlaxoSmithKline: Employment. Brainsky:GlaxoSmithKline: Employment.

Description: Introduction: Daratumumab (DARA) is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action. The addition of DARA to standard-of-care regimens in phase 3 studies reduced the risk of disease progression or death by ≥44%, nearly doubled the rate of complete response or better, and induced a ≥3-fold increase in minimal residual disease (MRD)-negativity rates versus standard of care alone in patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM) and relapsed/refractory multiple myeloma. In the primary analysis of the phase 3 ALCYONE study (median follow-up: 16.5 months), a significant progression-free survival (PFS) benefit (median not reached vs 18.1 months; hazard ratio [HR], 0.50; P 36 months of follow-up from ALCYONE, including analysis of overall survival (OS) from a prespecified interim analysis. Methods: Patients with NDMM ineligible for high-dose chemotherapy and autologous stem cell transplantation due to age (≥65 years) or comorbidities were randomized 1:1 to receive up to nine 6-week cycles of VMP (bortezomib 1.3 mg/m2 subcutaneously on Days 1, 4, 8, 11, 22, 25, 29, and 32 of Cycle 1 and Days 1, 8, 22, and 29 of Cycles 2-9; melphalan 9 mg/m2 orally and prednisone 60 mg/m2 orally on Days 1-4 of Cycles 1-9) with or without DARA (16 mg/kg intravenously once weekly for Cycle 1, once every 3 weeks for Cycles 2-9, and once every 4 weeks for Cycles 10+ until disease progression). The primary endpoint was PFS. Secondary endpoints included overall response rate, rate of complete response or better, rate of very good partial response or better, MRD-negativity rate (10-5 threshold), PFS on subsequent line of therapy (PFS2), OS, and safety. Results: A total of 706 patients were enrolled in this study (D-VMP: n = 350; VMP: n = 356). Patient baseline characteristics were well balanced between treatment arms. The median (range) age was 71 (40-93) years, and 29.9% of patients were ≥75 years of age. 518 (84.1%) and 98 (15.9%) of 616 patients evaluated had standard and high (del17p, t[14;16], and/or t[4;14] positive) cytogenetic risk, respectively, as assessed via local fluorescence in-situ hybridization/karyotyping. Median PFS was 36.4 months with D-VMP versus 19.3 months with VMP after a median follow-up of 40.08 months (HR, 0.42; 95% confidence interval [CI], 0.34-0.51; P

Description: Introduction: DARA is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action. In the phase 3 ALCYONE study (median follow-up of 40.1 months), DARA in combination with VMP (D-VMP) reduced the risk of disease progression or death by 58% versus VMP alone (median 36.4 vs 19.3 months; HR, 0.42; 95% CI, 0.34-0.51; P