Kurzfassung: Introduction: Subcutaneous (SC) administration offers several potential advantages for patients (pts) and healthcare providers, including shorter administration times, reduced administration volume, and fewer infusion-related reactions. Daratumumab (DARA), a human IgGκ anti-CD38 monoclonal antibody, has direct on-tumor and immunomodulatory effects. DARA is approved for intravenous (IV) administration as monotherapy for RRMM and in combination with standard of care regimens for RR and newly diagnosed MM. Previous analyses demonstrated that maximum DARA trough concentration (Ctrough), which occurs at the end of weekly dosing, was highly correlated with efficacy in MM (Xu XS, et al. Clin Pharmacol Ther 2017. 101[6] :721-724), but no relationship was observed between DARA concentrations and adverse events. SC administration of DARA in combination with recombinant human hyaluronidase enzyme PH20 (rHuPH20; ENHANZE® drug delivery technology, Halozyme, Inc.) is being evaluated in an open-label, phase 1b trial (PAVO) to identify a fixed SC dose which is safe and achieves a similar or greater maximum Ctrough as compared with the 16 mg/kg IV dose. Here, we present the clinical pharmacology of SC DARA, including the development of a combined IV-SC population PK (PPK) model. Methods: In PAVO, eligible RRMM pts received ≥2 prior lines of therapy. In Part 1, 2 sequential cohorts received fixed dose regimens of a mix and deliver SC formulation of DARA and rHuPH20 (DARA MD) at 1,200 mg (n = 8; 60 mL) and 1,800 mg (n = 45; 90 mL) doses in 20 and 30 minutes, respectively, on the same schedule as the approved DARA monotherapy IV regimen (QW for Cycles 1-2, Q2W in Cycles 3-6, and Q4W thereafter; 4-week cycles). A dose that was safe and provided similar or greater Ctrough values on Cycle 3 Day 1 (C3D1) compared with the 16 mg/kg IV dose was selected for Part 2. In Part 2, a concentrated co-formulation of DARA (1,800 mg) and rHuPH20 (30,000 U; in 15 mL) in a single, pre-mixed vial (DARA SC) was administered over 3-5 minutes by manual SC injection. Co-primary endpoints were safety and Ctrough at the end of QW dosing. Serial PK sampling was performed after the first and last weekly dose; sparse PK and immunogenicity was collected at additional timepoints. A mixed-effects 2-compartment PK model based on Michaelis-Menten approximation of target-mediated drug disposition was developed, and PK data used in this PPK analysis were from Part 1 of PAVO (n = 53) and from GEN501/MMY2002 (IV DARA monotherapy; n = 223) studies. Model-based simulations were conducted to facilitate dose selection. Results: In Part 1, the mean C3D1 Ctrough following 1,800 mg DARA MD was similar or higher than that observed for 16 mg/kg IV (Table). The PPK model predicted approximately 88% of pts receiving DARA MD 1,800 mg would achieve the effective concentration of 274 μg/mL vs 73% of pts receiving DARA MD 1,200 mg and 80% of pts receiving 16 mg/kg IV. Simulated PK profiles indicated that both DARA MD doses result in smaller peak-to-trough fluctuation compared to IV dosing, and that 1,800 mg provides higher Ctrough throughout the dosing period without increasing Cmax compared to IV dosing (Usmani SZ, et al. ASH 2016. Abs. 1149). Across a range of simulated body weights, exposure following DARA MD 1,800 mg was similar or slightly higher than for 16 mg/kg IV. Based on these data, the 1,800 mg dose was selected for further evaluation in Part 2. The primary PK endpoint of mean C3D1 Ctrough was slightly higher for DARA SC 1,800 mg than the DARA MD 1,800 mg cohort and 16 mg/kg IV dose (Table). The range of Ctrough observations for the SC cohorts were within the range observed with 16 mg/kg IV (Figure). The observed Cmax of DARA SC 1,800 mg after the first and last weekly dose was within the range of that for 16 mg/kg IV; inter-pt variability for SC administered DARA was also similar across all cohorts. One pt (1%) was positive for DARA anti-drug antibodies and 13% of pts were positive for anti-rHuPH20 antibodies in PAVO; all had no apparent clinical complications. Conclusions: The fixed DARA SC 1,800 mg dose provided a similar or higher C3D1 Ctrough when compared to historical data with 16 mg/kg IV. A combined IV-SC PPK model using a concentration- and time-dependent clearance of DARA described the PAVO data well. Immunogenicity of DARA and rHuPH20 was similar to previous experience. These data validated the dose selection of 1,800 mg for ongoing phase 3 clinical trials of DARA SC in MM, smoldering MM, and amyloidosis. Disclosures Clemens: Janssen Research & Development, LLC: Employment. Xu:Janssen Research & Development, LLC: Employment. Luo:Janssen Research & Development, LLC: Employment. Chari:Array Biopharma: Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy; Pharmacyclics: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; The Binding Site: Consultancy; Amgen: Consultancy, 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, Research Funding. Usmani:Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding; Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy. Mateos:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. van de Donk:Janssen Pharmceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding. Kaufman:Abbvie: Consultancy; Roche: Consultancy; Janssen: Consultancy; Karyopharm: Other: data monitoring committee; BMS: Consultancy. Moreau: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; 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. Oriol:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Plesner:Janssen: Consultancy; Celgene: Other: Independent Response Assessment Comittee. San-Miguel:Celgene: Honoraria; Amgen: Honoraria; BMS: Honoraria; Novartis: Honoraria; Sanofi: Honoraria; Roche: Honoraria; Janssen: Honoraria. Sun:Janssen Research & Development, LLC: Employment. Farnsworth:Janssen Research & Development: Employment. Masterson:Janssen Research & Development, LLC: Employment. Hellemans:Janssen Research & Development: Employment. Qi:Janssen Research & Development, LLC: Employment.

Kurzfassung: Introduction : Daratumumab (DARA), a human CD38 IgG1κ monoclonal antibody, has demonstrated single agent efficacy while being highly tolerable as a monotherapy, and significant efficacy in combination with standard-of-care regimens in pts with multiple myeloma (MM) who have received ≥1 prior lines of therapy (Lokhorst HM. NEJM 2015, 373(13):1207-19; Lonial S. Lancet 2016, 387:1551-60;Palumbo A. NEJM 2016, in press; Dimopoulos MA. NEJM 2016, in press). DARA is currently administered as an intravenous (IV) infusion. Subcutaneous (SC) delivery of DARA is being tested in combination with the recombinant human hyaluronidase enzyme (rHuPH20) to facilitate systemic absorption of DARA after SC infusion into the abdominal wall. PAVO is the first study to assess the safety, pharmacokinetics, and efficacy of SC administration of DARA plus rHuPH20 (DARA-PH20) in pts with relapsed or refractory MM (RRMM). Methods : Pts had RRMM with ≥2 prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD). Part 1 of the 2 part study enrolled sequential cohorts at 1200 mg and 1800 mg DARA dose levels to determine the recommended SC dose for Part 2. DARA-PH20 was administered in 4-week treatment cycles: QW for 8 weeks, Q2W for 16 weeks, and Q4W thereafter. DARA-PH20 was infused in 1200 mg doses in 60 mL over 20 min or 1800 mg in 90 mL over 30 min, via a syringe pump at rotating sites on the abdomen. Pre- and/or post-infusion medications included paracetamol, diphenhydramine, montelukast, and methylprednisolone. In part 2, pts will be randomized 1:1 to receive the recommended phase 2 dose (RP2D) of SC DARA-PH20 or IV DARA (16 mg/kg). The RP2D of DARA-PH20 will be selected based on a cumulative review of the pharmacokinetic and safety data obtained from part 1 and should achieve a maximum serum Ctrough during weekly dosing that is similar to or higher than that observed for the approved 16 mg/kg IV dose. Primary endpoints were Ctrough of DARA up to Cycle 3 Day 1 and safety. Secondary endpoints included overall response rate (ORR). Results : To date, 41 pts were treated in part 1 with SC DARA-PH20 at the 1200 mg (n=8) and 1800 mg (n=33) dose levels. Infusion related reactions (IRRs) were reported in 9/41 pts (22%) and were mostly grade 1/2 in severity including chills, fever, rigors, vomiting, itching, edema of the tongue, non-cardiac chest pain and wheezing. One pt developed grade 3 dyspnea and 1 pt required hospitalization due to fever and chills (both grade 2) after the first infusion. All IRRs developed during or within 6 hours of the first SC infusion and were controlled with antihistamine, corticosteroid, antiemetic, or bronchodilator treatment. No IRRs were reported with subsequent infusions. Overall, the adverse event profile of DARA-PH20 was consistent with that of IV DARA. Grade 3 or higher drug-related adverse events were reported in 5/41 (12%) pts including fatigue (2 pts), influenza, hypertension, dyspnea, and tumor lysis syndrome. SC administration of DARA-PH20 was well tolerated at the abdominal wall injection site with 3/41 (7%) pts reporting grade 1 erythema, induration, or burning sensation. Analysis showed a higher max Ctrough in the 1800 mg cohort in comparison to the max Ctrough achieved following IV DARA (16 mg/kg). In the 1200 mg cohort of 8 pts (median of 5 lines of prior therapy [range 2-10]; prior ASCT, 63%; PI refractory only, 0%; IMiD refractory only, 13%; double refractory to PI and IMiD, 63%) a 25% ORR was observed including 2 partial responses (PR). Median time to response was 14 (range 8-20) weeks. Among 17 response evaluable pts in the 1800 mg cohort with cycle 3 day 1 assessments (median of 4 prior lines of therapy [range 2-7] ; prior ASCT, 76%; PI refractory only, 6%; IMiD refractory only, 12%; double refractory to PI and IMiD, 65%) a 41% ORR was observed consisting of 3 very good partial responses and 4 PRs. Median time to response was 4 (range 4-8) weeks. Conclusions : SC DARA-PH20 was well tolerated and achieved serum trough concentrations similar to or greater than IV DARA with a lower rate of IRRs compared to IV DARA over a significantly shorter infusion time. Preliminary data suggest that in this pt population SC DARA-PH20 may enable similar response rates to IV DARA monotherapy. The 1800 mg dose level of DARA-PH20 was selected as the RP2D for part 2 of the study. These early data support further study of SC DARA in clinical trials. Additional data on pts from part 1 will be presented at the meeting. Disclosures Usmani: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; BioPharma: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pharmacyclics: Research Funding; Britsol-Myers Squibb: Consultancy, Research Funding; Skyline: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Array: Research Funding; Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau. Mateos:Janssen, Celgene, Amgen, Takeda, BMS: Honoraria. Lokhorst:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genmab: Research Funding. Chari:Pharmacyclics: Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen Inc.: Honoraria, Research Funding; Novartis: Consultancy, Research Funding; Array Biopharma: Consultancy, Research Funding. Kaufman:Celgene: Consultancy, Research Funding; Pharmacyclics: Consultancy; Novartis: Consultancy, Research Funding; Incyte: Consultancy. Moreau:Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Janssen: Honoraria, Speakers Bureau. Oriol:Janssen: Honoraria, Other: Expert board committee; Amgen: Honoraria, Other: Expert board committee. Plesner:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hellemans:Janssen: Employment, Equity Ownership. Masterson:Janssen: Employment. Clemens:Janssen: Employment. Ahmadi:Janssen: Employment. Liu:Merck: Equity Ownership; Janssen: Employment; J & J: Equity Ownership. San-Miguel:Amgen: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

Kurzfassung: 8038 Background: High-risk cytogenetic abnormalities confer poor outcomes in MM patients (pts). In POLLUX, D-Rd demonstrated significant clinical benefit, including prolonged progression-free survival (PFS) vs lenalidomide and dexamethasone (Rd), and tolerability in RRMM pts. We present a subgroup analysis of POLLUX, based on cytogenetic risk. Methods: Pts had ≥1 prior line of therapy. Cytogenetic risk was based on a combined analysis of fluorescence in situ hybridization/karyotype testing and next-generation sequencing (NGS). High-risk pts had t(4;14), t(14;16), or del17p abnormalities; standard (std)-risk pts did not meet high-risk criteria. Minimal residual disease (MRD; 10 –5 ) was assessed via NGS using clonoSEQ ® assay V2.0. Results: In POLLUX (D-Rd, n = 286; Rd, n = 283), 17.1% of pts in the D-Rd group and 20.1% of pts in the Rd group had high-risk abnormalities. After 44.3 months (mo) of median follow up, D-Rd prolonged PFS vs Rd in pts with high- (median 26.8 vs 8.8 mo; HR, 0.54 [95% CI, 0.32-0.91]; P = 0.0175) or std-risk (median not reached [NR] vs 19.9 mo; HR, 0.41 [95% CI, 0.31-0.55]; P 〈 0.0001). Responses with D-Rd were deep, including higher rates of MRD negativity and sustained MRD negativity vs Rd (Table). D-Rd prolonged PFS in first relapse pts (high risk: median 46.0 vs 7.3 mo; HR, 0.26 [95% CI, 0.11-0.59]; P = 0.0005; std risk: median NR vs 20.6 mo; HR, 0.43 [95% CI, 0.28-0.66] ; P 〈 0.0001) and prolonged PFS2 vs Rd in high- (median 38.3 vs 22.1 mo; HR, 0.53 [95% CI, 0.30-0.93]; P = 0.0249) or std-risk (median NR vs 33.8 mo; HR, 0.53 [95% CI, 0.39-0.72] ; P 〈 0.0001) pts. Additional data will be presented. Conclusions: D-Rd demonstrates significant efficacy in high-risk RRMM. Among high-risk pts, MRD negativity was only achieved with D-Rd. Clinical trial information: NCT02076009. [Table: see text]

Kurzfassung: Daratumumab, a human monoclonal antibody targeting CD38, is approved as monotherapy and in combination regimens for patients with multiple myeloma (MM). Currently, daratumumab is administered IV. The phase 1b PAVO (MMY1004) study evaluated subcutaneously administered daratumumab in combination with the recombinant human hyaluronidase PH20 enzyme (rHuPH20) in patients with relapsed or refractory MM. Part 1 of the study, reported here, evaluated a mix-and-deliver (MD) formulation of daratumumab and rHuPH20 (DARA-MD) administered by subcutaneous infusion. Patients received subcutaneous daratumumab according to the approved IV monotherapy dosing schedule at 1200 mg (n = 8) or 1800 mg (n = 45). Primary end points were safety and pharmacokinetic (PK) variables. The most common treatment-emergent adverse events with DARA-MD 1200 mg were thrombocytopenia, upper respiratory tract infection, insomnia, and decreased appetite (37.5% each). Anemia (33.3%), upper respiratory tract infection, pyrexia, and diarrhea (26.7% each) were the most common treatment-emergent adverse events with DARA-MD 1800 mg. One patient in the 1200-mg dose group (12.5%) and 11 patients in the 1800-mg dose group (24.4%) experienced infusion-related reactions, which were generally grade 1/2 and typically occurred at the first infusion. The 1800 mg dose achieved similar or greater serum concentrations compared with the 16 mg/kg IV dose. Overall response rates of 25.0% and 42.2% were achieved with 1200-mg and 1800-mg DARA-MD, respectively. Subcutaneous administration of DARA-MD was well tolerated in patients with relapsed or refractory MM, with the 1800-mg dose exhibiting PK concentrations and responses consistent with IV daratumumab in a similar patient population. This study was registered at www.clinicaltrials.gov as #NCT02519452.

Kurzfassung: Introduction : Daratumumab (DARA), a CD38-targeted human monoclonal antibody, is approved as monotherapy and in combination with bortezomib (proteasome inhibitor; PI) or immunomodulatory drugs (IMiD; lenalidomide or pomalidomide) in pts with RRMM. DARA is administered intravenously (IV) and is associated with infusion related reactions (IRRs) in 46% of pts. We previously reported data from PAVO (NCT02519452), an open-label, multicenter, phase 1b study in RRMM, showing that subcutaneous (SC) delivery of DARA with recombinant human hyaluronidase enzyme (rHuPH20) by SC infusion of a mix and deliver formulation (DARA-MD) was well tolerated with low rates of IRRs (Usmani SZ, et al. ASH 2016; abstract 1149). DARA + rHuPH20 also demonstrated an efficacy profile consistent with IV DARA. We present updated data, including initial safety and efficacy findings from an additional cohort that received DARA co-formulated with rHuPH20 (DARA SC), which was delivered by manual SC injection. Methods : RRMM pts had an Eastern Cooperative Oncology Group performance status ≤2 and received ≥2 prior lines of therapy including a PI and an IMiD. To determine the recommended SC dose for Part 2 of this 2-part study, DARA-MD was administered via SC infusion through a syringe pump from 20 to 30 min in Part 1. Pts were administered DARA 1200 mg + rHuPH20 30000 U (in 60 mL) or DARA 1800 mg + rHuPH20 45000 U (in 90 mL) in 28-day cycles: weekly in Cycles 1-2, every 2 weeks in Cycles 3-6, and every 4 weeks thereafter. The 1,800 mg dose level was selected for Part 2. In Part 2, a concentrated co-formulation of the selected DARA SC (1800 mg in 15 mL) and rHuPH20 (30000 U) dose in a single, pre-mixed vial was administered in 3 to 5 minutes by manual SC injection. In both parts, the primary endpoints were Ctrough of DARA up to Cycle 3 Day 1 and safety. Secondary endpoints included overall response rate (ORR), rate of complete response (CR), and time to response. Results : At the clinical cut-off of June 30, 2017, 53 pts were enrolled in Part 1 (DARA-MD 1200 mg, n=8; DARA-MD 1800 mg, n=45) and 25 pts were enrolled in Part 2 (DARA SC 1800 mg). 0/8 (0%), 12/45 (27%), and 25/25 (100%) pts receiving DARA-MD 1200 mg, DARA-MD 1800 mg, and DARA SC 1800 mg, respectively, remain on treatment; the median duration of treatment was 2.6 (0.7-12.0), 5.4 (0.7-16.6+), and 1.4 (0.5-2.3+) months, respectively. In Part 1, 100% and 73% of pts discontinued treatment in the DARA-MD 1200 mg and DARA-MD 1800 mg dose cohorts, respectively, due to progressive disease (75% and 58%), physician decision (0% and 9%), death (13% and 2%), withdrawal by pt (13% and 2%), and other (0% and 2%); in Part 2 with shorter follow up, none discontinued treatment. One pt receiving DARA-MD 1200 mg died due to adverse event (aspiration pneumonia) and 2 pts receiving DARA-MD 1800 mg died due to disease progression; no deaths occurred in the DARA SC 1800 mg cohort. IRRs were reported in 13%, 24% and 4% pts receiving DARA-MD 1200 mg, DARA-MD 1800 mg, and DARA SC 1800 mg, respectively. One grade 3 IRR of dyspnea occurred in the DARA-MD 1200 mg cohort; no grade 3/4 IRRs occurred in pts receiving DARA-MD 1800 mg or DARA SC 1800 mg. SC administration was well tolerated in the DARA-MD 1200 mg, DARA-MD 1800 mg, and DARA SC 1800 mg cohorts, with 63%, 29%, and 20% of pts experiencing reversible erythema and 50%, 22%, and 0% of pts experiencing reversible induration at the infusion/injection site, respectively. Among DARA-MD 1200 mg, DARA-MD 1800 mg, and DARA SC 1800 mg cohorts, treatment-emergent adverse events (TEAEs) occurred in 100%, 98% and 84% pts, respectively; 63%, 49% and 32% were grade 3 or 4 (Table). Serious TEAEs occurred in 50%, 31%, and 4% pts. No pts discontinued treatment due to TEAEs. As of August 1, 2017, in the DARA-MD 1800 mg cohort, ORR was 42%, and the rates of ≥VGPR and ≥CR were 20% and 7%, respectively. In the DARA SC 1800 mg cohort, a preliminary ORR of 42% was observed which requires confirmation at follow up. Updated safety, efficacy and pharmacokinetic data will be presented at the meeting. Conclusions : SC administration of DARA + rHuPH20 was well tolerated, with lower than expected rates of IRRs in all groups, but particularly in those treated with DARA SC 1800 mg administered over only 3-5 minutes. Planned phase 3 studies will use DARA SC at the dose identified in Part 2. Disclosures Chari: Acetylon Pharmaceuticals: Other: Research funding (to AC's institution); Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Array BioPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Other: Research funding (to AC's institution); travel; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Onyx: Research Funding; Pharmacyclics: Research Funding; Biotest: Other: Research funding (to AC's institution); Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding. Mateos: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Lokhorst: Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen, Genmab: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kaufman: Amgen, Novartis: Research Funding; Amgen, Roche, BMS, Seattle Genetics, Sutro Biopharma, Pharmacyclics: Consultancy. Moreau: Takeda: Honoraria; Celgene, Janssen, Takeda, Novartis, Amgen, Roche: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Novartis: Consultancy, Honoraria; Onyx Pharmaceutical: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Oriol: Celgene: Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored symposia, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored symposia; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored symposia, Speakers Bureau. Plesner: Janssen: Research Funding; Janssen, Takeda: Consultancy; Janssen, Genmab: Membership on an entity's Board of Directors or advisory committees. Benboubker: Takeda, Celgene, Janssen, Amgen: Consultancy. Hellemans: Janssen: Employment. Masterson: Janssen: Employment. Clemens: Janssen: Employment. Liu: Janssen: Employment. San-Miguel: Takeda, Celgene, Novartis, Amgen, Janssen, Bristol-Myers Squibb: Consultancy. Usmani: Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Array BioPharma: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau.

Kurzfassung: Introduction: Daratumumab (DARA) is a human IgGκ anti-CD38 monoclonal antibody with a direct on-tumor and immunomodulatory mechanism of action. DARA (16 mg/kg administered intravenously [IV]) is approved in many countries as monotherapy and in combination with standard of care (SOC) treatment regimens for patients with relapsed/refractory (RR) multiple myeloma (MM) and newly diagnosed MM. Three phase 3 studies have now demonstrated that DARA in combination with SOC treatment doubles complete response (CR) rates, triples minimal residual disease-negative rates, and reduces the risk of progression or death by at least 50% vs SOC alone. The median durations of the first, second, and subsequent DARA IV infusions are 7.0, 4.3, and 3.4 hours, respectively. To determine whether the duration of infusion can be shortened without compromising the safety or efficacy of daratumumab, an open-label, multicenter, phase 1b clinical trial (PAVO; NCT02519452) was conducted to evaluate a subcutaneous (SC) formulation of DARA with recombinant human hyaluronidase enzyme PH20 (rHuPH20; ENHANZE® drug delivery technology, Halozyme, Inc.) in patients with RRMM. Part 1 of the study revealed that a mix-and-deliver SC administration was well tolerated, with low rates of infusion-related reactions (IRRs) and similar efficacy to DARA IV (Usmani et al. ASH 2016; abstract 1149). Here, we present updated safety and efficacy findings from Part 2 of the PAVO study, where a concentrated, pre-mixed SC co-formulation of DARA and rHuPH20 (DARA SC) was evaluated in patients with RRMM. Methods: Eligible RRMM patients had received ≥2 prior lines of therapy, including a proteasome inhibitor (PI) and immunomodulatory drug (IMiD). In Part 2 of the study, a concentrated co-formulation of DARA (1,800 mg) and rHuPH20 (30,000 U; in 15 mL) in a single, pre-mixed vial was administered over 3 to 5 minutes by manual SC injection into the abdomen. DARA SC was given QW during Cycles 1-2, Q2W during Cycles 3-6, and Q4W thereafter in 28-day cycles. Pre- and/or post infusion medications included acetaminophen, diphenhydramine, montelukast, and methylprednisolone. Co-primary endpoints were safety and Ctrough of DARA SC at the end of QW dosing. Secondary endpoints included the overall response rate (ORR) and CR rate according to the International Myeloma Working Group response criteria. Results: At the clinical cut-off date of December 13, 2017, 25 patients were enrolled in Part 2 of the study. Patients received a median of 3 (range: 2-9) prior lines of therapy, with 56% double refractory to both PI and IMiD. No treatment discontinuations occurred due to treatment-emergent adverse events (TEAEs). The most common (≥20%) TEAEs included lymphopenia (32%), thrombocytopenia (24%), fatigue, asthenia, back pain, diarrhea, nausea, headache, and viral upper respiratory tract infection (20% each). The incidence (16%) and severity of IRRs (mostly grade 1-2) with DARA SC was low, the majority of which occurred on Cycle 1 Day 1, and no discontinuations due to IRRs were observed. Transient grade 3 hypertension was reported as an IRR in 2 patients. Grade 1 injection-site TEAEs were reported with DARA SC in 3 patients (induration, erythema, injection-site discoloration, and hematoma [n = 1 each] ). At 6.5 months of median follow-up, the ORR was 52% (28% very good partial response; 24% partial response). Median progression-free survival (PFS) was not reached among all-treated patients, including among patients who were double refractory. Updated data will be presented at the meeting based on longer follow-up. Conclusions: DARA SC enabled dosing in 3-5 minutes and improves patient convenience. DARA SC was well-tolerated in patients with RRMM with low rates of IRRs and no new safety signals compared with DARA IV. Over 50% of patients responded to treatment and median PFS has not been reached after median follow-up of 6.5 months. These data inform ongoing phase 3 studies of DARA SC in RRMM (including a non-inferiority study of DARA SC vs DARA IV [COLUMBA; NCT03277105]), smoldering multiple myeloma, and AL amyloidosis. Disclosures Chari: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Array Biopharma: Research Funding; Janssen: Consultancy, 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; Pharmacyclics: Research Funding; The Binding Site: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mateos:GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, 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; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. van de Donk:Janssen Pharmceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding. Kaufman:Roche: Consultancy; Abbvie: Consultancy; Karyopharm: Other: data monitoring committee; Janssen: Consultancy; BMS: Consultancy. Moreau:Amgen: 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; Janssen: 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; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Oriol:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Plesner:Janssen: Consultancy; Celgene: Other: Independent Response Assessment Comittee. Tang:Janssen: Employment. Hellemans:Janssen Research & Development: Employment. Tromp:Janssen Research & Development: Employment. Clemens:Janssen Research & Development, LLC: Employment. Farnsworth:Janssen Research & Development: Employment. San-Miguel:Roche: Honoraria; Sanofi: Honoraria; Novartis: Honoraria; BMS: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Usmani:Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding; Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy.

Kurzfassung: High cytogenetic risk abnormalities confer poor outcomes in multiple myeloma patients. In POLLUX, daratumumab/lenalidomide/dexamethasone (D-Rd) demonstrated significant clinical benefit versus lenalidomide/dexamethasone (Rd) in relapsed/refractory multiple myeloma (RRMM) patients. We report an updated subgroup analysis of POLLUX based on cytogenetic risk. The cytogenetic risk was determined using fluorescence in situ hybridization/karyotyping; patients with high cytogenetic risk had t (4;14), t (14;16), or del17p abnormalities. Minimal residual disease (MRD; 10 –5 ) was assessed via the clonoSEQ ® assay V2.0. 569 patients were randomized (D-Rd, n  = 286; Rd, n  = 283); 35 (12%) patients per group had high cytogenetic risk. After a median follow-up of 44.3 months, D-Rd prolonged progression-free survival (PFS) versus Rd in standard cytogenetic risk (median: not estimable vs 18.6 months; hazard ratio [HR], 0.43; P   〈  0.0001) and high cytogenetic risk (median: 26.8 vs 8.3 months; HR, 0.34; P  = 0.0035) patients. Responses with D-Rd were deep, including higher MRD negativity and sustained MRD-negativity rates versus Rd, regardless of cytogenetic risk. PFS on subsequent line of therapy was improved with D-Rd versus Rd in both cytogenetic risk subgroups. The safety profile of D-Rd by cytogenetic risk was consistent with the overall population. These findings demonstrate the improved efficacy of daratumumab plus standard of care versus standard of care in RRMM, regardless of cytogenetic risk.