Raje, Noopur

Abstract PS-341 (bortezomib, Velcade™) is a promising novel agent for treatment of advanced multiple myeloma (MM); however, 65% of patients with relapsed refractory disease in a phase II study did not respond. Lysophosphatidic acid (LPA) is a phospholipid which mediates tumor cell migration and invasion. Recent studies have shown that inhibition of LPAAT-β inhibits both Ras/Raf/Erk and PI3K/Akt signaling cascades. We have previously shown that lysophosphatidic acid acyltransferase (LPAAT)-β inhibitor CT-32615 triggers caspase-dependent apoptosis, and can overcome resistance to conventional therapeutics (ie, dexamethasone, doxorubicin, melphalan) in MM cells. In this study, we determined whether CT-32615 could also overcome resistance to PS-341. We first characterized molecular mechanisms of resistance to PS-341 in DHL-4 lymphoma cells. DHL-4 cells express low levels of caspase-3 and caspase-8; furthermore, no cleavage in caspase-8, caspase-9, caspase-3, poly ADP-ribose polymerase (PARP), or DNA fragmentation factor (DFF) 45 is triggered by PS-341 treatment. We have previously shown that PS-341 treatment triggers phosphorylation of c-Jun NH2-terminal kinase (JNK), which subsequently induces caspase-dependent apoptosis; conversely, JNK inhibition blocks PS-341-induced apoptosis. Here we show that PS-341 does not induce phosphorylation of SEK-1, JNK, and c-Jun in DHL-4 cells, suggesting that it does not trigger a stress response. Importantly, CT-32615 inhibits growth of DHL-4 cells in a time- and dose-dependent fashion: a transient G2/M cell cycle arrest induced by CT-32615 is mediated via downregulation of cdc25c and cdc2. CT-32615 triggers swelling and cell membrane destruction in DHL-4 cells, without caspase/PARP cleavage or TUNEL-positivity, suggesting a necrotic response. Our studies therefore demonstrate that LPAAT-β inhibitor CT-32615 triggers necrosis even in PS-341-resistant DHL-4 cells, providing the framework for its evaluation to overcome clinical PS-341 resistance and improve patient outcome.

e19505 Background: CFZ combined with dexamethasone is approved to treat pts with RRMM, with CFZ given once-weekly at 70 mg/m2 (Kd70 QW) or twice-weekly at 56 mg/m2 (Kd56 BIW). No randomized trials have directly compared Kd70 QW with Kd56 BIW. We performed a post hoc comparison between pts who received Kd56 BIW in the ENDEAVOR trial and pts who received Kd70 QW in the A.R.R.O.W. or CHAMPION-1 trials. Methods: Data were analyzed from 3 trials of CFZ in RRMM: A.R.R.O.W. (240 pts in Kd70 QW arm; 2–3 prior therapies and refractory to most recent therapy), CHAMPION-1 (104 pts received Kd70 QW; 1–3 prior therapies), and ENDEAVOR (464 pts in Kd56 BIW arm; 1–3 prior therapies). Pts who received Kd70 QW in A.R.R.O.W. and CHAMPION-1 were pooled and compared with pts who received Kd56 BIW in ENDEAVOR. As study populations slightly varied among the 3 trials, an analysis of safety and efficacy was performed in a subgroup of pts who received 2–3 prior therapy lines and were not refractory to bortezomib (BTZ). Also, we performed regression analyses (controlling for age, ISS stage, BTZ and lenalidomide refractory status, and number of prior regimens) among all pts in the trials who received Kd70 QW or Kd56 BIW. Results: Among BTZ non-refractory pts with 2–3 lines of prior therapy, median progression-free survival (PFS) was 12.1 months (95% CI 8.4–14.3) for Kd70 QW (n = 146) and 14.5 months (95% CI 10.2–NE) for Kd56 BIW (n = 217), and the overall response rate (ORR) was 69.9% (95% CI 61.7–77.2) for Kd70 QW and 72.4% (95% CI 65.9–78.2) for Kd56 BIW. The rate of grade ≥3 adverse events (Kd70 QW vs Kd56 BIW) was 67.6% and 85.3%; among adverse events of interest, the grade ≥3 rate was 1.4% and 5.1% for cardiac failure, 3.4% and 6.0% for renal failure, and 5.5% and 15.7% for hypertension. Kd70 QW represents a convenient and well-tolerated treatment modality for pts with RRMM. In a Cox proportional hazards model, the hazard ratio for PFS (Kd70 QW vs Kd56 BIW) was 0.91 (95% CI 0.69–1.19), and in a logistic regression model the odds ratio for ORR (Kd70 QW vs Kd56 BIW) was 1.12 (95% CI 0.74–1.69). Conclusions: This post hoc analysis suggests that once-weekly Kd70 has a comparable benefit-risk profile to twice-weekly Kd56. Clinical trial information: NCT02412878, NCT01677858, NCT01568866.

8035 Background: D-Rd significantly reduced the risk of progression/death by 44% in transplant-ineligible NDMM pts vs Rd in the phase 3 MAIA study. To examine the impact of age on efficacy/safety of D-Rd vs Rd in this population, a subgroup analysis was conducted in pts <75 and ≥75 y of age. Methods: Transplant-ineligible NDMM pts were randomized 1:1 to Rd ± DARA; stratification was based on age (<75 vs ≥75 y), ISS (I, II, III), and region (North America vs Other). Pts received 28-day cycles of either R 25 or 10 mg (based on renal function) PO QD on Days 1-21 and either d 40 or 20 mg (based on age or BMI) PO/IV weekly until progression. In the D-Rd arm, pts received daratumumab 16 mg/kg IV QW for Cycles 1-2, Q2W for Cycles 3-6, and Q4W thereafter until progression. PFS is the primary endpoint. Results: Among 737 randomized pts (D-Rd, n=368; Rd, n=369), 321 (44%) were ≥75 y of age. For D-Rd vs Rd, relative median dose intensity for R was 79% vs 93% for <75 y subgroup and 66% vs 89% for ≥75 y subgroup, respectively. After median follow-up of 28 mo, significant PFS benefit of D-Rd vs Rd was maintained in both <75 and ≥75 y subgroups (Table). Deeper responses and MRD-negative rate (10-5 threshold) remained higher with D-Rd vs Rd in both subgroups (Table). Most common (≥10%; D-Rd/Rd) grade 3/4 TEAEs in ≥75 y pts were neutropenia (60%/41%), lymphopenia (19%/12%), anemia (16%/22%), pneumonia (15%/10%), leukopenia (12%/6%), and thrombocytopenia (8%/11%). Fewer pts receiving D-Rd vs Rd discontinued treatment due to TEAEs (<75 y: 5% vs 12%; ≥75 y: 10% vs 21%). Conclusions: D-Rd pts received less R vs Rd group regardless of age. Efficacy of D-Rd in <75 and ≥75 y pts was consistent with the ITT population, and D-Rd demonstrated acceptable tolerability regardless of age. Together with the phase 3 ALCYONE study, these studies confirm clinical benefit of daratumumab plus standard-of-care in transplant-ineligible NDMM pts ≥75 y of age. Clinical trial information: NCT02252172. [Table: see text]

8589 Background: Denosumab (dmab) is a fully human monoclonal antibody against RANKL and is superior to ZA in preventing skeletal-related events (SREs) as shown in 3 identically designed phase 3 trials (N=5723). Overall survival (OS) was balanced between treatment groups in the overall study populations of these trials. In the trial of patients (pts) with solid tumors (excluding breast and prostate) and multiple myeloma (MM), OS was longer for dmab pts with lung cancer, shorter for pts with MM, and balanced for pts with other solid tumors. This analysis further characterizes the results from the MM subset of this trial. Methods: Pts with solid tumors or MM were randomized (1:1) to receive 120 mg of SC dmab or 4 mg of IV ZA Q4W. Daily calcium and vit D supplements were strongly recommended. The primary endpoint was the time to first on-study SRE; results from the primary endpoint and lung cancer subset were previously reported. Results: Of 1776 randomized pts, 10% had MM (93 ZA, 87 dmab). OS favored ZA (hazard ratio: 2.26; 10 subject difference in deaths). 1-year OS was 83% dmab, 97% ZA. Imbalances in baseline prognostic characteristics were observed. More pts in the dmab arm had low baseline renal function (CrCl < 40 mL/min) (ZA 2 [2%], dmab 9 [10%]) and more ZA pts underwent stem cell transplant (ZA 23 [25%], dmab 15 [17%]). Additionally, more ZA pts had stage I tumors at diagnosis (ZA 13 [14%], dmab 9 [10%]) and better performance status (ECOG = 0; ZA 30 [32%], dmab 21 [24%]). Study discontinuations due to consent withdrawal or lost to follow-up were also higher in the ZA group (ZA 17 [18%], dmab 11 [13%]) and occurred earlier in the ZA arm (ZA 59%, dmab 45% within 9 months of randomization). Conclusions: In this SRE study of dmab vs ZA, pts were stratified by baseline characteristics known to affect SRE outcomes, but not by prognostic factors or concurrent anticancer therapy that may impact survival in MM. OS results in the MM cohort are difficult to interpret due to small sample size and imbalances in baseline disease characteristics, stem cell transplant therapy, and consent withdrawal or loss of follow-up that favored ZA. A phase 3 trial is currently underway, which controls for these factors in pts with MM. Clinical trial information: NCT00330759.

Abstract Combination of carfilzomib with dexamethasone (Kd) is approved for use in relapsed and/or refractory multiple myeloma (RRMM), with carfilzomib administered twice weekly at 56 mg/m 2 (Kd56 BIW) or once weekly at 70 mg/m 2 (Kd70 QW). Post hoc cross‐trial comparisons were performed to compare efficacy and safety profiles of Kd70 QW vs Kd56 BIW dosing schedules using data from three trials of patients with RRMM: A.R.R.O.W., CHAMPION‐1, and ENDEAVOR. To select for comparable patient populations, side‐by‐side efficacy and safety comparisons were performed in subgroups of patients with 2‐3 prior lines of therapy who were not refractory to bortezomib. The overall response rate (ORR) was 69.9% (95% confidence interval [CI], 61.7‐77.2) for Kd70 QW and 72.4% (95% CI, 65.9‐78.2) for Kd56 BIW. Median progression‐free survival (PFS) was 12.1 months (95% CI, 8.4‐14.3) for Kd70 QW and 14.5 months (95% CI, 10.2—not evaluable) for Kd56 BIW. Frequency of grade ≥ 3 adverse events (AEs) was 67.6% for Kd70 QW and 85.3% for Kd56 BIW. Regression analyses (adjusting for prognostic factors) of all patients in the trials who received Kd70 QW vs Kd56 BIW estimated a PFS hazard ratio of 0.91 (95% CI, 0.69‐1.19; P = .47) and an ORR odds ratio of 1.12 (95% CI, 0.74‐1.69; P = .61). These results suggest that Kd70 QW has a comparable efficacy profile compared with Kd56 BIW and represents a convenient and well‐tolerated treatment for patients with RRMM.

Introduction: Chimeric antigen receptor (CAR) T cell therapy directed against B cell maturation antigen (BCMA) has shown promising results for the treatment of relapsed refractory multiple myeloma (RRMM) in several phase 1 studies. Persistence of CAR T cells post infusion may be one determinant of duration of response. bb21217 is a next-generation anti-BCMA CAR T cell therapy based on investigational therapy idecabtagene vicleucel (bb2121) (Friedman 2018, Hum Gene Ther 29:585) that uses the same lentiviral CAR T design as bb2121, but adds the phosphoinositide 3-kinase inhibitor bb007 during ex vivo culture to enrich the drug product for memory-like T cells. Evidence suggests that CAR T cells with this phenotype may be more persistent and more potent than unselected CAR T cells. CRB-402 is a first-in-human study of bb21217 in patients with RRMM designed to assess safety, pharmacokinetics, efficacy and duration of effect. Methods: CRB-402 (NCT03274219) is an ongoing, multi-center phase 1 dose escalation trial of bb21217 planning to enroll 74 patients with RRMM who received ≥ 3 prior regimens, including a proteasome inhibitor and an immuno-modulatory agent, or are double-refractory to both classes. During dose escalation, enrollment is restricted to patients with ≥ 50% BCMA expression by IHC on malignant plasma cells. Peripheral blood mononuclear cells are collected via leukapheresis and sent to a central facility for transduction, expansion and release testing prior to being returned to the site for infusion. Patients undergo lymphodepletion with fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2) daily for 3 days, then receive bb21217 as a single infusion. Planned dose levels are 150, 450, 800, and 1,200 x 106 CAR+ T cells and intermediate dose levels are allowed. The primary outcome measure is incidence of adverse events (AEs), including dose-limiting toxicities (DLTs). Additional outcome measures are quality and duration of clinical response assessed according to the IMWG Uniform Response Criteria, evaluation of minimal residual disease (MRD), progression-free and overall survival, and quantification of CAR+ T cells in blood. Results: Asof April 20, 2019, 22 patients (median age 63 [min;max 42 to 74]) have received bb21217 (12 at 150, 6 at 300 and 4 at 450). Eleven had high tumor burden, defined as ≥ 50% bone marrow plasma cells pre-infusion. Patients had a median of 7 (min;max 4 to 17) prior lines of therapy and 18/22 had prior autologous stem cell transplant; 7/22 had high-risk cytogenetics. Of the 22 patients, 19 received prior daratumumab, 13 received prior Bort/Len/Car/Pom/Dara. Median follow-up after bb21217 infusion was 23 weeks (&lt;1 to 77 weeks). As of data cut-off, 13/22 patients developed cytokine release syndrome (CRS; 5 G1, 7 G2, 1 G3) and responded to supportive care, tocilizumab and/or corticosteroids. Five patients developed neurotoxicity [1 G1, 2 G2, 1 G3 (vertigo/dizziness), 1 G4 (encephalopathy, previously reported)]. For the 1 patient with G4 neurotoxicity, G3 CRS was also reported; both have resolved. A total of 18 patients were evaluable for response with ≥ 2 months of follow up or PD within 2 months. Fifteen (83%) patients demonstrated clinical response per IMWG criteria. Six of these subjects subsequently progressed. Nine patients remained in response, including 2 patients with ongoing response at months 15 and 18. MRD negative results at 10-5 nucleated cells or better were obtained by NGS in 10/10 evaluable responders at month 1. Overall, 6/8 patients evaluable at 6 months and 2/2 patients evaluable at 12 months had detectable CAR T cells in blood. Updated data from this study will be presented, including extended follow-up on the initial patients treated and early clinical and CAR T cell persistence data from at least 15 additional patients treated with up to 450 x 106 CAR+ T cells. Conclusions: The adverse events observed to date were manageable and consistent with known toxicities of CAR T therapies. Initial efficacy results with bb21217 CAR T therapy in heavily pretreated RRMM are encouraging, with 83% of patients demonstrating clinical response. Emerging data demonstrate long-term persistence of CAR T cells in long-term responders. Updated data to be presented will help determine whether treatment with bb21217 results in sustained CAR T cell persistence and durable clinical responses, and whether bb21217 is tolerated at higher doses. Disclosures Berdeja: AbbVie Inc, Amgen Inc, Acetylon Pharmaceuticals Inc, Bluebird Bio, Bristol-Myers Squibb Company, Celgene Corporation, Constellation Pharma, Curis Inc, Genentech, Glenmark Pharmaceuticals, Janssen Biotech Inc, Kesios Therapeutics, Lilly, Novartis, Poseida: Research Funding; Poseida: Research Funding; Amgen Inc, BioClinica, Celgene Corporation, CRISPR Therapeutics, Bristol-Myers Squibb Company, Janssen Biotech Inc, Karyopharm Therapeutics, Kite Pharma Inc, Prothena, Servier, Takeda Oncology: Consultancy. Alsina:Bristol-Myers Squibb: Research Funding; Janssen: Speakers Bureau; Amgen: Speakers Bureau. Shah:Celgene, Janssen, Bluebird Bio, Sutro Biopharma: Research Funding; Poseida: Research Funding; Bristol-Myers Squibb: 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; Nkarta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teneobio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Indapta Therapeutics: Equity Ownership; Genentech, Seattle Genetics, Oncopeptides, Karoypharm, Surface Oncology, Precision biosciences GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi: Membership on an entity's Board of Directors or advisory committees; University of California, San Francisco: Employment. Siegel:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: 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; Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Jagannath:Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Medicom: Speakers Bureau; Multiple Myeloma Research Foundation: Speakers Bureau; Merck: Consultancy. Madduri:Abbvie: Consultancy; Celgene: Consultancy; Takeda: Consultancy; undation Medicine: Consultancy. Kaufman:Janssen: Honoraria; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Takeda: Consultancy; Amgen: Consultancy; Winship Cancer Institute of Emory University: Employment; Bristol-Myers Squibb: Consultancy; Incyte: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy; Celgene: Consultancy. Munshi:Janssen: Consultancy; Amgen: Consultancy; Takeda: Consultancy; Oncopep: Consultancy; Celgene: Consultancy; Adaptive: Consultancy; Abbvie: Consultancy. Rosenblatt:BMS: Other: Advisory Board ; Parexel: Consultancy; Imaging Endpoint: Consultancy; Partner Tx: Other: Advisory Board; Dava Oncology: Other: Education; BMS: Research Funding; Amgen: Other: Advisory Board; Celgene: Research Funding; Merck: Other: Advisory Board. Turka:bluebird bio: Employment. Lam:bluebird bio: Employment. Massaro:bluebird bio: Employment. Campbell:Celgene Corporation: Employment, Equity Ownership. Hege:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties; Mersana Therapuetics: Membership on an entity's Board of Directors or advisory committees; Arcus Biosciences: Membership on an entity's Board of Directors or advisory committees; Society for Immunotherapy of Cancer: Membership on an entity's Board of Directors or advisory committees. Petrocca:bluebird bio: Employment. Raje:Amgen Inc.: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene Corporation: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Merck: Consultancy.

Background: Multiple myeloma (MM) is a heterogeneous disease with varying survival outcomes depending on the presence of certain genetic abnormalities. Common abnormalities include trisomies, translocations involving the chromosome 14, and amplifications or deletions of chromosomes 1, 13, and 17. t(11;14), occurring in 15% of patients with myeloma, had been considered a standard risk abnormality, but recent data suggest inferior outcome. This is important as new therapeutic options such as the BCL-2 inhibitor venetoclax has been shown to be particularly effective in t(11;14) patients. Methods: This was a multicenter study to identify the outcomes of patients with t(11;14), using a retrospectively assembled cohort. Patients with MM diagnosed between 2005 and 2015 with t(11;14) identified on FISH performed within six months of diagnosis, and with treatment details available and if alive, a minimum of 12 months of follow up, were enrolled. Results: The current analysis includes 1216 patients; median age of 62.56 years; 58.7% male. The median follow-up from diagnosis for the entire cohort was 51.9 months; 69.1% of the patients were alive at the last follow up. ISS stage distribution included: Stage I (35.7%), Stage II (34.0%) and Stage III (15.1%), data was missing for the rest. The distribution of concurrent FISH abnormalities included: trisomies (3.5%), del 13q (13.3%), 1q amp (8.8%), and del 17p or monosomy 17 (5.8%). Initial regimen included: 27.2% had an immunomodulatory (IMiD), 45.9% had a proteasome inhibitor (PI), 17.7% had both, and 9.0% had no novel agent. The drug classes by line of therapy are shown in Table 1. An early stem cell transplant (defined as within 12 months of start of first line treatment) was used in 49.4% of patients. The median time to next treatment (TTNT) after starting initial treatment was 26.6 (95% CI: 23.9 to 29.2) months. The median overall survival (OS) from diagnosis for the entire cohort was 95.1 (95% CI: 85.9 to 105.9) months; 4-year estimates for those diagnosed from January 2005 to December 2009, and from January 2010 to December 2014 were 77.5% and 78.6%, respectively. The median OS for those with any one high risk FISH lesion (del 17p/ 1q amp) was 67.5 (55.2, 97.1) versus 101.7 (89.7, 107.3) months. Patients with early SCT (within 12 months of diagnosis) had better OS: 108.3 (103.8, 133.0) vs. 69.8 (61.5, 80.3) months. Conclusion: Patients with t(11;14) without high risk FISH abnormalities have an excellent survival. Patients receiving a PI + IMiD combination and those receiving autologous SCT as part of initial therapy had best survival. Though numbers are limited, patients in the later lines receiving newer drugs such as venetoclax and daratumumab had high response rates and durable responses. Disclosures Kumar: Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding. Bittrich:Celgene: Other: Travel Funding, Research Funding; Else Kröner Fresenius Foundation: Research Funding; Otsuka Pharmaceuticals Europe: Other: N/A; SANOFI Aventis: Membership on an entity's Board of Directors or advisory committees, N/A, Research Funding; University Hospital Wuerzburg: Employment; Bristol Myers Squibb: Research Funding; Pfizer: Other: Travel Funding; AMGEN: Other: Travel Funding; JAZZ Pharmaceuticals: Other: Travel Funding; Wilhelm Sander Foundation: Research Funding; German Research Foundation (DFG): Other: N/A; University of Würzburg: Other: N/A. Goldschmidt:Mundipharma: Research Funding; Takeda: 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; John-Hopkins University: Research Funding; Dietmar-Hopp-Stiftung: Research Funding; Janssen: Consultancy, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Research Funding; Molecular Partners: Research Funding; John-Hopkins University: Research Funding; Amgen: Consultancy, Research Funding; Bristol-Myers Squibb: 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; Chugai: Honoraria, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Reece:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Otsuka: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; BMS: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Merck: Research Funding. Mateos:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: 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; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria; EDO: Membership on an entity's Board of Directors or advisory committees. Ludwig:Celgene: Speakers Bureau; Amgen: Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau; PharmaMar: Consultancy; Janssen: Speakers Bureau; BMS: Speakers Bureau. Mangiacavalli:celgene: Consultancy; Amgen: Consultancy; Janssen cilag: Consultancy. Dimopoulos:Sanofi Oncology: Research Funding. Kastritis:Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Honoraria; Prothena: Honoraria; Genesis: Honoraria. Yee:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Karyopharm: Consultancy; Adaptive: Consultancy. Raje:Amgen Inc.: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene Corporation: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Merck: Consultancy. Rosta:Cornerstone Research Group: Employment. Haltner:Cornerstone Research Group: Employment. Cameron:Cornerstone Research Group: Employment, Equity Ownership. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.

Abstract Introduction: Renal impairment (RI) is a classic clinicopathological feature of MM, is associated with poor prognosis and shorter survival (Eleutherakis-Papaiakovou Leuk Lymphoma 2007), and can complicate drug dosing and limit treatment options. In clinical trials, the proteasome inhibitors K and V have demonstrated efficacy in RRMM pts with RI, with superior efficacy observed in K-treated pts (Dimopoulos Blood 2017). K and V have also been observed to improve renal function in RRMM pts (Dimopoulos Clin Lymphoma Myeloma 2009; Dimopoulos Blood Advances 2017). However, few studies have investigated the real-world effectiveness of K- and V-based regimens in renal rescue. This study aimed to describe and compare renal response rates in RRMM pts treated with K + dexamethasone (Kd) and V + dexamethasone (Vd) in oncology clinics. Methods: The Oncology Services Comprehensive Electronic Records (OSCER) database (Lau Clin Epidemiol 2011) contains electronic medical records (EMR) from community- and hospital-affiliated oncology clinics in the United States. MM pts aged ≥18 who entered an OSCER clinic Jan 2012‒Feb 2018; initiated Kd or Vd treatment as line 2 (2L), 3L, or 4L; and had baseline renal impairment (Modification of Diet in Renal Disease Study estimated glomerular filtration rate [eGFR] <50 mL/min from the most recent baseline serum creatinine measurement) were included. Index date was the date of Kd or Vd initiation. The baseline period was 60 d prior to index to 30 d post-index. Follow-up was 30 d after index date to 60 d after completion of the same line. Primary outcome was renal response during follow-up. Renal response was defined according to the International Myeloma Working Group criteria (Dimopoulos J Clin Oncol 2016): complete response (RCR; baseline eGFR <50 mL/min and best post-treatment eGFR ≥60 mL/min), partial response (baseline eGFR <15 mL/min and best post-treatment eGFR 30‒59 mL/min), minor response (baseline eGFR <15 mL/min and best post-treatment eGFR 15‒29 mL/min, or baseline eGFR 15‒29 mL/min and best post-treatment eGFR 30‒59 mL/min). Renal response rates in Kd- and Vd-treated pts were evaluated using the Kaplan-Meier method and log-rank test. Incidence rate ratios (IRR) and 95% confidence intervals (CIs) were calculated for renal overall response (ROR) and RCR using multivariate Cox proportional hazard models adjusted for baseline covariates (demographics, Eastern Cooperative Oncology Group Performance Status, International Staging System stage, baseline renal function, V use in 1L, time from MM diagnosis to line initiation, use of intravenous bisphosphonates, and baseline serum calcium, serum free light chain ratio, lactate dehydrogenase, and whole blood hemoglobin measurements). Missing baseline values were estimated by multiple imputations. Results: 543 Kd-treated and 1005 Vd-treated pts were included. Baseline characteristics were similar between cohorts, with no difference in baseline eGFR stages. More Kd pts were <65 yrs of age at MM diagnosis. Median time from diagnosis to line initiation was longer in Kd pts (Kd: 17.1 mos; Vd 16.1 mos). V-based regimens were the most common therapies in 1L. Median (interquartile range) treatment duration was 4.4 (2.3-8.3) mos for Kd and 4.3 (2.1-8.3) mos for Vd. Pts treated with Kd at 2L were more likely than those treated with Vd to achieve both ROR (51.4% [178/346] vs 39.6% [327/825]; log-rank test p<0.0001) and RCR (26.6% [92/346] vs 22.2% [183/825]; log-rank test p=0.0229). This pattern persisted when 3L and 4L pts were included, (ROR: 48.4% [263/543] vs 39.8% [400/1005]; log-rank p<0.0001; RCR: 26% [141/543] vs 22.1% [222/1005]; log-rank p=0.0084) (Figures 1A and 1B). Following adjustment for potential baseline confounders, 2L Kd pts were 45% more likely to achieve ROR (IRR, 95% CI: 1.45, 1.18‒1.78) and 68% more likely to achieve RCR (1.68, 1.24‒2.28) vs 2L Vd pts (Figure 2). Kd pts in 2‒4L were 36% more likely to achieve ROR (1.36, 1.15‒1.62) and 52% more likely to achieve RCR (1.52, 1.19‒1.94). Conclusions: Using one of the most complete oncology EMR databases available, we found that RRMM pts with baseline RI treated with Kd had higher rates of overall and complete renal response, and were more likely to have a renal response, compared with pts treated with Vd. A limitation of the study is that we could not account for all concomitant medications or comorbidities that affect renal function, as some may not be captured in OSCER. Disclosures Kumar: AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding. Fu:Amgen: Employment, Equity Ownership. Mezzi:Amgen: Employment, Equity Ownership. Braunlin:Amgen: Employment. Kim:Amgen: Employment, Equity Ownership. Iskander:Amgen: Employment, Equity Ownership. Niesvizky:Amgen Inc.: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Jagannath:Celgene: Consultancy; Novartis: Consultancy; Merck: Consultancy; Medicom: Speakers Bureau; Multiple Myeloma Research Foundation: Speakers Bureau; Bristol-Myers Squibb: Consultancy. Boccia:Sandoz: Consultancy; Celgene: Speakers Bureau; Abbvie: Speakers Bureau; Genentech: Research Funding, Speakers Bureau; Amgen: Research Funding, Speakers Bureau; BMS: Research Funding; Pfizer: Consultancy; AstraZeneca: Research Funding, Speakers Bureau. Raje:Celgene: Consultancy; Janssen: Consultancy; Merck: Consultancy; Takeda: Consultancy; AstraZeneca: Research Funding; Research to Practice: Honoraria; Medscape: Honoraria; BMS: Consultancy; Amgen Inc.: Consultancy.

Abstract From 2013-2017, numerous new approvals and expanded indications have dramatically changed the treatment (tx) landscape for MM. Since that time, experienced MM physicians from leading academic institutions and cancer centers (experts) have annually updated and contributed tx recommendations for an online decision support tool designed to provide healthcare providers (HCPs) with patient-specific tx guidance. This MM tool is freely available online at www.clinicaloptions.com/myelomatool and HCPs can use the tool to enter details of a patient case, indicate their intended tx plan, and then expert tx recommendations for that case are provided. Methods This study includes analysis of tx recommendations from 5 MM experts for 270 unique MM case scenarios made during development of the 2018 update to this tool. We also aim to compare the evolving tx recommendations among the experts over time, from 2013-2017, and to determine practice patterns of HCPs using the tool over the same time span. Results Based on analysis of these annually updated MM tools, consensus (≥ 3 of 5 experts choosing the same tx for the same case) among experts has been increasing for induction tx since 2013. In ASCT-eligible patients with no specific comorbidities, experts recommended bortezomib/lenalidomide/dexamethasone (VRd) in 100% and 90% of tool cases in 2018 and 2017, respectively, which increased from 65% to 75% consensus in 2013-2015. In previous analyses, the percentage of HCPs using VRd has also increased, albeit more slowly than with experts. In 2017, 42% of HCPs indicated that they are using VRd as induction in this setting compared with 22% in 2015-2016 and 9% in 2014-2015. For ASCT-ineligible patients with ECOG > 2 but no specific comorbidities, all 5 experts recommend triplet therapy for all cases regardless of risk in 2018, but in 2017, 3 of 5 recommended triplet therapy and 2 of 5 recommended doublets for normal-risk disease. Expert recommendations for induction change, however, based on specific patient comorbidities. For patients with peripheral neuropathy, 4 of 5 experts recommended carfilzomib/lenalidomide/dexamethasone instead of VRd. For patients with renal insufficiency, 4 of 5 experts recommended bortezomib/cyclophosphamide/dexamethasone. For patients with cardiac dysfunction, all 5 experts continue to recommend VRd for patients with ECOG ≤ 2 while 2 of 5 change from VRd to Rd for patients with ECOG > 2. For patients who achieve VGPR or better to induction, all 5 experts recommend lenalidomide maintenance for standard risk disease. But for patients with high risk disease who achieve VGPR or better to induction, 3 of 5 experts recommend bortezomib/lenalidomide combination maintenance therapy regardless of induction regimen, 1 expert recommends single-agent bortezomib regardless of induction regimen, and 1 expert recommends bortezomib after a PI-based induction regimen or lenalidomide for an IMiD or IMiD/PI-based induction regimen. In the 2018 tool update, the number of R/R case scenarios with 100% expert consensus increased over previous years: 20% of cases had all 5 experts agreeing on tx vs 12% in 2017. In addition, 29% of cases had 3 of 5 experts agreeing and 8% had 2 pairs of experts agreeing in 2018 vs none with 3 of 5 experts agreeing and 21% with 2 pairs of experts agreeing in 2017. In 2018, experts recommended daratumumab/pomalidomide/dexamethasone all cases with 100% consensus, which comprises patients who are refractory to multiple agents including lenalidomide, bortezomib, and/or carfilzomib. Overall, 23 different regimens were recommended for R/R MM; and additional majority expert consensus included daratumumab/lenalidomide/dexamethasone, daratumumab/carfilzomib/dexamethasone, and carfilzomib/pomalidomide/dexamethasone (Table 1). Conclusions Practice patterns are changing rapidly and are more complex, particularly in the R/R setting, in response to the evolving tx landscape for MM. This analysis highlights several areas of expert consensus, but disparities remain for select cases. The newest approved therapies continue to have a strong impact on experts' recommendations as they have been fully integrated into their tx approaches. These analyses provide a real-time assessment of changing tx patterns among experts as well as HCPs. We will present analyses of cases entered in the 2018 online tool by HCPs and detailed comparisons of expert and the intended tx of clinicians using the tool. Disclosures Ghobrial: Takeda: Consultancy; Janssen: Consultancy; Celgene: Consultancy; BMS: Consultancy. Lonial:Amgen: Research Funding. Raje:Research to Practice: Honoraria; Takeda: Consultancy; AstraZeneca: Research Funding; Celgene: Consultancy; BMS: Consultancy; Merck: Consultancy; Janssen: Consultancy; Amgen Inc.: Consultancy; Medscape: Honoraria. Kumar:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Merck: 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; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding.

Abstract Abstract 1024 Background: The MMRC is a non-profit, disease-focused consortium founded in 2004. Sixteen North American member institutions with expertise in multiple myeloma (MM) work collaboratively with the MMRC Inc. (Norwalk, CT) and numerous pharmaceutical partners to speed development of new treatment options to MM patients. In December 2007, MMRC Inc. implemented business solutions to address barriers to rapid activation of phase I-II trials and established benchmarks for initiating and conducting these studies. In December 2010, we reported significantly faster trial start up and accrual data from previous years1,2. Today, we update and expand on MMRC performance data and analysis of progress. Methods: Twenty-five (25) trials conducted within the Consortium from May 2006 to July 2011 had sufficient start up trial data for review. FPFD was defined as the time from the member institutions' receipt of the final protocol (FP) from the trial sponsor, to the time the first patient was dosed on the trial at any participating MMRC member institution. With respect to enrollment, pre-study enrollment commitment (EC) established between MMRC and the study sponsor was defined as the total number of subjects committed to receive at least one dose of study drug across all participating MMRC centers on a trial; baseline enrollment timeline (BET) was prospectively defined as the target time period to attain EC. Results: Mean time to FPFD in the recent group of trials (RG; n=18; Sept 08-Jul 11) held steady at 131 calendar days from receipt of FP as compared to 181 days for the early group of trials (EG; n=7; Jun06-Sept08) representing a 28% reduction in time to FPFD. More importantly, there was a 20% decrease in time to FPFD by all participating MMRC centers on any MMRC trial from 189 days in the RG compared to 236 days in the EG representing an important achievement especially in the Phase I/II arena. MMRC trial accrual data was available for 17/25 trials (2 EG trials were missing data and 6 RG trials continue enrolling). The pre-study mean MMRC EC was 44 subjects per trial (n=19 trials; 849 patients); the mean actual MMRC enrollment was 49 subjects per trial (n=19; 935 patients through July 11) representing a 10% over enrollment versus committed enrollment. A total of 17/19 evaluable trials (89%) met their EC; 12/19 trials met EC within BET (71%) of which 8/12 trials (67%) reached EC 34% faster than their BET (representing a mean reduction of 4.5 months). The overall pre-study mean BET for 19 trials was 13.6 months. MMRC's actual mean enrollment timeline was 12.8 months for the group of 17 evaluable trials representing improvement over the original BET by a mean of 10%. Discussion: MMRC's acceleration of clinical trials provides physicians and patients with rapid access to novel compounds; industry with data for important drug development decisions; and academic institutions with more trials of high scientific interest. Even so, our data uncovered opportunities for improvement. The submission time from receipt of the final protocol from the trial sponsor to Scientific Review Committee (SRC) took an average 30 calendar days across all trials. A reduction to half this time could make a difference to patients and therefore warrants further exploration. Conclusion: Today, drug development in multiple myeloma is fast-paced and highly competitive. MMRC's frequent review of trial metrics provides valuable insight to continually speed answers to physicians, patients and industry. Disclosures: Richardson: Multiple Myeloma Research Consortium: Annual grant in support Clinical Trial Project Management. Vij:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Lonial:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Siegel:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Jakubowiak:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Reece:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Jagannath:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Hofmeister:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Stewart:Multiple Myeloma Research Consortium: Annual Grant in support of clinical trial Project Management. Wolf:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Krishnan:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Zimmerman:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Kumar:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Roy:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Fay:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Anderson:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management.