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Lenalidomide, bortezomib, and dexamethasone (RVd) followed by autologous stem cell transplantation (ASCT) is standard frontline therapy for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM). The addition of daratumumab (D) to RVd (D-RVd) in transplant-eligible NDMM patients was evaluated. Patients (N = 207) were randomized 1:1 to D-RVd or RVd induction (4 cycles), ASCT, D-RVd or RVd consolidation (2 cycles), and lenalidomide or lenalidomide plus D maintenance (26 cycles). The primary end point, stringent complete response (sCR) rate by the end of post-ASCT consolidation, favored D-RVd vs RVd (42.4% vs 32.0%; odds ratio, 1.57; 95% confidence interval, 0.87-2.82; 1-sided P = .068) and met the prespecified 1-sided α of 0.10. With longer follow-up (median, 22.1 months), responses deepened; sCR rates improved for D-RVd vs RVd (62.6% vs 45.4%; P = .0177), as did minimal residual disease (MRD) negativity (10−5 threshold) rates in the intent-to-treat population (51.0% vs 20.4%; P < .0001). Four patients (3.8%) in the D-RVd group and 7 patients (6.8%) in the RVd group progressed; respective 24-month progression-free survival rates were 95.8% and 89.8%. Grade 3/4 hematologic adverse events were more common with D-RVd. More infections occurred with D-RVd, but grade 3/4 infection rates were similar. Median CD34+ cell yield was 8.2 × 106/kg for D-RVd and 9.4 × 106/kg for RVd, although plerixafor use was more common with D-RVd. Median times to neutrophil and platelet engraftment were comparable. Daratumumab with RVd induction and consolidation improved depth of response in patients with transplant-eligible NDMM, with no new safety concerns. This trial was registered at www.clinicaltrials.gov as #NCT02874742.

Background: Autologous stem cell transplantation (ASCT) in multiple myeloma (MM) has been shown to improve survival compared to conventional chemotherapy alone. However, the ability to perform ASCT relies, in part, on collecting a sufficient number (#) of CD34+ hematopoietic stem cells (HSCs), typically from peripheral blood. The ideal HSC mobilization regimen would enable collection of optimal #s of HSCs (5-6x10 6 CD34+ cells/kg) within the minimum # of apheresis sessions possible. Yet, despite currently available G-CSF (G) based mobilization regimens and multiple apheresis days, many remain unable to collect optimal #s of HSCs. Motixafortide (M) is a novel CXCR4 inhibitor, with high affinity (IC 50 0.54-4.5 nM) and long receptor occupancy (>48 hours). Methods: In this prospective, phase 3, double blind, placebo controlled, multicenter trial, 122 patients were randomized (2:1) to receive either M+G or placebo (P)+G for HSC mobilization prior to ASCT for MM. All patients received G (10 mcg/kg) on days 1-5 (and 6-8, if needed). Patients received either M (1.25 mg/kg, subcutaneous injection) or P on day 4 (and 6, if needed). Apheresis began day 5, with the primary (PEP) and secondary (SEP) endpoints of collecting ≥6x10 6 CD34+ cells/kg in up to 2 apheresis days or 1 day, respectively. Apheresis continued on days 6-8 if needed. Total CD34+ cells/kg were analyzed on site to determine if patients mobilized to the goal and all samples were subsequently sent for assessment by central laboratory. Patients that did not collect ≥2x10 6 CD34+ cells/kg by day 8 proceeded to rescue mobilization. The # of CD34+ cells infused was determined independently by each investigator according to local practice (minimum ≥2x10 6 CD34+ cells/kg). Analyses of the PEP/SEPs were performed on an intent-to-treat basis. Results: Demographics between the 2 treatment arms were similar. Mobilization with M+G resulted in 92.5% of patients collecting ≥6x10 6 CD34+ cells/kg within 2 apheresis days vs 26.2% with P+G (Odds Ratio (OR) 53.3, 95% CI 14.12-201.33, p Conclusions: A single injection of M on top of G significantly increased the proportion of patients mobilizing ≥6x10 6 CD34+ cells/kg for ASCT (92.5%) vs G (26.2%) in up to 2 apheresis days (p Figure 1 Figure 1. Disclosures Crees: BioLineRx Ltd.: Research Funding. Larson: TORL biotherapeutics: Current holder of individual stocks in a privately-held company; Bioline: Research Funding; Abbvie: Research Funding; BMS: Research Funding; Celgene: Research Funding; GSK: Research Funding; Janssen: Research Funding; Juno: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Takeda: Research Funding. Illés: Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Stiff: Incyte: Research Funding; Cellectar: Research Funding; Seagen: Research Funding; Gamida Cell: Research Funding; Cellectar: Research Funding; Actinium: Research Funding; Bristol Myers Squibb: Research Funding; BioLineRX: Research Funding; Macrogenics: Research Funding; CRISPR Therapeutics: Consultancy, Honoraria; Amgen: Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Karyopharm: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria. Sborov: Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy; Sanofi: Consultancy; SkylineDx: Consultancy. Pereira: Jazz Pharmaceutical: Membership on an entity's Board of Directors or advisory committees. Mikala: Novartis: Consultancy; Takeda: Consultancy; Abbvie: Consultancy; Krka: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Celgene: Consultancy. Holtick: Celgene: Honoraria; Sanofi: Honoraria. Qazilbash: Amgen: Research Funding; Oncopeptides: Other: Advisory Board; Bristol-Myers Squibb: Other: Advisory Board; Biolline: Research Funding; Angiocrine: Research Funding; NexImmune: Research Funding; Janssen: Research Funding. Hardy: American Gene Technologies, International: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; InCyte: Membership on an entity's Board of Directors or advisory committees. Vainstein: BioLineRx LTD: Current Employment. Sorani: BioLineRx LTD: Current Employment. Gliko-Kabir: BioLineRx Ltd.: Current Employment. Goldstein: BioLineRx Ltd.: Current Employment. Kadosh: BioLineRx Ltd.: Current Employment.

Background: CD34+ hematopoietic stem and progenitor cell (HSPC) dose during hematopoietic cell transplantation (HCT) remains one of the most reliable clinical parameters to predict quality of engraftment. A minimum HSPC dose of 2-2.5x10 6 CD34+ cells/kg is considered necessary for reliable engraftment, while optimal doses of 5-6x10 6 CD34+ cells/kg are associated with faster engraftment, as well as fewer transfusions, infections, and antibiotic days. CXCR4 inhibition significantly improves the number (#) of CD34+ HSPCs mobilized for HCT, when added to G-CSF (G). Motixafortide (M), a novel CXCR4 antagonist, is a potent mobilizer of HSPCs recently evaluated in the phase 3, double blind, placebo controlled, multicenter GENESIS Trial as a mobilizing agent prior to autologous HCT (ASCT) in multiple myeloma (MM). Methods: Patients received G (10 mcg/kg) on days 1-5 (and days 6-8, if needed). On day 4 (and day 6, if needed), patients received either M (1.25 mg/kg) or placebo (P). Apheresis began day 5, with up to 4 days of apheresis if needed. The primary and secondary endpoints were collection of ³6x10 6 CD34+ cells/kg in up to 2 days of apheresis or 1 day, respectively. The # of CD34+ cells/kg infused was determined independently by each investigator according to local practice, but a minimum of ³2x10 6 CD34+ cells/kg was required. A post-hoc analysis was performed pooling data from both arms to evaluate time to platelet engraftment (TPE) (≥20x10 9/L without transfusions x7 days) and neutrophil engraftment (TNE) (ANC ≥0.5x10 9/L x3 days) based on total # of CD34+ cells/kg and # of specific CD34+ HSPC subsets infused. CD34+ HSPC immunophenotyping was performed via multicolor fluorescence-activated cell sorting (FACS). TPE/TNE was analyzed using Kaplan-Meier curves and Cox proportional hazards model. Results: 114 MM patients underwent apheresis, ASCT and were evaluable (M+G N=77; P+G N=37). M+G mobilization yielded a median of 10.8x10 6 CD34+ cells/kg collected in 1 apheresis vs 2.3x10 6 CD34+ cells/kg with P+G (p75 th percentile) of combined CD34+ HSC, MPP, CMP and GMP subsets was associated with faster TPE of 12 days vs 19 days with lower #s of these subsets (p=0.003) (Figure 2A). Furthermore, higher #s (>75 th percentile) of GMPs was individually associated with faster TPE of 13 days vs 19 days with lower GMP cell doses (p=0.0116) (Figure 2C). TNE was not impacted by increasing doses of total CD34+ HSPCs or any specific CD34+ HSPC subset (all p>0.05) (Figures 1B, 2B and 2D). Conclusions: M+G mobilization enabled significantly more CD34+ cells to be collected in 1 apheresis (median 10.8x10 6 CD34+ cells/kg) vs P+G (2.3x10 6 CD34+ cells/kg), as well as 3.5-5.6 fold higher #s of HSCs, MPPs, CMPs and GMPs (all p-values Figure 1 Figure 1. Disclosures Crees: BioLineRx Ltd.: Research Funding. Retting: BioLineRx Ltd.: Research Funding. Larson: TORL biotherapeutics: Current holder of individual stocks in a privately-held company; Abbvie, Bioline, BMS, Celgene, GSK, Janssen, Juno, Novartis, Pfizer, Takeda: Research Funding. Illes: Novartis, Janssen, Pfizer, Roche: Other: Travel, Accommodations, Expenses; Takeda, Seattle Genetics: Research Funding; Janssen, Celgene, Novartis, Pfizer, Takeda, Roche: Consultancy. Stiff: CRISPR: Consultancy; Gamida-Cell, Atara, Amgen, Incyte, Takeda, Macrogenetics, Eisai: Research Funding. Sborov: SkylineDx: Consultancy; GlaxoSmithKline: Consultancy; Sanofi: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Pereira: Jazz Pharmaceutical: Membership on an entity's Board of Directors or advisory committees. Mikala: Abbvie: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Krka: Consultancy; Novartis: Consultancy; Takeda: Consultancy. Holtick: Sanofi: Honoraria; Celgene: Honoraria. Qazilbash: Janssen: Research Funding; Oncopeptides: Other: Advisory Board; Biolline: Research Funding; Bristol-Myers Squibb: Other: Advisory Board; NexImmune: Research Funding; Amgen: Research Funding; Angiocrine: Research Funding. Hardy: Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; American Gene Technologies, International: Membership on an entity's Board of Directors or advisory committees; InCyte: Membership on an entity's Board of Directors or advisory committees. Sorani: BioLineRx LTD: Current Employment. Shemesh-Darvish: BioLineRx LTD: Current Employment. Vainstein: BioLineRx LTD: Current Employment; Enlivex: Consultancy. Kadosh: StatExcellence: Current holder of individual stocks in a privately-held company; BioLineRx: Honoraria.

Introduction: DARA is approved across lines of therapy for multiple myeloma, including in combination with standard-of-care regimens for NDMM. The CXCR4 receptor antagonist plerixafor is used in conjunction with granulocyte colony-stimulating factor (G-CSF) to increase stem cell mobilization for autologous stem cell transplant (ASCT) and can be given by upfront decision or as a rescue strategy. The phase 2 randomized GRIFFIN study (NCT02874742) evaluates frontline DARA in combination with lenalidomide, bortezomib, and dexamethasone (D-RVd) in transplant-eligible NDMM. In the primary analysis, more pts undergoing stem cell mobilization/collection in the D-RVd group received plerixafor compared with the RVd group (69.5% [66/95] vs 56.3% [45/80]) (Voorhees PM, et al. Blood. 2020). The phase 2 MASTER study (NCT03224507) evaluates DARA plus carfilzomib, lenalidomide, and dexamethasone (D-KRd) in transplant-eligible NDMM (Costa LJ, et al. EHA Library. 2020). Here, we present a summary of stem cell mobilization, collection yields, and ASCT data following frontline DARA-based induction therapy in GRIFFIN and MASTER. Methods: Eligible pts had NDMM and were candidates for ASCT. In GRIFFIN, pts were randomized 1:1 to receive D-RVd or RVd. Pts received 4 induction cycles (21 days) of lenalidomide (R; 25 mg PO on Days 1-14), bortezomib (1.3 mg/m 2 SC on Days 1, 4, 8, and 11), and dexamethasone (d; 40 mg PO QW) ± DARA (16 mg/kg IV QW in Cycles 1-4). After Cycle 4, pts underwent stem cell mobilization with G-CSF ± plerixafor, per institutional standards; if unsuccessful, chemo mobilization was permitted. Pts then received ASCT and subsequently 2 consolidation cycles (21 days) of D-RVd or RVd followed by maintenance therapy with R ± DARA. In the single-arm MASTER study, pts received 4 D-KRd induction cycles, ASCT, and 0, 4 or 8 D-KRd consolidation cycles followed by maintenance therapy with R, based upon achievement of minimal residual disease-negativity. In each 28-day cycle, all pts received carfilzomib (20/56 mg/m 2 IV QW), R (25 mg PO on Days 1-21), d (40 mg PO or IV QW), and DARA (16 mg/kg IV QW for Cycles 1-2, Q2W for Cycles 3-6, and Q4W for Cycles 7+). Mobilization was with G-CSF ± plerixafor as per institutional standards. Results: In GRIFFIN, among 207 (D-RVd, n=104; RVd, n=103) randomized pts, 91.3% (n=95) of D-RVd pts and 77.7% (n=80) of RVd pts underwent stem cell mobilization; of those mobilized, 98.9% (n=94) and 97.5% (n=78) underwent ASCT, respectively. In MASTER, 123 D-KRd pts enrolled and at last follow-up, 91.1% (n=112) underwent stem cell mobilization; of those mobilized, 98.2% (n=110) completed ASCT. In GRIFFIN, 46.3% (n=81) of mobilized pts received plerixafor upfront (D-RVd, 51.6%, n=49; RVd, 40.0%, n=32), and 18.3% (n=32 pts) received rescue plerixafor (D-RVd, 20.0%, n=19; RVd, 16.3%, n=13). In MASTER, 70.5% (n=79) D-KRd pts received upfront plerixafor and 25.9% (n=29) received rescue plerixafor. Median CD34 + cell yield was 8.3 × 10 6/kg for D-RVd and 9.4 ×10 6/kg for RVd in GRIFFIN, 6.0 ×10 6/kg for D-KRd in MASTER, and was numerically higher for pts who received upfront plerixafor. Median days for stem cell collection was 1 for pts receiving RVd and 2 for those receiving D-RVd or D-KRd. Median transplanted CD34 + cell count was 4.2 ×10 6/kg for D-RVd and 4.8 ×10 6/kg for RVd in GRIFFIN, and 3.2 ×10 6/kg for D-KRd in MASTER. In GRIFFIN, 93.7% of D-RVd pts and 98.8% of RVd pts reached the minimum institutional CD34 + threshold to perform a single ASCT, which was comparable to results in MASTER (95.5% of D-KRd pts) after first mobilization attempt; 85.3% of D-RVd pts, 92.5% of RVd pts, and 79.5% of D-KRd pts collected 2 times the minimum threshold of stem cells. Additional data by upfront and rescue plerixafor strategies are shown in the Table. Conclusion: The addition of DARA to proteasome inhibitor/immunomodulatory drug/dexamethasone-based induction therapy has a modest impact on stem cell mobilization, with a lower yield of stem cells and higher median number of days required for collection. Nonetheless, pts were able to undergo transplantation, and most pts collected sufficient stem cells for 2 transplants. Pts who received plerixafor by an upfront decision had numerically higher stem cell yields than pts who received plerixafor by a rescue strategy. An upfront plerixafor strategy for pts receiving DARA-based quadruplet induction therapy should be considered with allowance for additional days of apheresis as needed. Figure 1 Figure 1. Disclosures Chhabra: GSK: Honoraria. Costa: Janssen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Kaufman: BMS: Consultancy, Research Funding; Fortis Therapeutics: Research Funding; Roche/Genetech, Tecnopharma: Consultancy, Honoraria; Sutro, Takeda: Research Funding; Genentech, AbbVie, Janssen: Consultancy, Research Funding; Novartis: Research Funding; Incyte, celgene: Consultancy; Tecnofarma SAS, AbbVie: Honoraria; Janssen: Honoraria; Incyte, TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Heidelberg Pharma: Research Funding; Amgen: Research Funding. Sborov: Sanofi: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; SkylineDx: Consultancy; GlaxoSmithKline: Consultancy. Reeves: Incyte Corporation: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb: Speakers Bureau; Pharma Essentia: Consultancy, Honoraria. Rodriguez: Karyopharm: Consultancy, Speakers Bureau; Oncopeptides: Consultancy, Honoraria; Amgen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Chari: Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shattuck Labs: Consultancy, Membership on an entity's Board of Directors or advisory committees; Secura Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millenium/Takeda: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: 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; Novartis: Consultancy, Research Funding. Silbermann: Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Anderson: Celgene, BMS, Janssen, GSK, Karyopharm, Oncopeptides, Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Shah: Sutro Biopharma: Research Funding; Janssen: Research Funding; Indapta Therapeutics: Consultancy; CareDx: Consultancy; Sanofi: Consultancy; Kite: Consultancy; Poseida: Research Funding; Amgen: Consultancy; BMS/Celgene: Research Funding; Bluebird Bio: Research Funding; CSL Behring: Consultancy; GSK: Consultancy; Precision Biosciences: Research Funding; Teneobio: Research Funding; Oncopeptides: Consultancy; Nektar: Research Funding; Karyopharm: Consultancy. Bumma: Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees. Holstein: Oncopeptides: 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; Genentech, GSK, Janssen, Secura Bio, Sorrento: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Jakubowiak: BMS: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Gracell: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Wildes: Carevive: Consultancy; Seattle Genetics: Consultancy; Sanofi: Consultancy; Janssen: Consultancy. Orlowski: CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Other: Clinical research funding; Asylia Therapeutics, Inc., BioTheryX, Inc., and Heidelberg Pharma, AG.: Other: Laboratory research funding; Asylia Therapeutics, Inc.: Current holder of individual stocks in a privately-held company, Patents & Royalties; Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, Forma Therapeutics, Genzyme, GSK Biologicals, Janssen Biotech, Juno Therapeutics, Karyopharm Therapeutics, Inc., Kite Pharma, Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, I: Membership on an entity's Board of Directors or advisory committees; Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, EcoR1 Capital LLC, Genzyme, GSK Biologicals, Janssen Biotech, Karyopharm Therapeutics, Inc., Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, Inc., Sanofi-Aventis, and Takeda P: Consultancy, Honoraria. Shain: Novartis Pharmaceuticals Corporation: Consultancy; Karyopharm Therapeutics Inc.: Honoraria, Research Funding; Janssen oncology: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi Genzyme: Consultancy, Speakers Bureau; GlaxoSmithLine, LLC: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Adaptive Biotechnologies Corporation: Consultancy, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding. Cowan: Janssen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Cellectar: Consultancy; Harpoon: Research Funding; GSK: Consultancy; Secura Bio: Consultancy; BMS: Research Funding; Nektar: Research Funding. Dholaria: Takeda: Research Funding; Jazz: Speakers Bureau; MEI: Research Funding; Angiocrine: Research Funding; Poseida: Research Funding; Celgene: Speakers Bureau; Pfizer: Research Funding; Janssen: Research Funding. Pei: Janssen: Current Employment, Current equity holder in publicly-traded company. Cortoos: Janssen: Current Employment, Current equity holder in publicly-traded company. Patel: Janssen: Current Employment. Bartlett: Janssen: Current Employment. Vermeulen: Janssen: Current Employment, Current equity holder in publicly-traded company. Lin: Janssen: Current Employment. Richardson: AstraZeneca: Consultancy; Regeneron: Consultancy; Celgene/BMS: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; AbbVie: Consultancy; GlaxoSmithKline: Consultancy; Karyopharm: Consultancy, Research Funding; Protocol Intelligence: Consultancy; Janssen: Consultancy; Sanofi: Consultancy; Secura Bio: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding. Voorhees: Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, 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; Karyopharm: 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; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Secura Bio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: The specific regimen combination is not yet approved, but individual components are.

Introduction: DARA is approved for NDMM and previously treated MM. In the primary analysis of the phase 2 GRIFFIN trial (NCT02874742) in autologous stem cell transplant (ASCT)-eligible NDMM pts (median follow-up, 13.5 mo), DARA plus RVd (D-RVd) improved the rate of stringent complete response (sCR) by the end of post-ASCT consolidation versus RVd (42.4% vs 32.0%, 1-sided P=0.068) (Voorhees PM, et al. Blood. 2020). With longer follow-up (median, 27.4 mo), responses deepened and were improved for D-RVd versus RVd (sCR rate: 63.6% vs 47.4%, 2-sided P=0.0253), as did the MRD-negativity (10 -5) rate (62.5% vs 27.2%, P Methods: Pts with NDMM eligible for high-dose therapy (HDT) and ASCT were randomized 1:1 to receive RVd or D-RVd, stratified by ISS disease stage (I, II, or III) and creatinine clearance (30-50 or >50 mL/min). Pts received 4 RVd or D-RVd induction cycles, HDT, ASCT, 2 RVd or D-RVd consolidation cycles, and maintenance with lenalidomide (R) alone or with DARA (D-R) for 24 months. During induction and consolidation (21-day cycles), pts received R (25 mg PO on Days 1-14), bortezomib (1.3 mg/m 2 SC on Days 1, 4, 8, and 11), and dexamethasone (40 mg PO QW) ± DARA (16 mg/kg IV on Days 1, 8, and 15 of Cycles 1-4 and Day 1 of Cycles 5-6). During maintenance (Cycles 7-32; 28-day cycles), pts received R (10 mg PO on Days 1-21; if tolerated, 15 mg in Cycle 10+) ± DARA (16 mg/kg IV) Q8W (or Q4W per pt decision after protocol amendment 2) until disease progression or up to 24 months. The primary endpoint was sCR rate by the end of post-ASCT consolidation (tested at 1-sided α of 0.10). Responses were assessed per IMWG criteria by a validated computer algorithm. Key secondary endpoints included progression-free survival (PFS) and MRD negativity assessed by NGS at the minimum sensitivity threshold of 10 -5, at suspected complete response or better (≥CR), at the end of induction and consolidation, and after 12 and 24 months of maintenance, regardless of response. Secondary analyses were evaluated using 2-sided α of 0.05, not adjusted for multiplicity. Results: In total, 207 pts were randomized (D-RVd, n=104; RVd, n=103); baseline characteristics were well balanced. After 24 months of D-R or R maintenance therapy, the rate of sCR favored D-RVd versus RVd in the response-evaluable population (66.0% [66/100] vs 47.4% [46/97], 2-sided P=0.0096; Figure). In the intent-to-treat (ITT) population, MRD-negativity (10 -5) rates also remained higher for D-RVd versus RVd (64.4% [67/104] vs 30.1% [31/103], P3-fold higher for D-RVd versus RVd (44.2% vs 12.6%, P Conclusion: After 24 months of maintenance therapy, the addition of DARA to RVd induction and consolidation in conjunction with ASCT, followed by DARA plus R maintenance, continued to demonstrate deep and durable responses in pts with transplant-eligible NDMM, including sCR and MRD-negativity (10 -5 and 10 -6) rates. While this study was not powered for PFS, there is a positive trend towards improved PFS in the D-RVd group. No new safety concerns were observed with longer follow-up. These results support the use of D-RVd induction/consolidation and D-R maintenance in transplant-eligible NDMM pts. Figure 1 Figure 1. Disclosures Kaufman: Sutro, Takeda: Research Funding; Incyte, TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Research Funding; Amgen: Research Funding; Tecnofarma SAS, AbbVie: Honoraria; Janssen: Honoraria; Fortis Therapeutics: Research Funding; Novartis: Research Funding; Incyte, celgene: Consultancy; Heidelberg Pharma: Research Funding; Roche/Genetech, Tecnopharma: Consultancy, Honoraria; Genentech, AbbVie, Janssen: Consultancy, Research Funding. Sborov: Sanofi: Consultancy; SkylineDx: Consultancy; GlaxoSmithKline: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Reeves: Bristol-Myers Squibb: Speakers Bureau; Incyte Corporation: Honoraria; Takeda: Honoraria; Pharma Essentia: Consultancy, Honoraria. Rodriguez: Janssen: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Karyopharm: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Oncopeptides: Consultancy, Honoraria. Chari: Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Secura Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millenium/Takeda: Consultancy, Research Funding; Janssen Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Silbermann: Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees, Research Funding. Costa: Pfizer: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Anderson: Celgene, BMS, Janssen, GSK, Karyopharm, Oncopeptides, Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Shah: GSK: Consultancy; Nektar: Research Funding; Kite: Consultancy; CareDx: Consultancy; CSL Behring: Consultancy; Indapta Therapeutics: Consultancy; Janssen: Research Funding; Poseida: Research Funding; Karyopharm: Consultancy; BMS/Celgene: Research Funding; Bluebird Bio: Research Funding; Oncopeptides: Consultancy; Teneobio: Research Funding; Sanofi: Consultancy; Precision Biosciences: Research Funding; Sutro Biopharma: Research Funding; Amgen: Consultancy. Bumma: Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Holstein: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech, GSK, Janssen, Secura Bio, Sorrento: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding. Jakubowiak: Abbvie: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Gracell: Membership on an entity's Board of Directors or advisory committees. Wildes: Carevive: Consultancy; Seattle Genetics: Consultancy; Sanofi: Consultancy; Janssen: Consultancy. Orlowski: Asylia Therapeutics, Inc., BioTheryX, Inc., and Heidelberg Pharma, AG.: Other: Laboratory research funding; CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Other: Clinical research funding; Asylia Therapeutics, Inc.: Current holder of individual stocks in a privately-held company, Patents & Royalties; Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, Forma Therapeutics, Genzyme, GSK Biologicals, Janssen Biotech, Juno Therapeutics, Karyopharm Therapeutics, Inc., Kite Pharma, Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, I: Membership on an entity's Board of Directors or advisory committees; Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, EcoR1 Capital LLC, Genzyme, GSK Biologicals, Janssen Biotech, Karyopharm Therapeutics, Inc., Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, Inc., Sanofi-Aventis, and Takeda P: Consultancy, Honoraria. Shain: AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi Genzyme: Consultancy, Speakers Bureau; GlaxoSmithLine, LLC: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Adaptive Biotechnologies Corporation: Consultancy, Speakers Bureau; Janssen oncology: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm Therapeutics Inc.: Honoraria, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy. Cowan: BMS: Research Funding; Secura Bio: Consultancy; GSK: Consultancy; Harpoon: Research Funding; Cellectar: Consultancy; Sanofi: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Nektar: Research Funding. Pei: Janssen: Current Employment, Current equity holder in publicly-traded company. Cortoos: Janssen: Current Employment, Current equity holder in publicly-traded company. Patel: Janssen: Current Employment. Bartlett: Janssen: Current Employment. Vermeulen: Janssen: Current Employment, Current equity holder in publicly-traded company. Lin: Janssen: Current Employment. Richardson: Sanofi: Consultancy; Secura Bio: Consultancy; Regeneron: Consultancy; Karyopharm: Consultancy, Research Funding; Janssen: Consultancy; Protocol Intelligence: Consultancy; Celgene/BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; AstraZeneca: Consultancy; Oncopeptides: Consultancy, Research Funding; AbbVie: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding. Voorhees: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Secura Bio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, 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; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: The specific regimen combination is not yet approved, but individual components are.

Introduction: Despite dramatic treatment advances , multiple myeloma (MM) remains a significant source of morbidity and mortality with 13,000 deaths expected annually in the United States. We characterized patterns of mortality, palliative care involvement, and disease course at the end of life for patients with MM over the last decade. Methods: We assessed all consecutive deceased patients with a diagnosis of MM who received health care at a single health care institution from January 2010 to December 2020. Institutional Review Board approval was obtained prior to data review. Descriptive statistics were employed, and chi square was used to compare categorical variables. Results: A total of 456 patients were identified. Patient characteristics and outcomes are listed in Table 1. In the year prior to death, the prevalence of depression was 45.8% (209 patients), whereas 75.4% of patients were on opiates as an outpatient (344 patients). The mean number of lines of treatment received from diagnosis to death was 3 (range 0-12). Two-hundred eleven (46.3%) patients required red blood cell transfusions in the year prior to death. Palliative care physicians saw 207 (45.4%) patients, of which 97 (46.9%) were seen as outpatient (including those who saw both outpatient and inpatient), and 110 (53.1%) exclusively as an inpatient. The median time from first palliative care consultation to death was 10 days for inpatient palliative care (range 0-389 days), and 107 days for outpatient palliative care (range 2-2028 days). Only 42 (9.2%) patients saw palliative care ≥6 months prior to death. Compared to those patients who did not see palliative care, those that saw palliative care ≥6 months prior to death were more likely to be female (61.9 versus 42.2%, p=0.05), younger (median age at diagnosis 66 versus 71, p=0.03), and have a longer survival (46 months versus 35 months, p=0.006) (Table 1 and Figure 1). Amongst the patients for whom place of death was clearly reported (351, 77%), 117 patients (33.3%) died in the acute care setting, 110 (31.3%) died in a hospice facility, and 124 (35.3%) died at home. Outpatient palliative care consultation did not correlate with a statistically significant difference in deaths in an acute care setting (22/81, 27.2% seeing outpatient palliative care versus 57/174, 32.8% for those who did not, p=0.36), or in chemotherapy (any active treatment other than just steroids) utilization in last month of life (30.9% versus 29.7%, p=0.83). Conclusion: In our analysis of the entire trajectory of the MM patient experience from diagnosis to death, we found a substantial proportion of patients with MM report depression, need opiates for pain control, require blood transfusions and are repeatedly hospitalized in the year prior to their death. A fifth of all deaths occur within a year of diagnosis. With a median of three lines of therapy from diagnosis to death, patients may not live to experience therapies reserved for later lines of treatment. A minority of these patients see a palliative care physician during their treatment journey with the median time from palliative care consultation to death only a month. Palliative care referral at this health system is physician-initiated and not based on standard criteria, which may impact these findings. While there is no clear correlation that palliative care consultation impacted the rate of acute care deaths or decreased utilization of MM treatment in the last month of life, (two common but complicated proxies for quality of end-of-life care), further prospective research on optimal utilization of specialist palliative care is required. Figure 1 Figure 1. Disclosures Sborov: GlaxoSmithKline: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; SkylineDx: Consultancy; Sanofi: Consultancy.

Background Treatment at academic cancer centers (ACs) has been associated with improved outcomes across hematologic malignancies, including acute myeloid leukemia and non-Hodgkin lymphoma. ACs offer the benefit of high treatment volume in addition to enrollment in clinical trials, involvement in post-graduate education, and expanded access to diagnostic and treatment related services. Though studies on multiple myeloma (MM) have demonstrated a survival benefit with treatment at both high-volume centers and at NCCN designated cancer centers, this is the largest study to date examining the benefit of academic centers. Methods The National Cancer Database was utilized to obtain data on patients diagnosed with MM between 2004-2017 for which data on treatment facility type was available. Using the Commission on Cancer facility categories, patients treated at ACs were compared to those treated at non-academic centers (NACs), including small and large volume community cancer centers. Demographic and treatment characteristics were compared between centers, with median overall survival (OS) assessed by Kaplan Meier. Cox regression analysis was used to asses the HR for OS by facility type, and adjusted on multivariate analysis for age, sex, race, insurance, time to treatment, and use of autologous transplant. Results Of the 179,769 MM patients available, 42.4% were treated at ACs (p 75 years of age were more often treated at NACs (35.6% vs. 20.3%, p The time from diagnosis to treatment was longer at ACs, at 32.4 vs. 26.5 days (p Median OS at ACs was significantly longer than at NACs, with median OS of 67.8 months (95% CI 66.89-68.79 months) compared to 38.6 months (95% CI 38.15-39.13 months) at NACs, p Conclusion Patients with MM had significantly improved survival when treated at academic centers compared to all other facility types. The improvement in OS remained when controlled for available treatment and demographic features. Multiple factors, including specialized care, trial enrollment, and early access to autologous stem cell transplant may contribute to these improvements. Further investigations into the factors contributing to such disparities are required to standardize care and improve overall outcomes. Figure 1 Figure 1. Disclosures Tantravahi: CTI BioPharma: Research Funding; Novartis: Research Funding; BMS: Research Funding; Abbvie Inc.: Research Funding; Karyopharm Therapeutics Inc.: Consultancy, Honoraria, Research Funding. Sborov: SkylineDx: Consultancy; GlaxoSmithKline: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy.

Introduction: Daratumumab in combination with cyclophosphamide, bortezomib and dexamethasone (Dara/CyBorD) is the only FDA approved therapy for newly diagnosed systemic light-chain (AL) amyloidosis (N Engl J Med 2021;385:46). Belantamab mafodotin is a novel anti-BCMA immunoconjugate with humanized IgG1 anti-BCMA monoclonal antibody conjugated to a microtubule-disrupting agent, monomehtyl auristatin F (MMAF) via a non-cleavable linker (Blood 2014;123:3128). Phase I/II studies in heavily pre-treated multiple myeloma patients showed single agent clinical activity with overall response rates ranging from 30-60%, with majority of responses being durable at 13 months of follow-up. Toxicity profile included keratopathy, thrombocytopenia and anemia (Blood Cancer J 2019;9:37; Lancet Oncol 2020;21:207). Based on these results, belantamab mafadotin (BLM; Blenrep) was FDA approved for relapsed myeloma. A role for new agents such as BLM in AL has not been previously reported. Here we report outcomes of six patients who received BLM at different centers for relapsed refractory (RR) AL associated with myeloma. Methods: In this retrospective study we identified AL patients with RR disease who received at least one dose of BLM. In a multi-institutional collaboration we collected demographic, medical history, laboratory, pathologic and treatment/response data on patients with myeloma and biopsy-proven AL who had received BLM. Laboratory assessment including evaluations for hematologic and organ response was done as per standard criteria and toxicity assessed as per CTCAE v6.0. Results: We identified 6 patients, 3M/3F, from 4 centers; baseline characteristics and treatment data are provided in Table 1. Baseline median age was 61 years (range, 51-74) and median marrow plasmacytosis and iFLC were 40% (10-90) and 868mg/L (145-5324). Four patients had AL λ-type and 2 κ-type, and 5 of 6 had cardiac involvement while 3 had additional organ involvement (renal, GI, nervous system). Prior to initiating BLM the median number of lines of prior therapy was 6 (range, 5-10), including daratumumab, bortezomib and lenalidomide, and prior to initiating BLM marrow assessment showed a median plasmacytosis of 23%. BLM at 2.5 mg/kg was given as an intravenous infusion over the course of 30 minutes every three weeks after ophthalmologic exam clearance until discontinuation for progression or toxicity. At a median follow-up of 4.5 months, 5 patients (83%) achieved hematological responses (HR) with 3 (50%) achieving complete hematological responses (CR) by standard criteria (J Clin Oncol 2012;30:4541). Time to HR ranged from 3 to 150 days. Cardiac response was seen in all but 1 patient, with time to response ranging from 11 to 96 days. One patient had a renal response; response assessment is not yet available for 2 other patients with renal involvement. The most common toxicity was keratopathy (grade 1-2). BLM was held after the first dose in one patient who had been heavily pre-treated and had extensive cardiac and pulmonary AL and multiple sites of FDG-avid progressive myeloma bone disease. Two days after administration of the first dose of BLM, this 51-year-old man was admitted to hospital for dyspnea, developed atrial fibrillation and ventricular tachycardia, and briefly required cardiac resuscitation without intubation with return of spontaneous circulation after 6 minutes. This patient achieved a CR after one dose of BLM that has been stable for over 5 months with marked clinical improvement. A 62 year-old woman with cardiac and renal AL has achieved a CR durable for over 16 months with cardiac and renal responses. Conclusions: In this group of 6 patients with RR AL with myeloma, HR and cardiac response rates were impressive at 83% and 80%, respectively. One patient who had 24-hour urine protein evaluation also achieved a renal response. Time to response was rapid with 2 patients achieving HR within a week of starting treatment, and the rest within five months. Additionally, 3 of 6 patients achieved CR, 1 had no clonal plasma cells in the marrow and another clonal disease detectable only by MRD. In this retrospective multi-institutional cohort BLM resulted in rapid reduction of iFLC and induced critical organ responses. These data provide preliminary evidence for the clinical activity of BLM in RR AL. Results of the on-going phase 2 clinical trial in the European Myeloma Network (EMN27; NCT04617925) are awaited with great interest. Figure 1 Figure 1. Disclosures Sborov: Sanofi: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy; SkylineDx: Consultancy. Comenzo: Karyopharm: Research Funding; Prothena Biosciences: Consultancy, Research Funding; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Unum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Caelum: Consultancy, Research Funding; Janssen: Patents & Royalties: WO2016187546A1, Research Funding. Kansagra: Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Cota Health: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Alynylam: Membership on an entity's Board of Directors or advisory committees.

Introduction: DARA, a human IgGκ monoclonal antibody targeting CD38, is approved as monotherapy and in combination with standard-of-care regimens for relapsed/refractory multiple myeloma and NDMM. In the primary analysis of the phase 2 GRIFFIN study (NCT02874742) in patients with transplant-eligible NDMM, DARA plus RVd (D-RVd) significantly improved rates of stringent complete response (sCR) by the end of post-transplant consolidation therapy versus RVd (Voorhees P, Blood 2020). Here, we present updated efficacy and safety results following 12 months of maintenance therapy with lenalidomide (R) or DARA plus R (D-R). Methods: Patients with NDMM eligible for high-dose therapy (HDT) and autologous stem cell transplant (ASCT) were randomized 1:1 to RVd ± DARA, stratified by ISS stage and creatinine clearance rate. Patients received 4 induction cycles, HDT, ASCT, 2 consolidation cycles, and maintenance with R ± DARA for 24 months. During induction and consolidation, patients received R 25 mg PO on Days 1-14; V 1.3 mg/m2 SC on Days 1, 4, 8, and 11; and d 40 mg QW every 21 days. DARA 16 mg/kg IV was given on Days 1, 8, and 15 of Cycles 1-4 and Day 1 of Cycles 5-6. During maintenance (Cycles 7-32), patients received R 10 mg (15 mg in Cycles 10+ if tolerated) on Days 1-21 every 28 days ± DARA 16 mg/kg IV Q8W (or Q4W per patient decision after Amendment 2). The primary endpoint was rate of sCR at the end of post-ASCT consolidation per IMWG criteria, evaluated by a validated computer algorithm. Key secondary endpoints included progression-free survival (PFS) and rate of minimal residual disease (MRD) negativity (10-5 threshold per IMWG criteria) assessed by next-generation sequencing (clonoSEQ; Adaptive Biotechnologies). The primary hypothesis was tested at a 1-sided alpha of 0.10. All secondary analyses were evaluated using a 2-sided P value (alpha 0.05) and were not adjusted for multiplicity. Results: In total, 207 patients were randomized (D-RVd, n=104; RVd, n=103). Baseline demographics and disease characteristics were well balanced between arms. At the end of post-transplant consolidation (median follow-up, 13.5 months) in the response-evaluable population, the sCR rate favored D-RVd versus RVd (42.4% [42/99] vs 32.0% [31/97]; 1-sided P=0.0680). With additional D-R or R maintenance therapy, responses continued to deepen and remained higher for the D-RVd group versus the RVd group. At the 12-months-of-maintenance therapy data cut (median follow-up, 26.7 months), the sCR rate still favored D-RVd versus RVd (63.6% [63/99] vs 47.4% [46/97], 2-sided P=0.0253; Figure). MRD-negativity (10‒5) rates in the ITT population favored D-RVd versus RVd (62.5% [65/104] vs 27.2% [28/103], P Conclusions: After 26.7 months of median follow-up, the addition of DARA to RVd induction and consolidation, followed by D-R maintenance in patients with transplant-eligible NDMM continued to demonstrate deep and improved responses, including higher sCR and MRD negativity rates, compared with lenalidomide alone. Maintenance therapy increased sCR and MRD negativity rates, compared to post-consolidation rates. No new safety concerns were observed with longer follow-up. Support: Alliance Foundation Trials; https://acknowledgments.alliancefound.org; Janssen Oncology Disclosures Kaufman: Tecnopharma: Consultancy, Honoraria; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria; Sanofi/Genyzme: Consultancy, Honoraria; AbbVie: Consultancy; Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. Sborov:University of Utah: Current Employment; Celgene, Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees. Reeves:Incyte: Honoraria; Takeda: Honoraria; Bristol Myers Squibb: Speakers Bureau. Rodriguez:BMS, Takeda, Amgen: Consultancy, Speakers Bureau. Chari:Janssen, Celgene, Novartis, Amgen, Bristol-Myers Squibb, Karyopharm, Sanofi, Genzyme, Seattle Genetics, Oncopeptides, Millennium/Takeda, Antengene, Glaxo Smith Kline, Secura Bio: Consultancy; Janssen, Celgene, Novartis, Amgen, Pharmacyclics, Seattle Genetics, Millennium/Takeda: Research Funding. Silbermann:Karyopharm: Consultancy; Janssen: Consultancy; Sanofi-Aventis: Consultancy, Research Funding. Costa:AbbVie: Consultancy; Sanofi: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Genentech: Consultancy; BMS: Consultancy, Honoraria. Anderson:Amgen: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding. Shah:GSK, Amgen, Indapta Therapeutics, Sanofi, BMS, CareDx, Kite, Karyopharm: Consultancy; BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar: Research Funding. Efebera:Pharmacyclics: Research Funding; Ohio State University: Current Employment; Celgene: Research Funding; Takeda: Honoraria, Speakers Bureau. Holstein:Sorrento: Consultancy; Adaptive Biotechnologies: Consultancy; Takeda: Consultancy; GSK: Consultancy; Celgene: Consultancy; Genentech: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy, Research Funding. Costello:Takeda, Celgene: Consultancy, Honoraria. Jakubowiak:Adaptive, Juno: Consultancy, Honoraria; AbbVie, Amgen, BMS/Celgene, GSK, Janssen, Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Wildes:Seattle Genetics: Consultancy; Carevive Systems: Consultancy; Janssen: Research Funding. Orlowski:Founder of Asylia Therapeutics, Inc., with associated patents and an equity interest, though this technology does not bear on the current submission.: Current equity holder in private company, Patents & Royalties; STATinMED Research: Consultancy; Sanofi-Aventis, Servier, Takeda Pharmaceuticals North America, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen, Inc., AstraZeneca, BMS, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Regeneron Pharmaceuticals, Inc.,: Honoraria, Membership on an entity's Board of Directors or advisory committees; Laboratory research funding from BioTheryX, and clinical research funding from CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding. Shain:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; AbbVie: Research Funding; GlaxoSmithKline: Speakers Bureau; Adaptive: Consultancy, Honoraria; Sanofi/Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Karyopharm: Research Funding, Speakers Bureau; Amgen: Speakers Bureau. Cowan:Nektar: Research Funding; Janssen: Consultancy, Research Funding; Abbvie: Research Funding; Bristol-Myer Squibb: Research Funding; Celgene: Consultancy, Research Funding; Cellectar: Consultancy; Sanofi-Aventis: Consultancy. Lutska:Janssen: Current Employment. Bobba:Janssen: Current Employment. Pei:Janssen: Current Employment, Current equity holder in publicly-traded company. Ukropec:Janssen: Current Employment, Current equity holder in publicly-traded company. Vermeulen:Janssen: Current Employment, Current equity holder in publicly-traded company. Lin:Janssen Scientific Affairs: Current Employment, Current equity holder in publicly-traded company. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. Voorhees:TeneoBio: Other: Advisory Board; Oncopeptides: Consultancy, Honoraria; Novartis: Consultancy; Janssen: Other: Advisory Board; GSK: Honoraria; BMS: Other: Advisory Board; Adaptive Biotechnologies: Other: Advisory Board. OffLabel Disclosure: The specific regimen combination is not yet approved, but individual components are.

Introduction: Patients with heavily pretreated RRMM have a poor prognosis (median overall survival [OS]: 6-9 months) and a need for novel, well-tolerated treatments that induce lasting responses (Gandhi Leukemia 2019; Chari NEJM 2019). Belamaf (GSK2857916) is a first-in-class, B-cell maturation antigen-targeting, antibody-drug conjugate (ADC) containing monomethyl auristatin F (MMAF). In DREAMM-2 (NCT03525678), patients with heavily pretreated RRMM who responded to single-agent belamaf maintained deep and durable responses at 13-month follow-up (median OS: >13 months) with a manageable safety profile (Lonial ASCO 2020, Poster 436). Consistent with other MMAF-containing ADCs, ocular events were common (Farooq et al. Ophthal Ther 2020). These events included keratopathy (microcyst-like epithelial changes [MECs]: an eye exam finding with/without symptoms), best-corrected visual acuity (BCVA) changes, and symptoms (blurred vision and dry eye). Longer-term recovery data will help inform management strategies. Methods: In DREAMM-2, eye exams were conducted at baseline and prior to each dose in patients received single-agent belamaf (2.5 or 3.4 mg/kg Q3W) and included a corneal exam and assessment of BCVA change from baseline (Snellen visual acuity [VA]). Dose modifications (delays/reductions) were permitted to manage these events. The corneal events were graded per the Keratopathy and Visual Acuity (KVA) scale, which combined corneal exam findings and BCVA changes from baseline. Dose modifications were determined based on the most severe KVA scale grade. These events were followed until recovery, defined as any Grade 1 exam findings/no exam findings, and ≤1-line decline in Snellen VA compared with baseline. A change to a BCVA 20/50 or worse (ie, limiting driving ability) in the better-seeing eye (in patients with BCVA better than 20/50 at baseline) was considered one definition of clinically meaningful VA decrease. Recovery of these events was defined as BCVA improvement to better than 20/50 (better-seeing eye). We report ocular event outcomes for patients receiving belamaf 2.5 mg/kg (recommended dose for future clinical development) from a 13-month follow-up post-hoc analysis. Results: In patients receiving single-agent belamaf 2.5 mg/kg, 72% (68/95) experienced a treatment-related eye exam finding of keratopathy (MECs) (Farooq Ophthal Ther 2020).Fewer patients (56%; 53/95) had symptoms (eg, blurred vision or dry eye) and/or a ≥2-line BCVA decline (better-seeing eye). Treatment discontinuations due to ocular events were rare (3% [3/95] total; 1% [1/95] each due to keratopathy [MECs], blurred vision, and reduced BCVA (Farooq Ophthal Ther 2020). In patients with keratopathy (MEC) events Grade ≥2 per KVA, 48% (29/60) had >1 event. The first event recovered in 77% (46/60; Table; Farooq Ophthal Ther 2020). At last follow-up, 48% (29/60) had documented recovery of their most recent event (Farooq Ophthal Ther 2020). In patients with unrecovered events at last follow-up, 45% (14/31) are receiving treatment or in follow-up. The remaining 55% (17/31) are no longer in follow-up (9 died; 4 withdrew from study; 4 lost to follow-up). 84% (37/44) of patients with Grade 3/4 events were improving or had recovered events at last follow-up. Seventeen (18%) patients had a clinically meaningful BCVA decline, with no reports of complete permanent vision loss (Farooq Ophthal Ther 2020). Of these patients, 76% (13/17) had 1 event and 24% (4/17) had 2 events (no patients had >2 events). 82% (14/17) had recovery of their first event and 82% (14/17) had recovery at last follow-up (Farooq Ophthal Ther 2020). Of the remaining 3 patients with unrecovered events, 1 patient is receiving treatment and 2 patients are no longer in follow-up (1 died due to disease progression; 1 withdrew from study). Conclusions: Though keratopathy (MECs) were frequently observed on eye exam, the majority of patients did not experience a clinically meaningful BCVA decline, and events rarely led to treatment discontinuation. The first keratopathy (MEC) event or clinically meaningful BCVA decline recovered in the majority of patients with events. In this ongoing study, patients are being followed for recovery. Based on experience, it is anticipated these events will likely recover over time. Funding: GSK (205678); drug linker technology licensed from Seattle Genetics; mAb produced using POTELLIGENT Technology licensed from BioWa. Disclosures Lonial: Karyopharm: Consultancy; Sanofi: Consultancy; Amgen: Consultancy, Honoraria, Other: Personal fees; Onyx: Honoraria; Takeda: Consultancy, Other: Personal fees, Research Funding; Novartis: Consultancy, Honoraria, Other: Personal fees; Janssen: Consultancy, Honoraria, Other: Personal fees, Research Funding; BMS: Consultancy, Honoraria, Other: Personal fees, Research Funding; GSK: Consultancy, Honoraria, Other: Personal fees; Abbvie: Consultancy; Merck: Consultancy, Honoraria, Other: Personal fees; JUNO Therapeutics: Consultancy; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria; Genentech: Consultancy. Nooka:Spectrum Pharmaceuticals: Consultancy; Oncopeptides: Consultancy, Honoraria; Adaptive Technologies: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria, Other: Personal Fees: Travel/accomodations/expenses, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Karyopharm Therapeutics, Adaptive technologies: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding. Thulasi:Emory University: Current Employment. Badros:University of Maryland: Current Employment; Amgen: Consultancy. Jeng:Kedrion, Merck, GSK: Consultancy; University of Maryland: Current Employment; EyeGate: Current equity holder in publicly-traded company. Callander:University of Wisconsin: Current Employment; Cellectar: Research Funding. Sborov:University of Utah: Current Employment; Celgene, Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees. Zaugg:University of Utah: Current Employment. Popat:Celgene: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: Travel support, Research Funding; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); GSK: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); AbbVie: Consultancy, Honoraria. Degli Esposti:GlaxoSmithKline: Consultancy, Honoraria; Moorfields Eye Hospital: Current Employment. Byrne:Adaptimmune, Novartis: Current equity holder in publicly-traded company; GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Opalinska:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Baron:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Piontek:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Gupta:Novartis: Current equity holder in publicly-traded company; GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Dana:Kala: Consultancy; Alcon: Consultancy; GSK: Consultancy; Aramis Biosciences, Claris Biotherapeutics, GelMEDIX: Current equity holder in private company; Novartis: Consultancy; Dompe: Consultancy; Massachusetts Eye and Ear; Harvard Medical School Department of Ophthalmology: Current Employment; NIH, DOD, Allegan: Current equity holder in publicly-traded company. Farooq:GlaxoSmithKline: Consultancy; University of Chicago: Current Employment. Jakubowiak:Adaptive, Juno: Consultancy, Honoraria; AbbVie, Amgen, BMS/Celgene, GSK, Janssen, Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Introduction: DARA, a human IgGκ monoclonal antibody targeting CD38, is approved as monotherapy and in combination with standard-of-care (SoC) regimens for multiple myeloma (MM). In randomized studies, DARA-based regimens significantly improved response rates, depth of response including minimal residual disease (MRD) negativity, and progression-free survival (PFS) in NDMM and relapsed/refractory MM pts. RVd followed by high-dose therapy (HDT), autologous stem cell transplant (ASCT), and consolidation is a SoC regimen for US pts with NDMM. This phase 2, randomized study (GRIFFIN; NCT02874742) evaluated DARA plus RVd (D-RVd) in ASCT-eligible NDMM pts. A 16-pt safety run-in showed no safety concerns. Here, we present results that adding DARA to RVd improves responses rapidly, including depth of response, which increases with longer duration of therapy. Methods: Pts were randomized 1:1 to RVd ± DARA, stratified by ISS stage and creatinine clearance. Pts received 4 induction cycles, HDT, ASCT, 2 consolidation cycles, and maintenance with R ± DARA for 24 mo. During induction and consolidation (Cycles 1-6), pts received R 25 mg PO on Days 1-14; V 1.3 mg/m2 SC on Days 1, 4, 8, and 11; and d 40 mg QW every 21 days. DARA 16 mg/kg IV was given on Days 1, 8, and 15 of Cycles 1-4 and Day 1 of Cycles 5-6. During maintenance (Cycles 7-32), pts received R 10 mg (15 mg in Cycles 10+ if tolerated) on Days 1-21 every 28 days ± DARA 16 mg/kg IV Q8W (or Q4W per pt decision after Amendment 2). The primary endpoint was the stringent complete response (sCR) rate by the end of consolidation per IMWG computer algorithm. The study had 80% power to detect a 15% improvement with a 1-sided alpha of 0.1 (equivalent to 2-sided alpha of 0.2). MRD (10-5 per IMWG criteria) was assessed by next-generation sequencing (clonoSEQ; Adaptive Biotechnologies). Results: A total of 207 pts (D-RVd n = 104; RVd n =103) were randomized. Baseline demographics and disease characteristics were well balanced between arms. Median age was 60 yrs; 48%, 37%, and 14% of pts were ISS stage I, II, or III, respectively; 30 (15%) pts had high cytogenetic risk defined by FISH for del(17p), t(4;14), or t(14;16). The study met its primary endpoint; D-RVd improved the sCR rate by the end of consolidation (42.4% vs 32.0%; odds ratio 1.57; 95% CI, 0.87-2.82; 2-sided P = 0.1359); at the pre-set 2-sided alpha of 0.2. This improvement was observed in all pt subgroups except for the small subsets of ISS stage III or high-cytogenetic risk pts. Responses deepened over time (Figure); the sCR rate was 12% vs 7% with D-RVd vs RVd at the end of induction, increasing to 21% vs 14% after ASCT, and 50% vs 37% at the clinical cutoff (CCO; 13.5 mo median follow-up). D-RVd achieved higher overall response (99% vs 92%), ≥VGPR (91% vs 73%), and ≥CR (52% vs 42%) rates vs RVd by the end of consolidation. At the end of induction, 8/19 (42%) pts achieving ≥CR with D-RVd were MRD negative, compared to 1/13 (8%) pts achieving ≥CR with RVd. At the end of consolidation, 30/51 (59%) pts achieving ≥CR with D-RVd were MRD negative vs 10/41 (24%) pts achieving ≥CR with RVd. Due to the short median follow-up at CCO, PFS and OS were immature, with 6 PFS events in each arm. Median stem cell yield was 8.1 vs 9.4 × 106 cells/kg for D-RVd vs RVd. Median (range) time to platelet engraftment was 13 (2-31) and 12 (1-23) days for D-RVd vs RVd; median (range) time to neutrophil engraftment was 12 (3-31) and 12 (2-23) days for D-RVd vs RVd. Grade 3/4 TEAEs (≥10%) with D-RVd vs RVd included neutropenia (32% vs 15%), lymphopenia (23% vs 23%), thrombocytopenia (16% vs 8%), and leukopenia (15% vs 7%). There was no difference in the rate of grade 3/4 infections between arms. IRRs occurred in 41% of DARA-treated pts, which were primarily grade 1-2. Updated data will be presented. Conclusions: These data demonstrate that adding DARA to RVd significantly improves response rates and depth of response, including sCR and MRD negativity. As seen in other randomized studies, continued use of daratumumab improved depth of response. The overall safety profile of D-RVd is consistent with previous reports with DARA plus SoC. Likewise, similar to what was reported from CASSIOPEIA, stem cell mobilization and ASCT are feasible with D-RVd, without a significant effect on hematopoietic reconstitution. The study is ongoing, with pts continuing maintenance therapy. Disclosures Voorhees: BMS: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; GSK: Research Funding; Novartis: Consultancy; Oncopeptides: Consultancy; Takeda: Honoraria, Research Funding; TeneBio: Honoraria, Research Funding; Adaptive Biotechnologies: Honoraria. Kaufman:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Winship Cancer Institute of Emory University: Employment; Takeda: Consultancy; Janssen: Honoraria; Bristol-Myers Squibb: Consultancy; Incyte: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy; AbbVie: Consultancy; Amgen: Consultancy. Sborov:Celgene: Honoraria; Janssen: Consultancy. Reeves:Celgene: Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria. Rodriguez:Takeda, Amgen: Consultancy, Speakers Bureau. Chari:Janssen, Celgene, Novartis Pharmaceuticals, Amgen, Bristol Myers Squibb, Pharmacyclics, Karyopharm, Sanofi, Seattle Genetics, OncoPeptides, Millenium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Silbermann:Janssen, Sanofi: Other: Consultant/Advisor. Costa:Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy; Karyopharm: Consultancy; Fujimoto Pharmaceutical Corporation Japan: Other: Advisor. Anderson:Amgen, Janssen, Takeda, Celgene: Consultancy, Speakers Bureau. Shah: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; Celgene, Janssen, Bluebird Bio, Sutro Biopharma: Research Funding; Poseida: Research Funding; Indapta Therapeutics: Equity Ownership; University of California, San Francisco: Employment; 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. Efebera:Takeda: Honoraria; Akcea: Other: Advisory board, Speakers Bureau; Janssen: Speakers Bureau. Costello:Takeda: Honoraria, Research Funding; Janssen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Jakubowiak:Takeda: 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; GSK: Consultancy, Honoraria, 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; KaryoPharm Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Juno: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SkyLineDx: 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; Millennium: 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; Adaptive Biotechnologies: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Wildes:Carevive: Consultancy; Janssen: Research Funding. Orlowski:BioTheryX, Spectrum Pharma: Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; 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; Kita Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ionis Pharmaceuticals; Legend Biotech; Molecular Partners; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Sanofi-Aventis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Shain:Celgene: 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; Adaptive Biotechnologies: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Cowan:Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Abbvie: Research Funding; Juno: Research Funding; Sanofi: Consultancy; Cellectar: Consultancy. Murphy:Janssen: Employment, Equity Ownership. Lutska:Janssen: Employment. Pei:Janssen: Employment, Equity Ownership. Ukropec:Janssen: Employment, Equity Ownership. Vermeulen:Janssen R&D, LLC: Employment, Equity Ownership. de Boer:Janssen: Employment, Equity Ownership. Hoehn:Janssen: Employment, Equity Ownership. Lin:Janssen: Employment, Equity Ownership. Richardson:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: 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; Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding. OffLabel Disclosure: D-RVd is being investigated in transplant-eligible NDMM

INTRODUCTION: Pelareorep is the infusible form of human reovirus (RV). Our single-agent phase 1 RV trial in relapsed multiple myeloma (MM) showed that pelareorep treatment selectively infected MM cells, as viral RNA was found in myeloma cells and not the bone marrow (BM) stroma. However, we did not observe apoptosis. Our ongoing phase 1 trial, which combines the proteasome inhibitor carfilzomib with RV, has demonstrated RV infection, apoptosis, and clinical responses. We investigated the molecular mechanisms behind the role of a PI (carfilzomib) in this setting. RESULTS: In all MM cell lines we tested (n=4), independently from their sensitivity to RV infection (Stiff et al., Mol Cancer Ther, 2016), viral replication and apoptosis was impaired when MM cells were directly exposed to PIs (carfilzomib and bortezomib). When this experiment was repeated in the setting of the bone marrow cellular fraction or peripheral blood mononuclear cells (PBMCs), it had the opposite effect, as the addition of PI to RV increased RV replication and apoptosis in MM cells. When we washed PBMCs after overnight exposure to RV+PI or to either single agent, then added MM cells, we observed higher infection and apoptosis in cancer cells co-cultured with RV+PI compared to levels from PBMCs treated with each of the single agents, suggesting that PIs increase the ability of PBMCs to serve as a reservoir for infectious reovirus. Monocytes (CD14+) can engage in phagocytosis of reovirus (Berkeley et al., Cancer Immunol Res, 2018), and accordingly we found that RV genome and capsid protein production were detected in CD14+ cells, but not in CD14-depleted PBMCs, and increased upon PI treatment compared to that in RV-treated CD14+ cells. Given that the NF-κB complex is a key proinflammatory signaling pathway associated with the early innate-antiviral immune response, and because PIs can block the degradation of the NF-κB inhibitor IκBα upon phosphorylation, we investigated the effect of the specific IκBα inhibitor Bay-11 in RV viral replication. Our data show that either PI or Bay-11 can inhibit RV-induced IκBα phosphorylation and its subsequent degradation upon RV infection in CD14+ cells, an effect associated with higher capsid formation in RV-treated CD14+ cells in combination with PI or Bay-11, compared to levels from RV alone. Cytokine profiling in PBMCs and CD14+ cells treated with RV in combination with either PI or Bay-11 showed a significant decrease in IFN-α and IFN-β (IFNs) levels and a concomitant increase in RV replication, in contrast to levels from RV alone (p We then decided to investigate whether CD14 depletion could affect RV delivery to the cancer cells invivo. Upon intra-femoral injection of 5TGM1 MM cells into syngeneic C57BL/KaLwRij mice, the mice in which the monocytes were depleted by clodronate-liposome treatment before intravenous RV injection showed lower capsid protein formation in the BM MM cells compared to that in mice where the monocytic population was intact. Because monocytes respond to infection by dividing into macrophages to eliminate pathogens, we wanted to investigate whether PI could impair this effect. Intriguingly, although higher levels of viral genome were detected in PI+RV-treated CD14+ cells compared to RV-treated cells (p CONCLUSIONS: Here we report for the first time that PIs enhance pelareorep entry, infection, and killing of myeloma cells through its effect on the CD14+ fraction. Reovirus infection and replication within CD14+ cells are augmented by PI-induced NF-κB inhibition of the early innate pro-inflammatory immune response. We also report for the first time that carfilzomib induces direct T cell activation and potentiates T cell killing activity against RV-infected MM cells. Disclosures Krishnan: Takeda: Research Funding; Celgene, Z Predicta: Other: Stock Ownership; Amgen, Takeda: Speakers Bureau; Sutro BioPharma, zPredicta: Consultancy; Celgene, Janssen, Sanofi, BMS: Consultancy. Sborov:Celgene: Honoraria; Janssen: Consultancy. Hofmeister:Nektar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Imbrium: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees.

Rationale: Immune checkpoint inhibitors, including those targeting programmed cell death protein 1 (PD-1), are tempting in immunosuppressive cancers such as multiple myeloma (MM). PD-1 inhibition alone has not been effective (Lesokhin, JCO, 2016). Evidence suggests that tumor response is determined by tumor PD-L1 expression and presence of infiltrating cytotoxic T-cell lymphocytes (CTLs). Intravenous Pelareorep (Reolysin), the infusible form of reovirus (RV), has been shown to upregulate IFN-regulated gene expression, CTL infiltration, and the PD1/PD-L1 axis in myeloma cell lines (Kelly KR et al, Leukemia, 2018) and in patients with brain tumors (Samson A et al, Sci Trans Med, 2018). Introduction:Viral oncolytic therapy with Pelareorep is supported by preclinical data indicating that its antitumor activity results from direct cytolysis and immune responses against infected MM cells. Our phase 1 single agent Reolysin trial in patients with relapsed MM confirmed the tolerability of Pelareorep and demonstrated preferential infection into myeloma cells but not microenvironmental cells in the marrow by intracellular staining for RV genome. In PART ONE of our follow-up trial, Carfilzomib (Kyprolis)-sensitive patients were accrued. Correlative studies included bone marrow aspirate pretreatment on cycle 1 day 1 and day 9 to assess RV infection of myeloma cells, replication within myeloma cells, and PD-L1 expression on myeloma cell surface. Pelareorep, Carfilzomib, and 20 mg IV Dexamethasone were all infused per the standard Carfilzomib schedule on days 1, 2, 8, 9, 15 and 16 of a 28-day cycle. Part ONE: Carfilzomib-sensitive patients were infused at dose level one with Pelareorep 3 x 1010TCID50/day and Carfilzomib 20 mg/m2 on days 1 and 2 of cycle 1 and 27 mg/m2 thereafter, on days 1, 2, 8, 9, 15 and 16 of a 28-day cycle. The MTD will be determined as the highest dose combination with fewer than 33% DLTs observed in cycle 1. There were 2 VGPRs, 2 PRs, 1 MR, and one patient with stable disease after cycle 1. All evaluable patients showed RV infection and replication in the post-treatment BM aspirates. In the 4 bortezomib-refractory patients in the first cohort, all have shown viral replication, and this correlated directly with activated caspase-3 in the MM cells and clinical response. Part TWO: Carfilzomib-refractory patients were treated with Carfilzomib 20 mg/m2 on days 1 and 2 of cycle 1, and 56 mg/m2 thereafter. Seven patients have been enrolled to date. In 3 patients processed to date with both pre- and post-treatment biopsies available, RV infection was detected in myeloma cells (2 patients) and endothelial cells (one patient). Replication was not seen. In these patients there was no strong evidence of increased activated caspase-3 expression in myeloma cells, nor was there a statistically significant increased CD8 cell infiltration or checkpoint protein expression after treatment. Conclusion: An increase in viral infection, viral replication, and PD-L1 expression on the surface of myeloma cells has been demonstrated in patients that had a clinical response to protocol therapy. A future study to assess the safety and tolerability of PD-1 inhibition in relapsed myeloma patients is now open to accrual (NCT03605719). Dose escalation is ongoing and the effects of the addition of Reolysin to Carfilzomib/Dexamethasone will be determined in this trial. Disclosures Hofmeister: Bristol-Myers Squibb: Research Funding; Adaptive biotechnologies: 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; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Nuovo:Oncolytics Biotech Inc: Research Funding. Lonial:Amgen: Research Funding. Kaufman:Roche: Consultancy; Abbvie: Consultancy; Karyopharm: Other: data monitoring committee; Janssen: Consultancy; BMS: Consultancy. Nooka:GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive technologies: Consultancy, Membership on an entity's Board of Directors or advisory committees; Spectrum Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Heffner:Pharmacyclics: Research Funding; ADC Therapeutics: Research Funding; Genentech: Research Funding; Kite Pharma: Research Funding.

Introduction: Post autologous transplant maintenance therapy with lenalidomide for patients with multiple myeloma (MM) is standard of care (McCarthy et al, NEJM, 2012). Vorinostat (SAHA, Zolinza) is a HDAC inhibitor and preclinical data suggested that HDAC-I's increase MHC class I and class II expression, rendering tumor cells more susceptible to host innate immune killing. Lenalidomide activates NK cells via PP2A inhibition and induces CD56 expression in CD16+CD56- cells thereby enhancing NK cell-mediated ADCC. Initiating lenalidomide to enhance NK cell activity against tumor cells in the early post autologous transplant period may be particularly effective when the NK:myeloma cell ratios favor NK killing, especially if administered after increased MHC class I expression induced by HDAC-I pretreatment. We hypothesized that the combination of vorinostat and lenalidomide would be both tolerable and effective in the post-transplant setting. We have published the initial report of this combination (Sborov, BJH, 2015). We now present the long term follow up. Methods: This was a non-randomized, open-label phase I trial for patients with myeloma who have received high dose IV melphalan followed by autologous peripheral blood stem cell transplant (ASCT) following the three-and-three up-and-down phase I design. Vorinostat was administered beginning at 200 mg starting day +90 after HSCT for days 1-7 and 15-21 of a 28-day cycle combined with lenalidomide 10 mg days 1-21 of a 28-day cycle until progression or clinically significant toxicity. The initial dose of lenalidomide could be increased from 10 mg after cycle 1 and escalated as tolerated up to 25 mg. Results: Sixteen patients were enrolled after autologous transplant with a median age 58 y.o. (range 41-67), with a median number of prior therapies at enrollment of 2 (range 1-8) and mean ISS stage 1.5 (range 1-3). Twelve patients had trisomies on CD138-selected FISH, one patient had normal cytogenetics, and three patients had high risk features [complicated karyotype, t(4;14), or abnormal chromosome 1]. All patients started with 10 mg of lenalidomide and 14 patients received more than one cycle of therapy. 11/14 (78%) were able to escalate the lenalidomide dose. 4/11 (36%) were able to escalate to 25 mg of lenalidomide. The tolerability, toxicities and adverse events have been previously reported (Sborov, BJH, 2015). With a median follow up of 84 months (range 17 - 88), 9 patients (56%) have progressed and 5(31%) have died due to disease progression. Seven patients (44%) remain in complete remission with 5 currently on continued maintenance more than 72 months from ASCT. The median progression-free survival (PFS) is 46.5 months (range 2 - 88) and the median overall survival (OS) has not been reached (17 to NR) (Figure 1). Conclusions: The combination of lenalidomide and vorinostat is well tolerated, with prolonged PFS and OS. Details on the current seven patients still in remission and on continued maintenance will be presented at the meeting. Disclosures Hofmeister: Adaptive biotechnologies: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: 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; Bristol-Myers Squibb: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees.

Introduction: For fit multiple myeloma (MM) patients, autologous hematopoietic stem cell transplant (HSCT) is standard of care as part of first line therapy, demonstrating longer progression-free survival when compared to upfront bortezomib, lenalidomide, and dexamethasone (IFM/DFCI 2009, ASH 2015). The use of granulocyte colony stimulating factor (G-CSF) after HSCT accelerates time to neutrophil recovery by 1 - 6 days when compared with control (Klumpp TR et al, JCO, 1995 & Schmitz N et al, BMT 2004). The American Society of Clinical Oncology guidelines recommend that G-CSF should be initiated 1-5 days after administration of high-dose chemotherapy and should be continued until the absolute neutrophil count (ANC) is 2000-3000/mm3 (Smith TJ, JCO, 2015). We have evaluated the role of G-CSF starting day +1, day +5, and day +7 post-transplant in three sequential cohorts of MM patients focusing on the duration of severe neutropenia (rather than the time to neutrophil engraftment), infections, and mucositis. Methods: As part of changes in the standard of care institutional protocols for autologous HSCT of myeloma patients at Ohio State University, three sequential cohorts of myeloma patients were identified that received G-CSF daily post-transplant until ANC>1500/mm3 or WBC>5/mm3. Two hundred twenty-six (226) patients received G-CSF on day +1 (n=43), day +5 (n=78), and day +7 (n=105) from May 2012 to August 2015. The majority of the patients received levofloxacin, acyclovir and fluconazole as prophylaxis. We evaluated the duration of severe neutropenia (ANC Results:The cohort of patients receiving G-CSF on day +5 had a shorter median follow up (455 days versus 979 days in the day +1 and 1355 days in the day +7 cohorts), since the patients were enrolled at a later timepoint. No statistically significant difference was noted in terms of age, gender, cytogenetic or ISS stage distribution, number of infused cells per kg, and melphalan dose among the three cohorts of patients. The duration of severe neutropenia was significantly increased for patients receiving G-CSF on day +7 (mean 153.4 hrs, SD 36.9) compared to those receiving G-CSF on day +1 (mean: 104.8 hrs, SD 19.4; p-value of 5 x 106 cells). Patients who received G-CSF on day +1 or day +5 had a significantly decreased incidence of grade 2 or higher mucositis (4.65% vs 10.3%) for day +1 and day +5 versus 21.9% for day +7 (fisher-test, p = 0.014 and 0.0255). Similarly, the incidence of bacteremia was decreased in those patients treated with G-CSF on days +1 and +5 versus day +7 (21.8%, 23.2%, and 33.3% for those treated on days +1, +5, and +7, respectively; p = 0.09). The group of patients who received G-CSF on day +5 had a longer length of stay, with two patients with prolonged hospitalization (mean 17.7 days, SD 5.6 days, range 12-49) when compared to the other groups (day +1 group mean 13.88 days, SD 2.8 days, range 10-21 versus day +7 group mean 15.2 days, SD 2.7 days, range 11-21 days; Two-tailed t-test p = 0.012). Lastly, our data indicates a trend, though not statistically significant, toward a longer time to biochemical progression in patients who received G-CSF on day +1 when compared to the other two groups. Conclusion: We conclude that starting G-CSF injections the day after stem cell infusion (day +1) decreases the duration of severe neutropenia, infections, and mucositis in comparison to day +5 and day +7 in patients receiving autologous transplant for MM. A prospective trial would definitively test this, but a multi-institution meta-analysis via CIBMTR would be more cost-effective, acknowledging that differing anti-infective prophylaxis regimens would prevent effective between institution comparisons of infection. Disclosures No relevant conflicts of interest to declare.

Introduction: Hypogonadism, i.e. low total testosterone, is present in approximately a quarter of men older than 70 years (Harman SM et al, J. Clin Endo & Met, 2001, PMID 11158037 and Wu FCW et al, J Clin Endo & M et, 2008, PMID 18270261). Myeloma patients are known to suffer from fatigue and decreased functional performance, mood disturbances, and anemia; similar trends have been found in people with hypogonadism. Cytogenetically high risk myeloma characterized by the amplification of 1q21 is associated with increased serum levels of soluble IL-6 receptor (sIL-6r) (Stephens OW, Blood, 2012, PMID 22072558). We hypothesized that total testosterone levels will be associated with overall survival from the time of diagnosis, presence of 1q21 amplification by CD138-selected FISH, anemia, and anti-depressant use. Methods: The Buckeye Myeloma Registry (OSU 10115) opened in 2011 to enroll any patient with a plasma cell dyscrasia. Serum total testosterone was measured at the time of the initial clinic visit to the myeloma group at Ohio State. Less than 325 ng/dL was defined as the hypogonadal range, and testosterone was divided into 60 ng/dL (group 3). A retrospective chart review was initiated to review all myeloma patients with a serum testosterone drawn at the time of their initial clinic visit to OSU. Results: Among 418 male MM patients, median age was 65 y.o. (range 24-95), 86% were Caucasian and 14% African-American, and the distribution of ISS stage was 32% stage 1, 22% stage 2, and 19% stage 3 with 28% missing staging data. Cytogenetic data was missing from 28% of patients. Out of 418 male MM patients, 29 (7%) had serum testosterone 325 ng/dL. Out of 172 female MM patients, 44 (26%) had an undetectable serum testosterone, 120 (70%) with testosterone 10-60, and 8 (5%) with testosterone > 60. Among male MM patients, log-rank [Mantel-Cox] analysis of overall survival with serum testosterone including all 4 groups demonstrated no significant differences (p=0.917) with only 80 events. Among 275 male MM patients with cytogenetic information available, there was no correlation between presence of 1q21 trisomies or tetrasomies and overall survival (r=0.0714, p=0.238). There was a strong and expected correlation between testosterone and BMI (r=0.14, p=0.00468). Among 161 total female MM patients, log-rank analysis with serum testosterone including all 3 groups also demonstrated no differences (p=0.416) with only 29 events in total. Among 101 females with cytogenetic information, there was also no correlation with 1q21 amplification (r=0.0895, p=0.373). Conclusion: The majority of male MM patients (74%) have secondary hypogonadism and approximately half have total testosterone levels Disclosures No relevant conflicts of interest to declare.

Introduction: Since a link between solar radiation, vitamin D production, and decreased colon cancer mortality was established in 1980, there has been increasing interest in vitamin D and cancer, suggesting that higher vitamin D levels improve overall survival, specifically in breast and colorectal cancer (Maalmi H et al, Eur J Canc, May-2014, PMID 24582912), but also in follicular lymphoma (Kelly JL, J Clin Onc, 1-May-2015, PMID 25823738). In myeloma, largest published series is from the Mayo Clinic reporting on 148 newly diagnosed MM patients for which no survival association was found, but there were associations between low 25-OH-Vit D ( Methods: The Buckeye Myeloma Registry (OSU 10115) opened in 2011 to enroll any patient with a plasma cell dyscrasia. Serum total 25-OH-Vitamin D was measured at the time of the initial clinic visit to the myeloma group at Ohio State. Results: Of a total of 843 patients, 115 (13.6%), 53 (6.3%) with SMM, and 675 (80.1%) with MM. In the 675 MM patients, the median age was 64 y.o. (range 28-95), 14.5% African-American and the remainder Caucasian, with 28.6% ISS stage 1, 48.7% ISS stage 2, 21.9% ISS stage 3, and 24.5% unknown. At diagnosis for the MM patients, 67% presented with lytic bone disease. Out of 675 MM patients, there were 52 (7.7%) patients with < 10 ng/mL 25-OH-Vit D, 394 (51%) with low vit D (10-30 ng/mL), and 229 (39%) for 25-OH-Vit D 30-100 ng/mL. There was no correlation between 25-OH-Vit D and BMI or creatinine, but there was a strong correlation with race (r=0.18, p Among the MM patients, log-rank [Mantel-Cox] analysis of overall survival with serum 25-OH-Vit D including all groups demonstrated no significant differences (p=0.9725) with only 101 events. There was no correlation between 25-OH-Vit D and the presence on CD138-selected FISH of 1q21 amplification (p=0.196), 17p (p53) deletion (p=0.68), or 13q deletion (p=0.812). Conclusion: The majority of myeloma patients are vitamin D deficient, but this was not associated with worsened overall survival or with high risk cytogenetics. Cox proportional hazards analyses of survival adjusted for significant univariate covariates will be presented at the meeting. Correlations with presence or absence of diffuse lytic bone disease, severity of renal insufficiency, and race will also be presented at the meeting. Disclosures No relevant conflicts of interest to declare.

Introduction. The viral oncolytic agent, Reolysin (RV), is a promising novel therapeutic that selectively proliferates in myeloma cells. Our group conducted a phase 1 clinical trial of single agent RV in patients with relapsed and refractory multiple myeloma (MM), and reported that treatment was well tolerated and associated with prolonged disease stability in 25% of patients. Objective responses were not evident, likely because the viral RNA present in the myeloma cells was not producing infectious viral particles. Proteasome inhibitors can lead to myeloma cell death due to increased endoplasmic reticulum (ER) stress and induction of ER-stress related apoptosis (Kelly, Oncogene, 2012). We confirmed this effect preclinically with Carfilzomib (CFZ), and hypothesized that the addition of CFZ to RV would increase viral proliferation and MM cell death sufficiently to obtain objective response in patients with relapsed MM. Methods. For this pilot trial, patients were required to have relapsed myeloma with IMWG-defined measurable disease, ANC ≥ 1,000/uL, platelet count ≥ 50,000/uL, with no creatinine requirements. Cohorts of 6 patients each were planned. Cohort 1 included patients who were CFZ na•ve or had not progressed on a CFZ containing regimen. Intravenous CFZ (20 mg/m2 days 1 and 2 of cycle 1 and 27 mg/m2 thereafter), Reolysin (3 x 1010 TCID50/day), and dexamethasone (20 mg) were administered on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle (Table 1). In situ based methodologies were used to examine the distribution of CD138, CD8, NK cells (CD117 and IL-22), CD 68, PD L1, reoviral capsid protein, and reoviral RNA in bone marrow biopsies performed prior to treatment on days 1 and 9 of cycle 1. Results. Seven patients have been enrolled, four are male, and all are Caucasian. Patients have a median age of 64, and have received on average 2.4 prior lines of therapy and 4.4 prior treatments. All patients were previously exposed to Revlimid and Velcade, and 4 patients were Velcade refractory. One patient was previously treated with CFZ but was deemed to be CFZ sensitive, one patient has dialysis-dependent CKD, and all but one patient had evidence of high-risk cytogenetics on CD138-selected FISH at the time of enrollment. 6/7 patients suffered myalgias and fever after the first two doses of Reolysin, but these symptoms did not recur in any subsequent doses. Treatment has been well tolerated in 5 patients, but 2 patients were removed from study after 2 doses of combination therapy, one for congestive heart failure, and the other for gastrointestinal bleed in the setting of grade 4 thrombocytopenia and an arteriovenous malformation. Due to these 2 DLTs, patient 7 was enrolled at dose level -1 (Carfilzomib 20 mg/m2 and Reolysin 3 x 109 TCID50/day on days 1, 2, 8, 9, 15, and 16 of a 28 day cycle). Within the first 14 days following the initiation of treatment, the mean decrease in platelets for the 7 evaluable patients was 79 (50 - 139), and this included grade 4 (N = 1), and asymptomatic grade 2 (N = 3), and grade 1 (N = 3) events. All patients have had a reduction of the monoclonal protein, 5 patients remain on study, and the longest duration of response is currently 8 cycles. Responses are VGPR (N = 2), PR (N = 3), MR (N = 1), and SD (N = 1) (Figure 1). Intracellular viral replication will be reported at the meeting. Conclusion. This 3-drug regimen is relatively well tolerated in heavily treated patients with relapsed MM. Most patients experience low grade fever and myalgias after the first two doses, and patients have evidence of thrombocytopenia in cycle 1. Combination treatment is associated with reduction of the monoclonal protein in all patients, and 86% (6/7) CFZ-sensitive patients have evidence of objective response. Table 1. Combination treatment dose levels Dose level Dexamethasone (IVP) Carfilzomib (IVPB) Reolysin (IVPB) -1 20 mg/day 20 mg/m2 /day 3 x 109 TCID50/day 1 (starting dose) 20 mg/day C1 Day 1 & 2 - 20 mg/m2 /dayC1 Day 8 & onward - 27 mg/m2 /day 3 x 1010 TCID50/day Figure 1. Waterfall plot representing response of 7 patients with relapsed MM Figure 1. Waterfall plot representing response of 7 patients with relapsed MM Disclosures Off Label Use: Reolysin - oncolytic viral, anti-cancer agent.

A geriatric assessment (GA) is a global approach to improve healthy aging, wherein occult problems are assessed and intervened upon using a multidisciplinary method. A GA is feasible and can predict chemotherapy-induced toxicity and overall survival in cancer patients. Biomarkers of aging are also being explored as objective and reproducible measures of health and fitness. p16INK4a (p16) is a marker of cellular senescence that rises exponentially with chronologic age and is influenced by factors such as physical activity, smoking, and solid tumor chemotherapy. Here, we investigated the relationship of both the GA and molecular (i.e. p16) metrics in pre-bone marrow transplant (BMT) multiple myeloma (MM) patients. We selected this group for our studies as BMT patients are a vulnerable cohort in which transplant eligibility is subjective and age related. BMT patients are also at high risk for adverse events and treatment toxicity. In this preliminary analysis, we explored the predictive value of GA metrics and p16 with inpatient length of stay (LOS) during autologous BMT. Methods: We performed a pilot prospective cohort study on 55 MM patients during their pre-transplant evaluation. MM patients >18 years completed GA assessments related to physical function, distress, comorbidities, social support, and cognition. Patients completed surveys using the Brief Fatigue Inventory (BFI) (scale 1-10; moderate fatigue 4-6, severe fatigue 7+); Hospital Anxiety and Depression (HADS) (borderline case 8-10, definite case 11+); medical outcome study-social support survey (MOS-SSS) (scale 0-100, higher scores indicated greater support), Human Activity Profile (HAP) maximum activity score (MAS) and HAP-adjusted activity score (AAS), a 94-item questionnaire ranking tasks according to energy use validated in the BMT population, with higher scores indicating higher activity (Herzberg BBMT 2010). Objective measures of physical activity were measured using the Short Physical Performance Battery (SPPB) (range 0-12; impairment Results: The median patient age was 61 (range 42-76). Most patients exhibited early stage disease (ISS Stage 1 53%) with minimal comorbidities (HCT-CI median 1; range 0-8) and a median of 2 prior lines of treatment (range 1-11). Pre-transplant Karnofsky Performance Status (KPS) was reported as 70% (n=10), 80% (n=10), 90% (n=15) and 100% (n=12). 7 patients did not proceed with BMT, 1 inpatient for BMT. Patients reported moderate fatigue by BFI (median 4.3; range 0-9.8), with minimal anxiety or depression as measured by the HADS. Self-reported physical activity by HAP-MAS was 73 (range 30-94) and HAP-AAS was 64 (range 20-94). Patients reported high levels of social support (median 86.7%; range 18.2-100) by MOS-SSS. Objective measures of physical function were also high as measured by the SPPB (median 10; range 4-12) and no cognitive impairment was identified by the 3MS. p16 expression was adjusted for age and did not correlate with GA tools including BFI, HADS, HAP-AAS, HAP-MAS, MOS-SSS, SPPB or 3MS. The median length LOS during transplant was 16 days (range 12-36). Univariate analysis revealed that SPPB score was significantly associated with LOS, where each one unit increase in physical performance corresponded to an average LOS decrease of 0.63 days (p=0.04). Self-reported activity by HAP-AAS also correlated with LOS (p=0.05). LOS was not influenced by p16, age, KPS or HCT-CI. Age and HCT-CI had no relationship with SPPB scores, but KPS did (p=0.03727). Conclusions: A comprehensive GA can be used to identify factors that contribute to BMT outcomes. Physical function appears to be most predictive of hospital LOS as measured by SPPB or a detailed self-report of physical function. Baseline p16 levels had no relationship with GA metrics in this selected population. A standardized approach for determining patient fitness including SPPB and HAP-AAS assessments may improve treatment tolerance, reduce hospital LOS, and decrease the risk for adverse outcomes in BMT populations. Disclosures Jaglowski: Immunomedics: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Seattle Genetics: Consultancy.

Introduction: The first FDA-approved deacetylase inhibitor (HDACi), suberoylanilide hydroxamic acid (SAHA, Vorinostat), was shown to be effective in vitro by a number of anti-neoplastic mechanisms. Despite minimal single-agent activity in multiple myeloma (MM), phase 1b studies combining HDACi’s with bortezomib salvaged some relapsed patients and prolonged progression free survival (PFS) from days (Vorinostat) to months (Panobinostat), albeit at the cost of significant side effects including fatigue, nausea, and vomiting. Phase 1/2 studies in combination with lenalidomide have demonstrated tolerability and activity in lenalidomide-refractory patients, but randomized trials are lacking. In MM, the anti-neoplastic mechanism of action for HDACi’s is unknown, but at biologically achievable concentrations, it has been theorized that they sensitize MM cells to other drugs by interfering with cell adhesion mediated drug resistance (CAM-DR), primarily involving the integrins CD44, CD49d (VLA-4), CD54 (ICAM-1), and/or CD184 (CXCR4). AR-42 (ARNO Therapeutics) is a novel orally bioavailable phenylbutyrate-based class I/II HDAC inhibitor that has greater anti-proliferative effects compared to Vorinostat in vitro and in vivo. It has been previously shown that in MM cell lines, AR-42 down-regulates the expression of gp130, and inhibits IL-6 induced activation of STAT3 and downstream targets including BCL-XL and Cyclin-D1, with minimal effects on the PI3K/AKT and MAPK pathways. CD44 is a type I transmembrane glycoprotein, which is directly transcribed by β-catenin, and its role in cell adhesion-mediated drug resistance (CAM-DR) for MM as well as other cancers has been largely investigated. Recent published data have shown that CD44 forms a complex with STAT3 and p300 (acetyltransferase) causing STAT3 activation in a cytokine- and growth factor-independent manner, and that CD44 over-expression is one of the main molecular mechanisms that contributes to Lenalidomide resistance in MM cells. Hypothesis: We hypothesize that CD44 down-regulation, both surface expression on MM cells as well as the soluble form in the blood, is the primary effect of AR-42 at concentrations achievable in humans, explaining its weak single agent effect and its improvement when combined with other therapeutic agents in the clinic. Methods: As part of a single center, dose-escalating, first-in-man phase 1 trial of single agent oral AR-42 administered orally three times weekly in 28-day cycles (3 weeks of treatment followed by a 7-day off treatment period), patients were accrued at 20-70 mg TIW in a standard 3+3 cohort design. Using peripheral blood obtained during cycle 1 of therapy, nCounter® GX Human Immunology assays and nCounter miRNA expression profile was performed to assess differentially expressed genes after AR-42 treatment. Enzyme-linked immunoabsorbent assay (ELISA), qRT-PCR and luciferase assays were also performed.To examine whether AR-42 treatment could sensitize the cells to Lenalidomide in vivo, we used GFP+/Luc+ MM.1S cells engrafted in NOD-SCID mice. Results: AR-42 in relapsed MM showed no confirmed partial responses, but did result in marginal responses in 3 out of 13 MM patients. We found that AR-42 in MM cells modulates the expression of many genes coding for surface receptors including CD44, CD48, CD46 and TRAF5 and affects the expression of several miRNAs. Our data show a decrease of CD44 mRNA expression in the CD138+ MM plasma cells and of the soluble CD-44 in the serum of AR-42 treated patients. We also show that in MM cells CD44 down-regulation upon AR-42 treatment is associated with impairment of STAT-3 signaling pathways and direct targeting of its regulatory RNA binding protein, Insulin grow factor 3 binding protein 3 (IGF2BP3), by miR-9-5p. We found that miR-9-5p is up-regulated in vitro and in the cancer cells of MM patients after AR-42 treatment. Moreover we show that AR-42 in combination with Lenalidomide show synergistic apoptotic effect on MM cells, enhancing Lenalidomide anti-myeloma activity invivo. Conclusions: These findings show that CD44 is a therapeutic target for the HDACi AR-42 in MM patients, providing the rationale to support further clinical investigation of AR-42 in combination with IMiDs in patient cohorts with high pretreatment CD44 expression in the serum and on the surface of MM cells. Disclosures Hofmeister: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Honoraria, Research Funding; ARNO Therapeutics: Research Funding; Onyx: Membership on an entity's Board of Directors or advisory committees.

Introduction: Melphalan is an interstrand cross-link (ICL)-inducing agent and, in the setting of autologous stem cell transplantation for multiple myeloma, is one of the most effective treatments, providing 30 months of disease stability on average, but with a dramatic progression free survival (PFS) range of 6 months to 12 years. While 200 mg/m2 is the standard dose, there is extensive interpatient variability, and individual melphalan sensitivity with the ability to repair double-stand breaks in primary myeloma cells mirrored by a similar efficiency in peripheral blood mononuclear cells (PBMCs) (Gkotzamanidou M et al, Leukemia and BJC, 2013 and 2014). Our hypothesis is that our PK model will predict > 85% of interpatient variability, AUC achieved as well as measurements of DNA damage ex vivo will correlate with mucositis and duration of neutropenia, and we will be able to create an integrated model to personalize melphalan dosing to maximize myeloma cell killing while minimizing toxicities. Methods: We enrolled 146 patients on a prospective trial using a block randomization scheme based on fat-free mass, calculated creatinine clearance, and hemoglobin as known factors affecting melphalan disposition. Plasma was collected from all patients to assess melphalan pharmacokinetics, and PBMCs were collected to assess ex vivosensitivity to melphalan therapy, including p53 gene expression and WST-1-based cytotoxicity. DNA from PBMCs was collected to assess the presence of SLC7A5 polymorphisms associated with melphalan-induced enteritis (Giglia JL et al, BBMT, 2014). PK/PD modeling and identification of covariates contributing to observed variability in melphalan disposition and outcomes is being achieved using a nonlinear mixed effects approach Results: Melphalan has been quantified in samples from 119 patients, and this data was used in population modeling. Estimated PK parameters (CV%) for the model were ӨCL=0.445 L/min (33.6%), ӨV1=19.4 L (36.6%), ӨQ=0.392 L/min (34.5%) and ӨV2=17.4 L (36.9%). Creatinine clearance (normalized to 70 kg), hematocrit, fat free mass on CL, sex on V1, and body surface area on Q were chosen for the final covariate model. IC50value (CV%=31.2%), and the baseline of p53 mRNA level (47.3%) and viability (20.1%) in donor’s PBMCs were variable. Response of p53 mRNA expression and viability in donor’s PBMCs were dose-dependent. PD modeling, and covariate and SCLA5 polymorphism analyses are underway. Conclusions: This study represents the largest and most comprehensive for identifying variables associated with melphalan pharmacokinetics and pharmacologic activity. An integrated PK/PD model that incorporates PK/PD and other predictive factors form the basis of a prospective randomized clinical trial to validate that the model reduces toxicities while prolonging PFS. Disclosures Hofmeister: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Honoraria, Research Funding; ARNO therapeutics: Research Funding; Onyx: Membership on an entity's Board of Directors or advisory committees.

Introduction Multiple myeloma (MM) is a currently incurable malignancy arising from post germinal, terminally differentiated plasma cells. Despite the success of proteasome inhibitors and immune-modulating drugs such as bortezomib and thalidomide in the treatment of relapsed disease patients eventually become refractory to these drugs making new therapeutic agents a critical need. One potential new agent is Reovirus Serotype 3- Dearing Strain. While infection of immunocompetent hosts results in only minor respiratory illness it has been demonstrated that reovirus selectively replicates in and is cytopathic to Ras activated cells. This specificity is due at least in part to the inhibition of auto-phosphorylation of PKR. The minimal side effects and dependence of reovirus on Ras activation make it an interesting candidate for relapsed/refractory MM as it has been reported that at least 50% of relapsed MM patients have activating Ras mutations and most patients show activation at other Ras checkpoints including p38. While there has been limited investigation of reovirus treatment of MM cell lines there has been less analysis of resistance to reovirus treatment in MM. Methods MM cell lines were screened via MTS assay to identify cell lines sensitive, intermediate, and resistant to reovirus treatment. Cell lines were then treated at a MOI of 10 or 25 for 9 and 24 hours and analyzed by immunohistochemistry (IHC) for p38, reoviral protein, and caspase-3 as well as in situ hybridization (ISH) and qRT-PCR for reoviral RNA. Total RNA isolates of sensitive, intermediate, and resistant cell lines were used to perform a screening analysis of mRNA, microRNA (miRNA), and long non-coding RNA to identify differential expression. In addition, expression of the reovirus high affinity receptor JAM-1 was assessed in these cell lines by western blot and IHC. Following this analysis mRNA, miRNA, and long non-coding RNA expression was analyzed in bone marrow samples from relapsed/refractory MM patients enrolled in a reovirus monotherapy clinical trial before and after treatment. These results were correlated with patient response and compared to the results from the cell lines. Results MTS results clearly identified several cell lines as being sensitive (RPMI), intermediate (H929), and resistant (OPM2) to reovirus treatment according to percent viability. IHC revealed over 98% positivity for p38 in all cell lines indicating Ras activation and permissibility to reovirus infection regardless of sensitivity. IHC also showed a higher percentage of cells positive for reoviral protein in sensitive and intermediate cell lines compared to resistant cell lines. The increased reoviral protein expression in these cell lines correlated with these lines having a higher percentage of caspase-3 positive cells compared to both the controls and the resistant cell lines. ISH demonstrated that the relative signal intensity of reoviral RNA was proportional to the sensitivity of each cell line, and these results were consistent with qRT-PCR results. Conclusions Despite susceptibility to reovirus infection, as determined by p38 positivity, substantial variation was seen in response to reovirus treatment amongst cell lines. Given the correlation of cell line sensitivity with reoviral RNA levels and reoviral protein production it will be important to identify factors that drive these differences. Ongoing analysis is focused on determining the role of viral entry including expression of the reoviral receptor JAM-1 and subsequent viral trafficking and degradation. In addition, evaluation of differential expression of RNA molecules in cell lines and patient samples is ongoing as miRNA have been identified in the establishment of productive reoviral infections and cancer cell death (Nuovo et al. 2012). Disclosures: No relevant conflicts of interest to declare.

Introduction In relapsed/refractory multiple myeloma, approximately 50% of patients have Ras-family (NRAS and KRAS) activating gene mutations. Reovirus Serotype 3 - Dearing Strain (Reolysin) is the infusible form of the RNA human reovirus associated with minor respiratory infections in humans. Reovirus has been shown to replicate specifically in, and be cytopathic to, transformed cells possessing an activated Ras-signaling pathway. The specificity of the reovirus for Ras-activated cells makes it an attractive anti-cancer therapy candidate. Methods For this phase 1 trial, patients were required to have relapsed or refractory myeloma with IMWG-defined measurable disease, ANC ≥ 1,000/uL, platelet count ≥ 50,000/uL, with no creatinine requirements. Reolysin was administered intravenously over 60 minutes on days 1 - 5 every 28 days to 12 patients. It was started at 3 x 109 median tissue culture infective dose per day (TCID50/day) for 3 patients and then escalated to 3 x 1010 TCID50/day for the remaining 9 patients. In situ based methodologies were used to examine the distribution of CD138, p38, caspase-3, reoviral capsid protein, and reoviral RNA in bone marrow biopsies performed at screening and then on cycle 1 day 8. Neutralizing Anti-Reovirus Assay (NARA) was performed weekly during cycle 1. Results Twelve patients were enrolled with a median age of 61 (range 48 - 77), median number of prior therapies at enrollment of 4 (range 1 - 10) and mean ISS stage of 1.9 (range 1 - 3). No DLT's were experienced and all patients reached 3 x 1010 TCID50/day. Grade 2 toxicities included leukopenia, anemia and myalgias, and grade 3 toxicities (asymptomatic) included 3 patients with neutropenia and one patient each with thrombocytopenia and hypophosphatemia. Reoviral protein and RNA were found in post-Reolysin bone marrow biopsies but not at baseline. Reoviral RNA stained within 20 - 100% of myeloma cells, but only rare reoviral protein and caspase-3 staining was seen. Patients with 1:1 reoviral RNA:CD138 staining showed the most reduction in the percent of myeloma cells with treatment (Table 1). All patients developed NARA responses with 8 patients having endpoint titers greater than 2000 at 3 weeks post-treatment. Stable disease (SD) was evident in 5 (42%) patients (longest duration on treatment was 8 cycles). One patient had a minimal response after two cycles. Conclusions Treatment with single-agent Reolysin was well tolerated, reovirus infection of myeloma cells was proven in all patients, but there was minimal intracellular reoviral protein production. Patients with 100% co-expression of reoviral RNA and CD138 had the largest relative decrease in CD138+ cells suggesting an early cytotoxic T- or NK-cell antiviral effect. The lack of clinical response is expected because reoviral-induced oncolysis typically requires concomitant chemotherapy. Clinical experiments in solid tumors confirm the necessity of chemotherapy as a cellular stressor to induce viral protein production and subsequent apoptosis (Sei et al., Mol Cancer 2009). Given the preclinical synergy reported with bortezomib in myeloma cell lines, we are planning a phase 1b combination of Reolysin with Carfilzomib. Disclosures: No relevant conflicts of interest to declare.