Abstract: To improve patient outcomes in the otherwise incurable hematologic malignancy of multiple myeloma (MM), a key paradigm includes initial treatment to establish disease control rapidly followed by maintenance therapy to ensure durability of response with manageable toxicity. However, patient prognosis becomes worse after relapse, and the disease burden and drug toxicities are generally more challenging with subsequent lines of therapy. It is therefore particularly important that patients with newly diagnosed multiple myeloma (NDMM) receive optimal frontline therapy. The combination of lenalidomide, bortezomib, and dexamethasone (RVd) has consistently demonstrated a tolerable safety profile with significant and clinically relevant benefit, including deep and durable responses with improved survival in patients with NDMM regardless of their transplant eligibility. Furthermore, comparative studies evaluating this triplet against both doublets and other triplet regimens have established RVd as a standard of care in this setting based upon its remarkable and concordant efficacy. Given the breadth of clinical data, physician familiarity, inclusion in treatment guidelines, and the emerging potential of RVd-containing quadruplet regimens, RVd will likely continue as a key cornerstone of NDMM therapy, and its role will therefore likely continue to grow as a therapeutic backbone in the initial treatment of MM.

Abstract: 8507 Background: The introduction of immunomodulatory agents, proteasome inhibitors, and autologous stem cell transplantation (ASCT) has improved outcomes for patients with multiple myeloma (MM), but those with high risk MM (HRMM) have a poor long-term prognosis. To date, no trials have addressed optimal treatment for these patients. Methods: S1211 is a randomized phase II trial (NCT01668719) comparing 8 cycles of lenalidomide, bortezomib and dexamethasone (RVd) induction followed by dose-attenuated RVd maintenance until disease progression with or without elotuzumab. Stem cell collection was allowed, but ASCT was deferred until progression. HRMM was defined by one of the following: gene expression profiling high-risk (GEP hi ), t(14; 16), t(14; 20), del(17p) or amplification 1q21, primary plasma cell leukemia (pPCL) and elevated serum LDH ( 〉 2X ULN). Median progression-free survival (PFS) was the primary end-point, using a one-sided stratified log-rank test at a one-sided significance level of 0.1. Secondary endpoints included overall response rate (ORR), adverse events (AE), serious adverse events (SAE) and OS. Response was assessed using the IMWG 2009 criteria. Results: S1211 enrolled 103 evaluable patients, RVd n = 54, RVd-Elo n = 49. 75% had ISS II/III, 47% amp1q21, 38% del17p, 12% t(14; 16), 9% GEP hi , 7% pPCL, 5% t(14; 20) and 4% elevated serum LDH (18.5% 〉 1 feature). With median follow-up of 53 months (mos.), no difference in median PFS was observed [RVd-Elo = 31 mos., RVd = 34 mos.,HR = 0.968 (80% CI = 0.697-1.344), p = 0.449]. No difference in OS was observed [RVd-Elo = 68 mos, RVd = not reached, HR = 1.279 (80% CI: 0.819, 2.000), p-value = 0.478] . 72% pts had 〉 Grade 3 AEs, no differences in the safety profile were observed except 〉 Grade 3 infections (RVd 8%, RVd-Elo 16%), 〉 Grade 3 sensory neuropathy (RVd 8%, RVd-Elo 13%). Conclusions: In the first randomized HRMM study reported to date, the addition of elotuzumab to RVd induction and maintenance did not improve patient outcomes. However, the PFS and OS seen in both arms of the study exceeded the original statistical assumptions and support the role for PI/IMiD combination maintenance therapy for this patient population. The S1211 data will serve as an important benchmark for future HRMM clinical trials. Clinical trial information: NCT01668719 .

Abstract: Introduction: Belantamab mafodotin (belamaf) is a B-cell maturation antigen (BCMA)-targeting antibody-drug conjugate approved in the United States (US) and Europe as a monotherapy for triple-class refractory adult patients with relapsed or refractory multiple myeloma (RRMM). This hypothesis-generating post-hoc analysis of DREAMM-2 trial (NCT03525678) data examined relationships between corneal exam findings (superficial punctate keratopathy and/or microcyst like epithelial changes), best-corrected visual acuity (BCVA), and direct patient-reported ocular symptoms per the Ocular Surface Disease Index (OSDI) questionnaire. This approach could provide insight into the relationship between corneal exam findings, BCVA, and ocular symptoms and their impact on quality of life to help determine if BCVA decline and symptoms could guide dosing. Currently, in the US, eye exams with eye-care professionals (ECPs) are required for each belamaf treatment, which can add to patients' therapy-related burden. Identifying a surrogate marker for results from corneal exam findings would help providers determine if dosing adjustments are necessary. Methods: Eye exams (including a corneal exam and BCVA assessment using the Snellen chart) were performed on all patients receiving single-agent belamaf (2.5 mg/kg) by ECPs at baseline (BL) and before each dose, administered q3w. Corneal exam findings (keratopathy) and BCVA were assessed per protocol-defined criteria, and grade (GR) assessment was based on the worst finding in the worse eye. BCVA and keratopathy grading were relative to BL. Patient-reported ocular symptoms and vision-related functioning, as per the OSDI, were used to evaluate the impact of treatment-related ocular toxicity. The OSDI is a patient-reported outcome questionnaire that assesses eye symptoms and effects on vision-related function in the past week and was performed in all patients before each belamaf dose. Items 1-5 address the frequency of eye-related symptoms (eg, painful or sore eyes, blurred vision) while items 6-9 address the frequency of functional limitations (eg, driving at night or reading). OSDI was considered positive, clinically meaningful, and potentially associated with treatment when at least one question 1-5 (ie, sensitivity to light, gritty or painful eyes, blurred or poor vision) was reported as experienced "all of the time" and at least one question 6-9 (ie, driving at night, reading, working with PC, or watching TV) was reported as experienced "most of the time." Results: Overall, GR 3-4 (severe) keratopathy was observed only 5% of the time in patients who did not report frequent ocular symptoms as measured by the OSDI questionnaire (no items 1-9 ≥ "most of the time"). A further breakdown of the questions revealed that, in patients who reported no items 1-5 "all of the time" AND no items 6-9 ≥ "most of the time" (OSDI negative), GR 3-4 keratopathy was observed only 6% of the time (Table). When considering individual OSDI items, in patients who reported "no deterioration from BL" for any of the OSDI eye-related symptoms or functional limitations, GR 3-4 keratopathy was observed ~3%-7% of the time while GR 0-2 (mild) keratopathy was observed ~23%-34% of the time. Similar results were observed in patients with BCVA ≤20/30 at BL who reported "no deterioration from BL" for any eye-related adverse events (AEs) or functional limitations (GR 3-4 keratopathy: ~2%-6% of the time; GR 0-2 keratopathy: ~19%-28% of the time); patients with worse visual acuity at BL (BCVA & gt;20/30) who reported "no deterioration" for items 1-9 had lower incidence of GR 3-4 and GR 0-2 keratopathy (~0%-1% and ~3%-8%, respectively). Conclusions: The results from this hypothesis-generating post-hoc analysis suggest that hematologists/oncologists may be able to use clinical indicators/tools (eg, ocular symptoms, the OSDI tool) as potential surrogate markers for eye exam results to help determine whether dosing changes are needed. This approach will be explored in trials with other belamaf dose regimens that are currently under evaluation. If the results are validated, it may be possible for hematologists/oncologists to manage belamaf dose modifications, due to ocular AEs, without a confirmatory eye exam by the ECP, reducing the patient burden. Funding Source: GSK (205678). Drug linker technology licensed from Seagen; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Figure 1 Figure 1. Disclosures Popat: Takeda: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; AbbVie, BMS, Janssen, Oncopeptides, and Amgen: Honoraria; Abbvie, Takeda, Janssen, and Celgene: Consultancy; Janssen and BMS: Other: travel expenses. Badros: GlaxoSmithKline: Research Funding; BMS: Research Funding; Janssen: Research Funding; J & J: Research Funding. Kumar: Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tenebio: Research Funding; Antengene: Consultancy, Honoraria; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Carsgen: Research Funding; Roche-Genentech: Consultancy, Research Funding; Beigene: Consultancy; BMS: Consultancy, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Oncopeptides: Consultancy; Astra-Zeneca: Consultancy, 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; Novartis: Research Funding; Merck: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Rodríguez-Otero: Regeneron: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: 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; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel and other expenses. Cohen: BMS: Research Funding; GlaxoSmithKline: Other: Personal fees and other association with, Research Funding; Novartis: Research Funding; Celgene: Honoraria, Other: Personal fees and other association with; Janssen: Honoraria; Kite Pharma: Honoraria; Oncopeptides: Honoraria; Seattle Genetics: Honoraria; Takeda: Honoraria. Manier: Regeneron: Consultancy, Research Funding; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Celgene - Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Voorhees: Secura Bio: 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; Amgen: 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; GlaxoSmithKline: 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; 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; Pfizer: 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. Gay: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; 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; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria. Rifkin: Takeda: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Fresenius-Kabi: Membership on an entity's Board of Directors or advisory committees; Coherus: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb (Celgene): Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; McKesson: Current Employment, Current equity holder in publicly-traded company; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Martin: Janssen: Research Funding; Sanofi: Research Funding; Oncopeptides: Consultancy; Amgen: Research Funding; GlaxoSmithKline: Consultancy. Chari: Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Research Funding; GlaxoSmithKline: 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; Shattuck Labs: 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; AbbVie: 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; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Pharmacyclics: Research Funding; Millenium/Takeda: Consultancy, Research Funding; Sanofi Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: 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; Janssen Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Weisel: Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: 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; Karyopharm: 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, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; Novartis: Honoraria; Pfizer: Honoraria. Farooq: Five Prime Therapeutics/Amgen: Consultancy; GlaxoSmithKline: Consultancy. Jeng: OysterPoint: Consultancy; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy; Eyegate: Current equity holder in publicly-traded company. Chng: Abbvie: Consultancy; GlaxoSmithKline: Consultancy; Takeda: Consultancy; BMS/Celgene: Consultancy, Research Funding; Sanofi: Consultancy; Novartis: Research Funding; Johnson & Johnson: Consultancy, Research Funding; Amgen: Consultancy; Antengene: Consultancy; Pfizer: Consultancy; Aslan: Research Funding. Lee: Takeda Pharmaceuticals: Consultancy, Research Funding; Oncopetides: Consultancy; Sanofi: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Legend Biotech: Consultancy; Karyopharm: Consultancy; Janssen: Consultancy, Research Funding; Genentech: Consultancy; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Amgen: Consultancy, Research Funding; Regeneron: Research Funding. Berdeja: BMS: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Celularity: Research Funding; CRISPR Therapeutics: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Kite Pharma: Consultancy; Legend Biotech: Consultancy; SecuraBio: Consultancy; EMD Serono: Research Funding; Genentech: Research Funding; GlaxoSmithKline: Research Funding; Ichnos Sciences: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Poseida: Research Funding; Bluebird bio: Consultancy, Research Funding; Astex Pharmaceuticals: Research Funding; Amgen: Research Funding; Abbvie: Research Funding; Takeda: Consultancy; Sanofi: Research Funding; Acetylon: Research Funding; Teva: Research Funding; Lilly: Research Funding. Jadhav: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Tosolini: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Eliason: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Palumbo: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Dimopoulos: Beigene: Honoraria; BMS: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Takeda: Honoraria. Lonial: Merck: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Trudel: Amgen: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Amgen Canada: Honoraria; Sanofi: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Research Funding; Janssen: Honoraria, Research Funding; Genentech: Research Funding; Karyopharm: Honoraria. Richardson: Sanofi: Consultancy; Celgene/BMS: Consultancy, Research Funding; Protocol Intelligence: Consultancy; GlaxoSmithKline: Consultancy; Secura Bio: Consultancy; AbbVie: Consultancy; Karyopharm: Consultancy, Research Funding; Janssen: Consultancy; Oncopeptides: Consultancy, Research Funding; Regeneron: Consultancy; AstraZeneca: Consultancy; Takeda: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding. Terpos: Celgene: Consultancy, Honoraria, Research Funding; Genesis: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; BMS: Honoraria; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding.

Abstract: Background: Ricolinostat, an oral selective HDAC6 inhibitor, is well tolerated as monotherapy (Raje Blood 2012;120:4061) and demonstrates potent synergistic activity with lenalidomide (Len) and pomalidomide (Pom) in preclinical models (Quayle Blood 2013;122:1952). Immunomodulatory drugs (thalidomide, Len, and Pom) trigger anti-tumor activities in multiple myeloma (MM) in part by targeting cereblon, a component of an E3 ubiquitin ligase complex, leading to decreased levels of IZF1/3, c-Myc and IRF4, critical factors in MM proliferation. Preclinical models using ricolinostat in combination with Len was shown to both avoid cereblon downregulation caused by non-selective HDAC inhibitors, and enhance Len mediated downregulation of c-Myc, IRF4 and IZF1/3 to induce synergistic cytotoxicity in MM (Hideshima Blood Cancer J 2015;5:e312). Pan-HDAC inhibitors vorinostat and panobinostat are active in MM in combination with bortezomib (Btz) and Len, but toxicities (thrombocytopenia, fatigue, and GI events) limit dosing exposure. This trial explores activity of ricolinostat in combination with Len and dexamethasone (Dex) in patients with relapsed and relapsed-and refractory MM. Methods: Phase 1b was a 3+3 design which studied ricolinostat combined with Len (15-25 mg QD on Days 1-21 of a 28-day cycle) and Dex (40 mg weekly). In Regimen A, patients were treated with escalating doses of ricolinostat on Days 1-5 and 8-12 of a 28-day cycle with Len and Dex. In Regimen B, ricolinostat was also given on Days 15-19. Doses up to 240 mg QD and 160 mg BID were explored. In Regimen C, patients were treated with 160 mg ricolinostat BID or QD for 21 of 28 days with Len and Dex. Patients had measurable disease, adequate BM reserve, hepatic function, and CrCl ≥50 mL/min. Per the IMWG, refractory was defined as disease that is nonresponsive while on primary or salvage therapy, or progresses on or within 60 days of last therapy. Patients with non-secretory MM or prior HDAC inhibitor therapy were excluded. Peripheral blood samples were obtained for PK/PD assessment of acetylated tubulin and histones. Results: 33 patients have been enrolled to date. Median age was 63 with a median of 3 (2-9) lines of prior therapy. 22 patients were previously treated with Len, and 12 of these patients were refractory to Len as defined in the entry criteria. No MTD was observed at up to 160 mg BID. Common toxicities were predominately low grade and included fatigue (55%), neutropenia (36%), diarrhea (33%), upper respiratory tract infections (30%), and anemia (27%). Important grade 3/4 related toxicities included neutropenia (6 patients, 18%), fatigue (2 patients, 6%), diarrhea (2 patients, 6%), and vomiting (2 patients, 6%). 2 DLTs have been observed: grade 3 syncope in Regimen B at 160 mg BID on Days 1-5, 8-12 and 15-19 and grade 3 muscle cramps in Regimen C at 160 mg BID Days 1-21. The last cohort is being expanded at 160 mg QD Days 1-21 based on prior cohort expansions and other trials of ricolinostat in combination with Btz and Pom where 160 mg ricolinostat QD is better tolerated than BID dosing (Vogl Blood 2014;124:4764). PK for ricolinostat is similar to that observed in Phase 1a monotherapy, indicating that co-administration of Len does not significantly impact ricolinostat exposure. Maximal blood levels of ricolinostat were ≥0.5 µM at ≥80 mg correlating with a 〉 2x increase acetylated tubulin (HDAC6 PD marker) with minimal increase in acetylated histones (class 1 HDAC PD marker). 31 patients were evaluable for response with ORR (≥PR) was 55% with 1 sCR and 7 VGPR and clinical benefit rate (≥MR) was 61% with 71% SD or better. The median follow-up of all 31 patients compared to the 17 responders was 6 (1-33) months and 12 (1-33) months, respectively. 19 patients were previously naïve or responsive (≥MR) to Len with median follow-up of 11 (1-33) months had ORR (≥PR) of 68% and clinical benefit rate (≥MR) of 74%. 12 patients refractory to Len with median follow-up of 5 (3-10) months had ORR (≥PR) of 33% and clinical benefit rate (≥MR) of 42% with 67% SD or better. Conclusion: Ricolinostat is an active and safe oral agent in combination with Len and Dex in relapsed and relapsed-and-refractory MM. No MTD has been identified. A dose of 160 mg QD on Days 1-21 of a 28-day cycle is proposed for phase 2 based on excellent tolerability. The median duration on study for responders was a year, with some patients continuing up to 33 months. Disclosures Bensinger: Sanofi: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Research Funding; BMS: Research Funding; Novartis: Research Funding; Sanofi: Research Funding; Onyx: Research Funding; Celgene: Research Funding; Acetylon Pharmaceuticals, Inc: Research Funding. Voorhees:Millennium Pharmaceuticals: Consultancy, Research Funding; Onyx Pharmaceuticals: Research Funding; Celgene: Research Funding; Oncopeptides: Research Funding; Acetylon Pharmaceuticals, Inc.: Research Funding; Janssen: Research Funding; GSK: Research Funding; Oncopeptides: Consultancy; Array BioPharma: Consultancy; Novartis: Consultancy; Celgene: Consultancy; A Takeda Oncology Company: Consultancy, Research Funding; GSK: Consultancy. Berdeja:BMS: Research Funding; Acetylon: Research Funding; Array: Research Funding; Janssen: Research Funding; Curis: Research Funding; Celgene: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; MEI: Research Funding; Takeda: Research Funding; Onyx: Research Funding. Richardson:Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding. Tamang:Acetylon Pharmaceuticals, Inc.: Employment. Jones:Acetylon Pharmaceuticals, Inc.: Employment, Equity Ownership. Wheeler:Acetylon Pharmaceuticals, INC: Employment. Markelewicz:Acetylon Pharmaceuticals, Inc: Employment. Raje:AstraZeneca: Research Funding; Acetylon: Research Funding; Onyx: Consultancy; Novartis: Consultancy; Celgene Corporation: Consultancy; Takeda: Consultancy; Millenium: Consultancy; Eli Lilly: Research Funding; Amgen: Consultancy; BMS: Consultancy.

Abstract: Due to recent treatment advances, MM patients (pts) are living longer (Kumar et al, Blood 2008), underscoring the importance of patient quality of life and management of adverse events (AEs) related to MM therapy. MM pts are at risk of cardiac events due to age and disease-related factors, as well as cardiotoxicity from treatments including anthracyclines, proteasome inhibitors (PIs), and high-dose therapy. Both of the US FDA-approved PIs, Btz and carfilzomib, have been associated with cardiac events in MM pts, with cardiac toxicity and cardiac adverse reactions included under ‘Warnings and Precautions’ in the respective US labels. The development of Btz, a reversible boronate peptide PI, involved numerous large, controlled clinical trials, providing a benchmark for the expected incidence of heart failure with PIs. Here, we report a retrospective analysis of the risk of heart failure associated with Btz in phase 2 and 3 MM studies leading to regulatory approvals in the US and EU. Methods Study databases were retrospectively analyzed for AEs of grade ≥3 heart failure. In the relapsed/refractory setting, the following studies were included: the phase 2 SUMMIT trial (Btz ± dexamethasone; Richardson et al, NEJM 2003), and the phase 3 APEX (Btz vs dexamethasone; Richardson et al, NEJM 2005), MMY-3001 (Btz + liposomal doxorubicin vs Btz; Orlowski et al, J Clin Oncol 2007), and MMY-3021 (subcutaneous [SC] vs intravenous [IV] Btz; Moreau et al, Lancet Oncol 2011) trials. In the upfront setting, the phase 3 VISTA trial (Btz-melphalan-prednisone [VMP] vs MP; San Miguel et al, NEJM 2008) in transplant-ineligible pts and a pooled analysis of three phase 3 trials (IFM 2005-01, HOVON-65/GMMG-HD4, PETHEMA GEM2005MENOS65) of Btz-based vs non-Btz-based induction (N=779 vs 776; Sonneveld et al, IMW 2013) in transplant-eligible pts were included. Cardiac exclusion criteria typically included NYHA class III/IV (≥II in MMY-3001), myocardial infarction within 6 mos, and ECG evidence of acute ischemia. Heart function tests (primarily ECG) were incorporated in study designs. Heart failure events were analyzed and re-coded for consistency across studies, using standardized MedDRA (v4.0, 8.0, 8.1, 9.0, 9.1, and 10.0) query preferred terms with grouping of clinically related events. Results 2509 pts treated with Btz in the specified phase 2 and 3 trials and an additional 1445 pts treated with non-Btz-based therapies in the control arms of the phase 3 studies were included in this analysis. Pt characteristics and rates of grade ≥3 heart failure by study arm are shown in the table. Among all Btz-treated pts, the rate of grade ≥3 heart failure was 2.0%; the rate was 2.0% in newly diagnosed pts and 1.9% in relapsed and/or refractory pts. In the comparative studies (APEX, VISTA) and pooled pre-ASCT induction analysis, the overall rates across the Btz and non-Btz arms were 2.0% and 1.6%, respectively (p=0.41). Risk factors, including prior anthracycline exposure and history of cardiac complications, were balanced between Btz and non-Btz arms. Conclusions In this retrospective analysis of data from key phase 2 and 3 studies, Btz was associated with a low rate of grade ≥3 heart failure in both the newly diagnosed (2.0%) and relapsed and/or refractory (1.9%) settings. Importantly, across comparative studies, the rate was only marginally higher and not statistically different from the background rate in non-Btz comparator arms. Data from ongoing prospective and comparative studies are necessary to determine whether PIs – including Btz, carfilzomib, and PIs at earlier stages of clinical development – have different cardiotoxicity profiles. Disclosures: San Miguel: Millennium: The Takeda Oncology Company: 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; Janssen: 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; Onyx: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Sonneveld:Jansssen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Onyx: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Orlowski:Bristol-Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millennium: The Takeda Oncology Company: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Resverlogix: Research Funding; Array Biopharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Merck: Membership on an entity’s Board of Directors or advisory committees. Moreau:Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Millennium: The Takeda Oncology Company: Membership on an entity’s Board of Directors or advisory committees; Onyx: Membership on an entity’s Board of Directors or advisory committees. Rosiñol:Janssen: Honoraria; Celgene: Honoraria. Moslehi:Alnylam: Consultancy; Novartis: Consultancy; Millennium: The Takeda Oncology Company: Consultancy; Forest Laboratories: Research Funding. Faber:Celgene: Consultancy, Honoraria; Millennium: The Takeda Oncology Company: Consultancy, Honoraria; Onyx: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria. Voorhees:Acetylon: Research Funding; Millennium: The Takeda Oncology Company: Research Funding; Merck: Research Funding; Janssen: Research Funding; Prolexys Pharmaceuticals: Research Funding; GlaxoSmithKline: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Abbott Laboratories: Consultancy. Marquez:Johnson & Johnson: Equity Ownership; Janssen: Employment. Desai:Janssen: Employment; Johnson & Johnson: Equity Ownership. van de Velde:Janssen: Employment; Johnson & Johnson: Equity Ownership. Elliott:Millennium: The Takeda Oncology Company: Employment. Shi:Millennium: The Takeda Oncology Company: Employment. Dow:Millennium: The Takeda Oncology Company: Employment. Jobanputra:Millennium: The Takeda Oncology Company: Employment. Esseltine:Millennium: The Takeda Oncology Company: Employment; The Takeda Pharmaceutical Company: Equity Ownership. Niculescu:Millennium: The Takeda Oncology Company: Employment. Anderson:Celgene: Consultancy; Onyx Pharmaceuticals: Consultancy; Sanofi-Aventis: Consultancy; Gilead: Consultancy; Acetylon Pharmaceuticals: Equity Ownership; Oncopep: Equity Ownership. Lonial:Merck: Consultancy; Onyx Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Millennium: The Takeda Oncology Company: Consultancy. Richardson:Millennium: The Takeda Oncology Company: Membership on an entity’s Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees.

Abstract: Background: Patients with multiple myeloma (MM) who have relapsed after conventional treatment have limited therapeutic options for long-term disease control. Melflufen is a lipophilic peptide-conjugated alkylator that rapidly delivers a highly cytotoxic payload into myeloma cells through peptidase activity. In the first report of efficacy and safety for the phase 1/2 study O-12-M1 (median follow-up, 28 months), melflufen and dexamethasone demonstrated an overall response rate of 31%, a median PFS of 5.7 months, and a median OS of 20.7 months, with acceptable safety for patients with RRMM (Richardson PG, et al. Blood. 2017; Abstract 3150). Here, updated OS and PFS results from the O-12-M1 study are reported, with 18 months of additional follow-up of the patients who were still participating in long-term follow-up at the time of the final database lock in November 2017. Methods: Eligible patients had RRMM, measurable disease, and ≥2 prior lines of therapy, including bortezomib and lenalidomide. Patients must have had progressive disease (PD) on or within 60 days of completion of last therapy. Patients received melflufen 40 mg intravenously on day 1 of each 28-day cycle and oral dexamethasone 40 mg weekly for up to 8 cycles or longer at the discretion of the investigator and sponsor. Treatment continued until PD or unacceptable toxicity. Patients were followed up for 2 years after PD or start of subsequent therapy. PFS and OS were secondary end points in this study. Time to next treatment (TTNT), an exploratory end point defined as the time from start of melflufen and dexamethasone to first subsequent therapy or death, was retrospectively reviewed. Results: As of 15 May 2019, 45 patients were treated. Median age was 66 years (range, 47-78); 60% of patients had International Staging System stage II/III at study entry, and 44% had high-risk cytogenetics [del(17p), t(14;16), t(4;14), t(14;20), or gain(1q)]. The median time since initial diagnosis was 5.0 years (range, 1-21). Patients received a median of 4 prior lines of therapy (range, 2-14). All patients were exposed to IMiDs, 98% to proteasome inhibitors (PIs), 93% to alkylators (any dose of melphalan, cyclophosphamide, or bendamustine), and 80% to melphalan; 87% were refractory to last line of therapy, and 91%, 67%, and 7% were single (IMiD or PI), double (IMiD and PI), and triple (IMiD, PI, and daratumumab) refractory, respectively. After a median follow-up of 30.1 months, median PFS was 5.7 months (95% CI, 3.7-9.3; 98% events). Median OS was 20.7 months (95% CI, 13.6-not reached; 58% events; Figure). Updated PFS, OS, and TTNT data will be presented. No new adverse events (AEs) were reported. Conclusion: Melflufen and dexamethasone resulted in sustained long-term benefits (median OS, 20.7 months) and no new AEs with 1.5 years of additional follow-up of patients with late-stage, heavily pretreated RRMM who have relapsed on conventional therapy including bortezomib and lenalidomide. Further trials are ongoing to evaluate efficacy and safety of melflufen, including the phase 3 study OCEAN (OP-103; NCT03151811) of melflufen plus dexamethasone versus pomalidomide plus dexamethasone in patients with RRMM refractory to lenalidomide. Figure Disclosures Bringhen: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Voorhees:Novartis: Consultancy; Oncopeptides: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TeneoBio: Consultancy, Research Funding; Amgen: Research Funding; GSK: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees. Plesner:AbbVie: Consultancy; Genmab: Consultancy; Takeda: Consultancy; Oncopeptides: Consultancy; Celgene: Consultancy; Janssen: Consultancy, Research Funding. Mellqvist:Amgen, Janssen, Oncopeptides, Sanofi, Sandoz, Takeda: Honoraria. Reeves:Celgene: Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria. Sonneveld:Amgen: Honoraria, Research Funding; SkylineDx: Research Funding; Takeda: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria. Byrne:Oncopeptides: Consultancy; Takeda: Consultancy. Nordström:Oncopeptides: Employment, Equity Ownership. Harmenberg:Oncopeptides: Consultancy, Equity Ownership. Obermüller:Oncopeptides: Employment. Richardson:Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: 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; Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: This is a Phase 1/2 investigational study of melflufen in RRMM

Abstract: Patients with multiple myeloma are at increased risk of vascular thromboembolic events (VTEs). This post hoc analysis evaluated VTEs in the randomised phase 2 GRIFFIN study ( ClinicalTrials.gov Identifier: NCT02874742) that investigated lenalidomide/bortezomib/dexamethasone (RVd) ± daratumumab (D). Patients with newly diagnosed multiple myeloma who were eligible for autologous stem cell transplantation (ASCT) received D‐RVd/RVd induction, high‐dose therapy and ASCT, D‐RVd/RVd consolidation and up to 2 years of lenalidomide maintenance therapy ± D. VTE prophylaxis was recommended (at least aspirin, ≥162 mg daily) in accordance with International Myeloma Working Group guidelines. In the safety population (D‐RVd, n  = 99; RVd, n  = 102), VTEs occurred in 10.1% of D‐RVd patients and 15.7% of RVd patients; grade 2–4 VTEs occurred in 9.1% and 14.7%, respectively. Median time to the first onset of VTE was longer for D‐RVd versus RVd patients (305 days vs 119 days). Anti‐thrombosis prophylaxis use was similar between arms (D‐RVd, 84.8% vs RVd, 83.3%); among patients with VTEs, prophylaxis use at time of first VTE onset was 60.0% for D‐RVd and 68.8% for RVd. In summary, the addition of daratumumab to RVd did not increase the incidence of VTEs, but the cumulative VTE incidence was relatively high in this cohort and anti‐thrombotic prophylaxis use was suboptimal.