ALBERT

Description: Key Points Presented are results from the phase 2 dose-expansion study of the combination of carfilzomib, lenalidomide, and dexamethasone (CRd). CRd was well tolerated with robust, rapid, and durable responses.

Description: Key Points Weekly oral proteasome inhibitor ixazomib appears generally well tolerated with manageable toxicity, limited grade 1/2 neuropathy. Data show that more than 25% of 30 evaluable relapsed/refractory myeloma patients who received the MTD had clinically meaningful responses.

Description: Introduction: Filgrastim is widely used for mobilizing CD34+ cells into the peripheral blood that are easily collected by apheresis for allogeneic transplantation. With case reports documenting splenomegaly with life-threatening complications in normal donors, we prospectively evaluated spleen size using ultrasonography and clinical examination during PBPC mobilization and collection in a single-arm trial. Methods: Subjects ≥18 yrs eligible to be PBPC donors per institutional guidelines enrolled. Splenic assessments were done before, during, and after PBPC mobilization. Filgrastim dose and schedule and leukapheresis (LK) procedures were per institutional practice. The primary endpoint was fold change from baseline in splenic volume in post-baseline measurements during mobilization (measured by ultrasound [US]). Spleen size by US was measured in 3 dimensions similarly by all centers: longitudinal (craniocaudal), transverse, and diagonal (perpendicular to transverse in transverse image) diameters. Splenic volume was estimated by taking the cross-product of 3 dimensions and multiplying by 0.52, approximating the volume of an ellipse. Physical examination was performed on US days, assessing spleen palpability. US and palpation results were blinded from each other at assessment times. Timepoints included baseline (before first filgrastim dose), first LK (done before LK, typically day 4 or 5 of filgrastim), 2 and 4 days after first LK, and 7 days after last LK. Timepoints in the post-amendment cohort (n=219) were reduced to facilitate enrollment and were baseline and day of first LK (before LK). Results: 309 donors enrolled, median age 44yrs (range 18 to 74), 56% male. Mean daily filgrastim dose was 11.4mcg/kg (SD=3.0). Median number of LK was 1.5 (range 1 to 4). In all donors, the median increase in each measured dimension on first LK day was 1.4cm, 1.4cm, and 0.6cm (12.8%, 12.6%, and 15.0%), and the median fold volume increase from baseline to first LK was 1.47, resolving to near baseline 1 week after last LK. There was no apparent relationship between volume fold change and filgrastim dose, ANC, or CD34+ yield. Of 861 splenic palpation assessments reported in all donors, 98% were reported as nonpalpable (842 assessments), and 2% were palpable (19 assessments, 2 at baseline). Reporting of palpable spleens did not correlate with increased spleen size. Tenderness or guarding upon splenic palpation was reported in 2 donors with a spleen considered palpable and in 6 donors with nonpalpable spleens. No donor experienced a splenic rupture. Adverse events related to filgrastim were generally mild to moderate. Conclusion: During PBPC mobilization with filgrastim in normal donors, the spleen increased a median of approximately 50% from baseline to day of first LK and returned to near baseline 1 week after last LK. Size change was not associated with significant clinical sequelae. Timepoint Median fold change from baseline in splenic volume (Q1, Q3) *statistically significant (p

Description: Introduction: Selinexor is a novel, first-in-class selective inhibitor of nuclear export (SINE), which blocks XPO1, forcing the nuclear retention and activation of tumor suppressor proteins. Selinexor in combination with low dose dexamethasone (Sel-dex) was recently approved based on data from the STORM study, wherein Sel-dex induced an overall response rate (ORR) of 26.2% in patients with penta-exposed, triple-class refractory multiple myeloma (MM). The recommended phase 2 dose (RP2D) of twice-weekly combination of selinexor, carfilzomib, and dexamethasone (SKd) was selinexor 60 mg, carfilzomib 20/27 mg/m2 and dexamethasone 20 mg (NCT02199665). The ORR of this regimen in patients with MM refractory to carfilzomib in last line of therapy (n=13) was 62% and clinical benefit response was 77% (Jakubowiak et al. Br J Haematol 2019). This is consistent with data from the combination of selinexor, bortezomib and dexamethasone where a 43% ORR was observed in bortezomib refractory disease. We conducted the STOMP study to assess the safety and preliminary efficacy of SKd combination using once weekly (QW) dosing in patients with relapsed/refractory MM. Methods: STOMP is a multicenter, open-label study. Patients with relapsed/refractory MM that was not refractory to carfilzomib, and who may have had prior proteasome inhibitor exposure were enrolled. Oral Selinexor was dosed QW at 80 or 100 mg. Carfilzomib was dosed QW (excluding day 22 of 28-day cycle) at 56 mg/m2 or 70 mg/m2. Dexamethasone was dosed at 40 mg QW. The primary objectives of the study are to assess the maximum tolerated dose, RP2D and evaluate the efficacy and safety of SKd in patients with relapsed/refractory MM. Results: As of July 01 2019, 12 patients were enrolled in the study. Of these, 5 were male and 7 were female. The median age was 70 years (range: 50-76 years). The median number of prior treatments was 4 (range: 2 - 8). Nine of 12 patients received prior autologous stem cell transplantation. All 12 patients were carfilzomib naïve. Nine of 12 patients had MM refractory to bortezomib; 11 patients had MM refractory to lenalidomide and/or pomalidomide including 5 patients with MM refractory to both; and 7 patients with MM refractory to daratumumab. Four dose limiting toxicities (DLTs) were observed across 3 dose cohorts (Table 1). Common treatment related adverse events (Grade 1/2 , Grade ≥3) included anemia (42%, 17%), thrombocytopenia (17%, 58%), leukopenia (17%, 17%), nausea (67%, 0%), decreased appetite (33%, 0%), insomnia (33%, 0%), hyperglycemia (25%, 17%), fatigue (25%, 8%), vomiting (25%, 8%), and pneumonia (0%, 17%). The ORR was 75% including 3 complete responses, 5 very good partial responses and 1 partial response. Two patients had stable disease and 1 patient had minimal response. As of July 01, 8 patients remain on treatment. Conclusions: The once weekly SKd combination demonstrated encouraging preliminary activity with an ORR of 75% including complete responses and very good partial responses. Most DLTs were thrombocytopenia and all the DLT events occurred in patients with baseline Grade 1/2 thrombocytopenia. This activity and manageable side effect profile with QW selinexor in combination with carfilzomib and dexamethasone is promising. Disclosures Gasparetto: Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Schiller:Gilead: Research Funding; Incyte: Research Funding; J&J: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Onconova: Research Funding; Pfizer Pharmaceuticals: Equity Ownership, Research Funding; Sangamo Therapeutics: Research Funding; Daiichi Sankyo: Research Funding; Eli Lilly and Company: Research Funding; FujiFilm: Research Funding; Genzyme: Research Funding; Agios: Research Funding, Speakers Bureau; Amgen: Other, Research Funding; Constellation Pharmaceutical: Research Funding; Astellas: Research Funding; Biomed Valley Discoveries: Research Funding; Bristol Myer Squibb: Research Funding; Celgene: Research Funding, Speakers Bureau. Lentzsch:Caelum Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Janssen: Consultancy; Takeda: Consultancy; BMS: Consultancy; Proclara: Consultancy; Abbvie: Consultancy; Clinical Care Options: Speakers Bureau; Sanofi: Consultancy, Research Funding; Multiple Myeloma Research Foundation: Honoraria; International Myeloma Foundation: Honoraria; Karyopharm: Research Funding; Columbia University: Patents & Royalties: 11-1F4mAb as anti-amyloid strategy. Tuchman:Roche: Research Funding; Alnylam: Honoraria, Research Funding; Karyopharm: Honoraria; Prothena: Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau; Amgen: Research Funding; Sanofi: Research Funding; Merck: Research Funding. Bahlis:Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. White:Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Chen:Amgen: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Baljevic:Cardinal Health Specialty Solutions: Consultancy; Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Other: Internal Review Committee participant. Kotb:Takeda: Honoraria; Amgen: Honoraria; Merck: Honoraria, Research Funding; Celgene: Honoraria; Janssen: Honoraria; Karyopharm: Equity Ownership. Leblanc:Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sebag:Janssen: 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; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Venner:Celgene: Honoraria; Janssen: Honoraria; Amgen: Honoraria, Research Funding; J&J: Research Funding; Sanofi: Honoraria; Takeda: Honoraria. Bensinger:Amgen, Celgene: Other: Personal Fees, Research Funding, Speakers Bureau; Takeda, Janssen: Speakers Bureau; Sanofi, Seattle Genetics, Merck, Karyopharm: Other: Grant. Sheehan:Karyopharm Therapeutics: Employment, Equity Ownership. Chai:Karyopharm Therapeutics: Employment, Equity Ownership. Kai:Karyopharm Therapeutics: Employment, Equity Ownership. Shah:Karyopharm Therapeutics: Employment, Equity Ownership. Shacham:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Lipe:Celgene: Consultancy; amgen: Consultancy; amgen: Research Funding.

Description: Abstract 4519 Background: Despite advances in our understanding of clinical, genetic, and molecular aspects of multiple myeloma (MM) coupled with availability of more effective therapies, it remains an incurable disease. Combining cytoreduction from high-dose (chemo- or chemoradio-) therapy with adoptive immunotherapy forms the basis of an autologous-allogeneic (auto-allo) hematopoietic cell transplantation (HCT) strategy. However, when an auto-allo HCT approach is compared to tandem autologous (auto-auto) HCT, conflicting results have been reported. Accordingly, we performed a systematic review of published studies comparing auto-auto HCT with auto-allo HCT in patients with newly diagnosed MM. Methods: A systematic search of MEDLINE thru Nov 5, 2011, and pertinent conference proceedings, was conducted. Included studies allocated newly diagnosed MM patients to auto-allo HCT if an HLA-matched sibling donor was available versus auto-auto if sibling donor was not available (biologic randomization). Independent, dual data extraction was performed. Pooling of data from similar outcomes was done using the random-effects model. Results: Our search identified 152 publications, of which five (manuscript=four, abstract=one) met inclusion criteria. The five included trials enrolled 1538 patients (auto-allo=565, auto-auto=973). At least a very good partial response was assessed in one study (522 patients) and did not differ among the treatment arms [risk ratio (RR) (95% CI) = 0.97 (0.87–1.09), p=0.66]; but complete remission, assessed in five studies (1130 patients), was higher in the auto-allo HCT arm [RR(95% CI) =1.65 (1.25–2.19), p=0.0005]. Event-free survival did not differ among auto-allo HCT group versus auto-auto HCT group on per-protocol analysis [hazard ratio (HR) (95% CI) = 0.78 (0.58–1.05)), p=0.11] of three trials (409 patients), or ITT analysis [HR(95% CI) = 0.83 (0.60–1.15), p=0.26] in three trials (1229 patients). Overall survival (OS) did not differ among these treatment arms whether analyzed on per-protocol [HR(95% CI) = 0.88 (0.33–2.35), p=0.79] in two trials (214 patients), or by ITT [HR(95% CI) = 0.80 (0.48–1.32), p=0.39] analysis in three trials (1229 patients). Non-relapse mortality (NRM) was worse with auto-allo HCT [RR(95%CI) = 3.55 (2.17–5.80), p

Description: Key Points KRd has a favorable benefit-risk profile compared with Rd, regardless of baseline cytogenetic risk status, in patients with relapsed MM. KRd improves but does not abrogate the poor prognosis associated with high-risk cytogenetics in patients with relapsed MM.

Description: Toxicities have limited the use of allogeneic hematopoietic cell transplantation (HCT) to younger, medically fit patients. In a canine HCT model, a combination of postgrafting mycophenolate mofetil (MMF) and cyclosporine (CSP) allowed stable allogeneic engraftment after minimally toxic conditioning with low-dose (200 cGy) total-body irradiation (TBI). These findings, together with the known antitumor effects of donor leukocyte infusions (DLIs), led to the design of this trial. Forty-five patients (median age 56 years) with hematologic malignancies, HLA-identical sibling donors, and relative contraindications to conventional HCT were treated. Immunosuppression involved TBI of 200 cGy before and CSP/MMF after HCT. DLIs were given after HCT for persistent malignancy, mixed chimerism, or both. Regimen toxicities and myelosuppression were mild, allowing 53% of eligible patients to have entirely outpatient transplantations. Nonfatal graft rejection occurred in 20% of patients. Grades II to III acute graft-versus-host disease (GVHD) occurred in 47% of patients with sustained engraftment. With median follow-up of 417 days, survival was 66.7%, nonrelapse mortality 6.7%, and relapse mortality 26.7%. Fifty-three percent of patients with sustained engraftment were in complete remission, including 8 with molecular remissions. This novel allografting approach, based on the use of postgrafting immunosuppression to control graft rejection and GVHD, has dramatically reduced the acute toxicities of allografting. HCT with the induction of potent graft-versus-tumor effects can be performed in previously ineligible patients, largely in an outpatient setting. Future protocol modifications should reduce rejection and GVHD, thereby facilitating studies of allogeneic immunotherapy for a variety of malignancies.

Description: This multicenter, first-in-human study evaluated the safety, tolerability, and pharmacokinetic and pharmacodynamic properties of the anti-CS1 monoclonal antibody elotuzumab. A standard 3 + 3 design was used to determine maximum tolerated dose; dose-limiting toxicities were assessed during cycle 1. Thirty-five patients with relapsed/refractory multiple myeloma were treated with intravenous elotuzumab at doses ranging from 0.5 to 20 mg/kg every 2 weeks. Patients who achieved at least stable disease after 4 treatments could receive another 4 treatments. No maximum tolerated dose was identified up to the maximum planned dose of 20 mg/kg. The most common adverse events, regardless of attribution, were cough, headache, back pain, fever, and chills. Adverse events were generally mild to moderate in severity, and adverse events attributed to study medication were primarily infusion-related. Plasma elotuzumab levels and terminal half-life increased with dose whereas clearance decreased, suggesting target-mediated clearance. CS1 on bone marrow–derived plasma cells was reliably saturated (≥ 95%) at the 10-mg/kg and 20-mg/kg dose levels. Using the European Group for Bone and Marrow Transplantation myeloma response criteria, 9 patients (26.5%) had stable disease. In summary, elotuzumab was generally well tolerated in this population, justifying further exploration of this agent in combination regimens.

Description: Introduction: BCMA is a tumor necrosis factor (TNF) receptor superfamily transmembrane glycoprotein essential for the maturation and survival of plasma cells. CC-93269 is an asymmetric 2-arm humanized IgG TCE that binds bivalently to BCMA and monovalently to CD3ε in a 2+1 format (Seckinger A, et al. Cancer Cell. 2017;31:396-410). The CC-93269-mediated interaction between T cells and BCMA-expressing myeloma cells induces T cell receptor/CD3 crosslinking leading to T cell activation, and release of proinflammatory cytokines and cytolytic enzymes, resulting in myeloma cell death. In preclinical studies with CC-93269 and related molecules, 2+1 BCMA TCEs induced tumor regression in animal models and promoted myeloma cell death in primary pt myeloma cells. Here we report interim results from a phase 1 dose-finding study (CC-93269-MM-001; NCT03486067) evaluating CC-93269 in pts with RRMM. Methods: Eligible pts had RRMM and had received ≥ 3 prior regimens without prior BCMA-directed therapy. In dose escalation, CC-93269 was administered intravenously over 2 hours on Days 1, 8, 15, and 22 for Cycles 1-3; Days 1 and 15 for Cycles 4-6; and on Day 1 for Cycle 7 and beyond, all in 28-day cycles. Dose escalation involved 2 stages: in stage 1, CC-93269 was given in fixed doses; in stage 2, pts received a fixed first dose on Cycle 1 Day 1, followed by intrapatient dose escalation on Cycle 1 Day 8. Primary objectives were to assess the safety and tolerability of CC-93269 and define the maximum tolerated dose (MTD), non-tolerated dose (NTD), and/or recommended phase 2 dose (RP2D). Minimal residual disease (MRD) was assessed after clinical response in pt bone marrow aspirate samples by Next Generation Flow using the EuroFlow panel. MRD negativity was reported only if a minimum sensitivity of 〈 1 tumor cell in 105 nucleated cells was achieved. Results: As of May 24, 2019, 19 pts had received CC-93269. Median age was 64 years (range 51-78), with a median of 6.2 years (range 1.4-13.9) since initial diagnosis. The median number of prior regimens was 6 (range 3-12) and included treatment with autologous stem cell transplantation (73.7%), allogenic stem cell transplantation (10.5%), lenalidomide (100%), pomalidomide (84.2%), bortezomib (100%), carfilzomib (84.2%), and daratumumab (DARA; 94.7%). All pts had MM refractory to their last line of therapy, with 16 (88.9%) refractory to DARA, 17 (89.5%) to their last proteasome inhibitor, and 16 (84.2%) to their last immunomodulatory agent. CC-93269 doses ranged from 0.15 to 10 mg; median duration of treatment was 14.6 weeks (range 1.6-32.0) with pts receiving a median of 4 cycles (range 1-8). Grade 3-4 treatment-emergent adverse events were reported in 15 (78.9%) pts and included 10 (52.6%) pts with neutropenia, 8 (42.1%) with anemia, 5 (26.3%) with infections, and 4 (21.1%) with thrombocytopenia. No pt required dose modifications. Cytokine release syndrome (CRS) was reported in 17 (89.5%) pts, the majority of whom reported a maximum grade 1 (n = 11 [57.9%]) or grade 2 (n = 5 [26.3%]), and occurred most frequently with the first or second dose (n = 22 of 27 events [81.5%]). CRS prophylaxis was implemented with dexamethasone for first dose and dose increases in pts receiving ≥ 6 mg. Of 27 CRS events, 8 (29.6%) were managed with dexamethasone and 10 (37.0%) with tocilizumab. One pt receiving 6 mg CC-93269 as first dose and 10 mg on Cycle 1 Day 8 died on study in the setting of CRS, with a potential infection as a contributing factor. Dose-related pharmacodynamic activity, including peripheral blood immune cell redistribution and transient release of pro- and anti-inflammatory cytokines, was observed in pts. Of the 12 pts treated with ≥ 6 mg CC-93269 in Cycle 1, 10 pts achieved a partial response (PR) or better (overall response rate; 83.3%), including 7 (58.3%) with a very good partial response (VGPR) or better and 4 (33.3%) with a stringent complete response (sCR) (Table); 9 (75.0%) pts achieved MRD negativity. The median time to response was 4.2 weeks (range 4.0-13.1), and 10 of 10 responses were ongoing with follow-up ranging from 2.1 to 4.7 months. The NTD, MTD, and RP2D have not yet been reached. Conclusions: CC-93269, a 2+1 BCMA TCE, shows a manageable safety profile and promising efficacy, including MRD-negative sCRs, in pts with heavily pretreated RRMM. The study continues to enroll in the dose escalation phase. Updated safety and efficacy data will be presented at the meeting. Disclosures Costa: Fujimoto Pharmaceutical Corporation Japan: Other: Advisor; Karyopharm: Consultancy; Abbvie: Consultancy; Sanofi: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Research Funding, Speakers Bureau. Wong:Genentech: Research Funding; Janssen: Research Funding; Celgene Corporation: Research Funding; Fortis: Research Funding; Juno: Research Funding. Bermúdez:MSD: Consultancy, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Fresenius: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. de la Rubia:AMGEN: Consultancy; Celgene Corporation: Consultancy; AbbVie: Consultancy; Takeda: Consultancy; Janssen: Consultancy. Mateos:Pharmamar: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria; EDO: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ocio:BMS: Honoraria; Sanofi: Research Funding; Mundipharma: Research Funding; Takeda: Consultancy, Honoraria; Seattle Genetics: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Array Pharmaceuticals: Research Funding; Pharmamar: Consultancy; Novartis: Consultancy, Honoraria; AbbVie: Consultancy; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Rodríguez-Otero:Celgene Corporation: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria; Takeda: Consultancy; BMS: Honoraria; Kite Pharma: Consultancy. San-Miguel:Amgen, Bristol-Myers Squibb, Celgene, Janssen, MSD, Novartis, Roche, Sanofi, and Takeda: Consultancy, Honoraria. Li:Celgene Corporation: Employment, Equity Ownership. Sarmiento:Celgene Corporation: Employment. Lardelli:Celgene Corporation: Employment, Equity Ownership. Gaudy:Celgene Corporation: Employment, Equity Ownership. Boss:Celgene Corporation: Employment, Equity Ownership. Kelly:Celgene Corporation: Employment. Burgess:University of California: Other: Volunteer clinical faculty, without salary, Patents & Royalties: Patent - T315A and F317I mutations of BCR-ABL kinase domain; Celgene Corporation: Employment, Equity Ownership, Patents & Royalties: Patent - CD47 antibodies and methods of use thereof. Hege:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties; Arcus Biosciences: Membership on an entity's Board of Directors or advisory committees; Society for Immunotherapy of Cancer: Membership on an entity's Board of Directors or advisory committees; Mersana Therapuetics: Membership on an entity's Board of Directors or advisory committees. Bensinger:Amgen, Celgene: Other: Personal Fees, Research Funding, Speakers Bureau; Takeda, Janssen: Speakers Bureau; Sanofi, Seattle Genetics, Merck, Karyopharm: Other: Grant.

Description: Background: The selective HDAC6 inhibitor ACY-241, a tablet, is structurally related to ricolinostat (ACY-1215), the first agent in this class in the clinic.Ricolinostat, an oral liquid, demonstrated clinical efficacy in a Phase 2 combination with pomalidomide (Pom) and dexamethasone (Dex) in patients (pts) with relapsed or relapsed-and-refractory multiple myeloma (RRMM) without toxicities greater than those reported with Pom and Dex alone (Raje et al., EHA 2016, S813). Preclinical data demonstrate synergistic activity of ACY-241 with Pom and lenalidomide (Len) in induction of cell cycle arrest and apoptosis in MM cells as well as significant extension of survival in a mouse xenograft model (Niesvizky et al., Blood 2015, 126: 3040). We present updated data on safety and efficacy of the ACY-241/Pom/Dex combination in pts with relapsed or RRMM (ACE-MM-200, NCT02400242). Aims:Determine the safety, tolerability, and preliminary efficacy of ACY-241 monotherapy and combination with Pom and Dex and the recommended dose for further development. Methods:Based on clinical experience with ricolinostat and non-clinical pharmacokinetics (PK) of ACY-241, we designed a first-in-human phase 1a/1b clinical trial of a single-cycle of ACY-241 monotherapy followed by ACY-241 in combination with Pom (4mg) and low-dose Dex in pts with relapsed or RRMM. The starting dose of ACY-241 was chosen to give similar exposure to the therapeutic dose of ricolinostat (160 mg QD). The trial design was chosen to grant pts access to combination therapy with an active regimen while exploring the safety, PK, and pharmacodynamic profile of ACY-241 alone and in combination with Pom/Dex. The PK of Pom and Dex was also assessed. Pts with relapsed or RRMM previously treated with ≥ 2 cycles of Len and a proteasome inhibitor were eligible. Cohorts of 3 pts had ACY-241 PO QD as monotherapy (180, 360 and 480 mg) on days 1-21 of a 28 day cycle. If no DLT was noted in cycle 1 with ACY-241, pts continued to cycle 2 of combo therapy with ACY-241/Pom/Dex. Pharmacodynamic assessments were acetylated tubulin (HDAC6 marker) and acetylated histones (Class 1 HDAC marker) in peripheral blood mononuclear cells. Results: Since June 2015, 40 pts have enrolled (34 safety-evaluable, 6 had no dosing information in the database). Median age was 62 (34-84) years and median number of prior regimens was 3 (1-7). 90% of pts were refractory to last treatment. 83% were refractory to Len and 50% to both bortezomib and Len. 20% of pts had high risk cytogenetics. No monotherapy DLTs were observed at the highest dose explored (480 mg). Common toxicities in the monotherapy safety population (N=15) were all grade 1/2, except 1 pt with grade 3 anemia at the 480 mg dose level. Toxicities included nausea (4 pts, 27%), anemia (3 pts, 20%), dizziness, fatigue, leukopenia and thrombocytopenia (2 pts each, 13%). Doses of 180 mg and 360 mg were explored in combination; one DLT (grade 4 thrombocytopenia) occurred at 360 mg. Common toxicities in the combination therapy safety population (N=33) included neutropenia (13 pts, 40%), fatigue (9 pts, 27%), anemia, leukopenia (6 pts each, 18%), cough, insomnia, rash (4 pts each, 12%), and hyperglycemia (3 pts, 9%). Grade 3/4 toxicities included neutropenia (10 pts, 30%), leukopenia (3 pts, 9%) and anemia (2 pts, 6%). PK results showed a dose-linear increase in exposure with increasing dose, no accumulation and no drug-drug interaction with Pom and Dex. Selective increase in acetylated tubulin was seen at 180 mg with increasing levels of acetylated tubulin and histones at higher doses. Confirmed efficacy data (median follow-up 3.5 months) for combination treatment (N=22, all refractory to last treatment regimen) shows 1 VGPR, 10 PR, 2 MR and 8 SD and 1 PD. Median PFS and duration of response were not reached at time of the data cut. Given the safety profile, PK exposure (Cmax~6 µM) and PD profile, the 360 mg QD dose level was recommended for further clinical exploration of ACY-241 in combination with Pom/Dex. Summary/Conclusion:ACY-241 is well tolerated in combination with Pom/Dex with dose proportional increase in drug exposure. Early response data to combination treatment parallel those observed with ricolinostat/Pom/Dex and compare favorably to historic controls of Pom/Dex. Cohort expansion at 360 mg ACY-241 with Pom/Dex is ongoing to confirm the dose and schedule for a planned pivotal trial of Pom/Dex +/- ACY-241 and to explore selected biomarkers. Disclosures Richardson: Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Nooka:Amgen: Consultancy; Spectrum: Consultancy; Novartis: Consultancy. Raab:Amgen: Consultancy, Research Funding; BMS: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Research Funding. Shain:Takeda/Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Speakers Bureau; Amgen/Onyx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Signal Genetics: Research Funding. Matous:Celgene: Consultancy, Speakers Bureau; Takeda Pharmaceuticals International Co.: Speakers Bureau; Seattle Genetics: Research Funding, Speakers Bureau. Agarwal:Celgene: Speakers Bureau; Onyx: Speakers Bureau; Janssen: Speakers Bureau; Amgen: Consultancy; Millennium: Consultancy; AbbVie: Honoraria, Research Funding. Madan:Amgen: Speakers Bureau; Onyx: Speakers Bureau; Takeda: Speakers Bureau; Celgene: Speakers Bureau. Moreau:Novartis: Honoraria; Takeda: Honoraria; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria. Mateos:Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Facon:Acetylon Pharmaceuticals Inc: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tamang:Acetylon Pharmaceutical Inc.: Employment. Jones:Acetylon Pharmaceuticals, Inc.: Employment, Equity Ownership. Markelewicz:Acetylon Pharmaceutical Inc.: Employment. Wheeler:Acetylon Pharmaceuticals Inc.: Employment. Trede:Acetylon Pharmaceutials Inc: Employment. Raje:Amgen: 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; Merck: Membership on an entity's Board of Directors or advisory committees; Novartis: 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; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Eli Lilly: Research Funding. Terpos:Amgen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Genesis: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Novartis: Honoraria; BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Takeda: Consultancy, Honoraria; Celgene: Honoraria. Bensinger:Amgen: Honoraria; Celgene: Honoraria; Acetylon Pharmaceuticals Inc.: Honoraria; Amgen: Consultancy; Celgene: Consultancy; Sanofi: Consultancy; Merck: Consultancy; Bristol-Meyers Squibb: Consultancy; Celgene: Speakers Bureau; Takeda: Speakers Bureau; Amgen: Speakers Bureau; Acetylon Pharmaceuticals Inc: Research Funding; Bristol-Meyers Squibb: Research Funding; Celgene: Research Funding; Karyopharm Therapeutics: Research Funding; Merck: Research Funding; Amgen: Research Funding; Sanofi: Research Funding; Takeda: Consultancy.