ALBERT

Description: Key Points Pomalidomide plus low-dose dexamethasone significantly improved PFS vs pomalidomide alone in relapsed and refractory multiple myeloma. Pomalidomide plus low-dose dexamethasone is an important new treatment option for RRMM patients who have received multiple prior therapies.

Description: Background: Donor grafts with more naive T cells and plasmacytoid dendritic cells were associated with improved overall survival after unrelated donor bone marrow, but not peripheral blood stem cell (PBSC) transplants (Waller, E JCO 2014). Here we present results on influence of innate and adaptive immune subsets in G-CSF mobilized allografts on incidence of acute GVHD (aGVHD) and chronic GVHD (cGVHD) in 238 patients (pts). Methods: We analyzed the absolute numbers and percentages of T, NK, NKT and B cells along with an extensive immunophenotypic characterization of their activation status in consecutive PBSC allografts obtained from sibling and unrelated donors between 2010 - 2014 and studied their association with the incidence of aGVHD and cGVHD. Wilcoxon rank sum tests were used to screen differential marker expression between those who did vs. did not develop aGVHD and similarly for cGVHD. Significant markers were evaluated in the multivariable (m.v.) setting along with known prognostic factors, including: recipient age, related vs. unrelated donor, female donor vs. not, Anti-thymocyte globulin (ATG) use (yes vs. no), and Reduced-intensity conditioning (RIC) vs. not. Cutpoints for markers were generated using recursive partitioning algorithms and evaluated in m.v. models. Results: Of the 238 alloSCT pts evaluated, most (71%) had unrelated donors, 64% received ATG, where most pts with unrelated donors received ATG (83%), and 78% received RIC. The incidence of aGVHD and cGVHD was 58% and 38% respectively. A total of 107 pts had grade II-IV aGVHD reported (71 II, 28 III, 8 IV), and 92 of 192 evaluable for cGVHD (at least 100 days of f/u) had reported cGVHD. Median follow-up in living pts was 21 months (range: 1.4 to 41.1 months). Table 1 shows dichotomized markers most influential on aGVHD. Higher absolute numbers of T cells, activated T cells, CD8+ cells, CD8+ cells expressing IL-7 receptor and CD27 were associated with higher incidence of aGVHD. Higher number of Stage 4 NK cells expressing stem cell factor receptor, and T-regs were associated with a lower incidence of aGVHD. Similar analyses were done for cGVHD (Table 2). Higher absolute numbers of activated T lymphocytes, activated B lymphocytes, KIR expressing CD3+ cells, CD8+ lymphocytes and activated NK cells were associated with higher incidence of cGVHD. When the percent of these makers in relation to total lymphocytes was evaluated regarding association with aGVHD, higher percent of T-regs (OR: 0.204, p=0.0018), effector memory T cells (OR: 0.45, p=0.024) and NKG2D positive NK cells (OR: 0.38, p=0.0008) conferred protection from aGVHD . Similar analysis for cGVHD showed higher percent of naïve CD4+ T cells conferred protection from cGVHD (OR: 0.44; p=0.0062) while higher percent of CD8+ cells (OR: 3.93; p=0.0032) and activated NK cells (OR: 2.08; p=0.024) was associated with cGVHD. Conclusions: These results show a protective role of donor T-regs, CD4+ T cells and Stage 4 NK cells from aGVHD. Additionally, higher content of activated T cells, CD8+ cells and B lymphocytes are associated with higher incidence of cGVHD. Higher content of activated NK cells seems to protect from aGVHD, but not from cGVHD. Updated results including multivariable analyses will be presented. These findings showing the influence of specific subsets in the allograft on aGVHD and cGVHD may provide opportunities for therapeutic interventions for graft engineering or pharmacologic methods for targeting specific immune subsets to decrease incidence of aGVHD and cGVHD. Table 1 Univariate model results for aGVHD with dichotomized markers using cutpoints: Marker Absolute OR p-value CD3+/CD5616- (T lymphocytes) 3.07 0.0013 CD3+/HLA DR+ (Activated T lymphocytes) 3.26 0.012 CD8+/CD45RA- (CD 8+ lymphocytes) 2.56 0.012 CD8+/CD27+ (Effector Memory CD8 cells) 3.25 0.0082 CD8+/CD127+ ( CD8 cells expressing IL-7 receptor) 2.92 0.073 CD4+/CD25+/CD127-(T regs) 0.43 0.057 CD3-/CD16-/CD56+/CD117+ (Stage 4 NK cells expressing Stem cell factor receptor) 0.12 0.0007 Table 2 Univariate model results for cGVHD with dichotomized markers using cutpoints: Marker Absolute OR p-value CD3+/HLA DR+ (Activated T lymphocytes) 4.41

Description: Abstract 2880 Poster Board II-856 Background: MM is increasing in incidence and remains incurable. .NK cells have modest killing activity against MM tumor cells in part because of inhibitory KIR receptors which recognize HLA class 1 antigens on MM tumor cell targets. However, experimental and clinical data in the allogeneic transplant setting suggest that NK cell stimulation by a mismatch between donor KIR and patient KIR ligand may improve outcomes for MM after a reduction of tumor burden by previously administered treatments. To mimic this effect with a pharmaceutical agent, 1-7F9/IPH2101, a fully human IgG4 anti-KIR mAb specific for KIR2DL1/2/3 (HLA-C specific KIRs) was generated (Romagne et al., Blood June, 2009). 1-7F9/IPH 2101 enhances patient NK cell cytotoxicity against autologous MM tumor cells in vitro. We present the interim results of the human phase I trial of this agent in patients with relapsed/refractory MM. Methods: An open-label, single-agent, dose-escalation, multiple dose safety and tolerability study of IPH2101 is being conducted in heavily pre-treated patients with relapsed/refractory MM. Dose escalation with IPH2101 (0.0003, 0.003, 0.015, 0.075, 0.3, 1, 3 mg/kg as IV infusion) is being studied using a 3+3 scheme. Re-dosing criteria (1/month x 4 months) are based on safety data from previous dosing. KIR occupancy, pharmacokinetics (PK), pharmacodynamics, effects on NK cell maturation, and biological effects of IPH 2101 are being monitored in all patients. Results: Currently, dose escalation is entering the final (3 mg/kg) cohort. Data from the first 22 treated patients are available. No Dose Limiting Toxicity (DLT) has been observed. 1 pt (at DL1) has been replaced and 3 additional pts have been enrolled (at DL4) due to an SAE an acute renal failure possibly related to drug. Related Adverse Events were seen in 4/22 patients (18%). 12/22 pts received at least 2 doses (6pts had 2, 1 pt had 3 and 5 pts had 4 cycles-median 2). KIR full occupancy (〉 90%) for at least 3 weeks is reached at 1mg /kg. In accordance with the pre-clinical PK/PD model there is a clear relationship between exposure (Cmax) and KIR occupancy. No deleterious effect on NK cell maturation has been seen. IPH 2101 has been well tolerated to date. In the cohorts accrued to date, two heavily pre-treated patients, both with high-risk cytogenetics, showed evidence to suggest disease stabilization while receiving IPH-2101. Conclusions: IPH 2101 improves autologous NK cell killing of MM tumor cells by blocking inhibitory KIR. In the on-going clinical trial, the antibody appears safe and well tolerated at the doses tested. Updated study results will be presented at the time of the meeting This immunotherapeutic approach may hold promise as treatment for MM and further study is warranted. Disclosures: Squiban: Innate pharma: Employment. Marzetto:Innate Pharma: Employment. Andre:Innate Pharma: Employment. Tollier:Innate Pharma: Employment.

Description: Background MLN9708 (ixazomib citrate) is an oral proteasome inhibitor that is being investigated in phase 3 trials. MLN9708 rapidly hydrolyzes to the biologically active form, MLN2238 (ixazomib). Preliminary findings from studies using weekly and twice-weekly schedules in relapsed/refractory MM have suggested evidence of single-agent activity (Kumar et al, ASCO 2013; Lonial et al, ASCO 2012), and a phase 1/2 study has suggested the feasibility and activity of weekly oral MLN9708 plus len-dex in newly diagnosed MM (Kumar et al, ASH 2012). Here we report the results of a phase 1/2 study, conducted in collaboration with the Multiple Myeloma Research Consortium, of twice-weekly oral MLN9708 plus len-dex (NCT01383928). Methods Phase 1 primary objectives were to determine safety, tolerability, the MTD, and the recommended phase 2 dose (RP2D); secondary objectives included characterizing MLN2238 pharmacokinetics (PK). Phase 2 primary objectives were to determine the combined CR+VGPR rate and further evaluate safety and tolerability; secondary objectives included overall response rate (≥PR), time to response, and duration of response (DOR). Pts aged ≥18 yrs who had no grade ≥2 peripheral neuropathy (PN) and no prior/concurrent DVT/pulmonary embolism received MLN9708 3.0 or 3.7 mg (d 1, 4, 8, 11), len 25 mg (d 1–14), and dex 20/10 mg (cycles 1–8/9–16; d 1, 2, 4, 5, 8, 9, 11, 12) for up to 16 21-day cycles, followed by MLN9708 maintenance (same schedule) until progression or unacceptable toxicity. Transplant-eligible pts could undergo stem cell collection after ≥4 cycles and discontinue for ASCT after ≥8 cycles. Responses were assessed per IMWG uniform response criteria. Adverse events (AEs) were graded per NCI-CTCAE v4.03. Blood samples for PK analysis were taken at multiple time points during cycles 1 and 2. Results 64 pts were enrolled; median age was 64 yrs (range 34–82), 63% were male, and 31%/16% had ISS stage II/III MM. In phase 1, 14 pts received MLN9708 3.0 mg (n=7) and 3.7 mg (n=7). No DLTs were seen in cycle 1; based on overall tolerability and incidence of rash at 3.7 mg, the RP2D was chosen as 3.0 mg. 50 pts were enrolled at this dose in phase 2. At data cut-off (July 1, 2013), the median follow-up was 6.9 months and median number of cycles received was 8 (range 1–26); 73% had received ≥8 cycles and 9% had received ≥16 cycles. At data cut-off, 22% of pts had discontinued to undergo ASCT (median CD34+ stem cell yield 14.9 x 106/kg [range 7–52 x 106]), a further 14%, 5%, and 19% had discontinued due to AEs, progressive disease, and other reasons, respectively, and the other 41% remained on treatment. In 58 response-evaluable pts, ≥PR rate to date was 93%, including 67% ≥VGPR (24% CR, including 14% sCR). 54% of pts had 100% decreases in M-protein or serum free light chain from baseline. Analysis of minimal residual disease is ongoing; data will be presented. Depth of response increased over the course of treatment; median time to first response (≥PR) was 0.69 mos and to best response to date was 2.07 mos. Median DOR to date was 5.9+ mos, ranging up to 18+ mos. Most common AEs were rash (61%; pooled high-level terms), fatigue, peripheral edema (each 50%), diarrhea (41%), and neuropathy peripheral (36%). Drug-related (to any drug in the regimen) grade 3 AEs were seen in 56% of pts, including rash (16%), hyperglycemia (8%), pneumonia (6%), and PN (5%; high-level term). No drug-related grade 4 AEs were seen; 58% of pts required dose reductions of at least one drug due to AEs including rash (16%), anxiety (11%), and PN (8%). AEs resulting in discontinuation were seen in 11%, with the majority reported as not related to therapy. There was 1 on-study death due to cardio-respiratory arrest, likely a pulmonary embolism, considered by the investigator to be unrelated to MLN9708 or dex, but probably len. Based on phase 1 preliminary PK data, MLN2238 was absorbed quickly with a Tmaxof 0.5–4 hours. Terminal half-life was 2–8 days. PK data were similar to single-agent twice-weekly dosing studies, suggesting no MLN2238 PK interaction with len or dex. Conclusions These data suggest that twice-weekly oral MLN9708 plus len-dex is feasible and active in pts with newly diagnosed MM. However, rates of rash, PN, and dose reductions appear higher than in the parallel study using weekly MLN9708, with similar response rates and better convenience, supporting use of weekly dosing in ongoing phase 3 trials. Disclosures: Richardson: Millennium: The Takeda Oncology Company: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity’s Board of Directors or advisory committees. Off Label Use: Investigational agent MLN9708 in combination with lenalidomide and dexamethasone for the first-line treatment of patients with multiple myeloma. Hofmeister:Celgene: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Rosenbaum:Janssen: Membership on an entity’s Board of Directors or advisory committees; Celgene: Speakers Bureau. Vesole:Millennium: The Takeda Oncology Company: Speakers Bureau; Celgene: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Onyx Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Liedtke:Celgene: Research Funding; Millennium: The Takeda Oncology Company: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Chari:Celgene: Consultancy, 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 Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees. Lebovic:Celgene: Membership on an entity’s Board of Directors or advisory committees; Onyx: Membership on an entity’s Board of Directors or advisory committees. Berg:Millennium: The Takeda Oncology Company: Employment. Liao:Millennium: The Takeda Oncology Company: Employment. Gupta:Millennium: The Takeda Oncology Company: Employment. Di Bacco:Millennium: The Takeda Oncology Company: Employment. Estevam:Millennium: The Takeda Oncology Company: Employment. Hui:Millennium: The Takeda Oncology Company: Employment. Baz:Celgene: Research Funding; Millennium: The Takeda Oncology Company: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Research Funding; Sanofi: Research Funding; Karyopharm: Research Funding.

Description: Abstract 727 Background: Pomalidomide (POM) is a distinct IMiD® immunomodulatory agent whose mechanism of action consists of 3 primary effects: potent direct anti-myeloma activity, inhibition of stromal cell-support, and immune modulation (Quach, Leukemia, 2010). Combining an immune modulator (lenalidomide), a proteasome inhibitor (bortezomib [BTZ]), and dexamethasone (DEX) has shown preclinical synergy as well as promising efficacy both as frontline and salvage treatment in myeloma patients (pts) (Mitsiades, Blood, 2002; Richardson, J Clin Oncol, 2009; Richardson, Blood, 2010). This phase 1 study was conducted in pts with relapsed or refractory multiple myeloma (RRMM) to identify the maximum tolerated dose (MTD) of POM in combination with BTZ and low dose DEX (LoDEX). Based on the MTD finding of this trial, POM + BTZ + LoDEX will be compared with BTZ + LoDEX in a large Phase III confirmatory trial with an estimated sample size of 782 RRMM pts. Methods: Eligible pts had 1–4 prior lines of therapy, were refractory to LEN, and must have been exposed to a proteasome inhibitor (PI) (but could not be BTZ-refractory). Refractory disease was defined as documented progressive disease (PD) during treatment or within 60 days of last dose. MTD determination will follow a traditional 3 + 3 design. Pts were treated with escalating doses of oral POM (cohort [CHT] 1: 1 mg; CHT 2: 2 mg; CHT 3: 3 mg; CHT 4 and 5: 4 mg) on days 1–14 and intravenous BTZ (CHTs 1–4: 1 mg/m2; CHTs 5: 1.3 mg/m2) on days 1, 4, 8, and 11 for cycles 1–8 then on days 1 and 8 for C9 and onward. All CHTs received oral DEX (20 mg or 10 mg for patients ≤ 75 or 〉 75 years of age, respectively) on days 1, 2, 4, 5, 8, 9, 11, and 12 in 21-day cycles. All pts received thromboprophylaxis with low-dose aspirin, low molecular weight heparin, or an equivalent agent. Herpes zoster prophylaxis was with acyclovir or equivalent per institutional guidelines. Dose-limiting toxicities (DLTs) were assessed during C1. Treatment was continued until PD or unacceptable toxicity. The primary objective was MTD determination. Secondary objectives included safety, response, overall survival, time to response, and duration of response. Results: Based on data available as of 31Jul2012, a total of 9 pts (3 men and 6 women) were enrolled in the first 3 dose CHTs. The median age was 61 years old (range: 36–75) with a median time from diagnosis of 48.9 months (range: 30.1–146.3). The median number of prior anti-MM regimens was 3 (range: 2–4). All 9 pts were refractory to LEN at study entry and had prior exposure to a PI, but were not BTZ refractory. As of 31Jul2012, 8 pts were on study treatment in the first 3 dose CHTs, with a median of 3 cycles (range 1 –6) of treatment. One pt (CHT 1) discontinued treatment at Cycle 5 (C5) due to PD. All pts enrolled in the first 3 CHTs, CHT 1 (n=3), CHT 2 (n=3), CHT 3 (n=3) completed at least 1 treatment cycle. No DLTs were observed in any pts in the first 3 CHTs. Pts in CHT 1, CHT 2 and CHT 3 have been treated for 4 to 6 cycles, 2 to 3 cycles, and 1 cycle respectively. Overall, 9 (100%) pts had at least 1 adverse event (AEs) of any grade reported, with Grade 3 or 4 AEs reported in 7 (78%) pts. No Grade 4 AEs were reported during C1. The following Grade 3 AEs were reported during C1: neutropenia (CHT 3), thrombocytopenia (CHT 3), and UTI (CHT 1). No ≥ Grade 3 peripheral neuropathy was reported. No thromboembolic AEs were reported. No pts required a reduction in POM dosing due to AE. Three pts required interruption of POM due to AE (after C1). Two pts required an interruption/reduction in BTZ dosing due to AEs (after C1). Disease response was assessed using the IMWG criteria by the investigators. In CHT 1, one pt achieved stable disease (SD) prior to discontinuing due to PD at C5; 2 pts achieved confirmed response (1 PR, 1 VGPR) and continue on therapy. In CHT 2, two pts have achieved SD, and 1 pt has reached an unconfirmed PR (uPR) with treatment ongoing in all 3. In CHT 3, one pt achieved SD and 2 pts attained uPR. Enrollment into CHT 4 (POM = 4mg) is underway at this time. Conclusions: POM in combination with 1mg/m2 of IV BTZ and oral LoDEX administered according to the classical schedule appears to be well tolerated from 1 mg up to 3 mg dose levels given daily for 14 days every 3 weeks. This combination shows rapid onset of response and promising clinical activity in LEN-refractory pts with prior exposure to PI therapy. The study is ongoing with rapid accrual; results for all dosing cohorts with longer follow-up will be presented at the meeting. Disclosures: Richardson: Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Pomalidomide is an investigational drug and is not approved for the treatment of patients with any condition. Hofmeister:Celgene: Advisory board Other, Honoraria. Siegel:BMS: Consultancy; Millennium: Consultancy; Novartis: Consultancy; Onyx: Consultancy; Celgene: Consultancy; Merck: Consultancy. Lonial:BMS: Consultancy; Onyx: Consultancy; Millennium: Consultancy; Novartis: Consultancy; Merck: Consultancy; Celgene Corp: Consultancy. Zaki:Celgene Corp: Employment, Equity Ownership. Hua:Celgene Corp: Employment, Equity Ownership. Shah:Celgene Corp: Employment, Equity Ownership. Wang:Celgene Corp: Employment, Equity Ownership. Anderson:Celgene Corp: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees.

Description: Abstract 450 Background: New antimyeloma treatments that re-establish tumor response are required to improve survival for pts with advanced, treatment-refractory MM. The MM-002 phase 2 study evaluated the safety and efficacy of oral pomalidomide, in combination with low-dose dexamethasone (POM+LoDex), in pts with relapsed and refractory multiple myeloma (RRMM) who have who have received ≥2 prior therapies including LEN and BORT (Richardson PG, et al. Blood 2011;118:abs 634). Updated results from March 2012 for pts and the outcomes of subgroup analyses are presented. Methods: Eligible pts with MM who had received at least 2 prior therapies (including LEN and BORT) and had disease progression within 60 days of their last treatment were randomized (1:1 ratio) to either POM+LoDEX (POM, 4 mg/day for days 1–21 of a 28-day cycle; LoDex, 40 mg/week) or POM alone. At progression, pts receiving POM alone could receive POM+LoDEX at investigator's discretion. Pts aged over 75 years received LoDex, 20 mg/week. All pts received mandatory thromboprophylaxis (daily low-dose aspirin). Pts were stratified within each treatment group according to age. The key efficacy endpoints included the objective response rate using European Bone Marrow Transplantation (EBMT) criteria, duration of response, progression free survival (PFS) and overall survival (OS), and safety. This updated analysis focused on pts on the POM+LoDex arm. Results: The intention-to-treat efficacy analysis included 113 pts in the POM+LoDex group. The mean age of pts treated with POM+LoDex was 64 years (range, 34–88); 99 pts (88%) were aged ≤75 years. Response rates, median duration of response, and age subgroups are presented in the Table. Median PFS and OS were 4.6 months (mos) and 16.5 mos, respectively, in the POM+LoDex group overall. In the age subgroup analysis of pts treated with POM+LoDex, the median PFS was 4.7 mos in pts aged ≤65 years, and 3.7 mos in pts 〉65 years. Median OS was 19.7 mos in pts aged ≤65 years and 11.8 mos in pts 〉65 years. The most common grade 3 or 4 adverse events (AEs) occurring in 〉5% of pts were neutropenia (41%), anemia (22%), pneumonia (22%), thrombocytopenia (19%), fatigue (14%), dyspnea (13%), leukopenia (10%), back pain (10%), and urinary tract infection (9%). AEs led to at least one dose reduction in 26% of pts; neutropenia was associated with a dose reduction in 4% of pts. Overall, 78% of pts who developed grade 3 or 4 neutropenia used G-CSF during study treatment. There were no reports of grade 3 or 4 peripheral neuropathy (PN); grade 1 or 2 PN occurred in 7% of pts treated with POM+LoDex. Deep vein thrombosis (any grade) occurred in 2 pts (2%), both aged ≤65 years. Grade 3 or 4 neutropenia occurred in 46% of pts aged ≤65 years and in 35% of pts aged 〉65 years. Despite this, only 1 pt in each age group developed febrile neutropenia (2%). The mean relative dose intensity (dose intensity/planned dose intensity) was 0.9 in both pt groups of ≤65 years and 〉 65 years receiving POM+LoDex. Overall, 21 pts (19%) of the POM+LoDex group died during the study. The most common cause of death was progressive MM (52%; only in 14% of all cases was it due to disease progression); other causes of death (48%) included infections, cerebral/intracranial/subarachonoid hemorrhage, acute respiratory distress syndrome, and suicide in one pt with a history of severe depression. Conclusions: POM, 4 mg/day for days 1–21 of a 28-day cycle in combination with LoDex, is clinically effective and generally well tolerated in pts with RRMM who have received multiple prior treatments including LEN and BORT. POM+LoDex represents an important potential new treatment option for pts with advanced MM and appears active in both younger and older pts, with tolerability similar across different age groups. Phase 3 studies of POM+LoDEX in combination with other agents (e.g. bortezomib) are ongoing. Disclosures: Jagannath: Millennium Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck Sharp & Dohme: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx Pharma: 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. Off Label Use: Pomalidomide is an investigational drug and is not approved for the treatment of patients with any condition. Hofmeister:Celgene: Advisory Board Other, Honoraria. Siegel:Onyx: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Millennium Pharma: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Celgene: Advisory Board Other, Honoraria, Speakers Bureau; Merck: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau. Vij:Onyx: Consultancy, Research Funding; Millennium Pharma: Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau. Lonial:Millennium, Celgene, Novartis, BMS, Onyx, Merck; all 〈 $10,000 per year and disclosed to my institution: Consultancy. Anderson:Acetylon, Oncopep: Scientific Founder, Scientific Founder Other; Celgene, Millennium, BMS, Onyx: Membership on an entity's Board of Directors or advisory committees. Chen:Celgene: Employment, Equity Ownership. Zaki:Celgene: Employment, Equity Ownership. Richardson:Celgene, Millennium, Johnson & Johnson: Advisory Board Other.

Description: Introduction: Multiple myeloma (MM) evolves from precursor disorders such as monoclonal gammopathy of undetermined significance (MGUS) and SMM (Landgren O, et al. Blood 2009. 113[22]:5412-5417). Currently, there are no approved therapies for SMM, and guidelines recommend close monitoring of SMM patients (pts) and initiating treatment only upon progression to MM. However, therapeutic intervention at the SMM stage, especially in pts at higher risk of progression to MM, may yield clinical benefit and prevent the development of MM-associated complications. DARA is a CD38-targeting IgG1κ monoclonal antibody with on-tumor and immunomodulatory mechanisms of action. Based on the demonstrated efficacy and favorable safety profile of DARA monotherapy in pts with relapsed/refractory MM (RRMM; Usmani SZ, et al. Blood 2016. 128[1]:37-44), we hypothesized that DARA could delay progression from SMM to MM. A prespecified primary analysis (15.8-month median follow-up) of the phase 2 CENTAURUS study (NCT02316106) revealed that DARA monotherapy was active and well tolerated in pts with intermediate- or high-risk SMM (Hofmeister CC, et al. ASH 2017. Abstract 510). Here, we present updated data from CENTAURUS based on 10 months of additional follow-up. Methods: Eligible pts had had a confirmed diagnosis of high-risk or intermediate-risk SMM for

Description: 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.

Description: Introduction Multiple myeloma (MM) remains an essentially incurable plasma cell malignancy. MM utilizes specific immunoevasive strategies to avoid natural killer (NK) cell immune surveillance and cytotoxicity. Immunomodulatory agents such as lenalidomide (LEN) may exert indirect anti-MM efficacy via expansion and activation of NK cells. However, these favorable effects may be diminished when LEN is co-administered with high doses of dexamethasone (DEX). IPH2101 is a monoclonal anti-inhibitory KIR antibody which prevents negative signaling in NK cells and enhances NK cell recognition and killing of MM cells. A single-agent, phase I study of IPH2101 demonstrated full KIR blockade with encouraging safety and tolerability, and 34% of heavily pre-treated patients achieved disease stabilization (Blood 2012;120:4324-33). Preclinical data demonstrate that LEN and IPH2101 exert anti-MM effects via complementary NK-cell immunomodulatory mechanisms (Blood 2011;118:6397-91). Herein, data are presented from the first clinical experience with IPH2101 and LEN in combination in patients with MM. Methods A 3+3 phase I dose-escalation trial was conducted. Patients (age 18-80) with measurable, progressive MM were enrolled having received one or two prior lines of therapy. Prior LEN exposure was permitted unless resistance or intolerance was observed. Patients must have had ECOG performance status ≤ 2, creatinine clearance ≥ 60 ml/min, platelets ≥ 75,000/uL (or ≥ 30,000/uL if 〉 50% bone marrow plasma cells), absolute neutrophil count ≥ 1,000/uL, bilirubin 〈 1.5 ULN, and ALT / AST 〈 3 ULN. Patients must have adhered to standard prescribing guidelines for LEN. Three dose levels included: IPH2101 0.2mg/kg IV q 28 days + LEN 10 mg PO days 1-21; IPH2101 0.2 mg/kg + LEN 25 mg, and IPH2101 1mg/kg + LEN 25 mg for 4 cycles. Responding patients were allowed to receive 4 additional cycles. Patients completing all 8 cycles were maintained on LEN thereafter. No administration of DEX or other systemic corticosteroids was permitted. Dose reductions of LEN were permitted per prescribing information. The primary objective was to determine the safety and tolerability of IPH2101 + LEN, the secondary objectives included pharmacokinetics (PK) and pharmacodynamics (PD) of IPH2101 and biologic correlates with LEN as well as to determine clinical activity by standard IMWG uniform response criteria. Results 15 patients (10 M, 5 F, median age 60) were enrolled, 8 in first relapse and 9 in second relapse. 9 had prior LEN exposure. Cohorts 1 and 3 were expanded to n=6 patients respectively due to occurrence of possible dose-limiting toxicity. In both cases, a patient experienced a similar, apparent infusion reaction on cycle 1, day 1, characterized by fever, chills, cytokine release, and leucopenia. Events resolved with supportive care and both patients continued on trial without recurrence. The protocol was amended to include premedication with anti-histamine and acetaminophen,and no further infusion reactions were observed. Most other observed adverse events were of low grade and generally investigator-attributed as possibly or probably related to LEN. IPH2101 PD were not affected by co-administration of LEN. Full KIR occupancy was achieved in cohort 3 across the dosing interval. Five patients achieved a response (2 VGPR, 3 PR) with a median duration of 15+ months (3-26+). Conclusion The combination of IPH2101 + LEN appears to be a safe and well tolerated, and steroid-free combination in MM patients. Infusion reactions have not been observed since the addition of premedication prior to IPH2101 dosing. IPH2101 PD do not appear to be altered by co-administration of LEN, and full KIR blockade over the dosing interval has been achieved. Although the study is small, response rate and response duration are encouraging. These findings support further investigation of antiKIR therapy with LEN as the first, steroid-sparing, dual immunotherapy for MM. Disclosures: Benson: Innate Pharma: Research Funding. Off Label Use: Lenalidomide without concomitant dexamethasone. Zerbib:Innate Pharma: Employment. Andre:Innate Pharma: Employment. Caligiuri:Innate Pharma: Membership on an entity’s Board of Directors or advisory committees.

Description: Background: Maintenance therapy with lenalidomide post-autologous stem cell transplantation (ASCT) has shown to improve progression-free survival (PFS) in multiple myeloma (MM), and has largely become the standard of care. However, toxicity leads to early discontinuation in nearly one-third of patients and additional options are needed (McCarthy, et al, JCO, 2017). Ixazomib is another maintenance option that has been shown to improve PFS; however, studies comparing lenalidomide and ixazomib are lacking. In this randomized phase 2 study, we analyzed the safety and efficacy of using lenalidomide and ixazomib as part of consolidation and maintenance therapies after ASCT (NCT02253316). Methods: Eligible patients, age 18-70 with newly diagnosed MM undergoing ASCT during first-line treatment, were consented prior to ASCT. Approximately 4 months following ASCT, patients received 4 cycles of consolidation therapy with IRd [ixazomib 4 mg on days 1, 8 and 15 of a 28-day cycle, lenalidomide 15 mg on days 1 through 21, and dexamethasone 40 mg on days 1, 8 and 15]. Primary data on IRd consolidation were presented at ASH 2018 (Abstract 109920). One month after the last consolidation cycle, patients were randomized (1:1) to maintenance therapy with single-agent ixazomib (4 mg on days 1, 8 and 15 of a 28-day cycle) or lenalidomide (10 mg daily months 1-3 followed by 15 mg for months 4+). The arms were stratified based on MRD-status post-consolidation. In total, 237 patients were enrolled from 10 US centers. This abstract coincides with planned interim analysis 3 which is the first comparison of ixazomib and lenalidomide maintenance. While the study was not powered to compare PFS between the two arms, the sample will provide a reasonable power to estimate non-inferiority. There is a planned stopping rule for non-inferiority set at a hazard ratio of 〉1.3 in favor of lenalidomide. Secondary end-points include MRD-negativity following 12 cycles and toxicity. Results: At time of abstract submission, 215 patients had completed IRd consolidation and 191 had begun maintenance. 90 were randomized to ixazomib and 94 to lenalidomide. 7 patients were not randomized due to toxicity during consolidation; data from these patients are not included in the analyses. The characteristics of the two arms are summarized in Table 1. Hematologic toxicity has been infrequent with ixazomib with neutropenia and thrombocytopenia occurring in 11% and 23% of patients. In comparison, neutropenia and thrombocytopenia occurred in 45% and 35% of patients on lenalidomide. The most common non-hematologic toxicities in both arms have been GI-related and infections, both expected events. 16% of patients on ixazomib have experienced Grade 3-4 non-hematologic toxicity compared to 34% on lenalidomide. No grade 3 or higher peripheral neuropathy has been reported in either arm. 11% of patients on ixazomib have discontinued due to toxicity and another 9% have required a dose reduction to 3mg. Lenalidomide toxicity has led to discontinuation in 15% of patients and another 12% were dose reduced to 5mg. Only 45% of patients receiving 4+ cycles of lenalidomide were able to titrate to the 15mg dose. After a median follow-up of 11.2 months from randomization (19.7 months post-ASCT), 30% of patients on ixazomib have discontinued treatment due to disease progression. After a median follow-up of 12.3 months from randomization (20.2 months post-ASCT), 18% patients on lenalidomide have discontinued treatment due to disease progression. Conclusion: Ixazomib and lenalidomide maintenance have been well tolerated to date. A comparison of PFS is currently being conducted as part of interim analysis 3 and final results will be presented, representing the first report directly comparing lenalidomide and ixazomib maintenance. Table 1: Disclosures Vij: Genentech: Honoraria; Karyopharm: Honoraria; Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Janssen: Honoraria; Sanofi: Honoraria. Martin:Amgen, Sanofi, Seattle Genetics: Research Funding; Roche and Juno: Consultancy. Fiala:Incyte: Research Funding. Deol:Novartis: Other: Advisory board; Kite: Other: Advisory board; Agios: Other: Advisory board. Kaufman:Celgene: Consultancy; Winship Cancer Institute of Emory University: Employment; Amgen: Consultancy; Bristol-Myers Squibb: Consultancy; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Janssen: Honoraria; Incyte: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy; Takeda: Consultancy. Hofmeister:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Nektar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Imbrium: Membership on an entity's Board of Directors or advisory committees. Gregory:Poseida: Research Funding; Celgene: Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau. Berdeja:AbbVie Inc, Amgen Inc, Acetylon Pharmaceuticals Inc, Bluebird Bio, Bristol-Myers Squibb Company, Celgene Corporation, Constellation Pharma, Curis Inc, Genentech, Glenmark Pharmaceuticals, Janssen Biotech Inc, Kesios Therapeutics, Lilly, Novartis, Poseida: Research Funding; Poseida: Research Funding; Amgen Inc, BioClinica, Celgene Corporation, CRISPR Therapeutics, Bristol-Myers Squibb Company, Janssen Biotech Inc, Karyopharm Therapeutics, Kite Pharma Inc, Prothena, Servier, Takeda Oncology: Consultancy. Chari:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: 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; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Array Biopharma: Research Funding; GlaxoSmithKline: Research Funding; Novartis Pharmaceuticals: Research Funding; Oncoceutics: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees. Rosko:Vyxeos: Other: Travel support.