Zimmerman, Todd M.

8054 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. Herein we provide survival outcomes on the first randomized trial in newly diagnosed HRMM, S1211, to follow-up on the previously reported progression-free survival (PFS) (NCT01668719, Usmani SZ et al, Lancet Haem 2021). Methods: S1211 is a randomized phase II trial comparing 8 cycles of lenalidomide, bortezomib and dexamethasone (RVd) induction followed by dose-attenuated RVd maintenance until disease progression with or without elotuzumab (RVd-Elo). Stem cell collection was allowed, but ASCT was deferred until progression. HRMM was defined by one of the following: gene expression profiling high-risk (GEPhi), t(14;16), t(14;20), del(17p), amplification 1q21, primary plasma cell leukemia (pPCL), or elevated serum LDH (> 2X ULN). Median PFS was the primary endpoint, 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. 74% had ISS II/III, 48% amp1q21, 38% del(17p), 11% t(14;16), 9% GEPhi, 7% pPCL, 5% t(14;20) and 4% elevated LDH (17% >1 feature). With median follow-up of 72 months (mos.), no difference in median PFS was observed [RVd-Elo=29 mos., RVd= 34 mos., HR = 1.11 (80% CI=0.82, 1.49, p=0.66]. No difference in OS was observed [RVd-Elo = median not reached (NR), RVd= 68 mos., HR = 0.85 (80% CI: 0.59, 1.23), p-value = 0.58]. 76% pts had >Grade 3 AEs, no differences in the safety profile were observed. Amongst patients with gain/amp 1q21, median PFS was [RVd-Elo=31 mos., RVd= 37 mos., HR = 1.48 (80% CI= 0.95, 2.31), p=0.25], median OS was [RVd-Elo = 61 mos., RVd= 68 mos., HR = 1.23 (80% CI: 0.72, 2.10), p-value = 0.63]. In patients with del(17p), median PFS was RVd-Elo=41 mos., RVd= 30 mos.[HR = 0.98 (80% CI= 0.60, 1.58), p=0.95], median OS RVd-Elo = NR, RVd= 72 mos., [HR = 0.77 (80% CI: 0.40, 1.48), p-value = 0.61]. Conclusions: In the first randomized HRMM study reported to date, the addition of Elo to RVd induction and maintenance did not improve PFS and OS with a median follow-up of 6 years. Although the median PFS for Del17p subgroup on RVd-Elo arm is higher than RVd, it did not achieve statistical significance. The PFS and OS observed for gain/amp 1q21 and del17p in the RVd control arm may serve as important benchmarks for future enrichment design HRMM clinical trials. The PFS and OS in both arms of the study exceeded the original statistical assumptions and support the role for PI/IMiD combination induction/maintenance therapy for this population. Clinical trial information: NCT01668719.

Abstract Introduction: Clinical availability of highly effective novel agents (including Bruton tyrosine kinase [BTK] and B-cell lymphoma 2 [BCL-2] inhibitors) is rapidly altering the therapeutic landscape of chronic lymphocytic leukemia (CLL) necessitating a review of treatment guidelines. However, there is limited real-world data to validate if the availability of these novel agents has translated to a true shift in treatment paradigm for patients treated in the community. As the majority of CLL patients are treated in non-academic community-based settings, we investigated the clinical adoption trends of commercially available FDA approved novel agents for treatment of CLL patients. In addition, given that the COVID-19 pandemic led to major alteration in clinical oncology practices, we further studied if this contributed to an alteration in the selection of therapeutic agents resulting in changes of CLL treatment patterns and the utilization of novel agents in the real-world setting. Thus, the objectives of this study were to examine the utilization pattern of various CLL therapies, as well as evaluate the pattern of adoption of novel agents for treatment and the impact of COVID. Methods: A retrospective observational study was conducted using the Flatiron Health database that comprised EHR-derived de-identified data. Adult patients (≥18 years) with newly diagnosed CLL from January 2014 to May 2021, with no prior treatment and who were continuously enrolled for at least 6 months before and 3 months after the index date, defined as the first date of CLL/SLL diagnosis were included. Treatment regimens were classified into seven mutually exclusive categories: bendamustine-based chemotherapy, other chemotherapy, anti-CD20-based therapy, ibrutinib, idelalisib, acalabrutinib and venetoclax. Further treatment categorization included chemotherapy vs. targeted therapy, and traditional IV vs. novel oral agents. The impact of the pandemic was examined by comparing the pre- and post-COVID cohorts (defined as 15 months pre- and post- of March 1, 2021). Descriptive analyses were conducted to examine the frequency of use of treatment regimens by quarter in each year, line of therapy and between different age, gender, US geographical region, insurance status, and race/ethnicity subgroups. Multivariable regression was conducted to examine factors associated with the likelihood of adoption of novel and oral agents. Statistical significance was determined at a p-value of less than 0.05. Results: A total of 3,037 newly diagnosed CLL patients (median age =73) were included in the study. Over half were male (62.3%), white (74.6%) and commercially-insured (54.1%). Patients were primarily treated in community practices (92%). Overall, a significant trend in adoption of novel agents was observed throughout the years following their approval (Figure 1A). Across the evaluation period, a significant decrease in chemotherapy use was observed from 61.3% (quarter 1, 2014) to 20% (quarter 2, 2021) in favor of targeted therapy as first-line therapy (Figure 1B). In contrast, the utilization of novel oral agents (vs. traditional IV agents) for first-line therapy increased from 9.5% to 70.9% for the same period (Figure 1C). Similar trends were observed for second-line and third-line therapies. Encouragingly, this change in treatment patterns was adopted comparably in all sociodemographic subgroups with no evidence of disparity. While there was no statistically significant difference between the pre- and post-COVID treatment landscape, the adoption of target and novel oral agents has been more pronounced with the COVID pandemic. Conclusions: Results from real-world data suggest that there is a clear shift towards the adoption of novel therapies with preference given to targeted agents and oral therapies in the US since 2014. Further research examining real-world outcomes associated with treatment regimens are needed to inform decision makers. Figure 1 Figure 1. Disclosures Chanan-Khan: Cellectar: Current equity holder in publicly-traded company; Alpha2 Pharmaceuticals, NonoDev, Starton: Current holder of stock options in a privately-held company; Ascentage: Research Funding; Alpha2 Pharmaceuticals: Patents & Royalties: Tabi; Ascentage, Starton, Cellectar, NonoDev, Alpha2 Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; BeiGene, Jansen, Ascentage: Honoraria; BieGene, Jansen, Ascentage: Consultancy. Yang: BeiGene, Ltd.: Current Employment. Liu: BeiGene, Ltd.: Current Employment. Zimmerman: BeiGene, Ltd.: Current Employment. Tang: BeiGene, Ltd.: Current Employment. Ailawadhi: Karyopharm: Consultancy; AbbVie: Consultancy; Genentech: Consultancy; Takeda: Consultancy; GSK: Consultancy, Research Funding; Xencor: Research Funding; Cellectar: Research Funding; Medimmune: Research Funding; Ascentage: Research Funding; Pharmacyclics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; BeiGene, Ltd.: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy.

Abstract Introduction: Prognostic testing, including immunoglobulin heavy-chain variable region gene (IgHV) mutation status, cytogenetic abnormalities by fluorescence in situ hybridization (FISH), and immunophenotyping has been recommended in all newly diagnosed patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) prior to treatment initiation, and even in previously treated patients in some settings. Recent data have shown that disease with high-risk genetic features is better managed with novel agents than traditional chemoimmunotherapy. As such, the need for testing has become more relevant for disease management. However, there is limited recent data on real-world patterns of testing for risk factor assessment and in-turn, patterns of evidence-based treatment selection. This study aimed to examine: (1) the frequency and results of testing, (2) timing of testing by line of therapy, and (3) factors associated with the receipt of testing. Methods: De-identified data from the Flatiron Health EHR-derived database was used to identify patients who were ≥18 years old with newly-diagnosed CLL/SLL, who had ≥6-month continuous enrollment, and no prior treatment from January 2014 to May 2021. Testing evaluated included IgHV mutation status, FISH cytogenetic (11q deletion [del(11q)], 13q deletion [del(13q)], 17p deletion [del(17p)], Trisomy 12 [+12]) and other biomarkers (including CD38 and ZAP-70) by immunophenotyping. Descriptive analyses were conducted to examine the frequency and results in the overall population, and compared by patient characteristics and across sociodemographic groups. Multivariable logistic regression was conducted to examine factors associated with the likelihood of receiving testing. Statistical significance was determined as a p-value of <0.05. Results: A total of 3,037 CLL patients were included (median age=73, 62.3% male, 74.6% white). The majority of patients (92%) received treatment in community practices, with 54.1% commercially-insured. We observed over half of CLL patients did not receive risk factor testing (Figure 1): IgHV mutation analyses (76.2%, n=2,315), FISH (61.5%, n=1,868) and immunophenotyping (72.1%, n=2,190). Of those who had testing, the majority (99%) had it done once prior to starting first-line therapy. Significant differences in the receipt of testing were observed between different age, gender, race/ethnicity, and regional subgroups (Table 1). Among patients who received testing, the presence of high-risk biomarkers was as follows: unmutated IgHV (56.1%), del(17p) present (14.4%), del(11q) present (16.9%), and CD38 present (30.8%). Compared to patients <65 years, testing results in elderly patients ≥65 years showed a lower presence of unmutated IgHV (53.8%) and del(11q) (15.7%) while higher del(17p) (14.7%) and +12 (28.1%). No significant disparity was observed in white vs. non-white patients except for a lower incidence of mutated IgHV and del(13q) presence. Compared to tested men, tested women had a lower presence of unmutated IgHV (53.9%), del(11q) (11.4%) and CD38+ (25.8%) while higher del(17p) (18.2%). We then investigated the impact of risk testing on therapy selection, and noted that patients with del(17p) had a higher likelihood than those who tested negative (73.6% vs. 48.4%) of being treated with novel agents (ibrutinib, acalabrutinib, or venetoclax). In contrast, 26.4% of those who tested del(17p) present and 39.8% among those who did not get tested received chemotherapy. Multivariable regression showed that patients who were older (≥65 years), female or those living in the west of U.S. were significantly less likely to receive testing. Conclusions: The NCCN guidelines recommend novel agents for patients with high-risk CLL/SLL. Thus, all patients are advised to complete risk-factor testing for both prognostication and selection of optimal, evidence-based therapy. Our real-world data highlights not only a significant gap in testing, but that this suboptimal testing is more common in vulnerable populations. We observed that despite identification of del(17), a quarter of CLL patients failed to receive novel agents in the frontline setting. Our analysis identified an unmet need for further education and refinement of clinical practice. This is necessary to achieve the best clinical outcome in CLL patients through robust risk-assessment testing and optimal therapeutic triaging. Figure 1 Figure 1. Disclosures Chanan-Khan: BieGene, Jansen, Ascentage: Consultancy; Ascentage, Starton, Cellectar, NonoDev, Alpha2 Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Alpha2 Pharmaceuticals: Patents & Royalties: Tabi; Ascentage: Research Funding; Cellectar: Current equity holder in publicly-traded company; Alpha2 Pharmaceuticals, NonoDev, Starton: Current holder of stock options in a privately-held company; BeiGene, Jansen, Ascentage: Honoraria. Yang: BeiGene, Ltd.: Current Employment. Liu: BeiGene, Ltd.: Current Employment. Zimmerman: BeiGene, Ltd.: Current Employment. Tang: BeiGene, Ltd.: Current Employment. Ailawadhi: Ascentage: Research Funding; Medimmune: Research Funding; Pharmacyclics: Consultancy, Research Funding; GSK: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Genentech: Consultancy; Xencor: Research Funding; BMS: Consultancy, Research Funding; Karyopharm: Consultancy; Cellectar: Research Funding; Sanofi: Consultancy; Janssen: Consultancy, Research Funding; AbbVie: Consultancy; Beigene: Consultancy; Takeda: Consultancy.

8514 Background: MLN9708 is an investigational, orally bioavailable, potent, reversible, specific inhibitor of the 20S proteasome that has demonstrated antitumor activity in in vivo models of MM. We report safety, activity and pharmacokinetics (PK) of weekly oral MLN9708 in a phase 1 trial in patients (pts) with relapsed and/or refractory MM after full enrollment (NCT00963820). Methods: Pts received MLN9708 (days 1, 8, 15; 28-day cycles) at 0.24–3.95 mg/m2 (dose-escalation phase) and at the MTD, 2.97 mg/m2, in relapsed and refractory (RR), bortezomib (btz)-relapsed, PI-naïve, and prior carfilzomib (CZ) expansion cohorts. Adverse events (AEs) were graded by NCI-CTCAE v3.0. Response was assessed by IMWG uniform criteria. Results: 60 pts (33 male, median age 64 yrs [40–79]) were enrolled, 32 in the dose-escalation phase and 31 to the expansion cohorts (11 RR, 10 btz-relapsed, 6 PI-naïve, 4 CZ; 2 RR and 1 btz-relapsed pts included from MTD dose-escalation cohort). Median time from MM diagnosis was 4.9 yrs (1.5–18.8). Median number of prior regimens was 6 (2–18), including btz, lenalidomide, thalidomide, and CZ in 83%, 95%, 52%, and 13%, respectively; 76% were refractory to last therapy (17% btz-refractory). At data cut-off (Nov 29, 2012) pts had received a median of 2 cycles (1–11); 5 pts remained on treatment. All-grade/grade ≥3 drug-related AEs were seen in 83%/52% of pts; common drug-related grade ≥3 AEs were thrombocytopenia (33%), diarrhea, neutropenia (17%), decreased appetite, fatigue, and lymphopenia (8%). 6 pts (10%) had drug-related PN (no grade ≥3). 5 pts discontinued due to drug-related AEs; 1 pt died on study due to an unrelated AE. By investigator assessment in 41 evaluable pts, responses included1 VGPR, 5 PR, 1 MR, and 15 with SD. MLN9708 was rapidly absorbed, with a terminal half-life of 4–12 days (supporting weekly dosing) and a proportional increase in plasma AUC with dose (0.8–3.95 mg/m2). PK data were similar across expansion cohorts. Conclusions: Current data suggest weekly oral MLN9708 is generally well tolerated with infrequent PN, and shows activity in this heavily pretreated population with prior exposure to immunomodulatory drugs and btz. Clinical trial information: NCT00963820.

8034 Background: Phase 1 studies are evaluating IV and oral dosing of the reversible proteasome inhibitor MLN9708 in multiple tumor types. We report the safety, MTD, pharmacokinetics (PK), pharmacodynamics, and preliminary responses with weekly oral MLN9708 in pts with relapsed/refractory MM (NCT00963820). Methods: Pts aged ≥18 yrs received MLN9708 on d 1, 8, and 15 of 28-d cycles. In the dose-escalation phase, pts required ≥2 prior therapies (including bortezomib, thalidomide/lenalidomide, and corticosteroids). At the MTD, pts were to be enrolled to relapsed and refractory (RR), bortezomib-relapsed (VR), proteasome inhibitor (PI) naïve, and carfilzomib (CZ) expansion cohorts. Results: 36 pts have been enrolled to date (data cut-off: Dec 1, 2011), 32 in the dose-escalation phase (0.24–3.95 mg/m2) and 8 to expansion cohorts (2 RR, 5 VR, 1 PI naïve; RR and VR cohorts each include 2 pts from MTD dose-escalation cohort). Median age was 64.5 yrs (range 40–79), 53% were male, and median number of prior lines of therapy was 3.5 (range 1-13), including 92%, 92%, 56%, and 8% who had prior bortezomib, lenalidomide, thalidomide, and carfilzomib, respectively. Pts have received a median of 2 cycles (range 1–11); 5 pts remain on treatment. Among 24 DLT-evaluable pts, 3 DLTs were seen: 2 at 3.95 mg/m2 (1 grade 3 rash, 1 grade 3 GI AEs) and 1 at 2.97 mg/m2 (grade 3 GI AEs). The MTD was determined as 2.97 mg/m2. Overall, 69% of pts had drug-related AEs, and 28% had related grade ≥3 AEs, including thrombocytopenia (17%), diarrhea (11%), nausea, neutropenia, and fatigue (each 8%). Only 3 (8%) pts had drug-related peripheral neuropathy (PN; no grade ≥3). 2 pts discontinued due to AEs. In 18 response-evaluable pts, 1 had a VGPR at 3.95 mg/m2, 1 had a PR at 2.97 mg/m2, and 8 have achieved SD durable for up to 9.5 mos. PK analyses showed linear plasma PK (0.8–3.95 mg/m2), Tmax of 0.5-2 hr, and terminal half-life of 7 d for MLN2238 (biologically active hydrolysis product). There was a trend for a dose-dependent increase in whole blood 20S proteasome inhibition. Conclusions: Current data suggest weekly oral MLN9708 is generally well tolerated with infrequent PN, and shows early signs of antitumor activity.

Abstract Background: Isatuximab (SAR650984) is a humanized IgG1 monoclonal antibody that binds selectively to a unique epitope on the human CD38 receptor. In the dose escalation part of the Phase I portion of the trial (NCT01749969), isatuximab ≥10 mg/kg IV given every other week (q2w) or 10 mg/kg weekly (qw) induced responses in 6/19 recipients (ORR 32%). Responses were noted at doses as low as 1 mg/kg q2w. The maximum tolerated dose (up to 20 mg/kg IV qw) was not reached. The most common treatment-emergent adverse events (TEAEs) were fatigue and nausea; few serious grade 3/4 TEAEs were reported (pneumonia 6%). The most common category of drug-related TEAE involved infusion-associated reactions (IARs) occurring in half of the patients, with grade 3/4 IARs in <5% of the patients. Based on promising Phase I activity, a Phase II dose finding study was added to investigate single-agent isatuximab in patients with relapsed or refractory myeloma (RRMM). Methods: In Phase II, eligible patients were originally randomly assigned (1:1:1) to one of 3 treatment groups: 3 mg/kg q2w, 10 mg/kg q2w, and 10 mg/kg q2w x 4 doses then q4w. A 4th treatment group was enrolled at a higher isatuximab dose with an optimized schedule of 20 mg/kg qw x 4 doses then q2w. Patient assignment was stratified by prior anti-myeloma therapy (Stratum 1: prior treatment with pomalidomide (POM) and/or carfilzomib (CAR); Stratum 2: no prior POM or CAR). Patients continued therapy until disease progression, unacceptable AEs or physician/patient decision. Eligible patients had measurable disease (serum M-protein >1 g/dL or urine M-protein ≥200 mg/24 h, or serum free light chain ≥10 mg/dL), prior exposure to ≥3 lines of anti-myeloma therapy or were double-refractory to immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs), prior treatment with an alkylating agent, and adequate baseline bone marrow reserve and organ function. Enrollment of 24 patients was planned for each treatment group. An interim efficacy analysis is planned when all patients have completed ≥2 disease assessments, with central review of these data currently ongoing. Enrollment has now been completed and all patients who completed at least 1 cycle of isatuximab at the cutoff date (5/29/15) are included in this preliminary analysis. Results: Patient characteristics (n=96): median age 62.5 yrs (range 38-85); median time from initial diagnosis to study treatment 5.85 yrs (1.2-24.1); 76% had IgA/G MM; 24% had light-chain only disease; and 22%, 22%, and 44% had Stage I, II, and III disease, respectively. The median number of prior lines of therapy was 5 (2-14) with 100%, 99%, and 98% having prior exposure to PIs, IMiDs, and alkylator-containing therapy, respectively. Overall, 78% of patients had previously received POM and/or CAR; 55% had been exposed to both of these agents. At data cut-off, 36.5% of patients remained on therapy and 53.1%, 6.3%, and 4.2% had discontinued therapy due to disease progression, AEs, or other reason, respectively. The median number of cycles received was 3 (1-9), with a median duration of treatment of 11.7 wks. Approximately 17% of patients required at least 1 dose delay and 7.3% of isatuximab infusions were interrupted. TEAEs occurred in 93% of patients, with 51% being grade ≥3. Drug-related TEAEs occurred in 61% of patients (grade ≥3, 10%). The most common drug-related TEAEs (>5% of patients) were nausea (14.6%), chills (14.6%), dyspnea (13.5%), chest discomfort (10.4%), flushing (7.3%), headache (7.3%), cough (6.3%), and vomiting (5.2%). The majority of the symptoms occurred within 24 h of isatuximab infusion and were attributed to an IAR. IARs occurred in 50% of patients, were predominantly grade 1/2 (grade ≥3, 3.1%), and were mostly limited to Cycle 1 (2 patients had IARs in Cycle 2). Pneumonia (6.3%) and sepsis (5.2%) were the most common serious TEAEs. Six deaths have occurred within 30 days of last dose, 4 due to disease progression, and 2 due to serious AEs unrelated to study therapy (cardiopulmonary arrest and cerebral hemorrhage). Conclusion: Isatuximab administered to heavily pre-treated patients with RRMM appears well tolerated. IARs are common in Cycle 1, but typically do not recur. Results by treatment arm, including interim analysis response data, will be presented. Disclosures Martin: Sanofi: Research Funding. Richter:Takeda: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Speakers Bureau; Amgen: Speakers Bureau; Novartis: Speakers Bureau. Vij:Millennium: Honoraria, Speakers Bureau; Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy; Takeda: Consultancy, Research Funding; Novartis: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Merck: Consultancy. Zonder:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS, Amgen, Prothena, Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Kaufman:Spectrum: Consultancy; Merck: Research Funding; Onyx: Consultancy, Research Funding; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Millenium: Consultancy. Bensinger:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acetylon: Research Funding; Sanofi: 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, Speakers Bureau; Onyx: Research Funding, Speakers Bureau; Millenium: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dimopoulos:Novartis: Honoraria; Amgen: Honoraria; Genesis: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Onyx: Honoraria; Janssen-Cilag: Honoraria. San Miguel:Millennium, Celgene, Novartis, Janssen, Onyx, BMS, MSD: Membership on an entity's Board of Directors or advisory committees. Zimmerman:Onyx: Honoraria; Celgene: Honoraria, Speakers Bureau; Millennium: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Hari:Celgene: Consultancy; Takeda: Consultancy; BMS: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Spectrum: Consultancy; Sanofi: Consultancy. Gasparetto:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Honoraria; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kumar:Skyline, Noxxon: Honoraria; Celgene, Millennium, Onyx, Janssen, Noxxon, Sanofi, BMS, Skyline: Consultancy; Celgene, Millennium, Onyx, Novartis, Janssen, Sanofi: Research Funding. Hsu:Sanofi: Employment. Charpentier:Sanofi: Employment. Strickland:Alexion Pharmaceuticals: Other: Advisory Board Particpation; Amgen: Other: Advisory Board Particpation; Daiichi-Sankyo: Other: Advisory Board Particpation; Boehringer-Ingelheim: Other: Advisory Board Particpation; Sunesis Pharmaceuticals: Other: Steering Committee and Advisory Board Participation. Mikhael:Sanofi: Research Funding; Onyx: Research Funding; Celgene: Research Funding; AbbVie: Research Funding.

Abstract Abstract 816 Background: Proteasome inhibition is a very effective therapeutic strategy in multiple myeloma (MM). The investigational agent MLN9708 is an oral, specific, reversible inhibitor of the 20S proteasome that has shown antitumor activity in solid tumor and hematologic malignancy xenograft models. Phase 1 trials are evaluating both intravenous and oral formulations using different dosing schedules in a variety of tumor types. Here we report the findings from the dose-escalation portion of a phase 1 trial of once-weekly, orally administered MLN9708 in patients with relapsed and/or refractory MM (NCT00963820). Methods: The primary objectives were to determine the maximum tolerated dose (MTD) and the safety/tolerability of MLN9708. Secondary objectives included determination of response rate, and characterization of the pharmacokinetics (PK, of MLN2238, the biologically active hydrolysis product) and pharmacodynamics (PD, 20S proteasome inhibition in blood) of once-weekly oral MLN9708. Patients with MM who had received ≥2 prior therapies, which must have included bortezomib, thalidomide or lenalidomide, and corticosteroids, were eligible. Treatment consisted of MLN9708 administered orally on days 1, 8, and 15 of a 28-day cycle. Dose-escalation proceeded from 0.24 mg/m2 using a standard 3+3 schema based on dose-limiting toxicities (DLTs) occurring in cycle 1. Adverse events (AEs) were graded by NCI-CTCAE v3. Response was assessed by modified EBMT/IMWG criteria. Blood samples were collected after dosing on days 1 and 15 of cycle 1 for PK and PD analyses; parameters were calculated using noncompartmental methods (WinNonlin software v5.3). Results: A total of 28 patients have been enrolled to date (data cut-off: June 29, 2011), including 3 each at dose levels of 0.24, 0.48, 0.80, and 1.20, 4 at 1.68, 3 at 2.23, 4 at 2.97, and 5 at 3.95 mg/m2. The median age was 63.5 years (range 40–76); 54% were male. The median number of prior regimens was 5 (range 2–15), and median time from diagnosis was 4.6 years. Nineteen (68%) patients had prior stem cell transplant, and 16 (59%) were refractory to their last prior therapy, including 7 (26%) to bortezomib and 11 (41%) to lenalidomide or thalidomide. The MTD has not been reached; the current cohort is receiving 3.95 mg/m2. No DLTs have been observed among 21 DLT-evaluable patients. Patients have received a median of 2 treatment cycles (range 1–11; mean 2.8). Four patients remain on treatment; discontinuation was mainly due to progressive disease (71%). All 28 patients are evaluable for toxicity; 26 (93%) experienced at least one AE, including 22 (79%) who experienced at least one drug-related AE. Drug-related AEs occurring in >20% of patients included fatigue (39%), thrombocytopenia (36%), nausea (32%), and diarrhea (29%). Two (7%) patients had drug-related peripheral neuropathy (PN, both grade 2); both had grade 1 PN at baseline. Ten (36%) patients experienced grade ≥3 AEs, 4 (14%) had AEs resulting in MLN9708 dose reductions, and 3 (11%) discontinued due to AEs. No on-study deaths have occurred. In 16 response-evaluable patients, one partial response has been seen, in a patient treated at 2.97 mg/m2 (who had three prior lines of therapy, thalidomide–dexamethasone, lenalidomide–dexamethasone –perifosine, and bortezomib–dexamethasone, to which the patient responded and relapsed); duration of response is 3.7 months, and the patient remains in response at cycle 8. A further five patients had a best response of stable disease, durable for up to 9.5 months. PK analyses showed that MLN9708 was rapidly absorbed, with MLN2238 Tmax of 0.5–2.0 hours and a terminal half-life after multiple dosing of approximately 7 days based on limited data (n=5). MLN2238 exposure appeared to increase proportionally with increasing MLN9708 dose over the range 0.8–2.97 mg/m2. Maximal 20S proteasome inhibition in blood was immediate and dose-dependent. Conclusions: Current data suggest that MLN9708 on a once-weekly schedule is generally well tolerated and has early signs of anti-tumor activity in this heavily pre-treated population with prior exposure to lenalidomide/thalidomide and bortezomib. To date, toxicity has been manageable, and no significant neuropathy signal has been observed. Updated data will be presented, with the MTD anticipated to be reached. Data from an analysis of candidate biomarkers of responsiveness to treatment with MLN9708 will also be presented. Disclosures: Kumar: Merck: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Genzyme: Research Funding; Novartis: Research Funding. Off Label Use: Use of the investigational agent MLN9708, an oral proteasome inhibitor, in the treatment of relapsed and/or refractory multiple myeloma. Bensinger:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Onyx Pharmaceuticals: Consultancy, Honoraria, Research Funding; Array: Research Funding; AstraZeneca: Research Funding; Genentech: Research Funding. Reeder:Celgene: Institutional research funding; Millennium Pharmaceuticals, Inc.: Institutional research funding; Novartis: Institutional research funding. Zimmerman:Novartis: Expert witness; Celgene: Honoraria, Speakers Bureau; Millennium Pharmaceuticals, Inc: Honoraria, Speakers Bureau. Berenson:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau; Onyx Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Medtronic: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck: Research Funding; Genentech: Research Funding. Berg:Millennium Pharmaceuticals, Inc.: Employment. Liu:Millennium Pharmaceuticals, Inc.: Employment. Gupta:Millennium Pharmaceuticals, Inc.: Employment. Di Bacco:Millennium Pharmaceuticals, Inc.: Employment. Hui:Millennium Pharmaceuticals, Inc.: Employment. Niesvizky:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx Pharmaceuticals: Research Funding.

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

Abstract Introduction Multiple Myeloma is not a single disease. There is increasing support for risk classification in combination with treatment decision making because of its impact on clinical outcomes. Here we demonstrate additional evidence of the prognostic value of SKY92, an established genetic marker of high risk Multiple Myeloma in a multicenter collection of samples with undisclosed treatments. Materials Methods A public GEP dataset (MMRC, MMGI portal) contained 114 cases of untreated Multiple Myeloma and was used for SKY92 high risk OS prediction (Kuiper et al. Leukemia 2012). In collaboration with MMRC, OS (with a minimum of at least 2 year follow-up) was collected for 91 of 114 cases for the purpose of this analysis. Briefly, CD138-positive plasma cells had been purified prior to total RNA extraction and subsequent gene expression profiling on Affymetrix U133Plus2.0 GeneChips. The 91 cases represented 9 different clinical sites and their CEL files were normalized as a single batch against a reference cohort of 329 cases after which the SKY92 risk scores were determined as either standard risk or high risk. Results SKY92 resulted in 19 high risk (20.9%) versus 72 standard risk (79.1%) cases in the unselected 91 case-cohort. Comparisons with other high risk GEP signatures will be performed. The OS analysis (Figure 1) shows that the HR cases have significantly shorter survival (Hazard Ratio 11, p = 7 x 10-5). Table 1 shows that high risk patients had more elevated B2M (26.3% vs 13.9%), more low albumin (26.3% vs 16.7%) and more high creatinine (26.3% vs 11.0%). There was no difference between high and standard groups in diagnosis dates (not shown). Cause of the 16 (84.2%) deaths among the high risk cases, and 21 (29.1%) deaths among the standard risk cases indicates that high risk contains less disease progression deaths (57.1% vs 31.3%), and more unknown deaths (56.3% vs 23.8%). Conclusions The SKY92 classifier identified 19 of 91 cases (21%) as high risk, recapitulating the percentage of high risk in previously studied cohorts (Kuiper et al. 2012). Moreover the hazard ratio of 11 when events up to 24 months or 8.18 when all events are considered, emphasizes the unmet medical need of high risk cases identified with SKY92 as 69% of all deaths within 2 years (9/13 death events) were in this category. Acknowledgments This research was performed within the framework of CTMM, the Center for Translational Molecular Medicine, project BioCHIP grant 03O-102. Rafael Fonseca is a Clinical Investigator of the Damon Runyon Cancer Research Fund. This work is supported by grants R01 CA83724, ECOG CA 21115T, Predolin Foundation, Mayo Clinic Cancer Center and the Mayo Foundation. Disclosures: van Beers: Skyline Diagnostics: Employment. Van Vliet:Skyline Diagnostics: Employment. Anderson:celgene: Consultancy; onyx: Consultancy; gilead: Consultancy; sanofi aventis: Consultancy; oncopep: Equity Ownership; acetylon: Equity Ownership. Jagannath:Celgene: Honoraria; Millennium: Honoraria. Jakubowiak:BMS: Consultancy, 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, Speakers Bureau; Millennium: Consultancy, 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, Speakers Bureau. Kumar:Celgene: Clinical Trial Support Other, Membership on an entity’s Board of Directors or advisory committees; Cephalon: Clinical Trial Support, Clinical Trial Support Other; Millennium: Clinical Trial Support, Clinical Trial Support Other, Membership on an entity’s Board of Directors or advisory committees; Novartis: Clinical Trial Support, Clinical Trial Support Other; Onyx: Clinical Trial Support Other, Membership on an entity’s Board of Directors or advisory committees. Lebovic:Celgene: Speakers Bureau; Onyx: Speakers Bureau. Lonial:Millennium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Sanofi: Consultancy; Onyx: Consultancy. Reece:Onyx: Honoraria; Novartis: Honoraria; Millennium: Research Funding; Merck: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Research Funding. Siegel:Celgene: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Millennium: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Onyx: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Vij:Celgene: Honoraria, Research Funding, Speakers Bureau; Millennium: Honoraria, Speakers Bureau; Onyx: Honoraria, Research Funding, Speakers Bureau. Zimmerman:Celgene: Honoraria; Millennium: Honoraria; Onyx: Honoraria. Fonseca:Medtronic: Consultancy; Otsuka: Consultancy; Celgene: Consultancy; Genzyme: Consultancy; BMS: Consultancy; Lilly: Consultancy; Onyx: Consultancy, Research Funding; Binding Site: Consultancy; Millennium: Consultancy; AMGEN: Consultancy; Cylene: Research Funding; Prognostication of MM based on genetic categorization of the disease: Prognostication of MM based on genetic categorization of the disease, Prognostication of MM based on genetic categorization of the disease Patents & Royalties.

Abstract Background BT062 (Biotest AG Dreieich, Germany) is an antibody-drug conjugate, comprising the anti-CD138 chimerized MAb (nBT062) and the maytansinoid DM4 as cytotoxic agent. Once bound to CD138 on a target cell, the conjugate is internalized and releases DM4, leading to target cell death. CD138 (Syndecan-1) is highly overexpressed on various solid tumors and in hematological malignancies, and represents one of the most specific target antigens for identification of multiple myeloma (MM) cells. Data from two studies investigating BT062 as single agent demonstrated an acceptable tolerability profile and evidence of clinical activity in patients with heavily pretreated relapsed and/or refractory MM (1, 2). Preclinical studies showed enhanced anti-MM activity when BT062 was combined with lenalidomide and dexamethasone (Len/Dex). Based on these data, a Phase I/IIa study in MM was initiated to evaluate the safety and efficacy of BT062 in combination with Len/Dex. Objectives To determine the dose-limiting toxicities (DLTs), the maximum tolerated dose (MTD), the recommended phase II dose (RPTD), pharmacokinetics (PK), and anti-MM activity of increasing doses of BT062 (days 1, 8, and 15, every 4 weeks) in combination with Len (25 mg, daily on days 1-21) and low dose Dex (40 mg on days 1, 8, 15, and 22) in patients with relapsed and/or refractory MM. Methods This is a prospective, open label, dose-escalation, multicenter Phase I/IIa study. The Phase I part includes dose escalation, and the Phase IIa the expansion of the MTD or RPTD cohort. Patients aged ≥18 years with relapsed and/or refractory MM who have failed at least one prior therapy were eligible to participate. Prior treatment with Len and/or Dex was allowed. Patients with clinical response (or no evidence of progressive disease) and without unacceptable toxicities were eligible for additional treatment cycles. Patients were enrolled in cohorts of at least 3 at each dose level; DLT in the first cycle triggered cohort expansion. Toxicities were assessed by CTCAE v4 and clinical response was assessed according to International Myeloma Working Group criteria. Results As of July 2013, a total of 15 patients have received BT062 at dose levels of 80 mg/m2 (N=3), 100 mg/m2 (N=6) or 120 mg/m2 (N=6). Two patients at the highest dose level discontinued study due to toxicity (DLT), another patient withdrew consent. The other 12 patients remain on treatment; median duration 144 days (range 8–385). The median number of prior therapies was 4 (range 1–11), 87% of patients had prior Len exposure, and 50% were Len/Dex refractory. The maximum administered dose (MAD) has been reached at 120 mg/m2, with mucosal inflammation (CTC grade 3) as DLT in one, and anemia (CTC grade 3) in a second of the 6 patients treated at this dose level. About 85% of reported Adverse Events (AE) were of CTC grade 1 or 2. The most common reported AEs were fatigue, hypokalemia, and diarrhea. Amongst the 9 patients currently evaluable for efficacy, responses were observed across all dose levels with a overall response rate (ORR) of 78%; including 1 patient with complete response (120 mg/m2), 1 patient with very good partial response (80 mg/m2), and 5 patients with partial response (80 and 100 mg/m2). Two other patients achieved disease stabilization, resulting in a clinical benefit in 100% of the evaluated patients. Interestingly, partial response was observed in 3 patients refractory to prior treatment with Len/Dex. The MTD has been defined as 100 mg/m2 and is currently expanded to further evaluate the safety and efficacy of BT062 at the RPTD. Conclusion Preliminary data from this ongoing study indicate that BT062 is well tolerated in combination with Len/Dex at dose levels that induce responses in patients with relapsed and/or refractory multiple myeloma, including Len/Dex-refractory patients. Updated results on safety and efficacy will be presented. References 1. Jagannath et al, BT062, an Antibody-Drug Conjugate Directed Against CD138, Shows Clinical Activity in Patients with Relapsed or Relapsed/Refractory Multiple Myeloma. Blood. 2011; 118: Abstract 305. 2. Heffner et al, BT062, an Antibody-Drug Conjugate Directed Against CD138, Given Weekly for 3 Weeks in Each 4 Week Cycle: Safety and Further Evidence of Clinical Activity. Blood. 2012; 120: Abstract 4042. Disclosures: Somlo: Celgene: Research Funding, Speakers Bureau; NIH: Research Funding; Millennium: Speakers Bureau. Heffner:Genentech: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Biotest: Honoraria, Research Funding; Onyx: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding. Siegel:Millennium: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Onyx: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Zimmerman:Celgene: Honoraria; Millennium: Honoraria; Onyx: Honoraria. Jagannath:Millennium: Honoraria; Celgene: Honoraria. Munshi:Celgene: Consultancy; Novartis: Consultancy; Millennium: Consultancy. Lonial:Millennium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Sanofi: Consultancy; Onyx: Consultancy. Ruehle:Biotest AG: Employment. Chavan:Biotest Pharmaceuticals: Employment. Patel:Biotest Pharmaceuticals: Employment. Rothenburger:Biotest AG: Employment. Wartenberg-Demand:Biotest AG: Employment. Haeder:Biotest AG: Employment. Anderson:Gilead: Consultancy; Sanofi Aventis: Consultancy; Onyx: Consultancy; Celgene: Consultancy; Acetylon: Equity Ownership; Oncopep: Equity Ownership.