Zimmerman, Todd M.

Abstract Abstract 3803 Background: The MMRC is a non-profit, disease-focused consortium founded in 2004 comprised of 13 North American centers with expertise in multiple myeloma (MM). The MMRC Inc. (Norwalk, CT), MMRC's member institutions, and several pharmaceutical partners work closely to speed early development of new treatment options for MM patients. In December 2007, MMRC headquarters staff implemented multiple project management (PM) business solutions to address trial barriers that delay activation of our phase I-II clinical trials and established trial metric benchmarks considered attainable at our member institutions. In November 2009, we reported initial data1 on trial activation: MMRC trials initiated between Sep08-Jul09 (n=5) demonstrated a 38% decrease in mean time to first patient dosed (FPFD), compared with the Early Group trials (EG) initiated before PM solutions (Jun06-Sept08; n=7 trials). These results also confirmed improvement over published metrics from Dilts et al 2,3. We present additional data on time to FPFD and now enrollment, to assess impact of the MMRC PM resources and processes on trial efficiency. Methods: Twenty-one (21) trials conducted within the MMRC from May 2006 to June 2010 had sufficient trial data for review. Data were collected by MMRC-funded project managers at the clinical centers using a web-based clinical trial management system (CTMS). 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 was 181 calendar days for the early group trials (EG, n=7) and 122 days for the recent group (RG) trials (n=14, Sep08 – Jun10), representing a 32% reduction of time to FPFD in the RG. Additionally, time from final protocol to first patient dosed at all MMRC centers on a trial decreased 18% from a mean of 7.7 months (EG) to 6.3 months (RG). With respect to MMRC trial enrollment, data was available for 16/21 trials (5 EG and 11 RG). 2 EG trials were missing data and 3 RG trials were still enrolling as of June 2010. The mean MMRC pre-study EC was 39 subjects per trial (n=16 trials; 626 enrollment target); the mean actual MMRC enrollment was 49 subjects per trial (n=16; 783 enrolled through Jun 29, 2010) representing a 25% increase in actual versus committed enrollment. Two trials did not meet MMRC EC: MMRC investigators discontinued their involvement in these trials at approximately 30% target EC due to trial complexity or low patient enrollment. 14/16 evaluable trials (88%) met their EC; 11/16 trials met EC within BET (69%) of which 8/16 trials (50%) reached EC 34% faster than their BET (representing a mean reduction of 4.5 months). The overall pre-study mean BET for 16 trials was 13.1 months. MMRC's actual mean enrollment timeline was 11.3 months for the group of 14 evaluable trials representing improvement over the original BET by a mean of 1.9 months (14%). We believe FP to FPFD is a more meaningful metric beyond that of first patient consented. Moreover, we believe that if all participating trial centers focus their efforts on dosing the first patient and within a targeted timeframe, it may improve our research efforts overall. Conclusion: Development of drugs in the clinical setting has become time and resource intensive. Activating and enrolling trials promptly is a priority for drug development. The MMRC's standardization of processes and support for site-based PM resources results in improved trial metrics. MMRC member centers met or exceeded pre-specified enrollment targets in 88% of the trials analyzed to date. Ongoing monitoring of trial conduct continues to reveal areas where increased focus is needed to realize further trial efficiencies. These trial metrics and measures to improve efficiency may be applied with similar expected benefit in all oncology disciplines. Disclosures: Wear: Multiple Myeloma Research Consortium (MMRC): Employment. Richardson:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC; 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; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Revta:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Vij:Multiple Myeloma Research Consortium (MMRC): Research Funding; Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Fiala:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Lonial:Bristo-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium Pharmaceuticals Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Francis:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Siegel:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC; Celgene: Speakers Bureau; Millennium: Speakers Bureau. Schramm:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Jakubowiak:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC, Research Funding; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Centocor Ortho-Biotech: Honoraria, Speakers Bureau; Exelixis: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Harvey:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Reece:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC; Celgene: Honoraria, Research Funding; Ortho Biotech: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Facet: Research Funding; Otsuka: Honoraria, Research Funding. Gul:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Jagannath:Celgene: Honoraria; Millenium: Honoraria; Orthobiotec: Honoraria; Onyx Pharma: Honoraria; Merck: Honoraria; Proteolix: Honoraria; Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. La:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Hofmeister:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Jansak:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Stewart:Millennium: Consultancy; Celgene: Honoraria; Multiple Myeloma Research Consortium: Member Institution of the MMRC. Hagerty:Mayo Clinic: Employment; Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Wolf:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC; Celgene: Speakers Bureau; Millennium: Speakers Bureau; Novartis: Speakers Bureau; Orthobiotech: Speakers Bureau. Davis:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Krishnan:Celgene: Speakers Bureau; Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Duarte:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Zimmerman:Millennium, Celgene: Speakers Bureau. Cisneros:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Kumar:Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding; Bayer: Research Funding; Multiple Myeloma Research Consortium: Member Institution of the MMRC. Birgin:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Ott:Multiple Myeloma Research Consortium (MMRC): Employment. Tasca:Multiple Myeloma Research Consortium (MMRC): Employment. Kelley:Multiple Myeloma Research Consortium (MMRC): Employment. Anderson:Millennium: Consultancy; Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC; Celgene: Consultancy; Novartis: Consultancy; Onyx: Consultancy; Merck: Consultancy; Bristol-Myers Squibb: Consultancy; Acetylon: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Giusti:Multiple Myeloma Research Consortium (MMRC): Employment.

Abstract Introduction Gene Expression Profiling studies have resulted in signatures capable of providing robust prognosis for Multiple Myeloma (MM) patients, such as the EMC92 [SKY92, Kuiper et al. Leukemia 2012]. Recently, data from 4720 MM patients from the HOVON-65/GMMG-HD4, UAMS-TT2, UAMS-TT3, MRC-IX, APEX and IFM trials were employed to assessed the majority of currently identified prognostic markers and their combinations (GEP, FISH, and biochemistry data, [Kuiper et al ASH 2014]). The "SKY92 + ISS" was identified and validated as the statistically most optimal (i.e. most significant and robust) prognostic marker combination for MM patients. The combination of the EMC92 (=SKY92) and ISS prognostic features proves to be a very powerful, unprecedented and straightforward prognostic system. It identifies four prognostic risk classes: low risk (ISS I-SKY92 standard risk (SR)), intermediate-low (ISS II-SKY92 SR), intermediate-high (ISS III-SKY92 SR) and high risk (ISS I-III, SKY92 high risk). Previously, the SKY92 has been validated on the 91 MM cases in the MMGI cohort [Van Beers et al. ASH 2013]. Here we present an extension of that validation with the SKY92 + ISS combination on the 78 MM cases for whom both GEP and ISS is available, by both assessing as the "4 risk group" model defined above, but also a "3 risk group" model (the two intermediate groups combined) as this may be more relevant and useful for clinical application. Materials and Methods A public untreated MM dataset (Multiple Myeloma Genomics Initiative, MMGI) had n=78 cases for which OS, GEP, and ISS were available for analysis. The prognostic markers SKY92 and ISS were applied as proposed [Kuiper et al ASH 2014] to classify cases into the risk categories. Results The risks for the 4 group classification model are shown in Table 1 and Figure 1, and the 3 risk group model is shown in Table 2 and Figure 1. In the 4 group model, the intermediate-low group (SKY92 standard + ISS II) was a small and not significantly different (p=0.79) from the low risk. The intermediate-high group (SKY92 standard + ISS III) was also a small group, with significantly worse outcome compared with the low risk group (p=0.012). Although stratification into four groups was statistically superior in the training and validation data [Kuiper et al ASH 2014] the interpretability benefits from aggregation of the middle two groups [Fig 1 right]. Table 1. Classification results for the four risk groups (Fig 1 left) Risk group n % Median OS HR vs low risk SKY92 High Risk regardless of ISS 19 24 28.4 m 10.8 SKY92 standard risk + ISS-III 10 13 63.0 m 4.1 SKY92 standard risk + ISS-II 16 21 NR (0.8) SKY92 standard risk + ISS-I (low risk) 33 42 NR NA NR= Not Reached at 96 months, HR= hazard ratio Table 2. Classification results for the three risk groups (Fig 1 right) Risk group n % Median OS HR vs low risk SKY92 High Risk regardless of ISS 19 24 28.4 m 10.1 SKY92 standard risk + ISS-II/III 26 34 78.5 m (1.8) SKY92 standard risk + ISS-I 33 42 NR NA NR= Not Reached at 96 months, HR= hazard ratio, () not significant Conclusions By applying the SKY92 + ISS risk stratification model in an independent validation cohort of newly diagnosed Multiple Myeloma patients, besides a high risk group of 19 patients (24%), a group of 33 patients (42%) with superior prognosis could be predicted (SKY92 standard risk and ISS I) that translated into 62% OS at 96 months. The 19 high risk (SKY92 high risk) cases had very poor prognosis (median survival of 28 months). The combination of SKY92 Standard Risk and ISS II and III seems useful for definition of "intermediate risk" although sample size currently is insufficient for significance compared to low risk. The intention is to also perform this validation on the relapsed samples from the MMGI cohort, once OS data has been collected. This validated risk model could play a role in the design of future treatment strategies for high and low risk MM patients. Figure 1. Kaplan Meier curves on the 78 MMGI cases, split into four (left) or three (right) risk groups based on the combination of SKY92 + ISS. Hazard Ratios (HR) are from a Cox proportional Hazards model comparing a particular group to the low risk group. Figure 1. Kaplan Meier curves on the 78 MMGI cases, split into four (left) or three (right) risk groups based on the combination of SKY92 + ISS. Hazard Ratios (HR) are from a Cox proportional Hazards model comparing a particular group to the low risk group. Disclosures van Beers: SkylineDx: Employment. van Vliet:SkylineDx: Employment. de Best:SkylineDx: Employment. Chari:Novartis: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biotest: Other: Institutional Research Funding; Array Biopharma: Consultancy, Other: Institutional Research Funding, Research Funding; Onyx: Consultancy, Research Funding. Jagganath:Millennium: Honoraria; Celgene: Honoraria. Jakubowiak:Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: institutional funding for support of clinical trial conduct, Speakers Bureau; SkylineDx: 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; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SkylineDx: 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, Research Funding, Speakers Bureau; Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kumar:Celgene, Millenium, Sanofi, Skyline, BMS, Onyx, Noxxon,: Other: Consultant, no compensation,; Janssen: Research Funding; AbbVie: Research Funding; Sanofi: Research Funding; Millenium/Takeda: Research Funding; Celgene: Research Funding; Onyx: Research Funding; Skyline, Noxxon: Honoraria. Lebovic:Onyx: Speakers Bureau; Celgene: Speakers Bureau. Lonial:Millennium: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Reece:Onyx: Honoraria; Novartis: Honoraria; Millennium: Research Funding; Merck: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Research Funding. Richardson:Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Siegel:Celgene Corporation: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Novartis: Speakers Bureau; Merck: Speakers Bureau. Stewart:SkylineDx: Membership on an entity's Board of Directors or advisory committees. Vij:Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium: Honoraria, Speakers Bureau; BMS: Consultancy; Takeda: Consultancy, Research Funding; Novartis: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Merck: Consultancy. Zimmerman:Celgene: Honoraria, Speakers Bureau; Millennium: Honoraria, Speakers Bureau; Onyx: Honoraria; Amgen: Honoraria, Speakers Bureau. Fonseca:Onyx/Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Binding Site: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Applied Biosciences: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.

Abstract Abstract 2965 Background: Alkylating agents have been the mainstay of multiple myeloma (MM) therapy for decades and despite introduction of several new therapies, it continues to play a significant role in its management as part of various drug combinations. While melphalan has been the most commonly used alkylator in MM, recent studies have suggested significant activity for bendamustine, a bifunctional alkylator. The combination of lenalidomide and melphalan has been associated with high response rates in relapse and newly diagnosed MM. Based on these promising results we designed a trial to evaluate the maximally tolerated dose of lenalidomide and bendamustine when used in combination as well as the efficacy of the combination in relapsed disease. Patients and Methods: Patients with relapsed MM and measurable disease were enrolled on this phase 1/2 trial provided they had not more than 4 prior lines of therapy for MM, had adequate performance status and organ and hematological function. Patients refractory to lenalidomide were allowed to enroll. The primary objectives were to (i) to determine the MTD of bendamustine and lenalidomide in combination with dexamethasone in subjects with relapsed MM (phase 1) and (ii) to evaluate the confirmed response rate of bendamustine in combination with lenalidomide and dexamethasone in patients with relapsed MM (phase 2). Bendamustine (B) was administered on days 1 and 2 of a 28-day cycle at doses of 50–100 mg/m2. Lenalidomide (R) was given days 1–21 at doses of 15–25 mg daily. Dexamethasone (D) was administered at 40 mg weekly. Dose escalation was done using a 3+3 design and MTD was defined as one dose level below that resulted in >=2 DLTS among 6 patients. The primary end point for this trial was the proportion of patients with confirmed hematologic response (sCR, CR, VGPR, or PR) over the first 6 cycles of treatment. Results: A total of 72 patients were accrued to this study from March 2010 to May 2012: 21 patients in phase 1 and 51 in phase 2. The 6 patients from the MTD dose level of phase 1 were also included in phase 2. The median age of all 72 patients was 62.1 (range, 40–86) and 57% were male. Majority (75%) of patients had previously been exposed to lenalidomide and 69% had prior exposure to bortezomib. Median # of prior therapies was 3 (range, 1–5) and 74% of patients had a prior autologous stem cell transplant. Patients have received a median of 4 cycles (range, 1–25), with 27 patients still continuing on active treatment. Disease progression led to study discontinuation in 22 (49%) and adverse events were the reason for discontinuation in 14 (31%). In phase I, two DLTs (Grade (Gr) 2 neuropathy and Gr 4 neutropenia) were seen at the highest dose level (100 mg/m2 B, 25 mg R), and the MTD was determined as 75 mg/m2 of B given days 1 and 2 and 25 mg of R days 1–21, along with D 40 mg weekly. Overall patients, 12/21 (57%) had a PR or better. In phase 2, 17 (40%) confirmed responses (>=PR) were seen among the 43 patients evaluable for response (received at least 6 cycles of treatment or have gone off study prior to 6 cycles); including 9 (21%) VGPR and 8 (19%) PR. An additional 5 patients had a minor response. Over all dose levels, a gr 3 or higher adverse event at least possibly attributed to the study was seen in 75% of patients. The most common toxicities were all hematological (thrombocytopenia and leukopenia), and most common non-hematological toxicity was infection. Prolonged time to recovery of blood counts was seen in a few patients, but majority of patients were able to tolerate the regimen with adequate dose reductions. Conclusion: The recommended dose of the combination for further studies is bendamustine at 75 mg/m2 days 1 and 2, lenalidomide 25 mg daily on days 1–21 and dexamethasone days 1, 8, 15, 22; with cycles repeated every 28 days. The regimen is well tolerated with hematological toxicity being the most common and manageable with dose reductions. The regimen is effective with high response rates and durable responses seen. Updated results with response rates and time to event analyses will be available for the entire cohort at the time of meeting. Disclosures: Kumar: Merck: Consultancy, Honoraria; Celgene: Research Funding; Millennium: Research Funding; Novartis: Research Funding; Cephalon: Research Funding; Genzyme: Research Funding. Krishnan:celgene: Consultancy, Speakers Bureau. Zimmerman:Celgene: Honoraria; Millennium: Honoraria; Novartis: Expert Testimony, Expert Testimony Other. Vij:Teva: Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Millennium: Speakers Bureau; Onyx: Honoraria, Research Funding.

Abstract Background: BT062 (Biotest AG, Dreieich, Germany) is an antibody-drug conjugate (ADC) comprising a CD138-binding chimerized antibody and the cytotoxic maytansinoid, DM4. It is designed to target and kill CD138-positive cancer cells. CD138 (Syndecan-1) is highly expressed on a number of solid tumors and hematological malignancies and is one of the most reliable markers for multiple myeloma (MM) cells. BT062 was previously evaluated as a monotherapy in patients with heavily pretreated relapsed/refractory MM and found to have an acceptable tolerability profile with preliminary evidence of activity (Heffner et al, Blood. 2012; 120: Abstract 4042). Phase I/IIa testing was initiated with BT062 in combination with lenalidomide (Len) and low-dose dexamethasone (dex). The combination was well tolerated at BT062 doses up to 100 mg/m², defined to be the recommended Phase 2 dose (RPTD), and induced meaningful responses, including in patients previously treated with both Len and bortezomib (Bort) (Kelly et al, Blood. 2014; 124: Abstract 4736). Based on these promising results, further investigation of BT062 in combination with pomalidomide (Pom) and dex was initiated in patients with prior Len and Bort exposure, a patient population known to have a poor outcome. Objectives: To evaluate the safety and activity of BT062 (on days 1, 8, and 15 in a 4-week cycle) used in combination with dex (20-40 mg on days 1, 8, 15, and 22) and Len (25 mg, daily on days 1-21) or Pom (4 mg, daily on days 1-21) in patients with relapsed/refractory MM. Methods: This is a prospective, open label, multicenter Phase I/IIa study. The RPTD of BT062 in combination with Len/dex was defined to be 100 mg/m², and 38 patients were treated with BT062/Len/dex at the BT062 RPTD. An additional 17 patients were treated with BT062/Pom/dex at the BT062 RPTD. Patients aged ≥18 years with relapsed/refractory MM were eligible to participate. Prior treatment with Len, Pom, and/or dexamethasone (any dose) was allowed. To qualify for treatment with BT062/Len/dex at the BT062 RPTD, patients must have received at least one but no more than six prior therapies.To qualify for treatment with BT062/Pom/dex, patients must have received at least two prior therapies, including both Len and Bort, and progressed on or within 60 days of completion of their last therapy, with no limit on number of prior therapies. Patients with clinical response (or no evidence of disease progression) without unacceptable toxicities were eligible to receive additional treatment cycles. Toxicities were assessed by CTCAE v4. Clinical response was assessed by the investigator according to International Myeloma Working Group criteria. Results: Sixty-four patients have received BT062 in combination with dex and Len or Pom in this ongoing study. The combinations have been generally well tolerated, with approximately 90% of adverse events (AEs) reported CTC grade 1 or 2. The most common AEs reported are diarrhea, fatigue, and nausea. Forty-seven patients have received BT062 with Len/Dex (3 at 80 mg/m², 38 at 100 mg/m², 6 at 120 mg/m²), with 8 patients still on treatment. Among these 47 patients, median progression-free survival (PFS) was 16.4 months. Forty-three patients completed at least two treatment cycles and were evaluable for response. Of these patients 33 achieved a partial response (PR) or better, with an overall response rate (ORR) of 77% and a median duration of response (DOR) of 21.0 months. Thirteen of the evaluable BT062/Len/dex-treated patients had prior exposure to both Len and Bort and progressed on or within 60 days of their last therapy. ORR was 54% among these patients, including 1 complete response (CR), 4 very good partial responses (VGPR) and 2 PRs. Seventeen patients were treated with BT062/Pom/dex, all had prior exposure to both Len and Bort and progressed on or within 60 days of their last therapy. ORR was 79%, with 4 VGPR and 7 PR among the 14 patients evaluable for efficacy. Median PFS has not been reached after 7.5 months median follow up, with 7 patients still on treatment. Updated safety and activity data will be presented. Conclusion: BT062 has been found to be well tolerated when used in combination with Len/dex or Pom/dex, with encouraging activity even in patients with Len- and Bort-pretreated disease progressing on or within 60 days of completion of their last therapy. Disclosures Kelly: Novartis: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Siegel:Novartis: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Merck: Honoraria. Somlo:Millennium: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Heffner:Millennium: Research Funding; AbbVie: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding. Madan:Onyx: Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Celgene: Speakers Bureau. Lonial:Celgene: Consultancy; Celgene: Consultancy; BMS: Consultancy; Onyx: Consultancy; Millenium: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Onyx: Consultancy; Janssen: Consultancy; Merck: Consultancy; BMS: Consultancy. Barmaki-Rad:Biotest AG: Employment. Rühle:Biotest AG: Employment. Herrmann:Biotest AG: Employment. Wartenberg-Demand:Biotest AG: Employment. Haeder:Biotest AG: Employment. Anderson:Celgene: Membership on an entity's Board of Directors or advisory committees; Oncoprep: Equity Ownership; Acetylon: Equity Ownership; Acetylon: Equity Ownership; Gilead: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Oncoprep: Equity Ownership; Millennuim: Membership on an entity's Board of Directors or advisory committees; Millennuim: Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Equity Ownership; C4 Therapeutics: Equity Ownership; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees.

Abstract BACKGROUND: The introduction of novel agents and proteasome inhibitors, and advances in high dose therapy administration has made an impact on the survival outcomes for MM patients. However, HRMM still remains a therapeutic challenge with poor prognosis. Even with aggressive approaches such as the Total Therapy protocols, patients with poor genomic risk have a 2-year event-free survival of ~50% (Nair et al, Blood 2010). A randomized Phase I/II trial was designed to evaluate the efficacy of adding immunotherapy into the first line for HRMM patients, comparing lenalidomide, bortezomib and dexamethasone (RVD) with or without addition of elotuzumab (Elo), a humanized monoclonal antibody that binds to SLAMF7/CS1. We are reporting on the Phase I portion of the study. PATIENTS & METHODS: The objective of Phase I was to determine the maximum tolerated dose (MTD) of RVD-Elo. Both low/standard risk MM and HRMM patients were eligible. HRMM was defined by one or more of the following: (1) poor risk genomics by the Arkansas 70-gene model, (2) translocation (14;16), translocation (14;20) and/or deletion (17p) by florescent in-situ hybridization (FISH), (3) primary plasma cell leukemia and (4) serum LDH > 2 times normal levels. The treatment consisted of induction chemotherapy for 8 cycles with RVD-Elo (lenalidomide 25 mg orally days 1-14 of every 21-day cycle; bortezomib 1.3 mg/m2 subcutaneously days 1,4,8,11; dexamethasone 20 mg orally days 1,2,4,5,8,9,11,12; elotuzumab 10 mg/kg intravenously days 1,8,15 cycles 1-2 then days 1,11 cycles 3-8) followed by dose-attenuated RVD-Elo maintenance (lenalidomide 25 mg orally days 1-14; bortezomib 1.0 mg/m2 subcutaneously days 1,8,15; dexamethasone 12 mg orally days 1,8,15; elotuzumab 10 mg/kg intravenously days 1,15) until disease relapse, progression or intolerance. Adverse events (AE) were recorded as per the NCI CTCAEv4.0. RESULTS: Eight newly diagnosed MM patients were enrolled on the Phase I run-in study. Six patients (Figure 1) were evaluable for dose limiting toxicities (DLT) during Cycle 1 as per protocol. The median age of patients was 67 years (range: 56-79 years), with 67% ≥65 years, Hgb was less than 10 g/dL in 50%, creatinine was greater than 2 mg/dL in all patients. ISS stage distribution was 17% (I), 33% (II) and 50% (III). Deletion 13 was observed in 1 patient (17%). The most common AEs (all grades) were fatigue (100%), peripheral sensory neuropathy (83%), edema (83%), lymphopenia (66%) and leukopenia (50%). The most common Grade 3 AEs were peripheral sensory neuropathy (33%), one of which was a DLT, neutropenia (17%) and thrombocytopenia (17%). One Grade 4 lymphopenia was observed. All 6 patients have completed 8 cycles of RVD-Elo induction therapy and 5 patients have completed at least 4 cycles of RVD-Elo maintenance. Overall median days on therapy per cycle were 13 days during induction and 20 days per cycle during maintenance. Dose adjustments were made in 83% of patients for bortezomib, 83% for lenalidomide and 33% for dexamethasone. There were no dose reductions for elotuzumab, although three patients had 1 event each of dose delays/missed dosing attributable to AE/SAE from RVD. Efficacy data will be released at the time that the phase II study of RVD +/- Elo is mature. Discussion/Conclusion: The RVD-Elo is a safe well-tolerated regimen for newly diagnosed MM patients without major additive AE/SAE beyond what is already known about RVD. This is the first report of the only phase I experience combining the triple-drug regimen RVD with the monoclonal antibody Elotuzumab for newly diagnosed MM. Support: NCI grants CA32102, CA38926, CA180821, CA31946, CA21076, CA180799, CA21115, CA180820 and in part by Bristol-Myers Squibb Company Disclosures Usmani: Celgene Corporation: Consultancy, Honoraria, Research Funding; Millennium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy; Array BioPharma: Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding. Off Label Use: Lenalidomide in newly diagnosed multiple myeloma patients. Ailawadhi:Millennium: Honoraria. Shah:Onyx Pharmaceuticals: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Array: Consultancy, Research Funding. Rosenzweig:Celgene: Speakers Bureau. Durie:IRC J&J: Membership on an entity's Board of Directors or advisory committees; Celgene Corp: Expert Board Committee Other; IRC Onyx: Membership on an entity's Board of Directors or advisory committees; DMC Millennium: Membership on an entity's Board of Directors or advisory committees. Orlowski:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: The Takeda Oncology Company: Membership on an entity's Board of Directors or advisory committees, Research Funding; Spectrum Pharmaceuticals: Research Funding; JW Pharmaceutical: Research Funding; Array BioPharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

Abstract Background: BT062 (Biotest AG Dreieich, Germany) is an antibody-drug conjugate (ADC), comprising the anti-CD138 chimerized MAb (nBT062) and the maytansinoid DM4 as a cytotoxic agent. It is designed to bind to CD138 on cancer cells, and then release DM4 after internalization to cause 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. BT062 was investigated as a single agent and found to have an acceptable tolerability profile and evidence of activity in patients with heavily pretreated relapsed and/or refractory MM (1). 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) used 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, multicenter Phase I/IIa study. The Phase I part includes dose escalation, and the Phase IIa the expansion of the 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: The maximum administered dose (MAD) was 120 mg/m². Two of six patients treated at this dose had a DLT: mucosal inflammation (CTC grade 3) and anemia (CTC grade 3). The MTD was defined as 100 mg/m² and selected as RPTD. Additional patients are being treated at this RPTD to further evaluate safety and efficacy. Enrollment into the study is ongoing. As of July 2014, a total of 45 patients had received BT062 at dose levels of 80 mg/m² (N=3), 100 mg/m² (N=36) or 120 mg/m² (N=6). Fifteen patients discontinued study treatment: 5 for disease progression, 7 for adverse events, 1 died (not treatment related) and 2 for withdrawal of consent. The other 30 patients remain on treatment. The median treatment duration was 123 days (range 1–597). The median number of prior therapies was 3 (range 1–11). 68% of patients had prior exposure to both Len and bortezomib, 73% of patients had prior Len exposure, and 30% were Len-refractory. According to preliminary data from this ongoing study, about 89% of reported Adverse Events (AEs) were CTC grade 1 or 2. The most common reported AEs were diarrhea, fatigue, nausea, and hypokalemia. Amongst the 36 patients across all dose levels currently evaluable for efficacy, the overall response rate (ORR) is 78%; including 1 stringent complete response, 2 complete responses, 10 very good partial responses, and 15 partial responses. Two patients achieved a minor response and 6 patients disease stabilization, resulting in a clinical benefit in 100% of the evaluable patients. The ORR was 83% among the 30 evaluable patients receiving the RPTD. Interestingly, the ORR was 70% among the 23 patients with prior exposure to Len and bortezomib, and among 10 patients refractory to prior treatment with Len. 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 patients with prior exposure to both Len and bortezomib and patients refractory to prior treatment with Len. Updated results on safety and efficacy will be presented. References 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 Kelly: Celgene: Speakers Bureau. Heffner:Amgen: Honoraria, Research Funding; Biotest: Research Funding; Dana Farber CI: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Idera: Research Funding; Janssen: Research Funding; Pfizer: Research Funding; Pharmacyclics: Honoraria, Research Funding; Onyx: Research Funding; Spectrum: Research Funding; Talon Therapeutics: Research Funding. Somlo:Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Siegel:Celgene: Honoraria, Speakers Bureau; Onyx: Honoraria, Speakers Bureau; Millennium: Honoraria, Speakers Bureau. Munshi:Celgene: Consultancy; Onyx: Consultancy; Janssen: Consultancy; Sanofi-Aventis: Consultancy; Ocopep: Consultancy, Equity Ownership, Patents & Royalties. Jagannath:Celgene: Consultancy; Millennium: Consultancy; Sanofi: Consultancy. Lonial:Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Ailawadhi:Millennium: Consultancy, Honoraria. Barmaki-Rad:Biotest AG: Employment. Chavan:Biotest Pharmaceuticals: Employment. Patel:Biotest Pharmaceuticals: Employment. Wartenberg-Demand:Biotest AG: Employment. Haeder:Biotest AG: Employment. Anderson:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Aventis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncopep: Equity Ownership; Acetylon: Equity Ownership.

Abstract Multiple myeloma (MM) is 2-3 times more common among African-Americans compared to non-Hispanic whites. The 2-3-fold increased risk among family members of cases suggests a genetic contribution to risk. Genome-wide association studies (GWAS) in populations of European ancestry have identified seven novel risk loci at 2p23.3 (rs6746082), 3q26.2 (rs10936599), 3p22.1 (rs1052501), 6p21.32 (rs2285803), 7p15.3 (rs4487645), 17p11.2 (rs4273077) and 22q13.1 (rs877529) (Broderick, et al. Nat Genet, 2011, Chubb, et al. Nat Genet, 2013), three of which were replicated in another European series (Martino et al., Br J Haematol, 2012). Here we examined the index signals and conducted fine-mapping for each locus in a case-control study of 1,049 multiple myeloma cases and 7,084 controls of African ancestry to identify better markers of risk and novel independent loci in seven previously reported regions in this high risk population. Incident cases were recruited from 10 clinical centers and SEER cancer registries from 2011 to 2013 and genotyped using the Illumina HumanCore GWAS array. Control data were obtained from previous genome-wide studies of breast and prostate cancer, genotyped using the Illumina 1M-Duo in 4425 male controls from the African Ancestry Prostate Cancer Consortium (consisting of 14 independent studies) and 2632 female controls from a breast cancer GWAS of African-American women (consisting of 9 independent studies). Imputation to 1000 Genomes (March 2012 release) was conducted for regions around six of the previously identified single nucleotide polymorphisms [SNPs] (the HLA region harboring rs2285803 is still being imputed, results will be presented). A case-control analysis of SNPs/indels >1% frequency within 250 kb of each index variant was conducted using unconditional multivariable logistic regression adjusting for age, sex and five leading principal components. Region-specific alpha levels were determined through permutation tests. The minimum alpha level across the six regions was α=0.002. All previously reported risk variants were common in African-Americans (minor allele frequency [MAF] >0.05). For five of the six SNPs, we had ≥94% power to detect the same effect observed in non-Hispanic whites, and 64% power for the less common variant rs10936599 (MAF=0.07). We observed directionally consistent effects (odds ratio [OR]>1) for the six risk variants tested, with three replicating at p≤0.05 (7p15.3, p=1.4x10-7; 17p11.2, p=0.05; 22q13.1, p=0.02). For three of the six regions, we observed better markers of risk in African-Americans that were correlated with the index SNP in Europeans (7p15.3, rs56333627, p=1.5x10-5, r2=0.89; 17p11.2, rs34562254, p=2.9x10-3, r2=0.90; 22q13.1, rs2092410, p=1.1x10-4 r2=.71). The missense variant identified in the 17p11.2 region (rs34562254, Pro251Leu) is located in TNFRSF13B, which encodes the protein TACI, a B cell surface receptor which plays a role in B cell maturation, apoptosis and antibody production by inducing activation of transcription factors including NFAT and NFκβ. In addition, there is evidence suggesting that TACI is involved in MM pathogenesis. Our results demonstrate that many of the risk loci for MM found in European ancestry populations are also risk loci in men and women of African ancestry and that by fine-mapping, we are able to identify variants that better capture risk in populations of African ancestry. Disclosures Terebelo: Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Lonial:Millennium: The Takeda Oncology Company: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding.

SummarySelinexor, an oral Selective Inhibitor of Nuclear Export, targets Exportin 1 (XPO1, also termed CRM1). Non‐clinical studies support combining selinexor with proteasome inhibitors (PIs) and corticosteroids to overcome resistance in relapsed/refractory multiple myeloma (RRMM). We conducted a phase I dose‐escalation trial of twice‐weekly selinexor in combination with carfilzomib and dexamethasone (SKd) to determine maximum tolerated dose in patients with RRMM (N = 21), with an expansion cohort to assess activity in carfilzomib‐refractory disease and identify a recommended phase II dose (RP2D). During dose escalation, there was one dose‐limiting toxicity (cardiac failure). The RP2D of twice‐weekly SKd was selinexor 60 mg, carfilzomib 20/27 mg/m2 and dexamethasone 20 mg. The most common grade 3/4 treatment‐emergent adverse events included thrombocytopenia (71%), anaemia (33%), lymphopenia (33%), neutropenia (33%) and infections (24%). Rates of ≥minimal response, ≥partial response and very good partial response were 71%, 48% and 14%, respectively; similar response outcomes were observed for dual‐class refractory (PI and immunomodulatory drug)/quad‐exposed (carfilzomib, bortezomib, lenalidomide and pomalidomide) patients (n = 17), and patients refractory to carfilzomib in last line of therapy (n = 13). Median progression‐free survival was 3·7 months, and overall survival was 22·4 months in the overall population. SKd was tolerable and re‐established disease control in RRMM patients, including carfilzomib‐refractory patients.Registered at ClinicalTrials.gov (NCT02199665)