Roy, Vivek

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: Outcomes in multiple myeloma (MM) have improved significantly over the years but disparities in outcomes exist among MM patients (pts) belonging to different racial subgroups. Previous studies have explored healthcare access and utilization disparities for pts of different races as potential causes, but genomic differences, which could alter disease biology and clinical behavior, have not been studied. We utilized the MMRF CoMMpass database, which prospectively captures clinical and molecular characteristics of MM patients to explore race-based differences at the genomic level. Methods: The publically available CoMMpass trial database (data release version IA8) was utilized. Pts with race category of White (total n=698) and non-White (total n=223, comprising 129 Blacks, 19 Asians and 45 others) were analyzed for genomics including cytogenetics (fluorescent in situ hybridization; FISH), tumor diploidy (conventional karyotyping), gene expression profiling (GEP), gene copy number variations (CNV), gene single nucleotide variations (SNV) and genomic translocations analysis focused on genes from the FoundationOne Heme panel¨ (402 genes). GEP was considered significantly different between categories for more than or equal to a 2-fold change for a given gene (p<0.05). Categorical variables for FISH probes and diploidy status were compared by Chi-square or Fischer exact test, wherever applicable. Results: GEP clustering analysis uncovered 67 genes differentially expressed between Whites vs. non-Whites (Fig 1A). Baseline cytogenetics aberrations between both race cohorts showed statistically insignificant differences. Multiple cytogenetic abnormalities were seen most commonly in both race groups (~31%) with the distribution of others (in descending order) as such: Del13 > No abnormalities > t(11;14) > 1q amplification > Del17p or p53 > t(4;14) > Del1p > t(14;16) > t(14;20). Aneuploidy status showed insignificant differences between race groups with ~34% of patients from both groups having no aneuploidy. SNV data was present for 90% of Whites and 57% of non-Whites. Overall, 84% of genes had>1 SNV (84%), 2% translocations only and 14% had neither SNVs or translocations. SNVs were classified as Non-specific Non-Synonymous coding (NNSCs), Splice-site (SS) or Tier 1 (T1, codon deletion, insertion, frame-shift, etc.). A total of 880 NNSCs SNVs were observed: 670 in Whites across 227 genes, 210 in non-Whites across 120 genes. In whites, 57% of NNSC SNVs consisted of transition-type mutations and 43% as transversions. In non-Whites, transition mutations comprised 64% of all NNSC SNVs and transversions in the remaining 36%. A total of 38 SS SNVs were observed, 30 in Whites and 8 in non-Whites observed in 25 and 6 genes, respectively. In Whites, 57% of SS SNVs were transition type and remaining 43% were transversion. In non-Whites, an equal % of SS transition and transversion mutations were noted. A total of 240 T1 SNVs were noted; 182 in Whites seen in 82 genes; 58 in non-Whites seen 6 genes. In both Whites and non-Whites, frameshifts (41% in Whites, 47% in non-Whites) and stop-gained (46% in Whites, 45% in non-Whites) SNVs were most common. A total of 17 genes with>10 distinct SNVs were identified in Whites; 5 genes in non-Whites and 4 genes commonly seen in both cohorts (Fig 1B). In Whites, 17 genes were found to have translocations (intrachromosomal TRAF3 and PIK3R2 most common); in non-Whites, 5 genes had translocations (intrachromosomal CIC and EMSY most common). CNV analysis demonstrated 21 genes that were significantly altered with either copy number gain or loss between Whites vs. non-Whites (Fig 1C). Conclusions: We present the first race-based comprehensive genomic analysis utilizing the public interface of the CoMMpass trial. We discovered genomic differences between Whites and non-Whites at several levels including GEP, SNV and CNV, but not at the level of cytogenetics, which are in fact the most commonly performed clinical genomic analysis. Correlation of these variations with MM pt outcomes would be invaluable in understanding disease biology and hopefully mitigating some of the outcome disparities by pt race. As the database grows and becomes more enriched, separate analyses for Blacks, Asians and Hispanics would be attempted. Acknowledgments: We would like to thank the MMRF, Ms. Mary Derome and Dr. Jonathan Keats for providing scientific overview and technical support. Disclosures Fonseca: Millennium, a Takeda Company: Consultancy; Millennium, a Takeda Company: Consultancy; AMGEN: Consultancy; AMGEN: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Celgene: Consultancy; BMS: Consultancy; Bayer: Consultancy; Novartis: Consultancy; Sanofi: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Millennium, a Takeda Company: Consultancy; BMS: Consultancy; AMGEN: Consultancy; Bayer: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Novartis: Consultancy; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Sanofi: Consultancy; Janssen: Consultancy; Millennium, a Takeda Company: Consultancy; AMGEN: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms. Ailawadhi:Takeda Oncology: Consultancy; Amgen Inc: Consultancy; Novartis: Consultancy; Pharmacyclics: Consultancy.

Abstract Introduction. In comparison toCLL, single agent clinical efficacy of venetoclax (a Bcl-2 inhibitor; Bcl-2i) in multiple myeloma (MM) has been modest (ORR of ~12%; Kumar et al ASCO 2016). Clinical experience to date unequivocally directs towards a combination strategy in MM for venetoclax. Our prior work has demonstrated that interaction between tumor and stromal cells upregulates phospho-Bcl-2 (pBcl-2, more stable than Bcl-2) which undermines activity of Bcl-2i. We also noted that this can be overcome using agents such as lenalidomide, which can impair the protective effect of stromal cells. Our goal in this investigation was to determine if the antitumor effect of lenalidomide/dexamethasone (Ld) regimen can be further optimized through leveraging the Bcl-2 targeting properties of venetoclax thereby sensitizing MM cells to enhanced lethality. Given the known effects of Ld on activating host immune effector cells, we hypothesized that immune mediated cytotoxicity (engaged by Ld) can be further enhanced through concurrent treatment with venetoclax. Data presented here provides preclinical rationale and proof-of-principle for clinical development of Bcl-2i in combination with Ld. Methodology. Malignant plasma cell cancer models (MM1.S, BCWM.1, KMS11) and stromal cell line (HS5) were used. Bcl-2 and pBcl-2 were determined by flow cytometry. Drug cytotoxicity was determined by MTS assay and/orAnnexin-V/PI staining. SCID mice were used for xenograft studies. Bcl-2 inhibitors (venetoclax; Bcl-2 specific inhibitor, AT-101; pan Bcl-2 inhibitor) as well asLd were purchased from commercial sources. Results. Tumor cell lines were treated with Bcl-2i for 24hrs and showed significant loss of viability (51 - 68%) and induction of apoptosis (~40%) in vitro. To replicate microenvironment conditions, we co-cultured tumor and stromal cells for 48hrs followed by treatment with Bcl-2i (1uM). Under these conditions, we noted a significant reduction in apoptosis (~50%) in Bcl-2i-treated cells indicating the protective effect of the stroma (Fig.1a). Under similar settings, we examined Bcl-2 species in tumor cells +/- stromal cells. The ratio of pBcl-2:Bcl-2 in tumor cells without stromal contact was 0.7, whereas, the ratio increased to 1.8 when tumor and stromal cells were cocultured suggesting increased pBcl-2 as a protective mechanism (Fig.1b,c). We then investigated the potential of Ld (1uM) +/- Bcl-2i to downregulate pBcl-2:Bcl-2 and whether this correlated with increased tumor lethality. While solo Bcl-2i treatment of tumor + stromal cells downregulated pBcl-2 and Bcl-2 (ratio 1.5), a marked reduction was noted in Ld + Bcl-2i treated tumor cells (ratio of 0.3). And this correlated with enhanced tumor cell apoptosis; analogous to that observed in tumor cells without stroma (Fig.1a and c). As these experiments indicated the triple combination to overcome protective effects of the stroma through decreasing bioavailability of pBcl-2 in vitro, we next validated these observations in a xenograft model. MM1.S cells were subcutaneously implanted in SCID mice with local tumor growth monitored by caliper measurement and systemic dissemination measured by Human-Ig lambda levels. DMSO-treated mice demonstrated tumors averaging ~410mm3 by Day 24 post-tumor implantation, whereas mice treated with Bcl-2i (35mg/kg QD, oral gavage) or Ld alone (Len 10mg/kg QD; Dex 0.5mg/kg QD, IP injection) showed tumors ~330mm3. In Ld + Bcl-2i- treated mice, tumor size was ~250mm3- significantly lower than DMSO (p<0.001) or Bcl-2i orLd group mice (p<0.054) (Fig.1d). A similar trend was seen when systemic Human-Ig-lambda was measured (Fig.1e). Notably, mice tolerated the triple combination treatment well; with no significant weight loss or other toxicities noted. Conclusions. Regulation of the Bcl-2 pathway is an important approach for controlling tumor cell proliferation; most recently validated with the approval of venetoclax for treatment of CLL. Herein we demonstrateLd as an attractive partner regimen to enhance the effects of not only Bcl-2i but also that ofLd in MM. Ongoing work is investigating the combination ofLd + venetoclax and preliminary in vitro results in venetoclax-insensitive MM cells (IC50 >5uM) show significant apoptosis induction with combination therapy (Fig.1f). Altogether our studies provide the rationale for clinical evaluation of this combination platform (Len/Dex + Bcl-2i). Disclosures Ailawadhi: Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy.

Abstract Background: Donor cell chimerisms are tested at frequent intervals after allogeneic hematopoietic stem cell transplantation (alloHSCT). However, the predictive value of this testing in patients with myelofibrosis (MF) is not well-defined. In this study, our primary objective is to evaluate the correlation of day 30 and day 100 donor cell chimerism and overall survival (OS) in patients (pts) who undergo alloHSCT for MF. Methods: Charts were reviewed for pts who underwent alloHSCT for MF at Mayo Clinic in Arizona, Minnesota and Florida between January 2005 and December 2015. Patients who died within 30 days of alloHSCT were excluded. Chimerism studies were evaluated in the peripheral blood for CD3 and CD33 fractions at day +30 (D30) and day +100 (D100). Cut-off value of 100% and less than 100% was used because of limited variability below 100%. Standard statistical methods were used to compare continuous and categorical variables. The Kaplan-Meier method was used to provide survival curves. Results: Baseline characteristics: Sixty three consecutive patients who underwent alloHSCT for MF since January 2005 until December 2015, and had D30 and/or D100 chimerism studies available were included in the study. Of these, 24 (38%) were female. Median age at diagnosis was 56 years (range, 19 - 73 years) and median age at AHSCT was 58 years (range, 19 - 73 years). Dynamic International Prognostic Scoring System-Plus (DIPSS-Plus) risk category at the time of alloHSCT was high in 31 (49%), intermediate-2 in 30 (48%) and intermediate-1 in 2 (3%) pts. JAK2 V617F mutation status was available in 61 pts and was positive in 35 (57%) pts. Nineteen (30%) pts had been treated with a JAK2 inhibitor prior to alloHSCT. Fifty-two (83%) pts had at least grade-2 fibrosis in bone marrow at the time of HCT. Transplantation: Median time from diagnosis to AHSCT was 12.9 months (range, 2.3 - 248.2 months). Fifty-five (87%) received a reduced intensity conditioning (RIC) regimen while 8 (13%) received myeloablative conditioning regimen. Of these 55 pts, RIC regimens used were busulfan fludarabine based regimen in 15 (27%), fludarabine melphalan based regimen in 18 (33%) and fludarabine melphalan carmustine in 22 (40%) pts. Donor source was matched related in 30 (48 %), matched unrelated in 28 (44%), single-antigen mismatched related in 4 (6%) and mismatched unrelated in 1 (2%). Peripheral blood stem cells were used in all AHSCTs. Outcomes: Median follow-up was 24.4 months (range, 1.5 - 83.6 months). Amongst pts who had <100% donor chimerism at D30 in CD33 fraction, 2 had 90%, 1 had 80% and 2 had zero% donor chimerism. At D100, 1 pt had 95%, 1 had 90%, 1 had 60%, 2 had 5% and 1 had zero% donor chimerism. Eighteen out of 57 (32%) pts who had 100% donor chimerism in CD33 fraction at D30 had died at the time of analysis compared to 4 out of 5 (80%) patients with less than 100% (p=0.03). Eight out of 38 pts (21%) who had 100% donor chimerism in CD33 fraction at D100 died versus 3 out of 6 (50%) with less than 100% (p=0.12). There was no significant survival effect of CD3 chimerism (p values=0.68, 0.59). Of the 23 deaths that had occurred at the time of analysis, cause of death was disease progression or relapse in 8 (35%), graft versus host disease in 6 (26%), transplant related (sepsis / engraftment failure) in 5 (22%) and unrelated causes in 4 (17%). Survival analysis: As depicted in the Kaplan Meier curve (figure 1), median overall survival (OS) for pts with 100% donor chimerism in CD33 fraction at day 30 was not reached while for <100% donor chimerism was 16 months (p=0.04). Survival at 3 years for patients with 100% CD33 donor chimerism at D30 was 65% while it was 40% for pts with less than 100%. Also, survival at 3 years for patients with 100% CD33 donor chimerism at day 100 was 75% compared to 50% for patients with less than 100%. Conclusions: In our study, 100% donor chimerism in CD33 fraction is associated with improved survival after alloHSCT for MF compared to pts with less than 100%. Further understanding regarding the reason for this relationship is critical. Larger studies to replicate these results would be imperative to validate these findings. Disclosures Mesa: Incyte: Research Funding; Ariad: Consultancy; Promedior: Research Funding; Novartis: Consultancy; Celgene: Research Funding; Gilead: Research Funding; CTI Biopharma: Research Funding; Galena: Consultancy.

Abstract Background: We have previously reported on ethnic disparities in outcomes of multiple myeloma (MM) pts (pts) and shown that Hispanics have the shortest median overall survival (OS) and myeloma-specific survival (MMS) while Asians have the longest. Ethnic minorities are increasing in number in the United States (US) and have been historically underrepresented in population databases with limited follow up since the introduction of novel agents for MM. We did an updated analysis with longer follow up for ethnic minorities to explore the changes in outcomes by race and also explored MM incidence rates, not reported previously. Methods: Surveillance Epidemiology and End Results (SEER) 13 Registry data (1973-2013) for adult pts (>18 yr) with confirmed diagnosis of MM was utilized. To avoid bias of under representation of ethnic minorities, analysis was restricted to pts diagnosed in 1992 or later. Years of diagnosis were 1992-1995 (pre-stem cell transplant; SCT), 1996-2002 (after SCT but before novel therapeutics) and 2003-2013 (after introduction of novel therapeutics). Cases that received a diagnosis at death certificate/autopsy, without follow-up records, lacking documentation on age at diagnosis, sex, or race/ethnicity were excluded. Cox proportional hazards models were used to evaluate association between patient characteristics and survival. All statistical tests utilized the SAS software (v9.4) and were two-sided with a significance level of 0.05. Results: The final analysis included 68431 MM pts (37300 males; 55%, 31131 females; 45%). Age-group cohorts included: 18-44 yr (2519; 4%), 45-54 yr (8131; 12%), 55-64 yr (15416; 23%), 65-74 yr (20214; 30%), and ≥75 yr (22151; 32%). Mutually exclusive racial subgroups included: non-Hispanic White (NHW; 44618, 65%), non-Hispanic African-American (AA; 13164, 19%), non-Hispanic Asian/Pacific Islanders (API; 3570, 5%), Hispanic (H; 6759, 10%) and Native American (NA; 320, 0.5%). Trends in age-specific incidence rates were similar for all races but except the 20-24 yr group, were highest for AA and lowest for API. (Figure 1) Survival analysis showed that females had a better median OS (3.4 vs 3 yr; p<0.001) and MMS (4.7 vs 4.4 yr; p<0.001) than males. Age was an independent predictor of OS (p<0.001) with the median OS changing from 7.3 yr in 18-44 to 1.9 yr in ≥75 age group. Similar results were seen for age groups and MMS as well (p<0.001). During the three pre-specified time periods for year of diagnosis, both the median OS and MMS progressively improved (P<0.001) suggesting improved outcomes secondary to treatment advancements. H and AA had the worst median OS (3.1 yr) as compared to NHW and API (3.3 yr) (p<0.001) and H had the worst median MMS (4.3 yr) while API had the best (5.1 yr) (p<0.001). Survival analyses were performed for ≥75 age group separately since it was the largest and traditionally with worst outcomes. The difference in median OS by gender was still significant (p<0.001) but less pronounced (1.8 vs 1.9 yr) and was not significant for MMS (p=0.33). Due to less SCT utilization, no incremental OS or MMS benefit was seen prior to advent of novel agents but since 2003 the ≥75 group did have a small benefit for OS (2 vs 1.6 yr, p<0.001) and MMS (3 vs 2.3 yr, p<0.001). Race no longer predicted for a statistically significant OS difference (p=0.52) while for MMS, H continued to have the worst (2.5 yr) and NA the best (3.8 yr) outcome (p<0.001). 5-year relative survival rates (RSR) over time showed an incremental improvement in recent years for all racial groups except API ≥70 yr (Figure 2) with generally an increased incremental benefit for the <70 yr age group than the elderly. For majority of races no incremental benefit was seen in 5-yr RSR for ≥70 yr pts between 1992-1995 and 1996-2003 but improvement was seen in 2004-2013. Conclusions: In a fast changing US demographic mix, significant disparities for MM incidence and outcomes exist by race/ethnicity. As compared to our previous analyses, new trends have emerged with Whites having an improved median OS than AA while H continue to have the worst MMS and API the best. Differences in median OS among races are no longer significant in elderly pts. A modest benefit in OS is being seen for elderly pts since the advent of novel therapeutics. Studies of ethnic disparities are important for evaluating management needs of specific patient populations as well as optimal triaging of healthcare resources. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Kelly: Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Speakers Bureau. Ailawadhi:Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy.

Abstract Background: Pomalidomide has demonstrated excellent activity in patients with relapsed, lenalidomide refractory, multiple myeloma (MM). Between November 2007 and March 2012, we enrolled 285 patients with relapsed MM on 5 sequential phase 2 trials; patients received pomalidomide at 2mg or 4 mg daily with weekly dexamethasone (Pom/dex). The approved dose of pomalidomide is 4 mg for 21 of 28 days. We wished to compare efficacy, tolerability and long-term outcomes between cohorts treated with 2 mg or 4mg daily continuously and 4mg daily for 21/28 days. Methods: After excluding two ineligible patients, 283 patients with lenalidomide refractory, relapsed MM from 5 sequential cohorts were analyzed. These patients were divided into 3 groups: Group1 received Pom 2mg for 28/28 day cycle (N= 69), Group 2 received Pom 4 mg for 28/28 day cycle (N= 95) and Group 3 received Pom 4mg for 21/28 day cycle (N= 119). All patients received oral dexamethasone given 40 mg daily on days 1, 8, 15, and 22. Response was assessed by the IMWG Uniform Response criteria. All patients received aspirin 325 mg daily for DVT prophylaxis or full dose anticoagulation. Results: The median age was 63 years (32-85); 35% were female. The median time from diagnosis was 53 months and the median number of prior regimens was 4. 127 (46%) had high-risk molecular markers. Prior therapies (% received) included lenalidomide (100%), thalidomide (46%), bortezomib (78%), autologous stem cell transplant (71%), and allogeneic transplant (4%). The median follow-up is 16.4 months (3.2-64.4). Forty eight percent are alive and 26% remain progression free; 15 patients are continuing to receive treatment. Frequency of AEs by groups are shown in Table 1. The most notable difference is grade 3+ neutropenia seen in 39% of group 1 and 56% and 57% of groups 2 and 3. Confirmed responses of PR or better were seen in 29% (group1), 35% (group2) and 24% (group3). Median duration of response (DOR) was 14.1 months (group1), 14.5 months (group2) and 10.2 months (group3). Median PFS was 5.5 months (group1), 6.9 months (group2) and 4.3 months (group3). Although the dose level cohorts were sequential rather than randomized, we compared OS between the dose levels in an exploratory manner. There was no significant difference in OS between dose levels (p=0.26). Median overall survival (OS) was 16.6 months (group1), 21.9 months (group2) and 16.0 months (group3). Conclusions: Pom/dex is active and well tolerated even in heavily pretreated patients Responses are durable. Response rates and overall toxicity are similar between the 2 mg and 4 mg doses. Neutropenia is more common in those receiving doses of 4mg daily or for 21/28 days compared to those receiving 2 mg daily. Table 1. All Grades Grade 3+ 2mg 28 Day 4mg 28 Day 4mg 21 Day 2mg 28 Day 4mg 28 Day 4mg 21 Day Anemia 68% 58% 74% 14% 15% 27% Lymphopenia 22% 51% 11% 16% 32% 8% Neutropenia 71% 82% 77% 39% 57% 56% Thrombocytopenia 51% 61% 63% 10% 9% 23% Leukopenia 59% 77% 72% 26% 38% 39% Pneumonia 7% 11% 12% 6% 7% 11% Fatigue 51% 65% 60% 9% 5% 8% Neuropathy 28% 32% 28% 0% 3% 0% Elevated Blood Glucose 10% 21% 8% 4% 6% 3% Pneumonitis 3% 2% 3% 3% 1% 1% VTE (Thrombosis) 3% 3% 3% 1% 3% 3% Secondary Malignancy 0% 2% 1% 0% 2% 1% Figure1. Kaplan Meier Overall Survival Curves Figure1. Kaplan Meier Overall Survival Curves Disclosures Lacy: Celgene: Research Funding. Fonseca:Medtronic, Otsuka, Celgene, Genzyme, BMS, Lilly, Onyx, Binding Site, Millennium, AMGEN: Consultancy, patent for the prognostication of MM based on genetic categorization of the disease. He also has sponsored research from Cylene and Onyx Other, Research Funding. Bergsagel:Novartis: Research Funding; Constellation Pharmaceutical: Research Funding; OncoEthix: Research Funding; MundiPharma: Research Funding. Stewart:Novartis: Consultancy; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Array BioPharma: Consultancy; Sanofi: Consultancy; Takeda Pharmaceuticals International Co.: Research Funding. Reeder:Millennium, Celgene, Novartis: Research Funding. Mikhael:Onyx: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Novartis: Research Funding.

Abstract Background Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of clonal B cells in the peripheral blood, bone marrow, lymph nodes, and spleen. This is due to a combined effect of deferred apoptosis with slow, but persistent proliferation of malignant cells. In CLL, tumor-sustaining homeostasis is critically maintained by the ubiquitin proteasome system. The proteasome mediates degradation of various transcription factors such as TP53 as well as upholding a balance between the anti and pro apoptotic proteins of the BCL2 family. Previous studies have demonstrated that the clinical course of the disease is negatively associated with malfunctioning apoptotic pathways that result in increased levels of BCL2. Thus, identification and correction of defects that affect programmed cell death offer therapeutic vantage to reset and engage cell death pathways in CLL. Aim Examination of the anti-CLL properties of the investigational agent MLN2238 (Millennium Pharmaceuticals, Inc., Cambridge, MA) and its ability to inhibit the proteasomal machinery; induce CLL cell death and downregulate BCL2. MLN2238 activity was also investigated in conjunction with anti-CLL therapies such as fludarabine and dexamethasone along with the BH3 mimetic BCL2 inhibitor, AT-101 (Ascenta Pharmaceuticals, Malvern, PA). Methods CLL cells with >90% CD19+ tumor population were obtained from 28 patients with a confirmed diagnosis of CLL. Proteasomal activity was measured using synthetic fluorogenic peptide substrates. Apoptosis was measured by annexin-v/PI staining, and mitochondrial membrane permeability (MOMP) was assessed using TMRM followed by flow cytometry. Protein profiles were ascertained by western blot. Results MLN2238 inhibited the chymotrypsin-like proteasomal activity by more than 90% (p<0.005) in all patient samples without altering PSMB5 protein levels. Moderate to minimal inhibitory effect on caspase-like and trypsin-like proteasomal activities, respectively, was also noted. CLL cells showed a concentration dependent decrease in viability in response to treatment with MLN2238 at an IC50 of 50 nM. MLN2238 treated cells underwent apoptosis in a dose dependent manner with a median dose effect (cell death) observed in 42% of cells at 25 nM (range 10% - 54%) and 60% of cells at a 50 nM concentration (range, 25% - 73%). PARP-1 and caspase-3 cleavage along with an increase in MOMP was also noted after CLL cells were treated with MLN2238; however, apoptosis was only partially blocked by the pan-caspase inhibitor z-VAD.fmk. BCL2 downregulation was dose-dependent and was observed as early as 12 hours. We sought to determine whether directly disrupting BCL2 function with AT-101 could enhance the anti-CLL effects of MLN2238. When used at sub-IC50 concentrations, AT1-10 synergized with MLN2238 to induce CLL cell death. Synergy was also observed when MLN2238 was paired with the cytotoxic agent fludarabine, whereas the combination of MLN2238 and dexamethasone resulted in additive anti-CLL activity. Conclusion While PI have made an important impact in various B cell cancers, their role in CLL has not been well established. We investigated preclinically, a novel PI and noted that targeting the proteasome with MLN2238 resulted in lethal events in CLL cells, which were further enhanced by disruption of the BCL2 prosurvival pathway. Moreover, proteasome disruption sensitized CLL cells to the cytotoxic effect of fludarabine, an important therapeutic in CLL. These data provides the mechanistic basis for evaluation of MLN2238 in CLL through rationale design of drug combination strategies based on CLL biology. We would like to acknowledge the Leukemia and Lymphoma Society (A.C.-K. is a Leukemia and Lymphoma Scholar in Clinical Research) for their ongoing support. We are also grateful to Mary Ella Mahoney Davidson (Millennium Pharmaceuticals) for providing logistical support. Disclosures: Foran: Celgene: Research Funding.

Abstract Background: Cost of cancer care is projected to reach $173 billion by 2020, a 39% increase from 2010. Several factors including psychiatric (psych) comorbidities contribute to this increase. Within the oncology setting, 29-38% of the patients (pts) are reported to have mood disorders and 15% have major depression. Depression alone is associated with increased healthcare utilization in pts with breast, colon, lung and prostate cancers. A 2015 report noted that the presence of at least one psychiatric comorbidity in 300 Leukemia pts was associated with an extra $55,000 per pt in just one year. Similarly, in pts treated with systemic steroids, the incidence of neuropsychiatric disorders can be as high as 75%. However, no such data is available for MM, where more than 90% of pts are treated with steroids, likely increasing risk for mood problems and impacting treatment cost. As such, the aim of our study was to analyze the SEER-Medicare database for healthcare utilization trends and acute cost of care (cost incurred during 6 months after MM diagnosis) in MM pts with or without psych comorbidities. Methods: Pts diagnosed with MM between 1991-2010 with continuous Medicare coverage (1 year prior to diagnosis-date of death/end of 2012) were included. Pts were categorized as: MM with any psych disorder (MM+P), MM with depression (MM+D) and MM only. Presence of ³1 inpatient (ipt) or ³2 outpatient (opt) ICD9 diagnosis codes were used to assign pts to the psych categories. Within MM+P and MM+D groups were subdivided by presence of psych or depression diagnosis prior to MM (MM+P PRE or MM+D PRE). Medicare claims adjusted for inflation (2013) within the first 6 months (mth)/total MM care were summed by drug and total charges. Univariate and multivariate logistic regression models (adjusted for age, year, sex, race, and the Charlson Comorbidity Index; CCI) were performed to determine associations with ipt, opt, and any emergency department (ED) charges after MM diagnosis. Associations between psych conditions prior to MM diagnosis and costs of care after MM diagnosis were assessed using univariate and multivariate proportional odds models. Results: The study population included 36,007 eligible MM pts with a median follow-up of 1.8 years. 15168 (42%) pts had a psych condition at any time (MM+P), while 9355 (26%) were diagnosed prior to MM diagnosis (MM+P PRE). Depression was present in 8421 pts (23%), 4546 (13%) of those occurring prior to MM diagnosis. In comparison to MM pts, MM+P and MM+D pts tended to be female, White, and had a higher CCI (all p<0.001). When compared to MM pts, those with MM+P PRE and MM+D PRE had significantly higher incidence of MM-related complications (hypercalcemia, renal dysfunction, anemia, fractures and dialysis) at the time of or after MM diagnosis and also required increased overall care (all p<0.001). Both, MM+P and MM+D had higher odds of ipt visits (OR 1.48 and 1.41, resp., p<0.001), ED care (OR 1.48 and 1.37, resp., p<0.001) and opt visits (OR 1.25 and 1.22, resp., p<0.001) as compared to MM only pts. Cost of care analysis showed that MM+P and MM+D pts had a significantly higher cost of opt (OR 1.36 and 1.39, resp., p<0.001), ipt (OR 1.49 and 1.54, resp., p<0.001) and total care (OR 1.52 and 1.55, resp., p<0.001) as compared to MM only pts during first 6 mth after MM diagnosis (Figure 1). Total costs of care for MM+P and MM+D were also higher than MM only but the differences were less significant. Cost of care differences existed within first 6 mth of MM diagnosis by pt race as well with MM+P among Hispanic and Asian pts being more strongly associated with higher costs than Whites and African-Americans (AA) (p<0.001). MM+D had similar trends but not significant after adjustment for multiple comparisons. Conclusion: Psych comorbidities are associated with significant increase in healthcare utilization and cost of care in MM pts and may contribute to higher MM-related complications. More research is needed to study whether a multidisciplinary approach to identify and manage MM pts with psych conditions may help mitigate these trends. Disclosures Ailawadhi: Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy.

Abstract Background: Patient (Pt) outcomes have improved significantly in multiple myeloma (MM) due to widespread use of novel therapeutic agents and stem cell transplant (SCT) butoutcome disparities among racial/ethnic groups exist. Differences in access to and utilization of novel therapeutics are likely contributing factors. We performed an analysis of the SEER-Medicare database to explore such differences. Methods: Pts with a confirmed MM diagnosis between 2007-2009 and continuous Medicare coverage from 1 year prior to diagnosis through end of 2012 were included. Medicare Part D data (oral medications) is not available prior to 2007 so utilization analysis of lenalidomide (LEN), thalidomide (THAL) and bortezomib (BORT) was performed from 2007-2009. Demographic/survival data (PEDSAF files) and drug/SCT utilization (NCH, OUTSAF, PDESAF files) were obtained (HCPCS/NCH codes). Categorical and continuous variables were compared using /Fisher tests and Wilcoxon tests, respectively. Gender, age, and year-adjusted p-values were calculated using logistic regression. A proportional odds model was used to detect time-dependent trends in drug usage within 12 months of MM diagnosis across year of diagnosis by race. Separate multivariate models were fit for each drug adjusting for gender, age, drug use and race. Associations between drug use and overall survival (OS) were examined using a time dependent proportional hazards model. Results: A total of 5358 MM pts were included (any Medicare claims) with 2733 (51%) males. Mutually exclusive race categories were White (W; 67%), African-American (AA; 18%), Hispanic (H; 10%) and Asian (A; 5%). Median follow up was 2.4 yrs. Baseline pt characteristics were significantly different for age with AA being the youngest at diagnosis (p<0.001) and for gender (p<0.001) with W having the largest (53.4%) and AA the smallest (45.2%) proportion of males. Medicare claims capture only pts without any supplemental insurance and so drug utilization in this database was much lower than expected for all subgroups. Year-wise comparison showed that LEN use within the first year of MM diagnosis increased from 2007 to 2009 (16.5% to 27.7%; p<0.001) and there was a significant decrease in median days to first dose (p=0.002). Over the same period, use of THAL decreased (26.6% to 14.6%; p<0.001) while use of BORT (7.8% to 15.4%; p<0.001), SCT (3.3% to 6.2%; p<0.001) and more than 1 novel agent (2.5% to 5.7%; p<0.001) increased significantly. Utilization patterns within first year of MM diagnosis were significantly different among racial subgroups for LEN, THAL, BORT, SCT and >1 novel agent use. (Figure 1) No significant difference was seen for days to first dose of LEN/THAL for any race but for BORT, H got first dose in median 117 days after diagnosis as compared to median 46-51 days for other races (p=0.025). During the first year after diagnosis, W and AA had higher BORT only usage while H and A had a higher LEN/THAL only usage (p<0.001). For drug use by year and race, a significant increase in LEN use was seen from 2007 to 2009 in W (p<0.001), AA (p=0.001) and A (p<0.001) but not H (p=0.26) while THAL use decreased significantly for all races. BORT use increased significantly for all except A (p=0.602) and SCT use increased significantly for all except AA (p=0.068). Inferior OS was significantly associated with older age (p<0.001) and males (p<0.001). LEN/THAL use within the first year of diagnosis did not affect OS while BORT use within the first year of diagnosis increased mortality risk (HR 1.18, p=0.021). SCT use improved OS (HR 0.52, p<0.001). Conclusions: In this comprehensive analysis of MM therapeutics utilization, we noted significant variability among different racial groups. The use of LEN, BORT and SCT has increased while THAL has decreased over time but disparities exist in utilization among different races, with lower use of LEN in AA, lower use of BORT in A and significantly delayed use of BORT in H, which are all notable since racial/ethnic minorities are fast growing in the US population mix and seem to have inequitable utilization and/or access. Inferior survival with early BORT use may represent selection bias of pts with more advanced/aggressive disease. These trends need to be examined in larger sample sizes especially from commercial payers to eliminate drug access and utilization disparities and achieve equitable benefit of therapeutic advances across all racial subgroups. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Ailawadhi: Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy.

Abstract Background: Pomalidomide is an immunomodulatory agent (IMiD®) that has been approved for treatment of relapsed and refractory multiple myeloma (MM). Combinations of IMiDs and proteasome inhibitors offer the potential for deeper and more durable responses due to enhanced efficacy. Preliminary results of a phase 1 study of twice weekly bortezomib with pomalidomide have been reported with promising results (Richardson, ASH 2012). This phase I/II trial was designed to evaluate the maximum tolerated doses (MTD) as well as safety and efficacy of the combination of pomalidomide, once weekly bortezomib and dexamethasone (PVD) in patients with relapsed, lenalidomide refractory, MM. Patients and methods: We included patients with relapsed MM who had 1-4 prior lines of therapy and were resistant or refractory to lenalidomide. In the phase I portion of the trial, dose level 1 consisted of pomalidomide 4 mg days 1-21 PO, bortezomib 1.0mg/m2 days 1,8,15, and 22 IV or SQ and dexamethasone 40 mg days 1,8,15, and 22 PO, given every 28 days. Bortezomib was increased to 1.3mg/m2 for dose level 2 and and was adopted for the phase 2 portion. The primary aim of the phase I cohort was to determine the MTD of the combination, and for the phase II cohort was to evaluate the confirmed response rate (PR, VGPR, or CR) in relapsed refractory MM. Response was assessed by the IMWG criteria and toxicity was graded using the CTCAE v4.0. Results: 50 patients were accrued between March 2012 and July 2014 (dose level (DL)1: 3, DL 2: 6, Phase II: 41). We describe results in 47 patients treated at MTD and phase II. Median age was 66, 51% were female and median time from diagnosis to study was 46 months (15-142). Twenty five percent had mSMART defined high-risk status. Median number of prior regimens was 3. All patients had prior lenalidomide, 68% had stem cell transplant, 17% received thalidomide, 56% had alkylators and 57% had bortezomib. With median follow up of 9 months, 72% remain progression free, 96% are alive and 66% remain on treatment. The most common AEs at least possibly attributable to the combination were anemia, fatigue, leukopenia and thrombocytopenia; however, the majority of these were grade 1-2. Grade ≥3 AEs (regardless of attribution) that occurred in at least 3 patients included neutropenia (29), leukopenia (15), lung infection (6), lymphopenia (8) dyspnea (3) and syncope (3). DVT/PE occurred in one patient. Among the 42 patients who were evaluable, confirmed responses (PR, VGPR, or CR) were seen in 34 (81%) including sCR (3), CR (5), VGPR (8), PR (18). Confirmed responses were seen in 9 of 11( 82%) high risk patients. Median progression free survival was 17.7 months (95%CI: 9.5-NA). Conclusions: PVD is a highly effective combination in patients refractory to lenalidomide with confirmed responses in over 80%. Weekly administration of bortezomib enhanced the tolerability and convenience of this regimen. Toxicities are manageable, mostly consisting of mild cytopenias with no significant neuropathy or DVT. PVD is a highly attractive option in patients with relapsed and refractory MM. Disclosures Lacy: Celgene: Research Funding. Lust:Senesco: PI Other. Fonseca:Medtronic, Otsuka, Celgene, Genzyme, BMS, Lilly, Onyx, Binding Site, Millennium, AMGEN: Consultancy, patent for the prognostication of MM based on genetic categorization of the disease. He also has sponsored research from Cylene and Onyx Other, Research Funding. Stewart:Celgene: Consultancy; Novartis: Consultancy; Array BioPharma: Consultancy; BMS: Consultancy; Millenium: Research Funding. Reeder:Millennium, Celgene, Novartis: Research Funding. Mikhael:Onyx: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Novartis: Research Funding.