Abstract: Thalidomide has direct antimyeloma and immunomodulatory effects. In addition, both thalidomide and metronomic chemotherapy inhibit angiogenesis. The synergy of such a combination may decrease toxicity while maintaining efficacy. The Hoosier Oncology Group conducted a phase II trial of oral cyclophosphamide (50 mg b.i.d. for 21 days), thalidomide (200 mg/day), and prednisone (50 mg q.o.d.) (CTP) per 28-day course in patients with relapsed multiple myeloma (MM). Of the 37 patients enrolled, 16 had prior stem cell transplantation. The median follow-up time was 25.3 months (95% confidence interval [CI] 23.2–27.7). Of 35 patients treated, 22 patients (62.9%) responded: 7 (20.0%) complete responses, 2 (5.7%) near-complete responses, and 13 (37.1%) partial responses. Eight patients (22.9%) had stable disease, and three (8.6%) had disease progression. Two patients withdrew from the study early due to reasons unrelated to progression or toxicity and were treated as nonresponders. The median time to best response and time to progression were 3.6 months (95% CI 2.8–10.9) and 13.2 months (95% CI 9.4–21.0), respectively. The median number of treatment cycles was seven (range 1–12 cycles). Grade III to IV toxicities included leukopenia (42.9%; febrile neutropenia, 11.4%), hyperglycemia (20%), sensory neuropathy (11.4%), thromboses (8%), and motor neuropathy (5.7%). No patient withdrew from the study due to toxicity. The efficacy and low toxicity of the CTP regimen support the future development of such an approach in MM.

Abstract: Introduction: Phase 3 trials demonstrated maintenance therapy after autologous stem cell transplant (ASCT) extended time to progression, progression-free survival, and in some cases overall survival for patients (pts) with multiple myeloma (MM) (Sonneveld, 2012; McCarthy, 2012; Attal, 2012; Palumbo, 2014; Attal, 2016). Maintenance treatment until progression has the potential to adversely impact health-related quality of life (HRQoL). Few HRQoL analyses have been published in MM, especially with regard to maintenance therapy after ASCT. Connect® MM is the first and largest multicenter, US-based, prospective observational cohort study designed to characterize treatment patterns and outcomes for pts with newly diagnosed MM (NDMM). This analysis evaluated HRQoL of pts who received Any maintenance therapy, lenalidomide (LEN) only, or No maintenance post-ASCT. Methods: Pts ≥ 18 years with NDMM within 60 days of diagnosis were eligible for enrollment in the registry. For this analysis, pts who completed induction therapy and first-line ASCT who may or may not have gone on to receive maintenance (yes/no) were included. Pts were evaluated in 3 groups: Any maintenance (including LEN-only), LEN-only maintenance, and No maintenance. Pt-reported HRQoL data were collected at protocol-defined quarterly visits. The primary HRQoL measure analyzed was the EQ-5D Index score. Secondary measures included the Functional Assessment of Cancer Therapy-Multiple Myeloma (FACT-MM) total score and the Brief Pain Inventory (BPI). HRQoL assessments were analyzed at study entry (study baseline); after induction therapy but prior to ASCT (analytic baseline); and quarterly from 100 days post-ASCT until the end of maintenance (maintenance groups) or until progressive disease, discontinuation, or death (all groups) (analytic period). SAS Proc Mixed with a random effects unstructured covariance matrix was used to estimate mixed regression models to test the null hypothesis of no HRQoL difference between pts receiving Any or LEN-only maintenance vs No maintenance. A quadratic growth model was used with time as a continuous variable (given that ASCT can occur at any fractional quarterly period post-enrollment and having a starting at 100 days post-ASCT), adjusted for potential confounders. Results: Between September 2009 and December 2011, Connect® MM enrolled 1493 pts in Cohort 1 from community (82%) and academic (17%) centers. Of the 540 pts who received ASCT, 238 met the analysis criteria for Any maintenance, 167 for LEN-only, and 138 for No maintenance. Median age (range) was 60 years (24-78); 61% were male, and 85% were white. The majority were Eastern Cooperative Oncology Group performance status 0/1 (64%) and International Staging System stage I/II (56%). A higher proportion of pts in the Any and LEN-only maintenance groups received triplet therapy as induction vs the No maintenance group (64%, 66%, and 51%, respectively). Median duration (range) of maintenance in the Any and LEN-only maintenance groups was 23.0 months (0.8-50.4) and 24.4 months (0.6-50.4), respectively. During the analytic period, the EQ-5D questionnaire completion rate across the 3 comparison groups was similar and decreased at a similar rate over time. The median number (range) of EQ-5D forms completed per patient was 4.5 (1.0-16.0), 5.0 (1.0-15) and 5.0 (1.0-16.0) for Any, LEN-only, and No maintenance groups, respectively. The mean baseline HRQoL scores for each measure were similar across the 3 groups, with ranges of EQ-5D (0.75-0.76), FACT-MM Total (114.8-119.7), and BPI (3.87-4.06). There were no significant differences in estimated mean post-ASCT scores when comparing Any or LEN-only with the No maintenance group for the EQ-5D Overall Index, the FACT-MM Total Score, or the BPI (Table and Figure). Conclusions: NDMM pts in the Connect® MM registry receiving Any or LEN-only maintenance therapy vs No maintenance after ASCT demonstrated generally similar HRQoL scores for the EQ-5D Index, FACT-MM, and BPI. These results suggest that there is no difference in HRQoL for those who received maintenance compared with those who did not despite the risks associated with continued active therapy. Save Disclosures Abonour: Celgene: Membership on an entity's Board of Directors or advisory committees. Jagannath:Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Merck: Consultancy. Terebelo:Celgene: Membership on an entity's Board of Directors or advisory committees. Gasparetto:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy; Bristol-Myers Squibb: Honoraria; Onyx: Honoraria; Janssen: Honoraria. Toomey:Celgene: Consultancy. Hardin:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kitali:Celgene: Employment, Equity Ownership. Gibson:Celgene: Employment, Equity Ownership; Sanofi: Other: Spouse employment . Srinivasan:Celgene: Employment; Individual Patent: Patents & Royalties: US7,495,673B1 Used for MM-Connect Treatment Patterns Abstract.. Swern:Celgene: Employment, Equity Ownership. Rifkin:Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen/ONYX: Membership on an entity's Board of Directors or advisory committees.

Abstract: Graft-versus-host disease (GVHD) remains the 2nd leading cause of mortality—after relapse/progression following allogeneic hematopoietic cell transplantation for the treatment of hematological malignancies. The incidence of clinically significant GVHD ranges from 10 to 80% and accounts for approximately 10-20% transplant related mortality. The combination calcineurin inhibitor and methotrexate is widely used as a GVHD preventive following myeloablative conditioning; however, there is no standard prophylaxis regimen for Cy/Flu minimal intensity nonablative transplants. The objective of the current study is to compare outcomes in patients treated at a single institution with identical conditioning regimens and supportive methods but different GVHD preventive regimens. Outcomes on 134 patients who underwent nonmyeloablative transplant between May 2000 and Nov 2011 were retrospectively analyzed. The primary endpoint was incidence and severity of acute GVHD (aGVHD). Secondary endpoints included incidence and severity of chronic GVHD (cGVHD), incidence of relapse, overall survival (OS), progression-free survival (PFS) and causes of death. Median follow-up was 49 months; the median age at transplant was 56 years, 66% of patient were not in remission at time of transplant (predominately myelodysplasia). Donors were peripheral blood mononuclear cell (PBMC, n=133) or bone marrow (n=1) HLA matched related or partially matched (9/10) donors. GVHD preventive regimens included the following: (1) single agent cyclosporine (CsA); (2) combination CsA/mycophenolate mofetil (MMF); (3) CsA+ basiliximab after ANC 〉 500/mm3; (4) CsA + basiliximab post-transplant, pre-engraftment; (5) sirolimus + tacrolimus. The incidence of grade III-IV acute GVHD was lower in patients who received sirolimus/tacrolimus than patients in the cyclosporine group (25% and 32%, respectively; p = .062). There was a significantly higher proportion of patients in the cyclosporine group who had clinical extensive chronic GVHD (62% vs. 25%, p = .008). The incidence of relapse trended higher in the sirolimus/tacrolimus group compared to CsA alone or CsA/MMF (50% vs. 28% vs. 30%, respectively, p= .519). There was a trend towards slightly better OS and PFS with the cyclosporine-based prophylaxis, but follow-up was longer with these regimens. Sirolimus/tacrolimus provides potent GVHD prophylaxis for nonmyeloablative Cy/Flu allogeneic transplantation; however, may be associated with higher relapse/progression rates. Larger numbers and/or comprehensive analyses of multicenter registry data might help further delineate differences in clinical outcomes between these regimens. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Abstract: Background: Immunomodulatory agents and proteasome inhibitors have significantly improved outcomes in the management of patients with multiple myeloma (MM). As a consequence, the role of upfront autologous stem cell transplant (ASCT) has become more controversial. The ECOG-ACRIN Cancer Research Group trial E4A03 demonstrated the superiority of lenalidomide (LEN) and low-dose dexamethasone (DEX; Ld) over LEN and high dose DEX (LD) in newly diagnosed MM (Rajkumar SV, Lancet Oncol, 2010). This led to the universal acceptance of Ld as a standard induction regimen. More recently, the FIRST study demonstrated the superiority of Ld as continuous therapy vs Ld given x 18 cycles and melphalan-thalidomide-prednisone x 12 cycles proving continuous Ld should be considered standard of care (Benboubker L, NEJM, 2014). Upon completion of four cycles of therapy, patients enrolled in E4A03 had the option of proceeding to ASCT or continuing on their assigned Ld or LD. A prior post-hoc retrospective landmark analysis (Siegel DS, Abstract, Blood 2010) comparing outcomes of early ASCT vs. no early ASCT showed that in patients 〈 65, 65-70, and 〉 70, the survival with early ASCT at 3 years appeared higher, supporting the role of early consolidative ASCT in newly diagnosed patients. This analysis is the long-term follow-up of the aforementioned study. Methods: A post hoc, retrospective landmark analysis was performed evaluating overall survival (OS) by early ASCT vs. no early ASCT overall and within age subgroups. The Kaplan-Meier method was used to estimate survival distributions and Cox regression for hazard ratio (HR) estimates. The landmark analysis included only patients surviving the first four cycles of therapy. Results: 21% of patients opted for early ASCT (n=90). At baseline (four cycles prior), early ASCT patients were younger (median 57.5y vs 66y), more fit (ECOG PS 0 45% vs 56%) and with less aggressive disease (ISS Stage 3 12% vs 28%). Median treatment duration was 7.6m for no early ASCT patients. The 1, 2, 3, 4, and 5-year survival probability estimates were higher for early ASCT vs. no early ASCT at 99%, 93%, 91%, 85%, and 80% vs. 94%, 84%, 75%, 65%, and 57%. The median OS in the early ASCT vs. no early ASCT was not reached vs. 5.8 years, respectively (Table 1). The survival hazard ratio (HR) for early ASCT was 0.55 [95%CI (0.38-0.80)]. In a further subgroup analysis of patients 〈 /= 65, 5-yr survival probability of those who had early ASCT vs. no early ASCT was 79% [95%CI (67-87)] vs. 62% [95%CI (54-69)] , respectively. In patients 〈 /= 65, median OS in the early ASCT vs. no early ASCT was not reached vs. 7.4 years and the survival HR was 0.74 [95%CI (0.48-1.15)]. For patients 〉 65, 5-yr survival probability of those who had early ASCT vs. no early ASCT was 83% [95%CI (56-94)] vs. 52% [95%CI (45-59)] , respectively. In patients 〉 65, median OS in the early ASCT vs. no early ASCT was not reached versus 5.2 years and the survival HR was 0.38 [95%CI (0.17-0.87)]. In all age groups, overall response rate was similar prior to the decision of proceeding with ASCT vs. no early ASCT. In a multivariable model adjusting for baseline prognostic factors, early ASCT retained marginal significance. Conclusions: The landmark analysis demonstrated that patients opting for ASCT after induction Ld/LD had a higher 1, 2, 3, 4, and 5- year survival probability and improvement in median OS regardless of DEX dose density. Results were stronger within the older age cohort and upheld in adjusted models. Limitations include lack of randomization and data on salvage therapy. At a time when lenalidomide and dexamethasone as induction is gaining worldwide acceptance in all age groups, early ASCT is safe and efficacious and should remain a standard of care for newly diagnosed MM even in the era of novel therapies. Table 1. Survival Probabilities (Time from Registration) for all Patients Included in the Landmark Analysis Median 1 year 2-year 3-year 4-year 5-year N Events Median (Yrs)(95% CI) Events Survival Probability(95% CI) Events Survival Probability(95% CI) Events Survival Probability(95% CI) Events Survival Probability(95% CI) Events Survival Probability(95% CI) No Early ASCT All 341 195 5.78(5.11 - 6.59) 22 0.94 (0.90 - 0.96) 53 0.84 (0.80-0.88) 84 0.75 (0.70-0.79) 119 0.65 (0.59-0.69) 144 0.57 (0.51 - 0.62) Early ASCT All 90 34 NR 1 0.99 (0.92 - 1.00) 6 0.93 (0.86 - 0.97) 8 0.91 (0.83 - 0.95) 13 0.85 (0.76 - 0.91) 18 0.80 (0.69 - 0.87) NR = not reached Disclosures Biran: Celgene: Speakers Bureau. Siegel:Celgene Corporation: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Novartis: Speakers Bureau; Merck: Speakers Bureau. Fonseca:Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; 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; Applied Biosciences: Membership on an entity's Board of Directors or advisory committees; Onyx/Amgen: 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; Bayer: 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. Vesole:Idera Pharmaceuticals: Research Funding; Celgene Corporation: Speakers Bureau. Williams:Celgene: Consultancy, Research Funding. Abonour:Celgene: Research Funding, Speakers Bureau.

Abstract: Abstract 1966 Introduction: A potent natural killer (NK) cell versus multiple myeloma (MM) effect has been reported in clinical observations and characterized mechanistically in translational studies. However, the NK cell versus MM effect is lost as the disease methodically progresses due, in part, to upregulation of MHC Class 1 antigens on MM tumor cells which serve as ligands to inhibitory KIR on NK cells. Our group has shown that IPH-2101, a novel IgG4 monoclonal blocking antibody against commonly expressed inhibitory KIR (KIR2DL-1, -2 and -3), may augment NK cell function against MM tumor cells. A single-agent phase 1 open-label, dose escalation study of IPH-2101 is nearing completion to determine the safety, tolerability and biologic effects of inhibitory KIR blockade as a novel form of therapy for MM. Methods: A single-agent, open-label, Phase 1 dose escalation study is being performed with 7 cohorts in standard 3+3 design. The protocol was amended to include 7 additional patients with less heavily pretreated disease in the final cohort. Doses from 0.0003 mg/kg to 3mg/kg are being evaluated. Patients enrolled on the 7 cohorts had heavily pre-treated, relapsed/refractory MM with at least one prior therapy, whereas 7 additional patients accrued to the final cohort are limited to one prior therapy only. IPH-2101 is administered intravenously once every 28 days, with 4 cycles of therapy possible as determined by safety, tolerability and disease characteristics. Extensive pharmacodynamic (PD), pharmacokinetic (PK), KIR occupancy, and correlative biologic data are being collected. Results: Currently, 32 patients have been enrolled, and 5 patients remain on study in the final cohort. IPH-2101 has been well tolerated without determination of a dose limiting toxicity (DLT). 1 patient at dose level 1 was replaced and 3 additional patients were enrolled at dose level 4 due to an SAE (acute renal failure) deemed possibly related to drug. PK and PD data closely approximate those predicted by preclinical modeling. Full KIR occupancy across the dosing interval appears to be achieved in most cases with the 1mg/kg dose. No evidence of autoimmunity and no deleterious effect on NK cell maturation has been observed to date. Ongoing correlative studies will characterize NK cell phenotype, cytotoxicity, and effects of IPH-2101 on immunomodulation. To date, no objective responses have been observed; however, preliminary analyses suggest that several patients may have achieved disease stabilization. Conclusions: IPH-2101 improves autologous NK cell-mediated cytotoxicity against MM tumor cells and appears to be well tolerated and safe with achievement of biologic endpoints independent of DLT or maximally tolerated dose. Preliminary data suggest that several patients may have disease stabilization on therapy. Updated correlative, biologic data will be presented at the meeting. Disclosures: No relevant conflicts of interest to declare.

Abstract: Abstract 1870 Poster Board I-895 Background: Enzastaurin is an oral serine/threonine kinase inhibitor that targets the PKC and PI3K/AKT pathways. Enzastaurin has demonstrated activity in preclinical models of multiple myeloma (MM), and clinical studies suggest activity and a favorable safety profile in a variety of hematological cancers. Enzastaurin has also demonstrated in-vitro synergy with bortezomib. Objectives: This phase I, open-label, multicenter, dose-escalation study was initiated to identify the recommended doses of enzastaurin and bortezomib in combination for phase II studies in patients (pts) with previously treated MM. Secondary objectives included evaluations of safety and response. Patients and Methods: A conventional dose-escalation scheme was applied. In dose level 1, pts received enzastaurin as a loading dose of 500 mg (250 mg po BID) on day 1 followed by daily doses of 125 mg po BID plus bortezomib 1.0 mg/m2 IV on days 8, 11, 15, and 18 in cycle 1 and days 1, 4, 8, and 11 thereafter. In dose level 2, pts received the same enzastaurin dose but a higher bortezomib dose (1.3 mg/m2). In dose level 3, pts received enzastaurin as a loading dose of 1125 mg (375 mg po TID) on day 1 followed by daily doses of 250 mg po BID plus 1.3 mg/m2 bortezomib. All treated pts were evaluated for response using the International Uniform Response Criteria (IURC; Durie et al. 2006) and European Group for Blood and Bone Marrow Transplantation (EBMT) criteria (Blade et al. 1998). All adverse events (AEs) were graded according to Common Toxicity Criteria for Adverse Events (CTCAE) v3.0. Results: A total of 23 pts, 4 in dose level 1, 3 in dose level 2, and 16 in dose level 3, were enrolled in the study, which is now closed to enrollment. There were 8 women and 15 men, with a median age of 62 years (range, 37–78 years); 91% of the pts had an ECOG performance status of 1 or 0, and the median number of prior systemic therapies was 3 (range, 2–12), with 17 pts previously treated with bortezomib. The median number of cycles completed was 4 (range, 1–20). No dose-limiting toxicities (DLTs) were observed; thus, dose level 3 was the recommended phase II dose. The combination was well tolerated with few grade 3/4 AEs. CTCAE drug-related grade 3/4 laboratory toxicities included: thrombocytopenia in 5 (22%) pts, anemia in 2 (9%) pts, increased creatinine in 1 (4%) pt, and hyponatremia in 1 (4%) pt. Drug-related grade 3/4 non-laboratory toxicities included: sensory neuropathy, prolonged QTc interval, and renal/genitourinary in 1 (4%) pt each. Serious drug-related AEs were increased serum creatinine and renal tubular necrosis in 1 (4%) pt and thrombocytopenia in 1 (4%) pt. The thrombocytopenia was not considered a DLT as the baseline platelet count was low secondary to MM. Five (22%) pts were discontinued from the study due to drug-related toxicities: renal tubular necrosis (also a serious AE) in 1 (4%) pt, peripheral neuropathy in 2 (9%) pts, neuralgia in 1 (4%) pt, and pain in extremity in 1 (4%) pt. There were no deaths on therapy; 1 pt died within 30 days of treatment due to progressive disease. Of the 23 enrolled pts, objective responses based on IURC criteria included 1 (4%) pt with a very good partial response (dose level 1), 2 (9%) pts with a partial response (in dose levels 2 and 3), 9 (39%) pts with stable disease, and 3 (13%) pts with progressive disease; 2 pts had no post-baseline response assessment, and 6 pts had unconfirmed stable disease or progressive disease. Two (9%) pts had a minimal response based on EBMT criteria. Activity was seen in pts regardless of prior exposure to bortezomib. Conclusions: The recommended phase II dose in patients with MM is enzastaurin 250 mg po BID with a loading dose of 1125 mg (375 mg po TID) on day 1 plus 1.3 mg/m2 bortezomib on days 1, 4, 8, and 11 (days 8, 11, 15, and 18 in cycle 1 only). The combination was generally well tolerated, and responses were observed. Disclosures: Ghobrial: Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Research Funding; Celgene: Honoraria, Speakers Bureau. Munshi:Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yuan:Eli Lilly and Company: Employment. Schlossman:Millenium: Speakers Bureau; Celgene: Speakers Bureau. Laubach:Novartis: Consultancy. Anderson:Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Millenium: Consultancy, Honoraria, Research Funding. Lin:Eli Lilly and Company: Employment. Wooldridge:Eli Lilly and Company: Employment. Richardson:Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keryx Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Meyers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gentium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.