ALBERT

Description: Abstract 4127 In the age of novel targeted agents, autologous stem cell transplant (ASCT) remains the standard of care for younger patients with newly diagnosed multiple myeloma (MM), offering similar treatment responses and overall survivals as standard chemotherapeutic agents but with the added benefit of a prolonged treatment-free period. Nevertheless, a standard of care for stem cell mobilization for ASCT has yet to be determined. Even in the era of new mobilization agents such as Plerixafor, Cyclophosphamide (Cy) and G-CSF combination remains the preferred mobilizing approach for patients with MM. Several studies have shown that Cy improves the stem cell yield at the expense of increased toxicity, but whether the administration of this chemotherapeutic agent pre-transplant has any impact on the long-term event-free and/or overall survival of myeloma patients remains controversial. In this study, we present a retrospective analysis of 186 patients with newly diagnosed MM who underwent ASCT with high-dose melphalan 200 mg/m2 (HDM) between December of 2000 and 2008 at our Institution. Eighty-three patients were mobilized with single agent G-CSF and 103 patients received high dose Cy (4 gm/m2) and G-CSF combination. Patient characteristics were similar between the treatment groups, including: age, gender, disease stage, and disease status prior to transplant. However, toxicity post-mobilization with Cy/G-CSF was significantly higher compared with G-SCF alone, including: febrile neutropenia (23%), hemorrhagic cystitis (8%), GI toxicity (57%), re-hospitalization due to complications and transplant delay (14%). The overall post-transplant toxicity was similar in the 2 groups, though the treatment related mortality was slightly higher in the Cy/G-CSF arm (4% versus 2%). Post transplant responses were not significantly different in the 2 groups, with 60% of patients achieving a VGPR or better after ASCT in the G-CSF group and 49% in the Cy/G-CSF group (p = 0.33). The median event-free survivals (EFS) for the Cy/G-CSF and G-CSF cohorts were 21.6 and 22.6 months, respectively, (p = 0.62) yielding no significant difference (Figure 1). Similarly, with a median follow up for surviving patients of 34.3 and 32.7 months, the median overall survivals were 68.2 and 62.3 months (p = 0.23) for the Cy/G-CSF and G-CSF cohorts, respectively (Figure 2). This retrospective analysis confirms that the addition of high dose Cy as part of the mobilizing regimen offers no improvement on the transplant outcome for patients with newly diagnosed myeloma and should therefore only be used in cases of difficult stem cell mobilization. Disclosures: No relevant conflicts of interest to declare.

Description: High-dose therapy plus autologous stem cell transplant (ASCT) is the standard of care for patients with multiple myeloma (MM) aged ≤65 years. Melphalan–prednisone (MP)-based therapy is the standard for non-ASCT candidates but is not typically used for transplant-eligible patients as prolonged therapy with melphalan can adversely affect stem cell collection. The phase 3 VISTA study demonstrated the superior efficacy of bortezomib plus MP (VMP) versus MP in previously untreated MM patients ineligible for ASCT. In this phase 2 study, we evaluated the efficacy of a shorter course of VMP on a different treatment schedule as induction therapy prior to ASCT or as frontline therapy in non- ASCT candidates. Patients aged ≥18 years with previously untreated MM received up to six 28-day cycles of bortezomib 1.3 mg/m2 IV, days 1, 4, 8, and 11, plus oral melphalan 6 mg/m2 and oral prednisone 60 mg/m2, days 1–7. After 2–6 cycles, ASCT-eligible patients could proceed to stem cell mobilization (G-CSF 10 mg/kg/day ± GM-CSF 250 mg/m2/ day or cyclophosphamide 4 g/m2 + GM-CSF) and conditioning with melphalan 200 mg/ m2 (140 mg/m2 if aged 〉65 years). Response was assessed every two cycles and post- ASCT by International Uniform Response Criteria. The primary end point was complete response (CR) rate to VMP. A total of 45 patients were enrolled; 27 were male. Median age was 63 years (range 33–75). MM subtype was 67% IgG, 16% IgA, and 9% each κ- and λ- light-chain; 37% of patients had ISS Stage III MM, 22% had ECOG performance status 〉1, and 70% had ≥40% plasma cells in bone marrow. In total, 20 patients proceeded to ASCT. Median duration of VMP was 4 cycles in both non-ASCT (range 1–6) and ASCT (range 2–6) patients. Response rate (best response) to VMP was 95% (42 of 44 evaluable patients), including 9% stringent CR (sCR), 9% CR (18% ≥CR [95% CI: 7%, 30%]), 27% very good partial response (VGPR), and 50% partial response (PR). Best response was achieved after cycle 2 in 10 patients, cycle 4 in 25 patients, and cycle 6 in 7 patients. All 20 ASCT patients had successful stem cell mobilization; median yield of CD34+ cells/ kg was 5.6 x 106 (range 2.3–12.2 x 106), in a median of 2 collection days. Post-transplant responses were 10% sCR, 20% CR, 55% VGPR, and 5% PR; the remaining 2 patients need further follow-up for response assessment. Response improved post-VMP to post-ASCT in 10 patients (6 PR to VGPR, 2 PR to CR, 2 VGPR to CR). After median follow-up of 14.0 months (range 7.4–47.7) and 14.6 months (range 8.2–42.9) in non-ASCT and ASCT patients, respectively, both median time to progression and progression-free survival were 19.8 months (95% CI: 14.3 months, not estimable [NE]) in non-ASCT patients and 27.9 months (95% CI: 14.6 months, NE) in ASCT patients. A total of 7 patients (5 non- ASCT, 2 ASCT) have died; 1-year survival rate was 82% (95% CI: 59%, 93%) in non- ASCT patients and 95% (95% CI: 69%, 99%) in ASCT patients. Most common grade 3/4 adverse events in all 45 patients during VMP therapy included peripheral neuropathy (24%), thrombocytopenia (20%), neutropenia (18%), and infection (9%). Only 1 patient had deep-vein thrombosis. In conclusion, VMP represents a highly effective therapy for previously untreated MM, with 45% of patients achieving VGPR or better, including 18% sCR/CR. Toxicities were predictable and generally manageable. Short-course VMP therapy did not negatively impact stem cell mobilization, supporting its use as induction therapy prior to ASCT. Very high post-transplant response rates were seen, with 85% of patients achieving ≥VGPR, including 30% sCR/CR. Since achievement of CR/VGPR is associated with improved long-term outcomes in MM, the preliminary outcome data presented here appear promising; however, longer follow-up is required.

Description: Abstract 2012 High dose chemotherapy (HDC) followed by autologous stem cell transplant (ASCT) remains a valid treatment option for patients with multiple myeloma (MM). HDC has improved response rate, event-free survival (EFS) and treatment free interval for patients with MM when compared with conventional chemotherapy. To date, Melphalan 200 mg/m2 (HDM) remains the standard ASCT preparative regimen as no other regimens have demonstrated improved outcomes with acceptable toxicity. Nevertheless, relapse remains inevitable with this approach prompting continued search for better therapies. To overcome resistance and early relapse we used a more aggressive alkylator based conditioning regimen. Here we summarize a retrospective study of the long-term follow-up of newly diagnosed MM patients treated with the preparative regimen Carmustine, 500 mg/m2 and Melphalan, 200 mg/m2 (BCNU/HDM) followed by ASCT versus a subsequent group of patients treated with HDM alone and ASCT. Methods: Between November of 1997 and December of 2008, 207 patients with MM underwent HDC followed by ASCT at our Institution, using either BCNU/HDM (n = 104, treated between 1997–2002) or HDM (n = 103, treated between 2002–2008) as the preparative regimen. Presenting patient characteristics were similar (age, gender, MM type, hemoglobin, creatinine, calcium, plasma cell infiltration, Durie-Salmon stage, and ISS stage). Patients treated with BCNU/HDM were diagnosed preceding the introduction of novel anti-MM agents such as thalidomide, lenalidomide, and bortezomib and thus did not receive these as induction therapy, while HDM patients received various combinations of novel agents as induction therapy. Results: With a median follow-up for surviving patients of 96 and 34 months for the BCNU/HDM and HDM cohorts, respectively, the event-free survival (EFS) was significantly increased with the BCNU/HDM conditioning regimen (41.7 months) as compared with the HDM regimen (21.6 months, p = 0.013) (Figure 1). Median overall survival (OS) was 83.1 months with BCNU/HDM vs. 68.2 months with HDM (p = 0.359 at current follow-up) with 34% of BCNU/HDM patients alive at 〉10 years (Figure 2). In the BCNU/HDM group, 47/104 patients achieved ≥VGPR and this subgroup had a median OS of 103 months. Nineteen patients in the BCNU/HDM group are ≥7 years from ASCT and 18 (17%) have never required treatment for progressive disease. Engraftment and transplant-related mortality were similar in both groups (3% TRM in the BCNU/HDM and 4% TRM in the HDM arm). The BCNU/HDM group had a higher incidence of pneumonitis (50%) vs. the HDM group (15%) but this was managed with short courses of steroids and was never fatal. Focusing on the subgroup of patients who proceeded to transplant immediately after only 1 induction course, the median OS was 103 months for the BCNU (80 patients) containing arm versus 69 months for the HDM (71 patients) arm (p=0.085), suggesting a clear trend further favoring this dose dense approach. Conclusions: EFS was superior with the BCNU/HDM regimen compared with HDM and a subgroup of patients treated with BCNU/HDM have achieved EFS 〉7 years without any additional therapy. Engraftment and treatment related mortality were similar in both groups despite advances in supportive care for the HDM group. Our findings suggest that BCNU/HDM should be compared in a randomized prospective fashion to HDM as an ASCT preparative regimen following optimal induction therapy with novel agents to determine whether this will lead to further improvements in EFS and OS following ASCT. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 3523 A high graft failure rate and treatment-related mortality (TRM) have historically been major pitfalls of myeloablative adult umbilical cord blood (UCB) transplantation. The goal of this prospective clinical trial was to identify an approach that addresses both of these problems. There is compelling evidence that increasing cell dose with the use of two partially matched UCB grafts reduces the graft failure rate. While non-myeloablative preparative regimens reduce TRM, this comes at the cost of an increased risk of disease relapse. Therefore, there is continued clinical need for myeloablative conditioning regimens that exert potent antitumor activity and provide sufficient immunosuppression to facilitate engraftment of mismatched unrelated UCB grafts. The combination of total body irradiation (TBI) (1320cGy)/fludarabine (Flu)/cyclophosphamide (Cy) has been studied extensively by other groups. In this trial, we hypothesized that elimination of Cy would improve tolerability yet maintain comparable anti-tumor effects and engraftment potential. Methods: The conditioning regimen consisted of TBI 1350cGy and Flu 40mg/m2 × 4 days. Two cord blood units at least HLA 4/6 matched with the recipient (low resolution class I and high resolution class II), with a minimum cryopreserved cell dose of 1.5 × 106/kg were selected for transplantation. Tacrolimus and mycophenolate mofetil were used for graft-versus-host disease (GVHD) prophylaxis and G-CSF was administered until the neutrophil count exceeded 1000/mm3. Disease-free and overall survival was estimated using the Kaplan-Meier method. In the analysis of cumulative incidence of neutrophil and platelet engraftment, a competing event was defined as relapse or death without an event of interest, whereas in the analysis of relapse and acute and chronic GVHD, a competing event was defined as death without an event of interest. Relapse was defined as a competing risk in the analysis of TRM. The Wilcoxon signed rank test was used to evaluate the effect of cell dose on the sustained engraftment of a single cord unit. Results: 27 patients from 2 centers (Duke-24, UBC-3) with a median age of 33 (range, 20–58) years with hematologic malignancies were enrolled on the trial. Fifteen had AML (CR1-1 and CR2-14), five had ALL (CR1-2 and 2CR–3), three had MDS, one had CML, and three had NHL. The median combined total nucleated cell dose was 4.3 (range, 3.2–7.7) × 107/kg. The cumulative incidence of neutrophil engraftment (≥500/μl) was 80% (95% confidence interval (CI), 58–91%), with a median of 24 (range, 13–45) days. The cumulative incidences of platelet engraftment ≥20,000 and ≥50,000/μl was 76% (95% CI, 54–88%) and 68% (95% CI, 46–83%), respectively, and a median day of platelet engraftment ≥50,000/μl was 52 (range, 33–78). A single cord blood unit represented ≥79% of hematopoiesis by day 100. Higher cryopreserved and infused total nucleated cell dose and infused CD3+ cell dose were significant factors associated with the predominant UCB unit (P = 0.032, 0.020, and 0.042, respectively). Three patients experienced graft failure, and hematopoiesis was restored in two patients with either autologous or haploidentical hematopoietic stem cells. The cumulative incidences of grades II–IV and grades III–IV acute GVHD were 37% (95%CI, 20–55%) and 11% (95% CI, 3–26%), respectively and that of chronic GVHD was 31% (95% CI, 15–49%). With a median follow-up period of 23 months, the overall and disease-free survival rates at 2 years were 58% (95% CI, 34–75%) and 52% (95% CI, 29–70%), respectively. The 180 day and 2-year incidence of TRM was 19% (95% CI, 7–35%) and 28% (95% CI, 12–47%), respectively. The relapse rate at 2 years was 20% (95% CI, 7–37%). As an indicator of tolerability of this modified myeloablative regimen, we observed a cumulative incidence of total parental nutrition usage of just 56%. In conclusion, we find that the modified myeloablative regimen of TBI (1350cGy)/fludarabine provides dual cord blood engraftment rates comparable to more conventional myeloablative regimens. In contrast to other reports, we found that graft size predicts for the predominant UCB unit. This study supports the use of TBI 1350cGy/fludarabine as an alternative to conventional myeloablative conditioning for dual UCB transplantation and provides justification for larger studies. Disclosures: Off Label Use: Fludarabine; used as part of the stem cell transplant conditioning regimen. Chao:Genzyme: Research Funding. Horwitz:Genzyme: Honoraria, Research Funding.

Description: Abstract 3541 We have previously shown that SCT from HLA-haploidentical related donors (HAPLO) after nonmyeloablative conditioning is feasible with a low incidence of grade III-IV acute GVHD or treatment-related mortality (TRM) (Rizzieri et al. JCO 2007). We now report our comparative study in patients who received SCT from a 6/6 HLA-matched related (MRD), 8–10/8 HLA-matched unrelated (MUD), or HAPLO donor, after nonmyeloablative conditioning. Methods: Patients with chemosensitive relapse or high risk disease with minimal residual disease at study entry were eligible. The conditioning regimen consisted of fludarabine, 40 mg/m2 for 4 days; melphalan, 140 mg/m2 for 1 day; and alemtuzumab, 20 mg for 4 days for patients with lymphoid or myelomatous diseases. Fludarabine and alemtuzumab at the same doses with busulfan, 130 mg/m2 for 2 days was used for patients with myeloid diseases. Mycophenolate mofetil was used for GVHD prophylaxis. Donor lymphocyte infusions were performed in 15 MRD patients and 4 HAPLO patients. Disease-free survival (DFS) and overall survival (OS) rates after SCT were estimated using the Kaplan–Meier method, and univariate comparisons were performed using the log-rank test. Cox proportional-hazards regression was used to evaluate variables that potentially affected the survival rates. Results: The lymphoid cohort included 52 patients with ALL (n = 6), lymphoma (n = 42), or myeloma (n = 4), whereas the myeloid cohort included 46 patients with AML/MDS (n = 40), and myeloproliferative disorder (MPD) (n = 6). The median subject age was 56.5 (range, 20–73) years with a median follow-up of 15 months among survivors. A total of 29, 40, and 29 patients received transplants from MRD, MUD, and HAPLO, respectively. All 29 patients engrafted after HCT from MRD. One of 40 patients who received SCT from MUD had a primary graft failure (GF), with 2 secondary GF and 1 early relapse. Two of them were rescued by subsequent nonmyeloablative SCT from the same MUD or new HAPLO donor. Among 28 HAPLO patients evaluable for engraftment, 8 had a primary GF, 6 of these had myeloid disease; 2 additional patients had donor cell recovery but without full recovery of normal blood counts. Three of the 8 were rescued with subsequent nonmyeloablative SCT from the same donor. The transplant regimen resulted in 11% TRM at day 100. Grade III-IV acute GVHD rates were 0/29 (0%), 4/40 (10%), and 5/29 (17%) in patients who received a transplant from a MRD, MUD, or HAPLO, respectively. CMV reactivation occurred in 57% of patients and 6% developed CMV disease. Other infectious complications included polyomavirus in 24% of patients, bacteria in 23%, respiratory viruses in 13%, and fungal infections in 7%. The common causes of death were progressive disease (30% for all cause of death) and infections (32%). The 1-year DFS rate after SCT from MRD, MUD, and HAPLO was 55% (95% CI, 33–73%), 39% (22–56%), and 34% (16–53%), respectively (Log-rank test, P = 0.094) (Figure 1); the corresponding 1-year OS rate was 66% (43–82%), 39% (21–55%), and 34% (16–53%), respectively (Log-rank test, P = 0.012) (Figure 2). Multivariate analysis revealed that SCT from MUD/HAPLO, compared with that from MRD, was the only adverse factor that affected the OS rate (HR for MUD, 2.62 (95% CI, 1.15–5.96), P = 0.022; HR for HAPLO, 3.17 (1.36–7.37), P = 0.007), but the OS rate after SCT from HAPLO did not significantly differ from that after SCT from MUD (P = 0.560). Other variables (recipient age, conditioning regimen, and disease status at transplant) were not significantly associated with the outcome. Conclusions: The results show the feasibility of this approach with this regimen and the clinical outcomes in patients who received transplants from HAPLO are comparable to patients who received transplants from MUD. Development of strategies to improve immune recovery remains a current challenge. Disclosures: Off Label Use: Alemtuzumab for conditioning in allogeneic stem cell transplantation. Horwitz:Genzyme: Honoraria, Research Funding. Chao:Genzyme: Research Funding. Rizzieri:Genzyme: Speakers Bureau.

Description: Purpose: To estimate the maximum tolerated duration (MTD) of gemcitabine given as a continuous infusion in combination with fludarabine and mitoxantrone for patients with relapsed or refractory leukemia. Patients and Methods: Patients received gemcitabine at 10mg/m2/min (day 1) with fludarabine at 25mg/m2/day for 5 days (days 1–5) and mitoxantrone at 10mg/m2/day for 3 days (days 1–3). The duration of gemcitabine infusion was escalated using the modified continuous assessment method (mCRM) at 3 hour increments (3, 6, 9, 12, and 15 hours). This three-drug regimen was build upon our previous studies with fludarabine, mitoxantrone and continuous infusion gemcitabine (Blood2003;102:250b Abstract). The MTD was estimated as the duration of gemcitabine infusion in combination with fludarabine and mitoxantrone at which 33% of the patients would experience a dose limiting toxicity (DLT). DLT was defined as either neutropenia for more than 28 days with less than 5% blasts in the marrow, a non-hematologic grade 4 toxicity lasting ≥ 3 days, or a non-hematologic grade 3 toxicity lasting ≥ 7 days. Results: Ten patients with relapsed or refractory leukemia have been treated so far since Aug 2004 and fully evaluated. The median age was 55 years (range 30 – 67). The median number of prior regimens was 3 (range 1 – 5) and the median range of prior cycles was 4 (range 1 – 6). As expected, hematologic toxicity, mucositis and nausea were common but did not meet criteria for DLT in any patient. One patient had parainfluenza lung infection with alveolar hemorrhage and this was the only DLT on the study. 2/10 patients achieved CR. Both patients are alive, 20 weeks and 52 weeks later, respectively but have received further therapy in the form of chemotherapy or allogeneic stem cell transplantation. Toxicity by Duration of Gemcitabine Infusion Duration of Infusion (hrs) # of Patients with DLT/Total Probability of Toxicity at this Dose Probability that Dose is MTD 3 0/1 0.001 0.0 6 0/2 0.009 0.005 9 0/3 0.1 0.22 12 1/4 0.36 0.59 15 0/0 0.6 0.18 Conclusion: Only one patient on this study had a DLT. This combination therapy is myelotoxic and has some anti-leukemia activity with 2/10 patients achieving CR. The duration of gemcitabine infusion as part of the above three drug regimen will be studied further on this ongoing study to more accurately estimate the MTD and determine if phase II trials are warranted.

Description: Abstract 4566 INTRODUCTION: Busulfan (Bu) has been used for almost 3 decades in the conditioning of hematopoietic stem cell transplant. Given orally, Bu exhibits highly variable bioavailability and diverse inter-individual systemic exposure, which prompted various therapeutic drug monitoring approaches. An intravenous (i.v.) formulation was developed to overcome these issues; however 10 to 30% of the adult patients receiving i.v. Bu will not have an AUC within the therapeutic window. Clearly, a need for therapeutic i.v. dose adjustment still persists. Instead of looking into AUC after the 1st therapeutic dose and adjusting the subsequent doses, a safer and potentially more successful approach is to use a sub-therapeutic test dose prior to the conditioning administration and determine a personalized therapeutic dose, maximizing the possibility of achieving an adequate exposure. Beri et al. [1] used a 0.8 mg/kg i.v. test dose (1/4 of the standard daily dose). Without the test dose, 23% of the 17 patients would have fallen below and 12% above the therapeutic range. With the test dose, no patients had a sub-therapeutic AUC and only 12% had an AUC above the therapeutic window. We investigated the bioequivalence of a very low sub-therapeutic test dose (1/10 of the standard daily dose) of i.v. Bu (Busulfex®) in order to reduce the unnecessary exposure and adverse effects of the test dose process. For this purpose we developed a sensitive and fast liquid chromatography tandem-mass spectrometry (LC-MS/MS) method which allowed us to measure Bu in a wide concentration range required in the study. EXPERIMENTAL: Utility of the new LC-MS/MS assay and bioequivalence of the test vs therapeutic regimens were investigated in the “Myeloid Cohort” (patients with a high chance of progressive myeloid diseases, marrow failure syndromes or myeloproliferative disorders) of the ongoing “Efficacy of T-Cell Depleted Allogeneic Non-Myeloablative Stem Cell Transplantation” study. The treatment flow chart is presented in Table 1. During both test and therapeutic Bu regimens, plasma was collected at pre-dose, 15 min, 1, 2, 4, and 24 hrs. To 100 μL of plasma sample, 100 ng of busulfan-d8 (internal standard) was added. After extraction of analytes by ethylacetate, evaporation of the solvent and reconstitution in LC mobile phase, 50 μL of the sample was injected into the LC-MS/MS system. Calibration samples in 1.6 ng/mL – 5 μg/mL range of pure Bu in plasma were run along the study samples. LLOQ of the method (80% accuracy) was 1.6 ng/mL. Pharmacokinetic (PK) parameters were calculated by non-compartmental approach using WinNonlin software. RESULTS: Presented here are results from 3 patients infused in consecutive days with 18 min long test dose and 180 min long therapeutic dose. Figure 1 shows a typical plasma Bu conc./time profile. Figure 2 is a semi-log (log conc. vs time) plot illustrating equal terminal slopes (elimination rate, clearance) for both test and therapeutic doses. Table 2 lists AUC values calculated within the boundaries of the PK sample collection time (24 hrs in case of both test and therapeutic regimens) as well as the AUCTEST/AUCTHERAP ratio. CONCLUSION: The newly developed LC-MS/MS assay proved to be optimal in terms of concentration range (1.6 ng/mL – 5 μg/mL), throughput (4 min per analytical run), and small sample size (100 μL plasma). PK calculations (AUC) show: 1) low inter-patient variability in both test and therapeutic doses and 2) promising value of the test dose in predicting exposure by the therapeutic dose (stable AUCTEST/AUCTHERAP ratio) although larger number of subjects is needed for accurate assessment. Disclosures: Spasojevic: Otsuka America Pharmaceuticals, Inc.: Research Funding. Horwitz:Otsuka America Pharmaceuticals, Inc.: Honoraria. Rizzieri:Otsuka America Pharmaceuticals, Inc.: Research Funding.

Description: Background Bendamustine, a bifunctional mechlorethamine derivative with alkylating properties and pomalidomide, an IMiD® immunomodulatory agent, have both demonstrated efficacy as single agents or in combination with dexamethasone in relapsed/refractory multiple myeloma(RRMM). Bendamustine in combination with lenalidomide, thalidomide, and bortezomib have had high response rates and good tolerability. We combined bendamustine and pomalidomide with dexamethasone (Ben-Pom-d) and hypothesized that this regimen would be highly effective in patients with RRMM. Dose-escalation started with 120mg/m2 bendamustine/3mg pomalidomide [or 4mg in the cohort 2]/40 mg dexamethasone using a standard 3+3 schema based on dose-limiting toxicities (DLTs) occurring in cycle 1. The MTD was 120mg/m2 bendamustine/3mg pomalidomide/40 mg dexamethasone. Here, we report our findings to date from the phase I/II trial of Ben-Pom-d in patients with RRMM (NCT01754402). Methods The primary objective of the phase I portion was to determine the MTD. Data for overall response, progression free survival, and overall survival, includes all patients treated on the phase I and II portions of the study. All patients had to be refractory to prior lenalidomide, and must have relapsed or were refractory to their most recent therapy. Patients had to be pomalidomide naïve. Treatment consisted of oral pomalidomide once daily on days 1-21, intravenous (IV) bendamustine given over 30 minutes on day 1 and dexamethasone 40 mg on days 1, 8, 15, and 22 of a 28-day cycle. Adverse events (AEs) were graded by NCI-CTCAE v4. Response was assessed by the modified International Uniform Response Criteria. Results A total of 9 patients were enrolled in the phase I portion. The MTD was the starting dose level (bendamustine 120 mg/m2, pomalidomide 3mg, dexamethasone 40 mg). In Phase II we enrolled an additional 16 patients resulting in a total study population of 25 patients evaluable for toxicity and 22 for efficacy, with 6 still receiving treatment. The median age was 65 years (range 43-81), 46% were male. The median number of prior regimens was 3 (range 2-6), median time from diagnosis is 3.9 years (range 1.1-9.10 years), 88% of patients had a prior stem cell transplant, 100% had prior bortezomib, 20% had prior carfilzomib and all were lenalidomide-refractory. Fifteen patients had high risk cytogenetic, including 8 patients with del17. Patients received a median of 6 cycles of therapy (range 1-18 cycles). Best response assessments in 22 evaluable patients for efficacy, showed 5 (23%) VGPR, 12 (55%) PR, 3 (14%) MR, and 2 (9%) SD, for an ORR of 77% and a ≥MR rate of 91%. The median follow-up of survivors is 10 months (range: 2-19+ months). Median PFS and OS were 4.5 months (range 1-15+ months) and 9.5 months (range 2-19+ months), respectively, for the entire cohort with 13 of 22 still alive in follow-up. The Median PFS for patient with del 17 is 5.5 months (range 2-15 months) with 〉MR rate of 88%. During the first cycle, 3 patients of all 25 evaluable enrolled experienced a DLT at the different doses, including 1 nausea/vomiting [cohort 1], and 2 with rash and fever in cohort 2. The therapy was tolerated well, but toxicities reported at any point while on therapy included 32% grade 4 neutropenia, 16% grade 4 thrombocytopenia, and half the patients requiring delay of subsequent cycles due to cytopenias and 17 of 22 (77%) had a dose reduction of pomalidomide per protocol guidelines at some point in the continuation cycles. The major non-hematologic Grade ≥3 drug-related AEs that occurred included febrile neutropenia in 12%, grade 3 mucositis in 8%, grade 3 pneumonia 16% and grade 4%, and grade 4 sepsis 4%. Conclusions The Ben-Pom-d regimen is a well-tolerated regimen and achieves a high response rate (ORR of 77%; ≥MR rate of 91%) in a heavily pre-treated Lenalidomide-refractory population with prior bortezomib exposure. Therapy is ongoing for many and longer follow-up is needed to better assess the true durability of this approach. Disclosures Gasparetto: Onyx: Honoraria, Other: Advisory Board; Millennium/takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; teva: Other: spouse-ad board and speaker bureau. Off Label Use: Bendamustine-pomalidomide-dexa for treatment of relapsed myeloma. Rizzieri:Teva: Other: ad board, Speakers Bureau; Celgene: Other: ad board, Speakers Bureau. Rao:novartis: Other: ad board; amgen: Other: ad board; Boehringer-Ingelheim: Other: Advisory Board. Tuchman:celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium/takeda: Honoraria, Research Funding, Speakers Bureau.

Description: Reliable engraftment following transplantation of partially matched umbilical cord blood is dependent upon adequate immunosuppression and myelosuppression. The lowest intensity conditioning regimen that will provide reliable cord blood engraftment in adult patients has not been determined. 26 adult patients with a contraindication for myeloablative marrow conditioning due to advanced age or comorbidities, underwent non-myeloablative umbilical cord blood transplantation for hematologic malignancies. The first 13 patients (Cohort 1) were conditioned with Fludarabine 120mg/m2, Cyclophosphamide 2g/m2 and horse Antithymocyte globulin 90mg/kg. Cyclosporine and Mycophenolate Mofetil was administered for GvHD prophylaxis. The median cell nucleated dose was 2.1 × 107/kg and median follow-up is 60 months (Chao 2004 BBMT 10:569). After protocol revision, 200 cGy total body irradiation was added to the regimen described above. In addition, the minimum nucleated cell dose provided from up to two cord blood units was increased to 3 × 107/kg (Cohort 2). With a median follow-up of 12 months, we now report the outcome of cohort 2. Fourteen patients with AML CR1 (2), CR≥2 (5), CML (1), MDS/AML (1), MDS (4), or Follicular Lymphoma (1) and a median age of 54 (range 21–72) were transplanted. Eight patients required dual cord blood grafts to achieve the minimum cell dose. All grafts were at least 4/6 HLA matches (antigen level class I, allele level class II) with the patient, and with each other (dual cord blood grafts). The median cryopreserved and infused nucleated cell dose was 3.6 × 107/kg and 3.5 × 107/kg respectively. Two patients were not evaluable for engraftment due to early toxic death. Two patients experienced primary graft failure. Acute GvHD (grade II skin) was observed in 2 patients. Limited chronic GvHD developed in 2 patients. Parainfluenza type 3 sinusitis and pneumonitis caused significant morbidity in 5 patients. Day 100 treatment-related mortality occurred in 4 patients (30%) due to; infection (2), hemorrhage (2). Relapse occurred in 5 patients (36%). The estimated one year overall and disease-free survival is 25% and 17%, respectively. T-cell recovery was slow. The median CD4 count/ul for engrafted patients was 44 (range 4–516) and 61(range 2–237) at 3 and 6 months following transplantation, respectively. The median CD8 count/ul was 7 (range 0–359) and 108 (range 0–728) at 3 and 6 months following transplantation, respectively. A comparison of results from the two cohorts is presented in the table. The addition of 200cGy and increasing the cell dose facilitated by dual cord blood transplantation doubled the chance for sustained donor engraftment. Improved engraftment was accompanied by increased treatment-related morbidity and mortality, erasing the potential for improved disease-free survival. Disease relapse, in part due to slow immune recovery resulting in impaired anti-tumor response, was the other major impediment to successful outcome. Techniques focused on enhancing immune recovery would significantly improve outcomes of adult cord blood transplantation. Comparison of Cohort 1 vs Cohort 2 Evaluable Patients Med. Nuc Cell Dose/kg D100 TRM(%) Sustained Donor Engraftment (%)† Disease-Free Survival(%)† †estimated (1yr) *P=0.08 **P=NS Flu / Cy / ATG (Cohort 1) 13 2.1 × 107 15 41 15 Flu/Cy/ATG/200cGy(Cohort 2) 12 3.5 × 107 30 83* 17**

Description: Introduction: Umbilical cord blood (UCB) extends the curative potential of stem cell transplantation to adult patients without a suitable donor. The most commonly used myeloablative preparative regimen results in an unacceptably high 6-month treatment related mortality rate of approximately 32% (Barker J et al. Br J Haematol. 2015). In an attempt to reduce treatment related mortality, we piloted a modified myeloablative regimen with total body irradiation (TBI), fludarabine, and thiotepa. We report clinical outcomes from a cohort of patients who received single or double UCBT after conditioning with this regimen. Methods: Thirty-one consecutive adult patients ≥ 18 years old with hematologic malignancies who underwent single or double umbilical cord blood transplantation at Duke University from 2010 to 2015 were included in this study. The conditioning regimen consisted of thiotepa 5 mg/kg/day i.v. x 2 days (days -11 to -10), TBI 150 cGy twice a day for total nine fractions (1350 cGy days -9 to -5), and fludarabine 40 mg/m2/day i.v. x 4 days (days -5 to -2). Cord blood units were matched to the recipient at 4 or more HLA loci (intermediate-resolution for A and B, high-resolution for DRB1). Graft versus host disease (GVHD) prophylaxis was with tacrolimus (target level 10-15 ng/ml) and mycophenolate mofetil 1000 mg TID. Antimicrobial prophylaxis and supportive care measures including GCSF administration until ANC 〉 1000 were conducted per institutional protocol. Probabilities of neutrophil and platelet recovery, acute and chronic GVHD, and treatment-related mortality were estimated by the cumulative incidence method. Relapse-free and overall survival rates were estimated by the Kaplan-Meier method. Results: Thirty-one patients (median age 46 years; range, 19-65) with hematologic malignancies were evaluated. Twenty-four patients (77%) had acute leukemia or myelodysplastic syndrome, while 7 patients (23%) had non-Hodgkin's lymphoma or multiple myeloma. By the "Disease Risk Index" (Armand P et al. Blood. 2014), 20 patients (65%) had low or intermediate risk disease, while 11 patients (35%) had high or very high risk disease. 30 patients underwent double UCB and 1 patient received single UCB transplantation. The median cryopreserved total nucleated cell dose was 5.4 x 107/kg (range: 3.2-8.4 x 107/kg). The cumulative incidence of neutrophil engraftment was 90% (95% CI, 82%-99%; Figure 1) at a median time of 21 days (95% CI, 19-26). Three patients did not have neutrophil engraftment; two patients had early death at days 7 and 14 prior to engraftment, while one patient had graft failure requiring second transplant. The cumulative incidence of platelet engraftment was 86% (95% CI, 75%-97%) at a median time of 47 days (95% CI, 37-73). Cumulative incidences of grades II-IV and grades III-IV acute GVHD were 48% (95% CI, 34%-69%) and 10% (95% CI, 3%-28%), respectively. The overall incidence of chronic GVHD was 40% (95% CI, 27%-59%), with 17% (95% CI, 8%-37%) of patients experiencing moderate to severe chronic GVHD. Treatment-related mortality at 6 months was 13% (Figure 2), while at 1 year and 3 years was 27% and 33%, respectively. With a median follow-up of 35.5 months (95% CI, 12.7-52.2), disease-free and overall survival at 3 years was 51% (95% CI, 29%-69%) and 57% (95% CI, 36%-73%), respectively. Conclusion: UCB transplantation with the modified myeloablative conditioning regimen of TBI, fludarabine, and thiotepa results in reliable neutrophil engraftment with reduced early treatment related mortality as compared to standard myeloablative conditioning consisting of TBI, fludarabine, and cyclophosphamide. It provides a promising disease-free and overall survival in an older (median age 46), heterogeneous patient population. This regimen represents a reasonable alternative to standard conditioning with TBI, fludarabine, and cyclophosphamide and warrants further study. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.