ALBERT

Description: Introduction: For patients with relapsed or refractory DLBCL with chemosensitive disease after 2nd line (salvage treatment), AutoHCT is considered the standard of care. Risk factors for progression following AutoHCT include primary refractory disease and early relapse (

Description: Key Points Isatuximab (anti-CD38 monoclonal antibody) given with lenalidomide/ dexamethasone is active in heavily pretreated relapsed/refractory myeloma Overall, the safety profile of this combination is similar to the characteristic safety profiles of the individual agents.

Description: Abstract 3877 Poster Board III-813 Background Renal impairment affects 20% of newly diagnosed MM pts and over 50% during the course of their disease. Renal impairment confers shorter survival due to high tumor load and the difficulty in delivering adequate doses of active drugs, such as alkylating agents and immunomodulatory drugs (IMiDs) due to enhanced side effects (Kyle, Mayo Clin 2003). Pts with renal insufficiency have been traditionally excluded from clinical trials. Carfilzomib (CFZ) is a novel peptide epoxyketone proteasome inhibitor designed to have a high level of selectivity for the proteasome. In previous Phase 2 studies, CFZ has demonstrated single agent activity in heavily pretreated MM pts including those with mild renal insufficiency. The primary objective of this study was to evaluate the tolerability and pharmacokinetic properties of CFZ in MM pts with renal insufficiency, including those on dialysis. Methods In this multicenter study, MM pts who had relapsed after at least two prior therapies were enrolled into 4 cohorts based on renal impairment: normal (CrCl 〉 80mL/min), mild (CrCl 50–80 mL/min), moderate (CrCl 30–49 mL/min), and severe (CrCl 〈 30 mL/min) including dialysis pts. The primary and secondary objectives of the study included pharmacokinetics (PK), safety, pharmacodynamics (PDn; proteasome inhibition in blood) and efficacy endpoints: ORR (overall response rate, ≥ PR) CBR (clinical benefit response, ≥ MR), duration of response (DOR) and time to progression (TTP). Pts received CFZ at a dose of 15 mg/m2 IV on day (D) 1, 2, 8, 9, 15 and 16 every 28 d for cycle (C) 1, with dose escalation to 20 mg/m2 in C2 and 27 mg/m2 in C3 and thereafter if tolerated. Pts received 40 mg of dexamethasone (Dex) in cycle 3 if they had less than a partial response (PR). Pts were followed for toxicity and efficacy over the course of the study. EKG changes from baseline including QT/QTc effects were assessed in C1 and C2. PK was measured on C1 D1,15 and C2 D15 and PDn was measured on C1 D1,2,8 and C2 D1. Results Nineteen pts received at least 1 dose of CFZ and were evaluable for safety; 18 pts completed at least 1 C of CFZ and were evaluable for response and PK/PDn. All pts had refractory MM and 42% had progressed during their last therapy. The median number of prior therapies was 5 (range 2–10). All pts had received bortezomib and 26% were refractory; all pts received at lease one IMiD (90% thalidomide and 85% lenalidomide). Seventy percent had prior stem cell transplant. To date, pts have received a median of 3 cycles (range 1–7+) of CFZ; 9 pts have completed ≥ 6 cycles. The most common adverse events were fatigue, anemia, back pain and fever. There was no appreciable difference in the safety profile between the 4 cohorts either in frequency of events or in CTC-AE grade. Two deaths from disease progression with 1 complicated by a parainfluenza upper respiratory tract infection occurred while on study. No treatment emergent QT/QTc prolongations were observed during C1 and C2 in any group. Sixteen pts had grade 1 or 2 peripheral neuropathy at study entry and no cases of newly emergent or exacerbations occurred on study. Two pts discontinued drug due to worsening renal failure, one in the mild and one in the moderate cohort; both were related to disease progression. In all cohorts, CFZ was cleared with a t½ of 30–60 minutes and reached undetectable levels in plasma within 3 hours. There was no accumulation of CFZ after two cycles. Proteasome inhibition measured 1 hr post-dose in whole blood and PBMC ranged from 75–89% at doses of 15–20 mg/m2. PK and PDn were similar between the cohorts of pts with varying degrees of renal impairment. The ORR was 16.6% and CBR was 33.3%. Two BTZ-refractory pts achieved PR. An additional 38.9% had stable disease across all groups despite entering the study with progressive disease. Seven of 18 pts received Dex in ≥ C3 with 2 exhibiting an upgraded response (1 PR and 1 MR). Conclusions CFZ can be administered to MM pts with substantial renal dysfunction and does not require dose adjustment. CFZ toxicities in this study were manageable and importantly, exacerbation of pre-existing PN or myelosuppression was not observed in these renally impaired MM patients. Responses in relapsed and refractory MM pts with renal insufficiency are encouraging. Further evaluation of CFZ in renally impaired patients is ongoing, including in patients receiving hemodialysis. Disclosures: Vij: Proteolix, Inc.: Consultancy, Research Funding. Zonder:Celgene: Speakers Bureau; Pfizer: Consultancy; Seattle Genetics, Inc.: Research Funding; Amgen: Consultancy; Millennium: Research Funding. Woo:Proteolix, Inc.: Employment. Wang:Proteolix, Inc.: Employment. Lee:Proteolix, Inc.: Employment. Wong:Proteolix, Inc.: Employment. Niesvizky:Millenium: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Seattle Genetics, Inc: Research Funding; Proteolix: Research Funding, data monitoring committee.

Description: Background: Maintenance therapy with lenalidomide post-autologous stem cell transplantation (ASCT) has shown to improve progression-free survival (PFS) in multiple myeloma (MM), and has largely become the standard of care. However, toxicity leads to early discontinuation in nearly one-third of patients and additional options are needed (McCarthy, et al, JCO, 2017). Ixazomib is another maintenance option that has been shown to improve PFS; however, studies comparing lenalidomide and ixazomib are lacking. In this randomized phase 2 study, we analyzed the safety and efficacy of using lenalidomide and ixazomib as part of consolidation and maintenance therapies after ASCT (NCT02253316). Methods: Eligible patients, age 18-70 with newly diagnosed MM undergoing ASCT during first-line treatment, were consented prior to ASCT. Approximately 4 months following ASCT, patients received 4 cycles of consolidation therapy with IRd [ixazomib 4 mg on days 1, 8 and 15 of a 28-day cycle, lenalidomide 15 mg on days 1 through 21, and dexamethasone 40 mg on days 1, 8 and 15]. Primary data on IRd consolidation were presented at ASH 2018 (Abstract 109920). One month after the last consolidation cycle, patients were randomized (1:1) to maintenance therapy with single-agent ixazomib (4 mg on days 1, 8 and 15 of a 28-day cycle) or lenalidomide (10 mg daily months 1-3 followed by 15 mg for months 4+). The arms were stratified based on MRD-status post-consolidation. In total, 237 patients were enrolled from 10 US centers. This abstract coincides with planned interim analysis 3 which is the first comparison of ixazomib and lenalidomide maintenance. While the study was not powered to compare PFS between the two arms, the sample will provide a reasonable power to estimate non-inferiority. There is a planned stopping rule for non-inferiority set at a hazard ratio of 〉1.3 in favor of lenalidomide. Secondary end-points include MRD-negativity following 12 cycles and toxicity. Results: At time of abstract submission, 215 patients had completed IRd consolidation and 191 had begun maintenance. 90 were randomized to ixazomib and 94 to lenalidomide. 7 patients were not randomized due to toxicity during consolidation; data from these patients are not included in the analyses. The characteristics of the two arms are summarized in Table 1. Hematologic toxicity has been infrequent with ixazomib with neutropenia and thrombocytopenia occurring in 11% and 23% of patients. In comparison, neutropenia and thrombocytopenia occurred in 45% and 35% of patients on lenalidomide. The most common non-hematologic toxicities in both arms have been GI-related and infections, both expected events. 16% of patients on ixazomib have experienced Grade 3-4 non-hematologic toxicity compared to 34% on lenalidomide. No grade 3 or higher peripheral neuropathy has been reported in either arm. 11% of patients on ixazomib have discontinued due to toxicity and another 9% have required a dose reduction to 3mg. Lenalidomide toxicity has led to discontinuation in 15% of patients and another 12% were dose reduced to 5mg. Only 45% of patients receiving 4+ cycles of lenalidomide were able to titrate to the 15mg dose. After a median follow-up of 11.2 months from randomization (19.7 months post-ASCT), 30% of patients on ixazomib have discontinued treatment due to disease progression. After a median follow-up of 12.3 months from randomization (20.2 months post-ASCT), 18% patients on lenalidomide have discontinued treatment due to disease progression. Conclusion: Ixazomib and lenalidomide maintenance have been well tolerated to date. A comparison of PFS is currently being conducted as part of interim analysis 3 and final results will be presented, representing the first report directly comparing lenalidomide and ixazomib maintenance. Table 1: Disclosures Vij: Genentech: Honoraria; Karyopharm: Honoraria; Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Janssen: Honoraria; Sanofi: Honoraria. Martin:Amgen, Sanofi, Seattle Genetics: Research Funding; Roche and Juno: Consultancy. Fiala:Incyte: Research Funding. Deol:Novartis: Other: Advisory board; Kite: Other: Advisory board; Agios: Other: Advisory board. Kaufman:Celgene: Consultancy; Winship Cancer Institute of Emory University: Employment; Amgen: Consultancy; Bristol-Myers Squibb: Consultancy; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Janssen: Honoraria; Incyte: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy; Takeda: Consultancy. Hofmeister:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Nektar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Imbrium: Membership on an entity's Board of Directors or advisory committees. Gregory:Poseida: Research Funding; Celgene: Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau. Berdeja:AbbVie Inc, Amgen Inc, Acetylon Pharmaceuticals Inc, Bluebird Bio, Bristol-Myers Squibb Company, Celgene Corporation, Constellation Pharma, Curis Inc, Genentech, Glenmark Pharmaceuticals, Janssen Biotech Inc, Kesios Therapeutics, Lilly, Novartis, Poseida: Research Funding; Poseida: Research Funding; Amgen Inc, BioClinica, Celgene Corporation, CRISPR Therapeutics, Bristol-Myers Squibb Company, Janssen Biotech Inc, Karyopharm Therapeutics, Kite Pharma Inc, Prothena, Servier, Takeda Oncology: Consultancy. Chari:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Array Biopharma: Research Funding; GlaxoSmithKline: Research Funding; Novartis Pharmaceuticals: Research Funding; Oncoceutics: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees. Rosko:Vyxeos: Other: Travel support.

Description: Introduction: Despite fluconazole prophylaxis, invasive fungal disease (IFD) following allogeneic transplantation (alloBMT) remains problematic. Voriconazole is a second-generation triazole with activity against yeast and molds. Since FDA approval, voriconazole (VORI) has been used as antifungal prophylaxis in AlloBMT patients at UCSF Med Ctr. The goals of this retrospective study were to evaluate the incidence of IFD and to assess organ toxicity in alloBMT patients receiving VORI. Patients and Methods: The charts of 72 patients who received VORI as antifungal prophylaxis for alloBMT were reviewed. The mean age was 54 years (range 19–70), including 44 males and 28 females. Thirty-nine patients received reduced-intensity preparative therapy and 31 received myeloablative therapy. Thirty-six patients received stem cells from an HLA-identical relative, and 36 from an HLA-matched unrelated donor. All patients received tacrolimus, methotrexate +/− MMF for GVHD prophylaxis, G-CSF, acyclovir and antibacterial prophylaxis. Voriconazole (4 mg/kg) BID was administered from day −2 through day +100 post-transplant as tolerated. EORTC criteria were utilized to assess for IFD. Results: Two patients (3%) developed definitive IFD (mucor and aspergillus) and 3 patients (4%) had possible fungal infections. No cases of probable IFD were identified. Both patients with definitive IFD died, one from severe Grade IV GVHD and the other from sepsis and multiorgan failure. The patient with aspergillus had discontinued VORI 〉1 month prior to IFI due to elevated liver tests (LFT’s). All the patients with possible IFD continued to receive VORI but received additional antimicrobial agents (i.e. caspofugin and antibacterials). One of these patients died from progressive pneumonia. Overall, voriconazole appeared well tolerated. Fifty-four of the 72 patients (75%) received VORI throughout transplant without interruption. Ten patients discontinued voriconazole within 30 days of alloBMT; increased LFT’s (n=7), prolonged QTc (n=2) and suspected new IFD (n=1). Four of the 10 patients were restarted on VORI and continued through day 100. Eight patients discontinued VORI after day 30 but before day 100; 2 planned taper, 1 died, 4 increased LFT’s and 1 for suspected IFD. Two of these patients restarted VORI. No significant cardiac toxicity was noted, despite a QTc of 〉500 msec in 10 patients. The mean increase in QTc after initiating VORI was 34 msec (n=36). The median bilirubin, alk. phos and AST values post-transplant were 1.3 mg/dL, 134 U/L and 34 U/L, respectively. Eight patients developed severe hyperbilirubinemia (〉6 mg/dL); 3 had VOD, 3 had GVHD. The mean peak creatinine was 1.5 mg/dL and four patients required hemodialysis. No severe or unexpected toxicity was noted. In addition, VORI increased serum tacrolimus levels necessitating a 60% reduction in standard tacrolimus dosing. The 100 and 180-day treatment related mortality rates in this study were 8% and 18%, respectively. Conclusions: In this cohort of 72 patients, VORI appears safe and effective as prophylaxis for alloBMT. A randomized trial comparing VORI to fluconazole as prophylaxis in alloBMT is currently ongoing. Recommendations regarding VORI administration in regards to QTc and LFT’s will be presented.

Description: Phase I/II studies using either liposomal doxorubicin (D) or oral melphalan (M) in combination with the proteasome inhibitor bortezomib (V) have found favorable efficacy and tolerance in patients with relapsed and refractory MM. Since these drugs have different mechanisms of action and toxicity profiles, we initiated a phase I/II study to examine the safety and efficacy of combining all three agents (DMV) in relapsed or refractory myeloma. Study Aims: Starting at 25–50% of the doses used in the two drug combination studies, the objective of this dose escalation study was to evaluate the safety/tolerability of DMV until the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) could be identified. Efficacy was also evaluated. Methods: Patients with relapsed/refractory MM and progressive disease requiring treatment were enrolled in the study. Dose level 1 consisted of D 10 mg/m2 and M 5 mg/m2 given IV on day 1 with V given by IV push on days 1, 4, 8, and 11. Cycles were repeated every 28 days up to a maximum of 6 cycles. Dose levels of D, M, V (mg/m2) in the subsequent three cohorts were (10, 10, 0.7), (20, 10, 0.7), and (20, 10, 1.0) respectively. Once the MTD has been identified, an additional 17 patients will be enrolled at this dose level in the phase II portion of the study. Results: 5 patients (2 males, median age 65, range 33–79) have been enrolled in the study thus far. The myeloma subtypes include 2 IgG, 1 IgA, and 2 with light chains only. In this heavily pretreated population (range 2–7 prior therapies), 4 patients received prior autologous stem cell transplantation, 2 had a prior nonmyeloablative allogenic transplant, 4 prior VAD, 1 prior bortezomib, 2 prior oral melphalan, 3 prior thalidomide, 2 prior CC-5013, and 2 prior spinal radiation. The first dose cohort has been completed without any DLT. One patient had 3 days of Grade 3 neutropenia. All other toxicities were Grade 1–2 including asthenia, vomiting, thrombocytopenia, and headache. Of note, a patient with baseline Grade 2 peripheral neuropathy and on hemodialysis remained stable. A patient with Grade 2 chronic graft versus host disease also remained stable. Four patients have been enrolled at dose level one. One patient, who had progressive disease after an autologous and a nonmyeloablative allogenic transplant as well as CC5013, had a near CR (IFE+) after the second cycle of DMV. Two patients have had stable disease. One had disease progression after one cycle and subsequently died. The patient on dose level two is too early to evaluate. Conclusion: Thus far, DMV appears to be well tolerated and no DLT has been observed even in elderly patients with significant comorbidities. The finding of a near CR and SD at only dose level 1 is encouraging particularly since the patients were significantly pretreated. Dose escalation continues to determine the MTD.

Description: Background: T cells from myeloma subjects can be activated and expanded ex vivo using the Xcellerate™ Process, in which peripheral blood mononuclear cells are incubated with anti-CD3 and anti-CD28 antibody-coated magnetic beads (Xcyte™-Dynabeads®). In a previous study (Borrello et al., ASCO 2004), Xcellerated T Cells administered to myeloma subjects following high dose chemotherapy and autologous stem cell transplantation led to accelerated lymphocyte recovery and restoration of the T cell receptor repertoire. In the current study, subjects with relapsed or refractory myeloma were randomized to Xcellerated T Cells with or without one cycle of fludarabine prior to Xcellerated T Cells. Fludarabine is being used to assess the influence of lymphoablation on the anti-tumor and immune reconstitution effects of T cell therapy; it has previously been reported to have no significant activty in myeloma (Kraut et al., Invest. New Drugs, 1990). Methods: Approximately 30 subjects are planned to receive treatment. Each receives a single dose of 60–100 x 109 Xcellerated T Cells. Subjects on the fludarabine arm receive a single cycle (5 days at 25 mg/m2), completed 4 days prior to the Xcellerated T Cell infusion. Results: 17 subjects have been enrolled and 13 treated to date, with median last f/u visit of 28 days (range 0–140). Xcellerated T Cells were successfully manufactured in all subjects, with T cell expansion 136 ± 61 fold (mean ± SD), with 79.2 ± 13.8 x 109 cells infused, and final product 98.0 ± 2.0% T cells (n=13). There have been no reported serious adverse events related to Xcellerated T Cells. In the fludarabine arm, lymphocytes decreased from 1,228 ± 290/mm3 (mean ± SEM) to 402 ± 164 following fludarabine, and then increased to 1,772 ± 278 on Day 14 following T cell infusion (n=7). In the non-fludarabine arm, lymphocyte counts increased from 1,186 ± 252 to 3,204 ± 545 on Day 14 (n=4). Lymphocytes were comprised of both CD4+ and CD8+ T cells. Increases were observed in NK cells from 77 ± 26 to 121 ± 25, monocytes from 166 ± 44 to 220 ± 30 and platelets from 218 ± 16 to 235 ± 24 by Day 14 (n=11). In the non-fludarabine arm, neutrophils increased from 3.6 ± 0.9 to 4.8 ± 0.6 on Day 1. On the fludarabine arm, 3 of 6 subjects developed Grade 4 neutropenia and one developed Grade 3 thrombocytopenia. Seven subjects were evaluable for serum M-protein measurements to Day 28. One of three fludarabine treated subjects had an M-protein decrease of 38%. Conclusions: Xcellerated T Cells were well-tolerated and led to increased lymphocytes, including T cells and NK cells. Increases in other hematologic parameters, including neutrophils and platelets were also observed. In this patient population, fludarabine is lymphoablative and also can cause neutropenia and thrombocytopenia. The fludarabine schedule has been decreased from 5 to 3 days. A decrease in M-protein has been observed in one of three fludarabine-treated subjects; data on additional subjects will be presented.

Description: While commonly used in other hematological malignancies, high dose chemotherapy followed by autologous hematopoietic cell transplantation (auto-HCT) has not been widely adopted in acute myeloid leukemia (AML) due to concerns regarding high post-transplant relapse rates. These relapses may be due, in part, to autograft contamination with AML. High sensitivity methods to detect residual AML have demonstrated the ability to correctly identify patients in morphological complete remission (CR) at risk of relapse. We sought to determine if testing of the graft prior to transplantation could predict post auto-HCT relapse. Prior studies investigating the utility of measurable residual disease (MRD) in auto-HCT have been limited by small patient cohorts and/or by the use of a single biomarker to detect AML, a heterogeneous cancer. We report here the largest retrospective study to date of adult auto-HCT AML patients tested for measurable residual disease (MRD) by both molecular methods (RQ-PCR) and multi-parameter flow cytometry (MPFC). Seventy-two patients transplanted between 2004-2013 at a single academic medical center (UCSF) were eligible for this study based on availability of cryopreserved GCSF mobilized autologous peripheral blood progenitor cell (PBPCs) specimens. All samples were collected on IRB approved research protocols. The median age at time of transplant was 48 (24-69), 54% were female, cytogenetics were known in 94% (of which 24% were favorable, 69% intermediate, 7% poor), 99% were in CR at the time of HCT (64/72 in CR1, 6 in CR2, 1 in CR3). Following auto-HCT 1 year RFS was 50% (1 year relapse rate 43%) and 2 year RFS was 40% (2 year relapse rate 47%). Wilms tumor 1 (WT1) is expressed in up to 90% of AML, but sufficiently over-expressed in peripheral blood to have utility as a sensitive marker of MRD in less than 50% of cases. RQ-PCR detectable WT1 above the previously established European LeukemiaNet threshold was found in 9 patients, of whom 6 relapsed in the first year after auto-HCT (19% sensitivity, 93% specificity, PPV: 67%, NPV: 60%). We have previously reported that multi-gene testing can augment WT1 based MRD detection in AML. We were unable however to use one component of our previously reported AML MRD panel, PR3, due to increased baseline expression in these GCSF stimulated PBPC products. Increased PR3 expression following GCSF administration, correlating with neutrophilia, was also observed in an independent cohort of healthy donors. Testing for PRAME, MSLN, CCNA1, t(8,21), Inv16, t(15:17) and NPM1 mutations A, B and D, as a supplement for WT1, in pre-HCT PBPCs resulted in substantially improved ability to predict post auto-HCT relapse (52% sensitivity, 80% specificity, PPV: 67%, NPV: 69%). Addition of these extra genes allowed for correct identification of 10 additional MRD+ patients who relapsed within 1yr after transplant, and added 5 false positive patients (1 of whom suffered early non-relapse mortality, and another who did relapse but more than 1 year after HCT). Finally, in expert hands, flow cytometry can identify residual AML with high sensitivity. Forty PBPC samples from the above cohort were also assessed for MRD using MPFC. CD34 positive cells comprised 0.05-12.5% of autograft specimen mononuclear cells. Due to immunophenotypic changes likely attributable to GCSF mobilization, and without leukemia associated immunophenotypes from diagnosis available, MPFC was unable to identify MRD in any of 40 patients tested. In summary, no single MRD test on autografts could completely predict post-HCT AML relapse. Auto-HCT presents unique challenges for AML MRD testing due to masking effects of GCSF on MPFC and RQ-PCR gene expression signatures. Additionally, detection of any AML autograft contamination must be extremely sensitive to be useful for predicting relapse given the absence of any potentially protective graft versus leukemia effect following an auto-HCT. Here we show combinations of molecular MRD assays can overcome some, but not all, of these limitations (Figure). Figure 1. Figure 1. Disclosures Radich: Incyte: Consultancy; Ariad: Consultancy; Novartis: Consultancy; Novartis: Other: Lab Contract. Andreadis:Cellerant: Consultancy; Novartis: Consultancy; McGraw Hill: Other: Publishers; Pharmacyclics: Honoraria. Damon:Sunesis: Research Funding; McGraw Hill: Other: Chapter Royalties; Atara: Consultancy; Sigms Tau: Research Funding. Logan:Jazz Pharmaceuticals: Consultancy; Amgen: Consultancy; Pharmacyclics: Consultancy. Martin:Sanofi: Consultancy.

Description: Abstract 1942 Background: The impact of cytogenetic abnormalities on the response to therapies and survival in patients (pts) with multiple myeloma (MM) has been well established in the literature. Bortezomib (BTZ), either alone or in combination with other agents, has been shown to overcome the adverse impact of several common unfavorable cytogenetic features. In addition, responses with lenalidomide (LEN)/dexamethasone and pomalidomide have also been reported in patients with unfavorable cytogenetic profiles. Carfilzomib (CFZ) is a novel and highly selective epoxyketone proteasome inhibitor which produces durable single-agent activity in pts with R/R MM. The objective of this analysis was to evaluate the influence of cytogenetics in a large Ph 2b study (PX-171-003-A1), with single-agent CFZ in pts with R/R MM. Methods: Of the 266 pts enrolled in the 003-A1 study, 229 pts (86%) were response evaluable and had available metaphase cytogenetics and/or fluorescence in situ hybridization (FISH) analyses for hypodiploidy, chromosome 13 deletions, del 17p13, t(4:14), and t(14;16) chromosomal abnormalities. Metaphase cytogenetic analyses were available for 200 pts (75%) and FISH results were available for 205 pts (77%). All pts received CFZ at 20 mg/m2 IV on days 1, 2, 8, 9, 15, and 16 in a 28-day cycle (C) in C1 followed by 27 mg/m2 in each C thereafter for up to 12 C. Pts who completed 12 C of therapy were eligible to continue CFZ on an extension study. For the analysis, overall response rate was defined as ≥PR by International Myeloma Working Group (IMWG) criteria. Clinical benefit response (CBR; ORR + MR as defined by EBMT criteria) was also assessed. All responses were assessed and confirmed by an Independent Response Review Committee (IRC). Results: The median age in this subpopulation was 64 yrs. Pts must have had disease that was relapsed after ≥2 regimens including BTZ and either thalidomide (THAL) or LEN, and must have been refractory to their most recent regimen. In this heavily pre-treated pt population, pts had received median of 13 prior anti-myeloma drugs and a median of 5 prior regimens. 99.6% of pts had previously received treatment with BTZ, 74% received prior thalidomide, 94% prior lenalidomide, and 74% prior stem cell transplantation. The ORR (≥PR) for the pts with available metaphase cytogenetics and/or FISH analyses was 25% and the CBR (≥MR) was 38%. 71 of 229 pts (31%) had at least one cytogenetic abnormality. Of these, 27/71 (38%) pts had abnormalities detected via metaphase cytogenetics, 24 (34%) pts were detected by FISH and 20 (28%) pts had abnormalities by both methods. The presence of deletion 13 or hypodiploidy by cytogenetics or del17p13, t(4;14), or t(14;16) by FISH did not significantly impact the ORR. Specifically, 30% of pts with ≥1 abnormality responded compared to 23% with none. The CBR was also unaffected at 34% vs. 39% for pts with ≥1 and no abnormalities, respectively. For all pts in this analysis, the median duration of response (DOR) was 8 months (95% CI 6–10). For pts with ≥1 abnormality, the DOR was 7 months (95% CI 4–10) and did not differ significantly from the DOR of 8 months (95% CI 6–not reached) in pts with no abnormalities. A complete breakdown of response categories and time-to-progression (TTP) will also be presented. Conclusions: CFZ demonstrated durable and comparable activity in pts with R/R MM in both the absence or presence of one or more cytogenetic abnormalities including hypodiploidy, chromosome 13 deletions, del 17p13, t(4:14), or t(14;16). Notably, these results are consistent with data obtained in another Ph2 study with CFZ in pts with relapsed MM following 1–3 prior therapies and who had abnormal cytogenetics (PX-171-004). The results of the present study suggest that durable responses to CFZ can be achieved in heavily pretreated patients and responses are not impacted by poor prognostic cytogenetic features. Disclosures: Jakubowiak: Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria; Centocor Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Martin:Celgene: Honoraria; Onyx: Consultancy. Singhal:Celgene: Speakers Bureau; Takeda/Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx : Research Funding. Wang:Celgene: Research Funding; Onyx: Research Funding; Millenium: Research Funding; Novartis: Research Funding. Vij:Onyx: Honoraria. Jagannath:Millenium, OrthoBiotec, Celgene, Merck, Onyx: Honoraria; Imedex, Medicom World Wide, Optum Health Education, PER Group: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Lonial:Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Kukreti:Celgene: Honoraria; Roche: Honoraria; Ortho Biotech: Honoraria. Bray:Onyx Pharmaceuticals: Employment. Vallone:Onyx Pharmaceuticals: Employment. Kauffman:Onyx Pharmaceuticals: Employment. Siegel:Millenium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria.

Description: Abstract 1172 Poster Board I-194 Introduction: Acute and chronic graft versus host disease (aGVHD and cGVHD, respectively) cause significant morbidity and mortality following nonmyeloablative unrelated donor transplantation (NMUDT). The incidence of severe aGVHD (grades II-IV) following non-myeloablative transplant and standard GVHD prophylaxis (cyclosporine or tacrolimus plus mini-methotrexate or mycophenolate mofetil (i.e. two drug prophylaxis)) ranges between 40-70%. The incidence of cGVHD ranges between 50-70%. In order to decrease the incidence and severity of acute and chronic GVHD following NMUDT, consecutive patients were given triple prophylaxis therapy with tacrolimus (TAC), mycophenolate mofetil (MMF) and mini-methotrexate (MTX). In addition, patients were given anti-thymocyte globulin (ATG, thymoglobulin 10 mg/kg) as part of preparative therapy. Patients and Methods: Thirty-five consecutive patients meeting eligibility criteria for NMUDT were prospectively enrolled. The majority of patients had advanced disease; 9AML, 4 MDS, 2CML, 2MPD, 4 MM, 3CLL, 9 Lymphoma and 2 with aplastic anemia. The mean age was 53 years (26-68); 18 males and 17 females. Preparative therapy consisted of Fludarabine (F) 150mg/m2, Busulfan (Bu) 6.4mg/kg IV and ATG. All patients received stem cells from allele-matched unrelated donors; 9/10 (n= 13) or 10/10 (n= 22) at HLA A, B, C, DR and DQ. Thirteen patients received bone marrow and 22 patients received G-CSF mobilized blood stem cells. All patients received TAC (target 5-10 ug/L), MTX (5mg/m2 d1,3,6,11) and MMF (15mg/kg bid day 0 to 60) for GVHD prophylaxis. Infectious disease prophylaxis included; G-CSF, acyclovir, anti-bacterials, voriconazole, and CMV pre-emptive therapy. Results: The F/Bu/ATG non-myeloablative regimen was well tolerated. On average, patients experienced little or no mucositis (15% 〉 grade 1), enteritis (3%〉 grade 1), skin toxicity (3% 〉grade 1) or liver toxicity (29% 〉 grade 1). No VOD was seen. The median total bilirubin, alkaline phosphatase, ALT, and AST values post-transplant were 1.4 mg/dL, 153 U/L, 91 U/L and 77 U/L, respectively. The incidence of Grades II-IV and III-IV aGVHD were 26% and 6% respectively. No difference in aGVHD for 9/10 vs. 10/10 allele matched donors or those receiving stem cells vs. bone marrow was detected. The 100 day non-relapse mortality (NRM) was 11% (2 GVHD, 1 infection, 1 neurotoxicity). The incidence of cGVHD was 52% (80% extensive cGVHD). The majority of these patients required immunosuppression for 〉1 year. The 1 year NRM was 20% (2 GVHD, 2 infection, 2 neurotoxicity). Disease relapse was the most common cause of mortality; 37% overall and 17% within the first year of transplantation. The overall survival at 4 years is 41%. Conclusions: In this prospective study of 35 patients undergoing matched unrelated donor transplantation, the GVHD prophylaxis regimen of TAC/MTX/MMF is safe and effective. The low incidence of aGVHD (26%) compares favorably to published results. Only two patients experienced Grade IV aGVHD within 100 days of transplantation. Chronic GVHD and disease relapse remain problematic. Better strategies to prevent and treat cGVHD and disease relapse are needed. Disclosures: No relevant conflicts of interest to declare.