ALBERT

Description: PU.1 is a hematopoietic cell–specific ets family transcription factor. Gene disruption of PU.1 results in a cell autonomous defect in hematopoietic progenitor cells that manifests as abnormal myeloid and B-lymphoid development. Of the myeloid lineages, no mature macrophages develop, and the neutrophils that develop are aberrantly and incompletely matured. One of the documented abnormalities of PU.1 null (deficient) hematopoietic cells is a failure to express receptors for granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage (GM)-CSF, and M-CSF. To elucidate the roles of the myeloid growth factor receptors in myeloid cell differentiation, and to distinguish their role from that of PU.1, we have restored expression of the G- and M-CSF receptors in PU.1-deficient cells using retroviral vectors. We have similarly expressed PU.1 in these cells. Whereas expression of growth factor receptors merely allows a PU.1-deficient cell line to survive and grow in the relevant growth factor, expression of PU.1 enables the development of F4/80+, Mac-1+/CD11b+ macrophages, expression of gp91phox and generation of superoxide, and expression of secondary granule genes for neutrophil collagenase and gelatinase. These studies reinforce the idea that availability of PU.1 is crucial for normal myeloid development and clarify some of the molecular events in developing neutrophils and macrophages that are critically dependent on PU.1.

Description: Abstract 862 Background: Carfilzomib (Cfz) is a novel, irreversible proteasome inhibitor that has demonstrated promising single-agent activity and favorable toxicity profile, including very low rates of peripheral neuropathy and neutropenia in relapsed/refractory multiple myeloma (MM). Combining Cfz with Lenalidomide (Revlimid®, Len), and Dexamethasone (Dex) into CRd shows an additive anti-MM effect in preclinical studies and lack of overlapping toxicity allowing for the use of these agents at full doses and for extended duration of time in relapsed/refractory MM (Niesvizky et al, ASH, 2009). This Phase I/II study was designed to determine the maximum tolerated dose (MTD) of CRd and to assess safety and evaluate efficacy of this combination in newly diagnosed MM. Methods: In Phase I, dose escalation follows the TITE-CRM algorithm, with Cfz as the only escalating agent starting at 20 mg/m2 (level 1), maximal planned dose 27 mg/m2 (level 2), and 15 mg/m2, if needed (level -1), given IV on days 1, 2, 8, 9, 15, 16 in 28-day cycles. Len is used at 25 mg PO (days 1–21), and Dex at 40/20 mg PO weekly (cycles 1–4/5-8) for all dose levels. Based on toxicity assessment, the study was amended to add dose level 3 with Cfz at 36 mg/m2 and the number of pts in the Phase I was increased to 35. A total of 36 pts are planned to be treated at the MTD in Phase I/II. Pts who achieve ≥ PR can proceed to stem cell collection (SCC) and autologous stem cell transplant (ASCT) after ≥ 4 cycles, although per protocol design, ASCT candidates are offered to continue CRd treatment after SCC. After completion of 8 cycles, pts receive 28-day maintenance cycles with Cfz (days 1, 2 15, 16), Len days 1–21, and Dex weekly at the doses tolerated at the end of 8 cycles. Responses are assessed by IMWG criteria with the addition of nCR. Results: The study has enrolled 24 pts to date, 4 pts at level 1 (Cfz 20), 14 at level 2 (Cfz 27) and at 6 at level 3 (Cfz 36). Toxicity data are available for 21 pts, of which 19 have completed at least the first cycle required for DLT assessment; 2 pts were removed during the first cycle for events unrelated to study therapy (1 at level 1 and 1 at level 2), and 3 are currently within their first cycle of treatment. There was a single DLT event at dose level 2 (non-febrile neutropenia requiring dose reduction of Len per protocol) and the MTD has not been reached. Hematologic toxicities were reversible and included Grade (G) 3/4 neutropenia in 3 pts, G3/4 thrombocytopenia in 3, and G3 anemia in 2. There have been additional G3 non-hematologic AEs including 1 case of DVT while on ASA prophylaxis, 1 fatigue, 1 mood alteration, and 5 glucose elevations; the last 2 AEs were related to Dex. There was no emergence of peripheral neuropathy (PN), even after prolonged treatment, except in 2 pts who developed G1 sensory PN. Twenty-three pts continue on treatment, most (20 pts) without need for any dose modifications. After a median of 4 (range 1–8) months of treatment, preliminary response rates by IMWG in 19 evaluable pts who completed at least 1 cycle are: 100% ≥ PR, 63% ≥ VGPR, 37% CR/nCR, including 3 pts with sCR. Responses were rapid with 17 of 19 pts achieving PR after 1 cycle and improving responses with continuing therapy in all pts. To date, 7 pts proceeded to SCC using growth factors only, with a median 6.3 × 106 CD34+ cells/kg collected (range 4.1–8.2), after a median of 4 cycles of CRd (range 4–8); all resumed CRd treatment after SCC. After a median of 4 months of follow-up, none of evaluable pts progressed and all are alive. Conclusion: CRd is well tolerated and highly active in newly diagnosed MM with ≥ PR of 100%, including 63% ≥VGPR and 37% CR/nCR. Accrual is ongoing, with updated toxicity and efficacy data to be presented at the meeting. The results of this study represent the first report of treatment of frontline myeloma with Cfz to date, and provide additional support to recently initiated Phase 3 trial of CRd vs. Rd in relapsed MM. Disclosures: Jakubowiak: Bristol-Myers Squibb: 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; Centocor OrthoBiotech: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Lenalidomide for newly diagnosed multiple myeloma. Jagannath:Millennium: Honoraria; OrthoBiotech (Canada): Honoraria; Celgene: Honoraria; Merck: Honoraria; Onyx Pharmaceuticals: Honoraria; Proteolix, Inc: Honoraria; Imedex: Speakers Bureau; Medicom World Wide: Speakers Bureau; Optum Health Education: Speakers Bureau; PER Group: Speakers Bureau. Vesole:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Anderson:Millennium: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau. Stockerl-Goldstein:Celgene: Speakers Bureau; Millennium: Speakers Bureau. Barrickman:Celgene: Employment, Equity Ownership. Kauffman:Onyx Pharmaceuticals: Employment, Equity Ownership. Vij:Proteolix: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Description: Abstract 631 Introduction: In relapsed and/or refractory MM, the combination of carfilzomib (CFZ) with lenalidomide (Len), and low-dose dexamethasone (Dex) (CRd) has shown very promising efficacy (78% ≥partial response [PR], 40% ≥very good partial response [VGPR], and 24% CR/nCR) and good tolerability including a low rate of peripheral neuropathy (Wang et al, ASCO, 2011). In a Phase I/II study of newly diagnosed MM, the regimen was well tolerated in the Phase I portion of the study up to a maximum dose of CFZ 36 mg/m2, Len 25 mg, and Dex 40 mg, and very active with 96% ≥PR, 70% ≥VGPR, and 55% CR/nCR (Jakubowiak et al, ASH 2010). The lack of overlapping toxicities has allowed these agents to be used at full doses and for extended periods. Here we report the results for all patients (pts) enrolled in both phases of this first prospective trial of CFZ combination in new MM. Methods: In the initial eight 28-day cycles, pts were treated with CFZ at 20 mg/m2, 27 mg/m2 (Phase I), and 36 mg/m2 (Phase I and II), given IV on days 1, 2, 8, 9, 15 and 16, Len at 25 mg PO (days 1–21), and Dex at 40/20 mg PO weekly (cycles 1–4/5–8). Pts achieving ≥PR could proceed to stem cell collection (SCC) using growth factors alone (protocol recommendation) and autologous stem cell transplant (ASCT) after 4 cycles. Per protocol, ASCT candidates were offered the option to continue CRd treatment after SCC. After 8 cycles, pts received 28-day maintenance cycles of CFZ (days 1, 2, 15, 16), Len days 1–21, and Dex weekly at the doses tolerated at the end of 8 cycles. Responses were assessed by IMWG criteria with the addition of nCR. Results: Enrollment was completed (53 pts): 4 pts at CFZ 20 mg/m2, 13 at CFZ 27 mg/m2 and 36 at CFZ 36 mg/m2 (18 in Phase I and 18 in Phase II). Median age was 59 years (range 35–81; 23 pts ≥65), 60% had ISS stage II/III, and 33% (of 49 with available data) had unfavorable cytogenetics: del 13 or hypodiploidy by metaphase, or t(4;14), t (14;16), del 17p by FISH. As of June 30, 2011, toxicity data (cycles 1–8) were available for 51 pts. Hematologic toxicities were reversible and included Grade (G) 3/4: anemia (18%), neutropenia (12%), and thrombocytopenia (10%). The most common non-hematologic toxicities (all G) were hyperglycemia (76%), hypophosphatemia (61%), and infection (53%). G3/4 non-hematologic AEs included hyperglycemia (24%), DVT/PE while on ASA prophylaxis (10%), infection (6%), and mood alteration (2%). PN was limited to G1/2 sensory (24%). Forty-five pts continue treatment with 22 pts in the maintenance phase. Six pts discontinued treatment: 2 proceeded to ASCT, 1 due to toxicity, and 3 due to events unrelated to treatment or per pt wish. The majority of pts did not require dose modifications, either in the initial (31%) or in the maintenance (25%) phase. After a median of 8 cycles (range 1–20), the best responses per IMWG criteria for 49 response-evaluable pts (all pts who completed 1+ cycle) are shown in the Table. Responses were rapid with 46/49 pts achieving at least PR after 1 cycle, and improved with the duration of treatment reaching 100% ≥PR after 4 cycles and 100% ≥VGPR, 79% CR/nCR after 12 cycles. Responses were deep even at the 2 lower dose levels with the majority of pts at 36 mg/m2 still early in treatment. Responses in pts with unfavorable cytogenetics were similar to response rates in all remaining pts and included a 100% ≥PR in 6 pts with del 17p. Twenty-four pts proceeded to SCC after a median of 5 cycles of CRd (range 4–9); using growth factors only in 23 pts and cyclophosphamide and growth factors in 1 pt, with a median 6.55 × 106 CD34+ cells/kg collected (range 3.75–9.6); all resumed CRd treatment. After a median of 9.5 months of follow-up, only 1 pt has progressed, and all are alive Conclusions: CRd is highly active and well-tolerated allowing the use of full doses for an extended time in newly-diagnosed MM pts with limited need for dose modification. Responses are rapid and improve over time reaching 100% ≥VGPR and early time-to-event data are very encouraging. These results compare favorably to the best frontline regimens in MM. Disclosures: Jakubowiak: Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Exelixis: Consultancy, Honoraria. Off Label Use: Use of the investigational agent carfilzomib, proteasome inhibitor, in the treatment of relapsed and/or refractory multiple myeloma. Jagannath:Millennium: Honoraria; Celgene: Honoraria; Onyx Pharmaceuticals: Honoraria; Merck: Honoraria; OrthoBiotec.Imedex: Membership on an entity's Board of Directors or advisory committees; Medicom World Wide: Membership on an entity's Board of Directors or advisory committees; Optum Health Education: Membership on an entity's Board of Directors or advisory committees; PER Group: Membership on an entity's Board of Directors or advisory committees. Vesole:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Speakers Bureau. Hussein:Celgene Corporation: Employment. Leveque:Onyx Pharmaceuticals: Employment. Vij:Onyx Pharmaceuticals: Consultancy, Research Funding; Celgene: Research Funding, Speakers Bureau; Millennium: Speakers Bureau.

Description: Abstract 1854 Background: Despite the introduction of novel agents and therapies, MM remains incurable. Approximately 15–20% of MM patients have detectable CD20 expression on their malignant cells. Additionally, preclinical studies evaluating the properties of clonogenic MM cells (“MM stem cells”) suggest that these cells express CD20. However, studies with rituximab, an anti-CD20 antibody have not clearly established CD20 as a valid target in MM. I-131 tositumomab is a radiolabeled murine anti-CD20 antibody which is highly effective in the treatment of low-grade B-cell NHL and has a well-characterized toxicity profile. In this study, we evaluated the safety and efficacy of consolidation treatment with I-131 tositumomab in patients with MM who had received ≥1 line of prior treatment. Methods: This was a single arm, phase II, single-center study. All patients had symptomatic MM and had received 1–3 prior treatment regimens. Patients were required to have a stable response to prior therapy of 〉 PR but 〈 CR on at least two evaluations with measurable disease at the time of study entry. Patients were required to have adequate hematologic, hepatic and renal function and ≤ 25% bone marrow involvement of their MM. All patients received I-131 tositumomab in standard fashion, comprised of a dosimetric dose followed within 1–2 weeks by a therapeutic dose of 75cGy of total body radiation. No maintenance therapy was administered. The primary endpoint was the rate of ≥25% reduction in monoclonal proteins (MR). Secondary endpoints included the rate of CR, DOR and PFS. Results: Between July 2006 and April 2012, sixteen patients were enrolled. Median age was 56 (45–77). Nine were male. The median number of prior treatments was 2. Six patients had CD20 positive MM. In the total population, results were as follows: PD=7, SD=4, MR=1, PR=2, CR=2, for an ORR of 31% (95% CI: 11%-59%). Of the 4 patients with SD, 3 had their data censored at 3 months because they proceeded to transplant, and the other patient has only 3 months of follow up to date. In the CD20 negative population, response rates were PD=6, SD=3, PR=1 for an ORR of 10% (95% CI:

Description: Background. Sinusoidal obstructive syndrome (SOS) is a life-threatening liver injury complication that affects up to 20% of patients receiving allogeneic HSCT in some centers. Symptoms may be variable in less severe cases and the etiology of abdominal pain, weight gain, and elevated bilirubin following HSCT presents a diagnostic challenge. Although a few potential biomarkers for SOS have been identified based on hypothesis-driven testing, there is still no validated blood test for SOS. Methods. We used a mass spectrometry-based proteomics discovery approach comparing plasma pooled from 19 patients with SOS to plasma pooled from 19 patients without SOS. Of 494 proteins quantified, 151 proteins showed at least 2-fold increase in the heavy/light isotope ratio, and 77 proteins showed a ratio of 0.5 or less. We selected 6 proteins [L-Ficolin, vascular cell adhesion molecule-1 (VCAM1), tissue inhibitor of metalloproteinase-1, von-Willebrand factor, intercellular adhesion molecule-1, and CD97] based on their ratio, their involvement in relevant pathway networks, and other information from published literature, and the availability of a sandwich ELISA. In addition, five endothelial markers [suppressor of tumorigenicity 2 (ST2), angiopoietin2 (ANG2), hyaluronic acid (HA), thrombomodulin (sCD141), and plasminogen activator inhibitor-1 (PAI-1)] were measured based on previous demonstrations of their involvement in SOS or in refractory GVHD. Using sequential ELISA, levels of these 11 proteins were measured in plasma from a validation set of 45 patients: 32 SOS patients at disease onset (days +14 to +21 post-HSCT) and from 13 time-matched controls. We tested the value of these proteins as diagnostic biomarkers of SOS using two-sample t-tests and by calculating the area under the receiver operating characteristic curve (AUC of the ROC). Next, we tested the prognostic significance of these biomarkers using Wilcoxon Rank-Sum analysis of their levels measured prior to the clinical signs (days 0 and +7 post-HSCT). We also examined these markers in an independent set of 35 patients (13 SOS+; 22 SOS-). Finally, a Naïve Bayes classifier implemented in Waikato Environment for Knowledge Analysis (WEKA) was developed for SOS prognosis based on a balanced subset of 24 patients (11 SOS-; 13 SOS+). The classifier performance was evaluated by doing a 10-fold cross-validation. Results. Of the 11 proteins tested, 8 were diagnostic markers of SOS with p-values

Description: Ape1/ref-1is a multifunctional base excision DNA repair protein that is involved in the repair of abasic sites in DNA. However, it also has a distinct role in the redox regulation of a variety of cellular proteins, such as Fos, Jun, p53, NFkB, PAX, HIF-1a, HLF, and others. Ape-1/ref-1 maintains these proteins in a reduced state thereby facilitating their DNA binding and transcriptional activation capability. HL-60 cells are known to respond to retinoic acid (RA) with terminal granulocytic differentiation and apoptosis, which is mediated through the RA receptors. Previous experiments suggested that Ape1/ref-1 expression is related to apoptosis. To further define this relationship, we used retroviral gene transduction to over-express HA-tagged Ape1/ref-1 in HL-60 myeloid leukemia cells. We observed that the RA-induced growth inhibition, apoptosis, and differentiation of HL-60 cells over-expressing Ape1/ref-1 was significantly enhanced compared to wild type HL-60 cells. To further understand the mechanism of this effect we performedgel shift experiments in vitro with Ape1/ref-1, retinoic acid receptor alpha (RAR-α), and a retinoic acid response element (RARE) under varying redox conditions andco-transfection experiments in CV-1 cells with Ape1/ref-1 and RAR-α using an RARE linked to a luciferase reporter. Results:gel shift experiments demonstrate a redox dependent binding of RXR-α and RAR-α to their RARE which is mediated by Ape1/ref-1;western blot analysis of transfected CV-1 cells revealed proper expression of each transfected construct including RAR-α, RXR-α and Ape1/ref-1; andexamination of RA-treated CV-1 cells for RARE-linked luciferase expression demonstrated Ape1/ref-1 enhancement of RAR activated transcription of the luciferase reporter. In conclusion, our data supports the contention that Ape1/ref-1 expression may be important for enhancing RA-induced myeloid differentiation and programmed cell death through a redox based mechanism in transcription of target genes.

Description: Abstract 1636 Background: Radioimmunotherapy (RIT) is effective treatment for relapsed and refractory indolent lymphomas. Results in aggressive lymphomas such as diffuse large B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) have been less impressive, with lower response rates and short duration of response. We hypothesized that administration of the proteasome inhibitor bortezomib as a radiosensitizer in patients receiving RIT would be tolerable and potentially improve efficacy in both aggressive and indolent lymphomas. Methods: We performed a Phase 1 dose escalation study to evaluate the maximum tolerated dose (MTD) of bortezomib in combination with 131I-tositumomab. The study underwent review and was approved by each institution's Institutional Review Board. Dose escalation proceeded using a Time to Event-Continuous Reassessment Model (TiTE-CRM). Patients with relapsed or refractory DLBCL, MCL or indolent B cell non-Hodgkin's lymphoma were eligible if they had not undergone prior stem cell transplant, organ function was preserved, and bone marrow involvement by lymphoma was less than 25% of the intertrabecular space. Neutrophil count at least 1500/uL and platelet count at least 150 × 103/uL were required. A dosimetric dose of 131I-tositumomab was administered on day 1, followed by three whole body gamma camera scans for purposes of dose calculation and evaluation of biodistribution. After an initial cohort received a reduced whole-body dose of 50 cGy 131I-tositumomab, patients received RIT at the standard dose of 75 cGy on day 8. Patients were treated with escalating doses of bortezomib (0.3 to 1.2 mg/m2) on days 6, 10, 13, 16 and 20. Dose limiting toxicity (DLT) was defined as any grade 3 or 4 non-hematologic toxicity, or grade 4 hematologic toxicity. Results: The study has completed enrollment, with 25 patients having received study treatment. These include 8 patients with DLBCL, 5 with MCL, 11 with follicular lymphoma (FL), and one with marginal zone lymphoma (MZL). Median age is 68 (range 40–81). Median number of prior therapies is 2 (range 1–4), and all but one had received prior rituximab. Twenty-three patients are evaluable for response, while two patients have not yet undergone restaging. Twenty-four patients are evaluable for the primary endpoint of MTD. One treated patient was not evaluable for toxicity due to early progression of disease and need for further therapy prior to the end of the observation period. Of 24 patients evaluable, 4 experienced DLT (Table), all at dose level 5 (1.2 mg/m2). These events included grade 3 hyponatremia, herpes zoster, and grade 4 thrombocytopenia. Grade 3 hematologic toxicities included two patients with leukopenia, three with neutropenia, one with anemia, and five with thrombocytopenia. Dose level 4 (0.9 mg/m2 bortezomib, 75 cGy 131I-tositumomab) was well tolerated, and this dose was identified as the MTD. Fourteen of 23 (61%) patients evaluable for response have responded, including 3/8 with DLBCL, 3/5 with MCL, and 8/9 with FL. Ten patients have achieved complete remission, including one patient with DLBCL, one with MCL, and 8 with FL. At median follow up of 8 months, median progression free survival is 6 months, and seven patients (50% of responders) remain in remission at 2 to 28 months. Conclusions: Bortezomib can be safely administered in combination with 131I-tositumomab. Responses were seen in a majority of patients, including those with aggressive histology. The MTD has been defined as 0.9 mg/m2 bortezomib plus 75 cGy 131I-tositumomab. This strategy of radiosensitization using bortezomib shows promise, and efficacy should be further evaluated in a Phase 2 trial. Disclosures: Off Label Use: Azacitidine is approved for use in MDS. Discussion here is off label. Leonard:Glaxo SmithKline: Consultancy, Honoraria. Martin:Cephalon: Consultancy; Celgene: Consultancy; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Lebovic:Genentech: Speakers Bureau. Coleman:Celgene Corp: Speakers Bureau. Kaminski:GlaxoSmithKline: Patents & Royalties, Research Funding.

Description: Introduction Benefits of carfilzomib (CFZ) and pomalidomide (POM) in heavily pretreated relapsed and refractory multiple myeloma (RRMM) are well established. The combination of these agents with dexamethasone (DEX) showed very promising activity in advanced disease after a median of 5 lines of prior therapy, including pts refractory to both bortezomib (BTZ) and lenalidomide (LEN) (Shah et al; ASH 2013:122[21]). The activity of this regimen in less-heavily pretreated pts is not known. In this phase 1b/2 study, we evaluate a similar KPd combination in pts in earlier stages of the disease, including a primary study population of PI-naive or -sensitive pts who were previously treated with LEN and/or are LEN-refractory. The primary objectives of the study are to establish the maximum tolerated dose (MTD) of KPd and provide preliminary assessment of the regimen’s activity in early relapse. Methods PI-naive or -sensitive pts with RRMM who have failed ≥1 prior therapies are eligible; LEN-refractory disease (progressing on LEN or within 60 days of discontinuation) is required for the 2nd line, or LEN exposure and/or progression on LEN maintenance for the 3rd or later line of treatment. The phase 1b dose escalation follows the TITE-CRM algorithm with pts receiving 3–4 mg POM PO (days 1–21), 20–36 mg/m2CFZ (given IV on days 1, 2, 8, 9, 15, 16 in cycles 1–8 and on days 1, 2, 15, 16 in cycles 9+), and 40/20 mg DEX PO weekly (cycles 1–4/5–8; for all dose levels) in 28-day cycles. Forty pts are planned for phase 1b, and 30 pts are planned to be treated at the MTD across phases 1 and 2. The primary objective of the phase 1b study is to evaluate the safety of KPd and identify the MTD. The primary objective of the phase 2 study is to assess response rates at the MTD after 4 cycles, defined per IMWG criteria with the addition of near complete response (nCR). As an exploratory end point, the study will evaluate KPd activity in an additional 30 pts refractory to PIs or POM. Results As of July 30, 2014, the study has enrolled 27 pts in the phase 1b study; 4 pts at level 1 (20 mg/m2 CFZ, 3 mg POM), 9 pts at level 2 (20 mg/m2 CFZ, 4 mg POM), and 14 pts at level 3 (20/27 mg/m2 CFZ, 4 mg POM). Pts had a median age of 63 (range, 51–79) and a median of 2 prior treatments (range, 1–6). Twenty-three pts met criteria for the primary study population of PI-naive/sensitive and LEN- refractory/exposed; 15 were LEN-refractory, and an additional 8 had progressed on LEN maintenance. Toxicity data were available for 26 pts, of whom 25 had completed ≥1 cycle. Twenty pts were DLT-evaluable (7 pts did not receive all scheduled cycle 1 doses and were thus not evaluable for DLTs, including 1 pt who was replaced due to noncompliance). There were 5 DLTs, all due to delay of cycle 2 initiation: 4 cases of grade (G) 3 neutropenia and 1 G4 thrombocytopenia on day 1 of cycle 2. The MTD has not yet been reached; current enrollment is at dose level 3 (20/27 mg/m2 CFZ, 4 mg POM, 40 mg DEX). Hematologic toxicities were reversible and included 23% neutropenia, 19% thrombocytopenia, and 27% anemia (all grades). Most common nonhematologic toxicities (all grades) were infection (54%), fatigue (50%), and dyspnea (35%). KPd-related G1/2 peripheral neuropathy (PN) was reported in 35% of pts; 1 pt with G2 sensory PN elected to come off study during cycle 7 while in nCR. After a median of 5 cycles (range, 1–17), response rates in all 25 evaluable pts who completed ≥1 cycle were 72% ≥partial response (PR), 28% ≥very good PR (VGPR), 12% CR/nCR; clinical benefit rate (CBR; ≥minor response) was 84%. In the primary study population of PI-naive/sensitive and LEN-refractory/exposed pts, 77% achieved ≥PR, 27% ≥VGPR, 9% CR/nCR; CBR was 91%. Responses were rapid, with 52% of pts achieving ≥PR after 1 cycle and improving with treatment; after 4 cycles, ≥PR was 79%, and CBR was 89% in 19 evaluable pts. After a median of 9.5 months of follow-up, 11 pts have progressed, and 2 died; 14 are still on treatment. Conclusion The KPd combination is overall well tolerated and highly active in RRMM, with 78% ≥PR in a primary study population of PI-naive/sensitive but LEN-refractory/exposed pts. Accrual is ongoing to determine the MTD, and enrollment will continue into phase 2 at the MTD. Updated toxicity and efficacy data based on cytogenetic risk will be presented. These results represent the first reported use of KPd to treat less-heavily pretreated pts with mostly LEN-refractory MM and/or progression on LEN maintenance in the era of increased use of extended LEN treatment. Disclosures Rosenbaum: Celgene: Speakers Bureau. Off Label Use: Carfilzomib is approved in the United States for the treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. The study presented here enrolled patients with multiple myeloma who had failed ≥1 prior regimen; patients could be proteasome inhibitor-naïve or –sensitive and lenalidomide-exposed and/or -refractory. Patients received carfilzomib in combination with pomalidomide and dexamethasone.. Kukreti:Onyx: Research Funding; Millennium Pharmaceuticals: Research Funding. Zonder:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria, Research Funding. Zimmerman:Celgene: Honoraria; Onyx: Honoraria. Jakubowiak:Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SkylineDx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Description: Introduction High rates of complete response (CR) have previously been demonstrated in KRd-treated NDMM pts in a phase 1/2 trial (trial 1; NCT01029054) and a phase 2 trial that combined KRd with autologous stem cell transplant (ASCT) (trial 2; NCT01816971). Here, we report results of extended follow-up from the 2 trials and correlate response and PFS with GEP performed using the MMprofiler GEP assay, which provides results for the SKY92 signature, 7 virtual karyotyping markers (t[4;14], t[11;14], t[14;16]/t[14;20], gain[1q], del[13q], del[17p], H-MM [virtual gain(9q)]), and 3 clusters (MF, MS, CD2). Previously, a combination of 5 markers (SKY92, virtual gain[1q], virtual t[14;16]/t[14;20], MF and CD2 clusters) was identified that predicts improved outcomes when treated with the proteasome inhibitor (PI) bortezomib (van Vliet et al, EHA 2014). We evaluated the SKY92 prognostic signature, virtual karyotyping markers, and this 5-marker PI predictor signature in order to confirm these markers as predictive signatures in the KRd setting. Materials and Methods In the consecutive trials 1 and 2, pts received 4 cycles of KRd induction, followed by extended KRd treatment with deferred ASCT (trial 1; NCT01029054) or ASCT followed by extended KRd treatment (trial 2; NCT01816971). In both trials, pts received single-agent lenalidomide as maintenance after completion of KRd. The MMprofiler GEP assay was performed on RNA from CD138+ purified plasma cells. As depth of response with KRd is associated with improved time-to-event outcomes (Jasielec et al, ASH 2013), data were analyzed for associations between any of the MMprofiler markers and the groups that achieved ≥near CR (nCR) vs

Description: Background: NDMM patients (pts) treated with KRd in a phase 1/2 trial (NCT01029054) demonstrated high rates of complete response (CR, 64%) and stringent complete response (sCR, 55%) that correlated with excellent estimated 3-year progression-free survival (PFS; 79%) and overall survival (OS; 96%) (Jakubowiak et al, Blood, 2012; Jasielec et al, Blood 2013; 122(21):3220). Furthermore, there was a trend towards superior outcomes in patients with multiparameter flow cytometry (MFC) MRD-negative disease with an estimated 3 year PFS of 84% and OS of 100%, suggesting the importance of MRD analysis in predicting relapse. In this post hoc, retrospective analysis, we present an updated evaluation of PFS based on minimal residual disease (MRD) status. Methods: Pts received 28-day cycles of carfilzomib (CFZ) 20–36 mg/m2 intravenously (days [d]1, 2, 8, 9, 15, 16), lenalidomide (LEN) 25 mg orally (PO; d1–21), and dexamethasone 40/20 mg PO weekly (cycles 1–4/5–8). For cycles 8–24, KRd was given with a modified CFZ schedule (d1, 2, 15, 16), and single-agent LEN was administered after cycle 24. Pts had the option to receive stem cell transplantation after cycle 4. MRD assessment at the time of complete response (CR) was performed using 10-color MFC and next-generation sequencing (NGS) analysis. Fresh bone marrow aspirate (BMA) was used for MFC analysis as previously reported, while archived BMA slides were used for NGS analysis. The LymphoSIGHT™ NGS method employed universal primer sets to assess clonal rearrangements at the immunoglobulin loci (IGH-VDJ, IGH-DJ and IGK) in diagnostic BMA slides. Myeloma clonotypes were identified in the diagnostic BMA sample of each patient based on high-frequency within the B-cell repertoire. The level of the myeloma clonotype was then quantified in BMA slides obtained at the time of CR. Results: Twenty-two pts with CR/sCR were evaluated for MRD by both MFC and NGS methods with a median follow-up of 40 months. Limited input DNA was obtained from BMA slides (range 2,189 to 1,870,960 cell equivalents). Concordance analysis in 21 patients with both MFC and NGS MRD data revealed 11 patients that were MRD-negative by both MFC and NGS, while 2 patients were concordantly MRD-positive. NGS demonstrated greater sensitivity compared to MFC, as 8 patients were MRD-positive by NGS but MRD-negative by MFC. Three of these 8 patients relapsed. We evaluated the correlation between MRD status by NGS and PFS. Six MRD samples had less than 40,000 input cell equivalents and were removed from the progression-free survival analysis due to insufficient sample amount. MRD negativity by NGS in KRd patients at the time of CR was associated with longer progression-free survival (median not reached vs 46 months, p = 0.055) (Figure 1). Conclusions: Our results suggest that achievement of MRD-negative disease by NGS in CR patients is associated with superior PFS. The NGS method appears more sensitive than MFC at detecting residual disease. Finally, MRD assessment by NGS in BMA slides is feasible although may not be the optimal method due to limited input DNA amount. MRD assessment by NGS will be performed on the remainder of the KRd cohort and results will be presented. Figure 1. Kaplan-Meier analysis of progression-free survival for 6 MRD negative (10-6) patients. Figure 1. Kaplan-Meier analysis of progression-free survival for 6 MRD negative (10-6) patients. Disclosures Faham: Sequenta, Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Lee:Sequenta, Inc.: Employment, Equity Ownership. Jakubowiak:Bristol Myers-Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SkylineDx: Honoraria, Membership on an entity's Board of Directors or advisory committees.