Citations

AbstractKidney paired donation (KPD) and the new kidney allocation system (KAS) in the United States have led to improved transplantation rates for highly sensitized candidates. We aimed to assess the potential need for other approaches to improve the transplantation rate of highly sensitized candidates such as desensitization. Using the UNOS STAR file, we analyzed transplant rates in a prevalent active waiting‐list cohort as of June 1, 2016, followed for 1 year. The overall transplantation rate was 18.9% (11 129/58769). However, only 9.7% (213/2204) of candidates with a calculated panel reactive antibody ≥99.9% received a transplant, and highly sensitized candidates were less likely to receive a living donor transplant. Among candidates with a CPRA ≥ 99.5% (ie. 100%), only 2.5% of transplants were from living donors (13 total, 7 from KPD). Nearly 4 years after KAS (6/30/2018), 1791 actively wait‐listed candidates had a CPRA of ≥99.9% and 34.6% (620/1791) of these had ≥5 years of waiting time. Thus, despite KPD and KAS, many sensitized candidates have not been transplanted even with prolonged waiting time. We conclude that candidates with a CPRA ≥ 99.9% and sensitized candidates with an incompatible living donor and prolonged waiting time may benefit from desensitization to improve their ability to receive a transplant.

Abstract Abstract 430 Background: Peripheral neuropathy (PN) is a feature of multiple myeloma (MM) itself as well as a debilitating side effect and major dose-limiting toxicity of thalidomide (THAL) and bortezomib (BTZ) (Chaudry et al, J Peripher Nerv Syst. 2008). Although the mechanism of BTZ-induced PN (BIPN) is unknown, PN may not be a proteasome inhibitor class effect. Carfilzomib (CFZ) is a highly selective proteasome inhibitor with activity in relapsed or refractory MM. CFZ overcomes BTZ-resistance in vitro (Kuhn et al, Blood 2007), lacks the off-target activities of BTZ (Kapur et al, Blood 2008), and does not cause neurotoxicity in long-term chronic (e.g. up to 9 months) animal toxicology studies (Kirk et al, Blood 2008). In Phase I and 1b/2 trials (total n=138), CFZ was not associated with dose-limiting PN. Here we report on the experience of CFZ treatment from two ongoing Phase 2 trials in relapsed or refractory MM. Methods: Patients with relapsed or refractory MM received CFZ, 20 mg/m2 IV, Days 1, 2, 8, 9, 15, and 16 in a 28-day cycle for up to 12 cycles on studies PX-171-003 and PX-171-004. Neuropathy history, neurological physical exam and PN-related quality of life data (FACT-GOG/NTx v 4.0 scores) were collected at screening. Prospective neurological exams and subjective reporting of PN using the FACT-GOG/Ntx subscale v.4 questionnaire occurred every 2 cycles until study discontinuation to proactively assess for PN. Adverse Event (AE) data were also collected. AEs reported as ‘neuropathy peripheral', ‘neuropathic pain', ‘neuropathy', and ‘peripheral sensory neuropathy' were included as PN. AE reports of ‘paraesthesias' and ‘dysesthesias' were counted separately. Results: To date, baseline data are availabel for 136 patients. At screening, 73 (54%) patients had active PN, including 64 (47%) with Grade (G) 1 and 9 (7%) with G2. 111 (82%) patients had a history of PN which was attributed to prior chemotherapy, 86 cases of which were attributed to either THAL or BTZ. THAL was implicated in 57 cases, BTZ in 45 cases, and both THAL and BTZ in 17 cases. For 27 of these patients, PN was the primary reason for THAL or BTZ discontinuation. The mean number of CFZ doses was 27 (4.5 four-week cycles) and 27 (20%) patients completed at least 8 cycles. Peripheral neuropathy AEs (all grades) were reported in 21 (15%) patients; 12 (9%) cases were considered possibly related to CFZ. Grade ≥ 3 PN was reported in only 3 (2%) patients. In one patient, the Grade 3 neuropathy lasted from treatment days 2 to 3 (i.e., < 36 hours) and resolved; the patient continued on CFZ at full dose for 30 days before discontinuing study due to progressive MM. In a second patient, Grade 3 neuropathy occurred on study day 91. The dose was reduced from 20 mg/m2 to 15 mg/m2, at the same twice-weekly frequency; the PN resolved to G1 and the patient continued on therapy until day 133. The third patient had G3 PN that occurred from days 260-281 and resolved to G1 while still on full dose CFZ. This patient completed the full 12-cycle protocol (∼1 year CFZ treatment). Paraesthesias and dysesthesia were reported in 10 (7%) patients; all were G1 or 2. There were no missed doses or CFZ treatment discontinuations due to PN, paraesthesias or dysesthesias. Comparative FACT-GOG/Ntx subscale scores were availabel for 95 patients. There was no statistically significant change in FACT-GOG/NTx scores from baseline to the end of the study. Neurological exams did not identify any additional peripheral neuropathy beyond those reported as AEs. Conclusions: In MM patients receiving CFZ therapy, reports of PN, paraesthesias and dysesthesia are generally mild and do not result in missed doses or CFZ discontinuation, allowing long-term treatment and prolonged disease control. These data, along with the experience from other clinical trials, indicate that PN is not a class effect of proteasome inhibitors. Disclosures: Vij: Proteolix: Consultancy, Research Funding. Wang:Proteolix, Inc.: Research Funding. Stewart:Genzyme, Celgene, Millenium, Proteolix: Honoraria; Takeda, Millenium: Research Funding; Takeda-Millenium, Celgene, Novartis, Amgen: Consultancy. Lonial:Celgene: Consultancy; Millennium: Consultancy, Research Funding; BMS: Consultancy; Novartis: Consultancy; Gloucester: Research Funding. Trudel:Celgene: Honoraria, Speakers Bureau; Ortho Biotech: Honoraria. Jakubowiak:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Centocor Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Exelixis: 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, Speakers Bureau. Belch:Ortho Biotech: Honoraria, Research Funding. Bahlis:Celgene: Honoraria, Speakers Bureau; Ortho Biotech: Honoraria, Speakers Bureau. Le:Proteolix, Inc.: Employment. Cruickshank:Proteolix, Inc.: Employment. Bennett:Proteolix: Employment. Molineaux:Proteolix, Inc.: Employment, Equity Ownership. Siegel:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Abstract Introduction: We employed a customized Multiple Myeloma (MM) specific Mutation-Panel (M3 P) to screen a homogenous cohort of refractory MM (rMM) patients in a timely and cost-effective manner. rMM was defined as progressive disease (PD) during therapy or within 60 days after discontinuation of therapy. The M3 P provides a practical alternative to whole genome/exome sequencing approaches and includes 88 genes selected for being either actionable targets, potentially related to drug response or part of known key pathways in MM biology. Patients and Methods: Tumor and germline samples of 50 rMM patients were screened using M3 P. Patients received a median of five lines of treatment at the time of tumor sampling (range 2-15 lines). All patients received at least one immunomodulatory agent (IMiD) and proteasome inhibitor (PI), and 88%, 76% and 66% were refractory to either an IMiD, PI or both. All patients had received lenalidomide and bortezomib, 48% and 34% were additionally exposed to pomalidomide and thalidomide and 18% to carfilzomib at any time prior to sampling. The majority of patients had a progressive and refractory disease immediately prior to sampling (82% and 78%), with 43% of them being IMiD-refractory and 46% being PI-refractory in the most recent line of therapy. Cytogenetic data at time of sampling were available from 78% of patients. Adverse cytogenetics were detectable in 82% of patients with gain 1q21 > 2 copies (62%), deletion 17p (33%), t(4;14) (13%) and t(14;16) (8%) being the most common. Results: An average sequencing depth of 750x was obtained across the samples. Our screening revealed an increased prevalence of mutations in the MAPK pathway (72%), including 34% of KRAS, 26% of NRAS, 18% of BRAF (with one patient carrying two BRAF mutations and 8% in actionable p.V600E). Additionally, two mutations (4%) were found in RASA2, a RAS inhibitor. Other potentially actionable mutations were seen in p.R132H IDH1 and p.R248C FGFR3 (2% each). Most prominently, the CRBN pathway was found mutated in 22% of cases, including CRBN (12%, one case with concomitant CUL4B mutations), CUL4B (4%), IRF4 (4%) and IKZF1 (2%). In CRBN we found four cases with mutations leading to a truncated protein (frameshift, nonsense and splicing) and two cases with missense mutations located within the thalidomide-binding domain, suggesting a causal effect on IMiD resistance. All CRBN mutated patients and 91% of the CRBN pathway mutated patients were at least once unresponsive to IMiD based treatment. In one patient with IRF4 mutation sensitivity to IMiDs remained unknown. A majority of patients were also resistant to PI treatment (76%), however mutations in proteasome subunits (PSMD1 and PSMB8) and XBP1 wererare (4%), but only a limited number of this gene family were represented in our panel. Other recurrently mutated genes were TP53 (26%), FAM46C (12%), ATM (10%) and TRAF3 (8%). Notably, DIS3 mutations were identified in only 6% of cases. As previously reported, TP53 mutations were associated with deletion 17p (8/13 cases, 62%). A correlation between the absolute number of mutations and previous lines of treatment was not observed (r=0.05, p=0.73). Conclusion: Targeted sequencing on a homogenous cohort of heavy pretreated rMM patients gives key insights in the landscape of the rMM genome, uncovering an increasing frequency of MAPK, TP53 and CRBN mutations. Importantly, this is the first study showing recurrent mutations in CRBN in patients unresponsive to IMiD treatment, supporting a potential association with resistance to IMiD based therapies. Disclosures Mai: Onyx: Other: Travel Grant; Janssen-Cilag: Other: Travel Grant; Celgene: Other: Travel Grant; Mundipharma: Other: Travel Grant. Merz:Janssen: Other: Travel grants; Celgene: Other: Travel grants. Hillengass:Takeda: Honoraria, Other: Travel support; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Janssen-Cilag: Honoraria, Other: Travel support; Celgene: Honoraria, Other: Travel support. Goldschmidt:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: 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, Research Funding, Speakers Bureau; Chugai: Research Funding, Speakers Bureau. Stewart:Oncospire Genomics: Research Funding.

Abstract Abstract 1938 Background: Carfilzomib (CFZ), a selective, epoxyketone proteasome inhibitor, produces potent, sustained proteasome inhibition and lacks many of the off-target activities associated with bortezomib (BTZ). Durable single-agent activity with CFZ has been observed in patients (pts) with relapsed/refractory multiple myeloma (R/R MM) who have received multiple prior therapies as well as in pts with advanced stage disease or significant comorbidities (Jagannath et al. ASCO 2009 Meeting. Abstract 8504). PX-171-004, is an ongoing Phase 2 study of single-agent CFZ in pts with relapsed or refractory MM following 1–3 prior therapies. Here we present updated data on the BTZ-naïve pts and report on activity observed in pts with significant comorbidities or poor-risk cytogenetic or FISH markers for myeloma. Methods: Enrolled pts received either 20 mg/m2 for all treatment cycles, or a stepped-up, dose-escalating regimen of 20 mg/m2 for Cycle 1 and 27 mg/m2 for all treatment cycles thereafter. CFZ was administered on Days 1, 2, 8, 9, 15 and 16 every 28 days (one cycle), for a maximum of 12 cycles. Dexamethasone, 4mg, was administered prior to CFZ in Cycle 1 only. For the present analyses, pts were stratified according to several baseline criteria including ECOG performance score, cytogenetic or FISH markers of high-risk disease per mSMART criteria [del17p, t(4;14), t(14;16), del13 by karyotype and hypodiploidy] and serum ß2-microglobulin. The primary endpoint was overall response rate (ORR) per International Uniform Response Criteria for Multiple Myeloma. Results: Data are available for 110 BTZ-naïve pts. Baseline pt characteristics included: 60% of ECOG PS ≥1; 53% baseline neuropathy Grade 1/2; 30% moderately impaired renal function (CrCl <60 mL/min), and 17% diabetes. Approximately 13% of pts had cytogenetic or FISH markers of poor prognosis. The ORR for the entire BTZ-naïve population was 48%; the ORR for BTZ-naïve pts receiving 20–27 mg/m2 was 54%. The ORRs stratified according to dose and baseline measurements are detailed in the following table. The most common treatment-emergent AEs, regardless of relationship to study drug, were fatigue (61%), nausea (43%), anemia (39%), dyspnea (36%), cough (34%), headache (31%), thrombocytopenia and upper respiratory infections (30% each) and were primarily ≤ Grade 2 in severity. Grade 3/4 AEs occurring in >5% of pts included lymphopenia, neutropenia, pneumonia, thrombocytopenia, anemia and fatigue. Of note, there were no discontinuations for peripheral neuropathy and only 1 pt with impaired renal function at baseline was discontinued for creatinine increases. Twenty-four pts remain on study and 23% have completed the protocol-specified 12 cycles of therapy. Seventeen pts (20%) elected to continue CFZ on an extended treatment protocol (PX-171-010); no cumulative toxicities have been noted. Conclusions: Single-agent CFZ achieves high response rates in BTZ-naïve pts with relapsed myeloma, with minimal neuropathy, even in the setting of high-risk disease. In addition, single-agent CFZ continues to demonstrate long-term tolerability even in pts with comorbid conditions, including renal insufficiency and diabetes, who may benefit from a steroid-sparing treatment regimen. The data from this ongoing trial show that CFZ is a promising new treatment for multiple myeloma in the relapsed or refractory setting. Disclosures: Vij: Onyx: Honoraria. Kaufman:Celgene: Consultancy, Research Funding; Millenium: Consultancy; Merck: Research Funding. Jakubowiak:Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria; Centocor Ortho Biotec: 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. 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. Kukreti:Celgene: Honoraria; Roche: Honoraria; Ortho Biotech: Honoraria. Alsina:Millenium: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy. Gabrail:Millenium: Research Funding. Vesole:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millenium: Speakers Bureau. Le:Onyx Pharmaceuticals: Employment. Wang:Celgene: Research Funding; Onyx: Research Funding; Millenium: Research Funding; Novartis: Research Funding.

Abstract Introduction: Customized gene panel sequencing is an attractive approach to genomic tumor characterization in clinical care. Based on published MM exome data we developed a MM Mutation Panel (M3 P) that includes the most commonly mutated genes, actionable drug targets, genes targeted by current standard of care (SOC) therapies and which allows tracking of clonal evolution, copy number and sample purity. Methods and Material: M3 P (v3.0) covers 88 genes (1327 amplicons, 181kb). MM samples from 504 patients (pts) have been analyzed (corresponding germline in 81%) through collaborations between Mayo Clinic and Hospital-12-de-Octubre (Madrid, Spain), the DSMM and GMMG (Würzburg, Ulm, Freiburg and Heidelberg, Germany) and the HOVON trial groups (Rotterdam, The Netherlands). The investigated cohort includes 410 untreated pts (81%), which includes a high risk cohort of 72 pts with del17p, 25 paired samples with later follow up from the same cohort, and 94 relapsed patients, of which 50 were relapsed and refractory. Results: Overall coverage per mutation averaged >500x depth. We identified 945 variants (1.9 per pt) and in 83% of the pts a mutation was found. Clonal heterogeneity was assessed with mutations ranging from 3%-100% variant reads suggesting the presence of a significant number of subclones (e.g. 21% of mutations were in < 10% of reads). The mutation incidence was compared with and closely resembles the most recent MM comprehensive genomic data from the MMRF CoMMpass study: We compare here all pts sequenced by M3 P, untreated pts sequenced by M3 P and CoMMpass: KRAS (24%/23%/24%), NRAS (20%/20%/18%), DIS3 (13%/14%/10%), BRAF (9%/7%/6%), FAM46C (6%/6%/8%) and TRAF3 (6%/6%/7%). TP53 mutation incidence, however, was significantly increased in our cohort (14%/12%/4.2%), a difference explained by the inclusion of del17p (untreated) and relapsed refractory MM in panel sequenced pts, cohorts with elevated incidences of TP53 mutations (32% / 26% respectively). Potentially actionable targets include BRAF mutationsin 43 patients (9%), with druggable p.V600E in 19 or 5%, 8 pts (2%) with FGFR3 (p.R248C and p.G375C one patient each), p.R132 mutation in 4 out of 5 IDH1 (1%) and p.R172K IDH2 mutation in 1 of 3 (1%) pts. Mutations in the MAPK pathway (NRAS, KRAS, BRAF) were detected in 59% of pts, ranging from 36% untreated MM to 72% in refractory MM. Similarly, the CRBN/CUL4B/IKZF1/IKZF3/IRF4 pathway, important for IMiD function, harbored a significant enrichment of mutations in advanced disease (6% untreated vs 17% relapsed), including CRBN mutations (0.5% vs 7%). Nine of 17 IRF4 mutations were located at the p.K123R hotspot, with minor difference between early or late disease (1% vs 3%). Notably, in 8 of 9 pts with CRBN mutation and clinical information, all were unresponsive to IMiD therapy, supporting association of these mutations with resistance to IMiDs. Conversely, M3 P genes related to other SOC therapies, including NR3C1 (targeted by steroids) and 5 proteasome subunit genes (proteasome inhibitors), were rarely mutated across the cohorts not exceeding 1% mutation incidence for each gene. Significant differences in DIS3 and FAM46C mutation incidences were observed across cohorts: DIS3 mutations are more common in untreated pts with a 1.7 fold increased predominance (14% untreated and 8% treated). FAM46C has an expected incidence of 8% but was rarely mutated in untreated del17p high risk disease with only one of 100 patients harboring both mutations. The significance of this finding needs to be determined but implies a possible overlap in function. Finally we assessed impact on survival of the mutation variants identified in 142 untreated Mayo patients and found STAT3 mutations negatively impacting PFS (p=0.034) and OS (p=0.001). This gene is rarely mutated in MM (2% of the total cohort) thus the sample size was small and this finding needs further validation. Conclusion: We here describe 504 MM patients sequenced using the M3 P gene panel, which identified mutations in >80% of investigated patients, overlaps well with published whole exome sequence data and provides clinically relevant information. New findings were the high frequency of minor clones, the relative lack of overlap of del17 and FAM46C mutation, a higher frequency of DIS3 mutation at diagnosis compared to relapse, the prognostic significance of STAT3 mutation and the frequent presence of CRBN pathway mutation in drug resistant relapsed patients. Disclosures Sonneveld: Janssen-Cilag, Celgene, Onyx, Karyopharm: Honoraria, Research Funding; novartis: Honoraria. Mai:Janssen-Cilag: Other: Travel Grant; Onyx: Other: Travel Grant; Mundipharma: Other: Travel Grant; Celgene: Other: Travel Grant. Goldschmidt:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, 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; Millenium: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Chugai: Honoraria, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Knop:Celgene Corporation: Consultancy. Kull:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Martinez-Lopez:Novartis: Honoraria, Research Funding; Bristol-Meyer Squibb: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Einsele:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen/Onyx: Consultancy, Honoraria, Speakers Bureau. Raab:Novartis: Research Funding. Stewart:Oncospire Inc.: Equity Ownership; Celgene: Consultancy; Novartis: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees.

Abstract Abstract 303 Background: Carfilzomib (CFZ) is a novel proteasome inhibitor that binds its target selectively and irreversibly, resulting in greater and more sustained proteasomal inhibition compared to BTZ (Demo et al, Cancer Res 2007). CFZ overcomes BTZ-resistance in vitro (Kuhn et al, Blood 2007) and in a previous Phase 2 study (PX-171-003), single-agent CFZ achieved durable responses and maintained disease control [e.g. ≥ Stable Disease (SD)] in patients with progressive multiple myeloma (MM) despite treatment with essentially all available agents. PX-171-004 is an ongoing Phase 2 study of CFZ monotherapy in MM patients with relapsed or refractory disease following 1–3 prior therapies. Here we report updated data for the BTZ-treated cohort. Methods: Patients with relapsed or refractory (defined as < 25% response or disease progression during therapy) MM were enrolled and stratified based on prior BTZ exposure (e.g. BTZ-naïve and BTZ-treated). For the BTZ-treated cohort, tolerability and response to prior BTZ [≥ Minor Response (MR)] was not required. CFZ 20 mg/m2 IV was administered on Days 1, 2, 8, 9, 15 and 16 every 28 days, for up to 12 cycles. The primary endpoint was Overall Response Rate (ORR) [≥ Partial Response (PR)] by IMWG criteria. Secondary endpoints included Clinical Benefit Response (CBR = ORR + MR) and safety. Results: Thirty-five BTZ-treated patients were enrolled. Six (17%) patients had previously received BTZ exclusively as a single agent, 15 (43%) received BTZ as part of a chemotherapy combination and 10 (29%) received BTZ as part of a stem cell transplant (SCT) regimen. An additional 4 (11%) received BTZ in a chemotherapy combination as well as part of a separate transplant regimen. Other prior therapies included alkylators (89%), SCT (81%), thalidomide (69%), lenalidomide (37%), and anthracyclines (31%). Six (17%) patients had disease refractory to BTZ and 9 (26%) additional patients had discontinued BTZ due to toxicities. At baseline, 19 (54 %) patients had an ECOG score ≥ 1, 17 (49%) patients had neuropathy of Grade ≥ 1, 9 (26%) patients had impaired renal function (CrCl <60 mL/min) and 9 (26%) had diabetes. The median time since diagnosis was 3.6 years (range 1.2–13.2). To date, the mean number of CFZ doses administered was 29.3 (∼5 four-week cycles; range 4–72 doses, 0.7–12 cycles). Thirty-three patients who initiated therapy were evaluable for response per protocol. The ORR was 18% (6/33), including 1 CR and 5 PRs. An additional 4 (12%) patients had MR (CBR= 30%) and 13 (39%) had SD for ≥ 6 weeks. For evaluable patients who were either refractory or intolerant to their prior BTZ therapy, responses to CFZ included 1 PR and 1 MR and 8 SDs. The most common adverse events (AEs) (≥ 30% patients) were primarily Grades 1/2 and included fatigue (57%), nausea (54%), vomiting (37%), dyspnea (34%), diarrhea (34%), anemia (31%), increased creatinine (31%) and upper respiratory tract infection (31%). Grade 3/4 AEs occurring in ≥ 10% of patients were anemia (14.3%) and neutropenia (11.4%). There were no reports of febrile neutropenia. Dose modifications were rarely required. Peripheral neuropathy (PN) was uncommon (4 patients, 11%); only 1 patient had a Grade 3 event that lasted < 36 hours and did not result in missed doses or dose modification. None of the 9 patients with baseline renal impairment were discontinued for renal AEs. To date, 6 (17%) patients have completed the full 12-cycle protocol at the initial dose and schedule, 6 (17%) remain on study and 1 patient has received > 19 cycles on a recently initiated extended treatment protocol. Conclusions: In a BTZ-exposed population that includes BTZ treatment failures and significant comorbidities (e.g. diabetes, renal insufficiency, etc), the 18% ORR (CBR 30%) is notable for this steroid- and anthracycline-sparing regimen. Single-agent CFZ is well tolerated, even in patients with renal insufficiency, and both myelosuppression and PN are uncommon. These data support the continuing evaluation of CFZ as a safe and effective treatment option in MM. Disclosures: Siegel: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Wang:Proteolix, Inc.: Research Funding. Stewart:Genzyme, Celgene, Millenium, Proteolix: Honoraria; Takeda, Millenium: Research Funding; Takeda-Millenium, Celgene, Novartis, Amgen: Consultancy. Kukreti:Celgene: Honoraria. Jakubowiak:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Centocor Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Exelixis: 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, Speakers Bureau. Jagannath:Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. McDonagh:Proteolix: Research Funding. Belch:Ortho Biotech: Honoraria, Research Funding. Bahlis:Celgene: Honoraria, Speakers Bureau; Ortho Biotech: Honoraria, Speakers Bureau. Le:Proteolix, Inc.: Employment. Kunkel:Proteolix: Consultancy, Employment. Bennett:Proteolix: Employment. Kauffman:Proteolix, Inc.: Employment. Vij:Proteolix, Inc.: Consultancy, Research Funding.

Abstract Abstract 302 Background: Carfilzomib (CFZ) is a proteasome inhibitor with unique target selectivity and an irreversible binding mechanism that results in sustained proteasome inhibition. In preclinical studies, CFZ lacks non-proteasome off-target activities associated with bortezomib (BTZ) (Kapur et al, Blood 2008). This may account for observed differences in tolerability with CFZ (e.g. minimal neuropathy and myelosuppression), permitting consecutive day dosing and treatment over an extended period of time. We previously observed higher response rates in multiple myeloma (MM) patients without prior BTZ exposure (BTZ-naïve) compared to those with relapsed disease following BTZ therapy (BTZ-treated). Here we present updated data on the BTZ-naïve cohort from PX-171-004, an ongoing Phase 2 study of single-agent CFZ in MM patients with relapsed or refractory disease following 1–3 prior therapies. Methods: Patients with relapsed or refractory (e.g, < 25% response or disease progression during last treatment) MM were enrolled and stratified into two cohorts: BTZ-naïve and BTZ-treated. CFZ 20 mg/m2 IV was administered on Days 1, 2, 8, 9, 15 and 16 every 28 days, for up to 12 cycles. The primary endpoint was Overall Response Rate [≥ Partial Response (PR)] per International Uniform Response Criteria for Multiple Myeloma. Secondary endpoints included Clinical Benefit Response [CBR = ORR + Minor Reponse (MR)] and safety. Results: Fifty-seven BTZ-naive patients have been enrolled and 56 subjects have received at least one dose of CFZ. Prior therapies included alkylators (81%), stem cell transplant (SCT) (77%), thalidomide (THAL) (67%), lenalidomide (LEN) (42%), and anthracyclines (23%). Ten (18%) patients had received both LEN and THAL and 18 (32%) patients were refractory to their most recent regimen prior to study entry. At baseline, 30 (53%) patients had an ECOG score ≥ 1, 21 (37%) had neuropathy Grade ≥ 1, 12 (21%) had impaired renal function (CrCl < 60 mL/min) and 10 (18%) had diabetes. The mean time from diagnosis was 4 years (range 0.7–24). To date, the mean number of CFZ doses administered was 29.2 (∼5 four-week cycles; range 2–72 doses, 1–12 cycles). Fifty-one patients initiated therapy and were evaluable for response per protocol. The ORR was 45% (23/51 patients) and included 1 CR, 4 VGPR and 18 PR. An additional 9 (18%) patients had MR and 10 (20%) had stable disease (SD) for ≥ 6 weeks. The most common (>25%) adverse events (AEs) were fatigue (59%), nausea (41%), dyspnea (36%), and anemia (29%), and were primarily ≤ Grade 2. Grade 3/4 AEs occurring in ≥ 5% of patients were thrombocytopenia (9%), fatigue (9%), neutropenia (7%), lymphopenia (7%), anemia (5%), pneumonia (5%) and hyperglycemia (5%). One (1.7%) patient had febrile neutropenia. Dose modifications were rarely required. Peripheral neuropathy (PN) of any grade was infrequent (7 patients, 12%) with a single case of Grade 3 PN (2%) in a pt with a history of THAL-induced PN that lasted 41 days. The CFZ dose was reduced and the event resolved to Grade 1 while on CFZ and prior to study discontinuation. Of the12 patients with impaired renal function at baseline, none required dose modifications due to renal AE. Overall, 5 patients have completed the full 12-cycle protocol and another 5 (9%) have completed ≥ 9 cycles; 17 patients (30%) are continuing on study. Conclusions: The 45% ORR (CBR 63%) is noteworthy for a single-agent regimen in patients with tumor progression despite therapy with novel combinations. CFZ can be safely administered to patients with significant comorbidities (e.g. peripheral neuropathy, leukopenia, renal dysfunction, diabetes) when other anti-myeloma agents may not be well tolerated. Enrollment to PX-171-004 is continuing and, based on the safety profile, subjects are now permitted to dose escalate to 27 mg/m2. Disclosures: Wang: Proteolix: Honoraria, Research Funding. Off Label Use: testing testing. Siegel:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jakubowiak:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Centocor Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Exelixis: 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, Speakers Bureau. Kukreti:Celgene: Honoraria. Bahlis:Celgene: Honoraria, Speakers Bureau; Ortho Biotech: Honoraria, Speakers Bureau. McDonagh:Proteolix: Research Funding. Belch:Ortho Biotech: Honoraria, Research Funding. Le:Proteolix, Inc.: Employment. Bennett:Proteolix: Employment. Kunkel:Proteolix: Consultancy, Employment. Kauffman:Proteolix, Inc.: Employment. Vij:Proteolix, Inc.: Consultancy, Research Funding.

Abstract Introduction: The BCR-ABL1 genomic fusion event in chronic myelogenous and B-lymphoblastic leukemias (CML, ALL) commonly produces the major chimeric transcript variants e13 (or e14)-a2 or e1-a2, which are translated respectively to p210 and p190 bcr-abl1 oncoproteins. However, substantial transcript heterogeneity is present including alternative splice forms in a given leukemia, as well as rare alternative chimeric transcript types. Relatively little is known regarding the molecular response of alternative transcript variants of BCR-ABL1 during tyrosine kinase inhibition (TKI) therapy, in part because of the lack of effective disease burden monitoring methods. We present an approach to detection of the various BCR-ABL1 mRNA types using a multiplex quantitative RT-PCR (QRT-PCR) methodology. This technique enables diagnosis and molecular tracking of unusual BCR-ABL1 variants and can improve our understanding of how these uncommon leukemias behave in response to TKI therapies. Furthermore, the method is more generally applicable for simultaneous QRT-PCR detection and measurement of different mRNA species. Methods: Patient samples for diagnostic evaluation were obtained and total RNA extraction was performed using the Qiagen RNeasy Mini Kit (Qiagen USA, Valencia, CA). Reverse transcription was done using Multiscribe Reverse Transcriptase (Life Technologies, Grand Island, NY). Eleven fluorescent primer and probe mixes were designed (e1a2-FAM, e6a2-Cyc 5, e13a2-FAM, e14a2-FAM, e19a2-Cyc 5, e1a3-FAM, e12a3-Cyc 5, e13a3-FAM, e14a3-FAM, e19a3-Cyc 5, and Gusb reference control-HEX). 10 uL reactions were performed (95 C X 10 min, 45 cycles of 95 C X 10 sec and 60 C X 30 sec) using four multiplex wells per sample. Double strand oligonucleotides (oligos) for each target type were synthesized (IDT, Coralville IA) and diluted in a range of 106, 105, 104, 103, 100, 10, 1 and 0.1 copies/uL. Results of the new multiplex QRT-PCR assay were compared against our standard method of qualitative multiplex RT-PCR and fluorescent probe hybridization. Results: Results for the target BCR-ABL1 oligo controls are summarized in the table. The data show a wide dynamic range of detection with reproducible copy number detection at very low level. All PCR targets had excellent correlation coefficients (R2) and good to excellent PCR efficiency. Specificity was excellent, except for some cross-reactivity of A3 templates. This minor interference did not detract from assay performance or interpretation. Thirty-two patient samples were evaluated using the multiplex QRT-PCR assay and the current lab method. For 13 known BCR-ABL1 negative and 19 positive patient samples, concordance/accuracy and specificity were 100%. Furthermore, relative quantification of transcript abundance was obtained by the multiplex QRT-PCR approach, enabling distinction between diagnostic and post-treatment mRNA levels. Alternative splicing events producing additional transcripts (e1-a2) were resolved in the same specimen and always quantified well below the primary transcript level. Table 1.Transcript TypeDynamic Range(log)Sensitivity(copies/uL)Specificity(%)R2Efficiencye1-a2 (p190)6101000.971.74e6-a2 (p195)711000.951.76e13-a2/ e14-a2 (p210)61010011.99e19-a2 (p230)610E19A3 also detected0.991.89e1-a3 (p190)6101000.981.90e13-a3/ e14-a3 (p210)610E12A3 also detected11.99e12-a3410001000.991.78e19-a3 (p230)61010011.95 Conclusions: We demonstrate a powerful and relatively simple method for concurrent detection and quantitative measurement of multiple common and unusual alternative BCR-ABL1 mRNA transcripts. The results of this study provide a basis for more detailed monitoring of molecular disease levels during TKI therapy in leukemic patients with rare BCR-ABL1 types, and in turn, potentially enhance the ability to more optimally individualize clinical management for these patients. The platform is flexible and novel BCR-ABL1 transcript types can also be incorporated relatively easily. A similar strategy is applicable to the detection of chimeric mRNA species in other types of leukemias. Our approach can also be used to evaluate targeted RNA expression profiles of other prognostic or theranostic tumor markers in individual patients. Disclosures No relevant conflicts of interest to declare.

Renal dysfunction is common in liver transplantation (LT) candidates, but differentiating between reversible and irreversible renal injury can be difficult. Kidney biopsy might be helpful in differentiating reversible from irreversible renal injury, but it is associated with significant complications. We aimed to identify pre‐LT predictors of potentially reversible renal injury using histological information obtained on pre‐LT renal biopsy. Data on 128 LT candidates who underwent pre‐LT kidney biopsy were retrospectively collected and correlated with renal histological findings. Indications for kidney biopsy were iothalamate glomerular filtration rate (iGFR) ≤40 mL/minute, proteinuria >500 mg/day, and/or hematuria. According to the biopsy diagnosis, patients were grouped into the following categories: normal (n = 13); acute tubular necrosis (ATN; n = 25); membranoproliferative glomerulonephritis (n = 19); minimal histological changes (n = 24); and advanced interstitial fibrosis (IF) and glomerulosclerosis (GS) (n = 47). Compared with patients having advanced IF/GS, patients with normal biopsies and those with ATN had lower systolic blood pressure (SBP) and diastolic blood pressure (DBP) and higher international normalized ratio and total bilirubin levels (<0.05 for all). Both SBP and DBP directly correlated with the degree of IF and GS (R = 0.3, P ≤ 0.02 for all). SBP ≤90 mm Hg was 100% sensitive and 98% specific in correlating with normal biopsies or ATN, whereas SBP ≥140 mm Hg was 22% sensitive and 90% specific in correlating with advanced IF/GS. Model for End‐Stage Liver Disease score, serum creatinine, iGFR, urinary sodium excretion, and renal size did not correlate with biopsy diagnosis or degree of IF or GS. In conclusion, SBP at the time of LT evaluation correlates with renal histology, and it should be included along with other clinical and laboratory markers in the decision‐making process to list patients with renal dysfunction for LT alone versus simultaneous liver‐kidney transplantation.