Reu, Frederic J.

Pediatric sarcomas are a heterogeneous group of rare mesodermal malignancies. These cancers, which affect children from infancy through adolescence and young adulthood, are in general challenging to treat with currently available therapies. Biologically, many are characterized by quiet genomes, fusion oncoproteins, immune “cold” microenvironments, and vast epigenetic deregulation that contributes to diverse and complex mechanistic drivers. Multifaceted advancements in research strategies, including high-throughput screening, new model systems, surfaceome profiling, and study of oncogenic fusion condensates have led to new opportunities for understanding the biology of pediatric sarcomas. To continue to make progress for these difficult to treat cancers, it will be critical to continue to improve access to bioinformatic data, approach patient care using innovative clinical trial frameworks, and foster interdisciplinary partnerships among medicinal chemists, scientists, clinicians, advocates, and industry partners.

TPS11580 Background: Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the gastrointestinal tract. KIT and platelet-derived growth factor receptor α ( PDGFRA ) mutations remain the key oncogenic drivers in the majority of patients with advanced GIST, with acquired secondary drug-resistant mutations contributing to the heterogeneity and complexity of the disease. The diversity of these resistance mutations allows escape from standard-of-care tyrosine kinase inhibitor (TKI) therapy, creating an unmet need for novel therapies that inhibit all clinically relevant GIST-driving mutations. DCC-3009 is an investigational, highly potent, and selective switch-control KIT and PDGFRA inhibitor designed to act against known clinically relevant primary and secondary GIST-driving mutations while limiting off-target effects. Preclinical data showed that DCC-3009 has strong antitumor effects in xenograft models driven by resistant KIT mutations, optimized solubility and oral bioavailability, and low risk of cytochrome P450 inhibition. Here, we describe an ongoing phase 1/2 study evaluating DCC-3009 as a monotherapy in patients with advanced GIST. Methods: This study is a multicohort, open-label, phase 1/2 trial evaluating the safety, tolerability, and efficacy of DCC-3009 in patients with advanced GIST (NCT06630234). This trial uses a modular approach, with each module defined according to the therapy (DCC-3009 alone or in combination with other anticancer agents) and divided into 2 parts (dose escalation and dose expansion). For inclusion in the DCC-3009 monotherapy dose escalation, adult patients (≥18 years) must have histologically or cytologically confirmed advanced GIST with documented KIT or PDGFRA mutation and progression on or intolerance to at least 1 approved TKI regimen in the advanced setting (imatinib if KIT -mutant). Patients must have at least 1 measurable lesion per modified Response Evaluation Criteria in Solid Tumors version 1.1 (mRECIST v1.1) and an Eastern Cooperative Oncology Group Performance Status of 0 or 1 at screening. Exclusion criteria include receiving systemic anticancer therapy (encompassing investigational agents) within 14 days or less than 5 half-lives, radiotherapy within 14 days prior to first dose of study drug, prior or concurrent malignancy requiring treatment or expected to need treatment for active cancer, known allergy or hypersensitivity to the study drug components or any of its excipients, and impaired oral absorption or malabsorption syndrome. Enrolled patients across monotherapy dose escalation will receive DCC-3009 orally in 28-day cycles. The primary outcome measures for monotherapy dose escalation include safety assessment. Secondary outcome measures include objective response rate, duration of response, and progression-free survival by mRECIST v1.1, as well as overall survival and pharmacokinetics. Clinical trial information: NCT06630234 .

8035 Background: Patients (pts) with relapsed and refractory multiple myeloma (RR MM) who are refractory or intolerant to both bortezomib (BTZ) and immunomodulators (IMiDs; thalidomide [Thal] or lenalidomide [Len]) (ie, “double-refractory/intolerant”), have few therapeutic options and a poor prognosis. Carfilzomib (CFZ), a next generation proteasome inhibitor (PI), has shown durable single-agent activity in clinical studies including 003-A1, an open-label, single-arm phase 2b trial in RR MM. The present analysis describes clinical activity in pts from 003-A1 with double-refractory/intolerant disease and in other groups of clinical interest including pts with disease refractory to all 5 approved classes of anti-MM tx (alkylators, anthracyclines, corticosteroids, IMiDs, and PIs) in clinical use (“refractory to all approved tx”). Methods: Pts from 003-A1 with double-refractory/intolerant disease were analyzed, as were pts with disease refractory to all approved tx. CFZ was given on days 1, 2, 8, 9, 15, 16 of 28-day cycles (C), (20 mg/m2 in C1; 27 mg/m2 in C2–12). Primary endpoint was overall response rate (ORR). Secondary endpoints included duration of response (DOR), overall survival, and safety. Results: The study ORR was 22.9% with median DOR of 7.8 mo (N=266). 228 pts (86%) with double-refractory/intolerant disease had ORRs of 20.6% and a median DOR of 7.4 mo. Conclusions: Single-agent CFZ demonstrated clinically meaningful, durable responses in pts with double-refractory/intolerant MM or disease refractory to all 5 approved classes of tx. The ORRs across groups of clinical interest were generally consistent with results for the entire study population. These results are notable for a next-generation PI and demonstrate the activity of single-agent CFZ in pts with advanced stage MM. [Table: see text]

Abstract Background: SWOG S0777, a randomized phase III trial, compared bortezomib, lenalidomide and dexamethasone (VRd) with lenalidomide and dexamethasone (Rd). The primary end point was progression-free survival (PFS) using a pre-specified one-sided stratified log rank test at a significance level of 0.02. The stratification factors were International Staging System (ISS) stage (I, II or III) and intent to transplant (yes or no), among a total of 6 strata. Overall response rate (ORR), overall survival (OS) and safety were secondary end points. Results of the primary analysis of this trial were published in Lancet (2016, Volume 389, Issue 10068, 519 - 527). Methods: This updated analysis includes 460 patients evaluable for survival endpoints: 225 eligible and analyzable patients were randomized to Rd and 235 patients to VRd. Rd patients received lenalidomide 25 mg/day on days 1-21 and dexamethasone 40 mg/day on days 1, 8, 15 and 22 of a 28-day cycle. VRd patients received lenalidomide 25 mg/day on days 1-14 and dexamethasone 20/mg/day on days 1, 2, 4, 5, 8, 9, 11 and 12 plus bortezomib 1.3 mg/m2 IV push on days 1, 4, 8 and 11 of a 21-day cycle. All patients received aspirin 325 mg/day and VRd patients received VZV prophylaxis per institutional standard. The 6-month induction was six 28-day cycles of Rd and eight 21-day cycles of VRd followed by Rd maintenance for all patients until progression, unacceptable toxicity or withdrawal of consent. Results: Between 2008 and 2012, 525 patients from 48 institutions were randomized. Patient data have been rigorously updated for this analysis based upon a May 15, 2018 datalock. The median follow up is now 84 months (7 years). The median PFS is 41 months for VRd and 29 months for Rd: stratified hazard ratio (96% Wald Confidence Interval) was 0.742 (0.594, 0.928) and one-sided stratified log-rank P-value 0.003 (see Figure 1). The median OS for VRd is still not reached with median OS for Rd being 69 months: stratified hazard ratio (96% Wald Confidence Interval) was 0.709 (0.543, 0.926) and stratified two-sided P-value was 0.0114 (see Figure 2). The impact of age was assessed in several ways including using 3 cutoffs (<65 years; 65-75 years; >75 years) and multivariate cox proportional hazards regression analyses adjusted for age. As in prior analyses, both PFS and OS were improved with VRd versus Rd adjusting for age (P-values: 0.013 [PFS]; 0.033 [OS])). Depth of response was assessed incorporating new serial data and additional bone marrow results. The CR plus VGPR was 74.9% for VRd versus CR plus VGPR of 53.7% for Rd (P-value 0.006 for response differences using a stratified Cochran-Mantel- Haenszel analysis). The median duration of lenalidomide plus dexamethasone maintenance was 17.4 months. The number of second cancers was 19/235 (8%) with VRd and 16/225 (7%) with Rd. Conclusion: The addition of bortezomib to lenalidomide dexamethasone for induction therapy in previously untreated myeloma results in a statistically significant and clinically meaningful improvement in PFS as well as better OS with follow up of 7 years. VRd had an acceptable safety and tolerability profile and continues to represent an appropriate standard of care irrespective of age. Disclosures Durie: Takeda: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Johnson & Johnson: Consultancy. Abidi:Millenium Takeda: Research Funding. Epstein:University of Arkansas for Medical Sciences: Employment. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Reu:Bristol Myers Squibb: Employment; Millenium Takeda: Consultancy; Novartis: Consultancy, Research Funding; Celgene: Research Funding. Orlowski:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millenium Pharmaceuticals: Consultancy, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioTheryX, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Janssen Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Poseida: Research Funding; Bristol Myers Squibb: Consultancy. Barlogie:Dana Farber Cancer Institute: Other: travel stipend; Celgene: Consultancy, Research Funding; International Workshop on Waldenström's Macroglobulinemia: Other: travel stipend; Multiple Myeloma Research Foundation: Other: travel stipend; European School of Haematology- International Conference on Multiple Myeloma: Other: travel stipend; Myeloma Health, LLC: Patents & Royalties: : Co-inventor of patents and patent applications related to use of GEP in cancer medicine licensed to Myeloma Health, LLC; ComtecMed- World Congress on Controversies in Hematology: Other: travel stipend; Millenium: Consultancy, Research Funding.

Abstract Abstract 813FN2 Introduction: Carfilzomib is a next-generation proteasome inhibitor that selectively and irreversibly binds to its target, resulting in sustained inhibition absent of off-target effects relative to bortezomib. Carfilzomib has demonstrated durable anti-tumor activity and an acceptable tolerability profile in patients with multiple myeloma (MM). Final results will be presented for the bortezomib-naïve group of PX-171-004, a phase 2 study of single-agent carfilzomib in patients with relapsed and/or refractory MM. Herein we report the most recent data analysis available at time of abstract submission. Updated final results for the bortezomib-naïve group of PX-171-004, including OS data, will be presented at the meeting. Methods: Patients received either 20 mg/m2 for all treatment cycles (Cohort 1) or a stepped-up dose-escalating regimen of 20 mg/m2 for Cycle 1 and 27 mg/m2 for all treatment cycles thereafter (Cohort 2). Carfilzomib was administered over 2–10 minutes on Days 1, 2, 8, 9, 15, and 16 of every 28-day cycle, for a maximum of 12 cycles. The primary endpoint was the best overall response rate (ORR; [CR + VGPR + PR]) determined according to the IMWG Uniform Response Criteria. Secondary endpoints included the clinical benefit response rate (CBR; [ORR + MR per EBMT criteria]), progression-free survival (PFS), time to progression (TTP), duration of response (DOR), OS, and safety. The result of efficacy analysis from disease assessment by the Independent Review Committee is presented in this abstract. Results: 127 of 129 enrolled bortezomib-naïve patients were evaluable for response. Prior therapies included thalidomide (59%), lenalidomide (59%), alkylating agents (81%), and stem cell transplant (73%). Patients had received a median of 2 prior regimens (1 in 54 patients, 2 in 40 patients, 3 in 28 patients, and ≥4 in 7 patients). 84 patients (65%) were disease refractory to their most recent therapy, defined as ≤25% response or progression during or within 60 days after completion of therapy. The median duration of carfilzomib treatment is 7 cycles (range 1−12) in Cohort 1; 8 patients were receiving drug as of February 2011 in Cohort 2 with a median treatment of 6.5 cycles (range 1−13) at that time. Best ORR was 42% in Cohort 1 and 52% in Cohort 2. Median TTP was 8.3 months and median DOR was 13.1 months in Cohort 1. The median TTP and DOR for Cohort 2 have not been reached at the time of this interim analysis; the lower bound of the 95% CI for the median TTP was 10.2 months, and 84% were estimated to have DOR ≥1 year at the time of data cutoff. Higher response rates for Cohort 2 compared with Cohort 1 do not appear to be associated with higher toxicities. Patients with unfavorable cytogenetic characteristics (≥1 abnormality) per mSMART criteria had an ORR of 37% and CBR of 42% compared with 50% and 65%, respectively, for patients with no abnormality. The most common treatment-emergent adverse events (AEs), regardless of relationship to carfilzomib in Cohorts 1 and 2, respectively, were fatigue (71%, 54%), nausea (54%, 43%), anemia (46%, 37%), and dyspnea (49%, 33%). These were primarily ≤Grade 2 in severity. The most common Grade 3/4 AEs were anemia (15%), lymphopenia (15%), thrombocytopenia (13%), pneumonia (12%) and neutropenia (12%). Treatment-emergent peripheral neuropathy (PN) was mild and infrequent (16%). Only 1 case of Grade 3 PN (0.8%) was observed. Overall, 38 patients (30%) completed 12 cycles and 22 of these patients continued to receive carfilzomib therapy under a safety extension protocol (PX-171-010), an ongoing, multicenter, open-label phase 2 study to monitor long-term use of single-agent carfilzomib. Conclusions: To date we have seen robust and durable single-agent activity for carfilzomib in bortezomib-naïve patients with relapsed and often refractory MM with an ORR of 42−52% and a CBR of 59−63% from 2 separate dose cohorts in a population wherein 92% received an immunomodulatry drug and 73% had undergone an autologous stem cell transplant previously. These data are suggestive of a dose–response relationship and are being further evaluated in the exploratory phase 1b/2 study PX-171-007. Carfilzomib was associated with minimal PN and excellent long-term tolerability, with nearly one-third of patients completing 12 cycles and 22 of these continuing treatment beyond 1 year in the extension protocol PX-171-010. Disclosures: Vij: Onyx Pharmaceuticals: Consultancy, Research Funding; Celgene: Research Funding, Speakers Bureau; Millennium: Speakers Bureau. Kaufman:Millenium: Consultancy; Onyx Pharmaceuticals: Consultancy; Novartis: Consultancy; Keryx: Consultancy; Merck: Research Funding; Celgene: Research Funding. Jakubowiak:Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx Pharmaceuticals: Consultancy, 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; Exelixis: Consultancy, Honoraria. Wang:Onyx Pharmaceuticals: Research Funding. 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. Kukreti:Celgene: Honoraria. Alsina:Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Allergan: Research Funding. Belch:Celgene: Research Funding; Onyx: Research Funding. Gabrail:Millennium: Research Funding. Matous:Celgene: Speakers Bureau; Millenium: Speakers Bureau; Cephalon: Speakers Bureau. Vesole:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Speakers Bureau. Orlowski:Onyx Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kunkel:VLST biothech: Consultancy; Threshold: Consultancy; Onyx Pharmaceuticals: Consultancy. Wong:Onyx Pharmaceuticals: Employment, Equity Ownership. Stewart:Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding.

Abstract Abstract 1875 Introduction: Carfilzomib (CFZ) is a next-generation proteasome inhibitor that has demonstrated durable single-agent antitumor activity in patients (pts) with relapsed and/or refractory multiple myeloma (R/R MM). Previously we have shown that unfavorable cytogenetic features, defined as presence of any of del 13 or hypodiploidy by metaphase cytogenetic analysis and/or del 17p13, t(4;14), t (14;16) by fluorescence in situ hybridization (FISH), did not appreciably affect overall (≥PR) and clinical benefit (≥MR) response rates (ORR and CBR) in PX-171-003-A1, a large phase 2 study of single-agent CFZ in pts with R/R MM (Jakubowiak et al. Ann Oncol. 2011;22(S4): Abstract 117). The objectives of the present analysis were to evaluate the impact of specific cytogenetic abnormalities on efficacy and treatment outcomes. Methods: Pts with unfavorable cytogenetic abnormalities (defined above) were eligible for inclusion in this analysis. All pts received CFZ at 20 mg/m2 IV on days 1, 2, 8, 9, 15, and 16 of 28-day cycles (C) and were dose-escalated to 27 mg/m2 at C2. Pts were treated for up to 12 C. Responses were assessed by International Myeloma Working Group criteria, with minimal response (MR) by European Group for Blood and Marrow Transplantation criteria. Assessments were confirmed by an Independent Review Committee (IRC). Results: A total of 234 pts were included in this analysis. Metaphase cytogenetic data were available for 203 pts (87%), and FISH data were available for 210 pts (90%); 178 pts had both (76%). Seventy-five of 234 pts (32%) had ≥1 abnormality and represented the unfavorable group in this analysis. Of these, 49 (65%) had abnormalities detected via metaphase cytogenetics, 47 (63%) by FISH, and 21 (28%) by both methods. Characteristics of pts in the unfavorable and normal/favorable groups were comparable overall, with the exception of a higher proportion of pts with International Staging System stage II/III in the unfavorable group (83% vs 64%). Response rates per the IRC, presented previously, included an ORR of 30% for pts with ≥1 abnormality compared with 23% for pts with none. The corresponding CBRs were 34% and 40%, respectively. Duration of response (DOR) and time to progression (TTP) values were 7 months (mo) (95% CI 4–9) and 4 mo (95% CI 3–6), respectively, for pts with ≥1 abnormality and 8 mo (95% CI 6–12) and 5 mo (95% CI 3–6), respectively, for pts with none. The ORRs, CBRs, and disease control rates (DCRs) according to specific cytogenetic abnormalities are presented below. Response rates were largely unaffected by the presence of specific unfavorable cytogenetic abnormalities, with the possible exceptions of trends toward a higher response rate for t(4;14) and a lower rate for t(14;16), although the latter abnormality was only noted in 3 pts. The trend for better response rates in pts with t(4;14) corresponded to a DOR of 5.6 mo (95% CI 2.8–10.2). In contrast, the DOR appeared shorter for the subgroup of pts with del 17p13 (4.6 mo, 95% CI: 3.7–Not reached). Time-to-event endpoints including TTP are being analyzed for these and the other subpopulations, and data on these will be presented, along with overall survival stratified by cytogenetic abnormality. Conclusions: CFZ demonstrated comparable response rates in pts with relapsed/refractory MM in both the absence and presence of unfavorable cytogenetic abnormalities in the 003-A1 study. Similarly, in the phase 2 PX-171-004 study, no significant difference in response rates between unfavorable and normal/favorable groups has been observed in a population of less heavily-pretreated pts with relapsed or R/R MM. Taken together, the results of these and other analyses to date suggest that responses to single-agent CFZ can be achieved in heavily pretreated pts and that overall, these responses appear not to be significantly influenced by poor prognostic cytogenetic features. Further analyses from studies with CFZ in newly diagnosed MM and in less heavily-pretreated pts are needed to determine whether a trend toward lower response rates and DOR for pts with del 17p13 is consistently observed in other populations. Disclosures: Jakubowiak: Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx Pharmaceuticals: Consultancy, 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; Exelixis: Consultancy, Honoraria. Off Label Use: Use of the investigational agent carfilzomib, proteasome inhibitor, in the treatment of relapsed and/or refractory multiple myeloma. Siegel: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. Singhal:Celgene: Speakers Bureau; Millennium: Speakers Bureau; Onyx Pharmaceuticals: Research Funding. Martin:Celgene: Honoraria; Onyx Pharmaceuticals: Consultancy. Lonial:Onyx: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Millennium Pharmaceuticals, Inc.: Consultancy; Merck: Consultancy. Kukreti:Celgene: Honoraria. Bahlis:Celgene: Honoraria, Speakers Bureau. Alsina:Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Allergan: Research Funding. Kunkel:Onyx Pharmaceuticals: Consultancy; Threshold: Consultancy; VLST biothech: Consultancy. Wong:Onyx Pharmaceuticals: Employment, Equity Ownership. Orlowski:Onyx Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Stewart:Celgene Corporation: Consultancy, Research Funding; Millenium: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. 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. Wang:Onyx Pharmaceuticals: Research Funding.

Abstract Abstract 985 Introduction: CFZ is a novel and highly selective epoxyketone proteasome inhibitor currently in clinical development for the treatment of multiple myeloma (MM). Ph 1 and 2 studies with CFZ have demonstrated durable single-agent antitumor activity in pts with relapsed or refractory (R/R) MM. The present study, PX-171-003-A1, was an open-label, single-arm Ph 2b trial and enrolled patients with multiply relapsed MM whose disease was refractory (defined as <25% response on, or progression during or <60 days after completion of, therapy) to their last treatment regimen. Patients must have received ≥2 prior therapies including: 1) bortezomib (BTZ) and either thalidomide (THAL) or lenalidomide (LEN), and 2) an alkylating agent. Materials and Methods: Pts received CFZ at 20 mg/m2 on a QDx2 schedule (Days 1, 2, 8, 9, 15, and 16 every 28 days) in cycle (C) 1 and were dose escalated to 27 mg/m2 on the same schedule thereafter for up to 12 C. Pts completing 12 C were eligible to enter an extension study (PX-171-010). The primary endpoint was overall response rate (ORR) (≥ partial response [PR]). Secondary endpoints included: clinical benefit response (CBR) (ORR + Minimal response [MR]), duration of response for ≥PR (DOR), overall survival (OS), time to progression (TTP), progression free survival (PFS), and safety. Responses and progression were determined according to the International Myeloma Working Group (IMWG) criteria and were assessed and confirmed by an Independent Response Committee (IRC). Results: 266 pts were enrolled with a median duration of MM of 5.4 years including 83% whose disease had progressed on or within 60 d of last therapy and 17% whose disease had achieved <25 % response to the regimen immediately preceding study entry. Of the 266 pts enrolled pts, 257 were evaluable for response; 9 patients were considered not evaluable based on missing baseline or lacking at least one post-baseline M-protein. An ORR (≥PR) of 24% with a median DOR of 7.4 mo (range 6.2–10.3) was determined. Responses are detailed in the table. The CBR (ORR + MR) was 36%. Median DOR of pts with MRs was 6.3 months, indicating that long-term MRs were observed. An additional 32% (83 pts) achieved SD for at least 6 wks. To date, 79 pts (30%) completed ≥6 C and >11% of pts have completed all 12 C of protocol specified therapy and most have entered the extension protocol; 15 pts remain on study (all >10 C). OS and TTP data for the overall population will also be reported. The enrolled pts in this study were heavily pretreated having received a median of 5 prior lines of therapy (range 1–20, median of 13 anti-myeloma agents). 85% of pts had received at least 2 and 37% had received at least 3 drugs in the regimen just prior to entering the study. Prior anti-myeloma agents included 99.6% (265/266 pts) BTZ (median 2 prior regimens containing BTZ), 99.6% either THAL (74%) or LEN (94%), 98% corticosteroids, 91% alkylating agents, and 74% stem cell transplant; 65% of pts were refractory to BTZ at any point in time prior to study entry. The most common treatment-emergent adverse events ≥ Grade (G) 3 regardless of relationship to study drug were predominantly hematologic and included thrombocytopenia (22%), anemia (20%), lymphopenia (10%), pneumonia (8%), neutropenia (8%), fatigue (7%), hyponatremia (5%), and hypercalcemia (5%). Although 206 pts (77%) had G1/2 peripheral neuropathy (PN) at baseline, new onset PN was infrequent and G ≥3 PN occurred in <1%. Interestingly, in this subset of patients, efficacy response was nearly identical to that seen in the full study population with an ORR (≥PR) of 24%. Conclusions: Single-agent CFZ achieved durable responses in pts with R/R MM whose disease had relapsed after all available therapies including BTZ and immunomodulatory agents. The CBR and median DOR achieved with this steroid-sparing regimen establish that CFZ has the potential to offer substantial clinical benefit to patients with relapsed or refractory disease. CFZ was well-tolerated and side effects were clinically manageable with no new or unexpected toxicities observed. Importantly, exacerbation of pre-existing PN was uncommon. Cumulative side effects were not observed, allowing prolonged single-agent dosing for chronic disease control. Disclosures: Siegel: Millenium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Martin:Celgene: Honoraria; Onyx: Consultancy. Wang:Celgene: Research Funding; Onyx: Research Funding; Millenium: Research Funding; Novartis: Research Funding. Vij:Onyx: Honoraria. 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. 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. Alsina:Millenium: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy. Zonder:Millenium: Consultancy, Honoraria, Research Funding; Cephalon: Research Funding; Celgene: Honoraria. Wong:Onyx Pharmaceuticals: Employment. Vallone:Onyx Pharmaceuticals: Employment. Chang:Onyx Pharmaceuticals: Employment. Kauffman:Onyx Pharmaceuticals: Employment. Stewart:Millennium: Consultancy; Celgene: Honoraria. Singhal:Celgene: Speakers Bureau; Takeda/Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx : Research Funding.

Abstract Background: Lenalidomide with dexamethasone (Rd) is a standard of care for patients with previously untreated multiple myeloma. SWOG S0777, a randomized phase III trial, has compared Rd with bortezomib, lenalidomide and dexamethasone (VRd). The primary end point is progression-free survival (PFS) using a pre-specified one-sided stratified log rank test at a significance level of 0.02. The stratification factors are International Staging System (ISS) stage (I, II or III) and intent to transplant (yes or no), a total of 6 strata. Overall response rate (ORR), overall survival (OS) and safety are secondary end points. Methods: This analysis includes 474 patients evaluable for survival endpoints: 232 patients were randomized to Rd and 242 patients to VRd. Rd patients received lenalidomide 25 mg/day on days 1-21 and dexamethasone 40 mg/day on days 1, 8, 15 and 22 of a 28-day cycle. VRd patients received lenalidomide 25 mg/day on days 1-14 and dexamethasone 20/mg/day on days 1, 2, 4, 5, 8, 9, 11 and 12 plus bortezomib 1.3 mg/m2 IV push on days 1, 4, 8 and 11 of a 21-day cycle. All patients received aspirin 325 mg/day and VRd patients received HSV prophylaxis per institutional standard. Induction was six 28-day cycles of Rd and eight 21-day cycles of VRd followed by Rd maintenance for all patients until progression, unacceptable toxicity or withdrawal of consent. Initial analyses utilized the pre-specified one-sided stratified log rank test. Results: Data are presented for VRd followed by Rd throughout. Between 2008 and 2012, 525 patients from 48 institutions were randomized. Fifty-one patients, 29 randomized to Rd and 22 randomized to RVd, were ineligible for the following reasons: missing, insufficient or early or late baseline labs (40); not meeting requirements of measurable disease (6); inadequate marrow function (1); inadequate creatinine clearance (1); prior malignancy (1); prior therapy (1); and more than 2 weeks of prior steroid therapy (1). The pre-specified significance level of 0.02 was reached in the log rank testing. The stratified hazard ratio (HR) was 0.742 (96% Wald confidence interval: 0.579, 0.951), and the one-sided stratified log rank p-value for PFS (VRd vs. Rd) was 0.0066. The OS was improved for VRd vs. Rd with HR = 0.666; two-sided log-rank p-value = 0.0114. The PFS and OS survival charts are displayed below. Median PFS was 43 months (VRd) versus 31 months (Rd). Median OS was not reached (VRd) versus 63 months (Rd). Patient characteristics were well-matched between VRd and Rd with the exception of fewer women (37% vs. 47%: P = 0.033) and fewer older patients (≥ 65 years 38% vs. 48%: P = 0.042) receiving VRd. With univariate Cox regression analysis correlates of better PFS/OS were: use of VRd (HR 0.72/0.65; P = 0.006); hemogoblin ≥10 g/dl (HR 1.17/1.43; P = 0.2/0.026) and lower ISS disease stage (HR 1.35/1.98; P = 0.014/< 0.001). The ORR for VRd was 71.07% versus 63.79% for Rd. The adverse events by CTC category and toxicity category were fairly well balanced. The most common hematologic adverse events (≥ Grade 3 and at least possibly attributable to therapy) were low hemoglobin (RVd=13%; Rd=16%), leukopenia (RVd=14%; Rd=16%), lymphopenia (RVd=23%; Rd=18%), neutropenia (RVd=19%; Rd=21%), and thrombocytopenia (RVd=18%; Rd=14%). The most common non-hematologic adverse events (≥ Grade 3 and at least possibly attributable to therapy) were: fatigue (RVd=16%; Rd=14%), sensory neuropathy (RVd=23%; Rd=3%), hyperglycemia (RVd=7%; Rd=11%), thrombosis/embolism (RVd=8%; Rd=9%), hypokalemia (RVd=9%; Rd=6%), muscle weakness (RVd=7%; Rd=4%), diarrhea (RVd=8%; Rd=2%), and dehydration (RVd=8%; Rd=2%). As expected ≥ Grade 3 neuropathy was more frequent with VRd (24% vs. 5%: P < 0.0001). Sixteen patients experienced a second primary malignancy, 7 (3%) on VRd and 9 (4%) on Rd. Conclusion: The addition of bortezomib to lenalidomide dexamethasone for induction therapy in previously untreated myeloma results in a statistically significant and clinically meaningful improvement in PFS as well as better OS. VRd had an acceptable safety and tolerability profile despite increased neurotoxicity and represents a potential new standard of care. Support: NIH/NCI/NCTN grants CA180888, CA180819, CA180821, CA180820; and in part by Millennium Pharmaceuticals, Inc., The Takeda Oncology Company, for provision of study drug. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Durie: Johnson & Johnson: Consultancy; Takeda: Consultancy; Onyx: Consultancy; Celgene: Consultancy. Abidi:Millennium: Research Funding. Epstein:University of Arkansas for Medical Sciences: Employment. Reu:Takeda/Millennium: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Orlowski:BioTheryX, Inc.: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Spectrum Pharmaceuticals: Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Millennium Pharmaceuticals: Consultancy, Research Funding; Acetylon: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Forma Therapeutics: Consultancy; Array BioPharma: Consultancy, Research Funding. Barlogie:Dana Farber Cancer Institute: Other: Travel Stipend; International Workshop on Waldenström's Macroglobulinemia: Other: Travel Stipend; ComtecMed- World Congress on Controversies in Hematology: Other: Travel Stipend; European School of Haematology- International Conference on Multiple Myeloma: Other: Travel Stipend; Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Myeloma Health, LLC: Patents & Royalties: Co-inventor of patents and patent applications related to use of GEP in cancer medicine licensed to Myeloma Health, LLC; Multiple Myeloma Research Foundation: Other: Travel Stipend.

Abstract Abstract 3031 Background: Treatment-induced peripheral neuropathy (TIPN) can be a debilitating side-effect as well as a therapy-limiting complication in multiple myeloma (MM). Thalidomide (THAL) and bortezomib (BTZ) are two therapies frequently associated with TIPN in MM. Carfilzomib (CFZ) is a novel and highly selective epoxyketone proteasome inhibitor that differs from BTZ both structurally and mechanistically. CFZ overcomes BTZ-resistance in vitro, lacks the off-target activities of BTZ in preclinical studies, and does not cause neurotoxicity in long-term (6–9 month) chronic animal toxicology studies (Kirk et al. Blood, 2008). Single-agent CFZ produces durable responses in relapsed or refractory (R/R) MM without dose-limiting PN. Here we report on the clinical experience with single-agent CFZ in the Ph 2b PX-171-003-A1 trial in patients (pts) with R/R MM and Grade (G) 1/2 PN at study entry. Methods: Pts received CFZ at 20 mg/m2 IV, on Days 1, 2, 8, 9, 15, and 16 in a 28-day cycle (C) for the first C followed by 27 mg/m2 thereafter for up to 12 C. Pts completing 12 C were eligible to enter an extension study. Responses and progression were determined according to the International Myeloma Working Group (IMWG) criteria and were assessed by an Independent Review Committee (IRC). PN data were collected for all pts on study and included neuropathy history, neurological physical exam and PN-related quality of life data (FACT-GOG/NTx v 4.0 scores) collected at screening. Prospective neurological exams and subjective reporting of PN occurred every 2 cycles until study discontinuation to proactively assess for PN. Adverse event (AE) data were also collected, with AEs reported as ‘neuropathy peripheral', ‘neuropathic pain', ‘neuropathy', and ‘peripheral sensory neuropathy' included as PN. AE reports of ‘paraesthesias' and ‘dysesthesias' were counted separately. Results: Of the 266 pts with R/R MM in PX-171-003-A1, 237 (89%) had a history of PN which was attributable to prior anti-myeloma therapy, including THAL (108 pts/41%), BTZ (134 pts/50%), or both BTZ and THAL (17 pts/6.4%). 206 of the 266 (77%) had G1/2 PN at baseline and a median disease duration of 5.9 years. This subset with active PN at baseline had received a median of 5 prior lines of therapy (range 1–20), with a median 13 anti-myeloma agents, and a median of 2 prior BTZ- and 1 prior THAL- containing regimens. Prior therapies included 100% BTZ, and 100% either THAL (77%) or prior lenalidomide (95%). Responses in the subset of pts with baseline PN were nearly identical to those seen in the full study population with an overall response rate (ORR; ≥ partial response [PR]) of 24% and a clinical benefit response rate (CBR; ≥ minimal response [MR]) of 36%. The median duration of response (≥PR) was 7.4 mo (95% CI 5.6–not reached) and median duration of MR was 6.3 months in both the overall and PN-baseline cohorts. OS and TTP data will also be reported. The most common treatment-emergent ≥G3 adverse events regardless of relationship to study drug were primarily hematologic and were as follows: thrombocytopenia (24%), anemia (21%), lymphopenia (11%), pneumonia (9%), neutropenia (9%), fatigue (7%), hypercalcemia (7%), and hyponatremia (6%). Although 77% of pts had G1/2 PN at baseline, new onset PN was infrequent with PN AEs of any grade reported in 31 (15%) pts and G3 PN reported in only 1 (0.4%) pt. New onset or worsening of paraesthesias (6.8%) and dysesthesias (0%) was also infrequent. Conclusions: Analysis of the subset of pts (77%) with active PN (G1/2) in this single-agent Ph 2 trial of CFZ in pts with R/R MM demonstrated that PN has no impact on depth or durability of responses, or on the tolerability of CFZ, in heavily pretreated pts with multiply relapsed and refractory MM. Reports of new or worsening PN were very uncommon, and paraesthesias and dysesthesia were generally infrequent and mild. CFZ can be given to pts with baseline PN with little risk of exacerbation; prolonged therapy is possible in this population. Disclosures: 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. Vij:Onyx: Honoraria. Wang:Celgene: Research Funding; Onyx: Research Funding; Millenium: Research Funding; Novartis: Research Funding. Stewart:Millennium: Consultancy; Celgene: 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. 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. Kukreti:Celgene: Honoraria; Roche: Honoraria; Ortho Biotech: Honoraria. Alsina:Millenium: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy. Zonder:Millenium: Consultancy, Honoraria, Research Funding; Cephalon: Research Funding; Celgene: Honoraria. Wong:Onyx Pharmaceuticals: Employment. Vallone:Onyx Pharmaceuticals: Employment. Chang:Onyx Pharmaceuticals: Employment. Kauffman:Onyx Pharmaceuticals: Employment. Siegel:Millenium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria.

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.