Abstract: Abstract 1024 Background: The MMRC is a non-profit, disease-focused consortium founded in 2004. Sixteen North American member institutions with expertise in multiple myeloma (MM) work collaboratively with the MMRC Inc. (Norwalk, CT) and numerous pharmaceutical partners to speed development of new treatment options to MM patients. In December 2007, MMRC Inc. implemented business solutions to address barriers to rapid activation of phase I-II trials and established benchmarks for initiating and conducting these studies. In December 2010, we reported significantly faster trial start up and accrual data from previous years1,2. Today, we update and expand on MMRC performance data and analysis of progress. Methods: Twenty-five (25) trials conducted within the Consortium from May 2006 to July 2011 had sufficient start up trial data for review. FPFD was defined as the time from the member institutions' receipt of the final protocol (FP) from the trial sponsor, to the time the first patient was dosed on the trial at any participating MMRC member institution. With respect to enrollment, pre-study enrollment commitment (EC) established between MMRC and the study sponsor was defined as the total number of subjects committed to receive at least one dose of study drug across all participating MMRC centers on a trial; baseline enrollment timeline (BET) was prospectively defined as the target time period to attain EC. Results: Mean time to FPFD in the recent group of trials (RG; n=18; Sept 08-Jul 11) held steady at 131 calendar days from receipt of FP as compared to 181 days for the early group of trials (EG; n=7; Jun06-Sept08) representing a 28% reduction in time to FPFD. More importantly, there was a 20% decrease in time to FPFD by all participating MMRC centers on any MMRC trial from 189 days in the RG compared to 236 days in the EG representing an important achievement especially in the Phase I/II arena. MMRC trial accrual data was available for 17/25 trials (2 EG trials were missing data and 6 RG trials continue enrolling). The pre-study mean MMRC EC was 44 subjects per trial (n=19 trials; 849 patients); the mean actual MMRC enrollment was 49 subjects per trial (n=19; 935 patients through July 11) representing a 10% over enrollment versus committed enrollment. A total of 17/19 evaluable trials (89%) met their EC; 12/19 trials met EC within BET (71%) of which 8/12 trials (67%) reached EC 34% faster than their BET (representing a mean reduction of 4.5 months). The overall pre-study mean BET for 19 trials was 13.6 months. MMRC's actual mean enrollment timeline was 12.8 months for the group of 17 evaluable trials representing improvement over the original BET by a mean of 10%. Discussion: MMRC's acceleration of clinical trials provides physicians and patients with rapid access to novel compounds; industry with data for important drug development decisions; and academic institutions with more trials of high scientific interest. Even so, our data uncovered opportunities for improvement. The submission time from receipt of the final protocol from the trial sponsor to Scientific Review Committee (SRC) took an average 30 calendar days across all trials. A reduction to half this time could make a difference to patients and therefore warrants further exploration. Conclusion: Today, drug development in multiple myeloma is fast-paced and highly competitive. MMRC's frequent review of trial metrics provides valuable insight to continually speed answers to physicians, patients and industry. Disclosures: Richardson: Multiple Myeloma Research Consortium: Annual grant in support Clinical Trial Project Management. Vij:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Lonial:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Siegel:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Jakubowiak:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Reece:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Jagannath:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Hofmeister:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Stewart:Multiple Myeloma Research Consortium: Annual Grant in support of clinical trial Project Management. Wolf:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Krishnan:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Zimmerman:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Kumar:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Roy:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Fay:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Anderson:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management.

Abstract: 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.

Abstract: This phase 1/2 trial evaluated combination lenalidomide, bortezomib, pegylated liposomal doxorubicin, and dexamethasone (RVDD) in newly diagnosed multiple myeloma (MM) patients. Patients received RVDD at 4 dose levels, including the maximum tolerated dose (MTD). Patients with a very good partial response or better (≥ VGPR) after cycle 4 proceeded to autologous stem cell transplantation or continued treatment. The primary objectives were MTD evaluation and response to RVDD after 4 and 8 cycles. Seventy-two patients received a median of 4.5 cycles. The MTDs were lenalidomide 25 mg, bortezomib 1.3 mg/m2, pegylated liposomal doxorubicin 30 mg/m2, and dexamethasone 20/10 mg, as established with 3-week cycles. The most common adverse events were fatigue, constipation, sensory neuropathy, and infection; there was no treatment-related mortality. Response rates after 4 and 8 cycles were 96% and 95% partial response or better, 57% and 65% ≥ VGPR, and 29% and 35% complete or near-complete response, respectively. After a median follow-up of 15.5 months, median progression-free survival (PFS) and overall survival (OS) were not reached. The estimated 18-month PFS and OS were 80.8% and 98.6%, respectively. RVDD was generally well tolerated and highly active, warranting further study in newly diagnosed MM patients. This trial was registered at www.clinicaltrials.gov as NCT00724568.

Abstract: Carfilzomib is a selective proteasome inhibitor that binds irreversibly to its target. In phase 1 studies, carfilzomib elicited promising responses and an acceptable toxicity profile in patients with relapsed and/or refractory multiple myeloma (R/R MM). In the present phase 2, multicenter, open-label study, 129 bortezomib-naive patients with R/R MM (median of 2 prior therapies) were separated into Cohort 1, scheduled to receive intravenous carfilzomib 20 mg/m2 for all treatment cycles, and Cohort 2, scheduled to receive 20 mg/m2 for cycle 1 and then 27 mg/m2 for all subsequent cycles. The primary end point was an overall response rate (≥ partial response) of 42.4% in Cohort 1 and 52.2% in Cohort 2. The clinical benefit response (overall response rate + minimal response) was 59.3% and 64.2% in Cohorts 1 and 2, respectively. Median duration of response was 13.1 months and not reached, and median time to progression was 8.3 months and not reached, respectively. The most common treatment-emergent adverse events were fatigue (62.0%) and nausea (48.8%). Single-agent carfilzomib elicited a low incidence of peripheral neuropathy—17.1% overall (1 grade 3; no grade 4)—in these pretreated bortezomib-naive patients. The results of the present study support the use of carfilzomib in R/R MM patients. This trial is registered at www.clinicaltrials.gov as NCT00530816.

Abstract: Abstract 480 Introduction: Vorinostat (VOR), an oral inhibitor of histone deacetylase (HDAC) class I and class II proteins, affects pathways regulating cell proliferation and apoptosis in a diverse array of tumor types. Phase 1/2 trials in multiple myeloma (MM) have indicated clinical activity of vorinostat, as both a single agent and in combination with bortezomib (BTZ) and immunomodulatory drugs (IMiDs). Materials and methods: The present study (MK-0683 PN095) was an open-label, single-arm phase 2b trial of VOR plus BTZ in BTZ-refractory patients (defined as 〈 25% response on therapy, or progression during or 〈 60 days after completion of therapy) and patients considered to be refractory, intolerant, or ineligible for IMiD-based therapy regimens. Eligible patients were aged ≥ 18 years, had measurable secretory MM, had received ≥ 2 prior anti-myeloma regimens, and relapsed or progressed following prior systemic therapy. Patients received 21-day cycles of BTZ (1.3 mg/m2 intravenously [IV]; days 1, 4, 8, and 11) plus oral VOR 400 mg/d on days 1 to 14. If patient had no change as the best response after 4 cycles of treatment or progressive disease after 2 cycles of treatment, oral dexamethasone 20 mg on the day of and day after each dose of BTZ could be added to the treatment regimen. Patients were treated until disease progression, unacceptable toxicities, or withdrawal from the study. The primary endpoint was overall response rate (ORR; ≥ partial response). Secondary and exploratory endpoints included clinical benefit response (ORR + minimal response), 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 criteria and the European Bone and Marrow Transplantation Group criteria. All efficacy data will be confirmed by an Independent Adjudication Committee. Results: Between January 2009 and October 2010, 143 patients were enrolled from 41 centers in 12 countries across Asia-Pacific, Europe, and North America. Median duration of MM for the entire study population was 4.6 years, including 31% whose disease had progressed on or within 60 days of last therapy and 66% whose disease had achieved 〈 25% response to the regimen immediately preceding study entry. The study population was heavily pretreated, having received a median of 4 prior lines of therapy (range 2–17, ≥ 4 prior regimens: 69%). Prior anti-myeloma agents included 100% BTZ (median 2 prior regimens containing BTZ), 100% IMiDs (thalidomide [85%], lenalidomide [71%] , or pomalidomide [4%]), and 74% stem cell transplant. As of July 2011, 142 of the enrolled patients received study medication, with a median exposure of 4 cycles (mean 6.2 cycles; range 1–26 cycles). The most common treatment-emergent adverse events regardless of relationship to study drug were predominantly hematologic and gastrointestinal disorders. Of interest, peripheral neuropathy was infrequent and grade ≥ 3 PN occurred in 2 patients (1.6%). The final efficacy evaluation of the IAC will occur in September 2011. Conclusions: Final data for all primary and secondary endpoints, including response assessment and time-to-event data for PFS/TTP, OS, and duration of response will be available at the annual ASH meeting. Disclosures: Siegel: Millenium: Honoraria, Research Funding, Speakers Bureau; Merck: Honoraria. Off Label Use: Vorinostat, an inhibitor of histone deacetylase, is approved in the US for the treatment of cutaneous manifestations in patients with cutaneous T cell lymphoma (CTCL) who have progressive, persistent or recurrent disease on or following two systemic therapies. Vorinostat is currently under investigation for the treatment of relapsed malignant pleural mesothelioma, relapsed/refractory B cell lymphoma (in combination with other chemotherapy agents), and relapsed/refractory multiple myeloma (in combination with bortezomib and other chemotherapy agents). Dimopoulos:Celgene, Ortho-Biotech: Consultancy, Honoraria. Yoon:NK Bio: Consultancy; Celgene: Consultancy. Kaufman:Merck; Celgene: Research Funding; Millenium; Onxy; Novartis; Keryx: Consultancy. Goldschmidt:Amgen, Novartis, Chugai: Research Funding; Janssen-Cilag, Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Reece:Merck: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding. Leleu:Janssen Cilag, Celgene, Novartis-Amgen, Leo Pharma, Chugai, Roche: Honoraria, Research Funding. Cavo:Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jagannath:Merck: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees. Graef:Merck: Employment. Houp:Merck: Employment. Sun:Merck & Co., Inc.: Employment. Howe:Merck: Employment. Anderson:Celgene: Consultancy; Millennium: Consultancy; Novartis: Consultancy; BMS: Consultancy; Onyx: Consultancy; Merck: Consultancy; Acetylon: .

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 302 Background: Marizomib has a novel, non-peptide based, bicyclic structure and compared to other proteasome inhibitors, unique properties of clinical relevance. Specifically, marizomib produces rapid, broad and prolonged inhibition of all 3 20S proteasome catalytic activities, and markedly different safety and efficacy profiles, including activity against MM resistant to bortezomib (BZ) both in vitro and in vivo. Materials and Methods: Marizomib was given IV over 1–120 minutes on days 1, 4, 8 and 11 of 21-day cycles in 2 separate and parallel dose escalation studies performed in Australia and the United States in patients with relapsed and refractory MM. In addition to standard safety and efficacy monitoring, pharmacokinetics (PK) and proteasome inhibition as part of pharmacodynamics (PD) were assessed. Dexamethasone (20 mg) was given the day prior to and day of treatment in one study and could be added for patients who did not achieve a minimal response (MR) or better after 2 cycles in the other study. Toxicity evaluation was performed using CTCAE v3.0 and response was assessed by modified European Group for Blood and Marrow Transplantation (EBMT) and Uniform Criteria (UC). Results: 34 patients (16 men and 18 women) have been treated at doses of 0.075 to 0.6 mg/m2/dose BIW with a median age of 62.5 years, in both studies. Patients received a median of 6 prior regimens; 30 patients (88%) had been exposed to prior BZ, including 24 (71%) who were BZ -refractory. The maximum tolerated dose of marizomib was found to be 0.4 mg/m2 over a 60 minute infusion time and 0.5 mg/m2 over a 120 minute infusion. Dose limiting toxicities included transient hallucinations, cognitive changes and loss of balance, all of which proved reversible. The most common drug-related adverse events were fatigue, nausea, vomiting, dizziness, headache, diarrhea, constipation, insomnia, anorexia, and dyspnea, which proved manageable with supportive care and/or dose reduction. Importantly, marizomib did not appear to induce myelosuppression, peripheral neuropathy (PN) or thrombocytopenia. PK analysis demonstrated a rapid elimination half-life ( 〈 20 minutes) and large volume of distribution, with PD analyses of packed whole blood (PWB) and peripheral blood mononuclear cells (PBMC) confirming dose dependent proteasome inhibition. At interim analysis, of 22 patients with evaluable disease for best response to marizomib +/− dexamethasone, 3 had achieved partial response (PR) by EBMT/UC (14%). In the active dose range of 0.4–0.6 mg/m2, 15 pts were evaluable with PR in 3 pts (20%), all of whom were refractory to prior BZ. Median time on treatment was 1.5 months, with stable disease or better documented in 16 pts (73%). Conclusions: The safety profile of marizomib clearly differs from BZ, without significant treatment–emergent PN or myelosuppression described. Preliminary results suggest anti-myeloma activity, with responses seen in patients in whom BZ had previously failed, as well as interesting PK/PD characteristics and tissue distribution supporting a possible role in patients with different disease characteristics (such as extramedullary spread). The efficacy and safety of 0.5 mg/m2 of marizomib given twice weekly, alone or with low dose dexamethasone, warrants further study, and continues to be investigated. Future directions will include combination approaches with lenalidomide and dexamethasone. Disclosures: Richardson: Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees. Cannell:Nereus Pharmaceuticals: Investigator. Harrison:Nereus Pharmaceuticals: Research Funding. Jakubowiak:Ortho Biotech: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Millennium Pharmaceuticals: 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. Palladino:Nereus Pharmaceuticals, Inc: Employment, Equity Ownership. Longenecker:Nereus Pharmaceuticals, Inc: Employment, Equity Ownership. Lay:Nereus Pharmaceuticals, Inc: Employment, Equity Ownership. Lloyd:Nereus Pharmaceuticals, Inc: Employment, Equity Ownership. Hannah:Nereus Pharmaceuticals, Inc.: Consultancy. Reich:Nereus Pharmaceuticals: Consultancy. Spear:Nereus Pharmaceuticals, Inc: Employment, Equity Ownership. Anderson:Onyx: Consultancy; Merck: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acetylon: Founder; Nereus Pharmaceuticals, Inc: Consultancy; Millennium: Consultancy; Celgene: Consultancy.

Abstract: Abstract 132 Background: The RVD combination of Lenalidomide (Revlimid®, Len), Bortezomib, (Velcade®, Bz), and Dexamethasone (Dex) and the VDD combination of Bz, pegylated liposomal doxorubicin (Doxil®, PLD), and Dex are among the most active in newly diagnosed multiple myeloma (MM). Pre-clinical studies suggest that combining 4 drugs from RVD and VDD into RVDD may produce even higher activity. The aims of this Phase I/II trial were to determine the maximum tolerated dose (MTD) of the RVDD regimen and to assess its safety and evaluate efficacy in newly diagnosed MM. Methods: Patients (Pts) received Len 15–25 mg (days 1–14), Bz 1.3 mg/m2 (days 1, 4, 8, 11), Dex 20/10 mg (cycles 1–4/5–8; days of and after Bz), PLD 20 or 30 mg/m2 (day 4) at 4 dose levels for up to eight 21-day cycles. In the Phase I portion of the study, pts were assigned to dose levels 1-4 according to the TITE-CRM algorithm. Responses were assessed by modified European Group for Blood and Marrow Transplantation (EBMT) and Uniform Criteria. Pts who achieved at least partial response (PR) could proceed to autologus stem cell transplant (ASCT) after ≥ 4 cycles. After 8 cycles, pts could continue treatment using 21-day maintenance cycles with Len (days 1–14), Bz (day 1 and 8), and Dex (days of and after Bz) at the doses tolerated by the end of initial treatment. Results: The study has enrolled 68 pts to date (median age 61; 52% ISS II/III), 42 pts in phase I (including 6 pts treated at the MTD) and 26 pts in phase II, for a total of 32 of 38 planned pts at the MTD. Pts received a median of 4 cycles (range 1–16); 48 completed at least 4 cycles, 11 completed all 8 cycles, and 34 have discontinued/completed therapy. Seven patients remain on maintenance therapy. Toxicity data are available for 55 pts. In the phase I, 4 pts were assigned to level 1 (Len/PLD 15/20), 11 to level 2 (Len/PLD 20/20, 21 to level 3 (Len/PLD 25/20), and 6 to level 4 (Len/PLD 25/30). Two pts were not evaluable for DLT per protocol criteria and were replaced; 1 at level 2 and 1 at level 3, leaving 40 pts evaluable for DLTs. There were no DLTs at level 1, 2 at level 2, 3 at level 3, consisting of 2 grade (G) 3 asymptomatic neutropenia on day 1 cycle 2, 1 G3 elevation of transaminases, 1 G3 drug fever, and 1 grade 3 hypophosphatemia and none at level 4. Based on the pre-determined definition of maximum tolerated dose (MTD) and probability estimates of DLTs of 4.7% for level 1, 9.7% for level 2, 13.7% for level 3, and 17.9% for level 4, the maximum planned dose level 4 was selected as the MTD for the phase II portion of the study as the closest to, but not exceeding, a target rate of 20% of DLTs. Overall, toxicities have been manageable with G3/4 toxicities in 3–18% of all pts including neutropenia (18%), thrombocytopenia (7%) , infections (16 %) , DVT (2%). There was 4% G3 and no G4 peripheral neuropathy reported, 24% G 1/2 palmar-plantar erythrodysesthesia, and no treatment-related mortality. Response rates in 57 pts evaluable for response were as follows: 96% ≥ PR, 58% ≥ VGPR, and 30% CR/nCR. In 48 pts who completed 4 cycles, defined in the protocol for efficacy assessment, response rates were: 98% ≥ PR, 58% ≥ VGPR and 29% CR/nCR; at MTD ≥PR is 100%. Response rates were not statistically different in a subset of pts (24) with 13q deletion or t(4;14) or t(14;16) or 17p del, with PR, VGPR, and CR/nCR rates 92%, 67%, and 33%, respectively. Twenty four pts proceeded to stem cell collection with 7.5 × 106 CD34+ cells/kg collected after a median of 4 cycles of RVDD (range 3–10). After a median of 6 months of follow-up, median progresssion-free survival and overall survival have not been reached. Conclusion: RVDD is well tolerated in newly diagnosed MM and appears highly active with ≥ PR of 96%, including 58% ≥VGPR, which is unaffected by adverse cytogenetic status. Pts treated at the MTD ,which was determined as Len 25 mg, Bz 1.3 mg/m2, Dex 20 mg, and PLD 30 mg/m2, and completed at least 4 cycles, show 100% ≥PR. Stem cell mobilization and collection was successful in all pts, with unremarkable transplant course reported to date. Updated toxicity and efficacy data will be presented at the meeting. 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, Speakers Bureau. Off Label Use: Lenalidomide for newly diagnosed multiple myeloma. Reece:Ortho Biotech: Honoraria, Research Funding. Lonial:Novartis: Consultancy; Gloucester: Research Funding; Bristol Myers - Squibb : Consultancy; Millennium: Consultancy, Research Funding; Celgene: Consultancy. Zimmerman:Celgene: Speakers Bureau; Millennium: Speakers Bureau; Centocor: Speakers Bureau. Schlossman:Millennium: Speakers Bureau; Celgene: Speakers Bureau. Laubach:Novartis: Advisory Board. Raje:Celgene, Norvartis, Astrazeneca: Research Funding. Anderson:Millennium: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau. Barrickman:Celgene: Employment, Equity Ownership. Tendler:Johnson and Johnson: Employment, Equity Ownership. Esseltine:Johnson and Johnson: Equity Ownership; Milllennium: Employment, Equity Ownership. Kelley:Bristol-Myers Squibb: Equity Ownership. Anderson:Millennium: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Richardson:Bristol Myers-Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keryx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Abstract: Background: NPI-0052 is a novel proteasome inhibitor that produces prolonged inhibition of all three catalytic activities (C-L, T-L, CT-L) of the 20S proteasome. Preclinical data suggest NPI-0052 may demonstrate an improved therapeutic ratio, with significant activity in hematologic and solid tumor malignancies including multiple myeloma (MM) resistant to bortezomib and other agents (Chauhan et al, Blood 2006). Studies have therefore been initiated in patients with multiple myeloma, lymphoma, leukemia and solid tumors. Materials and Methods: This Phase 1 dose escalation study evaluated NPI-0052 monotherapy in patients with relapsed and relapsed/refractory MM, including those that have received bortezomib and/or lenalidomide. Patients were assessed for safety, pharmacodynamics (including ex vivo proteasome inhibition), plasma pharmacokinetics (PK), and clinical activity (with response assessed by modified EBMT criteria). Patients were treated with NPI-0052 administered as a weekly IV injection on Days 1, 8 and 15 every 4 weeks with concomitant hydration. The dose of NPI-0052 was escalated in cohorts of 3 patients dependent on observed adverse events utilizing a 3+3 design. Proteasome inhibition and PK were assayed after the 1st and 3rd dose and upon any intra-patient dose escalation. Proteasome inhibition was also assessed in CD138 positive cells isolated from bone marrow aspirates obtained at baseline and after the 3rd dose in a subset of patients. Preliminary Results: To date, 10 patients have been treated at doses ranging from 0.025 mg/m2 to 0.075 mg/m2 without reaching an MTD. One patient experienced reversible elevation in serum creatinine that responded to drug cessation and steroids; this event may have been related to progression of his underlying light chain nephropathy (as interval worsening of renal function was noted prior to enrollment). Drug-related adverse events have been otherwise unremarkable at all dose levels tested. PK data demonstrate a rapid elimination half life (estimated to be 3–4 minutes) with clearance between 8–21 mL/min and Vz of 44–99L; no change in PK has been observed comparing the 1st and 3rd injection. Proteasome inhibition in whole blood suggests drug-dependent CT-L inhibition, with inhibition up to 28% observed (inhibition up to 100% at doses of up to 0.7 mg/m2 has been observed in other clinical trials with NPI-0052 without producing the profile of toxicity reported with standard doses of bortezomib). Whilst no responses have been confirmed, two patients with relapse/refractory MM remained on study for over 6 months and one year, respectively, with stable disease and no significant toxicity. Importantly, no peripheral neuropathy or myelosuppression has been seen in 41 treatment cycles in patients to date. Conclusions: In patients with relapsed and relapsed, refractory MM, NPI-0052 affects parameters relevant to pharmacodynamics, PK and demonstrated potential clinical benefit at doses well below the MTD anticipated from Phase 1 clinical trials with NPI-0052 in lymphoma and solid tumors. Drug administration to date has been well tolerated. Dose escalation continues to define DLT and MTD, and to recommend a phase 2 dose for further study in patients with advanced MM.

Abstract: Abstract 3803 Background: The MMRC is a non-profit, disease-focused consortium founded in 2004 comprised of 13 North American centers with expertise in multiple myeloma (MM). The MMRC Inc. (Norwalk, CT), MMRC's member institutions, and several pharmaceutical partners work closely to speed early development of new treatment options for MM patients. In December 2007, MMRC headquarters staff implemented multiple project management (PM) business solutions to address trial barriers that delay activation of our phase I-II clinical trials and established trial metric benchmarks considered attainable at our member institutions. In November 2009, we reported initial data1 on trial activation: MMRC trials initiated between Sep08-Jul09 (n=5) demonstrated a 38% decrease in mean time to first patient dosed (FPFD), compared with the Early Group trials (EG) initiated before PM solutions (Jun06-Sept08; n=7 trials). These results also confirmed improvement over published metrics from Dilts et al 2,3. We present additional data on time to FPFD and now enrollment, to assess impact of the MMRC PM resources and processes on trial efficiency. Methods: Twenty-one (21) trials conducted within the MMRC from May 2006 to June 2010 had sufficient trial data for review. Data were collected by MMRC-funded project managers at the clinical centers using a web-based clinical trial management system (CTMS). FPFD was defined as the time from the member institutions' receipt of the final protocol (FP) from the trial sponsor, to the time the first patient was dosed on the trial at any participating MMRC member institution. With respect to enrollment, pre-study enrollment commitment (EC) established between MMRC and the study sponsor was defined as the total number of subjects committed to receive at least one dose of study drug across all participating MMRC centers on a trial; baseline enrollment timeline (BET) was prospectively defined as the target time period to attain EC. Results: Mean time to FPFD was 181 calendar days for the early group trials (EG, n=7) and 122 days for the recent group (RG) trials (n=14, Sep08 – Jun10), representing a 32% reduction of time to FPFD in the RG. Additionally, time from final protocol to first patient dosed at all MMRC centers on a trial decreased 18% from a mean of 7.7 months (EG) to 6.3 months (RG). With respect to MMRC trial enrollment, data was available for 16/21 trials (5 EG and 11 RG). 2 EG trials were missing data and 3 RG trials were still enrolling as of June 2010. The mean MMRC pre-study EC was 39 subjects per trial (n=16 trials; 626 enrollment target); the mean actual MMRC enrollment was 49 subjects per trial (n=16; 783 enrolled through Jun 29, 2010) representing a 25% increase in actual versus committed enrollment. Two trials did not meet MMRC EC: MMRC investigators discontinued their involvement in these trials at approximately 30% target EC due to trial complexity or low patient enrollment. 14/16 evaluable trials (88%) met their EC; 11/16 trials met EC within BET (69%) of which 8/16 trials (50%) reached EC 34% faster than their BET (representing a mean reduction of 4.5 months). The overall pre-study mean BET for 16 trials was 13.1 months. MMRC's actual mean enrollment timeline was 11.3 months for the group of 14 evaluable trials representing improvement over the original BET by a mean of 1.9 months (14%). We believe FP to FPFD is a more meaningful metric beyond that of first patient consented. Moreover, we believe that if all participating trial centers focus their efforts on dosing the first patient and within a targeted timeframe, it may improve our research efforts overall. Conclusion: Development of drugs in the clinical setting has become time and resource intensive. Activating and enrolling trials promptly is a priority for drug development. The MMRC's standardization of processes and support for site-based PM resources results in improved trial metrics. MMRC member centers met or exceeded pre-specified enrollment targets in 88% of the trials analyzed to date. Ongoing monitoring of trial conduct continues to reveal areas where increased focus is needed to realize further trial efficiencies. These trial metrics and measures to improve efficiency may be applied with similar expected benefit in all oncology disciplines. Disclosures: Wear: Multiple Myeloma Research Consortium (MMRC): Employment. Richardson:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC; Millennium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Revta:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Vij:Multiple Myeloma Research Consortium (MMRC): Research Funding; Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Fiala:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Lonial:Bristo-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium Pharmaceuticals Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Francis:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Siegel:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC; Celgene: Speakers Bureau; Millennium: Speakers Bureau. Schramm:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Jakubowiak:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC, Research Funding; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Centocor Ortho-Biotech: Honoraria, Speakers Bureau; Exelixis: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Harvey:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Reece:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC; Celgene: Honoraria, Research Funding; Ortho Biotech: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Facet: Research Funding; Otsuka: Honoraria, Research Funding. Gul:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Jagannath:Celgene: Honoraria; Millenium: Honoraria; Orthobiotec: Honoraria; Onyx Pharma: Honoraria; Merck: Honoraria; Proteolix: Honoraria; Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. La:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Hofmeister:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Jansak:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Stewart:Millennium: Consultancy; Celgene: Honoraria; Multiple Myeloma Research Consortium: Member Institution of the MMRC. Hagerty:Mayo Clinic: Employment; Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Wolf:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC; Celgene: Speakers Bureau; Millennium: Speakers Bureau; Novartis: Speakers Bureau; Orthobiotech: Speakers Bureau. Davis:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Krishnan:Celgene: Speakers Bureau; Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Duarte:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Zimmerman:Millennium, Celgene: Speakers Bureau. Cisneros:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Kumar:Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding; Bayer: Research Funding; Multiple Myeloma Research Consortium: Member Institution of the MMRC. Birgin:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Ott:Multiple Myeloma Research Consortium (MMRC): Employment. Tasca:Multiple Myeloma Research Consortium (MMRC): Employment. Kelley:Multiple Myeloma Research Consortium (MMRC): Employment. Anderson:Millennium: Consultancy; Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC; Celgene: Consultancy; Novartis: Consultancy; Onyx: Consultancy; Merck: Consultancy; Bristol-Myers Squibb: Consultancy; Acetylon: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Giusti:Multiple Myeloma Research Consortium (MMRC): Employment.