Citations

Abstract Abstract 3884 Poster Board III-820 Background and Objective Thalidomide/dexamethasone (thal/dex) combination has shown high activity in newly diagnosed multiple myeloma (MM) (Rajkumar SV. at al, J Clin Oncol 2006;24:431-436). In newly diagnosed patients, lenalidomide/dexamethasone (len/dex) has demonstrated superiority compared with high-dose dexamethasone alone (Zonder JA et al, Blood 2007;110:77). Although both thal/dex and len/dex are active in newly diagnosed MM, no randomized trial has been reported comparing these two regimens, and unfortunately none are ongoing or planned. We compared the efficacy and the toxicity of thal/dex and len/dex as primary therapy in 411 newly diagnosed MM patients treated at the Mayo Clinic. Patients and methods 411 consecutive patients seen at Mayo Clinic between 2001 and 2008, who received induction with thal/dex (n=183) or len/dex (n=288) were retrospectively studied. Thalidomide was given at a dose ranging from 100 mg/day to 400 mg/day continuously; the lenalidomide dose was 25 mg/day, days 1-21 on a 28-day cycle. All patients received dexamethasone, either at high-dose (40 mg orally on days 1-4, 9-12, and 17-20) or at low-dose (40 mg orally day 1, 8, 15, 22); each cycle was repeated every 4 weeks. In addition, a case-matched subgroup analysis that adjusted for age, gender and transplantation status was performed among patients who received high-dose dexamethasone comparing the thal/dex (n=72) and len/dex (n=72) groups. Outcome was analyzed on an intention-to-treat basis. The Chi-square or the rank sum tests were used to compare variables. Time-to-event analysis was performed using the Kaplan-Meier method and all comparisons were determined by the log-rank test and by the Cox proportional hazards model. Results On intention-to-treat analysis, of 411 patients, 80.3% versus 61.2% patients, respectively in the len/dex group and in the thal/dex group (p < 0.001), achieved at least a partial response. A significant difference between the 2 groups was found in terms of both very good partial response or better (34.2% vs 12.0%, p < 0.001) and complete response rate (13.6% vs 3.3%, p < 0.001). Duration of therapy was significantly longer in len/dex patients as compared to thal/dex patients: 36.7% vs 12.6% of patients who did not stop treatment to receive SCT were still receiving therapy at 1 year (p < 0.001).Time-to-progression was significantly better in the len/dex group than in patients receiving thal/dex (median 27.4 vs 17.2 months, HR 0.64; 95% CI 0.44-0.93; p = 0.019). Similarly, progression-free-survival was significantly higher in len/dex patients (median 26.7 vs 17.1 months, HR 0.69; 95% CI 0.48-0.98; p = 0.036). This translated into an increase in overall survival (OS) (median not reached for len/dex group compared to 57.2 months in thal/dex patients, HR 0.60; 95% CI 0.40-0.92; p = 0.018). Survival advantages were evident in patients presenting with International Staging System Stage (ISS) I/II (HR 0.57; 95% CI 0.32-1.00; p = 0.052) at diagnosis but not in patients with ISS stage III in subgroup analysis. There was a trend toward better OS in len/dex group compared to thal/dex group both for patients who underwent transplant and for patients who did not. A similar rate of patients experienced at least one grade 3 or higher adverse event (57.5% vs 54.6% in len/dex and thal/dex groups, respectively, p = 0.568). However, the toxicity profile was different in the two groups: major grade 3-4 toxicities of len/dex were hematological, in particular neutropenia (14% with len/dex vs 0.6% with thal/dex, p<0.001) while the most common toxicities in thal/dex were venous thromboembolism (15.3% vs 9.2%, p = 0.058) and peripheral neuropathy (10.4% vs 0.9%, p < 0.001). The data on efficacy and safety shown above were also confirmed in the subgroup case-matched analysis which included only high-dose dexamethasone patients. Conclusions This cohort study shows the superiority of len/dex in terms of response rates and survival, compared to thal/dex. The toxicity profile of the 2 regimens is different and len/dex treatment, although more active, was not associated with increased toxicity (grade 3-4 AEs). These data need to be carefully evaluated and randomized prospective phase III studies are necessary to confirm these results and determine the optimal initial therapy for MM. Disclosures: Off Label Use: research drugs in combination to standard care. Lacy:celgene: Research Funding. Gertz:celgene: Honoraria; genzyme: Honoraria; millenium: Honoraria; amgen: Honoraria. Kumar:celgene: Research Funding; millenium: Research Funding; bayer: Research Funding; Novartis: Research Funding; Genzyme: Research Funding. Dispenzieri:celgene: Research Funding. Bergsagel:amgen: Membership on an entity's Board of Directors or advisory committees; genetech: Membership on an entity's Board of Directors or advisory committees; merck: Research Funding; celgene: Membership on an entity's Board of Directors or advisory committees. Witzig:celgene: Research Funding. Fonseca:medtronic: Consultancy; genzyme: Consultancy; celgene: Consultancy; amgen: Consultancy; BMS: Consultancy; otsuka: Consultancy. Greipp:celgene: Research Funding.

Abstract Abstract 429 Background: Patients with MM who have progressed after multiple novel agents have limited treatment options. Pomalidomide (CC4047) is the newest immunomodulatory (IMiD) agent that has demonstrated response rates of 63% in a Phase 2 trial of Pom/dex in patients with relapsed MM (in press, JCO). To better define the response rate in this group, we treated an additional cohort of patients who were truly resistant/refractory to lenalidomide. Methods: To be eligible, patients must:be refractory to lenalidomide therapy defined as relapsing on or within 60 days of stopping lenalidomide. Pomalidomide was given orally 2 mg daily on days 1–28 of a 28-day cycle. Dexamethasone was given orally at a dose of 40 mg daily on days 1, 8, 15 and 22 of each cycle. Response was assessed by the International Myeloma Working Group Uniform Response criteria. All patients received aspirin 325 mg daily as prophylaxis against DVT. Pom/dex regimen would be declared promising if we observed at least 4 confirmed responses out of 34 patients based on a single stage Fleming design. Results: 34 patients (23 male and 11 female) resistant/refractory to lenalidomide were enrolled. The median age was 62 years (range, 39-77). The median time from diagnosis to enrollment was 62 months (range 8-179). 12 patients had high risk molecular markers including loss of 17p (6 pts), t(4;14) (1 pt) and del 13 by cytogenetics (5 pts). 70% had ≥3 prior regimens including 38% with ≥5 prior regimens; 56% had prior thalidomide, 59% had prior bortezomib, and 68% had prior SCT. Toxicity (at least possibly related to treatment) was mild and consisted primarily of myelosuppression: grade 3/4 neutropenia (21%); grade 3 thrombocytopenia (9%); and grade 3 anemia (12%). Grade 3/4 non-hematologic toxicities occurred in 24%: pneumonia (3%), non-infectious pneumonitis (3%), hyperglycemia (3%), edema(3%), fatigue(9%) skin rash(3%). Neuropathy occurred in 18% (12% grade 1; 6% grade 2). No thromboembolic events have occurred so far. Nine (26%) patients were confirmed responders (all PR), surpassing the threshold for a positive trial, and 18 (53%) had SD. With a median follow-up of 4 months (range:0-8), 65% remain progression free; 88% remain alive; and 12% have died, all due to progressive MM. Conclusions: Pom/dex is active and well tolerated in this heavily pre-treated population of lenalidomide-refractory MM patients. The majority of patients have not progressed and objective responses are seen in 26%. This study confirms that pomalidomide has non-cross resistance with lenalidomide and offers benefit for patients who have relapsed after other novel therapies. Disclosures: Lacy: Celgene: Research Funding. Gertz:celgene: Honoraria; millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kumar:celgene: Honoraria; millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bergsagel:Genentech, Inc.: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Merck: Research Funding. Stewart:Takeda-Millenium, Celgene, Novartis, Amgen: Consultancy; Takeda, Millenium: Research Funding; Genzyme, Celgene, Millenium, Proteolix: Honoraria.

Abstract Abstract 616 Background: We have shown the three drug combination of cyclophosphamide, bortezomib and dexamethasone (CyBorD) to be highly active therapy in newly diagnosed myeloma while allowing stem cell harvest and transplantation (Reeder et al. Leukemia 2009; 23:1337-1341). However, twice weekly bortezomib and high dose dexamethasone have been shown to cause significant toxicities. In a prospective Phase II we modified CyBorD by using bortezomib once weekly and reducing the dexamethasone to “low dose dex” after the first two cycles in an attempt to reduce toxicity (cohort 2). We report the efficacy and toxicity of this modified regimen and compare the results to standard CyBorD (cohort 1). Patients and methods: 63 untreated symptomatic patients were enrolled on this Phase II trial (33 on cohort 1 and 30 on cohort 2). All are evaluable for response and toxicity. Treatment on cohort 2 consisted of oral cyclophosphamide 300 mg/m2 and IV bortezomib 1.5 mg/m2 days 1, 8, 15 and 22 and dexamethasone 40 mg by mouth days 1-4, 9-12, 17-20 in cycles 1 and 2, then 40 mg po days 1, 8, 15, 22 in cycles 3 and beyond. Cohort 1 used standard dosing of bortezomib and high dose dexamethasone throughout. Each cycle was 28 days. Acyclovir and a quinolone antibiotic prophylaxis were routinely used. Patients were evaluated for response and toxicity every cycle and were offered stem cell harvest and transplant after the 4th cycle but could continue up to 12 cycles maximum. Results: The median age for all 63 patients was 61 (36-74) years and 48% were female. Durie-Salmon stages were 47% II and 50% III and ISS stages I 43%, II 36%, and III 21%. Twenty-four percent of patients were genetic high risk (t(4;14) or deletion 17). Cohorts I and II were matched for age, gender and ECOG PS. ISS stages were higher in cohort 1 than cohort 2 (II/III 67% vs. 44%). The intent to treat (ITT) ORR (≥PR) for all 63 patients (cohorts 1 and 2) is 90% with 60% ≥VGPR. For cohort 2 (modified CyBorD) the ITT overall response (≥PR) was 93% (CR: 5, nCR: 7, VGPR: 6, PR: 10) with 60% ≥VGPR and 40% ≥ nCR. Those completing all 4 cycles of therapy had 92% ORR (24/26) and 65% (17/26) ≥VGPR. A comparison of response rates in cohorts 1 and 2 is shown in table 1. These high and comparable response rates were associated with fewer grade 3+ adverse events (AE's) than in cohort 1 (37% vs. 48%) and no grade 3 peripheral neuropathy (PN). The median follow-up for all 63 patients is 12.4 (2.8-29.2) months and 95% of patients are alive with 87% free from progression. Conclusions: Modified CyBorD with weekly bortezomib and reduced dexamethasone retains the high activity seen in standard CyBorD, but is less toxic and more convenient. Interestingly, this modified regimen allowed higher overall doses of bortezomib (5.2 vs. 6.0 mg/m2 per cycle) yet overall neuropathy rates were similar. This combination of a weekly alkylating agent with bortezomib and dexamethasone is well tolerated and produces high response rates in newly diagnosed patients with multiple myeloma. Disclosures: Reeder: Millennium (MPI): Research Funding; Celgene: Research Funding. Reece:Ortho Biotech: Honoraria, Research Funding. Chen:Celgene: Honoraria, Research Funding; Ortho Biotech: Honoraria. Hentz:Millennium (MPI): Research Funding. Fonseca:Otsuka: Consultancy; BMS: Consultancy; Amgen: Consultancy; Medtronic: Consultancy; Genzyme: Consultancy. Bergsagel:Merck: Research Funding; Amgen: Consultancy; Genentech: Consultancy; Celgene: Consultancy. Stewart:Proteolix: Honoraria; Millennium (MPI): Research Funding.

Abstract In approximately 50% of Multiple Myeloma (MM), translocation of non random genes into the IgH locus is believed to be the seminal event in the pathogenesis of the disease. Another 50% of cases are hyperdiploid and trisomic to certain autosomes, but do not harbor any translocation and thus are believed to have genetic alterations in unidentified loci. These observations, together with the finding of somatic mutations in FGFR3, N- and K-RAS, MYC, TP53 and CDKN2C/p18INK4C during the later stages of MM indicate that defective signaling pathways likely play a role in the progression of this malignancy. Of relevance then, in recent years recurrent mutations in kinases have frequently been implicated in malignancies including notably colon cancer and melanoma. We have therefore begun a comprehensive effort to sequence the tyrosine kinome for mutations and genetic polymorphisms in MM. Of particular interest are 90 receptor tyrosine kinases, 43 receptor tyrosine kinase-like, 5 receptor guanylate cyclase, and a lipid kinase. We report here results from our pilot high throughput exon scanning in 32 human MM cell lines which initially focused on 13 kinases known to be somatically mutated in human cancers. To date we have expanded this effort to assess 30 genes with sequence obtained which currently spans 80% coverage of the kinase domains of these genes. A total of 1.9 million bp have been sequenced across 235 exons. No recurrent mutations have been identified in the kinase domains of the cancer-associated genes: SRC, ILK1, KIT, GUCY2F, PDGFRA; in the genetic disorder-associated kinases: BTK, EPHA4, LAMA2, EPHB6, ACVR2; and in the mutation hot spots of frequently mutated cancer gene PIK3CA. A novel missense mutation is however identified upstream of the kinase domain of FGFR3 changing a Ser residue to Arg at codon 433. This residue, which is conserved across species and in FGFR1 and FGFR2, has not been reported in myeloma and in thanatophoric dysplasia, but the biological significance of this mutation is unknown. Several single nucleotide polymorphisms were identified in the coding regions of some of these kinases. Notably, synonymous polymorphisms in the kinase domains of EPHA4, PDGFRA3, KIT, MLK1, ILK1, NTRK3, FLT3, ABL1, FES, MLK4, and EGFR1 were identified that changed a codon but not the amino acid. More importantly, we identified non-synonymous amino acid variations in the kinase domains of EPHA4, GUCY2F, PTK2, and PIK3CA genes that are more likely to effect variability in the activity of these kinases. In summary, no recurrent kinase mutations of significance in Myeloma development or progression have yet been identified. Sequencing of the known cancer associated kinases in MGUS and hyperdiploid MM patients is now underway and our data set is being expanded to include all 139 kinases.

Abstract Background: The combination of lenalidomide and dexamethasone (RD) has been shown to be highly effective as initial therapy for multiple myeloma. More recently, a phase III trial demonstrated improved survival with use of lenalidomide and low dose dexamethasone (Rd). Further improvements by incorporating other active agents may increase the depth of response and may improve long-term outcome. We report the results from a phase II trial combining lenalidomide and low dose dexamethasone with cyclophosphamide (RCd) as initial therapy for newly diagnosed MM. Methods: The trial was initiated in July 2006 and completed the initial target accrual of 33 patients by July 2007 (Cohort 1). Due to high rate of dose reductions in cohort 1, between July 2007 and May 2008 an additional 20 patients were enrolled with lower doses of cyclophosphamide (Cohort 2). The treatment protocol consisted of lenalidomide given orally at a dose of 25 mg daily on days 1–21 of a 28-day cycle. Dex was given orally at a dose of 40 mg on days 1, 8, 15, and 22 of each cycle. Cyclophosphamide at a dose of 300 mg/m2 was given on days 1, 8, and 15 of each cycle in cohort 1 and 300 mg on days 1, 8, and 15 of each cycle in cohort 2. Patients also received an aspirin once daily as thromboprophylaxis. Response was defined as a decrease in serum monoclonal (M) protein by 50% or higher and a decrease in urine M protein by at least 90% or to a level less than 200 mg/24 hours. Responses were assessed on intent to treat basis. Results: 53 patients were enrolled. The median age was 64 years (range, 37–82). 14 patients (29%) had ISS stage III disease. The median number of cycles was 4 (range: 1 – 20). The best response based on all enrolled patients on an intent to treat basis was 83%, including CR:1 (2%), VGPR: 20 (38%), PR: 23 (43%), and less than PR: 9 (17%). The CR plus VGPR rate was 40%. Among the 20 patients in cohort 2 who were enrolled after optimization of the cyclophosphamide dosing, 16 (80%) have already achieved a partial response or better with 17 patients in this cohort still receiving study treatment. Overall, 25 of the 53 enrolled patients have discontinued study treatment. Reasons for ending treatment are: completed study per protocol (14), disease progression (5), adverse event (3) and alternate treatment (3). This includes 3 patients from cohort 2, one completed treatment per protocol, one went to alternate therapy and one patient went off for progression. Hematological toxicity was the most common with grade 4 toxicity seen in 8 patients (only 1 from cohort 2). Non-hematological toxicities included neuropathy, diarrhea, cystitis, and thrombosis. There were 6 patients with grade 4 non-hematological toxicities (none from cohort 2) attributed to the drug (thrombosis, confusion, depression and sepsis). Thirteen patients had dose adjustments, most commonly due to hematological toxicity attributed to lenalidomide or cyclophosphamide. One patient has died off study, of intracranial hemorrhage. The median follow-up for the remaining patients is 7.8 months. Conclusions: The combination of lenalidomide, cyclophosphamide, and dexamethasone (RCd) has excellent activity in the setting of newly diagnosed myeloma. Seventeen patients continue on study and the response rates are likely to be higher with additional followup. Myelosuppression was a significant toxicity leading to dose reductions and cycle delays, and is lower with decreased dose of CTX in cohort 2 without any apparent loss of responses.

Abstract Background: Thalidomide and its analogue lenalidomide have high response rates among patients with newly diagnosed as well as previously treated myeloma. Pomalidomide (CC4047) is the newest immunomodulatory (IMiD) agent that has shown single-agent activity in phase I studies. We report on the first Phase 2 trial of pomalidomide combined with low dose dexamethasone (Pom/dex) in patients with relapsed or refractory multiple myeloma. Methods: 37 patients (21 male and 16 female) were enrolled. Pomalidomide was given orally 2 mg daily on days 1–28 of a 28-day cycle. Dexamethasone was given orally at a dose of 40 mg daily on days 1, 8, 15 and 22 of each cycle. Response was assessed by the International Myeloma Working Group Uniform Response criteria. All patients received aspirin 325 mg daily as prophylaxis against DVT. Results: The median age was 66 years (range, 40 – 88). All patients were evaluable for response and toxicity, and all analysis were done on intent to treat basis. All patients had received prior therapy; 38% had 3 prior regimens; 35% had 2 prior regimens and 27% had one prior regimen. 76% had previous autologous stem cell transplant (ASCT) and 24% had 2 prior ASCT. 62% had previous IMiD therapy. Toxicity was mild and consisted primarily of myelosuppression. Grade 3 neutropenia occurred in 31%; grade 3 thrombocytopenia 3%; grade 3 anemia 3 %. Other grade 3/4 toxicities seen in less than 5% pts included: diarrhea, atrial fibrillation, pneumonia, dehydration and renal insufficiency. 16 % had grade 1/2 neuropathy. No grade 3 neuropathy was seen and there have been no thromboembolic events. Thirty (81%) patients are continuing study treatment. Seven patients have discontinued treatment due to: disease progression (5), died on study (1) and the medical doctor’s discretion (1). Twenty three of 37 patients (62%) achieved an objective response to therapy; including 9 (24%) with VGPR; 14 patients (38%) with PR; 6 (16%) with stable disease. Objective responses were seen in 4 of 13 patients (29%) who were refractory to lenalidomide. Conclusions: Pomalidomide plus dexamethasone (Pom/dex) is highly active and well tolerated for treatment of relapsed/refractory multiple myeloma with an objective responserate of 62%, including a 29% response rate among patients who are lenalidomiderefractory.

Abstract Background: (CFZ) is a novel proteasome inhibitor of the epoxyketone class that exhibits a high level of selectivity for the proteasome and has been shown in a phase 1 study to result in greater than 80% proteasome inhibition on a QDx2 consecutive day schedule. We piloted this agent in MM patients with relapsed disease after one to three prior therapies. Methods: PX-171-004 is an open-label, multicenter study. Pts are stratified into bortezomib (BTZ) naïve, BTZ responsive (> 6 month response) or BTZ non-responsive(< 6 months response) cohorts. Pts received CFZ 20 mg/m2 IV Days 1, 2, 8, 9, 15 and 16 every 28 days, for up to 12 cycles. Dexamethasone 4 mg po was administered prior to each dose in cycle 1. Responses were evaluated by the International Uniform Response Criteria for Multiple Myeloma. Results: 31 patients were enrolled, including 45% BTZ naïve, 45% BTZ responsive, and 10% BTZ non-responsive. 29 pts initiated therapy, completed at least one cycle of CFZ, had measurable M-protein and were evaluable for response. The mean number of prior therapies (excluding transplant) was 2.4;65% received prior thalidomide(THAL), 36% prior lenalidomide (LEN) and 87% prior stem cell transplant (SCT).To date, pts received a median of 4 cycles (range 1–8) of CFZ. 19 pts started at least 4 cycles, and 17 remain on therapy. In the evaluable BTZ naïve population (n=13), the overall response rate (ORR) was 54%, including 1 complete response (CR), 2 very good partial responses (VGPR), and 4 partial responses (PR). There were 4 additional pts with stable disease (SD). In 1 pt with insufficient data to evaluate response, due to tumor lysis syndrome (TLS) onset after 2 CFZ doses, an M-protein drop was noted that suggested a PR. Time to response was rapid, frequently occurring in the 1st cycle. There have been no progressions in this subset. With a median follow-up of 109 days, the time-to-progression(TTP) has not yet been reached, and all responders remain in remission. In 16 evaluable BTZ prior treated pts, 3 pts (19%) achieved PR, 1 (6%) pt achieved a minimal response (MR, as defined by EBMT criteria), and 9 pts had SD. The median TTP is 169 days for this subset. CFZ was generally well tolerated. The most common non-hematologic adverse events (AEs) were fatigue (61%), nausea (58%), vomiting (36%), and insomnia (32%). Worsening of hematologic parameters: neutropenia (32%), anemia (29%), and thrombocytopenia (23%) were primarily Grade 1/2; Grade 3/4 occurred in 10% or less of pts. Reports of peripheral neuropathy (PN) were uncommon. Increased creatinine, both drug and non-drug related, was seen in 5 pts (16%), but treatment was discontinued in only 1 pt due to a renal adverse event. Possible tumor lysis was reported in 2 BTZ naïve patients and resulted in early drug discontinuation in 1 pt, as described above; the 2nd event was fatal. Conclusions: The preliminary results of this trial indicate that CFZ has substantial activity as a single agent in relapsed MM patients, with an ORR of >50% in BTZ naïve patients, indicating better activity in this pt population. CFZ was generally well tolerated, and toxicities were manageable. TLS, which was observed in 2 pts, may be a reflection of the robust drug activity of CFZ. As observed in prior studies with CFZ, reports of PN were uncommon. These observations support further evaluation of CFZ as a promising new agent in MM. Enrollment in this study is ongoing, and additional studies of CFZ in combination with other chemotherapy agents in MM pts are underway.

Abstract Background: Carfilzomib (CFZ) is a novel proteasome inhibitor of the epoxyketone class that exhibits a high level of selectivity for the proteasome and has been shown in a phase 1 study to result in greater than 80% proteasome inhibition on a QDx2 consecutive day schedule. We piloted this agent in MM patients with relapsed and refractory disease, who had failed bortezomib (BTZ) and at least one immunomodulatory (IMiD) agent, e.g., thalidomide (THAL) and/or lenalidomide (LEN). Methods: PX-171-003 is an open-label, multicenter study enrolling pts with MM who have relapsed from at least 2 prior therapies and who are refractory; defined as progressing on or within 60 days of last therapy or<25% response to the last therapy. Pts received CFZ 20 mg/m2 IV Days 1, 2, 8, 9, 15 and 16 every 28 days, for up to 12 cycles. Dexamethasone 4 mg po was administered prior to each dose in Cycle 1. Responses were evaluated by the International Uniform Response Criteria for Multiple Myeloma. Clinical benefit response (CBR) was defined as complete response (CR) + partial/very good partial response (PR/VGPR) + minimal response (MR, as defined by EBMT criteria). Responses were adjudicated by an independent review committee. Results: 46 pts were enrolled, including 78% with progression on or within 60days of last therapy and 22% with no response to last therapy. 39 pts initiated treatment, completed at least one cycle of CFZ, had measurable M-protein, and were evaluable (eval) for response. The mean number of prior therapies (excluding transplant) was 6.4(range 1 to 18). 100% of pts received prior BTZ, 91% prior THAL, 89% prior LEN, and 83% prior stem cell transplantation (SCT). To date, pts received a median of 3 cycles(range 1–9) of CFZ; 22 started at least 4 cycles. The CBR was 26% (10/39 eval pts), including 5 pts achieving PR, 5 pts achieving MR, and 16 additional patients achieving stable disease (SD). Time to response was rapid, frequently occurring in the 1st cycle. CFZ was generally well tolerated; the most common adverse events (AEs) were fatigue(65%), nausea (37%), upper respiratory infection (37%), and diarrhea (33%). Worsening of hematologic parameters: anemia (65%); thrombocytopenia (46%) and neutropenia(20%) were predominantly Grades 1 and 2. Increased creatinine, both drug and non-drug related, was seen in 15/46 pts (33%), but treatment was discontinued in only 3 patients due to a renal adverse event. Acute renal failure was documented in 4 pts (9%), 2 (4%) of whom also had possible tumor lysis. 78% of pts had Grade 1 or 2 peripheral neuropathy (PN) at baseline. Exacerbation of PN was rare, and there were no study discontinuations or dose reductions due to PN. Conclusions: In the context of this heavily pre-treated MM population, single agent CFZ was able to induce CBR in 26% of MM patients, the majority of whom had failed BTZ, LEN, THAL, and SCT. CFZ was generally well-tolerated, and toxicities were manageable. Importantly, exacerbation of pre-existing PN was rare and did not result in dose reduction or discontinuation of therapy. These observations support further evaluation of CFZ as a promising new agent in MM. Enrollment is proceeding at an escalated dose (based on tolerability) in this trial. Additional studies of CFZ in patients who are less heavily pretreated and in combination with other chemotherapy agents are ongoing.

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

Abstract Abstract 601 A paucity of validated kinase targets in human multiple myeloma (MM) has delayed clinical deployment of kinase inhibitors in treatment strategies. We therefore conducted a kinome-wide small interfering RNA (siRNA) lethality study in MM tumor lines bearing common t(4;14), t(14;16) and t(11;14) translocations to identify critically vulnerable kinases in MM tumor cells without regard to preconceived mechanistic notions. Primary screening was performed in duplicate using an 1800-oligo siRNA library in a single-siRNA-per-well format. siRNA were transfected at low concentration (13nM) to minimize off-target effects using conditions that resulted in transfection of >95% cells and <5% background cytotoxicity. After 96 hours, viability was measured by ATP-dependent luminescence. Fifteen kinases were consistently vulnerable in MM cells, including AKT1, AK3L1, AURKA, AURKB, CDC2L1, CDK5R2, FES, FLT4, GAK, GRK6, HK1, PKN1, PLK1, SMG1, and TNK2. While several kinases (PLK1, HK1) were equally vulnerable in epithelial cells, others and particularly the G-protein coupled receptor kinase, GRK6, appeared selectively vulnerable in MM. GRK6 inhibition is selectively lethal to KMS11, OPM1, H929, KMS18 and OCI-MY5 myeloma cells and has minimal effect on 293, MCF7, SF767, A375 or A549 epithelial cells. Persistent expression of FLAG-GRK6 via cDNA rescued KMS11 cells from the lethal effect of a 3'UTR-targeted GRK6 siRNA, but not from control siRNA, validating identification of GRK6 as an essential myeloma survival kinase. Furthermore, concordant results were obtained using four different exon-based GRK6 siRNA, all of which induced GRK6 silencing and similar inhibition of KMS11 proliferation and viability. Significantly, GRK6 is ubiquitously expressed in lymphoid tissues and myeloma, but by comparison appears absent or only weakly expressed in most primary human somatic tissues. From co-immunoprecipitation experiments we demonstrate that GRK6 is highly expressed in myeloma cells via direct association with the HSP90 chaperone. Inhibition of HSP90 with geldanamycin blocks GRK6 protein expression. Importantly, direct GRK6 silencing causes rapid and selective suppression of STAT3 phosphorylation that is associated with sustained reductions in total MCL1 protein levels and MCL1 phosphorylation (within 24 hours), providing a potent mechanism for the cytotoxicity of GRK6 inhibition in MM tumor cells. GF109203X is an inhibitor of both protein kinase C and of GRK6 that causes near total inhibition of these kinases in vitro at distinct concentrations of 0.1μM and 1-10μM respectively. Notably, GF109203X was substantially cytotoxic to 10/14 myeloma tumor lines at concentrations most consistent with GRK6 inhibition (5-20μM), and was selectively more cytotoxic to myeloma tumor cells than to non-myeloma cell lines (P=0.01), highlighting the potential of GRK6 as a pharmaceutical target for selective therapeutic intervention in myeloma. As mice that lack GRK6 are healthy, inhibition of GRK6 represents a uniquely targeted novel therapeutic strategy in human multiple myeloma. Disclosures: Perkins: MMRC: Employment. Reeder:Celgene: Research Funding; Millennium: Research Funding. Fonseca:Otsuka: Consultancy; BMS: Consultancy; Amgen: Consultancy; Medtronic: Consultancy; Genzyme: Consultancy.