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Background: p38a mitogen-activated protein kinase (MAPK) mediates production of proinflammatory cytokines and other factors including PGE-2 induced RANKL and IL-1 induced IL-6. SCIO-469 inhibits p38a MAPK blocking synthesis of Il-1ß, PGE2, VEGF, MIP-1α and TNFα thus reducing in vitro MM tumor growth and survival, and drug resistance. Objectives: Assess efficacy, safety, tolerability of SCIO-469 as M or MB in patients (pts) with relapsed and refractory multiple myeloma. Methods: Pts were treated with SCIO-469 alone (60 mg po tid)and assessed on Days 15, 30, 52 and 73. Bortezomib (1.0–1.3mg/m2 d 1,4,8,11 q21d) was added to M for PD or SD. Pts who had clinical benefit on either M or MB at Day 73 were allowed to continue on extension study for up to a total of 168 d, to further evaluate efficacy and saftey of M or MB. Results: 62 pts were enrolled: 39 M, 23 F, median age was 63 years (range 48–84), D-S stage at Dx: I (6%), II (32), III (60%%); median time from diagnosis to treatment 3.1 years; median # prior Rx = 5; including 29% with > 6; 71% prior transplant. 27 had received prior bortezomib and 17 were considered refractory. All 62 pts received study drug; 34 pts received MB at some time during the treatment period. 5 of the 28 (18%) pts treated with M and 25 of 34 (74%) pts treated with MB continued on the extension study. Median time on study was 77.5 d (range 7–304) for M and 180.5 d (range 34–275) for MB. Best response (EBMT; Blade 1998) to M was stable disease in 24% of pts; the best response to MB was 9/34 PR (26%), 2/34 MR (6%),3/34 SD (9%). Median time to progression (TTP) was 50 days for M compared to 140 days for MB. Safety/Tolerability: Adverse events on M were tabulated separately from those on MB. Neutropenia was minimal, < 3% with either regimen; anemia (47 vs 29%) and thrombocytopenia (26 vs 16%) were more prevalent with MB vs M, respectively. Epistaxis, fatigue and diarrhea were seen in > 15% of pts receiving M. Nausea, vomiting, diarrhea, constipation, abdominal pain, fatigue, pyrexia, anorexia, URI, arthralgia, muscle cramp, dizziness, peripheral neuropathy and headache occurred in > 15% pts receiving MB. 10 pts died on study, 9 during primary phase and 1 during extension phase. 3 deaths were the result of sepsis, the remaining 7 were due to progressive disease. Conclusions: SCIO-469, 60 mg tid, as monotherapy or in combination with Bortezomib was well tolerated. Although there were no objective responses in M (compared to 32% (11/34) in MB-including 4 patients who had failed prior bortezomib), 24% had stable disease at the end of monotherapy. Further studies to refine the dose of SCIO-469 as monotherapy and of SCIO-469 in combination with other agents are warranted.

17502 Background: CHIR-258 is an orally active small molecule receptor tyrosine kinase (RTK) inhibitor which has potent activity against multiple RTKs involved in tumor growth and angiogenesis (IC50 ≤13 nM for FGFR, VEGFR, PDGFR, C-KIT, and FLT3). Approximately 15% of newly diagnosed MM patients harbor a t(4;14) translocation, which results in ectopic expression of FGFR3 and MMSET and is associated with poor treatment outcome [0]and reduced survival. CHIR-258 inhibits proliferation and induces apoptosis in FGFR3-expressing MM tumor xenografts as well as FGFR3-expressing primary MM cells (Trudel et al, Blood 2005). CHIR-258 was synergistic with dexamethasone (dex) in vitro. Methods: CHIR-258 was administered once daily in a dose-escalating phase 1 study to patients with relapsed/refractory MM. Drug tolerability and safety, pharmacokinetics (PK) and pharmacodynamics (PD) were assessed. Results: as of December 2005, 9 total pts have been treated (50, 100, and 200mg qd cohorts) [6M, 3F; median age: 58 (range: 44–68), median of 3 prior therapies(range:1–7)]. Prior tx: 9/9 pts-thalidomide; 8/9 -Velcade; 8/9-transplant; 8/9- had progressed through dex. 4 of 9 pts treated were FGFR3+ and 4 pts remain on study (3 are FGFR3+). No CR or PR have been observed; stable disease has been noted. CHIR-258 has been generally well tolerated, and most drug related AEs were CTC grade 1 or 2, including: headache, dysgeusia, fatigue and anorexia. No neuropathy. One DLT has been observed to date: neutropenia (200mg cohort). Five pts had dex added to CHIR-258 of which 3 are ongoing (all FGFR3+). FGFR3+ pts receiving dex and CHIR-258 have a greater decline in urine and serum paraproteins (pp) vs CHIR-258 alone. Plasma exposure and Cmax increased proportionally across the doses. Conclusions: CHIR-258 is a novel inhibitor of RTKs involved in MM growth and proliferation. FGFR3+ pts have a more marked reduction in pp than FGFR3- pts. CHIR-258 has generally been well tolerated and further accrual continues. [Table: see text]

7546 Background: The phase 3 international APEX trial demonstrated significantly superior overall survival (OS), time to progression (TTP), and overall response rate (ORR: CR+PR, EBMT criteria) with bortezomib (VELCADE [Vc]) therapy for relapsed myeloma compared with dexamethasone (Dex). ASCT is a common component of initial therapy and may affect the outcome of salvage therapies. Methods: This analysis aimed to evaluate the impact of prior ASCT on the APEX results. TTP, OS, and ORR were analyzed by prior ASCT treatment. Results: Of 669 randomized patients, 451 (67%) had received prior ASCT (median follow-up in survivors was 21.9 months); in this group, Vc led to higher ORR compared with Dex (41% vs 18%, p < 0.001), higher CR rate (8% vs 0.5%, p < 0.001), and longer TTP and OS (see table), the latter despite crossover to Vc of >62% of patients originally assigned to Dex. A subset of 156 (23%) patients had ASCT as their only prior line of therapy (median follow-up in survivors was 20.0 months), with similar superiority of Vc compared with Dex in ORR (48% vs 29%, p = 0.004), CR rate (6% vs 2%, p > 0.05), and TTP. Among 218 (33%) patients with no prior ASCT (median follow-up in survivors was 21.7 months), Vc was also superior to Dex in ORR (32% vs 18%, p = 0.025), CR rate (4% vs 1%, p > 0.05), and TTP. Conclusions: Vc is consistently superior to Dex in ORR, CR rate, and TTP, regardless of prior ASCT status, and OS is superior in patients who had received prior ASCT. Vc is an effective therapy for myeloma relapsing after ASCT. NE = not estimable. [Table: see text] [Table: see text]

3066 Background: KOS-953 (17-AAG in Cremophor) inhibits HSP90 chaperone function, resulting in disruption of protein complexes and proteasomal degradation. Single-agent 17-AAG is active in relapsed/refractory MM patients (pts) (ASH 2005 A#361), with a recommended dose ≥ 275 mg/m2. In vitro, BZ + KOS-953 show additive cytotoxicity of myeloma cells. Objectives: Define phase 2 dose of BZ+KOS-953 in pts with relapsed refractory MM. Determine PK of KOS-953 and its active metabolite. Evaluate proteasome inhibition in whole blood lysates and explore changes in intracellular signaling proteins in pt PBMCs and MM cells. Methods: Pts received BZ as IV bolus followed by 1-hour infusion KOS-953 twice weekly for 2 out of 3 weeks. Dose escalation occurred in a step-wise manner. PK and collection of surrogates are performed following the 1st and 4th infusion. Pts assessed for response by EBMT criteria. Results: 20 pts were enrolled in 4 cohorts: BZ+KOS-953 (mg/m2): 0.7+100 (n=3); 1.0+100 (n=3); 1.0+150 (n=8); and 1.3+150 (n=6), receiving a total of 103+ cycles (median 5 cycles; range 2, end of infusion): 50% decrease (similar to predicted values). Response was seen in 6 out of 12 BZ-refractory patients (1 nCR, 5 MR) and 3 out of 4 BZ-naïve pts (1 nCR, 2 MR). Conclusions: Dose escalation continues with no additive toxicity or PK interactions to date. Similar inhibition of the 20S proteasome is observed compared to BZ alone. Encouraging activity is seen in both BZ-naïve and BZ-refractory heavily pre-treated MM pts. [Table: see text]

Introduction: Bortezomib (Bz, VELCADE®) is a novel proteasome inhibitor that has demonstrated safety and efficacy for patients (pts) with relapsed and/or refractory multiple myeloma (MM) in phase 2 and 3 trials. Bz was associated with transient, cyclical thrombocytopenia in SUMMIT (NEJM.2003;348:2609) and CREST (BJH.2004;127:165). This analysis evaluated the hematologic profiles in pts treated with Bz or high-dose dexamethasone (Dex) in APEX, the largest phase 3 MM trial in relapsed pts. (NEJM.2005;352:2487). Methods:669 pts with relapsed MM were randomized to Bz 1.3 mg/m2 d 1, 4, 8, 11 q3wk for 8 cycles, then 3 cycles on d 1, 8, 15, 22 q5wk, or Dex 40 mg d 1–4, 9–12, 17–20 q5wk for 4 cycles, then 5 cycles on d 1–4 q28d. Data were collected at baseline and regularly through therapy for adverse events, laboratory values, and transfusion (tf) experience. Results:Thrombocytopenia, anemia, and neutropenia reported as adverse events, all grades (G) and those ≥ G3 in pts are shown (Table). Bz-associated thrombocytopenia was cyclical, with recovery toward baseline during the rest period of each cycle. Overall, 15% of pts on Bz and 1% of those on Dex received platelet (plt) tfs and 33% of pts on Bz and 20% of those on Dex received blood tfs. The majority of plt and blood tfs were completed in the first 2 cycles in both treatment arms. Although the number of plt tfs was higher with Bz, the number of clinically significant bleeding events was similar in the 2 arms. Pts on Bz with complete or partial response experienced an increase in mean hemoglobin over time and the requirement for blood tfs decreased from 21% in cycle 1 to 0% after cycle 4. Median duration of therapy for plt transfused pts was 3.8 and 3.4 mo in the Bz and Dex arms, respectively. Bz-associated neutropenia was also transient and cyclical, and febrile neutropenia was rare. Bz was otherwise not associated with severe myelosuppression. Conclusions:Bz is associated with transient, reversible thrombocytopenia and neutropenia—both with a periodicity related to drug administration—but with rapid recovery and few complications compared with Dex. When clinically indicated, plt tf support, rather than dose reduction, particularly in the first 2 cycles, may be warranted to maximize the benefit of Bz therapy. Impact on plts does not appear to be cumulative, and the mechanism of the cyclic variation in neutrophil counts needs further study. Event Bz (n = 331) Dex (n = 332) *Tfs between baseline and last dose of treatment. Thrombocytopenia, n (%) 116 (35) 36 (11) G3/4 98 (30) 22 (7) Neutropenia, n (%) 63 (19) 6 (2) G3/4 49 (15) 5 (2) Anemia, n (%) 92 (28) 77 (23) G3/4 33 (10) 39 (12) Median plt count, x 109/L (range) Baseline count in blood transfused pts 132 146 Baseline count in plt transfused pts 99 74.5 Responders Baseline 205 162.5 First response 195 175 Last assessment 199 198

The pathogenesis of microangiopathy following stem cell transplantation is poorly understood. Endothelial injury is probably an important factor. The spectrum of transplantation-associated microangiopathy (TAM) extends from minor laboratory findings to life-threatening clinical complications. TAM has not been properly defined, a large number of definitions have been used, and the reported incidences and outcomes of this complication have varied greatly. For purposes of clinical study, and to hasten the development of prophylaxis and therapy for this complication, widely accepted and uniform criteria for TAM are essential. An International Working Group was, therefore, formed with the goal of developing a consensus formulation of the criteria necessary for the diagnosis of TAM. Using a mail-only process, 14 experts in microangiopathic disorders and/or transplantation were asked to propose a list of candidate diagnostic criteria, to select those considered necessary, and to rank those considered optional in order to identify a core set of criteria. The three necessary criteria in the core set consisted of: 1)”increased percentage (>4%) of schistocytes in the blood”; 2)”de novo, prolonged, or progressive thrombocytopenia (platelet count ≤50x109/l or a 50% or greater reduction from previous counts)”; and 3)”sudden and persistent increase in LDH”. The four most highly ranked optional criteria were: “decrease in Hb concentration or increased red cell transfusion requirement”, “decrease in serum haptoglobin”, “sudden and persistent increase in BUN or creatinine”, and “neurological symptoms”. In an appropriateness panel process, the experts were then asked to score the diagnosis of 16 patient profiles as appropriate or not appropriate for TAM. Using the experts’ consensus, the performance (sensitivity and specificity) of 24 possible definitions of the disorder obtained from the core set of criteria was evaluated. The definition of TAM with the highest final score was: the three necessary criteria, plus decrease in Hb concentration or increased red cell transfusion requirement plus decrease in serum haptoglobin. The Working Group, consequently, proposes that the diagnosis of TAM requires fulfilment of all of the following criteria: 1) increased percentage (>4%) of schistocytes in the blood; 2) de novo, prolonged, or progressive thrombocytopenia (platelet count ≤50x109/l or 50% or greater reduction from previous counts); 3) sudden and persistent increase in LDH; 4) decrease in Hb concentration or increased red blood cell transfusion requirement; and 5) decrease in serum haptoglobin. This definition has >80% sensitivity and specificity.

Introduction: Bortezomib (Bz, VELCADE) is a proteasome inhibitor proven safe and effective for patients (pts) with relapsed and/or refractory multiple myeloma (MM). Pts in SUMMIT (NEJM 2003;348:2609) and CREST (BJH 2004;127:165) underwent rigorous testing (neurologic evaluations, FACT/GOG-Ntx questionnaires, nerve conduction studies) to determine the incidence, characteristics and reversibility of PN. In these phase 2 trials, the PN rate was 31–41% (grade [G] ≥ 3 in 11–12%). Specific dose modification (DM) guidelines for PN were not incorporated into the phase 2 trials but were developed for subsequent studies. The objective of this report was to evaluate the frequency, characteristics and reversibility of PN in an updated analysis of the randomized phase 3 APEX trial (NEJM 2005;352:2487), in which specific DM guidelines for PN were implemented. Methods: Pts with relapsed MM were randomized to Bz 1.3 mg/m2 IV on d 1, 4, 8, 11 q3wk for 8 cycles then 3 cycles on d 1, 8, 15, 22 q5wk, or dexamethasone (Dex) 40 mg PO on d 1–4, 9–12, 17–20 q5wk for 4 cycles, then 5 cycles on d 1–4 q4wk. Pts with G ≥ 2 PN were excluded. Data were collected on incidence, severity and reversibility of PN. Results: Of 331 pts safety evaluable enrolled on Bz, 120 (36%) developed PN, including 30 (9%) with G ≥ 3. PN was classified as sensory or not specified in the vast majority of cases; motor neuropathies were rare. Of 91 pts with G ≥ 2 PN, 68 had DM, including 37 with doses reduced, held or schedule modification and 31 with Bz discontinuation (DC); 23 pts not following DM protocol. The majority (58 pts; 64%) of the 91 pts improved (9%) or had complete resolution (55%) of symptoms. Of 37 pts with DM without Bz DC, the majority (26 pts; 70%) had improvement, all with complete resolution of PN to baseline, with a median time to resolution of 78 d. Of 31 pts requiring Bz DC, 2 (6%) improved and 17 (55%) had complete resolution of PN with a median time to improvement/resolution of 121 d. Of 23 pts who did not follow the DM protocol, 12 (52%) had complete resolution with a median time to resolution of 106 d. The rates of PN (any G, G ≥ 3) were similar regardless of pt age or number/type of prior therapies (Table). The median TTP of 91 pts with G ≥ 2 PN, 68 pts with DM, and the Bz arm overall were 6.2, 6.9 and 6.2 months, respectively. Conclusion: The overall rate of PN in APEX was similar to that of SUMMIT and CREST, but the rate of G ≥ 3 PN was lower, perhaps because of specific DM guidelines. PN was reversible in the majority of pts, and DM did not compromise efficacy. Pt age or number/type of prior therapies did not appear to affect the rate or severity of PN. | | PN | |:----------------- | --------- | ------- | | Bz Subgroup | Any G*, % | G ≥3, % | | *Bz related | | ge; 65 y | 35 | 9 | | < 65 y | 37 | 9 | | > 1 prior therapy | 36 | 10 | | 1 prior therapy | 37 | 8 | | Steroids | 38 | 7 | | Alkylating agent | 35 | 7 | | Anthracycline | 39 | 7 | | Vinca alkaloid | 38 | 8 | | Thalidomide | 44 | 8 | | Transplantation | 37 | 7

Introduction and objectives : Plitidepsin is a cyclic depsipeptide originally isolated from the marine tunicate, Aplidium albicans. It appears very potent against multiple myeloma (MM) cells. Specifically, it was observed that it was active against a broad panel of 35 human MM cell lines, which included MM cells resistant to conventional anti-MM agents and novel agents (i.e. thalidomide, bortezomib). Plitidepsin also induced cell death in primary MM tumor cells freshly isolated from patients resistant to thalidomide or its analogs and/or proteasome inhibitors. Phase I has been completed exploring 4 different schedules of administration. Muscle and liver (transaminases and/or alkaline phosphatase) toxicities were the main DLTs. Hematological toxicity was not observed at the recommended dose. The aim of this trial was to explore the activity of plitidepsin in patients with previously treated refractory/relapsed MM. Material and Methods: This is a non-randomized two-stage Phase II, multicenter, clinical and pharmacokinetic trial, with Aplidin® (APLD) 5 mg/m2 as a 3 h intravenous infusion every 2 weeks, with antiemetic and antihistaminic prophylaxis. In the first stage 16 patients evaluable for efficacy were included. At least one response was requested in order to proceed with the second stage, in which a total of 37 patients will be included. Results: Between June’04 and June’05, 19 patients have been enrolled and data are available for 18 patient (7 men and 11 women, median age was 65.7y, range 48–82). Patients were previously relapsed/refractory. Prior treatments included: stem cell transplantation 64.7%, thalidomide 35.28% and bortezomib 17.64%. The median previous chemotherapy lines received were 3, range 1–6. The APLD median number of cycles received 4, range 1–16. Thirteen patients are currently evaluable for efficacy. One patient (7.7%) achieved a partial response (PR) with a 70% reduction in M-component lasting 8 months. Stable disease lasting between 3–5 months was observed in 3 patients (23.0%). In 2 patients (15.38%) a stabilization lasting 2.5 months was stated and the remaining 7 patients (53.8%) progressed. NCI-CTC grade 3–4 related toxicities were reported for n=17 patients and were mainly fatigue in 2 patients (11.8%), myalgia in 1 patient (5.9%), elevation of CPK in 1 patient (5.9%) and transient transaminases increase in 9 patients (52.9%). Significant hematological toxicity did not occurred in spite of 2 patients included and treated with thrombopenia grade 3–4 and 2 patient with neutropenia grade 3. Conclusions: First stage data shows that APLD presents hints of activity in patients with refractory/relapsed MM, with acceptable toxicity profile, thus meeting the criteria for proceeding to second stage recruitment. The absence of significant hematological toxicity is a well known feature of this drug and is being confirmed in this trial.

Introduction: We investigated tumor gene expression profiling (PGx) to identify predictive classifiers of response and elucidate the mechanism of efficacy of proteasome inhibition in multiple myeloma (MM) by bortezomib, a first-in-class proteasome inhibitor. Analysis of 44 samples from the SUMMIT phase 2 trial identified predictive classifiers of response in patients (pts) with refractory MM (ASH 2002, Abstr 1519). We now report on the PGx analysis of the SUMMIT-derived classifier in an independent sample set from the APEX phase 3 trial, a multicenter randomized study of 669 pts that demonstrated the superiority of bortezomib to high-dose dex for relapsed MM following 1 to 3 prior therapies (Richardson NEJM 2005). As well, we report on a new classifier of response built by combining samples from SUMMIT and MLN34101-040 (040) (a study of bortezomib in pts who failed dex in APEX or were not eligible for APEX) and tested in the APEX samples. Methods: 93 participating clinical centers collected pretreatment bone marrow aspirates and enriched tumor cells on site before centralized RNA extraction and microarray analysis. Approximately 85% of pts consented to whole-genome analysis. Quality control for RNA integrity and quantity, microarray data quality, and tumor cell purity resulted in 129 patient samples from APEX evaluable for PGx; 67 were from the bortezomib arm and 62 from the dex arm. 48 samples were evaluable from 040. Patient characteristics of this subset were similar to those of the overall study population. Predictive classifiers were identified and tested via separate training and test datasets. Results: Consistent with the SUMMIT analysis, the APEX and 040 datasets exhibit biologic features expected of MM, including the overexpression of translocation target genes such as cyclin D1, MAF, and MMSET/FGFR3. Classifiers built using only the SUMMIT samples predict the outcome of pts in the APEX bortezomib arm with an overall accuracy of 51% (sensitivity [Sn] = 49%, specificity [Sp] = 55%; P = .81) and in the dex arm with an overall accuracy of 56% (Sn = 64%, Sp = 50%; P = .31). If the classifier was built using data from both the SUMMIT and 040 trials (87 total samples), the prediction of response in the APEX bortezomib arm was statistically significant (66% accuracy, Sn = 89%, Sp = 42%; P = .006). The same classifier only predicts the response of dex-treated pts with an overall accuracy of 46% (Sn = 72%, Sp = 28%; P = .88), suggesting specificity for bortezomib. Many of the overexpressed genes associated with bortezomib insensitivity relate to protein synthesis (EIF4B, RPL5) and RNA binding (SFRS10, CPSF6). Future Directions: This work highlights practical and scientific issues that inform future efforts to implement PGx in clinical trials. Predictive accuracy may be influenced by the clinical end point, limited sample size, and/or technical considerations associated with distinct trials and genomic data. The influence of study differences (relating to pts’ time from diagnosis, number of prior therapies, molecular subtypes, or hybridization characteristics) on the ability to build classifiers and identify biologic pathways related to response are being examined; these and potential insights on drug mechanisms will be presented.

Introduction: Bortezomib (VELCADE®), a novel proteasome inhibitor, is currently approved for treatment of multiple myeloma (MM) patients in first relapse in the US and EU. At presentation, up to 50% of patients with MM have decreased creatinine clearance, and 20–30% have concomitant renal failure. Although bortezomib has been reported to be safe and effective in patients with renal insufficiency and creatinine clearance as low as 14 mL/min, there is currently little information on its use in patients with advanced renal failure requiring hemodialysis. We conducted a multicenter, retrospective review to investigate the safety and efficacy of bortezomib in renal failure patients requiring hemodialysis. Patients and Methods: Patients were identified by the treating physicians at the participating centers. MM patients with advanced renal failure with or without hemodialysis support who were treated with bortezomib or a bortezomib containing regimen were eligible. Patients had to be ≥ 18 years. Demographic data, dose of bortezomib, response (by EBMT criteria) and duration of response as well as available toxicity data were to be collected for a maximum of 30 patients. Results: Thus far, all data are available for 15 MM patients. The median age was 59 years (range 51–78) and 60% were male. The MM type was IgG in 7 patients, light chain disease in 5, IgA in 2, and IgD in 1. The MM subtype was kappa in 6 patients, lambda in 3, and not specified in 6. All patients had relapsed after a median of 2 prior therapies (range 1–5). All had advanced renal failure while 11 patients were receiving hemodialysis at the time of bortezomib administration. Bortezomib was given after hemodialysis in 10 patients; the timing was not specified in 1. One patient was not evaluable for response. Of the 14 evaluable patients, 2 (14%) achieved a complete response (CR), 1 (7%) had a near CR (nCR) and 2 (14%) had a partial response (PR) for an overall response rate of 36%. Five patients (36%) had stable disease and 4 (27%) had progressive disease. The response durations for the 2 patients achieving CR were 12+ and 17+ months, and for the patient with nCR was 9+ months. The duration of response for those with PR were 2 and 12+ months. One patient died due to progressive disease. One patient (7%) discontinued due to neuropathic pain at cycle 4, and 2 patients (14%) had doses held due to peripheral neuropathy, both at cycle 4. Bortezomib was otherwise generally well tolerated. One patient scheduled for hemodialysis achieved a CR with normalization of renal function without needing dialysis. Conclusion: Although there is no pharmacokinetic (PK) data available and the number of patients studied is relatively small, the information gathered from this study suggests that bortezomib can be given safely to patients with renal failure on hemodialysis who may benefit from this therapy. A formal prospective study with PK is warranted in this patient population to establish a comprehensive safety and efficacy profile and this is ongoing under the auspices of the NCI.

6535 Background: A large randomized phase 3 study (APEX) (Blood 2004;104: Abstract 336.5) in relapsed MM demonstrated significant clinical benefits (time to progression, response, and survival) associated with bortezomib therapy over high-dose dexamethasone, with comparable grade 3 and 4 toxicities. HRQL data were prospectively collected during the study. Methods: Two HRQL instruments (EORTC QLQ-C30 and FACT/GOG-NTX) were administered at baseline, weeks 6, 12, 18, 24, 30, 36, and 42, or until discontinuation of protocol treatment. Data were analyzed based on modified intention-to-treat analysis; 44 of 642 patients were excluded due to no baseline or no follow-up HRQL data. At baseline, the 2 treatment groups were comparable on demographic and clinical characteristics, NTX score, and on most EORTC scores. There were substantial missing HRQL data (from 12.5% at week 6 to 75.6% at week 42), primarily due to premature closure of the study and disease progression. Extensive statistical analyses were undertaken...

6501 Background: Deletion of chromosome 13 [del(13)] by conventional cytogenetics is an important adverse prognostic factor for survival in multiple myeloma (MM) patients (pts) regardless of treatment (conventional chemotherapy and autologous or mini-allogeneic transplantation). However, in a phase 2 trial with bortezomib (VELCADE) (SUMMIT), del(13) did not adversely affect survival or response rate (RR). Therefore, we wanted to support this observation in the recently concluded large phase 3 trial, APEX, which allowed us the opportunity to evaluate the prognostic value of del(13) in both the conventional treatment arm (dexamethasone, dex) and the bortezomib arm. Methods: The APEX trial was a randomized multi-center international phase 3 trial comparing bortezomib and high-dose dex in 669 pts with relapsed MM. This study demonstrated improved survival of pts on bortezomib vs those on dex. Metaphase cytogenetics (MCG) in 168 evaluable pts showed del(13) in 24 (14%). A match-paired analysis of 21 of the 24 ...

3122 Multiple Myeloma (MM) remains fatal despite all available therapies, and novel approaches which target mechanisms regulating MM cell growth, survival, and apoptosis are urgently needed. Protea...

6533 Background: Adverse prognostic factors in multiple myeloma (MM) include advanced age, increased β2-microglobulin (β2-M), and prior treatment (tx) failure. Bortezomib (VELCADE, Vc), a first-in-class proteasome inhibitor, provided improved time to progression (TTP) and higher response rates (RR) compared with high-dose dexamethasone (Dex) in patients (pts) with relapsed MM in a large randomized international multicenter phase 3 trial (APEX). The safety and efficacy of Vc were compared with Dex in elderly (≥ 65 y) and other high-risk pts in a subgroup analysis of this trial. Methods: 669 pts received either Vc 1.3 mg/m2 IV on d 1, 4, 8, and 11 for up to eight 3-wk cycles, followed by tx on d 1, 8, 15, and 22 for up to three 5-wk cycles, or Dex 40 mg po on d 1–4, 9–12, and 17–20 for up to four 5-wk cycles, followed by tx on d 1–4 for up to five 4-wk cycles. Pts were stratified at entry by therapeutic history (1 vs > 1 prior line), β2-M (≤ 2.5 vs > 2.5 mg/L), and response to last tx regimen (refractory vs...

6610 Introduction: Bortezomib (VELCADE, btz) is a first-in-class proteasome inhibitor with efficacy in multiple myeloma (MM). Btz has been associated with transient, cyclical thrombocytopenia (TP)....

Irradiation with 200 keV electrons induced amorphism in natural beryl and cordierite, at fluences of ∼ 1026e/m2, a factor of ≈ 10 times that required to produce a similar effect in quartz. After dehydration of the beryl and cordierite by heating at 1050°C, the fluence required to induce amorphism was increased to ∼ 1027e/m2. The electron fluence required to produce amorphism in both materials decreased with decreasing electron energy, as expected if solid-phase radiolysis is responsible. CsAlSi5O12, prepared by dry-firing ceramic techniques, was rendered amorphous at a fluence of 3 × 1024 e/m2 (E = 200 keV). However, there was little apparent dependence of the electron fluence required to produce amorphism on electron energy over the 50–200 keV range, and Cs+ migration may play a critical role in the crystalline ← amorphous transformation. A natural sphene was unaffected structurally by irradiation to a fluence of 2 × 1027 e/m2 (E = 200 keV). The data are consistent with established theories that...