Richardson, Paul Gerard Guy

Abstract Abstract 621 Background: Two- and three-drug regimens incorporating bortezomib (Velcade®, V), lenalidomide (Revlimid®, R), dexamethasone (D), or cyclophosphamide (C) have been shown to be effective and well tolerated in previously untreated multiple myeloma (MM). Combining all four drugs in a single regimen (VDCR) may further enhance efficacy. Published results from the phase 1 dose-escalation portion of the non-comparative, multi-center EVOLUTION study showed that the VDCR regimen was highly active and generally well tolerated (Kumar et al Leukemia 2010). Here we present updated results from the phase 2 portion of the trial, focusing on efficacy and safety of the VDCR, VDR, and VDC regimens. Methods: Previously untreated patients with measurable disease were randomized to one of four treatment groups receiving up to eight 21-d cycles of VDCR (V 1.3 mg/m2 d 1, 4, 8, 11; D 40 mg d 1, 8, 15; R 15 mg d 1–14; C 500 mg/m2 d 1, 8), VDR (VD as in VDCR but with R 25 mg d 1–14), VDC (VDC as in VDCR), or VDC-mod (as for VDC but with an additional dose of C on d 15) as induction therapy, followed by four 42-d maintenance cycles of V 1.3 mg/m2 (d 1, 8, 15, 22) (all treatment arms). Patients eligible for autologous stem cell transplant (SCT) could undergo stem cell mobilization any time after cycle 2 and SCT any time after cycle 4. The primary endpoint was the combined complete response (CR) + very good partial response (VGPR) rate; secondary endpoints included safety/tolerability, time to response, duration of response, progression-free survival, and rate of minimal residual disease (MRD) negativity. Responses were assessed according to International Myeloma Working Group (IMWG) uniform criteria using an automated computer algorithm. Adverse events (AEs) were graded using the CTCAE v3.0. Results: Patient characteristics were similar among the groups with respect to age, performance status, ISS stage, and proportion of patients with high-risk cytogenetic features. Patients received a median of 5, 6, 6, and 6 treatment cycles in the VDCR, VDR, VDC, and VDC-mod arms, respectively; 65%, 60%, 52%, and 47% of patients had dose reductions of any drug. In the VDCR, VDR, VDC, and VDC-mod arms, respectively, 52%, 62%, 58%, and 65% of patients completed treatment; 31%, 43%, 24%, and 41%, respectively, underwent SCT. In the phase 2 response-evaluable patients (n=132), all treatment regimens showed substantial efficacy, with CR+VGPR rates of 59% (VDCR), 50% (VDR), 41% (VDC), and 59% (VDC-mod) (Table) (includes pre-transplant responses only in SCT patients). Of MRD-assessed patients, 46% (21/46) of those who achieved CR (including sCR) or nCR were MRD-negative; 48% (10/21), 75% (9/12), 0% (0/7) and 33% (2/6) in the VDCR, VDR, VDC and VDC-mod arms, respectively. Median time to first response was similar across arms (range 1.6–1.8 months); median time to best response of CR+VGPR was 4.0 months (VDCR), 3.4 months (VDR), 5.1 months (VDC), and 3.1 months (VDC-mod). Median duration of response has not been reached in any arm to date. All treatment regimens were generally well tolerated. In the VDCR, VDR, VDC, and VDC-mod arms, at least one grade ≥3 AE was observed in 81%, 76%, 79%, and 88% of enrolled patients, respectively; serious AEs were experienced by 42%, 40%, 21%, and 41% of patients, and AEs resulting in study discontinuation were reported for 19%, 17%, 12%, and 6% of patients. The five most common all-grade AEs across all treatment groups were fatigue (range 47–67%), nausea (36–67%), constipation (40–62%), diarrhea NOS (42–65%), and neutropenia (19–52%). The incidence of grade ≥3 (grade ≥2) peripheral neuropathy (PN) was 13% (40%) in the VDCR arm, 14% (45%) VDR, 9% (48%) VDC, and 18% (41%) VDC-mod; there was no grade 4 PN. Rates of grade ≥3 neutropenia/thrombocytopenia were 42%/10% for VDCR, 7%/7% VDR, 36%/12% VDC, and 65%/18% VDC-mod. Conclusions: All regimens appear highly active and generally well tolerated in previously untreated MM patients. The four-drug combination did not result in a substantial increase in response rate and was associated with a modest increase in the incidence of hematologic toxicities. Continuous weekly C in the VDC regimen was associated with high response rates and rapid responses, comparable to the VDR and VDCR arms. Outcome data will be presented following longer follow-up. Disclosures: Kumar: Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding; Bayer: Research Funding. Off Label Use: Lenalidomide for treatment of newly diagnosed myeloma. Flinn:Millennium Pharmaceuticals, Inc.: Research Funding. Richardson:Celgene, Millennium, Novartis, Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Hari:Celgene: Research Funding. Callander:Millennium Pharmaceuticals, Inc.: Research Funding. Noga:Amgen: Honoraria, Research Funding, Speakers Bureau; Millennium: Consultancy, Honoraria, Research Funding, Speakers Bureau; Ortho-Centicor: Honoraria, Speakers Bureau; Cephalon: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau. Stewart:Millennium Pharmaceuticals, Inc.: Honoraria, Research Funding; Celgene: Honoraria. Rifkin:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau; Amgen: Speakers Bureau; Cephalon: Speakers Bureau; Dendreon: Speakers Bureau. Wolf:Millennium Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Genentech and Multiple Myeloma Research: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Speakers Bureau; OrthoBiotech: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau. Estevam:Millennium Pharmaceuticals: Employment. Mulligan:Millennium Pharmaceuticals, Inc.: Employment. Shi:Millennium Pharmaceuticals: Employment. Webb:Millennium Pharmaceuticals: Employment.

Abstract Introduction Gene Expression Profiling studies have resulted in signatures capable of providing robust prognosis for Multiple Myeloma (MM) patients, such as the EMC92 [SKY92, Kuiper et al. Leukemia 2012]. Recently, data from 4720 MM patients from the HOVON-65/GMMG-HD4, UAMS-TT2, UAMS-TT3, MRC-IX, APEX and IFM trials were employed to assessed the majority of currently identified prognostic markers and their combinations (GEP, FISH, and biochemistry data, [Kuiper et al ASH 2014]). The "SKY92 + ISS" was identified and validated as the statistically most optimal (i.e. most significant and robust) prognostic marker combination for MM patients. The combination of the EMC92 (=SKY92) and ISS prognostic features proves to be a very powerful, unprecedented and straightforward prognostic system. It identifies four prognostic risk classes: low risk (ISS I-SKY92 standard risk (SR)), intermediate-low (ISS II-SKY92 SR), intermediate-high (ISS III-SKY92 SR) and high risk (ISS I-III, SKY92 high risk). Previously, the SKY92 has been validated on the 91 MM cases in the MMGI cohort [Van Beers et al. ASH 2013]. Here we present an extension of that validation with the SKY92 + ISS combination on the 78 MM cases for whom both GEP and ISS is available, by both assessing as the "4 risk group" model defined above, but also a "3 risk group" model (the two intermediate groups combined) as this may be more relevant and useful for clinical application. Materials and Methods A public untreated MM dataset (Multiple Myeloma Genomics Initiative, MMGI) had n=78 cases for which OS, GEP, and ISS were available for analysis. The prognostic markers SKY92 and ISS were applied as proposed [Kuiper et al ASH 2014] to classify cases into the risk categories. Results The risks for the 4 group classification model are shown in Table 1 and Figure 1, and the 3 risk group model is shown in Table 2 and Figure 1. In the 4 group model, the intermediate-low group (SKY92 standard + ISS II) was a small and not significantly different (p=0.79) from the low risk. The intermediate-high group (SKY92 standard + ISS III) was also a small group, with significantly worse outcome compared with the low risk group (p=0.012). Although stratification into four groups was statistically superior in the training and validation data [Kuiper et al ASH 2014] the interpretability benefits from aggregation of the middle two groups [Fig 1 right]. Table 1. Classification results for the four risk groups (Fig 1 left) Risk group n % Median OS HR vs low risk SKY92 High Risk regardless of ISS 19 24 28.4 m 10.8 SKY92 standard risk + ISS-III 10 13 63.0 m 4.1 SKY92 standard risk + ISS-II 16 21 NR (0.8) SKY92 standard risk + ISS-I (low risk) 33 42 NR NA NR= Not Reached at 96 months, HR= hazard ratio Table 2. Classification results for the three risk groups (Fig 1 right) Risk group n % Median OS HR vs low risk SKY92 High Risk regardless of ISS 19 24 28.4 m 10.1 SKY92 standard risk + ISS-II/III 26 34 78.5 m (1.8) SKY92 standard risk + ISS-I 33 42 NR NA NR= Not Reached at 96 months, HR= hazard ratio, () not significant Conclusions By applying the SKY92 + ISS risk stratification model in an independent validation cohort of newly diagnosed Multiple Myeloma patients, besides a high risk group of 19 patients (24%), a group of 33 patients (42%) with superior prognosis could be predicted (SKY92 standard risk and ISS I) that translated into 62% OS at 96 months. The 19 high risk (SKY92 high risk) cases had very poor prognosis (median survival of 28 months). The combination of SKY92 Standard Risk and ISS II and III seems useful for definition of "intermediate risk" although sample size currently is insufficient for significance compared to low risk. The intention is to also perform this validation on the relapsed samples from the MMGI cohort, once OS data has been collected. This validated risk model could play a role in the design of future treatment strategies for high and low risk MM patients. Figure 1. Kaplan Meier curves on the 78 MMGI cases, split into four (left) or three (right) risk groups based on the combination of SKY92 + ISS. Hazard Ratios (HR) are from a Cox proportional Hazards model comparing a particular group to the low risk group. Figure 1. Kaplan Meier curves on the 78 MMGI cases, split into four (left) or three (right) risk groups based on the combination of SKY92 + ISS. Hazard Ratios (HR) are from a Cox proportional Hazards model comparing a particular group to the low risk group. Disclosures van Beers: SkylineDx: Employment. van Vliet:SkylineDx: Employment. de Best:SkylineDx: Employment. Chari:Novartis: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biotest: Other: Institutional Research Funding; Array Biopharma: Consultancy, Other: Institutional Research Funding, Research Funding; Onyx: Consultancy, Research Funding. Jagganath:Millennium: Honoraria; Celgene: Honoraria. Jakubowiak:Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: 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, Other: institutional funding for support of clinical trial conduct, Speakers Bureau; SkylineDx: 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, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SkylineDx: Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kumar:Celgene, Millenium, Sanofi, Skyline, BMS, Onyx, Noxxon,: Other: Consultant, no compensation,; Janssen: Research Funding; AbbVie: Research Funding; Sanofi: Research Funding; Millenium/Takeda: Research Funding; Celgene: Research Funding; Onyx: Research Funding; Skyline, Noxxon: Honoraria. Lebovic:Onyx: Speakers Bureau; Celgene: Speakers Bureau. Lonial:Millennium: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Reece:Onyx: Honoraria; Novartis: Honoraria; Millennium: Research Funding; Merck: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Research Funding. Richardson:Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Siegel:Celgene Corporation: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Novartis: Speakers Bureau; Merck: Speakers Bureau. Stewart:SkylineDx: Membership on an entity's Board of Directors or advisory committees. Vij:Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium: Honoraria, Speakers Bureau; BMS: Consultancy; Takeda: Consultancy, Research Funding; Novartis: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Merck: Consultancy. Zimmerman:Celgene: Honoraria, Speakers Bureau; Millennium: Honoraria, Speakers Bureau; Onyx: Honoraria; Amgen: Honoraria, Speakers Bureau. Fonseca:Onyx/Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Binding Site: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Applied Biosciences: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.

Abstract Abstract 127 Two- and three-drug regimens incorporating bortezomib (Velcade®, Vc), lenalidomide (Revlimid®, Rev), dexamethasone (Dex), and cyclophosphamide (Cy) (Vc–Dex, Rev–Dex, Vc–Dex–Rev [VDR], and Vc–Dex–Cy [VDC]), have been shown to be effective and well tolerated in previously untreated multiple myeloma (MM). Combining Vc and Dex with Rev and Cy in a novel four-drug regimen (VDCR) may result in even greater activity with improved quality and duration of response. Results from the phase 1 dose-escalation portion of the multi-center EVOLUTION study showed that the VDCR regimen is a highly active and generally well-tolerated induction therapy in previously untreated MM patients (pts). Here we report the efficacy and safety of VDR, VDC, and VDCR from the non-comparative phase 2 portion of the study. Methods: Pts were randomized to receive up to eight 21-d cycles of VDR (Vc 1.3 mg/m2 d 1, 4, 8, 11; Dex 40 mg d 1, 8, 15; Rev 25 mg d 1–14) or VDC (VD as in VDR, plus Cy 500 mg/m2 d 1, 8) or VDCR (VDC plus Rev 15 mg d 1–14) as induction therapy, followed by Vc 1.3 mg/m2 (d 1, 8, 15, 22) for four 42-d maintenance cycles in all treatment arms. Pts received prophylactic antibiotics, acyclovir, transfusion support, and anticoagulants as required. Eligible pts wishing to undergo autologous stem cell transplant (ASCT) could undergo stem cell mobilization any time after cycle 2, and undergo ASCT any time after cycle 4. Response categories were based on the IMWG Criteria with the addition of near complete response (nCR). Adverse events (AEs) were graded using the CTCAE v3.0. Results: In the VDR, VDC, and VDCR arms 42, 32, and 43 pts (including 6 pts treated at the maximum planned dose of Cy (500 mg/m2) from phase 1) have been treated, and 42, 31, and 33 are evaluable for response, respectively, as of data cut-off (31 July 2009). Median ages in the VDR, VDC, and VDCR arms were 60, 62, and 62 years, respectively; 62%, 63%, and 66% had International Staging System stage lI/III disease, and 38%, 25%, and 33% had Karnofsky Performance Status ≤80%, respectively. The median number of VDR, VDC, and VDCR cycles received is 4.5, 6, and 4, respectively (range 1–12). Best unconfirmed response rates are shown in the Table; patients categorized as very good partial response (VGPR) include those who have no measurable M-protein but have not yet had bone marrow assessments to confirm CR/nCR status. The overall rates of treatment-emergent AEs were 95%, 97%, and 88% for the VDR, VDC, and VDCR arms, respectively, with ≥grade 3 reported in 67%, 59%, and 65%. Peripheral neuropathy (PN) was reported as grade 2/3 in 12%/12% in the VDR, 31%/3% in the VDC, and 12%/9% in the VDCR arms; there was no grade 4 PN reported. Grade 3/4 neutropenia was reported in 5%/5%, 28%/13%, and 23%/9% of pts in the VDR, VDC, and VDCR arms, and grade 3/4 thrombocytopenia in 5%/2%, 9%/0%, and 5%/0% of pts, respectively. One case of grade 3 deep-vein thrombosis was reported in the VDCR arm. Overall rates of serious AEs were 24%, 13%, and 37% in the VDR, VDC, and VDCR arms, respectively. Two pts have died in the VDCR arm, both due to renal failure, considered possibly treatment-related. To date, 6 pts have undergone ASCT in the VDR arm, 5 in the VDC arm, and 3 in the VDCR arm. Median CD34+ yield was 4.7, 6.3, and 6.8 × 106/kg in the VDR, VDC, and VDCR arms, respectively. Conclusions: VDR, VDC, and VDCR are highly active and generally well-tolerated regimens in previously untreated MM. Response rates in the VDCR arm appeared somewhat higher than in the VDR and VDC arms at this early time point, although there also appeared to be higher rates of serious AEs, including possible treatment-related mortality in the VDCR arm. Following an interim analysis, dosing in the VDC arm was modified to include Cy on day 15 to examine if this will improve CR rates. Ten pts have been enrolled to date. Disclosures: Kumar: CELGENE: Research Funding; MILLENNIUM: Research Funding; BAYER: Research Funding; GENZYME: Research Funding; NOVARTIS: Research Funding. Flinn:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hari:Milennium Pharmaceuticals Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Callander:Millenium: Research Funding. Noga:Millennium Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Stewart:Takeda-Millenium, Celgene, Novartis, Amgen: Consultancy; Takeda, Millenium: Research Funding; Genzyme, Celgene, Millenium, Proteolix: Honoraria. Raje:Celgene: Research Funding; Novartis: Research Funding; AstraZeneca: Research Funding. Rifkin:Millennium Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Cephalon: Speakers Bureau. Shi:Millennium Pharmaceutical Inc.: Employment. Webb:Millennium: Employment, Equity Ownership. Richardson:Keryx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: 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; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Abstract Abstract 2878 Poster Board II-854 Background: Significant advances have been made in the treatment of myeloma with the introduction of thalidomide, its analogue, lenalidomide, and the proteasome inhibitor bortezomib. While these new drugs have improved the outcome of patients with myeloma, the disease still remains incurable. Effectiveness of upcoming new therapies will need to be assessed in the context of anticipated outcome with the currently available therapies. However, given the rapid pace of development over the past decade, outcome of patients who have relapsed on the new therapies remain unclear. Methods: In order to further study this group of patients, we undertook a study of patients who have relapsed on or are refractory to one of the IMiDs (thalidomide or lenalidomide) as well as bortezomib. A total of 300 cases from 8 sites in the US, 5 sites in Europe and one site in Asia were identified for this study. Enrolled patients had relapsed and refractory multiple myeloma, per the EBMT or IMWG response criteria, after at least 2 prior treatments. Patients were refractory to bortezomib, defined as having no response on a prior bortezomib-containing regimen or experiencing disease progression within 60 days of a bortezomib-containing regimen. Patients also should have relapsed, refractory, intolerant, and/or ineligible in the opinion of the investigator, to other therapies, including an IMiD (thalidomide or lenalidomide). Clinical and laboratory data pertaining to the time of diagnosis and from the time of individual relapses were obtained from the clinical records. The date patients satisfied the above entry criteria was defined as time zero. Results: The current analysis includes the first 119 patients with complete data available. The median age at initial diagnosis was 59 years (range, 31-86 yr); 71% were males. The ISS stage distribution at diagnosis was 33%, 39% and 28% for stages 1, 2, and 3 respectively. 19 patients (37%) had high risk disease by FISH [t(4;14), t(14;16), del17p] or by cytogenetics [del 13, hypodiploidy]. The median time from diagnosis to time zero was 3.8 yrs (range 0.2-18.7 yr) and the median reported lines of therapy before time zero was 2. 74% patients had at least 1 autologous stem cell transplant prior to becoming eligible for the study. Following time zero, 77 (65%) pts had a treatment recorded, including an autologous SCT in 21 (18%), with the treatment regimen starting at a median of 1 month after time zero. A variety of treatment regimens were utilized beyond time zero (median=1; range 0-7). Thirty-two (27%) patients had a response any time following time zero, and only 8 had a subsequent response. Response to the first treatment, or supportive care for patients not treated, recorded following time zero included minor response or stable disease (n=14; 12%), PR (n=17, 14%), and VGPR or better (n=6, 5%). Patients treated with SCT had a higher rate of PR or better compared to patients receiving other treatments (85%; 17/20 vs. 26%; 15/57). In a multivariate analysis, the only significant predictor of a PR or better after time zero was younger age (<60 yrs). The median overall survival (OS) and event free survival (EFS) were 6 mos (95% CI, 4-7 mos) and 1 month (95% CI,1-2 mos) respectively. In a multivariate analysis normal creatinine predicted for a better overall survival and having an IgG M protein type predicted for better EFS. A complete analysis from all 300 patients will be presented at the meeting. Conclusions: This study confirms the poor outcome of patients once they become relapsed and refractory to agents that have become the mainstay of myeloma therapy. The findings highlight the incurable nature of the disease and urgent need to develop newer effective therapeutic agents for this group of patients, who currently do not have effective treatment options. Disclosures: Kumar: CELGENE: Research Funding; MILLENNIUM: Research Funding; BAYER: Research Funding; GENZYME: Research Funding; NOVARTIS: Research Funding. Jagannath:Merck: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees. Laubach:Novartis: . Palumbo:Ortho Biotech, Janssen-Cilag: Honoraria; Celgene: Honoraria, Speakers Bureau. Richardson:Millennium Pharmaceuticals, Inc.: Consultancy, 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; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: 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. San Miguel:Millennium: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Siegel:Celgene: Speakers Bureau; Millennium: Speakers Bureau. Sonneveld:Janssen-Cilag: Honoraria. Durie:Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees.

Abstract Abstract 479 Background: MLN9708 is an investigational, oral, potent, reversible, and specific 20S proteasome inhibitor, which immediately hydrolyzes to MLN2238, the biologically active dipeptidyl leucine boronic acid. In preclinical studies, MLN2238 has shown faster proteasome dissociation and greater tissue penetration than bortezomib. Current phase 1 data indicate that oral administration of single-agent MLN9708 was generally well tolerated, with no grade ≥3 peripheral neuropathy, and showed signs of antitumor activity in some patients with relapsed and/or refractory MM. Bortezomib in combination with lenalidomide and dexamethasone demonstrated a 100% partial response or better (≥PR) rate in patients with previously untreated MM, providing the rationale for evaluating oral MLN9708 in place of bortezomib in this combination. Here we report phase 1 data from the first combination study of MLN9708 (ClinicalTrials.gov: NCT01217957). Methods: Primary phase 1 objectives were to determine the safety, tolerability, and maximum tolerated dose (MTD) of weekly MLN9708 in combination with lenalidomide and dexamethasone; secondary objectives included characterization of the pharmacokinetic (PK)/pharmacodynamic (PD) profile of MLN9708, assessment of PK interaction and response. Adults aged ≥18 years with ECOG performance status of 0 to 2, and adequate renal, hepatic, and hematologic function were eligible. Patients with grade ≥2 peripheral neuropathy or prior/concurrent deep vein thrombosis (DVT)/pulmonary embolism were excluded. Patients received oral MLN9708 weekly on days 1, 8, and 15, lenalidomide 25 mg on days 1–21, and dexamethasone 40 mg on days 1, 8, 15, and 22, for up to twelve 28-day cycles. Patients received thromboprophylaxis with aspirin or low molecular weight heparin. Transplant-eligible patients could undergo stem cell transplant after six cycles. MLN9708 dose escalation, from a starting dose of 1.68 mg/m2, followed a 3+3 scheme based on the occurrence of dose-limiting toxicities (DLTs) in cycle 1. Adverse events (AEs) were evaluated according to NCI-CTCAE v4.0. Response was assessed according to modified EBMT criteria. Results: At data cut-off (June 29, 2011), 10 patients have been enrolled and treated: three each at 1.68, 2.23, and 2.97 mg/m2 and one at 3.95 mg/m2; median age was 66 years (range 59–77). Patients completed a median of 3 cycles (range 1–6), with three having received 6 cycles; treatment is ongoing in six patients. A DLT of grade 3 fainting was observed in a patient treated at 3.95 mg/m2. The MTD has not yet been reached; the current cohort is receiving 3.95 mg/m2. Drug-related AEs included rash in four patients (two maculopapular, two erythematous); vomiting and fatigue in three patients each; and diarrhea, constipation, and nausea in two patients each. Grade 1 treatment-related peripheral neuropathy was reported in one patient. Serious AEs were seen in four patients: one at 3.95 mg/m2 (DLT of grade 3 fainting), one at 2.23 mg/m2 (grade 3 DVT) unrelated to MLN9708, and two unrelated at 1.68 mg/m2 (grade 3 hypotension; grade 3 gastrointestinal hemorrhage resulting in discontinuation). Two patients required lenalidomide dose reductions to 15 mg due to erythematous rash; no dose reductions were required for MLN9708 or dexamethasone. There were no on-study deaths. Of nine response-evaluable patients, all nine achieved ≥PR, including three very good PR (VGPR) and one complete response. Time to response was rapid; all responders achieved a ≥50% decrease in M-protein in cycle 1, and best response was reached by the end of cycle 4. No patient has progressed to date. One patient with confirmed VGPR discontinued at cycle 6 to undergo stem cell transplant. Conclusions: MLN9708 administered weekly in combination with lenalidomide and dexamethasone appears to be generally well tolerated in previously untreated MM patients at the MLN9708 dose levels studied, with evidence of antitumor activity in the dose-escalation cohorts. Evaluation continues to determine the MTD of MLN9708 in this combination. Updated results, PK data, assessment of PK interaction, and PD data will be presented. Disclosures: Off Label Use: Use of the investigational agent MLN9708 for the treatment of previously untreated multiple myeloma. Richardson: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 Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Lonial:Millennium Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Onyx: Consultancy; Merck: Consultancy. Niesvizky:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Research Funding. Hui:Millennium Pharmaceuticals, Inc.: Employment. Berg:Millennium Pharmaceuticals, Inc.: Employment. Gupta:Millennium Pharmaceuticals, Inc.: Employment. Liu:Millennium Pharmaceuticals, Inc.: Employment. Di Bacco:Millennium Pharmaceuticals, Inc.: Employment. Kumar:Merck: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Genzyme: Research Funding; Novartis: Research Funding.

Abstract Abstract 487FN2 Background: Given the life-threatening nature of severe VOD (sVOD) and multi-organ failure (MOF), DF was made available in the US through a prospective treatment IND protocol (T-IND) to gather additional safety and response data from SCT patients (pts) with sVOD who were not eligible for a pivotal Phase 3 trial. Following completion of this Phase 3 trial, the T-IND protocol has continued and been amended to include pts who would have met eligibility criteria for the completed phase 3 trial, as well as pts with non-severe VOD and non-SCT pts who develop VOD after chemotherapy (chemo). This is the largest prospective evaluation of DF for the treatment of sVOD/MOF post SCT and non-SCT pts to date. Methods: Pts were initially required to have a diagnosis of VOD by Baltimore criteria (total bilirubin > 2.0 mg/dL with > 2 of the following: hepatomegaly, ascites or 5% weight gain) with MOF (either renal and/or pulmonary failure) that followed SCT. Following treatment of 104 pts, an amendment expanded eligibility criteria to include pts with VOD after chemo and pts with non-severe VOD (defined as no MOF). Key exclusion criteria included clinically significant bleeding or >1 pressor to maintain BP. CR was defined as bilirubin < 2 mg/dL + resolution of MOF (if applicable). Mortality was assessed at Day +100 (D+100) in all pts. DF was given at 6.25 mg/kg IV q6h (25 mg/kg/d) with treatment duration recommended for at least 21d. Results: This interim analysis is based on 269 pts enrolled between December 2007 and March 2011 at 67 centers. Nearly all pts (n=251) had undergone SCT (with allogeneic SCT in 225, 90%); 18 developed VOD after chemo alone. Of the 269 cases of VOD, 200 were severe at study entry, with 25% (66/269) of all pts dialysis dependent and 31% (83/269) ventilator dependent. Median age was 16 years (range 0.1 – 70); 55% were male. In the SCT pts, the most common diagnosis was leukemia (29% AML; 22% ALL; CML 3%; 4% other), with conditioning of CY (71%), BU (46%) and TBI (38%) respectively; 18% had undergone multiple SCTs (>1 SCT). Median onset of VOD was 15 d post-SCT. When presenting after chemo alone (n=18), median onset of VOD was 16 d after the first dose, most frequently after CY (61%), cytarabine (44%) and vincristine (39%), and for treatment of leukemia (AML 33%, ALL 33%, other 6%). Overall mean number of days of DF administration in all pts was 22 (range 1–88).Of 269 pts, 32% (85/269) achieved a CR and 50% [ by Kaplan-Meier estimate] survived to D+100. In the subgroup of SCT pts, 31% (78/251) achieved CR and 50% survived to D+100; 134 pts met entry criteria for the original Phase 3 trial and comparison to the Phase 3 historical control showed a statistically improved outcome in CR (30% vs 9%, p=0.0006) and D+100 survival (46% vs 25%; p=0.006). Of 200 pts with sVOD, CR was 28% and D+100 survival was 44%. In the 18 chemo only pts, CR was 39% and D+100 survival was 50%. CR rate and D+100 survival for the 69 pts with non-severe VOD were 42% and 62%, respectively. Delay of >2 d (vs < 2 d) in the start of DF after VOD diagnosis resulted in reduced CR (23% vs 35%, p=0.0339) and survival (37% vs 56%, p=0.01). Children as compared to adults had higher rates in CR (35% vs 29%) and survival (55% vs 43%). Toxicity proved generally manageable: 22% of pts experienced a total of 81 related AEs, primarily consisting of hemorrhage (19%) and hypotension (4%). Hemorrhage included pulmonary bleeding (6%), GI hemorrhage (3%), epistaxis (3%) and hematuria (3%). Similar to the observation of decreased GvHD in other studies, the incidence of all grade GvHD in the allogeneic SCT pts was 8%. Conclusions: In 269 pts with mainly sVOD/MOF, DF therapy achieved significantly improved outcome compared to an untreated historical control. Importantly, CR and survival were improved in pts who were treated within 2d of VOD diagnosis (vs. later) and in pts who had not yet progressed to sVOD. As with prior studies, there was a low incidence of DF-associated toxicities. Interestingly, the incidence of GvHD in allo-SCT pts was low, consistent with the reduction of GvHD seen in the large randomized EBMT pediatric prevention study. These results confirm the findings of previous trials and strongly support early intervention with DF once the diagnosis of VOD is made after SCT, as well as its use in pts who have not progressed to advanced MOF. The use of DF for VOD following intensive chemotherapy without SCT also appears promising, but more research in this patient population is needed. Enrollment to the T-IND study continues. Disclosures: Richardson: Gentium: Membership on an entity's Board of Directors or advisory committees. Arai:Gentium: Research Funding. Symons:Otsuka Pharmaceuticals: Research Funding. Martin:Gentium: Research Funding. Massaro:Gentium: Consultancy. D'Agostino:Gentium: Membership on an entity's Board of Directors or advisory committees. Hannah:Gentium: Consultancy. Tudone:Gentium: Employment. Hume:Gentium: Employment. Iacobelli:Gentium SpA: Employment. Soiffer:Gentium: Honoraria.

Abstract Purpose: Deep vein thrombosis (DVT) is increasingly recognized as a major complication of thalidomide (T; Thal) and lenalidomide (R; Rev) based therapy for multiple myeloma. Estimated incidence varies widely in the literature. There is no consensus on specific risk factors, indications for thromboprophylaxis or the agent of choice for DVT prophylaxis. The purpose of this study was to develop a consensus among members of the IMWG. Patients and Methods: A survey was electronically mailed to 67 IMWG members on July 21, 2006 and consisted of 24 multiple-choice questions. Results: Twenty-three IMWG members (34%) sent in their responses by the cut-off date. All (100%) felt that DVT was an important question, but most (95%) did not avoid Thal/Rev based therapy because of the DVT risk. Overall results are summarized in the Table below. A majority of physicians felt that concomitant therapy with high dose dexamethasone (90% of physicians), alkylators (55%), doxorubicin/liposomal doxorubicin (90%), and erythropoietin (75%) increase the risk of DVT associated with Thal or Rev based therapy. Aspirin (81 mg or 325 mg per day) was the preferred choice of prophylaxis when necessary. However, 65% of respondents preferred warfarin to a therapeutic INR or LMW heparin if either doxorubicin or liposomal doxorubicin was added to the regimens. Most (95–100%) felt that DVT prophylaxis was not indicated for: VAD, MP, bortezomib +/− dexamethasone regimens. Seventy-five percent felt it to be safe to resume therapy with Thal/Rev after therapeutic anticoagulation. Most (95%) believed randomized trials were needed. Conclusion: DVT is recognized as a major clinical problem associated with Thal/Rev containing regimens. Most respondents felt that the DVT risk did not warrant any prophylaxis when either Thal or Rev were used as single agents. Aspirin was the preferred form of DVT prophylaxis for most Thal/Rev containing regimens, except when doxorubicin/liposomal doxorubicin or melphalan were added. Additional responses will be analyzed both electronically and by conference call prior to the meeting. Therapy Estimated incidence of DVT (% respondents) Choice of thromboprophylaxis (% respondents) Single agent thal <5% (61%) None (65%) Single agent Rev <5% (80%) None (65%) Thal-Dex 10–20% (52%) Aspirin (60%) Rev-Dex 10–20% (48%) Aspirin (60%) MPT 10–20% (65%) Aspirin (40%) R-MP 5–10% (57%) Aspirin (70%)

Abstract Background: Triplet regimens combining a proteasome inhibitor, an immunomodulatory drug, and a steroid have been shown to be active and well tolerated in previously untreated MM pts. Extended treatment represents an alternative paradigm to induction followed by ASCT in this setting; however, agents for continuous therapy need to be convenient and well tolerated. The investigational agent ixazomib is the first oral proteasome inhibitor to be studied clinically. Phase 1 studies have indicated single-agent activity in relapsed/refractory MM and shown ixazomib to be well tolerated with a manageable safety profile, including limited peripheral neuropathy (PN) (Richardson PG et al, Blood 2014; Kumar SK, et al, Blood 2014). Weekly ixazomib plus lenalidomide-dexamethasone has been investigated in a phase 1/2 study in previously untreated MM pts (NCT01217957); treatment comprised triplet induction therapy followed by single-agent ixazomib maintenance therapy. Results of induction therapy have been previously reported (Kumar SK, et al, ASH 2012). Here we report phase 2 efficacy and safety data in pts receiving ixazomib maintenance. Methods: In phase 2, pts aged ≥18 yrs with measurable disease and no grade ≥2 PN received oral ixazomib 4.0 mg on d 1, 8, 15, lenalidomide 25 mg on d 1–21, and dexamethasone 40 mg on d 1, 8, 15, 22, for up to twelve 28-d induction cycles, followed by maintenance ixazomib on d 1, 8, 15 every 28 d until progression at the dose last tolerated during induction. Transplant-eligible pts could discontinue from study for ASCT after 6 cycles. The primary objective was CR+VGPR rate. Responses were assessed by IMWG criteria. Adverse events (AEs) were graded by NCI-CTCAE v4.02. Results: Fifty pts were enrolled in phase 2; 29 discontinued during induction (cycles 1–12), primarily to undergo ASCT (n=14) or due to AEs (n=6) or pt withdrawal (n=4). Twenty-one pts received ixazomib maintenance therapy (cycle ≥13); 13 (62%) were male, and median age was 68 (range 34–77) years. At data cut-off (June 11, 2014), pts had received a median of 27 treatment cycles (range 15–32), including both induction and maintenance, with a median treatment duration of 26.6 mos (range 13.4–29.6). Mean ixazomib relative dose intensity was 95% and 89% in the induction and maintenance phases, respectively. The mean ixazomib dose administered during maintenance was 3.6 mg weekly. At data cut-off, 11 (52%) pts remained on ixazomib maintenance. Among 49 evaluable phase 2 pts, 44 (90%) achieved ≥PR, including 29 (59%) ≥VGPR. All 21 pts who received ixazomib maintenance had responded to induction therapy. Overall best confirmed/unconfirmed responses in the 21 pts included ≥CR in 11 (52%, of which 4 [19%] were stringent CRs [sCR]), ≥near-CR in 13 (62%), and ≥VGPR in 15 (71%), plus 6 (29%) PR. Responses were rapid and improved during treatment. Median time to first response (≥PR) was 0.99 mos (range 0.92–5.78) and to best response was 7.46 mos (range 1.02–24.74); 33% of pts improved their response during maintenance, including 2 VGPR to near-CR, 3 VGPR to CR, 1 VGPR to sCR, and 1 CR to sCR. At data cut-off, median duration of response was 26.5 mos (range 5.6–26.6+). Among 15 pts achieving ≥VGPR, 5 (33%) had progressed; median duration of ≥VGPR was 23.0 mos (range 3.7–26.1+). All pts were alive after follow-up of 24.6–30.3 mos, including a median follow-up from start of maintenance of 16.9 mos (range 12.9–18.9). Ixazomib maintenance was well tolerated; 15 (71%) pts had drug-related AEs, with only 2 (10%) pts with grade 3 drug-related AEs (hypokalemia, thrombocytopenia) and no grade 4 AEs. The most common (>1 pt) grade 1–2 drug-related AEs were diarrhea (n=8, 38%), nausea, pain in extremity (each n=3, 14%), anemia, and headache (each n=2, 10%). No PN was reported. Serious AEs were reported in 3 (14%) pts during maintenance, including grade 3 acute myocardial infarction, grade 3 pneumonia, and grade 3 orthostatic hypotension; all were considered not related to treatment. Only 1 pt required an ixazomib dose reduction due to an AE (neuralgia). Conclusions: These data indicate that single-agent ixazomib maintenance for up to 1.5 yrs was feasible and generally well tolerated, improved responses following ixazomib-lenalidomide-dexamethasone induction, and contributed to durable responses (median >2 yrs) in previously untreated MM pts not undergoing ASCT. The results support the ongoing phase 3 trial of ixazomib in the maintenance setting (NCT02181413). Disclosures Kumar: Celgene: Consultancy, Research Funding; Millennium: The Takeda Oncology Co.: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding; Sanofi-Aventis: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Skyline Diagnostics: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Investigational proteasome inhibitor ixazomib in combination with lenalidomide and dexamethasone and as maintenance therapy for patients with previously untreated multiple myeloma.. Niesvizky:Onyx Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium: The Takeda Oncology Company: Consultancy, Honoraria, Research Funding, Speakers Bureau. Lonial:Millennium: The Takeda Oncology Company: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding. Laubach:Novartis: Research Funding; Onyx Pharmaceuticals: Research Funding. Hamadani:Millennium: The Takeda Oncology Company: Research Funding. Stewart:Takeda Pharmaceuticals International Co.: Research Funding; Sanofi: Consultancy; Array BioPharma: Consultancy; Bristol Myers Squibb: Consultancy; Celgene: Consultancy; Novartis: Consultancy. Hari:Celgene: Consultancy, Honoraria, Research Funding; Onyx: Consultancy, Honoraria, Research Funding; Millennium: The Takeda Oncology Co.: Consultancy, Honoraria, Research Funding; Spectrum: Consultancy, Honoraria, Research Funding; Sanofi: Research Funding. Vescio:Celgene: Speakers Bureau; Millennium: The Takeda Oncology Co.: Speakers Bureau; Onyx Pharmaceuticals: Speakers Bureau. Kaufman:Millennium: The Takeda Oncology Co.: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Onyx: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Spectrum: Consultancy, Honoraria; Merck: Research Funding. Berg:Takeda Pharmaceuticals International Co.: Employment. Liao:Takeda Pharmaceuticals International Co.: Employment. Hui:Takeda Pharmaceuticals International Co.: Employment. Richardson:Millennium: The Takeda Oncology Co.: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

Abstract 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.

Abstract Multiple myeloma is a disease of the antibody producing plasma cells in the bone marrow. It has been characterized by frequent genomic alterations including gains and losses of chromosomes. Some of these alterations result in poor clinical prognosis. Bortezomib, a first in class proteasome inhibitor, is approved for the treatment of relapsed multiple myeloma. To better understand how the genome wide changes observed in myeloma relate to prognosis and treatment response, we have used single nucleotide polymorphism (SNP) array technology to assess genotypes and DNA copy number at up to 100,000 genomic loci. DNA from 147 bone marrow tumor biopsies collected in multi-center phase II and III clinical trials of relapsed multiple myeloma patients prior to treatment with Bortezomib were hybridized on SNP arrays to assess genomic aberrations. Commonly seen genomic alterations in myeloma were observed, including deletions of chromosome 13 (37%), 1p (25%), 6q (23%), and amplifications on 1q (35%). We found that 35% of this relapsed myeloma population exhibited a hyperdiploid genome characterized by gains of chromosomes 3, 5, 7, 9, 11, 15, and 19. Other notable genomic deletions included 17p (22%), 8p (27%) and 10p (16%). A correlation of response to bortezomib therapy in patients with differential gains and losses at the chromosomal level is ongoing. Consistent with previous reports, response to bortezomib was observed in patients with poor prognostic chr 13 deletions. A more in-depth analysis of specific loci associated with clinical outcome will be discussed. In summary, this data will help further define genomic aberrations in multiple myeloma and their association with treatment outcome.