Rajkumar, S. Vincent

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 Background: The use of low-dose dexamethasone (Dex) in combination with lenalidomide (Len), an immunomodulatory compound, improves overall survival (OS) compared with high-dose Dex plus Len in patients (pts) with newly diagnosed multiple myeloma (MM) (Rajkumar et al. 2007). Two phase III randomised trials of pts with relapsed/refractory MM showed that Len/Dex had significantly better overall response (OR), complete response (CR), OS and time to progression (TTP) than Dex alone. Dex dose reductions were permitted in relation to severity of adverse events (AEs). We investigated the effect of Dex dose reductions on efficacy and tolerability of Len/Dex in relapsed/refractory MM. Methods: Data were pooled from the MM-009/010 studies for pts treated in the Len/Dex group who had an unchanged Len dose (n=233). Pts were treated with Len (25mg/day on day 1–21 of each 28-day cycle) and Dex 40mg on day 1–4, 9–12, and 17–20 (for the first four cycles). After four cycles, Dex 40mg/day was administered only on day 1–4. Dex dose reductions were: 40mg day 1–4 every 2 weeks (level -1), 40mg day 1–4 every 4 weeks (level -2), and 20mg day 1–4 every 4 weeks (level -3). Response to therapy, TTP, OS, and progression-free survival (PFS), as well as AEs were assessed. Response rate and TTP were based on data obtained before unblinding (June/August 2005 [MM-009/010]. Results: Of 233 pts in this post-hoc analysis, 177 pts were treated with Dex 40 mg/day throughout the study and 46 received Dex dose reductions. Forty-one pts received a dose reduction due to AEs. Baseline characteristics were balanced between treatment groups. Pts who received Dex dose reductions had a significantly higher OR rate, including a higher CR, compared with those who received standard Dex dose (Table). Pts in the Dex reductions group had significantly longer median TTP, median OS, and median PFS, compared with those who received Dex at the assigned dose. At the end of the study, rates of serious AEs, grade 3–4 AEs, treatment-related AEs and withdrawals because of AEs were comparable between pts who received Dex dose reductions and those who received an unchanged Dex dose. Although most Dex dose reductions were made for an AE, by reducing the dose pts were able to maintain a similar safety profile to those who did not require dose reductions. Grade 3–4 haematological AEs in pts who received Dex dose reductions and those who did not were neutropenia (23.7% and 32.6%, respectively), thrombocytopenia (8.5% and 6.8%, respectively) and anaemia (6.8% and 6.2%, respectively). No febrile neutropenia was reported in these pts. Conclusion: Dex dose reductions improved the efficacy of Len/Dex without affecting tolerability in pts with relapsed/refractory MM. Len/Dex Dex unchanged (n=177) Dex reduced (n=46) P *Most conservative median estimate obtained assuming all censored patients die right right after the censor date Response, % OR 50.8 69.6 <0.05 CR 13.0 23.9 <0.01 nCR 19.8 37.0 <0.01 PR 18.1 8.7 <0.01 Median TTP, weeks* >24.1 >59.9 0.002 Median OS, weeks* >109.7 >121.9 0.19 Median PFS, weeks* >24.1 >59.9 0.001

Abstract Waldenström macroglobulinemia (WM) is a lymphoid neoplasm associated with accumulation of lymphoplasmacytic cells in the bone marrow and an elevated monoclonal IgM in the serum. Although the genetic and molecular mechanisms behind the pathogenesis of WM are not well understood, losses of the long arm of chromosome 6 have been found as the only recurrent genomic aberration. These deletions, mostly starting at 6q21, are observed in upwards of 50% of patients and involve the majority of the clonal cells. To better characterize pathologic gene expression signatures in different types of WM at the molecular level (6q deleted versus not), we examined gene expression level changes of more than 20000 human gene probes in bone marrow tissues of clinically proven WM patients. We used Affymetrix HG-U133A v2 chips (n = 24). Clonal cells were purified using a combination of anti-CD138 and anti-CD19 Miltenyi™ magnetic microbeads. Based on cIgM-FISH results, we classified samples into two groups - 6q normal (ND) group and 6q deletion (D) group. We then proceeded to identify genes that showed differential expression between the two groups. We selected 165 differentially expressed genes (DEG) using SAM, and underwent further investigation of biological annotations of them using Gene Ontology™ (GO) terms. Among165 DEG, only 32 showed high level of expression in ND group compared to D group while 133 showed high level of expression in D group. As expected, all genes that reside in 6q region showed under-expression in D group, constituting 53% (17 genes) of genes under-expressed in D group (32 genes). According to GO analysis, the 6q-deletion-induced under-expression affects many biological processes, and is associated with a transcriptional upregulation of downstream genetic cascades. This likely indicates release of regulatory control by a tumor suppressor gene. Genes involved in cell growth and maintenance, cell communication and morphogenesis are also over-expressed in D group. Interestingly, a gene that is involved in innate immune response and inflammatory response shows under-expression in D group but is not accounted for by other mechanisms. In similar vein, a gene that is involved in negative regulation of cytokine biosynthesis showed over-expression in D group. We think these transcriptional characteristics can provide basic framework for differentiating subtypes of WM and search for genes associated with WM pathogenesis

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.

Background: High dose chemotherapy and autologous stem cell transplant (SCT) remains the preferred therapy for eligible patients with multiple myeloma (MM). Several studies have demonstrated an improvement in median survival with use of SCT. Patients with myeloma may undergo SCT immediately following 4–6 cycles of ‘induction’ therapy or at the time of relapse from the initial plateau phase. Available evidence does not suggest a survival difference between the two approaches. Methods: We retrospectively evaluated our experience with autologous single SCT for MM to compare the results of delayed SCT to early SCT. We identified from our transplant database, 202 patients with MM, who underwent SCT between October 1992 and November 2002. 101 patients, who responded to induction chemotherapy, had stem cells collected in plateau phase, received maintenance chemotherapy and had SCT at the time of first relapse (delayed SCT group). The remaining 101 patients, after initially achieving a response underwent upfront SCT (early SCT group). Patients refractory to initial therapy were excluded from this study. Most of the early transplants were done in the recent years and hence this group has a shorter follow up. Results: The study cohort had a median age of 55 years (range 29 – 72) at diagnosis consisting of 126 males (62%), with no significant demographic difference between the two groups. As expected measures of tumor burden (M protein, B2M and marrow plasma cell percentage) were significantly higher in the delayed group. Plasma cell labeling indices and presence of abnormal cytogenetics were higher in the delayed SCT group as well at transplant. TBI containing regimens were used more often in the delayed group reflecting a difference in the time periods of transplant. There was no difference between the groups in terms of overall response to transplant though complete response rate was higher for the early transplants. (Table). There was no difference in the time to overall response between the groups (P=0.13, Kaplan Meier estimate). Though the median progression free survival (PFS) from transplant was shorter for the delyaed SCT group, the overall survival (OS) from diagnosis of MM was comparable for the two groups (Table). The overall survival estimate at 5 year from diagnosis was 60% for both groups. Conclusions: Review of our experience demonstrates comparable overall survival for an early SCT compared to SCT at the time of relapse. Although there is an advantage for early SCT in terms of more chemosensitive disease as shown by a longer PFS from SCT, there is no benefit in OS from time of diagnosis. Patient preference and other co-morbidities should play a role in the decision regarding timing of transplant. This study has the disadvantage of being retrospective in nature and the two groups being spread over different periods in time. Early (n=101) Delayed (n=101) P Overall Response 100 (99%) 94 (94%) 0.07 Complete Response 43 (42%) 28 (27%) 0.04 Median PFS (From Transplant) 26.7 months 14.8 months <0.0001 Median OS (From diagnosis) 67 months 70 months 0.1

Abstract Background: Patients with newly diagnosed multiple myeloma is at increased risk of thrombotic events, primarily venous thrombosis. The risk is significantly increased in patients receiving certain therapeutic regimens such as the combination of thalidomide and dexamethasone. Deep vein thrombosis, especially if complicated by pulmonary embolism, can result in death. It is not clear if venous thrombotic events can result in compromised survival in this group of patients. Methods: We studied patients enrolled in the Eastern Co-operative Group trial (E1A00) that randomized patients with newly diagnosed myeloma to single agent dexamethasone or thalidomide and dexamethasone. Patients with grade 3 or greater thrombotic events (DVT, or myocardial ischemia, or stroke) were identified. Wilcoxon rank sum test (for continuous variables) or Fisher’s exact test (for categorical variables) was used to compare age, baseline M-protein, hemoglobin, WBC, platelets count, creatinine, beta2-microglobulin, or ECOG PS between patients with and without thrombotic events. Results: Among the 207 patients enrolled, 36 patients (17.4%) had grade 3 or greater thrombotic events with any treatment attribution, of whom, 27 patients had DVT, 3 patients had an MI and 6 pts had a stroke. However, in only 31 of these patients were the event considered treatment-related (possible, probable, or definite) and among these 24 had a DVT. The baseline characteristics did not differ between the patients with thrombosis and those without, irrespective of its relationship to treatment. Similarly, the baseline characteristics did not diff for those with venous or arterial thrombosis. The overall survival was similar among the patients developing a DVT compared to those without a thrombotic event, when all DVT events were considered irrespective of the treatment attribution (Figure). However, majority of the patients with an arterial event (3 patients with MI and 6 with stroke) had a short overall survival. Conclusion: Venous thrombosis remains a common complication in patients with myeloma, especially when treated with thalidomide and dexamethasone. While occurrence of thrombosis clearly contributes to morbidity and often leads to dose reductions and missed doses, it does not appear to have an adverse impact on the overall survival of these patients. Figure Figure

Abstract Background: Combination 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 all shown substantial activity in previously untreated multiple myeloma (MM). A combination of all four agents (VDCR) may result in even greater activity. This randomized multi-center 3-arm phase I/II EVOLUTION study is investigating the efficacy and safety of VDR, VDC, and VDCR as initial therapy in previously untreated MM patients (pts). We now report safety and efficacy results from the phase l dose-escalation portion of the study, which sought to determine the maximum tolerated dose (MTD) of the VDCR regimen. These results represent the first clinical data with this novel 4-drug combination that includes bortezomib, lenalidomide, an alkylator, and a corticosteroid. Methods: Pts received Vc 1.3 mg/m2 IV (d 1, 4, 8, 11), Dex 40 mg PO (d 1, 8, 15), Rev 15 mg PO (d 1–14), plus Cy 100, 200, 300, 400, or 500 mg/m2 PO (d 1, 8) for up to eight 21-d cycles, followed by Vc 1.3 mg/m2 (d 1, 8, 15, 22) for four 42-d maintenance cycles. Pts received prophylactic antibiotics, acyclovir, transfusion support and concomitant anticoagulants as required. Eligible pts wishing to receive autologous stem cell transplant (ASCT) could undergo stem cell mobilization any time after cycle 2, and discontinue therapy for ASCT any time after cycle 4. The MTD was defined as the highest dose of Cy in combination with VDR resulting in ≤1 dose-limiting toxicity (DLT) in 6 pts. A DLT was defined as: platelet count <25,000/mm3 lasting >7 days or any platelet count <10,000/mm3; grade 4 neutropenia lasting >7 days; any ≥grade 3 non-hematologic toxicity considered to be related to Cy except for inadequately treated nausea, vomiting, and diarrhea, or any toxicity resulting in a >2 week treatment delay. Results: Twenty-six pts were enrolled; 1 pt was not dosed due to a heart problem and was excluded (dose level 4) and 4 pts were not evaluable for DLT. In the 25 treated pts, median age was 61 years (range 49–79); 52% were male; 48% had ISS Stage lI and 4% Stage III disease, and 44% had KPS ≤80%. At data cut-off, 11 pts remain on treatment and 9 have undergone successful ASCT. To date, median treatment duration is 4 cycles (range 2–11). Two pts experienced DLT: 1 grade 4 febrile neutropenia at dose level 4 (Cy 400 mg/m2), and 1 grade 3 herpes zoster virus reactivation despite antiviral prophylaxis at dose level 5 (Cy 500 mg/m2). The recommended phase II dose of Cy in the VDCR regimen was the highest planned dose of 500 mg/m2. The most common treatment-emergent AEs were constipation (64%), fatigue (60%), and nausea (52%). Hematologic toxicities were acceptable, with grade 3 neutropenia in 16% of patients, grade 4 in 4%, and grade 4 thrombocytopenia in 4%. Peripheral neuropathy (56%), included 8% grade 3 but no grade 4; no deep-vein thrombosis/pulmonary embolism events were reported. Overall rate of serious AEs was 40%; the only SAE reported in >1 pt was febrile neutropenia (2 pts). Best responses to date by International Uniform Response Criteria are shown in the table. Preliminary response rates are: 100% ≥PR, 68% ≥VGPR, 32% CR/nCR, 28% CR/stringent CR and 20% sCR. Ten pts have undergone stem cell mobilization with median CD34+ yield of 4.95×106/kg. Conclusions: VDCR was well tolerated and hematologic toxicities were manageable. The current study shows that the VDCR regimen is feasible and highly active in newly diagnosed myeloma and merits further testing in clinical trials. Enrollment to the 3 arms (VDR, VDC and VDCR) of the phase ll portion of the study and testing for minimal residual disease by flow cytometry are ongoing. Best unconfirmed response to date with VDCR Dose level 1 2 3 4 5 Cyclophosphamide dose, mg/m2 100 200 300 400 500 Enrolled 3 4 4 8 7 Treated 3 4 4 7 7 Still on treatment – 1 1 2 7 Best unconfirmed response to date CR (sCR) 2 (2) 1 (1) 1 (1) 2 1 (1) VGPR (nCR) 1 – 3 (1) 4 2 PR – 3 – 1 4

Abstract Abstract 3981 Background: Patients with multiple myeloma (MM) can present with life threatening complications including lethal infections during the disease course. The mortality is high during the early period following diagnosis, mostly as a result of complications of the disease or treatment. It is not clear if we can identify patients at the highest risk of early death based on the presenting clinical and laboratory features. Methods: From among 1545 patients seen at our institution between Jan 1999 and Dec 2008, we identified 265 patients who died within 12 months of diagnosis. For each of these patients we identified two “controls” who had at least 12 months of follow up, were alive at the time of last follow up and were closest to the ‘case' patient in terms of time of diagnosis. We performed logistic regression using the clinical and laboratory features, to identify parameters that predict for 12-month mortality and to determine the best cutoffs. Results: This study included 265 patients as cases and 530 controls. The gender distribution was similar in the two groups. We examined the impact of age, performance status (PS), hemoglobin, platelets, serum creatinine, calcium, LDH, albumin, B2M, free light chain difference, plasma cell labeling index, ISS stage, risk category and exposure to novel agents upfront. Based on the results of univariate and then multivariate analysis – age> 72, ECOG PS>2, Calcium >11.3 and ISS stage 3 were found to be significant. We developed the risk score using 1 point for each adverse factor, Age> 72, PS > 2, ISS 3, and Calcium > 11.3. The odds ratio of patients dying in the first year was 2.7, 9.2 and 37 in the presence of one, two and three or more risk factors compared to none of the risk factors. We then looked at the impact of the initial therapy on outcome. 279 patients (35%) received one of the novel agents (thalidomide, lenalidomide or bortezomib) as initial therapy. The odds ratio for dying in the first year was 0.35 for patients receiving a novel agent compared to the rest. The impact of the novel agent was independent of the risk score, with the risk score predicting outcome in both groups. Conclusions: In newly diagnosed MM advanced age, poor performance status, ISS stage and high calcium were associated with early mortality. If eligible all patients should get the benefit of use of novel agent upfront. Identifying these patients at the time of diagnosis is important and should help develop better risk-adapted strategies. Disclosures: No relevant conflicts of interest to declare.