Trudel, Suzanne

Abstract Abstract 39 Three randomized trials have previously reported a progression-free survival (PFS) advantage for patients receiving thalidomide (T) maintenance post ASCT in MM. Two trials reported an overall survival (OS) advantage but the largest trial reported shows no OS advantage and in very high risk MM the use of T was deleterious. Recent trial reports demonstrate a PFS but not yet an OS advantage for patients receiving maintenance lenalidomide. We report results of NCIC CTG MY.10 which compared treatment with T (200 mg daily) and prednisone (50 mg alternate days) (T/P) until progression versus observation alone when used as maintenance therapy following ASCT. Importantly, OS was the 1ry endpoint of this study, 2ry endpoints were PFS, quality of life (QoL), toxicity, and the incidence of venous thromboembolism events (VTE). Eligibility: Patients with MM who had ASCT within 1 year of beginning initial treatment for their disease. Patients were randomized 60–100 days post ASCT and had no other medical condition precluding long term use of T/P. Results: 332 patients were enrolled. Median age was 58 years and the arms were balanced. Patients were stratified by age (<60 or >60), and CR status post transplant. Median follow up is 4 years. Only 14% of patients were in CR post transplant. 111 patients died (50 versus 61 in T/P vs. observation). The median OS was 5 years for observation, and has not yet been reached for T/P, however T/P maintenance therapy did not significantly prolong OS: p = 0.18, HR of maintenance vs. observation 0.77 (95% CI 0.53–1.13). The 4 year survival rate was 68% for T/P and 60% for observation. Age and response to transplant had no significant association with OS (p=0.21), while higher disease stage was associated with shorter OS (p=0.03). The median PFS was 28 months for T/P versus 17 months for observation: p<0.0001, HR of T/P vs. observation 0.56 (95% CI 0.43 – 0.73). The 4 year PFS rate was 32% for T/P treated patients versus 14% for patients on observation. At relapse, treatment by arm (T/P vs observation) included lenalidomide (39 vs 34%), T (13 vs 22%) or bortezomib (50 versus 46%). Non hematologic toxicities were seen in more patients with treatment (Grade 3: 92% T/P vs 49% observation, grade 4: 16% vs 7%). Common toxicities of all grades that were significantly higher in T/P treated patients included hyperglycemia, edema, hypertension, fatigue, Cushingoid appearance, constipation, mouth dryness, dyspepsia, anxiety, memory loss, sensory neuropathy, tremor, blurred vision, depressed consciousness, cataracts, dyspnea and bruising. 7% of patients on maintenance T/P developed a VTE in the absence of prophylaxis versus 0% on observation. NCIC CTG standardized response analysis was use to compare QoL data between the 2 treatment arms. Overall, patients on T/P had worse QoL specifically in physical (p=0.07), role (p=0.08), cognitive (p = 0.01) and global (p=0.06) domains, and worse symptoms with dyspnea (p = 0.0007), constipation (p<0.0001), thirst (p=0.003), swelling in leg (p=0.03), numbness (p=0.02), dry mouth (p<0.0001), and balance problems (p<0.0001). However, patients on T/P reported improvement in appetite (p 0.02), and sleep (p=0.04). Conclusions: T/P maintenance did not improve overall survival, the primary objective of this trial, although a trend in favor of T/P was seen. In contrast, PFS was significantly improved in the T/P arm while toxicity was demonstrably increased and quality of life diminished. Disclosures: Stewart: Millennium: Consultancy; Celgene: Honoraria. Trudel:Celgene: Honoraria. Bahlis:Celgene: Honoraria, Research Funding, Speakers Bureau. White:Celgene: Honoraria, Research Funding. Meyer:Celgene: Honoraria.

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 3055 Lenalidomide (Revlimid®) and dexamethasone is an effective regimen for relapsed/refractory (rel/ref) multiple myeloma (MM) patients (pts) with an overall response rate of 60% and median time to progression of 13.4 months (Dimopoulos ME, et al. Leukemia 2009; 23: 2147-52). We combined lenalidomide with the alkylating agent combination of cyclophosphamide and prednisone—an older regimen with minimal cumulative myelosuppression and good activity as second or third line therapy (Trieu Y, et al, Mayo Clin Proc 2005; 80: 1582). The CPR regimen consisted of cyclophosphamide (CY) on days 1, 8, and 15, lenalidomide on days 1–21 and prednisone 100 mg q 2 days in a 28-day cycle. ASA 81 mg/day was given as DVT prophylaxis. Three dose levels were evaluated using a 3 × 3 dose escalation design. Thirty-two pts were entered between 11/2007-06/2009; median age was 64 (42-80) yrs, 60% were male, and immunoglobulin isotype was IgG in 19 (62%), IgA in 8 (25%) and light chain in 4 (13%) pts. Median β2-microglobulin level was 257 (92-767) nm/L, albumin 39 (34-48) g/L, creatinine 83 (50-126) μmol/L, platelet count 355 (75-479) × 109/L and ANC 2.5 (1.1-6.1) × 109/L. The median number of prior regimens was 2 (1-5). Prior therapy included: ASCT (single in 91%; double in 19%), thalidomide (28%) and bortezomib (50%). FISH cytogenetics were available in 13 pts; 1 had del 13q but none had t(4;14) or del p53. Table 1 summarizes protocol treatment delivered. Table 1. Dose level N Cyclophosphamide dose (mg/m2) Lenalidomide dose (mg) Prednisone dose (mg) Median # cycles given 1 3 150 15 100 12 (12–34+) 2 3 150 25 100 10 (9–23) 3 26 300 25 100 17 (5–28+) 1–3 (All) 32 150–300 15–25 100 19 (5–34+) Dose limiting toxicity was not observed during cycle 1 at any dose level. Grade 3–4 toxicities during the trial included: thrombocytopenia in 7 (22%) and neutropenia in 9 (29%), managed with dose reduction and/or growth factors; five episodes of febrile neutropenia occurred, all at dose level 3. In cohort 3, other grade 3–4 non-hematologic toxicities included 1 episode each of abdominal pain/bacteremia, hypokalemia, fatigue, sick sinus syndrome, cardiac amyloidosis, perforated diverticulum and 2 episodes of DVT. Two heavily pretreated pts developed 2° MDS, including 1 previously treated for lymphoma, 43 and 190 mos after the diagnosis of MM. The best response using modified EBMT criteria was documented at a median of 7 (1-26) cycles and included the following: dose level 1 (1 CR, 2 PR); dose level 2 (1 VGPR, 2 PR); dose level 3 (4 CR, 14 VGPR, 11 PR, 1 MR and 1 stable disease). At a median F/U of 16 (5-34) months, 13 pts remain on study and 18 have progressed at a median of 10 (2-23) mos; 1 was lost to F/U and 9 have died of progressive MM. The 1-year actuarial OS and PFS rates are 93% (95% CI 76–98%) and 78% (95% CI 60–89%), respectively. We conclude: 1) the combination of full doses of the agents in CPR can be given in a 28 day cycle with an acceptable safety profile; 2) the objective response rate (CR + PR + MR) in all 32 pts to date is 94%; 3) the 1-year OS of 93% and PFS of 78% compare favorably with other 3-drug combinations in rel/ref MM pts; 4) further evaluation of this regimen in newly diagnosed pts would be of interest. Disclosures: Reece: Celgene: Honoraria, Research Funding. Off Label Use: Combination of lenalidomide and cyclophosphamide and prednisone in relapsed and refractory myeloma patients. Chen:Celgene Corporation: Consultancy, Honoraria, Research Funding. Kukreti:Celgene: Honoraria.

Abstract Abstract 1874 Poster Board I-899 Lenalidomide (Revlimid®) and dexamethasone is an effective regimen in relapsed/refractory multiple myeloma (MM) patients (pts), with an overall response rate of 60.6% and median time to progression (TTP) of 13.4 months (Dimopoulos MA, et al, Leukemia 2009 Jul 23 [Epub ahead of print]). Oral cyclophosphamide and prednisone is an older regimen with excellent patient tolerance, and we sought to enhance the efficacy of lenalidomide by adding oral cyclophosphamide and prednisone in this phase I-II trial. The CPR regimen consisted of cyclophosphamide on days 1, 8 and 15; lenalidomide on days 1–21; and prednisone 100 mg every other day in a 28 day cycle. ASA 81 mg/day was given to all pts as DVT prophylaxis. Three dose levels were evaluated using a 3 by 3 dose escalation design. Between 11/2007–07/2009, 31 pts with relapsed/refractory MM who had not previously received lenalidomide were entered onto study. Median age was 61 (40–78) years and 61% were male. Immunoglobulin subtype was IgG in 19 pts (61%), IgA in 8 pts (26%) and light chain only in 4 pts (13%). Median number of prior regimens was 2 (1–5) and 28 pts had undergone previous ASCT, including double transplants in 6 pts. Prior therapy included thalidomide in 9 (29%) and bortezomib in 15 (48%). FISH cytogenetics were available in 13 pts; one had 13q deletion but none had t(4;14) or p53 deletion. At the time of protocol entry, median β 2-microglobulin level was 246 (92–767) nm/L, albumin 39 (34–48) g/L, creatinine 83 (50–126) μmol/L, platelet count 230 (75–337) × 109/L and ANC 2.5 (1.1–6.1) x 109/L. Protocol treatment is summarized in Table 1. Dose limiting toxicity was not observed during cycle 1 at any dose level. Grade 3–4 toxicities included thrombocytopenia in 5 pts (16%) and neutropenia in 9 pts (29%). These were managed with dose reduction and/or growth factor support. Four episodes of febrile neutropenia occurred. Other grade 3–4 non-hematologic toxicities included abdominal pain/bacteremia in 1 pt in cohort 1; hypokalemia in 1 pt in cohort 2; and DVT in 2 pts, dizziness in 2 pts and fatigue in 1 pt in cohort 3. Using the International uniform response criteria (Durie BG, et al, Leukemia 2006; 20:1467–1473), the best response was documented at a median of 6 (1–5) cycles and included the following: dose level 1 (1 CR, 2 PR); dose level 2 (1 VGPR, 2 PR); dose level 3 (5 CR, 9 VGPR, 9 PR, 1 MR and 1 stable disease). At a median follow-up (F/U) of 12 (8–21) months, 20 pts remain on study, 2 have withdrawn and 9 pts have progressed at a median of 9 (4–13) months; only 1 one has died (due to MM). We conclude: 1) the combination of full doses of the agents in CPR can be given in a 28 day cycle with minimal toxicity; 2) the overall response rate (CR + VGPR + PR) in 31 pts to date is 93%; 3) at a median F/U of 1 year, only 9 pts (29%) have progressed; 4) longer follow-up is required to assess the TTP and survival of the CPR regimen. Disclosures: Reece: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: Lenalidomide in combination with drugs other than dexamethasone. Anglin:Celgene: Honoraria. Chen:Celgene: Honoraria, Research Funding. Kukreti:Celgene: Honoraria. Mikhael:Celgene: Honoraria. Trudel:Celgene: Honoraria.

Abstract Abstract 2403 Immunoglobulin light chain amyloidosis (AL) is a monoclonal plasma cell disorder characterized by the accumulation of monoclonal light chain fragments that have undergone a conformational transformation and deposit as amyloid fibrils in different tissues. High-dose melphalan (HDM) with autologous hematopoietic stem-cell transplant (ASCT) is increasingly used to treat patients (pts) with AL Amyloidosis. However, transplant-related mortality (TRM) is high, ranging between 13% to 43%. The survival benefit of HDM has been attributed to a patient-selection bias. Recently, a randomized clinical trial by Jaccard A et al, showed longer survival in the group assigned to receive melphalan plus dexamethasone (Mel/Dex) than in the group assigned to receive HDM. The present is a retrospective study aiming to define which pts with AL are most likely to benefit from HDM. Patients and Methods We retrospectively reviewed the medical records of all the pts included in the Princess Margaret Hospital Amyloidosis Database who underwent ASCT from January 2004 to March 2010 to determine: a) TRM, b) Hematological response (HR) and Organ response (OR) and c) Overall survival (OS). We included transplanted pts who had received no more than two previous courses of any chemotherapy regimen who did not have concurrent myeloma, and who had an Eastern Cooperative Oncology Group (ECOG) performance-status score of 2 or better. As part of the ASCT the stem cells were obtained from the peripheral blood with granulocyte colony-stimulating factor (G-CSF) alone (5 μ g/kg subcutaneously, twice daily). Pts then received HDM, 200 mg/m2 given intravenously on day 0, and stem cells were infused on day 1. The HDM was reduced to 140 mg/m2 for pts 65 years of age or older and for those with an important decrease of the ejection fraction, a calculated creatinine clearance of less than 30 ml per minute, or severe liver disease. HR and OR was assessed using 2004 Amyloidosis Consensus Response Criteria (Gertz, M et al, 2004). For statistical evaluation, HR was defined as observing complete or partial remission (CR or PR); stable disease (SD) or progression was considered as no HR. All statistical tests were 2-sided X2 t test and P values less than .05 were considered to be statistically significant. Results Seventy seven pts were evaluated with a median age of 56 years (33-74). Clinical characteristics are seen in Table 1. Only 18/77 pts (23%) received induction therapy: Dexamethasone alone n=9, Cyclophosphamide and Prednisone n=2, Mel/Dex n=4, VAD n=2 and Melphalan and Prednisone n=1. TRM observed was 12% mainly due to congestive heart failure and sepsis. Complete HR was achieved in 38 cases (49%) and OR was seen in 59%. Among the most common complications to ASCT, febrile neutropenia was reported in 67%, transient renal impairment in 10% and congestive heart failure in 3%. Median OS was significantly lower for patients with B-type natriuretic peptide (BNP) >300 pg/ml (17.7 vs 64.46 months) (p0.0004), Troponin I >0.07 ng/ml (19.25 vs 97.4 months) (p0.00001) and those who achieved a complete HR (115 vs 88 months) (p0.0345). Multivariate Cox regression analysis showed that BNP>300 pg/ml and Troponin I >0.07 ng/ml (normal <0.07) were the most important factors to predict OS for patients with AL who underwent ASCT (p0.0002 and 0.04 respectively). Conclusions Based on this study of 77 patients, clinical selection is the most important factor to better improve outcomes for HDM in AL. Patients with BNP>300 pg/ml and/or abnormal levels of Troponin I (>0.07) should not be considered eligible for transplants due to a high degree of mortality. Our series showed a CR rate of 49% which is higher than 33% reported by Palladini et al with Mel/Dex. Stringent case selection may be the most important factor in decreasing mortality rate associated to ASCT leading to better outcomes. Table 1. Clinical Characteristics of patients with AL Amyloidosis undergoing ASCT (at initial diagnosis) Clinical Characteristics N Median Range % Age (years) 77 57 33–74 Hemoglobin (g/L) 77 138 104–182 Creatinine (μ mol/L) 77 129 37–700 **BNP (pg/ml) 44 180 10–1670 ***BMPC (%)– 77 7 1–30 24 Hr Proteinuria (g/d) 77 5.5 0–24.9 Intraventricular Septal Distance (mm) 77 13 9–23 Kappa/lambda ratio 53 4.4 0.001–71.2 Kidney Involvement 71 Heart Involvement 52 Liver involvement 23 GI involvement 10 3 or more organs involved by AL 16 ** B-Type Natriuretic Peptide *** BMPC: Bone marrow plasma cells Disclosures: Stewart: Millennium: Consultancy; Celgene: Honoraria. Reece: Celgene: Honoraria, Research Funding. Chen: Celgene Corporation: Consultancy, Honoraria, Research Funding. Kukreti: Celgene: Honoraria.

Abstract Abstract 2876 Poster Board II-852 Multiple myeloma (MM) patients (pts) are immunosuppressed given the underlying disease, previous treatments and myelosuppression seen on lenalidomide (Revlimid, Rev). We evaluated the infectious complications seen on Celgene's Expanded Access Rev program at Princess Margaret Hospital. We have treated 75 pts who had progressed after at least one prior therapy as part of a national study in Canada. At entry, pts were required to have a neutrophil count of ≥1.0 ×109/L. The median age was 61 yrs (range 35-79); 52% were males. Prior therapy included stem cell transplant in 65, thalidomide in 54 and bortezomib in 24. Number of lines of prior therapy were as follows: 24 (one), 29 (two), 16 (three), 8 (four) and one (five). Neupogen was used liberally (63%) after a patient had a dose delay on trial due to neutropenia. Patients were treated with full dose lenalidomide at entry onto clinical trial and were maintained on full dosing unless platelet counts were <30×109/L or ANC was <1.0×109/L. No other dose adjustments were made for renal dysfunction. Results: There were 32 pts (43%) who had a clinically evident infection; the majority (91%) was on prophylactic antibiotics (septra/ciprofloxacin) at the time. There were two deaths due to infection and 23 pts (72%) required hospitalization (range 2-27 days). The majority of infections occurred within the first 4 cycles of treatment (26 pts) and seemed to occur more in pts with several lines of prior therapy – 7/24 (29%) with 1 prior therapy, 14/29 (48%) with 2, 9/16 (56%) with 3 and 2/8 (25%) with 4 prior therapies. Sixteen were neutropenic of which 7 had febrile neutropenia (9%). The types of infections were: respiratory in 14 (1 with pneumocystis pneumonia), cellulitis in 4, herpes simplex and herpes zoster in 2 pts each. These included streptococcus pneumoniae (1), staphylococcus aureus (3), respiratory syncitial virus (1) and mycobacterium chelonae (1). Rev was held during the infection in 23 pts (72%). Conclusions: 1) Infections are frequent in this patient population (43%) and often lead to hospitalization (72%); respiratory infections accounted for a large majority (43%). 2) Early aggressive growth factor support and broader antibiotic prophylaxis may be of benefit especially in heavily pretreated patients. 3) Dose reduction of Rev in the context of serious infections should be further evaluated. Disclosures: Kukreti: Celgene: Honoraria. Trudel:Celgene: Honoraria, Speakers Bureau; Ortho Biotech: Honoraria. Chen:Celgene: Honoraria.

Abstract Abstract 2865 Poster Board II-841 BACKGROUND: The ubiquitin-proteasome pathway, which has been shown to be an essential cellular degradative system in myeloma cells, can also regulate bone formation through its effects on osteoblast differentiation. Retrospective analysis of variation of ALP during treatment with bortezomib indicates a close correlation between myeloma response and serum ALP levels which multiple studies have shown to be of bone origin. To determine if this effect is a class effect of proteasome inhibitors (PIs), this retrospective study analyzed variation of ALP in relationship to myeloma response during treatment with carfilzomib, the first in a new class of selective epoxyketone PIs that has demonstrated encouraging safety and efficacy in two phase 2 studies of relapsed or refractory myeloma patients. METHODS: Retrospective analysis of serum ALP was performed on relapsed or refractory myeloma patients enrolled on two phase 2 studies (PX-171-003 and PX- 171-004) evaluating the safety and efficacy of single agent carfilzomib. We analyzed data from 38 patients in the first cohort of the PX-171-003 study, a relapsed and refractory myeloma trial for patients who have received ≥ 3 prior therapies including bortezomib and an IMiD and 29 patients in PX-171-004, a relapsed or refractory myeloma trial that included bortezomib naïve patients. All patients received 20 mg/m2 of carfilzomib on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. RESULTS: Seventy-seven patients were enrolled. The median age was 63 years with a median time since diagnosis of 4.6 years, 52% were male, 84.% had relapsed after autologous transplants, 82.% were previously exposed to bortezomib, and 92% were previously exposed to an IMiD. Sixty seven patients with ALP data were evaluable for response. In PX-171-003 the ORR (≥PR) was 18% and the clinical benefit response (CBR; ≥MR) was 26%, while in PX-171-004 the ORR was 35.5% overall and 57% in bortezomib naive patients. ALP increment from baseline, which was most evident during the second cycle of treatment, was statistically different in patients who achieved ≥VGPR compared to all others on Days 1 (P=0.0049) and 8 (P=0.006) of Cycle 2. In all patients achieving a VGPR or better, ALP increased more than 15 units per liter at Cycle 2 Day 1 over baseline An ALP increase over the same period of time was seen in 26 %, 13%, and 11% of patients achieving PR, MR, and SD, respectively. None of the patients with progressive disease exhibited a similar increase. Our study indicates that response first assessed on Day 15 of Cycle 1 parallels the ALP elevation which returned to baseline levels at the end of Cycle 3. CONCLUSIONS: This retrospective analysis on a subset of patients in these ongoing phase 2 studies of single agent carfilzomib in relapsed or refractory multiple myeloma suggests that elevation in ALP may be associated with best response. Taken with previous publications describing bortezomib treatment, these results suggest that this specific anabolic bone phenomenon could be a class effect of proteasome inhibitors. These phase 2 studies are ongoing with a higher dose of carfilzomib (27 mg/m2) being evaluated. The data from this small subset analysis suggests that further exploration of this relationship is warranted. Disclosures: Zangari: Milllennium: Honoraria, Research Funding; Novartis: Research Funding; Celgene: Honoraria; OrthoBiotech: Honoraria; Optum Health: Honoraria; Educational Concepts Group, LLC: Membership on an entity's Board of Directors or advisory committees. Vij:Proteolix: Consultancy, Research Funding. Jagannath:Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Merck: Honoraria. Siegel:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Stewart:Millennium: Consultancy, Research Funding; Proteolix: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Honoraria. Wang:Proteolix: Honoraria, Research Funding. Belch:Ortho Biotech: Honoraria, Research Funding. Jakubowiak:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Centocor Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers-Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Trudel:Celgene: Honoraria, Speakers Bureau; Ortho Biotech: Honoraria. Bahlis:Celgene: Honoraria, Speakers Bureau; Ortho Biotech: Honoraria, Speakers Bureau. Lonial:Celgene: Consultancy; Millennium: Consultancy, Research Funding; BMS: Consultancy; Novartis: Consultancy; Gloucester: Research Funding. Singhal:Celgene: Speakers Bureau; Millennium: Speakers Bureau.

Abstract INTRODUCTION: PR-171 is a novel, irreversible proteasome inhibitor under investigation for the treatment of hematological malignancies. In preclinical studies, PR-171 was well tolerated in rats and monkeys when given daily × 5 (QDx5), every two weeks. Proteasome inhibition determined in blood and other tissues one hour after dosing at the maximum tolerated dose (MTD) was >80%. Despite the irreversible mechanism of action, the half-life of recovery of proteasome inhibition in tissues was approximately 24 hours. PR-171 was effective in suppression of tumor growth in xenograft studies in mice when administered QDx2 every week for three weeks. Two phase I dose-escalation studies have been initiated, aimed at determining the safety, tolerability, and clinical response to PR-171. METHODS: Two different dose-intensive schedules were employed in these phase I studies. In PX-171-001, PR-171 was administered on a two week cycle, QDx5 with nine days rest, while in PX-171-002, PR-171 was administered on a four week cycle, QDx2 weekly for three weeks with 12 days rest. The objective of these studies was to evaluate the safety and effectiveness of single-agent PR-171 administered according to a modified Fibonacci dose escalation scheme in cohorts of three. Patients with multiple myeloma (MM), non-Hodgkin Lymphoma (NHL), Hodgkin disease, or Waldenstrom’s Macroglobulinemia who received two or more prior treatments were eligible. RESULTS: Both studies were initiated with a dose of 1.2 mg/m2. Thus far, a total of 15 and 23 subjects have been enrolled in PX-171–001 and -002, respectively. PR-171 has been well tolerated at the highest doses thus far, 8.4 and 15 mg/m2, respectively. Proteasome inhibition in whole blood at the highest dose levels exceeded 75%, and in peripheral blood mononuclear cells inhibition exceeded 65%, one hour after the first dose. There have been no dose-limiting toxicities, no adverse events (AEs) considered probably related to study medication, no dose-related increases in the incidence or severity of AEs, and no incidence of painful peripheral neuropathy on either study. Although the MTD has not yet been identified on either study, preliminary evidence of efficacy has been observed with reduction in myeloma paraprotein levels and symptomatic improvement in patients on both protocols. Eleven subjects remain on study with stable disease (SD), which has been observed in MM and NHL patients on both studies, lasting up to eight months. CONCLUSION: PR-171 is well-tolerated in relapsed and refractory MM and NHL patients at proteasome inhibition levels of more than 75%. Several subjects have achieved long-lasting SD, reduction in paraprotein levels or symptomatic improvement. Further data from these ongoing trials will be discussed at the meeting.

Abstract Abstract 1217 Poster Board I-239 Background Single autologous stem cell transplant (ASCT) is considered the standard of care after induction therapy for younger multiple myeloma (MM) patients (pts). However, it is not curative and virtually all patients will ultimately relapse. As more options are available to treat relapsed disease, the role of a second ASCT as salvage therapy is unclear. Method Retrospective review of all MM pts who received a 2nd ASCT as salvage therapy at Princess Margaret Hospital. Results Between February 1997 and July 2009, 79 MM pts received a second ASCT for relapsed MM at our institution. Median age was 60 yrs (range 39-72) at second transplant. 48 pts (61%) were male. Immunoglobulin subtype included IgG (42), IgA (21), light chain (11), nonsecretory (3), IgM(1) and IgD (1). Transplant conditioning regimen for first transplant was high dose melphalan (MEL) 140-200 mg/m2 in 67, busulphan and cyclophosphamide in 1, and combinations of MEL with etoposide (E) or TBI in the rest. 2nd ASCT conditioning consisted of MEL alone in 76, the remaining 3 had MEL with either TBI or E. The median time to relapse after the first transplant was 2.72 years (0.81-8.26), with a median interval between transplants of 3.61 years (1.63-9.59). Response to first transplant in 78 evaluable patients was 13 CR/nCR (17%), 56 PR/VGPR (72%), 9 MR/SD (12%). Nineteen pts received maintenance therapy between transplants. Two transplant-related deaths occurred following 2nd ASCT. In 73 evaluable patients, response to second transplant was 11 CR/nCR (15%), 57 PR (78%), 6 MR/SD (8%). After 2nd ASCT, with median follow up 5.92 years (71 months), median progression-free survival (PFS) was 18.5 months and median overall survival (OS) was 4.4 years. Long term progression-free status based on the progression-free interval after 1st ASCT is summarized Table 1. PFS based on progression free interval after 1st ASCT is outlined in Figure 1. Conclusions 2nd ASCT is a feasible and safe salvage therapy in relapsed MM patients. It is effective in providing a median progression free survival of 18.5 months and median overall survival of 4.4 years (52.8 months) after 2nd ASCT. This is comparable if not better than modern salvage chemotherapies. The longer the disease free interval after 1st ASCT the more effective 2nd ASCT is at extending both progression free survival and overall survival. It is reasonable, therefore, to consider a 2nd ASCT if the time to progression is greater than 2 years after first ASCT. Disclosures Chen: Celgene: Honoraria, Research Funding; Ortho Biotech: Honoraria. Trudel:Celgene: Honoraria, Speakers Bureau; Ortho Biotech: Honoraria. Kukreti:Celgene: Honoraria.

Abstract The t[4;14] simultaneously deregulates fibroblast growth factor receptor 3 (FGFR3) and MMSET in 15% of patients (pts) with Multiple Myeloma (MM). Although oncogenic, FGFR3 expression is lost in ~25% of t[4;14] pts on gene expression profiling while MMSET is always retained. The t[4;14] is highly associated with poor prognosis, furthermore FGFR3 kinase inhibitors are in Phase I trials, thus detection of t[4;14] pts is increasingly important. The Multiple Myeloma Research Consortium (MMRC) therefore evaluated 4 competing methodologies for the diagnostic detection of t[4;14]. Bone marrow (BM) samples were collected in uniform fashion from 85 pts. FGFR3 immunocytochemistry (ICC) and flow cytometry (FC) were performed at the retrieval site, while split samples were shipped to the MMRC tissue bank and processed under GLP conditions. Processed samples were analyzed by cIg-FISH and quantitative IgH-MMSET RT-PCR (QPCR) on unsorted BM and blood. Of 60 samples with sufficient plasma cells for analysis, 8 were FISH +ve [13.3%]. Low % BM plasma cells prevented successful FISH in 25% of samples reflecting large volume harvests and hemodilution. Analysis was conducted in a blinded fashion. With FISH as the gold standard for detection of t[4;14] the sensitivity and specificity of the other diagnostic tests are: BM QPCR is most sensitive (7 of 8 FISH positive detected) and specific (42/43 negatives correctly identified). QPCR on peripheral blood is ongoing. FC is more sensitive to the detection of FGFR3 protein than ICC. Correlation between FC and ICC was only 0.46. Interestingly, 6 of 7 evaluable pts here and 13/14 (92%) in an expanded analysis of FISH +ve patients also expressed the FGFR3 protein. Given the discrepancy between this finding and previously reported loss of FGFR3 expression in 25% of pts we further explored t[4;14] stability. Clonal selection/heterogeneity was determined by the % plasma cells in each pt. with an unbalanced translocation (loss of one der chromosome). In 42 t[4;14] pts, 13 (31%) had a balanced translocation(>75% of cells with a double fusion), 14 (33%) had an unbalanced translocation (>75% cells with only one signal), and 15 (36%) had a chimeric picture. This heterogeneous pattern is suggestive of an evolution towards an unbalanced translocation. Despite this survival did not differ between pts with balanced or unbalanced translocation. Conclusions: These results indicate that the t[4;14] is highly heterogeneous with respect to balanced versus unbalanced translocations, which likely evolve over time. For detection, cIg-FISH continues to be the gold standard diagnostic methodology but may be limited by low plasma cell numbers in dilute BM or during MM remission. QPCR and FC appear most sensitive and specific for presence of t[4;14] and FGFR3 protein expression respectively. Surprisingly (given prior evidence of loss of FGFR3 expression in 25% of pts) 92% of t[4;14] pts in this series expressed FGFR3 protein. # Analyzed % Positive Sensitivity Specificity FISH 60 13 - - QPCR 65 14 87.5 97.6 Flow 82 15 85.7 91 ICC 85 15 62.5 92