Kumar, Shaji

Abstract Abstract 3980 Background: Nearly half of patients with multiple myeloma (MM) are over 70 years at the time of diagnosis. While the survival of patients with myeloma has improved in the last decade, several studies have suggested no significant change for the elderly patients. These patients often have other comorbidities and are less likely to tolerate standard treatment approaches. We retrospectively studied the treatment patterns, outcomes, and prognostic factors in patients over 75 years of age. PATIENTS AND METHODS: We identified 212 patients who were older than 75 years from among 1545 patients seen at the Mayo Clinic within 90 days of diagnosis during 1999 to 2008. We only included 139 patients in whom complete treatment details were available. RESULTS: The median age was 80 years (range: 76–94) with 20 (14%) patients older than 85 years; 79 (57%) were male. Thirty-five patients (25%) had a history or coexistence of one or more malignancies. Chromosome analysis and FISH were performed in 65% and 22% respectively. Abnormal cytogenetics were seen in 30 (33%) of the 90 tested patients. The median survival of the 139 elderly patients was 27 months (95% CI: 20∼35) compared to 62 months (56∼68) for 1,290 patients ≤ 75 years of age seen during the same period. Sixty-nine (50%) patients received one or more novel agents (thalidomide, lenalidomide, pomalidomide, bortezomib) and showed longer median survival (40 months vs 13 months) compared with those not receiving these agents (p=0.0008). Age over 85, initial poor performance score > 1, thrombocytopenia, elevated serum LDH or beta2-microglobulin, response more than stable disease to first therapy resulted in inferior survival. Among them, only performance status had the persistent significance in multivariate analysis. CONCLUSION: Older patients receiving newer therapies appear to have a better outcome, which is still lagging behind the younger patients. A poor performance score at diagnosis predicts for eventual poor outcome. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 3948 Background: Smoldering multiple myeloma (SMM) is an asymptomatic precursor disease of multiple myeloma, and is defined by excess bone marrow plasma cells and monoclonal protein without evidence of end-organ damage (hypercalcemia, renal insufficiency, anemia, or bone lesions [CRAB]). The identification of SMM patients with more aggressive underlying disease remains a challenge. We hypothesize that SMM is a clinical entity comprised of both premalignant, high-risk MGUS and early multiple myeloma in transition to malignant disease, which may be differentiated with the use of the serum FLC (FLC) ratio. Methods: This was a retrospective analysis of 586 patients with newly diagnosed SMM from 1970–2010 with available stored serum samples around the time of diagnosis to be utilized for quantification of FLC ratios. SMM was defined by the International Myeloma Working Group 2003 definition; serum M-protein ≥ 3 g/dL and/or ≥ 10% bone marrow plasma cells with no evidence of CRAB features. The immunoglobulin FLC assay (Binding Site, U.K.) was used for testing. The FLC ratio was calculated as κ/λ (reference range 0.26–1.65). The involved/uninvolved FLC ratio was recorded to simplify the reporting of data. Receiver Operating Characteristics (ROC) curves were created to assess the ability of the FLC ratio to discriminate patients who progressed to symptomatic multiple myeloma (MM) in the first 2 years or at any point during follow-up versus patients without evidence of progression. Patients with less than 24 months follow-up without progression were censored. The optimal diagnostic cut-point for FLC involved/uninvolved ratio to identify patients with progressive disease from the ROC curve was >88.6 (equivalent to <0.011 or >88.6). For ease of clinical application, the optimal value for involved/uninvolved FLC ratio was rounded to >100. Time to progression (TTP) from date of the initial FLC to active MM was calculated using Kaplan-Meier analysis and compared to patients with a high (>100) and low (<100) involved/uninvolved FLC ratio at time of SMM diagnosis. TTP within 24 months of the initial FLC was also calculated. Results: During the study period, 54% of patients progressed to active MM. On ROC analysis, a cut-point of >100 corresponded to a sensitivity of 25% (95% CI, 20.5–30.4) and specificity of 99.3% (97.3–99.9), with positive likelihood (+LR) ratio of 33.9 (38.1–41.0), negative likelihood ratio (−LR) of 0.75 (0.2–3.0), positive predictive value (PPV) of 97.6 (91.5–99.7) and negative predictive value of 53.0 (48.5–57.4). Using the ROC to assess progression to MM within 24 months (Figure 1), sensitivity was 29.6% (23.5–36.4), specificity 94.5% (91.7–96.5), +LR 5.36 (4.3–6.6), -LR 0.75 (0.5–1.1), PPV 85.8 (77.7–91.8), and NPV 54.3 (49.8–58.9). Median TTP to active MM in the FLC >100 group was 15 months (9–17) versus 52 months (44–60) in the FLC <100 group (p <.0001) [Figure 2]. In the FLC ratio >100 group, progression at 1 year was 47%, 76% at 2 years, and 90% at 3 years. Only 25% of the FLC <100 patients had progressed at 2 years. The most common progression event was bone disease (42%), followed by anemia (26%), renal impairment (23%), and hypercalcemia (5%). Conclusion: Elevation of the FLC ratio >100 (or <0.01) is highly specific for the future development of active MM, with 76% of these patients developing end-organ damage requiring therapy within 2 years. Risk of transformation to MM in the FLC <100 group was similar to previously reported rates of 10% per year for the first 5 years. Development of an FLC ratio >100 is associated with increasing disease burden and in this study behaved in a malignant fashion rather than a precursor state. The FLC is a simple and useful predictor of progression to MM in SMM, and patients with FLC ratios of <0.01 or >100 within the first 2 years of SMM diagnosis should be monitored especially closely. Future studies are needed to determine optimum cutoffs for FLC ratio to where a change in definition of MM could be considered. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 987 Background: IMiD® compounds are effective in immunoglobulin light-chain amyloidosis (AL), a systemic plasma cell disorder related to multiple myeloma (MM). Pomalidomide is a new IMiD® compound. Methods: Persons with symptomatic, biopsy-proved, previously-treated AL were eligible for treatment with pomalidomide if they had measurable hematologic disease, ECOG PS≥2, adequate hematologic reserve and creatinine ≤2.5 mg/dL. Pomalidomide, 2 mg/d, and dexamethasone, 40 mg/w, were given orally along with low-dose aspirin. Dose-escalation to 4 mg/d was allowed for non-responders. Exclusion-criteria were uncontrolled infection, cancer, NYHA classification >II, serum troponin-T >0.1 ng/mL, ≥grade-3 neuropathy, thrombosis or other AL therapy within 2 weeks of enrollment. 31 subjects enrolled, but only 29 are evaluble for toxicity and response due to recent enrollment. Results: Median age was 66 y (range, 52 82 y); 19 were male. Median time from diagnosis to study-entry was 36 mo (range, 0.9–104.1 mo). 24 had cardiac involvement, 10, renal involvement and 8, nerve involvement. Cardiac biomarker staging was: I, N=3, II, 21, and III, N=7. Subjects were extensively pretreated: 28 received an alkylator (including an autotransplant in 13), 15, prior lenalidomide or thalidomide and 12, prior bortezomib. 193 cycles of pomalidomide were given to 29 subjects. 11 subjects had protocol-specified dose-increases (no response) and 16, dose-reductions (AEs). 20 subjects had dexamethasone dose-reductions. ≥Grade-3 AE's ≥possibly attributed to therapy occurred in 21 subjects. 7 of these subjects had only hematologic AE's. Neutropenia was the most common severe AE (N=10); severe thrombocytopenia occurred in 2 subjects. Other grade-3/-4 AEs included infection/fever (N=3); fatigue (N=4), and pleural effusion, ascites/edema, and edema each in one patient. 1 subject each had dyspnea, increased creatinine, thrombosis, muscle weakness, atrial tachycardia, and diarrhea. There were 2 episodes of syncope attributed to AL rather than therapy. A subject died 5 d after beginning therapy presumably from cardiac AL. As of 7/27/010, median time on-study is 8.4 mo (range, 0.2–16.2 mo). 18 subjects discontinued therapy for: progression/death (N=9); consent withdrawal (N=4), AE (N=3) and physician choice (N=2). Overall hematologic response rate (N=29) is 38% (95% CI, 20–58%) There were 8 PRs and 3 VGPRs including 4 PRs and 2 VGPRs among 14 subjects failing prior lenalidomide and/or thalidomide. 3 subjects had confirmed organ responses (2 heart and 1 kidney) and 4 unconfirmed organ responses. 1 y survival and PFS are 77% (95% CI, 60–98) and 56% (95% CI, 36–85). Conclusion: These data suggest that pomalidomide could provide a safe and effective therapy in previously-treated persons with AL including those failing lenalidomide and/or thalidomide. Disclosures: Dispenzieri: Celgene: Honoraria, Research Funding; Binding Site: Honoraria. Off Label Use: Non-FDA approved indication. Gertz:Celgene: Honoraria. Kumar:Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Fonseca:Amgen: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy, Research Funding; Genzyme: Consultancy; Onyx: Research Funding; Otsuka: Consultancy; Medtronic: Consultancy. Bergsagel:Celgene: Consultancy; Centocor: Consultancy; Genentech: Consultancy; Amgen: Consultancy; Novartis: Consultancy. Stewart:Millennium: Consultancy; Celgene: Honoraria. Lacy:Celgene: Research Funding.

Abstract Abstract 3949 Acute kidney injury (AKI) is a common but serious sequela of multiple myeloma. Recently, the International Myeloma Working Group (IMWG) introduced a new renal response criteria with complete (CRenal), partial (PRenal) and minimal (MRenal) responses. This study compares the IMWG criteria with other models to determine their correlation with overall survival (OS). Patients with multiple myeloma and AKI were identified from centers around the world. OS was calculated from the day of AKI. Renal function was assessed by estimated glomerular filtration rate (eGFR) via MDRD method. Hematologic response was the best achieved as assessed by International Uniform Response Criteria for Multiple Myeloma. Only patients with peak serum creatinine (Scr) ≥ 2.0 mg/dl were included. Separate analyses were performed on the newly diagnosed (ND) versus previously treated (PT) patients. A total of 158 patients were collected from centers in United States, United Kingdom, France and Austria. Fourteen patients were excluded for having peak Scr < 2.0 mg/dl and one for repeated episodes of AKI. Median age of the 143 patients was 64 (34 – 87) years, 58.7% were male and 115 were newly diagnosed. Median Scr was 5.1 (2.0 to 18.6) mg/dl and median eGFR was 10.6 (2.8 – 36.5) ml/min/1.72 m2. Dialysis was required in 49.3%, and 72.9% were dialysis independent at the end of the study. By IMWG criteria, median OS ranged between 6.0 months (m) in PT patients with no renal response (NRenal) to 23.7m in patients with CRenal, p = 0.34 (Table 1). In ND patients, OS was 31.4m in NRenal vs 73.8m in CRenal (p = 0.08). However, OS was similar between PRenal and CRenal, p = 0.70 (Figure 1). If only patients with a hematologic PR or better were analyzed, the OS range was 6.0m in NRenal to 23.7m in CRenal in PT patients (p = 0.85) and 36.6m in NRenal to 73.8m in CRenal in ND patients, p = 0.73.Table 1.Previously TreatedNMedian SurvivalNMedian Survival (>PR) CRenal323.7 m323.7 m PRenal413.1 m312.8 m MRenal512.0 m119.2 m NRenal166.0 m56.0 m p-value0.340.85Newly Diagnosed CRenal2273.8 m2273.8 m PRenal27Not Reached23Not Reached MRenal2265.6 m1965.6 m NRenal4331.4 m2136.6 m p-value0.080.73Figure 1.Overall survival (OS) of 115 patients evaluated by the IMWG renal response criteria. OS was not significantly different by Log-Rank test between patients with CRenal and NRenal, p = 0.08.Figure 1. Overall survival (OS) of 115 patients evaluated by the IMWG renal response criteria. OS was not significantly different by Log-Rank test between patients with CRenal and NRenal, p = 0.08. The best model tested was one that defined renal response (RR) as regaining or maintaining dialysis independence and no response (NR) as dialysis dependence. RR was associated with a superior survival for both PT patients (13.5 m vs 6.0m (NR), p = 0.03) and ND patients (73.8m vs 20.1m (NR), p < 0.001). RR increased with the depth of hematologic response, p = 0.04. RR occurred in 75% of the PT patients with hematologic PR or better and 66.7% in those with less than PR, p = 0.64. In ND patients, RR occurred in 85.7% of those with PR or better and 54.6% of those with PR or less, p = 0.003. This may explain the differences in OS when hematologic response was considered. In PT patients with hematologic PR or better, renal response did not improve OS (21m vs 6m, p = 0.28) but it remained beneficial in the ND patients (73.8m vs 35.1m, p = 0.04, Figure 2). Renal response was not significantly associated with OS for any patient with hematologic response that was VGPR or better. In a multivariate analysis, RR (p = 0.001), ND (p <0.001) and PR or better hematologic response (p = 0.046) were associated with OS.Figure 2.In a separate model, 83 newly diagnosed patients with hematologic response of PR or better were evaluated. Patients who were dialysis independent achieved a renal response (RR) and those who remained on dialysis had no response (NR). Patients with RR had a superior overall survival than patients with NR. Renal response was independent of a hematologic response of PR or better.Figure 2. In a separate model, 83 newly diagnosed patients with hematologic response of PR or better were evaluated. Patients who were dialysis independent achieved a renal response (RR) and those who remained on dialysis had no response (NR). Patients with RR had a superior overall survival than patients with NR. Renal response was independent of a hematologic response of PR or better. The results of our study suggest renal response is important to OS but the depth of response was not as important. Renal response was most important when the hematologic response was less than a VGPR. This supports renal response as part of the overall response assessment in multiple myeloma patients. Based on our results, reducing the number of response categories and simplifying the current consensus criteria seems justified. Median survival of the 143 patients evaluated by the IMWG renal response criteria. Overall survival was calculated by Kaplan Meier method. Differences in survival were evaluated by Log-Rank test. Disclosures: Ludwig: Mundipharma, Janssen-Cilag: Research Funding, Speakers Bureau. Hutchison:The Binding Site: Honoraria.

Abstract Introduction: Localized immunoglobulin light chain amyloidosis (LAL) is a rare disease. Systematic data regarding its presentation, management and patient outcomes are limited to small case series. Our objective was to systematically describe the Mayo clinic experience of patients with LAL. Methods: We retrospectively reviewed clinical records of 403 patients with biopsy proven localized amyloidosis seen at the Mayo Clinic between 1969-2014. Median follow-up for survival and progression were 72 months and 39 months, respectively Results: OF 5551 patients with light chain amyloidosis seen at the Mayo clinic during the study period, 403 (7%) had LAL. Median age at diagnosis was 60 years (range, 13-93) and 51% of them were male. Sites involved included: urothelial (bladder, ureter, renal pelvis), 75 (19%), larynx, 51 (13%), lung parenchyma, 42 (11%), skin, 44 (11%), synovial tissue 36 (9%), tracheobronchial, 31 (8%), gastrointestinal tract, 30 (8%), seminal vesicles, 22 (6%), eyes, 23 (6%), pharynx 22 (6%) and other 24 (6%). Typing was performed in 178 (45%) cases. A monoclonal protein was detected in 23 of 351 (7%) evaluated cases, 5 of which had different light restriction from that of LAL. Thirty one (8%) patients had a co-existent autoimmune disease. No patients progressed to systemic AL. Of 403, 109 (27%) were observed or received supportive care only and 241 (60%) underwent local removal of the amyloid deposits. Sixty-four (16%) patients required repeated interventions (median 1, range 1-4, upper decile requiring 4 interventions) for progressive disease. The most common sites requiring repeated interventions were: urothelial (33%), laryngeal (19%) and tracheobronchial (8%). Ten year overall survival (OS) and progression free survival were 79% and 61%, respectively and there was no difference according to site of involvement. Of the 70 patients that died during the follow-up period, cause of death was known for 29 and death was attributed to LAL in only 2 cases. Conclusions: In the largest series of patients with LAL reported so far we demonstrated that LAL has an excellent prognosis but can sometimes be associated with significant morbidity. Although our study was limited by incomplete typing in 55% of cases, it appears that true LAL does not "progress" to systemic amyloidosis. However, systemic amyloidosis can frequently involve organs typical involved only in LAL;, therefore a complete work-up for systemic disease should be performed in all patients with LAL. Treatment usually involves local excision for symptom palliation. In 16% of cases, repeated interventions for relapse/progression were required and as a result, follow-up is recommended, especially for cases involving the urothelial and upper respiratory tract. Disclosures Kumar: Skyline, Noxxon: Honoraria; Celgene, Millennium, Onyx, Novartis, Janssen, Sanofi: Research Funding; Celgene, Millennium, Onyx, Janssen, Noxxon, Sanofi, BMS, Skyline: Consultancy.

Background Ixazomib is the first orally administered PI studied in the clinic. The feasibility of combining ixazomib weekly and lenalidomide-dexamethasone (Rd) in the first all-oral PI- and immunomodulatory drug-containing triplet regimen was evaluated in a phase 1/2 trial of 65 pts with newly diagnosed MM. Results indicated a 90% ORR (62% ≥VGPR) using ixazomib 4 mg (recommended phase 2/3 dose), with a manageable safety profile, including 14% gr ≥3 skin/subcutaneous tissue disorders and limited (4% gr 3) peripheral neuropathy (PN) (Kumar et al, Lancet Oncol 2014). These data provided the rationale for phase 3 investigation of IRd vs placebo-Rd in pts with RRMM in this randomized, double-blind, placebo-controlled, international, multicenter study. Methods Adults with RRMM after 1-3 prior lines of therapy who were not refractory to prior lenalidomide or PI-based therapy were randomized 1:1 to receive ixazomib 4 mg or matching placebo weekly on d 1, 8, and 15, plus lenalidomide 25 mg PO on d 1-21 (dose reduced for renal impairment per local label/practice) and dexamethasone 40 mg PO on d 1, 8, 15, and 22, in 28-d cycles. Randomization was stratified by number of prior therapies (1 vs 2/3), PI exposure (naïve vs exposed), and ISS disease stage (I/II vs III). Cycles were repeated until disease progression or unacceptable toxicity. Primary endpoint was PFS as assessed by an independent review committee blinded to treatment, per IMWG criteria. Key secondary endpoints were OS and OS in high-risk pts with del(17). Sample size was determined to provide 80% power for the OS endpoint and adequate power to test PFS. Three interim analyses (IAs) and a final analysis were planned to test PFS and OS; here, we report data from the first IA, the final analysis for PFS. Results 722 pts were randomized (360 IRd; 362 Rd). Baseline characteristics were balanced between groups; overall median age was 66 yrs (30-91), 70% were PI-exposed, 88% were ISS stage I/II, 59% had received 1 prior therapy, and 77%/11%/11% were relapsed/refractory/relapsed and refractory, with 6% primary refractory. Based primarily (97%) on central laboratory evaluation, 19% had high-risk cytogenetics by FISH (del(17), t(4;14), or t(14;16)), including 10% del(17). Prior therapies included 69% bortezomib, 45% thalidomide, and 12% lenalidomide. The study met the primary endpoint at the first IA (median follow-up 14.8 vs 14.6 mos with IRd vs Rd), demonstrating a 35% improvement in PFS with IRd vs Rd (HR 0.742; p=0.012; Table). In pts with high-risk cytogenetics, the PFS HR was 0.543 with IRd vs Rd (HR 0.596 in pts with del(17)), with a median PFS similar to the overall IRd group, indicating ixazomib may overcome the negative impact of cytogenetic alterations. OS data were not yet mature. Key response data are shown in the Table. Pts received a median of 13 (1-26) vs 12 (1-25) cycles of IRd vs Rd; 55% and 52% of pts remained on treatment. With IRd vs Rd, 68% vs 61% of pts had gr ≥3 AEs (driven by thrombocytopenia), 40% vs 44% had serious AEs, 13% vs 11% discontinued all study drugs due to AEs, and 3% vs 5% died on treatment. AEs observed with IRd were consistent with reported safety profiles for the individual agents. Common gr ≥3 AEs were neutropenia (19% vs 16%), anemia (9% vs 13%), thrombocytopenia (13% vs 5%), and pneumonia (6% vs 8%). Gastrointestinal events included 42% vs 36% diarrhea (6% vs 2% gr 3), 26% vs 21% nausea (2% vs 0% gr 3), and 22% vs 11% vomiting (1% vs <1% gr 3). PN rates were 28% vs 21% (2% vs 2% gr 3), 35% vs 21% had rash events (4% vs 1% gr 3), 4% vs 6% had renal failure (2% vs 3% gr ≥3), and 4% vs 3% had heart failure (2% vs 2% gr ≥3). Conclusion At this first prespecified IA, addition of ixazomib to Rd in pts with RRMM increased median PFS to 20.6 from 14.7 mos without a substantial increase in overall toxicity, including cardiac and PN toxicity. Benefit with IRd was also noted in pts with high-risk cytogenetics, including those with del(17), in whom median PFS was similar to all IRd-treated pts indicating that ixazomib may have a favorable impact on the adverse prognosis associated with genetic mutations. If approved, this all-oral combination of IRd may become a new standard of care in this setting. Table. Key efficacy data IRd Rd HR / OR Median PFS, mos 20.6 14.7 HR 0.742; 95% CI: 0.587-0.939; p=0.012 Confirmed ORR, % 78.3 71.5 OR 1.44; p=0.035 CR 11.7 6.6 OR 1.87; p=0.019 ≥VGPR 48.1 39.0 OR 1.45; p=0.014 Median time to first response (ITT analysis), mos 1.1 1.9 Median duration of response (≥PR), mos 20.5 15.0 Disclosures Moreau: Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Investigational proteasome inhibitor ixazomib in combination with lenalidomide and dexamethasone for patients with relapsed/refractory multiple myeloma. Masszi:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Bahlis:Johnson & Johnson: Speakers Bureau; Johnson & Johnson: Consultancy; Amgen: Consultancy; Johnson & Johnson: Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Sandhu:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Ganly:Novartis: Honoraria; Roche: Honoraria; Medipics: Equity Ownership. Baker:Janssen-Cilag New Zealand: Membership on an entity's Board of Directors or advisory committees. Stoppa:Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Simpson:Celgene: Honoraria; Janssen-Cilag: Honoraria; Onyx Pharmaceuticals: Research Funding; Roche: Honoraria. Gimsing:Amgen: Honoraria. Palumbo:Celgene, Millennium Pharmaceuticals, Amgen, Bristol-Myers Squibb, Genmab, Janssen-Cilag, Onyx Pharmaceuticals: Consultancy, Honoraria; Novartis, Sanofi Aventis: Honoraria. Garderet:Bristol-Myers Squibb: Consultancy. Cavo:Janssen-Cilag, Celgene, Amgen, BMS: Honoraria. Kumar:AbbVie: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Onyx: Research Funding; Celgene, Millenium, Sanofi, Skyline, BMS, Onyx, Noxxon,: Other: Consultant, no compensation,; Skyline, Noxxon: Honoraria; Millenium/Takeda: Research Funding. Touzeau:AbbVie: Research Funding. Laubach:Novartis: Research Funding; Onyx: Research Funding; Celgene: Research Funding; Millennium: Research Funding. Lin:Millennium Pharmaceuticals, Inc.: Employment. Berg:Millennium Pharmaceuticals, Inc.: Employment. DiBacco:Millennium Pharmaceuticals, Inc.: Employment. Hui:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Richardson: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; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Millennium Takeda: 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.

Abstract Background: The initial therapies for multiple myeloma have changed significantly in the recent years with routine incorporation of combinations containing IMiDs and proteasome inhibitors. However, patients with MM invariably relapse after their initial treatment and undergo successive therapies for continued control of their disease. The increasing access to new therapies for treatment of relapsed disease has led to improved survival of patients with MM. Many recent phase 3 trials have studied the impact of new agents on outcome of patients with MM who are relapsing after the initial lines of therapy for relapsed disease. However, the natural history of relapsed myeloma earlier in the course of relapsed disease has not been studied in detail. Patients and methods: We designed a global, multicenter, retrospective study to examine the current treatment approaches for initial relapses in MM and patient outcomes following application of successive treatment regimens. Patients with multiple myeloma who experience a first relapse between January 1, 2007 and December 31, 2011 were identified at participating sites. Clinical and laboratory data pertaining to the time of diagnosis and from the time of individual relapses up to and including the third relapse will be obtained from the clinical records. The first date of treatment with an anti-myeloma regimen for first disease relapse was termed time zero (T0). Results: Three hundred and fifteen patients were enrolled; median age at diagnosis was 59 years (range: 35 - 86), 59% were male. Patients were enrolled from North America (33%), Europe (35%) or Asia (32%). The patients were diagnosed between 1997 and 2011 and the median time to T0 from diagnosis was 23.9 months (range: 0.8 - 131.9 months). An IMiD (thalidomide or lenalidomide), bortezomib or alkylator (melphalan or cyclophosphamide) was part of the initial therapy in 63%, 36% and 51% of patients, respectively; 93 (33%) patients had stem cell transplantation as part of initial treatment. The median follow up from the study entry was 56 months; 117 were alive at the time of data extraction. A second line, third line and fourth line of treatment were recorded in 307, 163 and 84 patients respectively. An IMiD (thalidomide, lenalidomide, or pomalidomide), proteasome inhibitor (bortezomib or carfilzomib) or alkylator (melphalan or cyclophosphamide) was part of the therapy for first relapse in 50%, 59% and 33% of patients, respectively. The responses to the regimens after T0, the TTNT, PFS and OS to each line of therapy are provided in the Table. Conclusion: The current study provides an assessment of the current treatment approaches used for initial treatment of MM and the salvage treatment options utilized. The study again demonstrates the progressively shorter duration of disease control with each successive treatment regimen, reflecting ongoing development of drug resistance. The overall survival of over 3 years from the time of therapy for first relapse highlights the impact of the newer therapies that have been introduced for this disease. Table. Treatment outcomes after initial relapse Endpoint 2nd line therapyN=307 3rd line therapyN=163 4th line therapyN=84 Partial response or better Median in Months (95% Confidence Interval) Overall Survival 36.1 (30.2, 42.4) 18.4 (14.5, 26.8) 12.6 (10.4, 19.0) Progression-Free Survival 13.4 (11.8, 15.8) 8.3 (6.5, 11.2) 6.4 (5.0, 8.1) Time to Next Treatment 15 (12,17) 9.8 (7.4, 12.0) 6.6 (5.8, 8.7) Figure 1. Figure 1. Disclosures Kumar: Onyx: Consultancy, Research Funding; Skyline: Consultancy, Honoraria; BMS: Consultancy; Sanofi: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Novartis: Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Dimopoulos:Novartis: Honoraria; Amgen: Honoraria; Janssen-Cilag: Honoraria; Genesis: Honoraria; Janssen: Honoraria; Onyx: Honoraria; Celgene: Honoraria. Leleu:Janssen: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Amgen: Honoraria; TEVA: Honoraria; Novartis: Honoraria; BMS: Honoraria; Pierre Fabre: Honoraria; LeoPharma: Honoraria; Chugai: Honoraria. Moreau:Celgene, Janssen, Takeda, Novartis, Amgen: Membership on an entity's Board of Directors or advisory committees. Lahuerta:Janssen Cilag, Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Vij:Takeda, Onyx: Research Funding; Celgene, Onyx, Takeda, Novartis, BMS, Sanofi, Janssen, Merck: Consultancy.

Abstract Background Waldenström macroglobulinemia (WM) is a rare, indolent immunoglobulin M- associated lymphoplasmacytic lymphoma characterized by the alternation in the MYD88 locus in 90-95% of the cases. MYD88L265P is the most common alteration in WM patients and is considered a key molecular signature with a pathophysiological role in WM. Because of extremely low prevalence of WM with MYD88 wild type (WT) genotype there is a paucity of clinical and outcome data in this unique patient population. A recent study (Treon et al, Blood May, 2014), in an analysis based on the patients' MYD88 status, reported on the clinical features including older age at presentation and an unexpectedly higher mortality (38%) in the MYD88WTcohort compared to MYD88L265P patients (mortality 6%, P < .0001). However, the sample size of the MYD88WT WM cohort was small (n=15), with a few events during the short follow-up (median 4.84 years). Herein, we report on larger cohort of WM patients with this rare genotype. Methods This study included patients evaluated at Mayo Clinic, Rochester in whom the diagnosis of WM was established based on their clinicopathologic features and the MYD88 mutation status was determined through AS-PCR (assay sensitivity 1% mutant allele) performed on archived bone marrow samples obtained between 2007-2014. Patients with MYD88WT status were the focus of this study. Clinical data were collected from the patients' medical records. The Kaplan-Meir method was utilized for the survival analysis calculated from the time of diagnosis of WM. Outcomes of MYD88WT patients were compared with those harboring the MYD88L265Pmutation. Results Our cohort of 171 patients with an established diagnosis of WM and known MYD88 mutation status was found to be enriched for MYD88WT (n=40) patients. All patients required therapy. At diagnosis, the median age of the patients with MYD88 WT was 63 years (range 37.5-83.5 years; comparable to that of the MYD88L265P cohort, median 65 years, range: 32-92 years, p=0.16). Familial WM was identified in 10% of patients. Sixty four percent of patients presented with constitutional symptoms at diagnosis. These symptoms included fatigue (45%), weight loss (17%), night sweats (8%) dizziness (10%), dyspnea (23%), bleeding (10%), headache (10%) and hyper viscosity syndrome (5%). Splenomegaly and lymphadenopathy was observed in 20% and 27% of patients, respectively. Thirteen percent of patients had concomitant AL amyloidosis. Additional baseline characteristics are reported in Table 1. Transformation to a higher grade lymphoma was noted in 9 (23%) of patients, four of whom had received a purine analog and /or chlorambucil previously. The estimated median follow of MYD88WT patients was 8.1years (95% CI: 6.4-8.9) and their median overall survival (OS) was 8.5 years (95% CI: 6.4-29.4). No OS difference was evident between this cohort and the remainder of the patients with the MYD88L265Pmutation (n=131, median OS 11.7 years, 95% CI: 10-18, p=0.7; median follow-up 7.7 years 95% CI: 6.4-9.1, Figure 1). Conclusion In this relatively large cohort of WM MYD88WT patients with a prolonged follow-up, the MYD88mutation status was not found to be a determinant of patients' outcomes. Our findings contradict the results of a seminal previous study and require external validation, preferably through prospective studies. Disclosures Kapoor: Amgen: Research Funding; Takeda: Research Funding; Celgene: Research Funding. Ansell:BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Kumar:Sanofi: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Glycomimetics: Consultancy; Onyx: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy; Millennium: Consultancy, Research Funding; AbbVie: Research Funding; Kesios: Consultancy.

Abstract Abstract 4034 Natural Killer (NK) cells are lymphocytes of the innate immune system with anti-viral and anti-cancer activity. Over the past decade, they have gained interest as a promising cellular source for use in adoptive immunotherapy for the treatment of cancer. Most notably, NK cells play an important role in the graft-vs-tumor effect seen in allogeneic hematopoietic stem cell transplantation (allo-HSCT), and a better understanding of NK cell biology has translated into improved transplant outcomes in acute myelogenous leukemia (AML). Small studies have demonstrated a role for NK cell activity in multiple myeloma (MM) patients receiving allo-HSCT. Investigators have also utilized haplo-identical killer immunoglobulin-like receptor (KIR) mismatched NK cells for adoptive immunotherapy in patients with multiple myeloma (MM). Our group has focused on the development of NK cells from human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) as a novel starting source of lymphocytes for immunotherapy. We have previously demonstrated potent anti-tumor activity of hESC-derived NK cells in vitro and in vivo against a variety of different targets. We have also shown that iPSC-derived NK cells from a variety of different somatic cell starting sources posses potent anti-tumor and anti-viral activity. Here, we demonstrate hESC- and iPSC-derived NK cell development in a completely defined, feeder-free system that is amenable to clinical scale-up. These cultures contain a pure population of mature NK cells devoid of any T or B cell contamination, which are common adverse bystanders of cellular products isolated and enriched from peripheral blood. Our cultures are homogenous for their expression of CD56 and express high levels of effector molecules known to be important in anti-MM activity, including KIR, CD16, NKG2D, NKp46, NKp44, FasL and TRAIL. We have now tested the activity of hESC- and iPSC-derived NK cells against MM tumor cells in order to provide a universal source of lymphocytes for adoptive immunotherapy in patients with treatment refractory disease. We find that similar to peripheral blood NK cells (PB-NK), hESC- and iPSC-derived NK cells are cytotoxic against 3 distinct MM cell lines in a standard chromium release cytotoxicity assay. Specifically, activated PB-NK cells killed 48.5% of targets at 10 to 1 effector to target ratios, whereas hESC (46.3%) and iPSC (42.4%) derived NK cells also demonstrated significant anti-MM activity. Also, hESC- and iPSC-derived NK cells secrete cytokines (IFNγ and TNFα) and degranulate as demonstrated by CD107a surface expression in response to MM target cell stimulation. When tested against freshly isolated samples from MM patients, hESC- and IPSC-derived NK cells respond at a similar level as activated PB-NK cells, the current source of NK cells used in adoptive immunotherapy trials. These MM targets (both cell lines and primary tumor cells) are known to express defined ligands (MICA/B, DR4/5, ULBP-1, BAT3) for receptors expressed on NK cells as well as a number of undefined ligands for natural cytotoxicity receptors (NCRs) and KIR. As these receptor-ligand interactions drive the anti-MM activity of NK cells, we are currently evaluating expression of each of these molecules on the surface of both the effector and target cell populations. Not only do hESC- and iPSC-derived NK cells provide a unique, homogenous cell population to study these interactions, they also provide a genetically tractable source of lymphocytes for improvement of the graft-vs-myeloma effect and could be tailored on a patient specific basis using banks of hESC-or iPSC-derived NK cells with defined KIR genotypes for use as allogeneic or autologous effector cells. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 3989 Background: Treatment patterns of multiple myeloma (MM) vary across the globe, mostly dictated by the availability and patient access to different drug therapies. The outcomes of patients with MM, especially relapsed myeloma can be significantly affected by the availability of newer treatments, as well as potential biological differences related to ethnicity. We have previously shown that the outcome of patients relapsing after therapy with bortezomib (Bz) and one or more of the IMiDs remain poor with the currently available treatments and represent a difficult group of patients to treat. We undertook the current analysis on a set of patients from United States, several European countries and South Korea. Methods: We designed a multicenter, retrospective study that enrolled 294 patients with relapsed MM, from 14 sites (122 from Europe, 107 from US, and 65 from Korea). Patients were refractory to Bz, defined as no response to prior Bz-containing regimen or disease progression within 60 days of a Bz-containing regimen. Patients were also relapsed, refractory, intolerant, and/or ineligible, to treatment with an IMiD (thalidomide or lenalidomide). The date patients satisfied the above entry criteria was defined as time zero (T0). Clinical and laboratory data from diagnosis and individual relapses were collected along with details of all MM drug therapies before and after T0. Responses were assessed by IMWG or EBMT criteria. The goal of the study was to compare the characteristics of patients who satisfy the above inclusion criteria, the therapies employed prior to and after T0 and clinical outcome among these patients from different parts of the world. Results: The mean (median, range) time to reaching T0 from diagnosis was 4.5 (4.0, 12.8), 4.2 (3.2, 18.6), and 3.2 (2.8, 9.6) years from diagnosis for patients from US, Europe and Korea, respectively, P=0.021. The mean (median, range) number of therapies for the three groups were 8 (8, 13), 4 (4, 10), 5 (4, 7), respectively; P<0.001. The response rates (>=PR) to the initial therapy at diagnosis were 56%, 77% and 49% respectively for the US, European and Korean cohorts. Overall 220 patients had at least one therapy after T0, and 114 (52%) had a novel agent (Bz, len or thal) containing regimen as their first treatment after T0. Patients in US were more likely to receive additional therapies after the first post-T0 therapy; 62%, 32%, and 12% of patients from US, Europe and Korea, respectively, began a second post-T0 regimen within 2 years following time zero. The median number of therapies post T0 was 2, 1, and 1 for patients in US, Europe and Korea respectively. The response rates to the first regimen after T0 were 15%, 33% and 19% for the US, European and Korean cohorts, and were similar between those receiving a regimen with one of the novel drugs compared to rest. Patients younger than 60 years and those with prior transplants were more likely to respond to post T0 regimens. The median time to progression or death from T0was similar for the three patient cohorts, 5 months (Figure 1A). The median overall survival (95% CI) from T0 was 13 months (10, 16), 7 (5,9) and 8 (4,9) respectively for the US, European and Korean cohorts (Figure 1B). Conventional prognostic factors, especially the ISS stage was predictive of OS post T0. Additionally, presence of extramedullary disease was associated with a shorter overall survival. Conclusion: The results of the current study demonstrate significant differences between different parts of the world in terms of the treatment patterns both in the setting of initial therapy as well as treatment of relapsed disease. Patients in the US were more likely to receive multiple regimens both before and after T0. This is likely a reflection of increasing numbers of new drugs that have gone into clinical trials and thus enhancing options. The study further highlights the poor outcome of patients who have relapsed after the new drugs, irrespective of the geographical location. Disclosures: Kumar: Merck: Consultancy, Honoraria; Genzyme: Consultancy; Celgene: Consultancy. Richardson:Millennium: ; Celgene: ; Johnson & Johnson: ; Novartis: ; Bristol Myers Squibb:. Moreau:Millennium Pharmaceuticals, Inc.: Advisory board, Honoraria; Janssen: Advisory board, Honoraria. Sonneveld:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding. Siegel:Merck: Honoraria; Millenium: Honoraria, Research Funding, Speakers Bureau. San Miguel:Janssen-Cilag: Honoraria; Celgene: Honoraria. Palumbo:celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Durie:Celgene: Membership on an entity's Board of Directors or advisory committees.