Buadi, Francis K.

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 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 WM remains an incurable cancer despite recent advances. While a phase II trial has demonstrated efficacy of dexamethasone, rituximab and cyclophosphamide (DRC) in the treatment-naïve (TN) patients, this regimen has not been studied systematically in the relapsed/refractory (R/R) setting. Recent data has suggested the MYD88mutation status in WM patients can serve as a predictive marker with therapies such as ibrutinib. We examined the efficacy and tolerability of up to 6 cycles of DRC, with focus on R/R population and activity of this regimen with respect to the patients' MYD88L265Pstatus. Methods Records of WM patients seen consecutively at Mayo Clinic campuses in Rochester, Arizona and Florida from 01/2007 to 12/2014 were reviewed. MYD88L265P status, as assessed by AS-PCR, was recorded when available. Data obtained from symptomatic patients treated with DRC (dexamethasone 20 mg intravenously followed by rituximab 375 mg/m2 intravenously on day 1 and cyclophosphamide 100 mg/m2 orally bid on days 1 to 5) were analyzed. Time-to-event analyses were performed from DRC therapy using the Kaplan-Meier method. We used the Consensus response criteria (6th International Workshop). Results Of 100 symptomatic patients who received DRC, 50 had R/R WM (40% refractory) and 50 were TN. Table 1 shows the patients' baseline characteristics. In the R/R population, DRC was 2nd line (range 2-8) therapy in 58% of patients. The median IgM levels declined from 3,870 mg/dL to 1,846 mg/dL (p=0.0001) at best response. Median follow-up from DRC was 51 months (95% CI: 38-55). The median time-to-best response was 6.8 (0.5-28) months. Overall response rate (ORR) was 87% [VGPR 4%, PR 64%, MR 19%]. Four patients (9%) achieved SD and 2 patients (4%) had PD. Of the sixteen deaths (32%) noted at time of analysis, 11 were related to progressive disease. The median disease-specific survival (DSS) from DRC was not reached (NR) (95% CI: NR-NR). The median progression-free survival (PFS) and time-to-next-therapy (TTNT) were 32 months (95% CI: 15-51) and 50 months (95% CI: 35-60), respectively. In contrast, in the TN patients the median IgM levels declined from 4,130 mg/dL to 1,250 mg/dL (p=0.0001) at best response; median time to best response was 11 (0.6-47) months; median follow-up from DRC was 30 months (95% CI: 21-36). ORR was 96% [VGPR 17% (n=8), PR 70% (n=32), MR 9% (n=4)]. Of the 7 deaths (14%) at time of analysis, 4 were related to WM progression. Median DSS from DRC was NR (95% CI: NR-NR); median PFS and TTNT were 34 months (95% CI: 23-NR) and NR (95% CI: 37-NR), respectively. Among 29 genotyped patients in whom MYD88 mutation status was available, MYD88L265P was present in 25 patients (8 of 10 TN and 17 of 19 R/R patients). The response rates and the time-to-event outcomes were similar in the MYD88L265P and wild-type patients. Grade ≥3 adverse effects included neutropenia (20%), thrombocytopenia (7%) and infections (3%). Conclusions Similar to the frontline setting, DRC is an active and well-tolerated salvage regimen. In contrast to ibrutinib, DRC offers a less expensive, limited-duration treatment option, with preliminary data suggesting activity independent of patients' MYD88 mutation status. Disclosures Ailawadhi: Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy. Kumar:Glycomimetics: Consultancy; Sanofi: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Kesios: Consultancy; Array BioPharma: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy. Dispenzieri:Jannsen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; pfizer: Research Funding; Celgene: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Alnylam: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees. Ansell:BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Kapoor:Amgen: Research Funding; Celgene: Research Funding; Takeda: Research Funding.

Abstract Abstract 370 Background: Light chain (AL) amyloidosis is characterized by the deposition of amyloid derived from immunoglobulin light chains in various organs. Autologous peripheral blood stem cell transplantation (SCT) is a commonly used and effective treatment for AL. For patients (pts) undergoing this procedure, a proportion of pts receive treatment similar to induction therapy employed in pts with myeloma undergoing SCT. However, the significance of induction therapy and its impact on the overall survival (OS) in AL is unknown. We conducted this study to ascertain the role of pre-SCT therapy on the post-transplant outcomes in AL. Patients and methods: 435 pts with AL who underwent SCT at our institution between March 1996 and May 2010 form the study group. Groups were compared using Fisher's exact test or t-test, and survival was calculated using Kaplan Meier method. Survival curves were compared using log rank test. Result: The median (range) age of pts at the time of SCT was 57.4 years (26-75); 260 (60%) were males. The median (range) duration from AL diagnosis to SCT was 4 mos (1-87), and 284 (65%) pts were alive at the time of analysis. Melphalan 200/m2 (271 pts) or Mel/TBI (17 pts) was used for conditioning in 66% pts, whereas the remaining one-third had reduced doses of melphalan (100-160 mg/m2). The median OS for pts that received pre-SCT therapy (N=286) compared with those who did not (N=149) was 94.7 and 96.5 months, respectively (P=0.6) (Fig 1). Among the group of pts who underwent pre-SCT therapy and were evaluable for response, the median OS for those with a hematologic response (N=42) and no hematologic response (N=42) was 82.1 and 51 months (P=0.2), respectively (Fig 2). Conclusion: Our study demonstrates no difference in the OS of AL patients who received a pre-SCT therapy compared with those who received a SCT after their diagnosis of AL. In patients receiving pre-SCT therapy, there was a trend towards reduced OS among those with no hematologic response to pre-transplant therapy, but this difference was not significant. Disclosure: Kumar: Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Dispenzieri:Celgene: Honoraria, Research Funding; Binding Site: Honoraria.

Abstract Abstract 3554 Introduction: The role of SCT in the management of Ig light chain (AL) amyloidosis remains undefined. Patients: We report 422 patients (Table 1) who received SCT for AL amyloidosis to compare outcomes of patients treated before January 2006 with those of patients treated from January 2006 until December 1, 2009. Results: Day 100 all-cause mortality decreased over this time period from 12% to 7% (P=.09) figure 1. Survival at 2 years increased from 78% to 82%. Figure 2 The major determinants of early mortality (before day 100) were the presence of cardiac involvement with amyloid and increased levels of cardiac biomarkers, lower serum albumin, higher serum creatinine, and a higher number of organs involved. (Table 2) On multivariate survival analysis, higher levels of serum troponin T and N-terminal pro–brain natriuretic peptide were the only predictors of early mortality after SCT. Conclusion: Improved supportive care and refined patient selection has improved the safety margin for patients undergoing SCT; short-term mortality showed a more than 40% decrease after 2005. Recognition of this decrease in mortality is important for physicians caring for these patients as they weigh the pros and cons of SCT vs novel agent-based treatment in management of amyloidosis. Disclosures: Gertz: Celgene: Honoraria; Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lacy:Celgene: Research Funding. Dispenzieri:Celgene: Honoraria, Research Funding; Binding Site: Honoraria. Kumar:Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding.

Abstract Abstract 4990 Background: Although there have been improvements in 5-year overall survival (OS) rates among patients with AL amyloidosis over the past decades, OS is still poor, and death rates within the first 3–6 months after diagnosis have not changed significantly. This retrospective study was performed to identify risk factors for and causes of death during the first 90 days following diagnosis of AL amyloidosis. Method: From July 2002 to April 2009, 301 patients with a diagnosis of AL amyloidosis who were seen at Mayo Clinic within 30 days of diagnosis were identified from the dysproteinemia database. The 100 who died within 90 days were the focus of our study. The other 201 who were alive beyond 90 days were used as a comparator group. Outside physician offices were contacted to obtain further information pertaining to treatment and cause of death for our study group. Results: Of the 100 patients with early death, median age at diagnosis was 63.7 years (range: 34.7–89.4). 25 patients were diagnosed with concurrent multiple myeloma (MM) based on MM-specific end-organ damage. Overall, the number of patients with 2, 3 and 4 organs (cardiac, renal, nerve or liver) involved with amyloidosis was 37, 15 and 4, respectively. Using the cardiac biomarker staging system, 78% of 46 evaluable patients were stage III at diagnosis followed by 22% stage II and no stage I. Table 1 describes the characteristics of the studied population. Amyloid-related deaths were identified in 61 patients with the most common cause being cardiac arrest or sudden death (33%) followed by end-organ failure (24%). Treatment was started in 50% of patients; 34% received no treatment; and no treatment information was available for the remainder. OS was 54.5 days in patients who received treatment as compared to 7.5 days in those who received no treatment (p<0.0001); outcomes were similar in the group in whom no treatment information was available and those patients who were known to have received treatment. Melphalan with dexamethasone was the most common treatment (21%) and was associated with improved OS compared to other treatments including novel agents (57 vs. 26 days, p=0.003). Outcomes were no different if the patients had received novel therapies, but numbers were small. When compared to patients who lived for more than 90 days from their diagnosis, patients with early mortality had higher median intraventricular septum (IVS) (15 vs. 13 mm, p<0.0001), lower ejection fraction (EF) (50 vs. 64%, p<0.0001), and higher troponin-T (0.125 vs. 0.01 ng/ml, p<0.0001) and NT-proBNP (9020 vs. 1292 pg/ml, p<0.0001). We also found that patients who died within 90 days of their diagnosis had significantly higher plasma cell labeling index (PCLI), uric acid, beta-2 microglobulin, involved free light chain (FLC) and creatinine. Conclusion: This study highlights the characteristics of patients who died within 90 days of diagnosis of AL amyloidosis. The majority of patients died from arrhythmia and organ failure. This implies that other interventions aside from treatment of the underlying plasma cell (PC) disorder will likely be required to change the early outcomes of this disease. Disclosures: Lacy: Celgene: Research Funding. Kumar:Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Dispenzieri:Celgene: Honoraria, Research Funding; Binding Site: Honoraria.

Abstract Background Waldenstrom macroglobulinemia (WM) is an IgM-associated lymphoplasmacytic lymphoma, first described over seven decades ago. Although WM is typically a disease of the elderly, with a median age at diagnosis of ~ 67 years, approximately 10% of patients are ≤50 years (y) of age at diagnosis. Data for young patients are sparse and the few available studies demonstrate inconsistent findings, with potential overestimation of survival owing to inclusion of patients with smoldering WM. In this case-control study, we evaluate outcomes, prognostic features and impact of changing therapies in a large cohort of young symptomatic WM patients compared to matched older patients seen over the course of the past five decades. Methods The medical records of all WM patients seen consecutively at Mayo Clinic from 01/1960 to 10/2013 were reviewed. Of 1181 patients, 140 (11.8%) were ≤ 50 y of age at diagnosis. A cohort of patients 65 y or older at diagnosis, matched 1:1 by the time of diagnosis, served as the control population. The patients were divided into 3 groups based on the timing of initiation of therapy: Group 1 (1960-1977), Group 2 (1978-1995) and Group 3 (1996-2013). The baseline characteristics were compared. Initiation of frontline therapy was used for all time-to-event analysis using the Kaplan Meier method. Results Younger patients were more likely to present with adenopathy and splenomegaly, have higher IgM levels and hyperviscosity symptoms (Table 1). The median follow-up from the frontline therapy was similar (10.7 y vs. 10 y for the control population). At the time of analysis, 91% of the deaths for the younger cases were WM-related compared to 58% in the control arm (p=0.0001). Younger patients had a better OS with a median disease-specific survival (DSS) of 15.6 y (95% CI: 13-21; 10-y OS of 77%) vs. 11 y (95% CI: 7.8-12; 10-y OS of 51%) for the older patient (p=0.0003). Among the young patients, there was no difference in the median DSS across the 3 groups (p=0.42). However, the median DSS for the control group incrementally improved (p=0.02) over the 3 time periods (Table 1). In the younger patients, no improvement in DSS was noted with the use of either frontline rituximab-based therapy compared to non-rituximab based regimens [median NR (95% CI: 7.6-NR) vs. 15.8 y (95% CI: 13-22) with other regimens, p=0.30], or frontline chlorambucil-based compared to non-chlorambucil based regimens [median 16 y (95% CI: 12-22) vs 15.6 y (95% CI: 12-NR) with other regimens, p=0.73]. In the control group, however, there was significant difference in DSS among patients who received frontline rituximab-based compared to non-rituximab based regimens [median NR (95% CI: 8.3-NR) vs 9.1 y (95% CI: 5.6-12) with other regimens, p=0.04], or frontline chlorambucil-based vs non-chlorambucil based regimens [8 y (95% CI: 5-12) vs 12.3 y (95% CI: 11-NR) in other regimens; p=0.001]. Conclusion Striking differences in presentation are evident in young WM patients compared to their older counterparts. The incorporation of rituximab to the previously existing anti-WM regimens and the transition to non-chlorambucil based regimens has resulted in substantial survival gains in the older WM population over the past five decades. However, such improvement in outcome has not yet been observed in the young patients. The majority of younger patients, despite a protracted disease course, succumb to their disease. Disclosures Ansell: BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Ailawadhi:Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy. Reeder:Novartis: Research Funding; Celgene: Research Funding; BMS: Research Funding; Millennium: Research Funding. Kumar:Kesios: Consultancy; Janssen: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; AbbVie: Research Funding; BMS: Consultancy; Onyx: Consultancy, Research Funding; Glycomimetics: Consultancy; Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dispenzieri:Alnylam: Research Funding; Celgene: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; pfizer: Research Funding; Jannsen: Research Funding. Kapoor:Celgene: Research Funding; Takeda: Research Funding; Amgen: Research Funding.

Abstract Abstract 3469 Introduction: Stem cell transplantation is important in the management of multiple myeloma. In the United States, the standard of care is administration of growth factors to accelerate neutrophil recovery after stem cell transplant. The need for growth factors after transplant has not been investigated recently. Patients: We analyzed a cohort of 166 patients at our institution who underwent autologous transplant for multiple myeloma without receiving growth factors after transplant and compared them with 498 patients who received standard filgrastim beginning on posttransplant day 5. TABLE Results: A neutrophil count of 500/μL was achieved in a median of 12.5 days in patients receiving growth factor, compared with 13.5 days in those not receiving growth factor (P<.001) Fig 1. Platelet engraftment was identical (median, 14.5 days; P=.12) in both groups, despite a lower median number of CD34+ cells infused in patients who did not receive growth factors. Incidence of nonstaphylococcal bacteremia was identical in both groups. The median hospital stay was 3.5 days shorter in the group not receiving growth factor. Bacteremia impacted platelet but not neutrophil engraftment. Figure 2 Conclusion: It is feasible and reasonable to perform autologous stem cell transplant for multiple myeloma without administering growth factors. Estimated savings would be $4,600 for each transplanted patient. Growth factor administration is not required for a safe outcome and decreases the number and severity of some of the fluid-related complications after transplant such as acute respiratory distress syndrome, allergic reactions, alveolar hemorrhage, and rarely splenic rupture. Disclosures: Gertz: Celgene: Honoraria; Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lacy:Celgene: Research Funding. Dispenzieri:Celgene: Honoraria, Research Funding; Binding Site: Honoraria. Kumar:Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding.

Abstract Background Bendamustine/rituximab (BR) and dexamethasone/rituximab/cyclophosphamide (DRC) combination therapy are acceptable options for the treatment of WM, both in the frontline or salvage setting. Prospective data, however, are only available in treatment-naïve (TN) WM patients, and no direct comparison between BR and DRC has been reported. We compared outcomes of BR and DRC in relapsed/refractory (R/R) and TN WM patients seen at a single institution. Methods Records of WM patients seen consecutively at Mayo Clinic from 01/2007 to 12/2014 were reviewed. The MYD88L265P status, as assessed by AS-PCR, was recorded when available. The data obtained from symptomatic patients treated with DRC or BR were analyzed. The time-to-event analyses were performed from DRC or BR therapy using the Kaplan-Meier method. We used the Consensus criteria (6th International Workshop) for response assessment. Results Of 160 WM patients, 60 patients received BR (73% in R/R setting) and 100 patients received DRC (50% in R/R setting). In the R/R population, BR was the 2nd line (range 2-11) therapy in 47% of patients, while DRC was 2nd line (range 2-8) in 58% of patients. Rituximab monotherapy was the only prior line of therapy in 8 (20%) patients in the BR group and 20 (40%) in the DRC group (p=0.66). Baseline characteristics were similar in patients treated with BR or DRC (Table 1). Six patients received both BR and DRC during their disease course and overlapped between the 2 cohorts. Among the previous untreated patients, the median IgM levels decreased from 3,785 mg/dL to 724 mg/dL (p=0.0001) at best response with BR, while it decreased from 4,130 mg/dL to 1,250 mg/dL (p=0.001) with DRC. The median time to best response was 6.1 (1-25) months in the BR group and 11 (0.5-47) months in the DRC group (p=0.13). For patients treated with BR, the overall response rate (ORR) was 93% [VGPR 29% (n=4), PR 57% (n=8), MR 7% (n=1)]. One patient (7%) had progressive disease. For patients treated with DRC, ORR was 96% [VGPR 17% (n=8), PR 70% (n=32), MR 9% (n=4)]. One patient (4%) achieved SD. Median follow up in the BR and DRC groups were similar (30 months). The 2-year progression-free survival (PFS) was 88% and 61% in the BR and DRC groups, respectively (p=0.08). The 2-year time-to-next therapy (TTNT) was 88% and 76% in the BR and DRC groups, respectively (p=0.35). Median PFS, TTNT and disease specific survival (DSS) were not reached with either regimen. In the R/R setting, the median IgM levels decreased from 3,880 mg/dL to 659 mg/dL (p=0.0001) at best response with BR, and from 3,870 mg/dL to 1,846 mg/dL (p=0.001) with DRC. The median time to best response was similar [7 (1-39) months with BR and 7 (0.5-28) months with DRC (p=0.77)]. For patients treated with BR, ORR was 95% [CR 3% (n=1), VGPR 38% (n=14), PR 41% (n=15), MR 13% (n=5)]. Two patients (5%) had progressive disease. With DRC, the ORR was 87% [VGPR 4% (n=2), PR 64% (n=30), MR 19% (n=9)]. Four patients (9%) achieved SD and 2 patients (4%) had progressive disease. Median follow up from BR was 32 months and 51 months from DRC (p=0.24). The 2-year PFS was 66% and 53% in the BR and DRC groups, respectively (p=0.08). The 2-year TTNT was 75% and 68% in the BR and DRC groups, respectively (p=0.24). The median DSS in the BR group was 69 months (95% CI: 65-69) and NR (95% CI: NR-NR) in the DRC group (p=0.57). The proportion of patients with R/R disease was significantly higher in the BR cohort (Table 1). In a bivariate analysis of the entire cohort for PFS, incorporating the setting (TN vs. RR) and the regimen involved (BR vs. DRC), the latter emerged as a significant factor (hazard ratio 0.52, p=0.019) in favor of BR. Time-to-event outcomes and response rates were similar in the MYD88L265P and MYD88WT patients. Grade ≥ 3 adverse events were neutropenia (12%), infections (7%) and nausea/vomiting (2%) with BR, and neutropenia (20%), thrombocytopenia (7%) and infections (3%) with DRC. Conclusions Although both DRC and BR regimens show activity and comparable toxicities, BR regimen shows a trend for superior PFS in WM patients, both in the TN and R/R setting. No difference was seen in TTNT. MYD88 L265P mutation status does not appear to impact activity of BR or DRC. Randomized controlled trial(s) are needed to confirm our findings. Disclosures Ailawadhi: Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy. Ansell:BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Reeder:Millennium: Research Funding; BMS: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Dispenzieri:Jannsen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; pfizer: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Alnylam: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees. Kumar:Sanofi: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; AbbVie: Research Funding; Array BioPharma: Consultancy, Research Funding; BMS: Consultancy; Kesios: Consultancy; Glycomimetics: Consultancy; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Noxxon Pharma: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Kapoor:Celgene: Research Funding; Takeda: Research Funding; Amgen: Research Funding.