Citations

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

Abstract 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 Multiple myeloma (MM) is characterized by significant genetic diversity at subclonal levels that likely plays a defining role in the heterogeneity of tumor progression, clinical aggressiveness and drug sensitivity. Such heterogeneity is a driving factor in the evolution of MM, from founder clones through outgrowth of subclonal fractions. DNA Sequencing studies on MM samples have indeed demonstrated such heterogeneity in subclonal architecture at diagnosis based on recurrent mutations in pathologically relevant genes that may ultimately to lead to relapse. However, no study so far has reported a predictive gene expression signature that can identify, distinguish and quantify drug sensitive and drug-resistant subpopulations within a bulk population of myeloma cells. In recent years, our laboratory has successfully developed a gene expression profile (GEP)-based signature that could not only distinguish drug response of MM cell lines, but also was effective in stratifying patient outcomes when applied to GEP profiles from MM clinical trials using proteasome inhibitors (PI) as chemotherapeutic agents. Further, we noted myeloma cell lines that responded to the drug often contained residual sub-population of cells that did not respond, and likely were selectively propagated during drug treatment in vitro, and in patients. In this study, we performed targeted qRT-PCR analysis of single cells using a gene panel that included PI sensitivity genes and gene signatures that could discriminate between low and high-risk myeloma followed by intensive bioinformatics and statistical analysis for the classification and prediction of PI response in individual cells within bulk multiple myeloma tumors. Fluidigm's C1 Single-Cell Auto Prep System was used to perform automated single-cell capture, processing and cDNA synthesis on 576 pre-treatment cells from 12 cell lines representing a wide range of PI-sensitivity and 370 cells from 7 patient samples undergoing PI treatment followed by targeted gene expression profiling of single cells using automated, high-throughput on-chip qRT-PCR analysis using 96.96 Dynamic Array IFCs on the BioMark HD System. Probability of resistance for each individual cell was predicted using a pipeline that employed the machine learning methods Random Forest, Support Vector Machine (radial and sigmoidal), LASSO and kNN (k Nearest Neighbor) for making single-cell GEP data-driven predictions/ decisions. The weighted probabilities from each of the algorithms were used to quantify resistance of each individual cell and plotted using Ensemble forecasting algorithm. Using our drug response GEP signature at the single cell level, we could successfully identify distinct subpopulations of tumor cells that were predicted to be sensitive or resistant to PIs. Subsequently, we developed a R Statistical analysis package (http://cran.r-project.org), SCATTome (Single Cell Analysis of Targeted Transcriptome), that can restructure data obtained from Fluidigm qPCR analysis run, filter missing data, perform scaling of filtered data, build classification models and successfully predict drug response of individual cells and classify each cell's probability of response based on the targeted transcriptome. We will present the program output as graphical displays of single cell response probabilities. This package provides a novel classification method that has the potential to predict subclonal response to a variety of therapeutic agents. Disclosures Kumar: Skyline: Consultancy, Honoraria; BMS: Consultancy; Onyx: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Novartis: Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy, 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 3893 Background: When screening for clonal disease, the kappa (k) to lambda (l) FLC ratio (FLC-R) is employed to correct for both impaired catabolism (renal function) and non-specific production (generalized immune overstimulation). This adjustment makes it possible to identify patients with relative imbalances between k and l levels, which typically qualifies for clonal excess and has been of value in screening for and prognosticating in patients with most clonal plasma cell disorders. We previously performed a population-based study among Olmsted County residents to ascertain the prevalence of monoclonal gammopathy of undetermined significance (MGUS) and light chain MGUS. We hypothesized that by using this cohort, we could identify whether the FLC assay provides information that would be prognostic in a general population of people 50-years and older. Methods: The Olmsted MGUS prevalence cohort was comprised of 21,463 of the 28,038 enumerated individuals over the age of 50 who were living Olmsted between 1/1/95 and 11/21/2003. The final sample size of individuals for the present study was 15839 due to patient losses secondary to blinding, inadequate sample to perform the FLC assay, and known MGUS or LC-MGUS. For the multivariate analyses, another 772 were excluded due lack of coincident creatinine measurement. The FLC measurements were performed using the FLC assay (Binding Site, Birmingham, UK). The respective reference ranges for k FLC and l FLC are 0.33–1.94 mg/dL and 0.57–2.63; therefore, the reference range for the sum of k and l FLC (S FLC) is 0.90–4.57 mg/dL. Survival time was calculated from the time of sample ascertainment. Results: Forty-five percent of the cohort was male. The median age was 63 years (range 50, 109). On univariate analysis, the hazard ratio for death for those patients with the highest decile of S FLC relative to the other 90% of patients in the cohort was 4.3 (95%CI 4.01, 4.62), Figure 1. Because serum immunoglobulin FLC rise with age and with renal insufficiency, a multivariate analysis was performed to exclude the possibility that S FLC was merely a surrogate for these other parameters. Table 1 shows both univariate and multivariate risk for death. With these other variables included, the hazard ratio for death with highest S FLC decile was lower, but remained significant; hazard ratio, 2.0 (95%1.88, 2.2). Conclusions: The finding that S FLC above the normal range (i.e. highest decile) is associated with inferior overall survival among individuals above the age of 50, excluding patients with known MGUS or LC-MGUS, is important and merits further investigation. Although there is an association between S FLC, renal function, gender, and age, excess risk of death still exists after adjusting for these risk factors on multivariate analysis. The mechanism by which S FLC predicts for outcomes is uncertain, but one could postulate that conditions resulting in overactivation of the immune system contributes to excess risk of death. Whether the S FLC adds above and beyond other conventional inflammatory markers like ESR or CRP cannot be determined by the present study, but is worthy of further investigation. Disclosures: Dispenzieri: Celgene: Honoraria, Research Funding; Binding Site: Honoraria. Off Label Use: No FDA approved indication. Kumar:Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Mead:Binding Site: Employment. Bradwell:Binding Site: Equity Ownership, Patents & Royalties.

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.

Abstract Abstract 4518 Introduction: Autologous stem cell transplant (PBSCT) is an integral part of the management of Multiple Myeloma (MM). Available data suggest that the timing of PBSCT has no effect on overall outcome. Some patients currently opt to delay their transplant, especially in this era of proteosome inhibitors and iMIDs. In such patients the best time for stem cell collection is unknown. We conducted a retrospective study looking at early stem collection and storage compared to stem cell collection at the time of transplant in patients who opt to be transplanted at a later date. Method: All patients who had PBSCT performed more than one year from the time of diagnosis were reviewed. Two groups of interest were then evaluated. Early collection (ET): those who had stem cells collected within 6 months of diagnosis, and Late collection (LT): those who had stem cells collected more than 1 year from diagnosis and within 3 months of PBSCT. Results: Table 1 shows some patient characteristics. 334 patients were identified, ET (85) and LT (249). Gender distribution, Durie Salmon stage, immunoglobulin subtype and cytogenetic abnormalities were similar in both groups. The LT group was older 60 yrs compared to ET 56.6 yrs, P=0.02. More patients in the ET (77%) group were mobilized with cyclophosphamide compared to LT (51%) p<0.0001. Stem cell yield was similar in both groups 9.26 × 10(6) CD34/kg in ET and 8.19 × 10(6) in LT, P=0.16. Median number of collections was 3 in both. More patients in the LT (67%) received Melphalan 200 mg/m2 conditioning compared to ET (59%) p=0.03. Neutrophil engraftment occurred at day + 11 ET and +12 (LT) p<0.0001. ET patients achieved platelet engraftment on day + 13 compared to + 15 (LT) p=0.002. Complete response rates were similar 30% (ET) and 34% (LT). Duration of response after PBSCT was not different 12.6 months (ET) and 11.6 months (LT). Median overall survival from diagnosis was 70.5 months (ET) and 74.5 months (LT) p=0.5. Similarly there was no difference in overall survival post PBSCT 33.5 month (ET) and 32.2 months (LT). Conclusion: Stem cell collection and storage early in the disease course of multiple myeloma results in early engraftment compared to stem cell collection at the time of transplant in patients who opt for a delayed transplant. More studies looking at cost analysis will however be need to determine the cost effectiveness of early versus late stem cell collection. Disclosures: 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. Gertz:Celgene: Honoraria; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees.