Hayman, Suzanne R.

Background: Autologous stem cell transplantation is an effective treatment modality for patients with multiple myeloma. While most of the patients relapse after ASCT with a median time to progression of 2 years, there is a significant heterogeneity in the duration of response. It has been hypothesized that the effect of high dose alkylator therapy used for conditioning may have a dual effect on the myeloma cells as well as marrow microenvironment. It is also known that hematopoiesis, especially thrombopoiesis, depends to some extent on signals form the marrow microenvironment. We examined if there was any relationship between delayed platelet engraftment and outcome after ASCT. Methods: We examined the outcomes in a group of patients undergoing ASCT for myeloma at our institution to compare the response duration to platelet engraftment kinetics. We studied 687 patients undergoing ASCT with melphalan conditioning followed by peripheral blood stem cell transplant. Results: Among the 687 patients undergoing ASCT, 200 pts (29%) achieved a platelet count of 50,000 by day 21 (early group) and the rest achieved this level after 21 days or never engrafted (late group). The median time to progression (TTP) among the late group was 24.8 months (95% CI; 19.6, 30 months) vs. 16.8 months (95% CI; 15.1, 18.6 months) for the late group (p < 0.001) (Figure). Patients in the late engraftment group were more likely to achieve a complete response compared to the early group; 39% vs. 30%, p = 0.02. In a multivariate analysis examining factors predicting for longer time to progression after ASCT, delayed platelet engraftment was independent of transplant within 12 months of diagnosis, CR with ASCT, absence of cytogenetic abnormalities, B2M < 3.5 mg/L and a plasma cell labeling index < 1% at the time of ASCT (Table). Conclusions: In this study, we have demonstrated for the first time a relationship between delayed platelet engraftment after ASCT and the duration of response following ASCT. This intriguing finding raises several hypotheses. It is possible that the delayed platelet engraftment is a marker of marrow microenvironment dysfunction secondary to high dose therapy, given the role of marrow microenvironment on thrombopoiesis. It is possible that this is a surrogate marker for the biological effectiveness of the melphalan dose, which can affect the other cells in the marrow microenvironment as well. It is likely a reflection of the marrow microenvironment dependence on the myeloma cells for its survival. These findings should be confirmed in other larger patient groups. Predictors of progression Variable Hazard Ratio P Platelet Engraftment > 21 days 0.80 (0.60, 0.96) 0.02 Late transplant (>12 months from diagnosis) 1.6 (1.3, 2.0) <0.01 Plasma cell labeling index > 1% 1.9 (1.5, 2.4) <0.01 Complete response 0.41 (0.33, 0.51) <0.01 Abnormal Cytogenetics 1.8 (1.4, 2.3) <0.01 B2M > 3.5 1.2 (0.96, 1.5) 0.12 Figure Figure

Abstract Background: Pomalidomide is an immunomodulatory agent (IMiD®) that has been approved for treatment of relapsed and refractory multiple myeloma (MM). Combinations of IMiDs and proteasome inhibitors offer the potential for deeper and more durable responses due to enhanced efficacy. Preliminary results of a phase 1 study of twice weekly bortezomib with pomalidomide have been reported with promising results (Richardson, ASH 2012). This phase I/II trial was designed to evaluate the maximum tolerated doses (MTD) as well as safety and efficacy of the combination of pomalidomide, once weekly bortezomib and dexamethasone (PVD) in patients with relapsed, lenalidomide refractory, MM. Patients and methods: We included patients with relapsed MM who had 1-4 prior lines of therapy and were resistant or refractory to lenalidomide. In the phase I portion of the trial, dose level 1 consisted of pomalidomide 4 mg days 1-21 PO, bortezomib 1.0mg/m2 days 1,8,15, and 22 IV or SQ and dexamethasone 40 mg days 1,8,15, and 22 PO, given every 28 days. Bortezomib was increased to 1.3mg/m2 for dose level 2 and and was adopted for the phase 2 portion. The primary aim of the phase I cohort was to determine the MTD of the combination, and for the phase II cohort was to evaluate the confirmed response rate (PR, VGPR, or CR) in relapsed refractory MM. Response was assessed by the IMWG criteria and toxicity was graded using the CTCAE v4.0. Results: 50 patients were accrued between March 2012 and July 2014 (dose level (DL)1: 3, DL 2: 6, Phase II: 41). We describe results in 47 patients treated at MTD and phase II. Median age was 66, 51% were female and median time from diagnosis to study was 46 months (15-142). Twenty five percent had mSMART defined high-risk status. Median number of prior regimens was 3. All patients had prior lenalidomide, 68% had stem cell transplant, 17% received thalidomide, 56% had alkylators and 57% had bortezomib. With median follow up of 9 months, 72% remain progression free, 96% are alive and 66% remain on treatment. The most common AEs at least possibly attributable to the combination were anemia, fatigue, leukopenia and thrombocytopenia; however, the majority of these were grade 1-2. Grade ≥3 AEs (regardless of attribution) that occurred in at least 3 patients included neutropenia (29), leukopenia (15), lung infection (6), lymphopenia (8) dyspnea (3) and syncope (3). DVT/PE occurred in one patient. Among the 42 patients who were evaluable, confirmed responses (PR, VGPR, or CR) were seen in 34 (81%) including sCR (3), CR (5), VGPR (8), PR (18). Confirmed responses were seen in 9 of 11( 82%) high risk patients. Median progression free survival was 17.7 months (95%CI: 9.5-NA). Conclusions: PVD is a highly effective combination in patients refractory to lenalidomide with confirmed responses in over 80%. Weekly administration of bortezomib enhanced the tolerability and convenience of this regimen. Toxicities are manageable, mostly consisting of mild cytopenias with no significant neuropathy or DVT. PVD is a highly attractive option in patients with relapsed and refractory MM. Disclosures Lacy: Celgene: Research Funding. Lust:Senesco: PI Other. Fonseca:Medtronic, Otsuka, Celgene, Genzyme, BMS, Lilly, Onyx, Binding Site, Millennium, AMGEN: Consultancy, patent for the prognostication of MM based on genetic categorization of the disease. He also has sponsored research from Cylene and Onyx Other, Research Funding. Stewart:Celgene: Consultancy; Novartis: Consultancy; Array BioPharma: Consultancy; BMS: Consultancy; Millenium: Research Funding. Reeder:Millennium, Celgene, Novartis: Research Funding. Mikhael:Onyx: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Novartis: Research Funding.

Abstract Background: Previous studies have demonstrated inferior overall survival (OS) among patients with AL amyloidosis who have bone marrow plasmacytosis (BMPC) >10%. It is well recognized that AL patients who achieve the deepest hematologic responses have superior organ response and OS rate. Methods: We designed a study to determine if BMPC% affects CR rate post ASCT and whether pre-transplant induction therapy improves response rate and OS among patients with a higher baseline BMPC burden. Results: Among 415 AL patients who underwent ASCT at Mayo Clinic, Rochester within 12 months of diagnosis, 116 (28%) had BMPC>10% at diagnosis. The median age was 57.2 years. The median follow up for surviving patients was 67.3 months. There was no statistically significant difference in age, gender, time from diagnosis to transplant, or use of attenuated conditioning regimen between groups with high (>10%) and low (≤ 10%) bone marrow involvement. The high BMPC group tended to receive more induction chemotherapy before ASCT, and presented with greater value of albumin, beta-2 microglobulin and difference in serum free light chain (dFLC). A higher CR rate was observed in low BMPC group (44.6% versus 26.7%, p=0.0013). In patients with high BMPC, a higher CR rate (33.9% versus 17.7%, p<0.05) was seen in those who received pre-ASCT induction therapy compared with no induction therapy. Among 3 groups of patients who had: no pre-ASCT therapy; steroid only as induction; and induction chemotherapy, the 5-year OS rates were 50.5%, 40% & 67.5%, respectively, p<0.03. Conclusions: Lower bone marrow burden at diagnosis yielded a deeper response following ASCT. Compared to no therapy, patients who were treated with steroid only pre-ASCT had an inferior OS, but other induction regimens appeared to improve survival. These data would support the concept that using induction therapy prior to ASCT conditioning among patients with higher tumor burden may be of value. Figure 1. In BMPC > 10% at diagnosis, OS comparison between induction therapies pre-ASCT Figure 1. In BMPC > 10% at diagnosis, OS comparison between induction therapies pre-ASCT Figure 2. Figure 2. Figure 3. Figure 3. Disclosures Kumar: Celgene: Research Funding; Celgene, Millenium, Sanofi, Skyline, BMS, Onyx, Noxxon,: Other: Consultant, no compensation,; Sanofi: Research Funding; AbbVie: Research Funding; Millenium/Takeda: Research Funding; Onyx: Research Funding; Skyline, Noxxon: Honoraria; Janssen: Research Funding. Gertz:Celgene: Honoraria; millenium: Consultancy, Honoraria; Onyx: Honoraria; Novartis: Honoraria; Smith Kline: Honoraria.

Abstract Background: Patients with light chain amyloidosis (AL) often have delayed diagnosis and present with significant symptomatology; this may result in decreased quality of life (QOL). With improving treatment options providing longer survival, it is increasingly important to assess QOL. However there is paucity of data in the literature addressing QOL in AL patients. We prospectively employ a "Hematology Patient Reported Symptom Screen" (HPRSS) which consists of three questions about fatigue, pain and overall QOL. The aim of this study is to understand if HPRSS parameters predict various clinical outcomes. Methods: Eligibility for this retrospective study was as follows: 1) New diagnosis of AL between 2009-2014; 2) baseline HPRSS documented in the medical record; and 3) at least a year of follow-up, which included either death within or follow-up through 12 months after diagnosis. The HPRSS questions were rated on a 1-10 scale, with 10 being the worst for fatigue and pain, and 10 being the best for overall QOL. Scores were abstracted from visits at time of diagnosis, and at 12 months +/- 1 month post-diagnosis. We considered a 2-point difference in serial scores a "change" over time. Results: For the 302 patients in this study, the baseline median scores [interquartile range] for fatigue, pain, and QOL were 6 [3,7], 2 [0,5] and 5 [3,8], respectively. Median overall survival (OS) was 39.1 months, with 102 deaths in the first year. There were significant differences in baseline HPRSS between those who lived longer than one year and the early death patients in the domains of fatigue (5 [IQR 3, 7] vs. 7 [IQR 5, 8], p<0.0001) and QOL (6 [IQR 4, 8] vs. 5 [IQR 3, 7], p=0.006), but not in pain (2 [IQR 0, 5] vs. 2 [IQR 0, 5]). There were significant baseline differences in the early death group for alkaline phosphatase, bilirubin, creatinine, and Mayo stage. Patients who received ASCT had the best baseline fatigue 4 [2.5,6] and QOL 7 [5,8] scores and were significantly different from those who did not receive ASCT [fatigue p<0.0001) and QOL (p<0.0001)] On univariate analysis fatigue and QOL were prognostic for OS. On multivariate analysis Mayo 2012 staging, autologous stem cell transplant and baseline fatigue remained independently prognostic. When analyses were restricted to the 125 patients with HPRSS measurements at 12 months, we found that over time QOL scores improved significantly 6 [IQR 3.5, 8] to 7 [IQR 5, 8] (two sided Wilcoxon signed rank p=0.01), but fatigue (5 [IQR 2, 5] to 4.5 [IQR 3, 6]) and pain scores (2 [IQR 0 ,4] to 1.5 [IQR 0, 4]) did not. Patients with worse baseline parameters tended to have improvement in QOL by 12 months while those with the best baseline parameters tended to decline in QOL although not statistically significant. When we included the 102 patients who died within 12 months to the comparison, the early death patients had the worst baseline parameters and there were significant differences across all 4 groups for most characteristics (Table 1). There was no association between achieving hematologic or organ response with change in QOL. Conclusion: Asking patients with AL to rate their fatigue and QOL using a 10-point scale has predictive value. Patient reported fatigue at diagnosis is an independent prognostic factor for survival. Survival at one year was associated with significant improvement in QOL. Table 1. Baseline parameters between patients with early death and/or survive 12 months. Grouped by Patient Reported QOL at 12 months Relative to Baseline Dead by 12 months, n=102 Improved, n=44 Stable, n=55 Worsened, n=26 pa HPRSS scores [IQR] Baseline QOL Baseline fatigue Baseline pain 12 month QOL 12 month fatigue 12 month pain 5 [3,7] 7 [5,8] 2 [0,5] NA NA NA 4 [3-5] b,c,d6 [4-8] b,c2 [0-4] 7 [6-9] b,d4 [1.25-6] 1 [0-3] 7 [4-8] 4 [2-7] 2 [1-5] 7 [4-8] 5 [3-6] 2 [0-4] 8 [7-10] 2.5 [0-5.25] 2 [0-6.25] 5 [3-7] 5 [3-6] 2.5 [1-4] <0.0001 <0.0001 NS NS 0.001 NS dFLC, mg/dL 48 (2.89-726) 30 (1.1-494) 19 (36-455) 22 (0.2-2097) 0.008 Troponin, ng/mL 0.065 (<0.01-0.84) 0.02 (<0.01-1.6) 0.01 (<0.01-0.19) 0.01 (<0.01-0.14) <0.0001 NT-proBNP pg/mL 5222 (159-70,000) 1766 (26-16868) 1381 (24-19180) 496 (56-2973) <0.0001 Received Transplant (%) 4 (4) 13 (33) 36 (50) 13 (50) 0.0002 a Significant by Wilcoxon across all 4 categories; b Significant difference between Improved and Worsened; c Significant difference between Improved and Stable; d Significant difference between Worsened and Stable Disclosures Kumar: Millenium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Abbvie: Research Funding; Janssen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Research Funding; Onyx: Consultancy, Research Funding. Thompson:Kite Pharma: Research Funding.

Abstract Background: Both MM specific and patient specific parameters place patients at risk for death. Patient frailty has been delineated primarily by age and ECOG performance score (PS) and secondarily with creatinine, eGFR, and the International Staging System (ISS), which reflect both renal function and disease burden. In an attempt to improve upon these commonly used measures, a frailty score for elderly patients that combines functional status [Activity of Daily Living (ADL) and Instrumental Activity of Daily living scores], comorbidities [Charlson comorbidity index (CCI)] and age has been developed by the IMWG. Incorporation of these tools into a busy clinical practice is challenging due to time constraints. Therefore, the identification of frail patients with an easily applicable, rapid and objective tool remains a challenge and an unmet need. A reliable, non-invasively assessable, biochemical marker of frailty would be an ideal tool to identify patients at higher risk of death. It was our goal to determine the role of NT-proBNP, a well-established cardiovascular risk biomarker, as a marker of frailty in patients with MM and in predicting overall survival (OS). Methods: Patients were elegible for this retrospective study if they were seen at the Mayo Clinic, Rochester, MN within 30 days of their myeloma diagnosis during the interval between 1/1/2007 and 12/31/2011. As part of the Mayo Clinic registration, all patients complete forms containing their past medical history, symptoms, and ADLs. Data from that first visit was abstracted and used to calculate a CCI. We excluded all patients with a concomitant diagnosis of light-chain AL amyloidosis. NT-proBNP concentration was measured in frozen sera collected within 30 days of diagnosis. NT-proBNP assay was run on the E170 Modular analyzer (Roche Diagnostics, Penzberg, Germany). We evaluated the prognostic role of NT-proBNP and these indices on OS using the Kaplan-Meier method. Results: Among the 351 consecutive patients satisfying entry criteria, median age was 65 years (range 22-95), 33% were ≥70 years, and 56% were male. Twenty-eight percent were ISS stage III, 13% had a creatinine ≥2 mg/dL, 19% had PS ≥2, and 11% had ADL score ≥2, and 30% CCI ≥2. The median value of NT-proBNP was 109 ng/L (interquartile range: 30-375 ng/L). NT-proBNP concentrations differed in the three ISS stages (median: 122 ng/L stage I, 190 ng/L stage II and 1822 ng/L stage III, P<0.0001). Median OS was 5.6 years. The best cutoff of NT-proBNP predicting OS at one year was 301 ng/L (sensitivity: 57.88%, specificity: 74.29%; AUC=0.668) and distinguished two groups with different OS (median not reached vs. 35 months, P<0.0001). Variables predictive for OS are shown in the Table and included PS, age, CCI, ISS, NT-proBNP. On multivariate analysis, ISS and NT-proBNP were independent of each other as long as age, PS and/or CCI were excluded from the model. NT-proBNP withstood these clinical variables better than did ISS (data not shown). We built two different models (table). In model 1, NT-proBNP >301 ng/L was an independent predictor of survival while age ≥70 and PS ≥2 and CCI were not significant. However, if we considered ISS stage instead of NT-proBNP in the same model, ISS stage was not significant. Conclusions: In this unselected cohort of patients with newly diagnosed multiple myeloma, NT-proBNP was a useful predictor of survival independent of age and PS. The threshold of 301 ng/L is remarkably similar to the well-established cutoff for heart failure of 300 ng/L. NT-proBNP outperformed the CCI and the ISS as risk factors. NT-proBNP is a widely available biomarker that could be added to the panel of laboratory tests of newly diagnosed MM patients and serve as a simple means of determining patient frailty in a busy clinical practice. Table. Results of univariate and multivariate analysis of various prognostic factors (NS, not significant; NI, not included). Univariate Multivariate Multivariate RR (95% CI) P Model 1 P Model 2 P PS ≥2 3.4 (2.4-4.8) <0.0001 2.5 (1.7-3.6) <0.0001 2.8 (1.9-4.0) <0.0001 Age ≥70 2.7 (1.9-3.6) <0.0001 2.1 (1.5-2.9) <0.0001 1.9 (1.3-2.7) 0.0003 CCI >=2 1.9 (1.4-2.6) <0.0001 NS NS 1.5 (1.0-2.0) 0.03 ISS stage 1.1 (1.1-1.8) 0.0004 NI NI NS NS NT-proBNP >301 ng/L 2.3 (1.7-3.2) <0.0001 1.6 (1.1-2.2) 0.007 NI NI Disclosures Merlini: Janssen-Cilag: Honoraria; Prothena: Honoraria; Millennium-Takeda: Honoraria; Pfizer: Honoraria. Kumar:Janssen: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Millenium/Takeda: Research Funding; AbbVie: Research Funding; Onyx: Research Funding; Celgene, Millenium, Sanofi, Skyline, BMS, Onyx, Noxxon,: Other: Consultant, no compensation,; Skyline, Noxxon: Honoraria.

Abstract Abstract 201 Background: Pomalidomide at doses of 2 or 4 mg/d has demonstrated excellent activity in patients with relapsed multiple myeloma (MM). Between November 2007 and March 2012, we opened 6 sequential phase 2 trials and treated 345 patients with relapsed MM with pomalidomide at differing doses with weekly dexamethasone (Pom/dex). Results of 164 of these patients have been previously published. Here we describe long term follow up of these patients as well as results of an additional 181 patients with relapsed MM treated with the Pom/dex regimen. Methods: The six cohorts consisted of: Cohort 1 (N=60): relapsed MM with 1–3 prior regimens, 2 mg dose; Cohort 2 (N=34): lenalidomide (LEN) refractory, 2 mg dose; Cohort 3 (N=35): BZ)/LEN refractory, 2 mg dose; Cohort 4 (N=35): BZ/LEN refractory, 4 mg dose; Cohort 5 (N=60) LEN refractory, 1–3 prior regimens, 4 mg dose; and Cohort 6 (N=120) LEN refractory, 4 mg dose. Pomalidomide was given orally 2 mg daily or 4mg daily on days 1–28(cohorts 1–5) or 1–21 (cohort 6) of a 28-day cycle with oral dexamethasone given 40 mg daily on days 1, 8, 15 and 22. Response was assessed by the International Myeloma Working Group Uniform Response criteria. All patients received aspirin 325 mg daily for deep venous thrombosis (VTE) prophylaxis or full dose anticoagulation. Results: A total of 345 patients were enrolled across all 6 cohorts. One patient was ineligible and excluded from analysis. The median age was 64 years (32–88). The median time since diagnosis was 53 months. The median number of prior therapies was 3 (1–14). 147 (44%) had high-risk molecular markers by mSMART criteria. Prior therapies consisted of thalidomide 52%, lenalidomide 87%, bortezomib 75%, autologous stem cell transplant 70% and allogeneic transplant 3%. The median follow-up is 10.4 months (5.4–34 months). Sixty-seven percent are alive and 32% remain progression free. 46 patients are continuing to receive treatment. The most common toxicities (grade 3 or higher) were neutropenia (31%), anemia (16%), thrombocytopenia (12%), pneumonia (8%) and fatigue (8%). VTE was seen in 10 patients (3%). Outcomes are shown in Table 1. Across all 6 cohorts confirmed responses of partial response (PR) or better were seen in 34%. The response rate in all patients with mSMART high risk status was 30.6%. Responses and duration of response (DOR) in those with high risk molecular markers include: 17p– 19 of 56 (34%) DOR 8.2 months; t(4;14) 6 of 24 (25%) and DOR 4.8 months; t(14;16) 7 of 11(64%) and DOR 9.5 months; deletion 13 by cytogenetics 13 of 37 (35%) with DOR 8.2 months. In a multivariate analysis, only LDH > ULN, number of prior regimens, and prior BZ therapy were predictive of a shorter TTP and factors associated with a poor OS following initiation of pomalidomide therapy included B2M > 5.5, LDH > ULN,number of prior regimens, and prior BZ therapy. Conclusions: Pom/dex is active and well tolerated even in heavily pretreated patients and those with high risk molecular markers. Remissions are durable. Response rates and toxicity are similar between the 2 mg and 4 mg doses. Disclosures: Lacy: Celgene: Research Funding. Stewart:Celgene: Consultancy, Honoraria. Reeder:Celgene: Mayo Clinic receives funding from Celgene to support clinical trials Other, Research Funding.

Abstract Abstract 600 Background: Both MM and AL are plasma cell neoplasms. The underlying clone in both diseases appears to be different not only in terms of “tumor burden” but also in terms of their underlying biology. The overall “fitness” of patients with these two diseases is also different, with AL patients having more major organ dysfunction. Therapy for both diseases is directed at killing the underlying clone. ASCT is one method of reducing the clone size and thereby improving overall survival. Post-ASCT outcomes between the two diseases have never been formally compared. Methods: We compiled all patients with a diagnosis of AL or MM who received ASCT at the Mayo Clinic Rochester between June 1996 and January 2011 to compare outcomes. Patients were retrieved from two prospectively maintained clinical transplant data bases (M.A.G.). Differences between groups were compared using Fisher's exact and Wilcoxon tests. Survival was calculated using the method of Kaplan-Meier, and differences between survival outcomes were calculated by log rank. Cox regression modeling was done to determine how non-disease specific variables—i.e. age, time period of ASCT, number of prior regimens, time to ASCT from diagnosis and acquisition of complete response (CR)—affected outcomes. All statistical analyses were performed using JMP (SAS, NC) software. This study was approved by the Mayo IRB. Results: The data set was comprised of 454 patients with AL and 1116 patients with MM. There were significant differences between the two respective groups of patients in terms of number of prior regimens (0 vs 1, p<0.0001), time to ASCT (3.95 months vs 7.20 months, p<0.0001), intensity of conditioning regimen (non-attenuated in 69.4% vs 89.1%, p<0.0001), serum creatinine (1.1mg/dl vs 1mg/dl p<0.0001), creatinine clearance (72.5 ml/minute vs 80 ml/minute p<0.0001), albumin (2.61g/dl vs 3.50g/dl, p<0.0001) CRP (0.40mg/dl vs 0.63mg/dl p<0.0001), LDH (196 U/l vs 182U/l, p<0.0001), and bone marrow plasmacytosis at transplant (6% vs 9%, p<0.0001). Hematologic response rates were also significantly different between the groups, with higher overall hematologic response in the MM group (90.9% vs 79.5%, p<0.0001) and higher complete response (CR) rates (40.1% vs 29.4%, p<0.0001) in the AL group. With a median follow-up of surviving patients of 68 months, the respective median overall survival (OS) for the AL and MM patients was 113 and 59.5 months, p<0.0001. Notably, the 5-year OS of AL and MM patients achieving CR were 91.4% and 57.7%, respectively, p<0.0001. If only those patients who were transplanted within 1 year of their diagnosis are included in the analysis, the respective 5-year OS of AL and MM patients achieving CR were 90.4% and 61.3%, p<0.0001 (Figure 1). To correct for imbalances in non-disease specific parameters, 3 multivariate analyses were performed using: 1) all patients; 2) only those achieving CR; and 3) only those who achieved a CR and were transplanted within 12 months of their diagnosis (Table 1). Among those patients achieving CR, MM patients had nearly a 4-fold risk of death as compared to patients with AL. Conclusion: Although ASCT is not available to all patients with either AL or MM, there is a significant difference in outcomes based on the diagnosis. Patients with AL who undergo ASCT enjoy a superior survival as compared MM patients undergoing the same procedure. This difference is most notable among those patients who achieve CR suggesting very different plasma cell biology between the two diseases. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 599 Purpose: This study was undertaken to develop selection guidelines for transplant centers to determine eligibility for stem cell transplantation in patients with light chain amyloidosis. Patients and Methods: Patients with biopsy-confirmed immunoglobulin light chain amyloidosis who underwent stem cell transplantation between March 8, 1996, and December 31, 2011, were reviewed in 2 cohorts: those who underwent transplantation between March 8, 1996, and June 30, 2009, and those who underwent transplantation between July 1, 2009, and December 31, 2011 (table 1). A second comparison was undertaken among patients who died before posttransplant day 100 to determine features predictive of early death (table 2). Results: A total of 499 patients were identified, 410 in the earlier group and 89 in the later group. After July 1, 2009, significantly fewer transplant recipients had Mayo stage III cardiac involvement. Mortality before posttransplant day 100 was 10.5% (43/410) in the earlier group and 1.1% (1/89) in the later group. In the earlier group, one-quarter of transplant recipients with N-terminal pro-brain natriuretic peptide (NT-proBNP) levels higher than 5,000 pg/mL died by 10.3 months (fig 1, left). When the serum troponin T level was > 0.06 ng/mL, 25% died at 3.7 months (fig 2, right). Conclusion: The Mayo staging system is highly predictive for overall survival but not useful for selecting transplant recipients. Patients with serum troponin T levels higher than 0.06 ng/mL or NT-proBNP levels >5,000 pg/mL (not on dialysis) should not be considered acceptable candidates for stem cell transplantation because of unacceptable early mortality. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 3972 Background: The treatment paradigm for myeloma has undergone a dramatic shift in the past decade with the introduction of the novel agents and their application at every stage of the treatment. We and others had previously shown that survival of patients with myeloma had improved in the earlier half of the last decade and attributed this to a combination of novel therapies as well as increased use of stem cell transplant. It is not clear if this momentum in improving survival has been maintained. We examined the survival trends of patients with newly diagnosed myeloma seen within the past decade to examine this question. Patients and Methods: We studied 1056 patients with newly diagnosed myeloma, who were seen at Mayo Clinic between January 1, 2001 and December 31, 2010; who were seen within 30 days of their diagnosis. For examination of the time trends, we grouped the time interval into two five year periods, 2001–2005 and 2006–2010. Survival was estimated using Kaplan Meier method and survival curves were compared by log rank test. Impact of various prognostic factors was evaluated using Cox proportional hazards test. Results: The median age at diagnosis was 65 (range; 22–92), and 59% were male. The median estimated follow up for the entire cohort was 4.6 years (95% CI; 4.4, 4.9) and 57% of the patients were alive at last follow up. The median overall survival (OS) for the entire cohort was 5.4 years (95% CI; 5, 6.3). The overall survival for patients in the 2001–2005 group was 4.6 years compared with not reached for the 2006–2010 cohort (P< 0.001). The five-year estimated OS was 48% for the earlier group compared with 66% for the latter group. The estimated 1-year survival was 90% for the recent cohort compared with 83% for the earlier cohort, suggesting improvements in the early mortality. Interestingly, the improvement was predominantly seen in the older age group (>65 years; 49%). The 5-year survival of the older patients improved significantly from 31% (2001–2005) to 56% (2006–2010) (P<0.001). In contrast, among younger patients (≤65 years of age), the 5-year survival improved only marginally from 63% (2001–2005) to 73% (2006–2010) (P=NS). One or more novel agents (Lenalidomide, thalidomide or bortezomib) were used as part of initial therapy in 631 (62% of 1021 in whom treatment data was available). The OS among of this group was 7.3 years (95% CI; 5.9, NR) compared with 3.8 years (95% CI; 3.1, 4.6). In a multivariate model that included both use of novel agent and the year group, only the novel agent use was associated with improved survival suggesting that the improvement in the survival is related to the increased use of novel agents in the initial therapy. No significant differences were observed between the groups in terms of conventional prognostic factors. Conclusions: The current results confirm continued improvement in the overall survival of patients, even within the last 10 year period, and highlight the impact of initial therapy with novel agents. Most importantly, we demonstrate that the improved survival has primarily benefited older patients. Our study highlights that urgent need for additional new agents to provide further survival improvement for younger patients, and in order achieve a cure for this disease. Disclosures: Kumar: Merck: Consultancy, Honoraria; Celgene: Research Funding; Millennium: Research Funding; Novartis: Research Funding; Cephalon: Research Funding; Genzyme: Research Funding. Dispenzieri:Celgene: Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Janssen Research & Development: Research Funding. Gertz:Binding Site: Honoraria.

Abstract Abstract 1795 Background: Waldenstrom's macroglobulinemia (WM) is an indolent B-cell lymphoma characterized by a heterogeneous population of lymphocytes, plasmacytoid lymphocytes and plasma cells with variable CD20 expression. Rituximab (R) achieves an overall response rate (ORR) of 25–50% in relapsed/refractory WM and is associated with IgM flares, manifested by a rapid rise in IgM, potentially leading to complications of hyperviscosity. Ofatumumab (OFA) is a fully human monoclonal antibody that targets an epitope encompassing both the large and small extracellular loops of CD20 and effectively induces complement-dependent cytotoxicity of B-lymphoma cells. OFA is approved for the treatment of fludarabine- and alemtuzumab-refractory chronic lymphocytic leukemia (CLL) and has demonstrated clinical activity in non-Hodgkin's lymphoma. Given the efficacy of OFA in CLL, with its decreased CD20 antigen density, similar to WM where CD20 is down-regulated with differentiation of cells into plasma cells, a Phase II, open-label, single-arm trial of OFA in patients (pts) with WM was initiated to examine the safety and efficacy of OFA in this population. We report data from a planned interim analysis, which was performed to examine IgM flare, toxicity and response data. Methods: Pts (age ≥18 years) with WM requiring therapy by 2nd International Workshop on WM criteria were eligible. Pts received OFA 300 mg week 1 and 1000 mg weeks 2–4. Premedication included acetaminophen and antihistamine (all infusions) and glucocorticoid (infusions 1 and 2). Pts who experienced grade 3–4 infusion-related adverse events (AEs) during weeks 1 and 2 also received glucocorticoid during weeks 3 and 4. The primary endpoint was ORR assessed by 3rd International Workshop on WM criteria, and toxicity was assessed according to NCI-CTCAE, v3.0. Results: Fifteen pts were enrolled between March 2009 and January 2010. Median age was 59 years (range 43–85), and 9 pts were male. Pts had a median IgM level of 3.70 g/dL (range 1.21–6.62) and median hemoglobin (hgb) of 9.8 g/dL (range 5.3–11.7). Three pts were previously untreated; 12 pts had received a median of 3 therapies (range 2–5), including 11 pts who had received R, and 7 pts who had received a purine analog. Fourteen pts completed all 4 infusions of OFA. One pt withdrew from study after infusion 3 due to a drug-related serious AE (SAE). One pt had cryoglobulinemia, which interfered with IgM assessment. Of the 14 pts with evaluable IgM levels, 3 achieved partial response (PR), and 3 achieved minor response (ORR=43%) 8 weeks to 5 months after start of OFA therapy. One of 3 previously untreated pts and 5 of 12 relapsed pts responded. Four of 11 pts who had received prior R and 2 of 4 R-naïve pts responded. Five of 9 pts with IgM <4 g/dL and 1 of 5 pts with IgM >4 g/dL responded. Four pts with a median hgb of 8.0 g/dL (range 5.3–9.2) experienced ≥2.8 g/dL increase in hgb, including 3 pts who had >5 g/dL increase; median time to reach hgb ≥11.0 was 4 weeks. Infusion-related events occurred with dose 1 (300 mg) in 12 pts and with dose 2 (1000 mg) in 7 pts; all infusion events were grade 1–2 except 2 grade 3 events (rash, serum sickness). Nine pts developed 11 infections: 7 URI, 2 UTI, 1 sinusitis, 1 oral candidiasis (all grade 2). One pt developed grade 3 febrile neutropenia. Two pts developed SAEs possibly related to OFA. One pt developed grade 3 Coombs-negative hemolytic anemia after infusion 3 resulting in study withdrawal, and 1 pt with a baseline IgM level of 6.62 g/dL developed grade 3 renal insufficiency due to a rapid rise in IgM and cast nephropathy 6 weeks after starting OFA. One additional pt, with a baseline IgM level of 4.69 g/dL, developed a rapid rise in IgM and hyperviscosity symptoms. Both pts with a rapid rise in IgM underwent plasmapheresis with resolution of symptoms. No other OFA-related hematologic toxicity was observed. Conclusions: OFA has an acceptable toxicity profile, although a rapid rise in IgM requiring plasmapheresis was observed in 2 pts with high baseline IgM levels. OFA shows clinical activity in pts with WM, including those who relapse after R therapy, with rapid improvement in hgb and slower reduction of IgM levels. Based on the acceptable safety profile in this study and the dose of OFA approved for refractory CLL, the study was amended to increase the OFA dose to 2000 mg and allow a 2nd cycle of therapy for pts who do not attain PR after cycle 1. Accrual to the amended study is ongoing. Disclosures: Furman: GlaxoSmithKline: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Cephalon, Inc.: Speakers Bureau; Celegene: Consultancy; Calistoga: Consultancy. Off Label Use: Ofatumumab is an investigational anti-CD20 monoclonal antibody, currently under development for the treatment of B-cell malignancies (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Waldenstroms macroglobulinemia and follicular lymphoma) as well as autoimmune diseases (rheumatoid arthritis and multiple sclerosis). Switzky:GlaxoSmithKline: Employment, Research Funding; Genmab: Employment, Research Funding. Leonard:GlaxoSmithKline: Consultancy. Liao:GSK: Employment. Shah:GlaxoSmithKline: Employment; Genmab: Research Funding. Brownell-Buttich:GlaxoSmithKline: Employment. Lisby:Genmab A/S: Employment. Lin:GlaxoSmithKline: Consultancy, Employment.