Citations

Abstract Abstract 3557 Introduction: Autologous stem cell transplantation for patients with amyloidosis results in high reported hematologic and organ response rates compared with conventional chemotherapy. Patients: Four-hundred and thirty-four patients have undergone transplantation between March 8, 1996, and April 13, 2010 Table 1. Clinical parameters seen in patients with amyloid are given in Table 2. The overall day-100 mortality seen in this group of patients is 44 of 434 patients (10%). Results: The most important determinant of outcome is stage defined by BNP and troponin levels. Figure 1 demonstrates the survival for patients for all 3 cardiac stages. Troponin <.035; NT-proBNP <332. Stage 1 both low, Stage 3 both elevated. The survival of all patients based on whether they achieved a complete response, a partial response (>50%), or no response was analyzed. Median survival has not been reached for the complete response group, is 107 months for the partial response group, and is 32 months for the no response group (p<0.0001). Figure 2, divides the patients at the median dFLC level of 13.5 mg/dL demonstrating that for patients with a higher level of free light chain, the median survival is 87.6 months and has not been reached for those with a lower level of free light chain. A proportional hazards model for variables that impact on survival was done in all patients, and the only relevant predictor of outcome was stage (p<0.0001). When the same analysis was performed using a landmark of 6 months, the only predictor of outcome was stage (p=0.0005). When best response was incorporated into the landmark model, it was the strongest predictor of survival. The amyloid stage predicted survival (p= 0.0005), and the best response to therapy (p <0.0001). When the same analysis was performed in the entire group of 434, stage and best response each remained significant (p<0.0001). Discussion: There is a high response rate associated with high-dose therapy that was not observed in the melphalan and prednisone era. For eligible patients who can be transplanted safely, high-dose melphalan is an effective therapy for many patients with amyloidosis. Best response and stage at diagnosis are the best predictors of overall survival. Disclosures: 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 1893 Background: Recent data has shown that the level of immunoglobulin free light chain (FLC) is a prognostic factor for patients with AL amyloidosis. Approximately 25% of patients with AL amyloidosis have coexistent multiple myeloma (MM) with myeloma-related end-organ damage and patients may also present with 310% plasma cells (PC) in the bone marrow (BM) in the absence of any MM features. The goal of this study was to determine the effect of increased BM plasmacytosis in the absence of MM end-organ damage on early mortality. Methods: We performed a retrospective study of 263 consecutive patients with AL amyloidosis seen at Mayo Clinic within 30 days of diagnosis from July 2002 – April 2009, to compare the effect of PC burden among those who died within 90 days of diagnosis (n=88) and those who survived more than 90 days after diagnosis (n=175). Only those patients with documented BM PC were included in this study. MM end-organ damage was defined according to the CRAB criteria. Results: In those who died <90 days after diagnosis and patients who lived beyond 90 days, the proportion of patients with 310% BM PC were 57% and 55%, respectively. Overall survival (OS) was significantly shorter in the early mortality group when there was 310% BM PC present at diagnosis (25 vs. 54 days, p=0.006), but this was not observed in the group who survived beyond 90 days (Figure 1). In patients with 310% BM PC, troponin-T, ejection fraction (EF), and hemoglobin (Hgb) were significantly worse in the early mortality cohort but patients who survived beyond 90 days had significant increase in intraventricular septal (IVS) thickness and beta-2 microglobulin (Table 1). As expected, patients with 310% BM PC in both cohorts had significantly higher serum M-spike and involved FLC (Table). The same cohort of patients were analyzed substituting MM-related end-organ damage for 310% BM PC and similar results were observed with the exception of uric acid and calcium being significantly higher in the early mortality cohort with MM (results not shown). Conclusion: This study demonstrated that an excess of early—but not late—deaths occur in AL amyloidosis patients with 310% BM PC at diagnosis. In our cohort, this finding can be attributed to higher troponin-T levels, indicating more severe cardiac involvement as observed by worse cardiac function. These findings warrant additional investigation. 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: Light chain Amyloidosis (AL) is characterized by deposition of light chain derived amyloid fibrils in major organs and/or soft tissue. An observational study on natural history and outcome of localized immunoglobulin light-chain amyloidosis without vital organ (liver, heart, kidney, peripheral and autonomic nervous system) involvement has shown extremely low rate of progression (1%) to systemic amyloidosis at a median follow-up of 74.4 months (Mahmood S et al. The Lancet Haematology; 2015; 6:e241-e250). There is, however, limited evidence in published literature on natural history of AL amyloidosis confined to fat and/or bone marrow biopsy, without involvement of vital organs or other soft tissues. Methods: We retrospectively identified patients with AL amyloidosis limited to fat and/or bone marrow aspirate in a single-institution database. Patients were evaluated for progression to systemic amyloidosis. Statistical analysis was done using JMP 10.0.0 (SAS Institute Inc.). Results: We identified 117 patients, with a median age of 70 years, who had light chain amyloidosis detected in abdominal fat aspirate and/or bone marrow biopsy, without systemic involvement. Amyloid was seen in fat only in 39%, marrow only in 54% and in both sites in 7%. The median follow up was 45.6 months (95% CI-38.1-57.7) from detection of amyloid. Of these, 64% were alive at the time of analysis. Among 117 patients, 65 were treated for a diagnosis of another plasma cell disorder made prior to or concurrent with detection of amyloid. The remaining 52 patients only had isolated fat or marrow amyloid. Among 65 patients with another diagnosis of plasma cell disorder requiring treatment, 3 progressed to systemic amyloidosis, one each with cardiac, renal and lymph node (LN) involvement detected at 32, 42 and 65 months respectively from the detection of amyloid. The first 2 patients had underlying multiple myeloma, and the third patient with LN involvement had underlying Waldenström macroglobulinemia. Among 52 patients without another diagnosis of a plasma cell disorder requiring treatment, at a median follow up of 32 months, no progression to systemic amyloidosis was observed. Median overall survival (OS) in 117 patients from detection of amyloid, using Kaplan-Meier survival estimates, was 60.2 months (95% CI-48.9-146.1). Conclusion: Our study highlights the fact that isolated amyloidosis detected in fat and/or bone marrow aspirate, in the absence of another plasma cell dyscrasias that require therapy, is unlikely to progress to systemic amyloidosis. Watchful waiting might be considered in such patients after a thorough evaluation to rule out systemic involvement. Disclosures Gertz: Smith Kline: Honoraria; Novartis: Honoraria; Onyx: Honoraria; millenium: Consultancy, Honoraria; Celgene: Honoraria. Kumar:Celgene: Consultancy, Research Funding; Abbvie: Research Funding; Millenium: Consultancy, Research Funding; Novartis: Research Funding; Onyx: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; BMS: Consultancy, Research Funding.

Abstract Introduction Gene Expression Profiling studies have resulted in signatures capable of providing robust prognosis for Multiple Myeloma (MM) patients, such as the EMC92 [SKY92, Kuiper et al. Leukemia 2012]. Recently, data from 4720 MM patients from the HOVON-65/GMMG-HD4, UAMS-TT2, UAMS-TT3, MRC-IX, APEX and IFM trials were employed to assessed the majority of currently identified prognostic markers and their combinations (GEP, FISH, and biochemistry data, [Kuiper et al ASH 2014]). The "SKY92 + ISS" was identified and validated as the statistically most optimal (i.e. most significant and robust) prognostic marker combination for MM patients. The combination of the EMC92 (=SKY92) and ISS prognostic features proves to be a very powerful, unprecedented and straightforward prognostic system. It identifies four prognostic risk classes: low risk (ISS I-SKY92 standard risk (SR)), intermediate-low (ISS II-SKY92 SR), intermediate-high (ISS III-SKY92 SR) and high risk (ISS I-III, SKY92 high risk). Previously, the SKY92 has been validated on the 91 MM cases in the MMGI cohort [Van Beers et al. ASH 2013]. Here we present an extension of that validation with the SKY92 + ISS combination on the 78 MM cases for whom both GEP and ISS is available, by both assessing as the "4 risk group" model defined above, but also a "3 risk group" model (the two intermediate groups combined) as this may be more relevant and useful for clinical application. Materials and Methods A public untreated MM dataset (Multiple Myeloma Genomics Initiative, MMGI) had n=78 cases for which OS, GEP, and ISS were available for analysis. The prognostic markers SKY92 and ISS were applied as proposed [Kuiper et al ASH 2014] to classify cases into the risk categories. Results The risks for the 4 group classification model are shown in Table 1 and Figure 1, and the 3 risk group model is shown in Table 2 and Figure 1. In the 4 group model, the intermediate-low group (SKY92 standard + ISS II) was a small and not significantly different (p=0.79) from the low risk. The intermediate-high group (SKY92 standard + ISS III) was also a small group, with significantly worse outcome compared with the low risk group (p=0.012). Although stratification into four groups was statistically superior in the training and validation data [Kuiper et al ASH 2014] the interpretability benefits from aggregation of the middle two groups [Fig 1 right]. Table 1. Classification results for the four risk groups (Fig 1 left) Risk group n % Median OS HR vs low risk SKY92 High Risk regardless of ISS 19 24 28.4 m 10.8 SKY92 standard risk + ISS-III 10 13 63.0 m 4.1 SKY92 standard risk + ISS-II 16 21 NR (0.8) SKY92 standard risk + ISS-I (low risk) 33 42 NR NA NR= Not Reached at 96 months, HR= hazard ratio Table 2. Classification results for the three risk groups (Fig 1 right) Risk group n % Median OS HR vs low risk SKY92 High Risk regardless of ISS 19 24 28.4 m 10.1 SKY92 standard risk + ISS-II/III 26 34 78.5 m (1.8) SKY92 standard risk + ISS-I 33 42 NR NA NR= Not Reached at 96 months, HR= hazard ratio, () not significant Conclusions By applying the SKY92 + ISS risk stratification model in an independent validation cohort of newly diagnosed Multiple Myeloma patients, besides a high risk group of 19 patients (24%), a group of 33 patients (42%) with superior prognosis could be predicted (SKY92 standard risk and ISS I) that translated into 62% OS at 96 months. The 19 high risk (SKY92 high risk) cases had very poor prognosis (median survival of 28 months). The combination of SKY92 Standard Risk and ISS II and III seems useful for definition of "intermediate risk" although sample size currently is insufficient for significance compared to low risk. The intention is to also perform this validation on the relapsed samples from the MMGI cohort, once OS data has been collected. This validated risk model could play a role in the design of future treatment strategies for high and low risk MM patients. Figure 1. Kaplan Meier curves on the 78 MMGI cases, split into four (left) or three (right) risk groups based on the combination of SKY92 + ISS. Hazard Ratios (HR) are from a Cox proportional Hazards model comparing a particular group to the low risk group. Figure 1. Kaplan Meier curves on the 78 MMGI cases, split into four (left) or three (right) risk groups based on the combination of SKY92 + ISS. Hazard Ratios (HR) are from a Cox proportional Hazards model comparing a particular group to the low risk group. Disclosures van Beers: SkylineDx: Employment. van Vliet:SkylineDx: Employment. de Best:SkylineDx: Employment. Chari:Novartis: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biotest: Other: Institutional Research Funding; Array Biopharma: Consultancy, Other: Institutional Research Funding, Research Funding; Onyx: Consultancy, Research Funding. Jagganath:Millennium: Honoraria; Celgene: Honoraria. Jakubowiak:Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: institutional funding for support of clinical trial conduct, Speakers Bureau; SkylineDx: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SkylineDx: Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kumar:Celgene, Millenium, Sanofi, Skyline, BMS, Onyx, Noxxon,: Other: Consultant, no compensation,; Janssen: Research Funding; AbbVie: Research Funding; Sanofi: Research Funding; Millenium/Takeda: Research Funding; Celgene: Research Funding; Onyx: Research Funding; Skyline, Noxxon: Honoraria. Lebovic:Onyx: Speakers Bureau; Celgene: Speakers Bureau. Lonial:Millennium: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Reece:Onyx: Honoraria; Novartis: Honoraria; Millennium: Research Funding; Merck: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Research Funding. Richardson:Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Siegel:Celgene Corporation: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Novartis: Speakers Bureau; Merck: Speakers Bureau. Stewart:SkylineDx: Membership on an entity's Board of Directors or advisory committees. Vij:Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium: Honoraria, Speakers Bureau; BMS: Consultancy; Takeda: Consultancy, Research Funding; Novartis: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Merck: Consultancy. Zimmerman:Celgene: Honoraria, Speakers Bureau; Millennium: Honoraria, Speakers Bureau; Onyx: Honoraria; Amgen: Honoraria, Speakers Bureau. Fonseca:Onyx/Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Binding Site: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Applied Biosciences: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.

Abstract Abstract 2970 Background: Over a quarter of patients (pts) with symptomatic multiple myeloma (MM) have some degree of renal insufficiency at the time of diagnosis. Multiple studies show that presence of renal failure is strong predictor of inferior overall survival in MM. With effective therapy, renal function improves in a considerable number of patients. It is not clear if the return of renal function to normal levels will improve their outcome to that expected for patients without renal dysfunction. Methods: We evaluated 1478 patients with newly diagnosed myeloma seen at Mayo Clinic within 90 days of diagnosis, between January 1999 and January 2009. We examined these patients for improvement in renal function and identified the lowest serum creatinine obtained during the disease course. The outcomes were analyzed with respect to the renal function improvements. Results: The median age at diagnosis was 64 years (range; 22–93) and 50% were male. The median estimated follow up for the entire cohort was 53 months, with 781 patients alive at the time of analysis with a median follow of 3 years. The serum creatinine was over 1.5 mg/dL at diagnosis in 333 (22.5%) pts and over 2.5 mg/dL in 148 (10%) pts. The median overall survival for the 333 patients was 37 mos (95% CI; 28, 40) compared to 56 mos (95% CI; 51, 63) for those < 1.5 mg/dL; P < 0.001. Among the 333 pts with baseline Cr > 1.5 mg/dl, any improvement in Cr was seen in 263 (79%) including an improvement of at least 0.5 mg/dL in 208 (62%) pts. Among the 263 pts with any improvement, the median time to lowest Cr was 4 months (range; 1–13). The median survival of the group of patients with Cr <= 1.5 mg/dl, over 1.5 mg/dL at diagnosis but improved to <= 1.5 mg/dL, or remained >1.5 mg/dL were 56., 40 and 27 mos respectively; P < 0.001, Figure). We then examined the impact of renal function improvement in the group of patients where the baseline Cr was >2.5 mg/dL. The median OS for the 42 (out of 148 pts with Cr > 2.5 at diagnosis) who had improved to <=1.5 mg/dL was 40 mos compared to 56 mos for those with a Cr <= 1.5 mg/dL at diagnosis and 27.4 mos for the 106 pts whose Cr did not decrease to <= 1.5 mg/dL; P < 0.001. Conclusion: The results of this study point toward improved outcome among patients with renal dysfunction in whom renal function improves. However, it shows that this improvement in renal function does not necessarily improve survival to that observed for the patients with a comparable level of serum creatinine at diagnosis. While early treatment of asymptomatic myeloma has been shown to have little impact on overall survival, a strategy of waiting for serious features of target organ damage to appear before initiation of treatment may have a negative impact on survival in some patients, especially patients with high light chain production who have a higher predilection for renal insufficiency. Disclosures: Kumar: Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Off Label Use: Lenalidomide for treatment of newly diagnosed myeloma. Dispenzieri:Celgene: Honoraria, Research Funding; Binding Site: Honoraria. Lacy:Celgene: Research Funding.

Abstract Abstract 2998 Background: Multiple myeloma remains incurable with current therapies and novel approaches based on disease biology are needed. Inhibitors of apoptosis (IAP) proteins represent a conserved group of proteins that are important regulators of apoptosis. X-linked IAP (XIAP) is the best studied IAP and inhibits pro-apoptotic caspases 3, 7 and 9. Multiple myeloma (MM) cell lines express high levels of XIAP and levels are further increased when stimulated by cytokines IL6 and IGF-1, both secreted in copious amounts in the myeloma microenvironment. IL6 and IGF1 up-regulate XIAP by activating the NF-κB, MAPK and PI3K signaling pathways that are commonly aberrant in MM and other tumors. XIAP mRNA contains an internal ribosomal entry site (IRES) sequence in the 5` untranslated region. IRES sequences enable direct ribosome recruitment and aid in translation that is independent of cap-mediated translation. Thus, molecules like mTOR inhibitors might not lead to XIAP downregulation. This was observed when rapamycin, an mTOR inhibitor, was used on MM cell lines. XIAP protein levels were not reduced due to the IRES sequence which leads to translation that is independent of the 5` cap and 4EBP1. Thus XIAP inhibitors might be able to overcome resistance associated with rapamycin treatment. Methods: LC161 was synthesized by Novartis Inc. (Basel, Switzerland). Stock solutions were made in DMSO, and subsequently diluted in RPMI-1640 medium for use. MM cell lines were cultured in RPMI 1640 containing 10% fetal bovine serum (20% serum for primary patient cells) supplemented with L-Glutamine, penicillin, and streptomycin. Cytotoxicity was measured using the MTT viability assay and proliferation using thymidine uptake. Apoptosis was measured using flow cytometry upon cell staining with Annexin V-FITC and propidium iodide (PI). Immunoblotting was done on cell extracts at various time points following incubation with the drug in order to study the cell signaling pathways. Results: LC161 treatment resulted in a dose and time dependent inhibition of cell growth in the MM cell lines tested. Most of the cytotoxicity was evident by 72 hours, with minimal increase seen up to 96 hours of incubation. At 72 hours of incubation, the median inhibitory concentration varied considerably between various cell lines with an IC50 range of 2.5–25μ M. The IC50s were maintained when the cells were treated in co-culture with stromal cells or in the presence of IL6, IGF or VEGF. Dose-dependent decrease in proliferation of the cell lines was evidenced by decreased thymidine incorporation. Apoptotic changes in cells following drug treatment was confirmed by flow cytometry for Annexin and PI. Cleavage of caspases 3, 8 and 9 were confirmed on flow cytometry. Primary myeloma cells from patients were treated with increasing doses of the drug and dose dependent increase in apoptosis was observed. Immunoblotting studies demonstrated dose dependent significant down regulation of Xiap, cIAP1, cIAP2 and surviving and up-regulation of activated caspases 3, 8 and 9 and PARP. Furthermore, LC161 resulted in down regulation of pAkt, canonical and non-canonical NF-κB, pJNK, p-p38MAPK, c-Myc, Bcl-xL and Mcl1 and up-regulation of pErk and Bcl-2. We are currently examining basal levels of expression of the IAP proteins (Xiap, cIAP1 and cIAP2), pAkt and pErk in various MM cell lines to identify marker proteins that might predict response to this class of drug. In addition, our initial studies of LC161 in combination with the proteasome inhibitor bortezomib demonstrated synergy in killing MM cells in vitro. Additional combinations including inhibitors of the Akt/mTOR pathway and MEK/Erk pathway are currently been done. Conclusion: These studies demonstrate significant in vitro activity of LC161 in MM. Our results suggest the presence of two populations one very sensitive to IAP inhibition and one relatively less sensitive. Our current studies will help identify marker proteins that might predict response to LC161 treatment. We are currently testing LC261 in combination with known inhibitors of the other important signaling pathways implicated in MM disease biology as well as in-vivo experiments in mouse models. Performing these experiments will further validate the efficacy of LC161 as an anti-MM agent and form the basis for it to be taken up for clinical evaluation either as a single agent or in combination with other agent(s). Disclosures: Kumar: Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding.

Abstract Abstract 3053 Background: Patients with smoldering multiple myeloma (SMM) have a higher chance of progression to active MM than patients with monoclonal gammopathy of undetermined significance (MGUS). Since active MM remains incurable and since patients with SMM can have a long time to requiring treatment, observation remains an option for these patients. Bisphosphonates can prevent the bone complications of myeloma. The immunomodulatory (IMiD) drugs are well-tolerated and have documented anti-tumor activity in active MM. We hypothesized that treatment with the IMiD THAL and a bisphosphonate (ZLD) would prolong the time to progression (TTP) over the control arm of ZLD alone. This is the first report of this phase III trial of THAL/ZLD vs ZLD alone for patients with untreated SMM. Goals: The primary goal of this trial was to compare the TTP between patients treated with THAL/ZLD versus ZLD alone in asymptomatic MM. Secondary goals were progression rate at one year, response rate, duration of response, time to next therapy, and toxicity. Methods: Patients were required to have measurable disease as defined by either a serum monoclonal protein >1.0 g by protein electrophoresis or nephelometry or >200 mg of monoclonal protein in the urine on 24 hour electrophoresis or a measurable soft tissue plasmacytoma; >10% plasma cells as measured on the bone marrow aspirate, bone marrow biopsy, or labeling index; absolute neutrophil count >1500/μL; platelet count >100,000/μL; creatinine <2.0 mg/dL, and a performance status of 0, 1, or 2. Patients could not have symptomatic MM that required chemotherapy. The statistical plan was to accrue 120 eligible patients (60 per arm) over 4 years and after a minimum follow-up of 12 months the study would provide >90% power at a type I error rate of 0.05 to detect an increase in the median TTP from 12 months (ZLD) to 24 months (THAL/ZLD), and >80% power to detect an increase in median TTP from 12 to 21 months). Results: The study was activated in July 2003 and closed March 2009 due to slow accrual. Sixty-eight patients (35 Thal/ZLD; 33 ZLD) with a median age 63 years (range, 47–84) were randomized. The median TTP for Thal/ZLD versus ZLD was 2.4 years versus 1.2 years, respectively, P=0.02 one-sided log-rank. After adjusting for pre-specified stratification factors, the hazard ratio for TTP was 2.2 (one-sided p value = 0.01, univariate stratified Cox PH model) for ZLD compared to Thal/ZLD. 89% of patients on the Thal/ZLD arm were progression-free survival (PFS) at one year compared to 55% on ZLD alone (one-sided p<0.001, chi-square). Similar results were obtained (Table and Figures) when the CRAB (calcium, renal, anemia, bone) criteria were applied. Confirmed response was evaluated using the first 12 months of treatment. In the Thal/ZLD arm the response rate was 31% with a median duration of response of 5.1 years (95% CI: 1.9 - NA). There were no confirmed responses in the ZLD alone arm. The median overall survival has not been reached for either arm. In regards to toxicity, no grade 5 adverse events (AEs) have been reported. Thirty patients have reported grade 3+ AEs (17 Thal/ZLD; 13 ZLD, Fisher's exact p-value 0.47). Eight patients have reported grade 4 adverse events (5 Thal/ZLD; 3 ZLD, Fisher's exact p-value 0.71). Overall, only one grade 4 event was felt to be at least possibly related to study treatment – grade 4 neutropenia in Thal/ZLD. Conclusions: While the trial did not meet its planned accrual goals, there was a significant improvement in improved in outcomes in the Thal/ZLD arm compared to control (ZLD). Thal/ZLD produces anti-tumor responses that are quite durable with the median response duration of over 5 years. ZLD alone did not produce any anti-tumor responses. This study indicates that a non-chemotherapy approach can be effective in SMM and may be a useful strategy to test in future studies. Disclosures: Off Label Use: Thalidomide for smoldering myeloma. 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. Gertz:Celgene: Honoraria; Millennium: Honoraria.

Abstract Background: The use of clinical trial results to guide clinical practice is based on the assumption that results are externally valid and clinical trial subjects are a representative sample of patients to whom results can be applied. Multiple myeloma (MM) is primarily a disease of the elderly, and both tolerance to therapy and overall prognosis are influenced by age. MM biological characteristics and possibly response to therapy are different between Whites and racial-ethnic minorities (REM), particularly Blacks. We analyzed recent MM trials performed in the US to assess to what extent they included a representative sample of the MM population. Methods: We retrieved all therapeutic clinical trials performed exclusively in the US and published between 2007 and 2014 for information on age, gender and racial-ethnic distribution of subjects. For the latter, subjects were classified as Whites or REM (defined as Hispanic and/or non-White). Data on unselected patients with newly diagnosed MM from the Surveillance Epidemiology and End Results (SEER-18) program were used to estimate the expected proportion of REM and each gender for the clinical trial population. Results: We identified 128 published MM trials (8,869 subjects). Age of subjects was reported in 127 (99.2%) and gender distribution in 120 (93.8%) of trials, but racial-ethnic composition was reported in only 51 (39.8%) of trials (4,853 subjects). Trials reporting accrual of REM were larger (median 54 subjects, IQR 34.5-84.5) than other trials (median 35, IQR 24-50), P=0.004. Among industry-sponsored trials a higher proportion (57.1 %) reported REM accrual, than among NCI-sponsored (41.2%) or investigator-sponsored (29.0%) trials (overall P=0.013, P=0.003 for investigator vs. industry comparison). First line therapy trials had similar likelihood of reporting on accrual of REM (33.3%) than trials enrolling relapsed/refractory subjects (44.9%) or a mixed population (34.6%), P=0.4. Among subjects in the 51 trials that reported accrual of REM, 19.1% were minorities vs. expected 36.7% (ratio 0.52, 95% C.I. 0.49-0.55). In investigator-sponsored trials, the proportion of minorities was 15.9% (ratio 0.43, 95%CI 0.37-0.49) while among NCI-sponsored trials the proportion was 18.7% (ratio 0.50, 95% C.I. 0.45-0.50) and among industry-sponsored trials the proportion was 22.0% (ratio 0.61, 95% C.I. 0.55-0.68). Among subjects in the 120 trials that reported gender distribution, 56.7% were man vs. expected 56.9% (ratio 1.02, 95% C.I. 0.99-1.05).Median of median age of subjects enrolled in clinical trials was 61 years, in sharp contrast with the median age for MM diagnosis during the period that was 69 years. Only 9 (7.1%) trials the median age of subjects enrolled was higher than 65 years. Conclusions: The participation of REM in MM trials is greatly under reported, particularly among investigator-sponsored trials. REM and older individuals are underrepresented in MM trials, potentially compromising external validity of resuts.l Disclosures Hari: BMS: Consultancy; Takeda: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Spectrum: Consultancy; Sanofi: Consultancy. Kumar:Skyline, Noxxon: Honoraria; Celgene, Millennium, Onyx, Janssen, Noxxon, Sanofi, BMS, Skyline: Consultancy; Celgene, Millennium, Onyx, Novartis, Janssen, Sanofi: Research Funding.

Abstract Background: Amyloidosis is a multisystem disease with extracellular deposition of pathological insoluble beta-fibrillar proteins. Involvement of the heart is seen in more than one-half of the patients with systemic AL amyloidosis and it is the most important determinant of clinical outcome. Cardiac amyloidosis is a restrictive infiltrative cardiomyopathy in which, despite declines in stroke volume that accompany disease progression, the ejection fraction (EF) often remains preserved even in advanced stages of the disease. King et al. proposed a novel index of myocardial function, the myocardial contraction fraction (MCF), defined as the ratio of stroke volume (SV) to myocardial volume (MV). MCF is a measure of myocardial shortening, which differentiated myocardial performance in patients with similar degrees of hypertrophy and in a recent small cohort of AL amyloidosis patients appeared superior to left ventricular ejection fraction (EF) in predicting overall survival (OS). It was our goal to assess the prognostic role of MCF in a large cohort of patients with AL amyloidosis in the context of other prognostic variables. Methods: Patients seen between 4/1/1999 and 2/1/2015 were eligible for this retrospective study if they had an ECHO at the Mayo Clinic, Rochester, MN within 30 days of their AL amyloidosis diagnosis with measurements of left ventricular chamber size and wall thickness needed to calculate MCF, EF, and the presence or absence of pericardial effusion. To capture the full cohort, modeling was done first excluding Mayo (2012) staging and global averaged left ventricular longitudinal peak systolic strain (LV strain) since limited numbers of patients had these studies, 342 and 294, respectively. Thresholds of continuous variables were chosen based on receiver operator curves targeting death at 1-year. Cox proportional hazards analysis was used to identify factors that were prognostic for OS. Statistical analyses were done using JMP 9.0 (SAS, Cary, NC). Results: Among the 722 patients satisfying entry criteria,median age was 64 years (range 32-94) and 66% were male. The best cutoff for MCF was 21% (sensitivity: 74%, specificity: 60%; AUC=0.699) and distinguished two groups with different OS (median 53 vs. 9 months, P<0.0001; Figure). On univariate analysis the baseline ECHO variables predicting OS were interventricular septum thickness (IVS) >12 mm (RR 1.8, P=0.0002), EF <60% (RR 1.7), MCF ≤21% (RR 2.1), and presence of pericardial effusion (RR 2.0), all with P<0.0001. On multivariate MCF ≤21% (RR 1.6, P <0.0001), EF <60% (RR 1.4, P=0.0007) and the presence of pericardial effusion (RR 1.3, P=0.002) were independent predictors of OS. Additional modeling was done with the subset of 342 patients who were assessable for Mayo (2012) staging, (i.e. measurements of immunoglobulin free light chain, NT-proBNP, and troponin T). On univariate analysis, patients with a Mayo (2012) stage ≥ 3 had a RR 2.1, p<0.0001. On multivariate, only MCF ≤21% (RR 1.5, P =0.01), Mayo (2012) stage ≥ 3 (RR 1.5, P=0.01) and EF<60% (RR 1.7, P=0.0006) were independent prognostic determinants. Finally, we addressed LV-strain among the 294 patients in whom the study was performed. There was a significant correlation between MCF and LV strain (rho =-0.86, P<0.0001). On univariate, LV-strain less negative than -13 generated a RR of 2.3, p<0.0001. In contrast to the model containing MCF, on LV-strain multivariate, EF was no longer significant, but LV-strain less negative than -13 (RR 2.0, P=0.008) and Mayo (2012) stage ≥ 3 (RR 2.0, P=0.008) predicted independently OS. Conclusions: MCF ≤21% identified a subgroup of patients with a high mortality risk, and it was independent of the Mayo (2012) staging but highly correlated with LV strain. An advantage of MCF, which is a novel volumetric measurement of the left ventricular chamber, is that, unlike LV-strain, MCF is simple to calculate from routine ECHO measures. Figure 1. Overall survival of 722 patients according to MCF<21%. Figure 1. Overall survival of 722 patients according to MCF<21%. Disclosures Kumar: AbbVie: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Skyline, Noxxon: Honoraria; Celgene, Millenium, Sanofi, Skyline, BMS, Onyx, Noxxon,: Other: Consultant, no compensation,; Sanofi: Research Funding; Millenium/Takeda: Research Funding; Onyx: Research Funding.

Abstract Abstract 2253 Background: Lenalidomide based combinations are among the most common initial therapies for myeloma. Previous studies have suggested that lenalidomide therapy can result in suboptimal stem cell collection in patients eligible to undergo autologous stem cell transplantation, especially older patients after prolonged exposure to the drug. Many salvage approaches are used when attempting repeat stem cell collection in this patient group. Patients and Methods: Two hundred twenty four patients who underwent stem cell collection following lenalidomide-dexamethasone induction from July 2004 and December 2009 were included in the current analysis. Data pertaining to the duration of lenalidomide therapy, stem cell mobilization regimen, and the collection yields were collected from the medical records. Results: The median age at mobilization was 60.6 years (range; 29, 76) and 136 (60%) were male. There were a total of 245 collection attempts from among 224 patients, 21 (9.8%) patients attempting to remobilize after failing to collect the desired numbers of stem cells at the first attempt. We first analyzed the results of the initial collection attempt. The median duration of lenalidomide therapy prior to stem cell collection was 4 months (range; 1, 26). The mobilization strategies were GCSF (Granulocyte Colony Stimulating Factor) alone in 151 (67%) patients, cyclophosphamide (CTX) followed by GCSF in 29 (13%) patients, and GCSF plus AMD3100 in 44 (20%) patients. Among those receiving AMD3100, it was added either due to peripheral blood CD34 cell count not reaching the threshold for initiation of harvest or for poor first day CD34 cells collection in 34 patients and given in a planned fashion in 10 patients. Overall 15 patients (7%) failed to reach the peripheral CD34 cell counts required to initiate apheresis, and among those starting apheresis 6 patients failed to collect at least 2 million CD34 cells/kg; a cumulative failure rate of 9%. Another 18 (8%) patients failed to collect at least 4 million CD34 cells /kg. The CD34 cells yield on day 1, the total yield, number of collections, the average daily yield and the percentage of the targeted cells collected for each mobilization strategy including failure rates are detailed in the table. Twenty-one patients reattempted stem cell mobilization; including 14 that failed a first attempt and 7 did who not achieve the intended goal even though they collected more than 2 million CD34 cells/kg. The mobilization regimens were GCSF alone, CTX + GCSF, GCSF + GM-CSF (Granulocyte Macrophage Colony Stimulating Factor) and GCSF + AMD in 5, 8, 3, and 4 patients respectively. All patients collected at least 2 million CD34 cells /kg and 14 patients (70%) collected more than 4 million CD34 cells /kg. The median CD34 cells collected with the second attempt was 5.4 million/kg (rang; 2, 19.5) bringing the median total collection for these 21 patients to 9.6 million/kg (2.6-19.6). Overall, of the 224 patients studied, all but the 6 patients who failed initially and did not attempt a second collection collected at least 2 million CD34 cells /kg and 197 (88%) collected at least 4 million CD34 cells/kg. Conclusion: While the overall failure rate of stem cell collection in patients receiving initial therapy with lenalidomide is 10%, a risk adapted approach of adding AMD3100 appear to decrease the risk of failure. However, majority of patients failing a stem cell harvest attempt can be salvaged with a second collection allowing these patients to proceed to a stem cell transplant if desired. Disclosures: Gertz: Celgene: Honoraria; Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genzyme: Research Funding. Lacy: Celgene: Research Funding. Dispenzieri: Celgene: Honoraria, Research Funding; Binding Site: Honoraria. Micallef: Genzyme: Membership on an entity's Board of Directors or advisory committees. Kumar: Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding.