ALBERT

Description: Background. POEMS syndrome is a rare form of B cell dyscrasia combining a proliferation usually of plasma cells, a polyneuropathy, osteocondensing bone lesions and multiple other clinical signs. The pathogenesis is not well understood but VEGF plays a major role. In patients with one or two sclerotic plasmacytoma and no bone marrow involvement, first line therapy should include radiation. For patients with diffuse sclerotic lesions, bone marrow involvement or absence of any bone lesion and for those who have not demonstrated stabilization of their disease 3 to 6 months after completing radiation systemic therapy is indicated, the most effective being high dose chemotherapy with autologous stem cell transplant (ASCT). Radiation of a single lesion is effective in about every other case and is accompanied by a fairly slow improvement of the neurological symptoms, often after initial worsening. ASCT seems to be accompanied by a number of important complications, in particular engraftment syndrome. Outside these 2 treatments there is no consensus therapy. Lenalidomide (LEN), a drug without serious neurological toxicity, has the advantage of being both anti-angiogenic and cytotoxic to malignant plasma cells (Richardson PG, Blood 2002;100(9):3063-7). We have recently reported a series of 20 French patients with POEMS syndrome treated by LEN with a good efficacy. We now report the first 27 patients of a prospective phase II trial using LEN + dexamethasone (LEN-DEX), 2 cycles preceding radiation or high dose treatment trying to obtain a rapid clinical response and to avoid engraftment syndrome or 9 cycles followed by 1 year LENalone in patients who cannot receive radiation or ASCT. Methods. Newly diagnosed or relapsing patients with POEMS syndrome who needed to be treated were eligible. Patients who can be treated by local radiation or intensive treatment with stem cell support receive two 28 day cycles of LEN 25 mg PO Days 1-21 and DEX 40 mg PO Days 1,8,15,22 before radiation or intensive treatment (Group 1), the other patients receive 9 cycles of the same LEN-DEX (Group 2) and then 12 cycles of continuous low dose LEN (10 mg). LEN dose was tapered to 10 mg for patients with a creatinine clearance between 30 and 50 ml/min and DEX to 20 mg for patients above 75 years of age and for those who were frail patients. Main eligibility criteria included a diagnosis of POEMS syndrome according to criteria by Dispenzieri et al (Am J Hematol 2012;87(8):804-14), an age of 18 or more, a creatinine clearance above 30 ml/min, no prior treatment with or contraindication to LEN and no uncontrolled thrombosis. Serum and plasma VEGF, serum electrophoresis, immunofixation and free light chain measurements were centrally monitored. Neurologic evaluations were performed using the Overall Neuropathy Limitations Scale (ONLS), the Neurological Impairment Scale (NIS) and the 10 meter walk test (10MWT). The primary endpoint was evaluation of the effectiveness of LEN-DEX combination using biological responses (decrease of monoclonal protein and serum VEGF level) and secondary endpoints were clinical and particularly neurological responses. Results. Twenty-seven patients have been included in 12 centres, median age was 61 (range 32-75), the median follow-up was 6.6 months (range 2-24). Eighteen patients were in group 1, with radiotherapy in 10 patients and ASCT in 8 patients; 9 patients were in group 2. Nineteen patients were in first line and 8 already treated. Only 2 patients experienced grade 3-4 adverse events due to LEN (cytopenia) and 2 patients had allergic rashes, no thrombotic event occurred. No engraftment syndrome was noted in the 5 patients already treated with ASCT. To date, no patient have died. Evolution of VEGF median values in serum and plasma, M-spike and dFLC levels and evolution of neurological measurements are reported in table 1. Neurological improvement was very rapid in some patients, using ONLS and 10MWT 11/18 evaluable patients had a neurological improvement after 2 cycles with an improvement of 1 or more of the ONLS score and/or change of 0.1 m/s or more in the 10MWT. Only one patient who progressed after nine cycles received another therapy. Conclusion. This is the first prospective trial of LEN-DEX in POEMS syndrome. This combination seems well tolerated in this disease with a good efficacy on VEGF measurements and rapid neurological improvement in the majority of patients. Updated data will be presented at the meeting. Figure 1 Figure 1. Disclosures Jaccard: Celgene: Drug supply to Trial Other. Tournilhac:mundipharma: Honoraria, Other, Research Funding; GSK: Honoraria, Other, Research Funding; Roche: Honoraria, Other, Research Funding. Moreau:celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Description: Abstract 2934 Introduction: Len combined with Dexamethasone (Dex) is becoming a standard treatment in multiple myeloma (MM). As Len is mainly excreted by the kidneys, its dose should be adjusted according to renal function. Current dosing recommendations are based on a study conducted in non-malignant patients (pts) and on modelling/simulations. To assess whether these recommendations are actually valid in MM pts, we conducted a prospective study evaluating pharmacokinetics (PK), safety and efficacy of Len+Dex in pts with various degrees of renal impairment (RI). We also compared the glomerular filtration rate (GFR) estimated either by the Modification of Diet in Renal Disease (MDRD) dosage (GFR/MDRD) or by the Cockroft and Gault (CG) equation (GFR/CG) for determining Len dosage. Methods: 37 Caucasian pts (median age 65 yrs) with symptomatic MM who had received ≥ 1 previous line of treatment, were enrolled. All had stable renal function over 4 weeks prior to inclusion. They were divided in 5 groups according to GFR/CG at baseline: group 1, 〉 80mL/min (N = 10); group 2, ≥ 50 & ≤ 80 mL/min (N = 10); group 3, ≥ 30 & 〈 50 mL/min (N = 7); group 4, 〈 30 mL/min (N = 5); group 5, chronic hemodialysis (N = 5). Cast nephropathy and light chain deposition disease were documented by kidney biopsy as the respective cause of RI in 6 and 1 of the 17 pts from groups 3, 4 and 5. Pt characteristics were similar, except for pts in group 4 who were significantly older (p = 0.01). All pts received ≥ 3 cycles of oral Len+Dex (40 mg weekly) regimen from Days 1–21 of each 28-day cycle. Len starting dose was defined according to the current dosing guideline, i.e.: group 1 and 2: 25 mg/d; group 3: 10 mg/d; group 4: 15 mg/qod; group 5: 5 mg/d. Blood samples were collected on a dosing day in the first cycle for PK analyses, as follows: at pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 24 h (and 36 and 48 h in groups 3–5) after the Len dose on day 5, and at predose and 2 h (near tmax) after the Len dose on days 9 and 15. Results: Len clearance was highly correlated to GFR/CG (R2 = 0.86, p 〈 0.001). Mean Len clearance declined from 239 mL/min in group 1, to 160, 93, 54, and 41 mL/min, and mean terminal half life was prolonged from 3 h to 5, 7, 10, and 24h in groups 2, 3, 4 and 5, respectively. These findings were consistent with those reported for pts with RI due to non-malignant conditions. The average daily AUC values for groups 2–5 were 103–149% of that for group 1 (1794 h*ng/mL). No difference was found in mean plasma Len concentrations at 2 h post-dose between day 9 (Len alone) and day 15 (Len+Dex) across groups. GFR/MDRD and GFR/CG were highly correlated (R2 = 0.85, slope = 0.89) and similarly predicted Len clearance (slope = 2.38 and 2.15, respectively). When the same cutoff values were used for GFR/MDRD and GFR/CG, the % reduction in Len clearance in groups 3–5 compared with the combined groups 1 and 2 was very similar for GFR/MDRD- and GFR/CG-based renal function classifications. However, a dosage discordance between GFR/MDRD and GFR/CG would occur in 5/32 non-dialysis pts. All the 5 pts would be assigned to a lower starting dose according to GFR/MDRD. The estimated resulting AUC levels would have been reduced to 68–94% of the mean AUC in group 1 from the observed 91–238%. These estimated AUC levels would be considered to be in the therapeutic range. After 3 cycles of Len+Dex, hematological response rate (≥ PR) was 73% (VGPR 27%). Response rates were 70% in pts with 〈 50ml/min. Renal function remained stable in all pts. A total of 22 serious (≥ grade 3) adverse events (SAEs), including 16 hematological SAEs, occurred in 12 pts, leading to dose reduction in 7 cases. Of these, 2 pts would have been assigned to a lower starting dose according to GFR/MDRD. The frequency of SAEs was not significantly increased in group 5 compared to the other groups (60% vs 45%, p = 0.3). After a median follow-up of 10 months, pts had received a mean number of 7.6 ± 4.3 cycles, and 5 had died, because of MM progression in 4 cases. Conclusion: The study demonstrated that the effect of RI on the Len PK in MM patients receiving concomitant Dex was similar to that in non-malignant pts receiving Len alone. The recommended dose adjustments achieved the appropriate plasma exposure with similar efficacy and safety across different renal function groups in MM pts. GFR/MDRD and GFR/CG may be interchangeable for determining the Len dosage. Disclosures: Chen: Celgene Corporation: Employment. Alakl:Celgene Corporation: Employment. Neel:Celgene Corporation: Employment. Jaccard:Celgene Corporation: Consultancy.

Description: Extranodal NK/T-cell lymphoma, nasal type, is a rare and highly aggressive disease with a grim prognosis. No therapeutic strategy is currently identified in relapsing patients. We report the results of a French prospective phase II trial of an L-asparaginase-containing regimen in 19 patients with relapsed or refractory disease treated in 13 centers. Eleven patients were in relapse and 8 patients were refractory to their first line of treatment. L-Asparaginase–based treatment yielded objective responses in 14 of the 18 evaluable patients after 3 cycles. Eleven patients entered complete remission (61%), and only 4 of them relapsed. The median overall survival time was 1 year, with a median response duration of 12 months. The main adverse events were hepatitis, cytopenia, and allergy. The absence of antiasparaginase antibodies and the disappearance of Epstein-Barr virus serum DNA were significantly associated with a better outcome. These data confirm the excellent activity of L-asparaginase–containing regimens in extranodal NK/T-cell lymphoma. L-Asparaginase–based treatment should thus be considered for salvage therapy, especially in patients with disseminated disease. First-line L-asparaginase combination therapy for extranodal NK/T-cell lymphoma warrants evaluation in prospective trials. This trial is registered at www.clinicaltrials.gov as #NCT00283985.

Description: Abstract 1344 In September 2007 we published the results of a prospective randomized trial comparing in 100 AL amyloidosis patients, enrolled between January 2000 and January 2005, high dose melphalan with ASCT and the oral regimen M-Dex (melphalan 10 mg per square meter of body-surface area and dexamethasone 40 mg per day, on days 1 to 4). With a median follow-up of 3 years the median survival was better in the M-Dex arm (56.9 months) than in the ASCT arm (22.2) months (p=0.04). The hematological responses were not statistically different between the 2 arms and the higher toxicity of the ASCT arm was responsible for the shorter median survival. This study has been criticised because of the high treatment related mortality (TRM) in the ASCT arm but a landmark analysis of patients who survived for at least 6 months and who received their assigned treatment, did not show any difference in survival. A second frequent criticism was that too severe patients, who were not able to go through the high dose procedure, have been included. A separate analysis done within the 59 good risk patients showed a nonsignificant difference between the two groups in overall survival at 3 years (58% in the group assigned to receive ASCT vs. 80% in the group assigned to receive M-Dex; P = 0.13). A third concern was related to the duration of response, should high dose treatment, giving slightly more complete responses, results in more sustained responses and, with a prolonged follow-up, in a better long term survival ? To answer this question we extended the follow-up of the surviving patients. The new cut off date was August 1st, 2010, more than 5 and a half years after the last inclusion. Only 1 patient has been lost to follow-up. We did again the landmark analysis with the longer follow-up and we looked, in this population of 65 patients with 100% feasibility and 0 % TRM, at survival and remission duration. As the follow-up was very long and the biologic surveillance not planned after 2006 we took unequivocal events as censor points for the event-free survival analysis: deaths and second line treatment. At the first cutoff date, in 2006, 49 patients were alive, 30 in the M-Dex arm and 19 in the HDT arm. At the new cutoff date in 2010, 38 patients are alive, 22 in the M-Dex arm and 16 in the intensive arm, with a median follow-up of 49 months for the entire cohort and 86 months for surviving patients (figure 1). The majority of late deaths were amyloid related, but 3 patients in the M-Dex arm died of unrelated lung and digestive cancer. The median survival in the 2 arms has not been modified (56.9 month in the M-Dex arm and 22.2 month in ASCT arm, p=0.15). For the 65 patients included in the landmark analysis the median survival is not different in the 2 arms (103 month in the M-Dex arm and 97 month in ASCT arm) and the median event free survival is 56 months in the M-Dex arm and 26 months in the intensive arm (p=0.3, figure 2). Eleven surviving patients in the M-Dex arm and 6 in the intensive have not received a second treatment, 9 of these patients in the M-Dex arm and 5 in the ASCT arm have normal free light chain measurement at their last visit. Only 1 patient, assigned to receive ASCT, has been diagnosed with myelodysplasia. With a longer follow-up we did not found any superiority in the intensive arm in survival or remission duration even in the landmark analysis eliminating treatment related mortality. In the area of very efficient new drugs this analysis reinforces our choice to propose conventional treatment to amyloidosis patient avoiding the risk of intensive treatment.Figure 1.Survival according to treatment groupFigure 1. Survival according to treatment groupFigure 2.Event-Free Survival According to Treatment Group in the Landmark AnalysisFigure 2. Event-Free Survival According to Treatment Group in the Landmark Analysis Disclosures: Leblond: roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; mundipharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; genzyme: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; jansen: Membership on an entity's Board of Directors or advisory committees. Leleu:Celgene: Consultancy, Research Funding; Janssen Cilag: Consultancy, Research Funding; Leo Pharma: Consultancy; Amgen: Consultancy; Chugai: Research Funding; Roche: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

Description: Abstract 4621 Background: Primary systemic amyloidosis (AL) is a severe plasma cell disorder characterized by amyloid fibrils extracellular deposition in different organs. Myocardial involvement is frequent and has major impact on prognosis. Echocardiography (TTE) is the most common test performed when cardiac involvement is suspected. We hypothesized that a simple measurement of left atrium enlargement (LA) by TTE may provide an important risk marker for this disease. Methods and results: Between 1997 and 2010, 114 patients were diagnosed with systemic AL. Sixty one patients of the cohort (54%) had cardiac involvement on the basis of standard criteria defined as: mean LV wall thickness 〉12mm with no other cardiac causes. They had first TTE within 16 days of diagnosis. Patients were mainly treated with conventional chemotherapy (M-Dex) or with new agents for refractory or relapsing patients We retrospectively collected demographic baseline characteristics along with biological and echo data of these patients. Mean age was 61±11 years; 60% were male; 19% had hypertension. Mean left ventricular ejection fraction and mean LV wall thickness were respectively 58±13% and 15±3 mm. Mean follow up time was 2.1±2 years. None had significant valvular heart disease. LA enlargement was defined by M mode as 〉 40 mm in male and 〉 36 mm in female. Patients with enlarged LA had significantly more hypertension and lower ejection fraction and more hypertrophied LV walls (All P〈 0.05). At 3 years, survival rate was markedly reduced in patients with enlarged LA vs. those with normal LA: 34±9% vs.75 ±9% (P =0.02). By multivariate analysis, after adjusting for age, gender, and presence of hypertension, LA enlargement remained an independent predictor of overall mortality at 3 years (HR=2.88; CI (1.12-8.84); P=0.03). Conclusion: In patients with systemic AL amyloidosis and cardiac involvement, LA enlargement, a surrogate marker of diastolic dysfunction and elevated LV filling pressure, is a powerful independent predictor of long-term mortality. Therefore LA enlargement may help to enhance risk stratification in patients presenting with this disease. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 3632 Introduction: Although Hodgkin Lymphoma (HL) is highly curable, about 15% of patients (pts) are refractory or relapsed after first line treatment. Classic prognostic scores (e.g. IPS) are useful for identifying high risk pts, who need intensive treatment, and low risk pts, who beneficiate de-escalation to minimize side effects. However, they are not enough suitable to predict outcomes. Consequently, finding new complementary tools for detecting refractory or relapsing pts, remains a challenge. Fluorodeoxyglucose (FDG)-PET/CT involvement in initial staging has been widely studied. Although clinical or CT tumor volume is an important prognostic factor, metabolic tumor volume (MTV) is not enough explored. We performed a study to 1) determine whether MTV and maximum standardized uptake value (SUV) max could be new prognostic markers and 2) compare metabolic tissue heterogeneity with CD68 expression, a promising new prognostic factor linked with inflammatory microenvironment. Patients and methods: Among 456 histologically proven HL pts registered in the Regional Lymphoma database of Limousin (SRRLL, France) since 1990's, 158 have an available sample for CD68 staining. Among the 106 pts who have undergone FDG-PET, 43 pts have available quantitative initial and early response (post-C2) SUV FDG-PET/CT data. The median follow-up was 21 months (6–72.5). Pts were classified following Ann Arbor stages I: 4 pts, II: 17 pts, III: 9 pts, IV: 13 pts. FDG-PET/CT exams were performed with a biograph6 Siemens® device and analyzed with Siemens MI® application. MTV was computed for all pts with a 2D delineation technique and using a thresholding method. The threshold (T) corresponds to mean liver SUV (+3 sd) calculated into 50 cm3 of normal liver. All the tumor voxels (3D pixels) equal or greater than the T belong to MTV. MTV per pathological area (MTVa) was also analyzed. Pts with spleen lesions have an increased volume compared to the others. To minimize spleen's impact, MTV was calculated without spleen (MTVws). Quantitative FDG uptake is routinely measured by SUVmax. The mean SUVmax was also worked out into 1 cm3 around the tumor SUVmax. ROC curves were plotted for continuous variables such as age, erythrocyte sedimentation rate (ESR), MTV, SUVmax and mean SUVmax. CD68, tumor associated macrophage expression, was tested with a 25% threshold for positivity. Significant factors allowed dividing pts into favorable and unfavorable groups. Event free survival (EFS) studies were carried out for all binary variables using COX model. A univariate regression analysis was performed. Variables with a p

Description: Background: Approximately 20–40% of pts with NDMM present with RI, which is associated with a negative impact on survival (Rajkumar, 2005). In the pivotal phase 3 FIRST trial (median follow-up 37 months [mos]), continuous Rd improved progression-free survival (PFS) vs. melphalan-prednisone-thalidomide (MPT) in elderly NDMM pts by 28% (25.5 vs. 20.7 mos; HR = 0.72; P 〈 0.01) (Facon, Blood 2013). Although 121 pts receiving continuous Rd are still on Tx, the interim overall survival (OS) analysis showed a 22% reduction in the risk of death in favor of continuous Rd vs. MPT (HR = 0.78; P = 0.02). The present analysis was conducted to determine the impact of RI on PFS, OS, and time to 2nd antimyeloma Tx (AMT) as clinical study outcomes. Methods: Pts were randomized to 3 Tx arms: continuous Rd until progression (n = 535); Rd for 18 cycles (72 weeks) (Rd18; n = 541); or MPT for 12 cycles (72 weeks) (n = 547). Enrolled NDMM pts were categorized according to their renal function: 24% had normal renal function (creatinine clearance [CrCl] ≥ 80 mL/min), 44% presented with mild RI (≥ 50 and 〈 80 mL/min), 23% had moderate RI (≥ 30 and 〈 50 mL/min), and 9% had severe RI (〈 30 mL/min). Pts requiring dialysis were excluded. Lenalidomide starting dose was 25 mg QD for pts with normal renal function or mild RI, 10 mg QD for moderate RI, and 15 mg QOD for severe RI. Melphalan dose was reduced by 50% in pts with moderate or severe RI. The primary endpoint was PFS (continuous Rd vs. MPT); secondary endpoints were OS, overall response rate, time to response, duration of response, time to Tx failure, time to 2nd AMT, health-related quality of life, safety, and improvement in renal function from baseline. Improvement in RI was defined as shifts from baseline to most extreme post-baseline value of the calculated CrCl as a measure of renal function during the active Tx (N = 1484). Results: A PFS benefit favored continuous Rd vs. MPT irrespective of the degree of renal function (Table 1): there was a benefit in pts with normal renal function (HR = 0.72 (0.51–1.02); P = 0.06), and better in pts with mild RI (HR = 0.79 (0.62–1.00); P = 0.05) and moderate RI (HR = 0.62 (0.45–0.85); P 〈 0.01). A PFS benefit was also seen with continuous Rd vs. Rd18 (a secondary comparison) in pts with mild RI and moderate RI (P 〈 0.01 for both). An interim OS benefit with continuous Rd vs. MPT was observed in most renal subgroups. Similar results were observed between Rd18 and MPT in terms of PFS or interim OS in any of the renal subgroups. Continuous Rd, compared with Rd18 or MPT, extended time to 2nd AMT in most renal groups except severe RI (CrCl 〈 30mL/min) (Table 2). Improvement in RI was observed more frequently in pts treated with continuous Rd than those with Rd18 or MPT: improvement of mild RI, 48%, 43%, and 48%, respectively; of moderate RI, 67% 61%, and 62%; and of severe RI, 64%, 59%, and 56%. Overall, 〈 5% of pts in any Tx group experienced a worsening in renal function status during Tx (continuous Rd 2.2%; Rd18 2.8%; MPT 2.7%). The most common grade 3–4 adverse events (AEs) for these Txs were anemia, neutropenia, thrombocytopenia, deep-vein thrombosis/pulmonary embolism (DVT/PE), and peripheral sensory neuropathy (Table 3). Tx discontinuation due to AEs increased in pts with moderate and severe RI, regardless of the type of Tx (Table 3). Conclusions: PFS, OS (at interim analysis), and time to 2nd AMT outcomes generally improved continuous Rd vs. Rd18 or MPT in transplant-ineligible NDMM pts with normal renal function, and in those with mild or moderate RI. The small number of pts in the severe RI group precluded a meaningful conclusion. Continuous Rd was generally well tolerated and renal function improved in the majority of pts during Tx with continuous Rd vs. Rd18 or MPT. Disclosures Dimopoulos: Celgene Corporation: Consultancy, Honoraria. Off Label Use: Lenalidomide used in newly diagnosed multiple myeloma patients. Roussel:Celgene: Consultancy, Lecture fees Other, Research Funding. van der Jagt:Celgene Corporation: Research Funding. Jaccard:Celgene Corporation: Honoraria, Research Funding. Tosikyan:Celgene: Consultancy. Karlin:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bensinger:Celgene Corporation: Consultancy, Research Funding. Schots:Celgene: Research Funding. Chen:Celgene Corporation: Employment. Marek:Celgene Corporation: Employment, Equity Ownership. Ervin-Haynes:Celgene Corporation: Employment. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Description: Background Systemic AL amyloidosis is a life-threatening disease with limited treatment options. Response criteria have been recently updated and retrospectively validated (Palladini et al, J Clin Oncol 2012). Hematologic response (suppression of FLCs) has been shown to predict for both organ response and survival (ibid). Preliminary results from the present phase 1 study (NCT01318902) regarding the safety, tolerability, and maximum tolerated dose (MTD) of ixazomib (the first oral PI to be investigated in the clinic) in RRAL were reported previously (Merlini et al, ASH 2012). At that time, 11 pts had received the MTD/RP3D of ixazomib - 4.0 mg. Here we update the safety data (primary objective) and report hematologic and organ responses, progression-free survival (PFS), and overall survival (OS) (secondary objectives) for the extended population of 22 pts receiving the RP3D. Methods Pts with RRAL after ≥1 prior therapy and with measureable heart/kidney involvement and cardiac biomarker stage I/II disease were eligible. Two expansion cohorts (PI-naïve and PI-exposed) were enrolled at the RP3D. Pts received oral ixazomib on days 1, 8, and 15 for up to 12 x 28-day cycles; continuation until disease progression was allowed. Pts with less than partial response (PR) after 3 cycles received added dexamethasone (Dex) 40 mg, days 1–4 from cycle 4 onwards. Adverse events (AEs) were graded by NCI-CTCAE v4.03. Responses were assessed per standard criteria (Palladini et al, J Clin Oncol 2012). Results At data cut-off (Dec 6, 2013), 27 pts had been enrolled, 22 at the RP3D of ixazomib 4.0 mg; the other 5 pts were enrolled at 5.5 mg and are not included in these analyses. In pts who received ixazomib 4.0 mg, median age was 64.5 yrs (range 54–78); 13 were male. Mayo cardiac biomarker risk stage was I/II/III in 11/10/1 pts, respectively. Median baseline FLC differential (dFLC) and NT-proBNP were 146 mg/L (range 40–734) and 849 pg/mL (range 51–5691). Major organ involvement included heart, kidney, or both in 9, 8, and 5 pts, with a median of 2 (range 1–6) organ systems involved. Pts had received a median of 3 prior therapies, including transplantation in 16 pts; 16 pts had received prior bortezomib (PI exposed) and 6 were PI naïve. Other prior therapies included melphalan (n=21), Dex (n=16), IMiDs (n=11), and cyclophosphamide (n=10). Best hematologic response to prior therapy was complete response (CR) in 3 pts, very good PR (VGPR) in 4, PR in 14, and stable disease (SD) in 1 pt; organ response was achieved by 5 pts, with 12 pts having no response. Exposure and outcome data by prior PI exposure are shown in the table. Pts discontinued due to disease progression (n=6), pt withdrawal, symptomatic deterioration (each n=3), or unsatisfactory response (n=2); 5 pts completed 12 cycles; 3 pts are ongoing. Overall hematologic response rate (ORR) was 52%. After a median follow-up of 16.9 mos, the 9 pts who achieved ≥VGPR, had a median PFS of 17.0 mos compared with 10.7 mos in pts who achieved a lesser response (p=0.03). Cardiac/renal response was observed in 50%/18% of pts (all ≥VGPR). The most common drug-related AEs included diarrhea, nausea (each n=7), fatigue, thrombocytopenia (each n=6), peripheral neuropathy, and pyrexia (each n=4). Drug-related grade 3 AEs (〉1 pt) were thrombocytopenia (n=3), diarrhea, and maculo-papular rash (each n=2). Table.PI naïven=6PI exposed n=16TotalN=22Cycles received, median (range)12 (1–22)3.5 (1–16)5.5 (1–22)Dex added, n358Hematologic response-evaluable ptsn=5n=16N=21Response, n (%)ORR5 (100)6 (38)11 (52)CR2 (40)02 (10)VGPR3 (60)4 (25)7 (33)PR02 (13)2 (10)SD09 (56)9 (43)Cardiac response/heart evaluable, n/N (%)3/4 (75)3/8 (38)6/12 (50)Renal response/kidney evaluable, n/N (%)1/3 (33)1/8 (13)2/11 (18)1 yr hematologic PFS rate, %8341602 yr OS rate, %835157 Conclusions This is one of the first studies prospectively assessing hematologic and organ response according to the updated consensus criteria. These data suggest weekly oral ixazomib 4.0 mg is feasible and generally well tolerated in RRAL pts with vital organ dysfunction. High quality hematologic responses (≥VGPR) were observed in 43% of pts; these responses were sustained at 1 yr in 60% of this heavily-pretreated population. Achieving ≥VGPR was associated with cardiac response and extended PFS. These results warrant a phase 3 study of ixazomib plus Dex vs physician's choice of treatment, which is ongoing (NCT01659658). Disclosures Merlini: Pfizer: Honoraria; Millennium: the Takeda Oncology Company: Consultancy, Honoraria, Speakers Bureau. Off Label Use: Use of the investigational agent ixazomib, an oral proteasome inhibitor, in the treatment of relapsed or refractory light-chain amyloidosis. Sanchorawala:Celgene: Research Funding; Millennium: the Takeda Oncology Company: Research Funding; Onyx: Research Funding. Jeffrey:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees. Kukreti:Celgene: Consultancy, Honoraria. Schoenland:Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau. Jaccard:Celgene: Honoraria, Research Funding; Janssen: Honoraria. Dispenzieri:Millennium: the Takeda Oncology Company: Research Funding; Celgene: Research Funding; Pfizer: Research Funding; Janssen: Research Funding. Cohen:Onyx Pharmaceuticals: Advisory Board, Advisory Board Other; Bristol-Myers Squibb: Advisory Board, Advisory Board Other, Research Funding; Janssen: Advisory Board, Advisory Board Other; Celgene: Member, Independent Response Adjudication Committee Other. Berg:Takeda Pharmaceutical International Co.: Employment. Yuan:Takeda Pharmaceutical International Co.: Employment. Hui:Takeda Pharmaceutical International Co.: Employment. Comenzo:Millennium:the Takeda Oncology Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Teva: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Description: Abstract 1364 In light chain (AL) amyloidosis, as well as in multiple myeloma, response to treatment is increasingly being used as a surrogate endpoint in clinical trials. In 2005 a consensus statement of the International Society of Amyloidosis (ISA) established the criteria for hematologic and organ response. Since then, several studies emphasized the prognostic relevance of the measurement of the amyloidogenic precursor, the circulating free light chain (FLC). Moreover, it was reported that patients who with treatment achieved decreases in the cardiac biomarker N terminal natriuretic peptide type B (NT-proBNP) had longer survival, although echocardiographic criteria of response were not attained. The ISA Consensus Panel reconvened in 2010 to update hematologic and organ response criteria. The panel felt that any new criteria should be validated in a large patient population. Thus, we systematically gathered from 7 referral centers in Europe and in the United States a cohort of 649 patients with systemic AL amyloidosis who had been evaluated for hematologic and organ responses at diagnosis and 6 months after treatment initiation, excluding patients who died earlier. At diagnosis, 430 patients (66%) had heart involvement, 377 (58%) had NT-proBNP ≥650 ng/L, 455 (70%) had renal involvement (95, 15%, with glomerular filtration rate 30% and 〉300 ng/L, and a threshold of evaluability based on NT-proBNP baseline level 〉650 ng/L was chosen. The most powerful criteria for PR were those based on dFLC percent decrease, and a 50% cutoff was preferred because of easier clinical use. Among candidate criteria for VGPR, the best were based on iFLC absolute value achieved after therapy, but the performance of those based on dFLC absolute value was only slightly lower. Therefore, a definition of VGPR based on dFLC (

Description: New treatment options are required for primary systemic amyloid light chain (AL) amyloidosis. This phase 1/2 dose-escalation study aimed to determine the maximum tolerated dose (MTD) of lenalidomide in combination with melphalan and dexamethasone (M-dex), and assess the efficacy and tolerability of this therapy for patients with de novo AL amyloidosis. Twenty-six patients were enrolled across 4 cohorts: M-dex + lenalidomide 5, 10, 15, and 20 mg once daily on days 1 to 21 in a 28-day cycle. No dose limiting toxicity (DLT) was observed in cohorts 1, 2, and 3. 4. Seven patients in cohort 4, M-dex + lenalidomide 20 mg/day, experienced DLT. MTD was defined as 15 mg of lenalidomide. A complete hematologic response was achieved in 42% at the dose of 15 mg of lenalidomide per day. After a median follow-up of 19 months, estimated 2-year overall survival (OS) and event-free survival (EFS) were 80.8% and 53.8%, respectively. Hematologic and organ responses were both associated with superior EFS rates (P = .0001). A higher EFS was also observed in patients whose free light chains decreased by more than 50% during therapy (P = .019). Lenalidomide 15 mg/d + M-dex is a new effective combination therapy in patients with newly diagnosed AL amyloidosis. This study is registered at www.clinicaltrials.gov as NCT00621400.