Palladini, Giovanni

Introduction: Light chain deposition disease (LCDD) is a rare complication of monoclonal gammopathies, defined by non-amyloid linear monoclonal light chain (most commonly kappa) deposits in the kidney and other organs. The rarity of LCDD has hampered clinical studies and staging systems and response criteria are lacking. The International Kidney Myeloma Working Group (IKMG) started a clinical data collection from all participating centers in order to define the natural history of LCDD, and to establish prognostic factors and response criteria in a large, international, unselected patient population. Methods: Eight referral centers have yet participated in the data collection at the data lock of July 31, 2020. Patient inclusion is ongoing and expected accrual is 500 patients. The diagnosis of LCDD had to be biopsy-proven. The patients were diagnosed between 1992 to 2020. Response was assessed 6 months after treatment initiation according to the criteria used in light chain (AL) amyloidosis. Renal survival (RS) was defined as time from diagnosis to dialysis or last follow-up. Patients who died without requiring dialysis were censored at the time of death. The analysis of factors predicting RS was performed in patients whose baseline estimated glomerular filtration rate (eGFR) was >15 mL/min. The cutoffs of baseline variables, as well as the cutoffs measured at the time of response, best predicting RS or OS at 12 months were identified by means of Receiver Operator Characteristics (ROC) analyses. All patients gave written informed consent for their clinical data to be used for research purposes. Results: Overall, 359 patients have been included in this first analysis. Sixteen (4%) subjects had concomitant cast nephropathy. The main clinical characteristics are reported in the Table. Median overall survival (OS) was 13 years and RS was 12 years (Figure1 A and 1B) and median survival of living patients is 4.5 years. At univariate analysis the only baseline variables predicting RS were proteinuria [best cutoff 2.5 g/24h, HR 2.25 (95%CI 1.13-4.60), P=0.02], and eGFR [best cutoff >30 mL/min, HR 0.50 (95%CI 0.26-0.96) P=0.037], but at multivariate analysis only proteinuria predicted RS [HR 2.17 (95% CI 1.08, 4.33), P=0.027]. At univariate analysis, a higher bone marrow plasma cell infiltrate (best cutoff ≥20%) at diagnosis was associated with a significantly lower OS [HR 1.96 (95% CI 1.23-3.13) P=0.004], as was having end stage renal disease (ESRD) defined as an eGFR <15 mL/min [HR 1.81 (95%CI 1.11-2.92) P=0.015]. We then tested the ability of the hematologic response criteria for AL amyloidosis to discriminate groups with different survival after treatment in a 6 months landmark analysis. Our choice of adopting the amyloidosis response criteria was corroborated by the results of the ROC analysis showing that the difference between involved and uninvolved free light chains (dFLC) cutoff (40 mg/L) used in AL amyloidosis to define very good partial response (VGPR) had 87% sensitivity and 65% specificity in identifying patients who needed dialysis within 12 months. Partial response (PR, 19% requiring dialysis at 3 years) was not associated with a RS benefit over no-response (29% requiring dialysis at 3 years, P=0.511). However, VGPR conferred a significant RS advantage (10% requiring dialysis at 3 years) over PR (P=0.002). No significant difference in RS was seen between complete response (CR, 0% requiring dialysis at 3 years) and VGPR (P=0.178). Thus, achieving VGPR or CR by amyloidosis response criteria [post-treatment dFLC<40 mg/L (VGPR by AL criteria), with or without negative serum and urine immunofixation and normal FLC-ratio (CR by AL criteria)] was adopted as a provisional criterion for hematologic response in LCDD (Figure 1D). LCDD response was also associated with prolonged OS (Figure 1C). Conclusions: Almost one-third of patients with LCDD are diagnosed when they already have ESRD resulting in shorter OS. The degree of proteinuria and of bone marrow plasma cell infiltration predict RS and OS, respectively. Achievement of post treatment dFLC <40 mg/L or negative serum and urine immunofixation at 6 months is proposed as a provisional criterion for hematologic response, being able to predict both improved RS and OS. Planned expanded recruitment might allow a validation analysis of the results, the analysis of organ response data and the evaluation of different time-points for response assessment. Disclosures Milani: Celgene: Other: Travel support; Janssen: Other: Speaker honoraria; Pfizer: Other: Speaker honoraria. Kastritis:Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Consultancy, Honoraria. Schönland:Janssen, Prothena, Takeda: Honoraria, Other: travel support to meetings, Research Funding. Bridoux:Baxter: Consultancy; Janssen: Honoraria; Celgene: Honoraria. Tuchman:Celgene: Honoraria, Research Funding, Speakers Bureau; Oncopeptides: Consultancy; Amgen: Research Funding; Caelum: Honoraria; Sanofi: Honoraria, Research Funding; Janssen: Research Funding; Roche: Research Funding; Karyopharm: Honoraria, Research Funding. Jimenez-Zepeda:Janssen, Celgene, Amgen, Takeda: Honoraria. Palladini:Jannsen Cilag: Honoraria, Other; Celgene: Other: Travel support. Wechalekar:Celgene: Honoraria; Caelum: Other: Advisory; Janssen: Honoraria, Other: Advisory; Takeda: Honoraria, Other: Travel.

SummaryThe severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2)‐associated coronavirus disease 2019 (COVID‐19) is primarily manifested as a respiratory tract infection, but may affect and cause complications in multiple organ systems (cardiovascular, gastrointestinal, kidneys, haematopoietic and immune systems), while no proven specific therapy exists. The challenges associated with COVID‐19 are even greater for patients with light chain (AL) amyloidosis, a rare multisystemic disease affecting the heart, kidneys, liver, gastrointestinal and nervous system. Patients with AL amyloidosis may need to receive chemotherapy, which probably increases infection risk. Management of COVID‐19 may be particularly challenging in patients with AL amyloidosis, who often present with cardiac dysfunction, nephrotic syndrome, neuropathy, low blood pressure and gastrointestinal symptoms. In addition, patients with AL amyloidosis may be more susceptible to toxicities of drugs used to manage COVID‐19. Access to health care may be difficult or limited, diagnosis of AL amyloidosis may be delayed with detrimental consequences and treatment administration may need modification. Both patients and treating physicians need to adapt in a new reality.

8546 Background: The PI bortezomib is commonly used in first-line therapy of AL, but new therapies are needed that are tolerable in the context of multi-organ dysfunction and that, in RRAL, offer improved outcomes following prior bortezomib. Ixazomib is an oral PI, and in TOURMALINE-AL1, the first phase 3 trial conducted in RRAL, while the first primary endpoint of hematologic overall response rate (ORR) was not met, all clinically relevant time-to-event endpoint data favored Ixa-Dex vs PC (Dispenzieri et al, ASH 2019). Methods: RRAL pts with 1–2 prior therapies were randomized (1:1) to Ixa-Dex (n = 85) or PC (n = 83; Dex plus lenalidomide [n = 47], melphalan [n = 24], cyclophosphamide [n = 10], or thalidomide [n = 2]), stratified by cardiac stage, relapsed vs refractory disease, and prior PI exposure. The primary endpoints were hematologic ORR and 2-yr rate of vital organ deterioration or death. We report subgroup analyses of ORR and outcomes by prior PI exposure. Results: Of the 168 pts enrolled, 90 were PI-naïve and 78 PI-exposed (46 and 39 in the Ixa-Dex arm; 44 and 39 in the PC arm) per stratification; 28 and 27 pts in the Ixa-Dex and PC arms had received bortezomib in their last prior line. Hematologic ORR was 63% vs 50% for Ixa-Dex vs PC (odds ratio [OR] 1.71; 95% confidence interval [CI] 0.74–3.96) in PI-naïve pts, and 41% vs 51% (OR 0.66; 95% CI 0.27–1.62) in PI-exposed pts. For time-to-event outcomes (Table), hazard ratios (HRs) were 0.46–0.85 in favor of Ixa-Dex vs PC in both PI-naïve and PI-exposed pts. Conclusions: Hematologic ORR was higher with Ixa-Dex vs PC in PI-naïve pts but lower in PI-exposed pts (although not statistically significant), and long-term clinically relevant outcomes favored Ixa-Dex in both groups. Based on HRs, the magnitude of benefit appeared similar or greater in PI-naïve vs PI-exposed pts. Clinical trial information: NCT01659658 . [Table: see text]

Abstract Background Electrophoretic methods to detect, characterize and quantify M-proteins play an important role in the management of patients with monoclonal gammopathies (MGs). Significant uncertainty in the quantification and limit of detection (LOD) is documented when M-proteins are <10 g/L. Using spiked sera, we aimed to assess the variability in intact M-protein quantification and LOD across 16 laboratories. Methods Sera with normal, hypo- or hyper-gammaglobulinemia were spiked with daratumumab or elotuzumab, with concentrations from 0.125 to 10 g/L (n = 62) along with a beta-migrating sample (n = 9). Laboratories blindly analyzed samples according to their serum protein electrophoresis (SPEP)/isotyping standard operating procedures. LOD and intra-laboratory percent coefficient of variation (%CV) were calculated and further specified with regard to the method (gel/capillary electrophoresis [CZE]), gating strategy (perpendicular drop [PD]/tangent skimming [TS]), isotyping (immunofixation/immunosubtraction [ISUB]) and manufacturer (Helena/Sebia). Results All M-proteins ≥1 g/L were detected by SPEP. With isotyping the LOD was moderately more sensitive than with SPEP. The intensity of polyclonal background had the biggest negative impact on LOD. Independent of the method used, the intra-laboratory imprecision of M-protein quantification was small (mean CV = 5.0%). Low M-protein concentration and high polyclonal background had the strongest negative impact on intra-laboratory precision. All laboratories were able to follow trend of M-protein concentrations down to 1 g/L. Conclusions In this study, we describe a large variation in the reported LOD for both SPEP and isotyping; overall LOD is most affected by the polyclonal immunoglobulin background. Satisfactory intra-laboratory precision was demonstrated. This indicates that the quantification of small M-proteins to monitor patients over time is appropriate, when subsequent testing is performed within the same laboratory.

Abstract Background Serum protein electrophoresis (SPEP) is used to quantify the serum monoclonal component or M-protein, for diagnosis and monitoring of monoclonal gammopathies. Significant imprecision and inaccuracy pose challenges in reporting small M-proteins. Using therapeutic monoclonal antibody-spiked sera and a pooled beta-migrating M-protein, we aimed to assess SPEP limitations and variability across 16 laboratories in three continents. Methods Sera with normal, hypo- or hypergammaglobulinemia were spiked with daratumumab, Dara (cathodal migrating), or elotuzumab, Elo (central-gamma migrating), with concentrations from 0.125 to 10 g/L (n = 62) along with a beta-migrating sample (n = 9). Provided with total protein (reverse biuret, Siemens), laboratories blindly analyzed samples according to their SPEP and immunofixation (IFE) or immunosubtraction (ISUB) standard operating procedures. Sixteen laboratories reported the perpendicular drop (PD) method of gating the M-protein, while 10 used tangent skimming (TS). A mean percent recovery range of 80%–120% was set as acceptable. The inter-laboratory %CV was calculated. Results Gamma globulin background, migration pattern and concentration all affect the precision and accuracy of quantifying M-proteins by SPEP. As the background increases, imprecision increases and accuracy decreases leading to overestimation of M-protein quantitation especially evident in hypergamma samples, and more prominent with PD. Cathodal migrating M-proteins were associated with less imprecision and higher accuracy compared to central-gamma migrating M-proteins, which is attributed to the increased gamma background contribution in M-proteins migrating in the middle of the gamma fraction. There is greater imprecision and loss of accuracy at lower M-protein concentrations. Conclusions This study suggests that quantifying exceedingly low concentrations of M-proteins, although possible, may not yield adequate accuracy and precision between laboratories.

Abstract 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.

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 731 Background: Treatment with bortezomib achieves high hematologic response rates and rapid and durable responses in AL patients (pts), providing the rationale for proteasome inhibition in this population. MLN9708 is an investigational, oral, potent, reversible, and specific 20S proteasome inhibitor (PI). In preclinical studies, MLN9708 has shown improved antitumor activity compared to bortezomib in a range of xenograft models. This phase 1 study (NCT01318902) assessed weekly doses of oral MLN9708 in pts with relapsed or refractory AL. Methods: Pts aged ≥18 years with relapsed or refractory AL after ≥1 prior therapy, cardiac biomarker stage I/II disease, and measurable major organ (heart/kidney) involvement, received increasing doses of oral MLN9708 (standard 3+3 dose escalation fixed doses of 4.0 and 5.5 mg), on days 1, 8, and 15 of 28-day cycles for up to 12 cycles. Pts with no major hematologic response (<PR) after 3 cycles received dexamethasone (dex; 40 mg, days 1–4). Two expansion cohorts of PI-naïve and PI-exposed pts were enrolled at the MTD. The primary objectives were to determine the safety, tolerability, and MTD. Secondary objectives included analysis of plasma pharmacokinetic (PK) and whole blood pharmacodynamic effects of MLN9708, and assessment of overall hematologic response rate, time to and duration of hematologic and organ response. Adverse events (AEs) were graded using NCI-CTCAE version 4.03. Blood samples were collected at multiple timepoints pre- and post-MLN9708 dosing for PK analysis during cycle 1. Hematologic response and amyloid-related organ assessments were performed according to standardized criteria. Results: At data cut-off (June 29, 2012) 16 pts had been enrolled and received ≥1 MLN9708 dose (safety population). The median age was 66.5 years (range 54–78) and 7 were male. Median number of prior therapies was 3 (range 1–7); 10 received prior transplant, 7 received prior bortezomib. Major organ involvement, defined by standard criteria, included heart, kidney, or both in 7/5/4 pts, respectively, with a median of 2 (range 1–5) involved organ systems, and Mayo cardiac biomarker risk stage was I, II, III in 6, 9, 1 pts. Five pts were treated in the 5.5 mg cohort and 11 pts were treated in the 4.0 mg (n=6 dose escalation; n=5 dose expansion) cohorts. Of the 11 pts treated at 4.0 mg, 4 were PI-naïve, 7 were PI-exposed. Pts received a median of 3 cycles (range 1–12); 5 pts received ≥5 cycles, and 8 pts remain on treatment. Dex was added in 4 pts (2 in each MLN9708 dose level). There were no on-study deaths. Pts discontinued due to disease progression (n=5), AE, withdrawal by pt, or unsatisfactory response (each n=1); 2 pts completed planned 1 year of therapy. One pt in the 4.0 mg cohort experienced a DLT of grade 3 thrombocytopenia. Two pts in the 5.5 mg dose cohort experienced DLTs: grade 3 diarrhea in 1 pt, and renal failure, respiratory failure (both grade 2), and cardiac arrest (grade 4) in another pt. The MTD was determined as 4.0 mg. AEs were reported in 14 pts. The most common drug-related AEs included nausea (n=5), diarrhea and thrombocytopenia (each n=4), abdominal pain and fatigue (each n=3). Grade ≥3 AEs (any cause) reported in >1 pt were thrombocytopenia (n=4), dyspnea (n=3), maculo-papular rash, dehydration, and abdominal pain (each n=2); all were grade 3. Preliminary response data are shown in the table. At data cut-off, one responder had progressed, and the median duration of hematologic response was 7.4 months (range 1.3–11.5+); 2 pts had cardiac organ response. Preliminary PK data showed that MLN9708 was rapidly absorbed, with a median Tmax of 1 hr (range 0.5–6). MLN9708 day 15 plasma Cmax was 73.6 ± 40.2 ng/mL (mean ± SD) and AUC0–168was 1250 ±530 ng*hr/mL (n=8 at 4.0 mg dose cohort). MLN9708 PK parameter values in this study appear similar to other MLN9708 studies in myeloma pts. Conclusions: These data suggest weekly oral administration of MLN9708 is feasible in pts with relapsed or refractory AL. The MLN9708 MTD was determined as 4.0 mg. Assessment is ongoing, with preliminary evidence of hematologic responses noted. A phase 3 study of MLN9708 plus dex versus physician's choice of treatment is planned (NCT01659658). Disclosures: Merlini: Millennium Pharmaceuticals, Inc.: Consultancy. Off Label Use: Use of the investigational agent MLN9708, an oral proteasome inhibitor, in the treatment of relapsed or refractory light-chain amyloidosis. Sanchorawala:Celgene: Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Onyx: Research Funding. Zonder:Celgene: Research Funding; Millennium Pharmaceuticals, Inc: Consultancy, Research Funding. Kukreti:Roche: Consultancy, Honoraria; Celgene: Honoraria; Janssen: Honoraria. Schonland:Celgene: Honoraria, Research Funding; Janssen: Honoraria. Dispenzieri:Janssen Research & Development: Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Celgene: Research Funding. Cohen:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees. Berg:Millennium Pharmaceuticals, Inc.: Employment. Liu:Millennium Pharmaceuticals, Inc.: Employment. Di Bacco:Millennium Pharmaceuticals, Inc.: Employment. Gupta:Millennium Pharmaceuticals, Inc.: Employment. Hui:Millennium Pharmaceuticals, Inc.: Employment. Comenzo:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.