AL Amyloidosis Amyloidosis Research Articles

Cardiopulmonary exercise test findings are not the same in distinct types of cardiac amyloidosis

Abstract Background Cardiopulmonary exercise testing (CPET) is a widely used tool for risk stratification and prognosis in patients with chronic heart failure. In amyloid patients, cardiac amyloid deposits are associated with poor prognosis, increased risk for arrhythmias, sudden death, and subsequent exercise limitation due to restrictive cardiomyopathy. The type of amyloidosis and its affectation of the heart are different, and little is known about the CPET parameters according to the type of cardiac amyloidosis. Purpose In this study, we aim to compare CPET data in different types of amyloidosis to determine if CPET variables evaluated could have a significant difference that could impact the follow-up or prognosis of the patients based on the type of amyloidosis. Methods We conducted a retrospective cohort study of 194 patients with a diagnosis of cardiac amyloidosis referred for CPET from February 2010 to February 2024. Patients with at least one CPET data were included in our analysis. The type of amyloidosis, comorbidities, and echocardiogram data were retrieved from medical records. Patients were divided into 3 different groups according to the type of amyloidosis: AL Amyloidosis(AL), Variant TTR Amyloidosis (vTRR), and Wild Type TTR Amyloidosis (wtTTR). Individuals with CPET studies after heart transplant were excluded from the analysis. Fisher’s exact test or chi-square was used to compare categorical variables. ANOVA and Tukey-Kramer (TK) were used to compare continuous variables. Adjustment using General Linear Models (GLM) procedure was used to identify any confounder that could affect the results. A p-value <0.05 was considered significant. Results Out of the 194 patients, 66 had AL Amyloidosis, 40 had vTTR Amyloidosis, and 88 had wtTTR Amyloidosis. Most of the patients were male, and the male predominance was higher in the wtTRR group. There were 41 (62.1%) males in the AL group, 35 (87.5%) in the vTRR group, and 83 (94.3%) in the wtTTR group (p<0.0001). Comorbidities were balanced among the groups. Additional demographic and comorbidities data are shown in Table 1. From the evaluated CPET variables, VE/VCO2 nadir and slope were significantly higher in the wtTTR group when compared to the other groups, as well as Peak VE and Peak TV(Figure A). However, after adjusting for sex, BMI, and age, VE/VCO2 nadir was still significantly higher in the wtTRR group (p=0.003) compared to the other groups, as well as Peak VE, which was higher again in vTTR patients (p=0.001), and Peak TV (Table 2). Conclusion Ventilation variables evaluated in CPET showed alterations in the wtTTR group. These findings suggest that wtTRR amyloid patients could have a severe problem in ventilation that could be of significant relevance in future prognosis.

Belantamab Mafodotin in Relapsed/Refractory AL Amyloidosis: Real-World Multi-Center Experience and Review of the Literature

Introduction: Treatment for relapsed/refractory AL amyloidosis (AL) is an unmet need. The safety and efficacy of belantamab mafodotin (BLM) in multiple myeloma are known, whereas in AL data are limited. Methods: We report a multi-center cohort of AL patients receiving BLM, and review all previous data on BLM therapy in AL. Results: Twelve patients with a median of 3 (range 2–9) prior lines of therapy were included. The overall hematological response rate (ORR) was 75% (9/12), including 5 complete responses. Six of the 10 evaluable patients had organ responses. The median event-free survivals/overall survivals were 22.3 and 28.8 months, respectively. Grade 3 toxicities were mostly infections and keratopathy, occurring in 7/12 (58%). Hematological toxicities were rare. No grade 4/5 toxicities occurred. The review of the previous series reveals BLM provides an ORR of 60–83% with similar rates of corneal toxicity. Conclusion: BLM, being an off-the-shelf therapy, with acceptable toxicity even in frail patients, may be a valuable option in AL, with a high ORR, and a signal for durable responses and high-quality organ responses.

Long-term outcomes after cardiac transplantation in AL amyloidosis.

7572 Background: Systemic AL amyloidosis can lead to progressive multi-organ dysfunction including advanced heart failure which may require orthotopic heart transplantation (OHT). Hematologic outcomes of AL amyloidosis post-OHT are not well described. Methods: We report outcomes for patients with AL amyloidosis with cardiac involvement post-OHT from Nov 2008 - Jun 2023 at Vanderbilt University Medical Center. Hematologic response was graded per the ISA guidelines. Results: Fourteen pts underwent OHT of whom 13 had lambda light chain disease. Three (21%) pts had isolated AL amyloidosis (AL) without myeloma (MM), while 11 (79%) also had MM: 6 with bone marrow plasma cells (BMPCs) 10-19% (AL-PCMM-10) and 5 with BMPC ≥20% (AL-PCMM-20). One each with AL-PCMM-10 and AL-PCMM-20 had lytic lesions (AL-CRAB). Median age at OHT was 55.5 yrs (range 37-74). Median time from diagnosis to OHT was 18 mo (range 3-62). Five (35%) pts had biopsy-proven extracardiac amyloid involvement. Median difference in serum free light chains at first evaluation was 70 mg/dL (range 9-289). Three pts were Mayo 2012 stage II, 4 stage III, and 7 stage IV. Four pts had t(11;14) and 1 had 1q gain. Ten (71%) pts received triplet therapy (VCd or VRd) and 3 (21%) received quadruplet therapy (Dara-VCd or Isa-VCd) pre-OHT. Six (43%) pts had autologous stem cell transplantation (ASCT); 1 pre-OHT and 5 post-OHT. Of ASCT pts, 1 pt achieved CHR, 1 VGPR, 2 PR, and 1 had PD pre-ASCT. Pre-OHT, 4 pts achieved CHR, 6 VGPR, 3 PR, and 1 had PD. Eleven pts (79%) received maintenance therapy post-OHT (5 proteosome inhibitors, 6 anti-CD38). At last follow-up, 8 pts were in CHR, 3 in VGPR, 1 in PR, and 2 had PD. Four (29%) pts died post-OHT: 2 from AL recurrence (1 each with AL and AL-PCMM-10), 1 from cardiac allograft vasculopathy (AL-CRAB), and 1 from renal failure (AL-CRAB). Three (21%) pts had hematologic relapse 5, 21 and 48 mo post-OHT, and of those, 2 had recurrent cardiac amyloid in graft 37 and 71 mo post-OHT. Of those with hematologic relapse, 2 had AL-PCMM-10 and 1 had AL. One pt had post-transplant lymphoproliferative disorder 126 mo post-OHT, requiring treatment. Median follow-up and survival of the cohort post-OHT was 2.25 yrs (range 0.5-13.8). Conclusions: In this single-center analysis of pts undergoing OHT for cardiac AL amyloidosis, we demonstrate feasibility of excellent long-term outcomes, in predominantly high-risk AL pts where majority harbored high-risk disease with MM overlap, either by AL-CRAB or AL-BMPC. Induction alone led to ≥VGPR response in 10 (71%) pts pre-OHT and further therapy deepened this to 11 (79%) pts. Both AL-CRAB pts died during follow-up, highlighting the overall poor prognosis in this specific subgroup. In our cohort, non-relapse related mortality was seen in only 2 (14%) pts, demonstrating acceptable post-OHT risk and overall ability to achieve far improved outcomes in the high-risk cardiac AL amyloidosis patient population that otherwise suffers from rapid and universal mortality.

Sequence diversity of kappa light chains from patients with AL amyloidosis and multiple myeloma

Background AL amyloidosis (AL) results from the misfolding of immunoglobulin light chains (IG LCs). Aim of this study was to comprehensively analyse kappa LC sequences from AL patients in comparison with multiple myeloma (MM). Objective We analysed IGKV/IGKJ usage and associated organ tropism and IGKV1/D-33 in terms of mutational analysis and theoretical biochemical properties. Material and Methods cDNA and bulk RNA sequencing of the LCs of AL and MM patients. Results We studied 41 AL and 83 MM patients showing that IGKV1 was most expressed among kappa AL and MM, with higher frequency in AL (80% vs. 53%, p = .002). IGKV3 was underrepresented in AL (10% vs. 30%, p = .014). IGKJ2 was more commonly used in AL than in MM (39% vs. 29%). Patients with IGKV1/D-33 were associated with heart involvement (75%, p = .024). IGKV1/D-33-segments of AL had a higher mutation count (AL = 12.0 vs. MM = 10.0). FR3 and CDR3 were most frequently mutated in both, with a median mutation count in FR3 being the highest (AL = 4.0; MM = 3.5) and one mutation hotspot (FR3 (83I)) for IGKV1/D-33/IGKJ2 was associated with cardiac involvement. Conclusion This study confirmed that germline usage has an influence on AL amyloidosis risk and organ involvement.

Abstract B112: SNAP23-dependent SNARE complex is a novel molecular target in AL Amyloidosis and Multiple Myeloma by blocking free light chain secretion and triggering a terminal unfolded protein response

Abstract The goal of this study was to investigate whether SNARE proteins are necessary for immunoglobulin (Ig) free light chain (FLC) secretion, thus representing a yet unexplored therapeutic target in AL amyloidosis (AL) and Multiple myeloma (MM). Both these disorders are incurable, and in the former, pathogenesis is invariably related to deposition of Ig FLC fibrils in target organs. The molecular mechanisms underlying FLC folding/secretion have not been studied, and no therapies directly target this intrinsic vulnerability. We hypothesize that FLC secretion is at least in part mediated by SNARE proteins, and their inhibition would block FLC exocytosis, causing retention of FLC-loaded vesicles, leading to activation of a terminal unfolded protein response (UPR) and apoptosis. We therefore hypothesized that novel, effective targets for MM and AL therapy could be identified within SNAREs. As a tool to study SNARE function, we stably expressed 7 distinct, tetracycline-inducible botulinum neurotoxin (BoNT) serotypes (BoNT/A-F) in FLC-secreting AL (ALMC1, ALMC2) and MM (U266, KMS11) cell lines. To monitor BoNT expression, a bicistronic lentiviral vector with a P2A-GFP was used. Upon doxycycline administration, we performed growth competition assay in polyclonally transduced cells and assessed kinetics of GFP expression over time and apoptosis via flow cytometry in monoclones. Western blot (WB) was used to assess cleavage of SNAREs upon expression of each BoNT. We used WB and ELISA to assess FLC secretion on a per-cell base upon BoNT expression. We used TurboID proximity labeling followed by mass spectrometry to identify cytotoxic BoNT interacting partners and CRISPR-Cas9 gene editing to validate putative BoNT targets. By querying the IFM170 gene expression database of newly diagnosed MM patients, we identified VAMP2, VAMP3, SYNTAXIN4, and SNAP23 as the top expressed SNARE and confirmed their high expression in a panel of AL and MM cell lines. Expression of all BoNT serotypes, except BoNT B, led to rapid apoptosis of AL and MM cells, with BoNT F standing out for extent and rapidity of cytotoxicity. Concurrent cleavage of SNAP23, VAMP3, and SYNTAXIN4 correlated with cytotoxicity of BoNT in AL and MM cell lines. Mechanistically, we showed that cytotoxic BoNTs, but not BoNT B, blocked FLC secretion and triggered the PERK-mediated terminal UPR with induction of CHOP and GADD34 followed by massive apoptosis. We identified SNAP23 as an interacting partner of cytotoxic BoNT F, but not BoNT B. Single SNAP23 KO did not completely recapitulate cytotoxic BoNT phenotype, as it was only partially cytotoxic. Based on our preliminary data, we hypothesize SYNTAXIN4 and VAMP3 to be synthetic lethal with SNAP23. Our data provide proof of concept that blocking FLC secretion in AL and MM cells is feasible and results in rapid cell apoptosis by triggering a terminal UPR, thus representing a promising, novel therapeutic approach. Using BoNT as a biological tool, we identified SNAP23 as a critical component of FLC exocytosis, paving the way for the design of novel therapeutics. Citation Format: Emre Karayol, Maria Moscvin, Tianzeng Chen, Peter G. Czarnecki, Annamaria Gulla, Kenneth C. Anderson, Giada Bianchi. SNAP23-dependent SNARE complex is a novel molecular target in AL Amyloidosis and Multiple Myeloma by blocking free light chain secretion and triggering a terminal unfolded protein response [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B112.

Curability of Light Chain (AL) Amyloidosis with Conventional Dose Regimens

Novel immunotherapies in AL amyloidosis (AL) are associated with improved outcomes while the use of ASCT in selected patients can offer long term remissions. Since the plasma cell clones are usually small or modest, sustained hematologic remissions are not uncommon in AL amyloidosis; however, the “curability” of the disease remains to be demonstrated: even in patients (pts) who achieve deep and sustained hematologic responses, irreversible organ damage can lead to inferior survival. To identify clinical and disease characteristics that are associated with potential “functional cure” (“cure”) of the disease we analyzed a cohort of patients with AL treated without ASCT and with a follow up of at least 5 years. We defined“ ”cure“ as survival of at least 5 years without hematologic disease progression (PD) and without need for any salvage therapy. The analysis included consecutive pts with AL, treated in the Department of Clinical Therapeutics, Athens Greece, diagnosed until 6/2018; pts who survived < 6 months were excluded to adjust for early mortality associated with severe cardiac involvement. The final cohort included 210 pts and we focused on pts who: had not had hematologic PD, had not received any salvage therapy, were still alive or had died from causes not related to AL. These pts were defined as “functionally cured” while the rest as “non-cured”. Among the “cured” we identified a group of pts that despite hematologic response they progressed to end-stage renal disease. We considered that this was “predetermined” due to the advanced organ damage already at diagnosis. Lastly, we compared the outcome of “cured” pts with the outcome of “non-cured” pts who were on CR/VGPR and had ≥1-year or ≥5-year OS. The rate of “curability” was 17% (N=35). “Cured” pts had more often renal (84% vs 61%, p=0.045) and less frequent cardiac involvement (53% vs 62%, p=0.049), lower BM infiltration (8% vs 15%, p<0.001) and lower baseline dFLC (p=0.031) but higher levels of baseline proteinuria (p=0.031). The characteristics as well as the differences between “cured” and “non-cured” pts, are shown in Table 1. Most “cured” pts received bortezomib-based therapies (27 pts, 77%), oral melphalan was given in 4 pts (11%), while in 15 pts (42%) treatment also included lenalidomide and in 7 (20%) daratumumab (with or without bortezomib). Regarding hematologic response, 33 (94%) “cured” pts had achieved ≥ VGPR (CR: 22, VGPR: 11) vs 46% for “non-cured” (p<0.001), 18 pts (51%) had ≥ VGPR with low dFLC response criteria (dFLC <10mg/L) vs 20% (p<0.001); 6 pts (17%) had only low dFLC VGPR and 4 (11%) were not evaluable for response due to low dFLC levels. At 1- and 3-months from start of therapy, 24 (68%) and 27 pts (77%) “cured” pts had achieved ≥VGPR. MRD evaluation was available in 19 “cured” pts, and 11 (31%) were MRD negative (vs 3 (2%) for “non-cured” pts, p<0.001). Cardiac response was observed in 9 pts (25%) and renal response in 18 “cured” pts (51%). Among “cured” pts there was a group of 7 pts (20%) with end-stage renal disease; 1 (2.8%) was already on dialysis at the time of diagnosis, while 6 (17%) initiated dialysis during disease course, despite deep hematologic responses (3 CR, 3 VGPR); 3 pts were renal stage 2 and 3 were renal stage 3. Median time to dialysis was 27 months. Baseline clinical and disease characteristics were comparable among pts with and without end-stage renal disease. The median follow-up of the whole cohort was 88 months, and among “cured” pts, 3 (8.5%) died from causes unrelated to AL amyloidosis. The 7- year OS rate for “cured” pts was 100% and for “non-cured” was 41%, respectively. In 1- and 5-year landmark survival analysis, “cured” pts had significantly superior outcome compared to “non-cured” pts with CR/VGPR, with median OS not reached vs 66 months (p<0.001) and not reached vs 98 months (p=0.014), respectively (Fig 1). In conclusion, a subgroup of pts with AL, not treated with ASCT, can have long-term survival (≥ 5 years) without need for additional or salvage therapy. Such patients could be considered as functionally “cured”. High rates of rapid and deep hematologic responses, relatively high rates of MRD negativity and relatively low tumor and free light chain burden characterize this subset, further emphasizing the need for early diagnosis and active therapy to maximize clonal responses. Thus, “curability” in AL amyloidosis is feasible, especially in the era of novel therapies.

Belantamab Mafodotin in Relapse/Refractory AL Amyloidosis- Real-Life Multi-Center Experience

Introduction: Bortezomib and daratumumab revolutionized the therapy for AL amyloidosis (AL). However, relapsed/refractory AL resistant to both drugs is an unmet clinical need, with limited options due to the frailty of these patients and paucity of prospective data. The safety profile and efficacy of belantamab mafodotin (BLM) in multiple myeloma (MM) are well known. In contrast, published data for AL are currently limited to case series of 6 (Zhang, Ann Hematol. 2022) and 12 patients only (Khwaga, Blood Cancer J. 2022). Here, we report a multicenter real-world data on 12 AL patients treated with BLM and compare these to the prior reports. Methods: We retrospectively identified all AL amyloidosis patients who received BLM outside a clinical trial, between Feb 2020-Sep 2022. The diagnosis, staging, hematologic and organ responses and progression of AL were evaluated according to consensus criteria. Event-free survival (EFS) was defined as the time from the first day of BLM administration to hematologic progression or therapy change for inadequate response or death. Results: Twelve AL patients from 5 centers in Israel and Italy were included. The median age at BLM initiation was 66 y (range 54-70). The most common FISH aberrations were 1q gain in 8 patients (67%) and t(11;14) in 5 (42%). All patients except one had cardiac involvement (92%) and 9 (75%) had renal involvement. The median number of prior lines of therapy was 3 (range 2-9). All patients previously received bortezomib, an alkylator and daratumumab, 11 (92%) received lenalidomide, 10 (83%) received pomalidomide and 9 (75%) underwent prior autologous transplant. Seven patients (58%) had Eastern cooperative oncology group performance status (ECOG-PS) of at least 2 at BLM initiation and half of the patients had AL Mayo stage of at least 3a. Most patients (10/12) received BLM as a single agent at 2.5mg/kg q3 weeks. The overall hematological response rate (ORR) to BLM was 75% (9/12), including 5 patients with complete response, 3 with very good partial response, and 1 with partial response (Figure 1). Detailed biomarker-based evaluation of organ responses was missing in many patients, yet, of 4 evaluable patients, 3 cardiac responses were observed. An additional patient had marked clinical improvement of heart failure. Four renal responses (out of 5 evaluable patients) and 2 hepatic responses (out of 2 evaluable) were also observed. With a median follow-up of 13.0 months (m) from initiation of BLM therapy (range 1.1-33.8m), the median EFS was 22.3m and the median OS was 28.8m. At data cutoff 6/12 (50%) were still on therapy, 9/12 patients (75%) were alive, all 3 deaths were due to heart disease. Seven patients (58%) had at least one grade 3 toxicity, included mostly infections/corneal toxicity. Apart from one event of grade 3 thrombocytopenia, there were no grade ≥3 hematological toxicities. No grade 4/5 toxicities were observed. Most patients (10/12, 83%) had corneal toxicity (6 patients- grade 1-2; 4 patients- grade 3), and dose reductions/delays were frequent (4/12 and 6/12, respectively). However, 7/10 patients with corneal toxicity improved overtime, no permanent visual disabilities were observed and only one patient stopped BLM due to keratopathy. Discussion: While BLM provides an ORR of 30-45% in triple-refractory MM patients, it might have a greater efficacy in AL patients. The ORR in our heavily pre-treated AL patients, as well as in other studies (2 small, retrospective + preliminary results of the EMN27 prospective study (Kastritis, EHA conference 2023) approached 60-83%, and the EFS was also encouraging. This difference may be attributed to the lower burden of disease in AL compared to MM. Alternatively, AL plasma cells may be more sensitive to BLM, in a mechanism that still merits further exploration. Corneal toxicity was similar to what was seen in MM, and overall manageable. Hematological toxicity was significantly milder than that observed in MM, probably related to the better marrow reserve in AL. Conclusions: BLM, being an off-the shelf immune therapy, with acceptable toxicity even in frail patients, can be a valuable option in AL, with a high ORR, and a signal for durable responses and high-quality organ responses in these patients.

Feasibility of a Novel Academic Anti-BCMA Chimeric Antigen Receptor T-Cell (CART) (HBI0101) for the Treatment of Relapsed and Refractory AL Amyloidosis

BACKGROUND: While anti-BCMA chimeric antigen receptor T-cell therapy (CART) have proven safe and efficient in multiple myeloma (MM), its application to AL amyloidosis (AL), has been restricted due to the frailty of this population and rarity of disease. HBI0101 therapy is a novel anti-BCMA CART-based therapy developed at Hadassah Medical Center and Bar-Ilan University for MM treatment. In a phase Ia-b/2 study (NCT04720313), HBI0101 has demonstrated manageable safety with therapeutic efficacy in over 70 MM patients. Although BCMA targeting in AL has been questioned because of relatively low expression of this antigen on AL plasma cells (PC), we have previously reported that this level of expression is sufficient to enable PC eradication by HBI0101 CART ex vivo. Based on this observation, we have treated 9 AL patients in our study, which represent the largest cohort of AL treated with anti-BCMA CART reported so far. METHODS: The patients were treated within the following cohorts: 1 received 150x10^6 CART cells, 2 received 450x10^6 CART cells and 6 received 800x10^6 CART cells. Two of the patients were treated on a compassionate basis due to concomitant myelodysplastic syndrome (MDS) / ECOG 4 performance status. Patients with creatinine clearance ≥30ml/min (n=7) received lymphodepletion with fludarabine 25mg/m 2 and cyclophosphamide 250mg/m 2 on days -5 to -3 before infusion, and patients with creatinine clearance <30ml/min (n=2) received lymphodepletion with bendamustine 90mg/m 2 and on days -4 and -3 before infusion. Two patients with NYHA stage 3 and MAYO stage 3b AL-related heart failure were admitted electively to the intensive care unit before infusion for close monitoring. RESULTS: Nine AL patients with relapsed/refractory disease were included, with a median of 6 prior lines of therapy (range: 3-10), all refractory to their last line of therapy. All patients were triple refractory to PI, IMiD and anti-CD38 antibody, 6 were penta-refractory and 5 were refractory to the anti-BCMA antibody drug conjugate belantamab mafodotin. Seven had cardiac involvement, including 4 with MAYO-stage 3a/3b at study entry. Hematologic adverse events included: grade 3-4 neutropenia in 5 patients, Grade 2-3 anemia in 3 patients, and worsening of pre-existing thrombocytopenia to grade 4 in 1 patient. Three patients developed AL-related organ deterioration (kidney- 2, heart- 1), subsequently resolved to baseline function. Cytokine-released syndrome (CRS) was observed in 7/9 (grade 1-2- 5 patients; grade 3- 2 patients). None of the patients developed immune effector cell-associated neurotoxicity syndrome (ICANs). There were no treatment-related deaths. Eight out of nine patients were evaluable for efficacy (one patient has not yet completed the first post-treatment evaluation). The overall hematological response rate was 100%, including complete responses in 5 patients, very good partial responses in 2, and partial response in 1 patient. Minimal residual disease (MRD) negativity based on flow cytometry 10^-5 was achieved in 5/8. Best hematological response was achieved after 17 to 57 days (median- 28.5 days). The hematologic responses translated into clinical improvement in all patients, whereas 6/8 met the official criteria for organ responses. With a median follow-up of 7.3 months (range: 2.5-16.5), the median duration of response thus far is 5m (range: 2.5-16.5). Updated results will be communicated at the presentation time. CONCLUSION: In the largest cohort of AL patients treated with CART reported to date, we demonstrated acceptable toxicity in this frail population, with a remarkable hematologic efficacy, leading to organ responses in most participants. Our data suggests that anti-BCMA CART modality may become a powerful clinical tool to improve organ function and survival, even in advanced AL patients.

Risk factors for severe infection and mortality In patients with COVID-19 in patients with multiple myeloma and AL amyloidosis.

Patients with multiple myeloma (MM) have a lower efficacy from COVID-19 vaccination and a high rate of mortality from COVID-19 in hospitalized patients. However, the overall rate and severity of COVID-19 infection in all settings (including non-hospitalized patients) and the independent impact of plasma cell-directed therapies on outcomes needs further study. We reviewed the medical records of 9225 patients with MM or AL amyloidosis (AL) seen at Mayo Clinic Rochester, Arizona, and Florida between 12/01/2019 and 8/31/2021 and identified 187 patients with a COVID-19 infection (n= 174 MM, n= 13 AL). The infection rate in our cohort was relatively low at 2% but one-fourth of the COVID-19 infections were severe. Nineteen (10%) patients required intensive care unit (ICU) admission and 5 (3%) patients required mechanical ventilation. The mortality rate among hospitalized patients with COVID-19 was 22% (16/72 patients). Among patients that were fully vaccinated at the time of infection (n= 12), two (17%) developed severe COVID-19 infection, without any COVID-related death. On multivariable analysis, treatment with CD38 antibody within 6months of COVID-19 infection [Risk ratio (RR) 3.6 (95% CI: 1.2, 10.5), p= .02], cardiac [RR 4.1 (95% CI: 1.3, 12.4), p= .014] or pulmonary comorbidities [RR 3.6 (95% CI 1.1, 11.6); p= .029] were independent predictors for ICU admission. Cardiac comorbidity [RR 2.6 (95% CI: 1.1, 6.5), p= .038] was an independent predictor of mortality whereas MM/AL in remission was associated with lower mortality [RR 0.4 (95% CI: 0.2-0.8); p= .008].

OAB-042: Targeting free light chain secretion via Botulinum Neurotoxin is a novel therapeutic strategy in AL amyloidosis by inducing a terminal unfolded protein response

<h3>Background</h3> AL amyloidosis (AL) is an incurable plasma cell (PC) disorder. The solely pathogenic mechanism in AL is deposition of immunoglobulin free light chains (FLC) organized in fibrils in target organs. Surprisingly, therapeutic strategies directly targeting FLC secretion are not available. SNARE proteins, which are the specific target of botulinum neurotoxin (BoNT), are involved in the docking and fusion of secretory vesicles. We hypothesized that certain BoNT serotypes may block FLC exocytosis, causing retention of FLC-loaded vesicles and triggering a terminal unfolded protein response (UPR). <h3>Methods</h3> Gene expression profiling in a cohort of 170 newly diagnosed multiple myeloma (MM) patients (IFM170) was used to interrogate SNAREs expression in malignant plasma cells. Western blotting (WB) was used to assess SNARE expression across MM and AL cell lines. We developed tetracycline inducible, lentiviral vectors expressing distinct BoNT serotypes (BoNT/A-F), T2A and GFP. Lentivirally transduced cells would express BoNT in a 1:1 stochiometric ratio with GFP, upon doxycycline (dox) administration, allowing for flow cytometry-based analysis. A vector comprising solely T2A and GFP was used as negative control. We transduced AL cell lines with Tet-On lentivirus expressing 7 distinct BoNTs and performed two sets of experiments. First, we performed time-course viability assays on polyclonally transduced cells and compared relative proportion of GFP+ cells over time. Then, we single-cell sorted transduced cells, triggered BoNT expression and assessed GFP kinetic and apoptosis via AnnexinV/DAPI flow cytometry at 24, 48 and 72 hours post dox. SNAREs cleavage following induction of BoNT expression was evaluated via WB in GFP+ clones. To assess if BoNT cytotoxicity correlated with cessation of FLC secretion, we performed a secretion assay in monoclones expressing distinct BoNTs. <h3>Results</h3> IFM170 GEP analysis showed VAMP2, VAMP3 and SNAP23 as the top expressed SNAREs. This was further confirmed in AL/MM cell lines. By using polyclonally transduced cells, we show that GFP+ cells are rapidly depleted over time after dox, across all serotypes, except BoNT/B, consistent with cytotoxic effect. Similarly, we observed rapid apoptosis in monoclones expressing any BoNT serotypes, except BoNT/B. We noted an association between SNAP23 and VAMP3 cleavage and BoNT toxicity, suggesting that dual targeting of SNAP23/VAMP3 may be necessary to mediate BoNT cytotoxicity. We next show that only BoNTs causing early cytotoxicity significantly inhibited FLC secretion. Cytotoxic BoNTs, activated PERK pathway with eIF2a phosphorylation (p-eIF2a); CHOP and GADD34 upregulation, presumably through FLC retention. <h3>Conclusions</h3> We show that cytotoxic BoNTs block FLC secretion, trigger a terminal UPR and induce apoptosis in AL and MM models. We provide proof of concept that targeting FLC secretion has a potential clinical translatability.

Therapeutic Strategies For Initial Treatment Of AL Amyloidosis: Implications Of Therapy and Response On Outcome

▪ BackgroundTreatment of AL amyloidosis (AL) has typically followed the treatment patterns used in myeloma, but has changed in a disease specific manner during the past few years with increasing use of Melphalan-Dexamethasone (MD) combination as well as bortezomib (Btz) and IMiD based regimens. It is not clear how the more recent approaches have impacted the outcome of patients with AL. MethodsWe reviewed the medical records of 555 patients with AL seen at Mayo Clinic between Jan 2004 and Dec 2010 and within 30 days of diagnosis. Details regarding the laboratory findings, treatments and response to therapy were extracted by a review of their medical records and from an existing database. We further grouped patients into two groups: those diagnosed during the initial half (Jan 2004 to June 2007) and those diagnosed after that (July 2007 to Dec 2010) to study time trends in survival and treatment patterns. ResultsThe median estimated follow up for the entire group was 67 months (95% CI; 59, 72) and 182 (33%) were alive at the time of analysis. The median age was 64 years (range; 32-95). The median overall survival (OS) for the entire cohort was 21 months and was nearly identical for the patients included in the two time groups; P=0.5. The 2-year mortality was 52% for both groups. The median OS was NR, NR, 24 mos. and 6 mos. respectively for patients in the revised Mayo stages 1, 2, 3, and 4. Treatment details/ follow up were either not available or no treatment was employed for 131 (24%) patients. The median OS for this group was 3 mos. compared with 36 mos. for the rest. The first line of therapy was alkylator based (mostly Mel-Dex) in 212 patients (51%), autologous transplant (SCT) in 99 (24%) patients, IMiD based in 37(9%), Btz based in 36 (9%) and steroid based in 29 (7%). Comparing the two time periods, the treatments were similar with the following exceptions: 32/36 patients receiving Btz based therapy were in the later group; and 26/29 patients treated with steroids alone were in the former group. A hematologic response could be determined in 275 (65%) patients; with the best response of CR (17%), VGPR (18%), PR (14%) and no response (17%). The median OS from diagnosis for these response categories were 99, 53, 27 and 12 mos respectively (p<0.01). A VGPR or CR was seen among 55%, 39%, 29%, 26% and 10% respectively in patients treated with SCT, Btz, Alkylators, IMiDs and steroids. The median OS from diagnosis was 99, 34, 25, 25, and 6 months respectively for patients treated with SCT, Btz, Alkylators, IMiDs and steroids, P<0.01 (Figure). The results were similar using a 4-month landmark to exclude patients who have not had adequate time to respond. Among the 146 patients evaluable for an NT-PRoBNP response, patients with a decrease of 30% had median OS that was not reached compared with 27 mos for those failing to achieve the response (4 month landmark). ConclusionThe current data form a more recent cohort of patients seen at a single referral institution serves to highlight the shift in the therapeutic approaches, with the increased use of Btz based combinations. The results confirm the prior observations of the impact of hematologic response depth and outcome as well as the effect of an NT-ProBNP response. While patients undergoing SCT have a better outcome, likely a result of the selection bias of excluding high-risk patients from SCT, the OS do not appear significantly different between patients receiving alkylator therapy, IMiD based therapy or Btz based therapy. The lack of difference may also reflect the relatively shorter follow up s well as the small numbers of patients in each group. [Display omitted] Disclosures:Kumar:Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding.

Cardiac Magnetic Resonance Predicting Outcomes Among Patients at Risk for Cardiac AL Amyloidosis.

Introduction: Patients with systemic AL amyloidosis (AL) should be evaluated for cardiac amyloidosis (CA), as prognosis is strongly related to cardiac involvement. We assessed the characteristics of patients referred to cardiac magnetic resonance (CMR) with suspected CA from a cancer center and determine predictors of mortality/heart failure hospitalizations (HFH).Methods: Forty-four consecutive patients referred for CMR with suspected CA were retrospectively included. Variables collected included cardiac biomarkers, in addition to echocardiographic and CMR variables. Survival analyses were performed to determine which variables were more predictive of mortality and HFH.Results: Of the 44 patients included, 55% were females. 73% of patients were diagnosed with CA by CMR; 56% of them had an established diagnosis of AL. Patients with CA by CMR had higher native T1, higher extracellular volume (ECV) fraction, higher T2, less negative GLS by Echo, and higher troponin I and B-type natriuretic peptide (BNP). Kaplan-Meier survival analysis revealed that the following were predictive of mortality: an ECV ≥ 0.50 (p = 0.0098), CMR LVEF < 50% (p = 0.0010), T2/ECV ≤ 100 (p = 0.0001), and troponin I > 0.03 (p = 0.0025). In a stepwise conditional Cox logistic regression model, the only variable predictive of a composite of mortality and HFH was ECV (HR: 1.17, 95% CI = 1.02–1.34 p = 0.030).Conclusion: ECV seems to be an important biomarker that could be a predictor of outcomes in cardiac AL amyloidosis. In combination, CMR and serum cardiac biomarkers might help to establish prognosis in patients with CA.

Prolonged Progression Free Survival and Time to Next Treatment Are Achievable Outcomes in Patients with Systemic AL Amyloidosis Treated with Novel Agent Chemotherapy: Analysis of the Alchemy Study

BackgroundSystemic AL amyloidosis (AL) is associated with an underlying plasma cell dyscrasia and caused by deposition of abnormally folded monoclonal immunoglobulin light chains. Novel chemotherapy has improved overall survival (OS) and haematological responses in recent years but little is known about durability of treatment response in this disease. In multiple myeloma, progression free survival (PFS) without ASCT is short. We report data on PFS and time to next treatment (TNT) in a predominantly non-ASCT population from the ALChemy study, a large prospective study of patients with AL.MethodsAll patients with newly diagnosed AL amyloidosis from January 2009 to March 2016 were included. All underwent serial organ function assessment, imaging and biomarkers. Organ involvement and responses were defined by international amyloidosis consensus criteria. Survival was calculated by Kaplan-Meier analysis. All outcomes are reported on an intention-to-treat (ITT) basis (patients who died before response assessment were assessed as non-responders). Progression free survival (PFS) was defined as time to death or progression to next line of chemotherapy. Time to next treatment (TNT) was defined as time from the beginning of first line therapy to the next line.Results1203 patients were recruited. Median age was 66.3 years (29.5-89.4), M:F 58%:42%, median NT-proBNP was 1974ng/L and median dFLC was 181.7mg/L. 62 patients (5.2%) died before treatment initiation. Treatments were: bortezomib-based regimen (mainly CyBorD) - 57.6%, immunomodulatory (IMID)-based (mainly CTD) - 32.4%, oral melphalan-dexamethasone - 5%, rituximab-based regimen - 3.2%, upfront ASCT - 1.3%, other - 0.5%. Median number of chemotherapy cycles was 5. Overall haematological response (FLC and M-protein response) at 6 months on an ITT basis (n=1037) was: CR 17.6%, VGPR 15.3%, PR 17.7% and non-response 49.4%. On an evaluable basis, overall haematological response at 6 months (n=723) was: CR 25.3%, VGPR 22%, PR 27.1% and non-response 25.6%.260 patients (21.6%) died within 6 months of diagnosis. Median OS was 47 months. Median PFS and TNT of the whole cohort was 17 months and 54 months respectively (Fig 1a and 1b). Median TNT in Mayo Stage 1, 2, 3A and 3B was 44, 46, 48 months and not reached (no second line treatment by 5 years = 54%), (p=0.63). Median PFS in Mayo Stage 1, 2, 3A and 3B was 34, 26, 14 and 4 months respectively (p<0.001).Median OS was not reached in patients who achieved an overall PR, VGPR or CR at 6 months, compared to median OS of 8 months in non-responders (p<0.001). Median PFS in patients who achieved an overall CR, VGPR, PR or non response at 6 months was: not reached (5 year PFS = 77%), 54 months, 20 months and 5 months respectively (p<0.001) (Fig. 1c). Median TNT in patients in overall CR, VGPR, PR or non response at 6 months was as follows: not reached (66% at 5 yrs), not reached (55% at 5 yrs), 26 months and 15 months (p<0.001) (Fig. 1d).Median OS in patients treated with bortezomib, IMID and melphalan was: 83 months, 55 months and 42 months respectively (p=0.11). Median OS in Stage 3 patients treated with bortezomib and IMID was 38 and 12 months respectively (p=0.001). Median PFS in patients treated with bortezomib, IMID and melphalan was: 21, 15 and 14 months (p=0.04). Among patients with stage 3 disease, median PFS in patients treated with bortezomib and IMID was 15 and 7 months respectively (p<0.001). Median TNT in patients treated with bortezomib, IMID and melphalan was: not reached (no second line by 5 years = 57%), 32 and 26 months (p=0.001). Among Stage 3 patients, median TNT in patients treated with bortezomib and IMID therapy was not reached (no second line by 5 years = 63%) and 28 months respectively (p<0.001).ConclusionThese prospectively collected data from a real world setting report on progression free survival and time to next treatment in AL with predominant non-transplant novel agent based regimens, which has thus far been lacking. Patients treated with bortezomib based therapy had superior PFS, TNT and OS. Median TNT was 4.5 years. Strikingly, PFS and TNT were remarkably long in patients achieving a complete haematological response (PFS 77% at 5 years) - akin to those previously reported in patients treated with upfront ASCT and perhaps raising questions about the role of upfront ASCT. These data confirm the efficacy of bortezomib based regimens in AL amyloidosis and the value of CR as the goal of induction therapy in this disease. [Display omitted] DisclosuresWechalekar:Celgene: Honoraria; Janssen: Honoraria.

Pharmacokinetics and Toxicities after Evomela® (propylene glycol free melphalan) with Autologous Hematopoietic Stem Cell Transplant (AHCT) for Multiple Myeloma and AL Amyloidosis

Background: Melphalan exposure as measured by area under the curve (AUC) has a 5-fold variability between patients, with higher AUCs associated with improved outcomes but increased toxicity (Shaw BBMT 2012). Propylene glycol free melphalan (Evomela®, PGF-MEL) is an intravenous formulation with improved stability and possibly less toxicity related to the solubilizing agent. We have switched to PGF-MEL as conditioning prior to AHCT for multiple myeloma (MM) and AL amyloidosis (AL) and aimed to determine the pharmacokinetics (PK) and relationship between exposure and toxicities with this formulation in order to optimize dosing and personalize care in the future.Methods: Serum samples were prospectively drawn at 5, 15, 30, 40, 75, and 150 min after administration of PGF-MEL given as a single dose on day -2 prior to AHCT. We calculated the MEL concentration in each sample using liquid chromatography tandem mass spectrometry, and AUC PK modeling was done with Phoenix WinNonlin v6.4. Toxicities were retrospectively collected using CTCAE v4 through day +100 after AHCT and compared by using either a T-test or Fisher's exact test between patients above and below the median AUC, 1st MEL level, and 6th MEL level.Results: Twenty-two patients (19 MM, 3 AL) with 68% male, median age 57yr (range 40-75), median creatinine 0.85mg/dL (range 0.6-2.9), median albumin 3.9g/dL (range 2.4-4.6), median weight 85.7kg (range 55-114kg), median body surface area 2.03 (range 1.6-2.3), received PGF-Mel at 140 (14%) or 200mg/m2 (86%). Median PGF-MEL AUC, 1st MEL level, and 6th MEL level were 12.35mg/L*h (range 6.9-15.6, Figure 1), 9750 ng/mL (range 5645-25000), and 1045 ng/mL (546-1566), respectively. Baseline characteristics and lab values were not statistically significant between patients with AUC above and below the median. Neutrophil engraftment occurred at a median of 10 (range 8-10) vs 9 (range 8-11) days post AHCT and length of stay was 16 (range 14-30) vs 16 (13-19) days for patients with AUC above and below the median, respectively. The median total number of unique grade ≥3 toxicities up to day 100 was 3 (range 0-9) vs 1 (1-6). Cardiovascular, infectious, metabolic, oral/gastrointestinal (GI), pulmonary, renal, and skin toxicities were seen in 36 vs 45% (p=.99), 45 vs 27% (p=0.66), 45 vs 36% (p=0.99), 55 vs 55% (0.99), 0 vs 9% (0.99), 9 vs 0% (0.99), and 55 vs 9% (p=0.06), for patients with above and below the median AUC. More patients had fevers (45 vs 18%), ≥500ml of diarrhea per day (64 vs 36%), grade ≥3 mucositis (27 vs 9%), and need for patient controlled analgesia (18 vs 9%), but these were not statistically significantly different between the groups (Table 1). As a surrogate for fluid overload, we measured the % weight change at discharge from the AHCT admission. Most patients lost weight with a median weight change of 1.4% (range 0-18.3%) vs 1.2% (range 0-9%) in those above and below median AUC, respectively. Engraftment syndrome occurred in 50% of patients overall (55% above vs 45% below median AUC). Comparisons above and below median 1st and 6th MEL levels were also not statistically significant. No patients progressed or died during the 100 day follow-up.Conclusion: In this study, PGF-MEL had less variability in AUC than previously published for PG-MEL. Baseline characteristics were not different between patients with higher or lower MEL exposure. Toxicities occurred more frequently in patients with higher than the median AUC, but these differences were not statistically significant, likely due to the small number of patients. Longer follow-up is needed to assess disease response and outcomes. Ongoing assessment may identify optimal dosing and allow for personalization of therapy and better quality of life during the AHCT process. Additional patients with longer follow-up will be presented at the meeting. [Display omitted] DisclosuresLandau:Spectrum Pharmaceuticals: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board; Karyopharm: Consultancy; Pfizer: Honoraria; Takeda: Research Funding; Amgen: Research Funding; Janssen: Honoraria. Koehne:Atara: Consultancy, Patents & Royalties.

Feasibility, Tolerability, and Patient-Reported Outcomes with Pharmacokinetic (PK)-Directed Dosing of Evomela® (propylene glycol free melphalan) for Multiple Myeloma and AL Amyloidosis Patients Undergoing Autologous Hematopoietic Stem Cell Transplant (AHCT)

Background: For multiple myeloma (MM) and AL amyloidosis (AL) patients undergoing autologous hematopoietic stem cell transplant (AHCT), high-dose melphalan is given at a fixed dose based on body surface area with five-fold inter-patient variability in exposure, as measured by area under the curve (AUC). Patients with higher than the median AUC (12.85mg/L*h) have prolonged survival, but increased toxicity (Shaw et al., BBMT 2012). Pharmacokinetically (PK)-directed dosing has the potential to achieve an optimal concentration in each patient. We prospectively evaluated the feasibility of PK-directed dosing of propylene glycol free melphalan (Evomela®, PGF-MEL), a more stable and possibly less toxic intravenous formulation of melphalan, to personalize therapy for maximum efficacy and tolerability.Methods: MM and AL patients age 18-75 received a 10mg/m2 test dose of PGF-MEL within 14 days of AHCT. Serum samples were drawn at 5, 15, 30, 40, 75, and 150 min after PGF-MEL administration. Liquid chromatography tandem mass spectrometry was used to measure MEL concentrations. AUC PK modeling with Phoenix WinNonlin v6.4 was used to determine a target dose to achieve an AUC of 13.5mg/L*h (+/-1), which was given on day -2 prior to AHCT. PK samples were collected after the target dose at the same time points as after the test dose. AHCT with 3-10 x10^6 CD34+ cells/kg was conducted per institutional guidelines. Patient-reported symptom burden was collected prospectively using the MD Anderson Symptom Inventory - MM (MDASI-MM) on day +1, 6, 11, 30, 60, and 90. Toxicities were collected by chart review through day +100 after AHCT and compared using either a T-test or Fisher's exact test between patients above and below AUC 14.5 mg/L*h.Results: Ten patients (7 MM, 3 AL) with 50% male, median age 67yr (range 53-74), and median body surface area 1.95 (range 1.56-2.35) had a median of 4.5 days (range 1-24) between the test and target doses of PGF-MEL. Target doses were calculated for 90% of patients and 70% received the calculated dose. The reasons for not administering the calculated dose were inability to calculate a test dose AUC (N=1), toxicity after the test dose (N=1), and target dose outside study safety parameters (N=1). Median test and target dose AUCs were 0.655 (range 0.447-0.869) and 15.65mg/L*h (range 10.1-17.2, Figure 1), respectively. No patients receiving the calculated target dose had an AUC within the goal range. MDASI-MM AUCs were calculated for fatigue, pain, sleep, appetite, drowsiness, and the average of these 5 symptoms. Overall, higher scores were seen in patients with MEL AUCs above 14.5mg/L*h compared with below (Figure 2). More patients with higher AUCs had fevers (83 vs 50%), ≥500ml of diarrhea per day (83 vs 75%), grade ≥3 mucositis (50 vs 25%), and need for patient-controlled analgesia (33 vs 25%), but these were not statistically significantly different between the groups (Table 1). Neutrophil engraftment occurred at a median of 10 (range 9-11) days post AHCT in both groups; patients with AUCs above 14.5mg/L*h required more pRBC and platelet transfusions. With a median follow-up of 217 days (range 179-250) in surviving patients, no patients progressed, and one AL patient died of failure to thrive at 134 days post AHCT.Conclusion: Collection of PK levels and calculation of a target dose was feasible. However, using a 10mg/m2 test dose we did not achieve the target AUC in our patients. This could be due to the small test dose which may have been insufficient to saturate the two-compartment model, rendering the PK analysis inaccurate. Patients with higher AUCs required more transfusions, had more toxicities, and had prolonged patient-reported symptom burden. Due to the small number of patients, these differences were not statistically significant, but suggest there may be an ideal concentration to minimize toxicity and maximize efficacy. Disease response and outcome data continue to be collected. Further study is needed to determine the optimum test dose and schedule, and modifications to the schema are ongoing. [Display omitted] DisclosuresKoehne:Atara: Consultancy, Patents & Royalties. Landau:Janssen: Honoraria; Takeda: Research Funding; Spectrum Pharmaceuticals: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board; Pfizer: Honoraria; Karyopharm: Consultancy; Amgen: Research Funding.

Identifying Clinical Gaps in the Diagnosis, Monitoring, and Management of Immunoglobulin Light Chain (AL) Amyloidosis Among Hematologist/Oncologists

Background: AL amyloidosis (AL) remains an incurable and devastating disease that is often misdiagnosed or diagnosed late. Keys to better long-term outcomes include early diagnosis, multispecialty collaboration, and effective interventions; however, it is unclear how prepared clinicians are to manage AL. A study was undertaken to assess hematologists/oncologists (hem/onc) ability to diagnose, monitor, refer, and manage patients with AL.Methods: An incentivized survey was developed utilizing current evidence-base and best practices in AL. The assessment included both multiple choice and free form text questions that clinicians completed confidentially on-line starting on May 10, 2017. The survey continues to recruit participants. Thirteen questions were asked regarding diagnosis, education interests, referral approaches, monitoring, and treatment of patients with AL.Results: As of July 2017, 51 hem/oncs participated in the assessment: 47% were from private/group practice, 27% local/community, and 25% from the academic setting. 88% of respondents work with other specialists to manage AL, which included nephrologists, cardiologists and neurologists (84%, 80%, and 42%, respectively). The number of patients with AL seen by study participants each year was: 0 (10%), 1-3 (31%), 4-7 (37%), 8-12 (18%), and > 12 (4%). After diagnosing AL, the majority (76%) of respondents would manage the patient at their clinic. Selection of therapy varied on patient presentation. At diagnosis, the majority selected bortezomib-based therapy in patients with cardiac or renal involvement (33% and 49%, respectively); however, in patients with neuropathy, hem/oncs chose a variety of therapies. In patients with AL after relapse on bortezomib therapy, the majority selected autologous stem cell transplant (ASCT) (27%). In a patient that relapsed after ASCT, the majority selected daratumumab-based therapy or clinical trial (29% or 24%, respectively) (Table 1). Respondents' primary goals of therapy included: improvement in overall survival (78%), improving quality of life (67%), organ response (65%), hematologic response (24%), and minimizing therapy side effects (18%). When asked about which biomarkers they follow, respondents chose free light chains (86%), proteinuria (67%), B-Natriuretic Peptide (BNP) (47%), N-terminal pro-brain BNP (NT-proBNP) (45%), and troponins (37%). Clinicians also expressed interest in education on a variety of emerging therapies including NE0D001 (55%), daratumumab (51%), GSK2398852, CAEL101 (41%), and izaxomib (41%). The top education needs cited were awareness/understanding of current treatment options (47%), emerging therapies (45%), diagnosis (37%), clinical trials (35%), and assessing organ response (31%). Finally, the respondents indicated that the top three unmet needs in diagnosing and caring for patients with AL included education on treatment options, differential diagnosis, and managing therapy side effects.Conclusions: AL is a complex disorder that requires a high clinical acumen to diagnose and manage. This research identified that apart from consensus to use a bortezomib-based regimen, there is significant heterogeneity in selection of therapies. Biomarker use for monitoring is inconsistent, especially for NT-proBNP. Although referral to specialists are critical to care, such referrals are variable. The lack of approved therapies for AL and an absence of consensus treatment guidelines may be contributing to the disparate treatment approaches. Education to increase awareness of clinical gaps of hem/oncs as well as development of consensus guidelines that address referral, biomarkers and therapeutic options are needed.Table 1. Treatment Selection in AL after ASCT Relapse [Display omitted] DisclosuresGertz:Celgene, Novartis, Smith-Kline, Prothena, Ionis, Amgen: Honoraria; Millennium: Consultancy, Honoraria.

Safety and Efficacy of Deferred Autologous Stem Cell Transplantation in Patients with Systemic AL Amyloidosis with Significant Cardiac Involvement at Presentation

Safety and Efficacy of Deferred Autologous Stem Cell Transplantation in Patients with Systemic AL Amyloidosis with Significant Cardiac Involvement at Presentation

Rain (Renal AL Amyloid Involvement And NEOD001): A Multicenter, Randomized, Phase 2b Study of NEOD001 in Previously Treated Subjects With Systemic AL Amyloidosis and Persistent Renal Involvement

Background: Systemic AL amyloidosis (AL) is a rare disease in which clonal plasma cells produce misfolded light chains that deposit in vital structures such as the heart and kidneys leading to progressive organ failure. Despite the achievement of hematologic responses, organ improvement is not assured. NEOD001 is a humanized monoclonal antibody that targets the abnormal light chains, promoting clearance of amyloid fibrils. Patients and Methods: Tufts Medical Center is sponsoring the RAIN trial: a randomized, placebo-controlled, phase 2b efficacy and safety study evaluating single agent NEOD001 versus placebo in patients with systemic AL amyloidosis who have achieved a stable hematologic response to prior therapy but still exhibit persistent kidney disease (> 500 mg of protein daily). Nine centers of excellence will participate across the country. NEOD001 (24mg/kg) or placebo will be administered every 28 days for 12 months. In an expansion phase, subjects will have the choice to receive active treatment with NEOD001 for an additional 12 months. We plan to randomize 100 subjects, 50 in each arm. The primary endpoint is achievement of a renal response defined as a > 30% reduction in proteinuria in the absence of a > 25% reduction in eGFR. Secondary endpoints include time to CKD 4 or 5, to eGFR < 15 mL/min/1.73 m2 or dialysis, to doubling of creatinine and to > 40% reduction in eGFR. Ancillary studies will focus on patient-reported outcomes and on histologic and molecular assessments using pre-treatment renal biopsies that may identify predictors of renal outcome. We anticipate the first patient will be enrolled in early July 2017. [Display omitted] DisclosuresDispenzieri:Celgene, Millenium, Pfizer, Janssen: Research Funding. Gertz:Millennium: Consultancy, Honoraria; Celgene, Novartis, Smith-Kline, Prothena, Ionis, Amgen: Honoraria. Landau:Celgene: Other: Advisory Board; Takeda: Research Funding; Spectrum Pharmaceuticals: Other: Advisory Board, Research Funding; Janssen: Honoraria; Amgen: Research Funding; Pfizer: Honoraria; Karyopharm: Consultancy. Leung:Prothena: Consultancy. Mikhael:Sanofie: Research Funding; Celgene: Research Funding; Abvvie: Research Funding. Weiss:Prothena: Honoraria; Janssen: Honoraria; Prothena: Research Funding; Alnylam: Honoraria; Janssen: Research Funding. Zonder:Celgene: Research Funding; Takeda: Other: Travel grant; Bristol-Myers Squibb: Research Funding. Comenzo:Prothena: Other: Scientific advisor; Janssen: Other: Scientific Advisor; Karyopharm: Research Funding; Janssen: Research Funding; Prothena: Research Funding.

Cyclophosphamide, Bortezomib and Methylprednisolone (CyBorMe) for the Treatment of AL Amyloidosis: Initial Experience From a Single Center.

The use of cyclophosphamide, bortezomib and dexamethasone (CyBorD) is widely accepted in the treatment of AL amyloidosis (AL). Recently, the substitution of dexamethasone by methylprednisolone (CyBorMe) appeared to improve response rates and survival outcomes. All consecutive newly diagnosed AL amyloidosis treated with CyBorMe from 01/19 to 08/20 were evaluated. A historic cohort of patients treated with CyBorD was used for comparison (01/13-08/20). Methylprednisolone was given IV at 500mg weekly for 4weeks in the CyBorMe group. 43 patients were treated with CyBorD and 14 with CyBorMe. After a median of 4 cycles of CyBorD and 3 cycles of CyBorMe, Hematological Response was seen in 90.6% and 92.8% of cases, including CR in 28.5% and 35.7%, VGPR in 33.3% and 35.7% and PR in 30.9% and 21.4% for CyBorD and CyBorMe, respectively. Time to first response was faster in the CyBorMe group (4 vs. 6weeks) and cardiac response was observed in 44% and 31% of patients treated with CyBorMe and CyBorD, respectively. CyBorMe appeared to be efficacious and well tolerated in patients with AL amyloidosis. Prospective studies with CyBorMe in the stage III/IV group are warranted aiming to minimize toxicity.

Serum Hevylite® assay in the differential diagnosis of patients with high suspicion of AL Amyloidosis.

AL amyloidosis (AL) is a malignant form of plasma cell dyscrasia (PCD). It is insidious, and its end-organ damage can mimic that of common diseases. At diagnosis, routine tests for monoclonal protein are insufficient for the differential diagnosis. We hypothesized that Hevylite® (HLC) isotype patterns may help discriminate between AL and benign PCD states. Serum samples of patients with a high clinical suspicion of AL were prospectively tested for IgGκ, IgGλ, IgAκ, IgAλ, IgMκ, and IgMλ concentrations and ratios using Hevylite® assays in a blinded manner. The results were correlated with the final diagnosis. Of the 99 samples analyzed, 46 were newly diagnosed AL, and the majority, 38 (82.6%), presented with suppression of at least one HLC isotype. Of the 53 benign PCD patients, 36 (67.9%) presented with elevation of at least one HLC isotype. By multivariate analysis, Hevylite® was the best independent test predictor of AL amyloidosis. HLC suppression had an odds ratio (OR) of 14.591, and elevation an OR of 10.149, and thus were significant variables in the diagnosis and exclusion of AL. Furthermore, patients with both HLC suppression, together with no elevation, had an OR of 316.69 to be diagnosed with AL rather than a benign PCD. Hevylite® HLC analysis for Ig isotypes patterns offers an effective non-invasive tool in the evaluation of patients with high suspicion of AL and may assist further explorative decisions for diagnosis.