AL Amyloidosis Amyloidosis Research Articles

Safety, Tolerability and Efficacy of Cael-101 in AL Amyloidosis Patients Treated on a Phase 2, Open-Label, Dose Selection Study to Evaluate the Safety and Tolerability of Cael-101 in Patients with AL Amyloidosis

Background: CAEL-101 is an AL amyloid fibril reactive IgG1 monoclonal antibody with potential for therapeutic immune clearance of AL amyloid deposits in AL amyloidosis (AL) patients. Phase I study of CAEL-101 did not identify any significant toxicity at doses up to 500 mg/m2 IV dosed weekly for 4 weeks as a single agent. Organ responses occurred in a majority of patients. The primary objective for this current dose escalation study (NCT04304144) is to provide a recommended phase III dose of CAEL-101 when given in combination with bortezomib, cyclophosphamide, and dexamethasone (CyBorD) for a planned randomized study in Mayo stage IIIa and IIIb AL patients. Methods: 13 AL patients (7 heart, 3 kidney, 3 both) were enrolled in a 3+3 dose escalation safety study allowing for an additional patient in each cohort if available. Five heart patients were Mayo stage IIIa with the remaining 5 Mayo stage II. Cohort 1 (n=4), 2 (n=3), and 3 (n=6) received CAEL-101 IV at 500 mg/m2, 750 mg/m2 and 1000 mg/m2 respectively over 2 hours, all weekly for 4 weeks then every other week for the remainder of the study. Premedication with diphenhydramine 25 mg po and acetaminophen 1 gram po were given 30 minutes prior to each CAEL-101 infusion. Pharmacokinetic and anti-drug antibody data will be reported separately. All patients were treated with CyBorD weekly, 3 of 5 weeks in the first cycle to align treatments with CAEL-101 and then 3 of 4 weeks for up to 6 cycles. Patients were permitted to receive up to 3 cycles of CyBorD immediately prior to enrollment. Only 3 of the 13 patients had hematologic measurable disease at enrollment. Hematologic and organ response data on assessable patients were evaluated per consensus criteria. Results: With the longest follow up of 91 days and all 13 patients receiving at least 4 doses of CAEL-101, no dose limiting toxicity has been seen with 6 patients dosed at the maximum planned 1000 mg/m2 dose. No infusion reactions occurred. Three significant adverse events occurred. One patient developed recurrent atrial fibrillation without rapid ventricular response at the 500 mg/m2 dose level not attributed to CAEL-101. Two other patients dosed at 1000 mg/m2 were hospitalized with Clostridium difficile colitis and enlarging pleural effusion not attributed to CAEL-101. Of the 3 patients with hematologic measurable disease, there have been 2 PR, and 1 that is too early to evaluate. One patient with PR had a response plateau after cycle 2 of CAEL and is the only patient off study due to need for change in anti-plasma cell therapy. Of the 7 patients currently evaluable for organ response, 2 have met organ response criteria in the 500 mg/m2 cohort (1 heart by NT pro BNP and 1 kidney by 24 hour urine protein). There is ongoing monitoring of organ responses and updated data will be presented at the meeting. Conclusions: CAEL-101 dosed at 1000 mg/m2 is the recommended phase 3 dose in combination with CyBorD for upcoming randomized, double blind, phase 3 trials. Hematologic responses do not seem to be affected by concurrent use of CAEL-101 with CyBorD. Organ responses have occurred early in the course of therapy and are expected to increase over time, particularly after completion of chemotherapy and dexamethasone. Longer follow up, the ongoing exposure to CAEL-101 after the conclusion of chemotherapy and planned phase III trials will provide more data on organ response, quality of life and survival. Disclosures Khouri: Sanofi Genzyme: Other: Advisory Board. Anwer:Astellas Pharma: Research Funding; AbbVie Pharmaceuticals: Research Funding; Seattle Genetics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Acetylon Pharmaceuticals: Research Funding; Celgene: Research Funding; Millennium Pharmaceuticals: Research Funding; Incyte Pharmaceuticals: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau. Sobolov:Caelum Biosciences: Current Employment, Current equity holder in private company. Jobes:Caelum Biosciences: Current Employment, Current equity holder in private company. Daniel:Caelum Biosciences: Current Employment, Current equity holder in private company. Spector:Caelum Biosciences: Current Employment, Current equity holder in private company. Valent:Amgen Inc.: Other: Teaching, Speakers Bureau; Takeda Pharmaceuticals: Other: Teaching, Speakers Bureau; Celgene: Other: Teaching, Speakers Bureau. OffLabel Disclosure: CAEL-101 is a monoclonal antibody directed against amyloid fibrils not yet FDA approved.

Diabetes Mellitus and Risk of Plasma Cell and Lymphoproliferative Disorders: A Population Based Study Including 94,579 Cases and 368,348 Matched Controls

Diabetes Mellitus and Risk of Plasma Cell and Lymphoproliferative Disorders: A Population Based Study Including 94,579 Cases and 368,348 Matched Controls

Hematopoietic Progenitor Cell Mobilization and Collection for Autologous Hematopoietic Cell Transplantation in AL Amyloidosis: A Single Center Experience

Hematopoietic Progenitor Cell Mobilization and Collection for Autologous Hematopoietic Cell Transplantation in AL Amyloidosis: A Single Center Experience

Impact of doxycycline on outcomes in AL amyloidosis.

e20568 Background: It has been shown in mouse models doxycycline(Doxy) interferes with amyloid fibril formation. Retrospective data suggests the addition of Doxy to standard chemotherapy(chemo) reduces mortality in cardiac amyloidosis. We examined the relationship between Doxy use, treatment, and OS in a cohort of AL Amyloidosis(AL) within an academic center. Methods: AL pts between 2008 and 2020 at Moffitt Cancer Center. For this study we included patients with AL, with all types of organ involvement. We excluded pts with non-AL Amyloidosis and pts with localized amyloidosis were excluded. Data on organ involved, organ response, date of death, treatment were obtained for each pt. OS was defined as time from AL diagnosis to date of death. Univariate comparisons were performed to identify differences in treatment and other prognostic variables between Doxy groups, where appropriate (Table). Results: 209 pts that met inclusion criteria, 13 pts(6%) had cardiac involvement with AL. Of those 13 pts, only 3 pts(23%) received Doxy in addition to standard of care chemo. For this study, we included all types of AL for total 209 pts. Of the 209 pts, 9.5% received Doxy in addition to standard of care chemo and 90.5% pts did not receive Doxy and had chemo alone. Pts who received Doxy had more proteinuria (suggesting more significant renal involvement) but other characteristics were not statistically different including cardiac biomarkers (table). A numerically higher rate of organ response (67% versus 43%) was noted in patients who received Doxy but this didn’t reach statistical significance. Further the OS was numerically higher for Doxy treated pts however again this didn’t meet statistical significance. Conclusions: We noted higher organ responses and overall survival in Doxy treated pts, we could not identify statistical differences in outcomes possibly because of the sample size. Nevertheless, further follow up is warranted and Doxy may be associated with improved outcomes in AL. [Table: see text]

Ixazomib-dexamethasone (Ixa-Dex) vs physician’s choice (PC) in relapsed/refractory (RR) primary systemic AL amyloidosis (AL) patients (pts) by prior proteasome inhibitor (PI) exposure in the phase III TOURMALINE-AL1 trial.

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]

AL Amyloidosis: The Prognostic Impact of Maintenance Therapy Following ASCT

Introduction Autologous stem cell transplantation (ASCT) remains an effective treatment option for many patients with systemic AL amyloidosis (AL). However, the decision to utilize maintenance therapy following ASCT remains controversial and largely unexplored. Furthermore, the growing relevance of cytogenetics in AL may help dictate this maintenance decision as well. It is also relevant to note the emergence of novel targeted therapy options for AL patients, including the plasma cell monoclonal antibody daratumumab, that offer an exciting option in combination therapies with ASCT. As such, the present study aims to a) determine the prognostic significance of utilizing maintenance therapy following ASCT b) assess the potential impact of cytogenetics on this decision, and c) present novel data on the survival benefits of daratumumab-treated patients who have undergone ASCT. Methods A retrospective chart review was performed on 50 consecutive AL patients who underwent ASCT at The Ohio State University. Patients received high dose Melphalan (140 or 200 mg/m2) prior to ASCT. Patients were divided into subgroups based on FISH, and whether or not they had received maintenance therapy following transplant. Primary endpoints were progression free survival (PFS) and overall survival (OS), both estimated via the Kaplan-Meier survival function. The log-rank test was used to test the equality of survivor functions between different groups of patients. Results Twenty-eight patients (56%) received maintenance and 22 (44%) did not. There was no difference in age, dose of melphalan used, disease stage and number of organs involved between the two groups. There was no statistically significant difference in OS (p=0.32) and PFS (p=0.66) between patients who received maintenance versus those patients who did not receive maintenance (Figure 1A). Among patients with abnormal FISH, there was no difference in survival between the two groups (OS-p=0.65; PFS-p=0.15) (Figure 1B). Patients with three or more organs with AL involvement had worse OS/PFS versus those with 2 or less (OS-p=0.001; PFS-p=0.015). However, among these patients with 2 or more organs involved, the decision to utilize maintenance vs not showed no difference in PFS/OS. Lastly, further evaluation of a subset of patients treated with daratumumab showed no difference in outcome whether or not they underwent ASCT or consolidation. Conclusion In this small retrospective analysis, maintenance therapy post ASCT had no impact on the PFS or OS of patients with AL, even when further stratified based on degree of organ involvement. Survival was also not affected by cytogenetic abnormalities or with addition of novel monoclonal-targeted therapies. It is clear that a larger prospective study is needed to assess the benefit of maintenance post ASCT in AL amyloid patients.

Dual Monoclonal Antibody Therapy in Patients With Systemic AL Amyloidosis and Cardiac Involvement

BackgroundSystemic AL amyloidosis (AL) is a rare disease in which clonal immunoglobulin light chains produced by monoclonal plasma cells circulate and misfold, resulting in direct toxicity and fibrillar deposition of amyloid in numerous tissues. Early mortality from cardiac damage remains high. As depth of organ response carries a prognostic significance, combining anti-plasma cell and anti-amyloid therapies might hold the key to achieving long lasting responses. We report a series of patients who received 2 monoclonal antibodies, anti-CD38 and anti-amyloid, simultaneously. Materials and MethodsWe describe the characteristics and outcomes of 19 patients who received daratumumab (anti-CD38) on progression with front-line therapy for AL, 9 of whom were on concurrent dual monoclonal antibody treatment with daratumumab and NEOD001 (anti-amyloid), and also provide data on the schedule, safety, and tolerability of intravenous infusions of these monoclonal antibodies. ResultsThe 9 patients who received treatment with dual monoclonal antibodies achieved a high rate (100%) of hematologic response in a median of 33 days. There was no significant toxicity to dual monoclonal antibody therapy. Seven of the 8 met criteria for cardiac response, achieved in less than 3 months of combined therapy. Ten patients who received daratumumab alone also had high rates of hematologic and organ responses. ConclusionsMonoclonal antibodies with distinctly different targets can be safely combined in patients with AL and cardiac involvement. Patients experienced high rates of hematologic and cardiac response with combined anti-CD38 and anti-amyloid monoclonal antibody therapies. Further study of this combined approach is warranted.

AL Amyloidosis: The Effects of Maintenance Therapy on Autologous Stem Cell Transplantation Outcomes

Introduction: Autologous stem cell transplantation (ASCT) remains an effective treatment option for many patients with systemic AL amyloidosis (AL). However, the decision to utilize maintenance therapy following ASCT remains controversial and largely unexplored. Studies have shown the benefit of post-ASCT maintenance therapy in multiple myeloma (MM) with lenalidomide, but to date, no study has evaluated maintenance in AL patients following ASCT. Furthermore, the growing relevance of cytogenetics in AL may help dictate the incorporation of maintenance therapy as well. It is also relevant to note the emergence of novel targeted therapy options for AL patients, including the plasma cell monoclonal antibody daratumumab, that could be a valuable addition to combination therapies. As such, the present study aims to a) determine the prognostic significance of utilizing maintenance therapy following ASCT b) assess the potential role of cytogenetics on the efficacy of maintenance treatment, and c) investigate the outcomes of daratumumab-treated patients who have undergone ASCT. Methods: A retrospective chart review was performed on 50 consecutive AL patients treated at The Ohio State University who underwent ASCT. Patients received high dose Melphalan (140 or 200 mg/m2) prior to ASCT. Patients were divided into subgroups based on FISH data obtained within 90 days of diagnosis, as well as whether or not they had received maintenance therapy following transplant, which was defined as therapy greater than six months following ASCT. Patients' characteristics were summarized using medians and ranges, or frequencies and percentages, and compared using Mann-Whitney rank sum test or fisher exact test. Primary endpoints were progression free survival (PFS) and overall survival (OS), per updated NCCN guidelines, including both organ and hematologic criteria. PFS was defined as the time from date of transplant to day of progression or death from any cause. OS was defined as the time from date of transplant to death from any cause, with censoring those who were still alive at the last follow up. Kaplan-Meier survival function was used to estimate the PFS and OS. The log-rank test was used to test the equality of survivor functions between different groups of patients. Results: Twenty-eight patients (56%) received maintenance and 22 (44%) did not. Majority of patients received lenalidomide maintenance. The median age at transplant was 58 (range 33-71) years, with 66% male. There was no difference in age, dose of melphalan used, disease stage and number of organs involved between the two groups. There was no statistically significant difference in OS (p=0.32) and PFS (p=0.66) between patients who received maintenance versus those patients who did not receive maintenance (Figure 1A). Among patients with abnormal FISH, there was no difference in survival between these two groups as well (OS: p=0.65; PFS: p=0.15) (Figure 1B). Finally, we tested the efficacy of daratumumab in combination therapy with ASCT in a small patient subset. There was no difference in OS or PFS among patients who underwent ASCT for consolidation, whether or not they received daratumumab. Conclusion: In this small retrospective analysis, maintenance therapy post ASCT had no impact on the PFS or OS of patients with AL. Furthermore, survival was not affected by maintenance in patients with cytogenetic abnormalities or addition of novel monoclonal antibodies. A larger prospective study is needed to assess the benefit of maintenance post ASCT and daratumumab in AL amyloid patients. Disclosures Rosko: Vyxeos: Other: Travel support. Efebera:Janssen: Speakers Bureau; Akcea: Other: Advisory board, Speakers Bureau; Takeda: Honoraria.

Bortezomib, cyclophosphamide, and dexamethasone (CyBorD) as front-line treatment for systemic AL amyloidosis (AL): a real-world experience at a single centre

Bortezomib, cyclophosphamide and dexamethasone (CyBorD) as first-line treatment for AL amyloidosis was reported to have excellent clonal responses (Venner et al, 2012; Mikael et al, 2012). We sought to undertake a

A Prospective Phase II of Daratumumab in Previously Treated Systemic Light-Chain (AL) Amyloidosis: Updated Results

Daratumumab (DARA) is a high-affinity human monoclonal antibody that specifically recognizes CD38. It has emerged as a breakthrough targeted therapy for multiple myeloma patients (pts). Monoclonal plasma cells in AL amyloidosis (AL) express CD38. We report here updated results of a prospective multi-center, phase 2 study of DARA in AL (NCT02816476).

Preliminary evidence of efficacy of venetoclax in relapsed and refractory AL amyloidosis.

AL Amyloidosis (AL) is a plasma cell dyscrasia marked by production and deposition of toxic free light chains in organs including the heart, kidney and nervous system. While treatment regimens are generally borrowed from multiple myeloma (MM), patients typically have difficulty tolerating many of these drugs, especially the immunomodulatory drugs (IMiDs) due to high cardiac and hematologic toxicities. Recently daratumumab has been shown to be active in AL, however for patients who become refractory to daratumumab, options remain bleak and more therapies are desperately needed.

Carfilzomib is an effective upfront treatment in AL amyloidosis patients with peripheral and autonomic neuropathy.

Bortezomib is standard treatment in AL amyloidosis (AL), but is contraindicated in patients with significant neuropathy. Carfilzomib, a second-generation proteosomal inhibitor, results in a lower incidence of neuropathy than bortezomib, but data in AL is scant. We report a cohort of five AL patients treated with upfront carfilzomib. All had cardiac, peripheral and autonomic neuropathy at presentation. All achieved at least a very good partial haematological response. There was no worsening in cardiac function, peripheral or autonomic neuropathy. Carfilzomib is an effective upfront treatment option in AL patients with peripheral and/or autonomic neuropathy (without severe cardiac or renal involvement).

Combined use of two monoclonal antibodies in patients with systemic AL amyloidosis and cardiac involvement.

8009 Background: Systemic AL amyloidosis (AL) is a rare disease in which circulating immunoglobulin light chains misfold, are directly toxic to key organs and also cause organ failure by mass effect. Patients with cardiac involvement have a poor prognosis; 25% of them die within 6 months of diagnosis. Depth of hematologic and organ response has prognostic significance and as new therapies become available, combining targeted therapies might hold the key to improve survival and deepen responses. Methods: We report the outcomes of 9 patients with AL amyloidosis who simultaneously received dual monoclonal antibody therapy with daratumumab and the investigational anti-fibril antibody NEOD001 at our institution. We also provide a descriptive comparison of 10 other AL amyloidosis patients who received treatment with daratumumab alone. Results: Of these 9 patients, there were 4 men/5 women with a median age of 68 years (range, 52-75) and a median of 261 days from diagnosis (range, 51-2037). Median NT-proBNP was 3807 pg/ml (range, 1326-13193). These 9 patients did not respond to initial therapy with a bortezomib-based regimen. Infusions of both monoclonals were separated by 2 days and were well tolerated without any unexpected toxicity. 88% of patients achieved ≥VGPR with daratumumab+NEOD001 in a median of 33 days and cardiac responses were achieved in < 90 days. In contrast, patients receiving daratumumab alone (n=10) achieved hematologic and cardiac responses at later times (Table). Conclusions: In conclusion, dual monoclonal antibodies targeting different epitopes can be safely combined in patients with systemic AL amyloidosis. Although this report features a small number of patients, high rates of hematologic and cardiac responses achieved suggest that this combination should be studied further, possibly in a prospective randomized trial. [Table: see text]

The frequency of chromosomal abnormalities in AL amyloidosis and their impact on treatment response.

e19539 Background: Chromosomal abnormalities (CA) found in AL amyloidosis (AL) are similar to those found in multiple myeloma (MM.) However, t(11;14) has been reported more frequently in AL, anywhere from 30% - 50% in studies. It has been reported that the presence of t(11;14) confers a lower hematologic response rate with bortezomib-based therapy (BBT) and a better hematologic response rate with high dose melphalan and autologous stem cell transplantation (HDM/SCT). Methods: We performed a retrospective review of 307 newly diagnosed patients seen at our center between January 2013 and December 2017, for whom interphase fluorescent in-situ hybridization (iFISH) data, performed on bone marrow aspirate using standard MM FISH probes on enriched plasma cells after magnetic separation, were available. Patients who already had iFISH performed prior to their visit with us were also included. We collected data on the incidence of CA, first line treatment, and hematologic response to this treatment. Results: Of the 307 patients, CA were not detected in 37%. 21% had t(11;14), 25% had 13q deletion, 21% had IgH rearrangements with an undetermined partner chromosome, and 11% had 1q21 gain. In those for whom initial treatment and hematologic response data were available, in patients with t(11;14), hematologic complete response (CR) was achieved by 18% following HDM/SCT and 27% following BBT. For those with 1q21 gain, CR was achieved by 33% following HDM/SCT and 19% following BBT. In contrast, hematologic CR was achieved by 47% following HDM/SCT and 40% following BBT for those who had no detectable CA with iFISH. Conclusions: Our study shows a lower incidence of t(11;14) in AL compared to other studies. This may be partly explained by the high number of patients with IgH rearrangements with undetermined partner chromosomes, some of whom may indeed harbor t(11;14). Our study also did not show a better hematologic response rate with HDM/SCT in t(11;14) patients compared with BBT. Hematologic response rates were much better both with HDM/SCT and BBT for those with no detected CA compared to patients who had t(11;14) or 1q21 gain.

Seeking light-chain amyloidosis very early: The SAVE trial—identifying clonal lambda light chain genes in patients with MGUS or smoldering multiple myeloma.

8010 Background: In systemic AL amyloidosis (AL), caused by clonal Ig free light chains (LC) produced in 75% of cases by λ clones, patients often present with advanced organ damage, making earlier diagnosis a critical unmet need. Five λ IGLV germline genes account for 75% of AL λ-type ( IGLV 6-57, 1-44, 2-14, 1-51, 3-1) (Blood 2017;129:299), representing 56% of all AL patients. Relative risk of AL versus MM with these clonal genes can be high (7.3, 6-57; 2.5, 1-44), intermediate (1.7, 2-14; 1.2, 1-51) or low (0.8, 3-1) (Amyloid 2009;16:1). Progression to AL from smoldering multiple myeloma (SMM) or monoclonal gammopathy of undetermined significance (MGUS) occurs but is not well appreciated (JCO 2014; 32:2679). SAVE is a trial for λ SMM or λ MGUS patients with a κ:λ FLC ratio < 0.26 and difference between involved and uninvolved FLC > 23mg/L (JCO 2014;32:2699). Methods: Eligible patients ship peripheral blood (PB) or bone marrow (BM) samples to us for RT-PCR with cDNA from CD138+ cells, using primers for the Vλ families (Blood 2001;98:714). Amplicons are sequenced and the IGLV germline genes identified in IMGT (ImMunoGene-Tics, www.imgt.org). If the germline gene is AL-related, further evaluation is pursued. Results: Twenty asymptomatic λ patients from 18 states have been enrolled (3M, 17F) and 23 PB and 4 BM specimens obtained. Medians of months from diagnosis, involved FLC, κ:λ ratios, MNC and CD138-selected cells were 20.5 months, 113mg/L, κ:λ 0.06, 8.1x106 (0.8-24) and 3x105 (0-30), respectively. Seventeen patients have had IGLV genes identified, 12 with the first and 5 with additional specimens including 4 BM. Increased risk of AL was identified in 7 patients, 2 of whom had undiagnosed AL (both with IGLV2-14 germline genes). One patient with SMM diagnosed in 2016 had AL λ-type with GI involvement and is 9 months status post MEL 200 stem cell transplant (SCT), and the second with SMM diagnosed in 2009 had cardiac AL λ-type by heart biopsy with an NT-proBNP 171 (but with a suggestive MRI) and is en route to SCT. Conclusions: The SAVE trial enables early diagnosis of AL λ-type based on the λ IGLV gene used by the clonal plasma cells. By RT-PCR in this pilot study we identified the clonal λ gene 85% of the time. Earlier diagnosis will enable treatment with effective therapy such as MEL 200 SCT. Clinical trial information: NCT02741999.

Incidence of cardiovascular events in patients implanted with pacemakers or cardiac defibrillators in cardiac amyloidosis

Cardiac amyloidosis is a fatal disease. It may represent 10% of non-ischemic heart diseases. Conduction and rhythm disorders are common causes of death. There are no real guidelines about PM or ICD indications in cardiac amyloidosis. Cardiac devices (PM/ICD) prolong survival by decreasing MACE (cardiovascular death; sudden cardiac death; delivered therapies by ICD; cardiac decompensation; heart transplant) by treating rhythmic and conductive events and improving cardiac hemodynamics. The aim was to demonstrate the benefit in terms of cardiovascular mortality or morbidity of implantation of cardiac devices (PM/DAI) in patients with different types of cardiac amyloidosis. A total of 1053 patients were screened for cardiac amyloidosis between 10/2010 and 12/2016 within Réseau Amylose Mondo r (CHU Henri-Mondor–Créteil). A total of 186 AL amyloidosis (AL), 225 hereditary amyloidosis (hTTR) and 168 senile amyloidosis (wtTTR) were included in our study and followed from inclusion in the database until their death or until 12/2016. Overall a total of 70/186 PM/ICD were implanted in AL amyloidosis (38%), 99/225 in hTTR (44%) and 96/168 in wtTTR (55%). Patients implanted with a PM/ICD had a 24-month risk of developing MACE almost twice as large as non-implanted patients, for any type of amyloidosis (HR 1.73 [1.28; 2.34]; P < 0,001). A propensity score was created to identify factors associated with prosthesis implantation. In multivariate analysis, incorporating the propensity score, the best statistical model for identifying the risk factors for MACE occurrence showed that the presence of a PM/ICD was not associated with the occurrence of MACE at 24 months (C-stat 0.75) ( Fig. 1 ). This study demonstrates that PM/ICD are not associated with an overdose of major cardiovascular complications, as suggested in some studies. Our data suggest that these prostheses have a place in this disease, provided to find the good criteria of selections of the patients to implant.

Achieving a Difference in Involved and Uninvolved Light Chains (dFLC) of Less Than 10mg/L Is the New Goal of Therapy in Systemic AL Amyloidosis: Analysis of 916 Patients Treated Upfront with Bortezomib-Based Therapy

BackgroundBased on international consensus criteria (ICC), the treatment goal in AL amyloidosis (AL) is at least a very good partial response (VGPR, defined by dFLC<40mg/L), associated with better organ responses and overall survival (OS). In patients presenting with low dFLC (<50mg/L), a low-dFLC partial response (PR, dFLC<10mg/L) predicts better renal and OS. Given emerging data on the impact of minimal residual disease in AL, we posited that a target of dFLC<10mg/L may be important in all AL patients, irrespective of baseline light chain levels. We therefore report outcomes in the largest cohort treated with upfront bortezomib-based therapy and explore the impact of dFLC<10mg/L as a potential therapy goal in AL.MethodsAll patients from a prospective observational study of newly diagnosed AL treated with upfront bortezomib regimes from 2010-2017 were included. All underwent serial organ function assessment and biomarkers. Organ responses were defined by ICC. Survival was calculated by Kaplan-Meier analysis. All outcomes are reported on an intention-to-treat (ITT) basis. Haematologic responses were assessed by ICC and absolute dFLC. Patients with presentation dFLC 20-50mg/L were regarded as achieving a low-dFLC PR if dFLC<10mg/L after treatment. Progression-free survival (PFS) was defined as time to death or progression to next therapy. Time-to-next-treatment (TNT) was defined as time from first-line therapy to second-line.Results916 patients were included. Median age was 66 years (29-89), M:F 59%:41%. The number of patients with cardiac, renal, liver, peripheral nerve and autonomic involvement was: 71%, 68%, 14%, 6% and 6%. The number of patients with Mayo Stage 1, 2 and 3 disease was 16%, 33% and 51%. The median NT-proBNP and dFLC were 2228ng/L (range 29-93776) and 180mg/L (0-15898), respectively. All received bortezomib-based therapy: CyBorD 95%, bortezomib-dexamethasone 3%, bortezomib-thalidomide-dexamethasone 1.3%, bortezomib-melphalan-prednisolone 0.3%, bortezomib-lenalidomide-dexamethasone 0.3% and bortezomib-melphalan-thalidomide-dexamethasone 0.1%. The median number of chemotherapy cycles was 5 (1-9).ITT haematologic responses by ICC at 6 months were: complete haematologic response (CR) 15%, VGPR 30%, partial response (PR) 16%, low-dFLC PR 4%, non-response 35% (including deaths 25%). Evaluable haematologic responses were: CR 21%, VGPR 40%, PR 21%, low-dfLC PR 5% and non-response 13%. Absolute dFLC responses were: dFLC <10 mg/L 30%; dFLC 10-20mg/L 11%; dFLC 20-30mg/L 6%; dFLC 30-40mg/L 5%, dFLC 40-50mg/L 3%, dFLC>50mg/L 20% and deaths 25%.Median OS, PFS and TNT were 72 months, 22 months and not reached (55% of evaluable patients not having progressed to next treatment at 7 years). Median OS was not reached in patients in a CR, VGPR or low-dFLC PR; median OS was 71 and 39 months in patients in a PR and non-response, respectively. Median OS in patients with 6 month dFLC<10mg/L, dFLC 10-40mg/L, and dFLC>40mg/L was not reached (86% alive at 6 years), not reached (61% alive at 6 years) and 53 months, respectively. Median PFS was not reached in patients in a CR or low-dFLC PR, and it was 48, 17 and 13 months in patients in a VGPR, PR and non-response, respectively. Median PFS in patients with 6 month dFLC<10mg/L, 10-40mg/L and dFLC> 40mg/L was not reached, 33 and 14 months, respectively. Median TNT in patients in a CR, VGPR and “low-dFLC” response was not reached; it was 16 and 13 months in those in a PR and non-response, respectively (Fig. 1A). Median TNT in patients with a 6 month dFLC<10mg/L, 10-40mg/L and dFLC>40mg/L was not reached, 38 months and 13 months (Fig. 1B).Median OS, PFS and TNT at 3 and 5 years in patients achieving CR vs dFLC<10mg/L was: 76% vs 82%, and 67% vs 76%. 32% achieved cardiac responses in total, compared to 61% in those with 6 month dFLC<10mg/L (p<0.0001). 15.4% achieved renal responses overall, compared to 27.4% in the 6 month dFLC<10mg/L group (p=0.0003).ConclusionIn this study, we report the largest cohort of AL patients treated with upfront bortezomib. On an evaluable basis, 66% of patients achieved CR/VGPR/low-dFLC response. The OS, PFS and TNT in patients in a CR are akin to those previously reported in ASCT. Strikingly, PFS, TNT and organ responses are markedly better in patients with dFLC<10mg/L after treatment, even compared to patients in a standard CR. We propose that dFLC<10mg/L should be evaluated in an international collaboration as the new therapy goal in AL. [Display omitted] DisclosuresWechalekar:Janssen: Honoraria.

Seeking AL Amyloidosis Very Early: The SAVE Trial — Identifying Clonal Lambda Light Chain Genes in Patients with MGUS or Smoldering Multiple Myeloma

INTRODUCTION: Currently patients with systemic AL amyloidosis (AL) are not identified until they are sick due to end-organ damage, usually a result of elevated clonal Ig free light chains (FLC) produced by λ clones in 75% of cases. Delays in diagnosis put patients at risk of developing irreversible organ damage making AL much harder to treat. Only about 25% of newly diagnosed AL patients are eligible for melphalan (MEL) based stem cell transplant (SCT). To extend the overall survival and quality of life of AL patients, early diagnosis is critical. A retrospective study of AL λ-type patients using the US Department of Defense serum repository showed that 100% of patients had a monoclonal FLC present for up to 4 years preceding diagnosis, 92% of whom had a difference between the pathologic and non-involved FLC (dFLC) of >23 mg/L (J Clin Oncol 2014;32:2699). Progression to AL from precursor states such as monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma (SMM) is well described but often not clinically appreciated. SAVE is an internet-based diagnostic trial (NCT02741999) for patients with λ MGUS or SMM with a κ:λ ratio < 0.26 and dFLC > 23mg/L. Using peripheral blood and, when available, marrow aspirates, we try to identify each patient's λ germline variable region (IGLV) donor gene. Five IGLV genes account for 75% of AL λ-type (IGLV1-44. 1-51, 2-14, 3-1, 6-57) (Blood 2017;129:299). Based on data in AL-Base, relative risk of AL versus myeloma with these clonal genes can be significantly high (7.3, 6-57; 2.5, 1-44), intermediate (1.6, 2-14; 1.2, 1-51) or low (0.8, 3-1) (Amyloid 2009;16:1).MATERIALS& METHODS: Patients provide written consent to be screened by medical records review. Eligible patients ship peripheral blood (PB) or marrow (BM) samples to us obtained only at times of routine clinical testing. We select CD138+ cells from PBMNC or BM for whole-cell RNA preparation (RNeasy Mini Kit, QIAGEN, Valencia, CA) and cDNA synthesis (ThermoScript RT-PCR System, Invitrogen Life Technologies, Carlsbad, CA) for storage at -80o C. Primer sets are degenerate FR1 and 5' CR primers for the Vλ1, Vλ2, Vλ3 and Vλ6 families (Blood 2001;98:714). Three RT-PCR products of appropriate size per clone are sent to our core facility for sequencing. We then use the sequences to search for the corresponding IGLV germline gene in IMGT (ImMunoGene-Tics, www.imgt.org). Patients and their MDs are notified of the results and, if the germline donor is associated with AL with high or intermediate risk, further evaluation for AL is discussed and pursued.RESULTS: Twenty asymptomatic λ patients from 13 states thus far have consented to be screened for SAVE, and 19 enrolled (3M, 16F). Twenty-three PB and 4 BM specimens have been obtained. Median months from diagnosis to receipt of first specimen was 15, involved FLC 107mg/L and κ:λ ratio 0.09. Median PBMNC and CD34-selected cells were 8x106 (2.6-24) and 3x105 (0-6) respectively. Twelve patients had IGLV genes identified by PCR with the first specimen; 5 sent additional specimens including 3 BM. There were no differences in CD34-selected cell numbers or λ light chain levels between first-specimen PCR successes and failures. Seventeen patients have had IGLV genes identified: four 2-14, three 1-44, two 3-1 and eight others. Increased risk of AL was identified in 7 patients who were screened with abdominal fat pad studies. One of the 7 (with IGLV2-14) had a positive fat pad and was then diagnosed with AL λ-type with GI involvement. She was induced with 4 cycles of bortezomib-based therapy and is now 3 months status post an uncomplicated MEL 200 SCT. Two SMM patients (of 19) have proceeded to symptomatic myeloma requiring therapy.CONCLUSIONS: The SAVE trial may enable early appreciation of risk of AL λ-type based on the variable region germline gene used by the clonal plasma cells. In λ MGUS and SMM patients with elevated lambda FLC, below normal ratios, and dFLC > 23mg/L, the clonal gene can be identified by RT-PCR with CD138-selected cells from a single peripheral blood specimen 70% of the time. Close follow up of patients at risk may reduce the likelihood of eventually being diagnosed with advanced organ involvement. Earlier diagnosis may permit prompt induction therapy if required and expanded application of MEL 200 SCT, a preferred treatment for patients with < 10% clonal marrow plasma cells at diagnosis or after induction (Biol Blood Marrow Transplant 2016;22:1729). DisclosuresNo relevant conflicts of interest to declare.

Identifying a Murine Xenograft Model Relevant to Light-Chain Specific Approaches to Human Ig Light-Chain Diseases

INTRODUCTIONIg light chain (LC) diseases such as systemic AL amyloidosis (AL) and κ light chain deposition disease (LCDD) cause organ damage and are treated with chemotherapeutic agents targeting the clonal plasma cells producing the LC. Not all patients respond to therapy and responding patients remain at risk of relapse. New treatments are needed. In theory, alternative approaches that directly target LC for reduction include novel enzymatic agents (Infect Immun. 2003;71:2563), agents that retard LC monomerization (eLife. 2015;4:e10935. doi:10.7554), anti-light chain monoclonal antibodies (Blood 2004;104:2416), and small interfering RNAs that impair LC production (Gene Therapy 2016;23:727). In order to study such approaches, murine xenograft models with circulating human LC can provide useful experimental systems even if the models do not recapitulate the organ damage of human disease. Alternative measures of tumor activity would be useful in such models in order to confirm the impact of interventions on LC. To provide an in vivo model, we tested RPMI 8226, ALMC-1, NCI-H929 and JJN3 human myeloma reporter cell lines stably expressing FFL and GFP in NOD scid γ (NSG) mice using different routes of inoculation. We sought an optimal xenograft model that would provide reliable tumor-take, brief latency for circulating LC, rapid short-term increase in LC levels, measurable β2-microglobulin (β2M) levels and ease of administration of multiple injections of investigational agents.MATERIALS & METHODS: Five-week old female NSG mice were obtained from Jackson Laboratories. RPMI 8226 (λ) and NCI-H929 (κ) human myeloma cell lines were obtained from ATCC (Manassas, VA, USA), and the JJN3 (κ) cell line from the German Collection of Microorganisms and Cell Cultures (Braunschweig, Germany). ALMC-1 cells (IgGλ+λ) were a gift from D Jellinek. All cells were tested for mycoplasma and cultured as directed. The cell lines were infected with a lentiviral construct expressing firefly luciferase and GFP (Biosettia, San Francisco, CA). Cells were introduced via flank injections (5x106 cells) with Matrigel or via intra-peritoneal (IP) injection (107 cells). Mice were regularly observed for health irregularities, were bled via submandibular vein and imaged with luciferin at intervals. Collected sera were tested by ELISA for λ or κ light chains (Bethyl Laboratories, Montgomery, TX) and for β-2 microglobulin (R&D Systems, Minneapolis, MN). RESULTSThe latency periods for flank plasmacytomas exceeded 3 weeks in all cases. The use of ALMC-1 cells in an IP model also was hampered by a lengthy latency period > 3 weeks. We were able to compare JJN3, RPMI 8226 and H929 cells in IP models. As shown in Table 1,the NSG JJN3 IP model has a 90% tumor-take and a 5-day LC latency. In this model, IP xenograft CD138+ cells are found in liver (subcapsular) and spleen at sacrifice on day 12. On day 5, the NSG JJN3 IP mice have median serum levels (Q1-Q3) of κ LC and β2M of 2.37μg/mL (1.68-3.32) and 1.56ρg/mL (0.58-5.38), values that strongly correlate (r=0.76, P<<0.01), as do the day 5 κ LC and FLUX values (r=0.88, P<<0.01). That RPMI 8226 cells make negligible amounts of β2M has been previously identified (Transplant Rev 1974;21:53). CONCLUSIONSThe ALMC-1, RPMI 8226 and H929 IP models did not meet the criteria we required in order to effectively test specific interventions on circulating LC (Table 1). The NSG JJN3 IP model had a short latency period for LC, β2M and FLUX measurements, and had significant correlations among these measurements. The NSG JJN3 model met our criteria. We are currently evaluating soluble BCMA levels in this model also, These measurements will allow investigators to distinguish the impact of interventions on LC specifically, independent of tumor cells. We have used this model successfully to test an RNAi approach to reducing κ LC by knocking down expression of the LC mRNA using siRNA specific for the LC constant region delivered via lipidoid nanoparticle. The feasibility of multiple IP injections of volumes as high as 600uL is also a strength of this model; tail vein injections in the 20g NSG mice are difficult to perform more than a small number of times. The major challenge of this model is the rapid tumor take and growth kinetics of JJN3 cells IP in NSG mice. DisclosuresMa:Tufts Medical Center: Patents & Royalties: Patent: 9593332.

Deferred autologous stem cell transplantation in systemic AL amyloidosis

High-dose melphalan with autologous stem cell transplantation (ASCT) can induce durable haematological and organ responses in systemic AL amyloidosis (AL). Stringent selection criteria have improved safety of ASCT in AL but most patients are transplant-ineligible. We report our experience of deferred ASCT in AL patients who were transplant-ineligible at presentation but had improvements in organ function after induction chemotherapy, enabling them to undergo ASCT. Twenty-two AL patients underwent deferred ASCT from 2011 to 2017. All had serial organ function and clonal response assessment. Organ involvement and responses were defined by amyloidosis consensus criteria. All patients were transplant-ineligible at presentation, predominantly due to advanced cardiac involvement. All received bortezomib-based therapy, with 100% haematologic response (86% complete response (CR)/very good partial response (VGPR)), enabling reversal of ASCT exclusion criteria. Patients underwent deferred ASCT for haematologic progression (45%) or consolidation (55%). There was no transplant-related mortality. Haematologic responses post-ASCT: CR 50%, VGPR 27%, PR 18%, non-response 5%. In all, 85.7% achieved cardiac responses. Median overall survival (OS) was not reached. Median progression-free survival (PFS) was 54 months. This selected cohort achieved excellent haematologic responses, organ responses, PFS and OS with deferred ASCT. If larger studies confirm these findings, this may widen the applicability of ASCT in AL.