Systemic AL Amyloidosis Amyloidosis Research Articles

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.

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.

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.

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

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.

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

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 &lt; 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]

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 &lt; 0.26 and difference between involved and uninvolved FLC &gt; 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.

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.

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.

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.

A pilot study demonstrating cardiac uptake with 18F-florbetapir PET in AL amyloidosis patients with cardiac involvement

18F-florbetapir is a promising tracer in amyloidosis. This study evaluates its use in patients with systemic AL amyloidosis (AL) before and after treatment as well as its serial utility in monitoring. Fifteen AL patients with cardiac involvement underwent 18F-florbetapir PET imaging and three patients underwent repeat imaging after chemotherapy. All patients had demonstrable cardiac uptake with 18F-florbetapir. Cardiac uptake appeared greater in chemotherapy-naïve vs. chemotherapy-established AL patients median (left ventricular retention index 0.21 vs. 0.14 min−1, respectively) and greater in patients that had not achieved at least a partial haematological response (left ventricular retention index 0.2 vs. 0.14 min−1, respectively). There was no interval difference in cardiac uptake and no correlation in cardiac uptake with cardiac biomarkers or serum free light chains. This is the largest study of 18F-florbetapir in patients with AL amyloidosis. It is the first study to include patients prior to starting chemotherapy and uniquely includes patients who underwent repeat imaging after chemotherapy. All patients had cardiac uptake with 18F-florbetapir, regardless of haematological or NT-proBNP response to chemotherapy. There was a suggestion that treatment-naïve patients may have higher cardiac uptake. Larger studies are required to establish the role of this tracer in screening patients with amyloidosis for cardiac involvement, discriminating between ATTR and AL amyloidosis, and in disease monitoring.

High-dose melphalan and stem cell transplantation in systemic AL amyloidosis in the era of novel anti-plasma cell therapy: a comprehensive review.

The application of high-dose melphalan and autologous stem cell transplant (SCT) to systemic AL amyloidosis (AL) has evolved over the past two decades and remains an important component of therapy for patients with AL. The era of novel agents created the opportunity to provide well -tolerated induction and post-SCT consolidation to AL patients eligible for SCT and the current availability of new monoclonal antibody therapies will likely provide additional opportunities to enhance the outcomes with SCT. In this review, we touch on the history of SCT for AL and examine the data on eligibility, mobilization, induction, risk-adapted melphalan dosing, engraftment, consolidation and maintenance, and long-term outcomes with SCT. We note that induction therapy may deprive some patients of the opportunity to proceed to SCT but is likely needed if the marrow plasmacytosis is > 10%, that risk-adapted melphalan dosing continues to be relevant, and that post-SCT consolidation improves the complete response rate as well as long-term overall survival. The importance of baseline cytogenetics is also highlighted, particularly for patients whose clonal plasma cells are ≤ 10% but harbor the t(11;14), because they may have improved survival with SCT.

Weekly Combination Chemotherapy with Cyclophosphamide, Bortezomib and Dexamethasone (CyBorD) for Newly Diagnosed Patients with Advanced Cardiac Disease Due to Systemic AL Amyloidosis

Abstract 5139The treatment of systemic AL amyloidosis (AL) with advanced cardiac involvement (cardiac biomarker stage III) at diagnosis remains challenging and unsatisfactory. Median survival with melphalan and dexamethasone (MDex) in stage III patients is about 10 months from diagnosis with one quarter of patients dying within 3 months of starting therapy (BJH 2008;143:369; Blood 2010;116:522). Bortezomib has been shown to be the most active single agent in the treatment of AL (Blood 2011;118:865) and, when incorporated into CyBorD, clinical studies have shown a > 90% hematologic response rate in both myeloma and in AL (Blood 2010;115:3416; Leukemia 2009;23:1337; Amyloid 2010;17(S1):171a). In addition, bortezomib has been shown to have limited cardiac toxicity and no arrhythmogenicity in patients with AL and cardiac involvement (QJM 2011 published online July 13, 2011). Based on these data we have used CyBorD as initial standard therapy in patients with newly diagnosed systemic AL amyloidosis with advanced (stage III) cardiac involvement who are ineligible for stem cell transplant or clinical trials. We now retrospectively report the outcomes in the 11 consecutive stage III patients who have been treated thus far with CyBorD as initial standard therapy (6F, 5M). Patients were a median of 57 years old (range, 44–74) with median brain natriuretic peptide (BNP) of 709 (145–1490), troponin I of 0.29 (0.11–0.77), involved free light chains of 322mg/L (101–4325) and marrow plasma cells of 20% (4–41%). Median left ventricular (LV) ejection fraction and LV wall thickness (average of IVSd+LVPWd) by echocardiogram were 52% (35–70%) and 1.7cm (1.2–2.1) respectively. Patients received CyBorD on a 35-day cycle on days 1, 8, 15 and 22 with cyclophosphamide (300mg/m2) and dexamethasone (20 or 40mg flat dose) given orally or IV and bortezomib (1.3mg/m2) given IV or subcutaneously. Routine prophylactics included acyclovir, fluconazole and omeprazole. Patients have received a median of 4 cycles (1–8). Of the 11 patients, 2 died suddenly at 1 and 5 months, and 9 are alive with a median follow up of 8 months (3–15). Three patients experienced worsening congestive heart failure requiring hospitalization, medication adjustments and in 1 case pericardiocentesis. The gastrointestinal (GI) side-effects of bloating and constipation were common and usually manageable although 1 patient stopped therapy after 2 cycles because of lower GI bleeding. Of 10 patients evaluable for hematologic response, 8 responded (1 CR, 4 VGPR, 3 PR) (response criteria from Blood 2010;116:586a) and 2 had no response. Median time to response was 1 cycle (1–3). Thus far, there have been 4 patients (2 VGPR, 2 PR) who within months of starting therapy have had BNP reductions of 40% to 76% of baseline (median BNP reduction of 434pg/ml (282–712)). In conclusion, these retrospective data are encouraging and hopefully will spur the development of phase II and III trials in newly diagnosed patients with advanced cardiac involvement due to AL. Disclosures:Off Label Use: Pentostatin and Extracorporeal photopheresis are not FDA approved for conditioning prior to allogeneic transplant.

Bortezomib in a phase 1 trial for patients with relapsed AL amyloidosis: cardiac responses and overall effects

Bortezomib is approved for the treatment of multiple myeloma and a role has been suggested in the treatment of systemic AL amyloidosis (AL). In this phase 1 dose-escalation portion of the first prospective study of single-agent bortezomib in AL, 31 patients with relapsed disease, including 14 (45%) with cardiac involvement, received bortezomib in seven dose cohorts on once-weekly (0.7, 1.0, 1.3, 1.6 mg/m(2)) and twice-weekly (0.7, 1.0, 1.3 mg/m(2)) schedules. Electrocardiographic, Holter and echocardiographic studies were evaluated in all patients to determine safety and response. During therapy (median treatment period 210 days), no patient developed significant ventricular or supraventricular rhythm disturbance on 24-h Holter monitoring; however, no patient satisfied study criteria for cardiac response using echocardiographic assessment or New York Heart Association classification. Seven patients (23%) had a ≥ 10% fall in left ventricular ejection fraction, but only one met criteria for cardiac deterioration. The predominant cardiac adverse events were peripheral edema (23%), orthostatic hypotension (13%) and hypotension (10%). Two patients developed grade 3 congestive heart failure, which resolved following treatment interruption. In this Phase 1 portion, the maximum tolerated dose of bortezomib on either schedule was not reached. Hematologic responses occurred in 14 patients (45%), including seven (23%) complete responses. In non-responders mean left ventricular wall thickness increased during the course of treatment. AL is frequently rapidly progressive; in these patients who had relapsed or progressed following previous conventional therapies, these results suggest that bortezomib may slow the progression of cardiac amyloid with limited toxicity.