scholarly journals Pattern of Use and Efficacy of Daratumumab-Based Therapy in Patients with AL Amyloidosis: A Single Institution Experience

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 44-45
Author(s):  
Danai Dima ◽  
Xiao Hu ◽  
Joshua Dower ◽  
Raymond L. Comenzo ◽  
Cindy Varga
Keyword(s):  
Median Time ◽  
Research Funding ◽  
Plasma Cells ◽  
Response Rate ◽  
Medical Center ◽  
Cardiac Response ◽  
Al Amyloidosis ◽  
Single Institution ◽  
Hematologic Response ◽  
Organ Response

Introduction: Light chain Amyloidosis (AL) is a systemic disease caused by abnormal clonal plasma cells which produce excessive light chains that further misfold and deposit into vital organs. Currently, treatment options for AL amyloidosis are relatively limited. Daratumumab (dara), a novel monoclonal antibody that targets CD38 on the surface of plasma cells, has shown remarkable efficacy in AL amyloidosis. Our objective was to explore the pattern of use, safety and efficacy of dara therapy among AL amyloid patients in a real-world setting at a single institution. Methods: We performed a retrospective analysis of patients with AL amyloidosis diagnosed by tissue biopsy who received dara-based therapy from 11/16/2015 to 3/16/2020 at Tufts Medical Center. The study was approved by the Tufts Medical Center Institutional Review Board. Baseline demographics, clinical characteristics and therapy-related data from patients were extracted from the electronic medical records. Kaplan-Meier method was used to estimate time to hematologic response, time to organ response and progression free survival (PFS) after dara initiation. Log-rank tests were applied to compare PFS among subgroups and to explore the impact of involved free light chain (iFLC) levels on organ response. Results were considered to be significant if two-sided P-value was less than or equal to 0.05. R software was used for statistics. Results: Forty AL patients were included in the study with a median age of 66 years, ranging from 35 to 80 years. Among these patients, 22 (55%) were male and 35 (87.5%) were non-Hispanic White. Cardiac involvement was present in 30 subjects (75%) and renal involvement was present in 20 (50%). By cytogenetic stratification, 10 (25%) individuals had translocation (11;14). Table 1 highlights the clinical characteristics of the study population including the combinations of dara with traditional therapies. Dara was well tolerated in the majority of cases with only one instance of discontinuation due to frequent upper respiratory tract infections. The major therapy-related adverse events are highlighted in table 2. The overall hematologic response rate was 87.5%, including 16 complete responses (CR), 15 very good partial responses (VGPR), and 4 partial responses (PR). The estimated median time to hematologic response was 1.5 months (95% confidence interval (1.0, 2.0 months). The overall cardiac response rate after dara treatment was 46.7%, and the estimated median time to cardiac response was 8.25 months (95% CI, 5.5, 13.0 months). Likewise, the overall renal response rate was 25.0% with the estimated median time to renal response being not evaluable (NE) (95% CI, 12.0, NE). There were 31 patients who had hematologic progression through the study period; the median PFS was 12.0 months (95% CI, 8.25, 18.50 months). The median PFS among those who had translocation (11;14) was 24.1 months. Further log-ranks tests showed that there was no significant difference in PFS when subgrouping patients based on line of treatment (1st vs. 2nd/3rd vs. >3rd, P = 0.322) or pattern of therapy (dara monotherapy vs. combination with PI vs. IMiD vs. PI + alkylating agents vs. NEOD001, P = 0.151). Among the subjects who achieved at least a VGPR, iFLC levels (<10 vs. 10-20 vs. >20) did not show significant impact on the rate and time to organ response (cardiac, P = 0.551 or renal, P = 0.260). In the same population, it was also found that line of treatment (1st vs. 2nd/3rd vs. >3rd) was not associated with organ response (cardiac, P=0.950 or renal, P=0.817). Conclusions: Among the AL amyloidosis patients at Tufts Medical Center treated with dara over the last 5 years, the overall hematologic response was high (87.5%) and the median time to response was rapid (1.5 months), consistent with findings from prior trials. Most importantly, dara was well-tolerated. Patients with t(11;14) had a mPFS that was double the rest of the population (24 vs. 12 months) These results are promising for the disseminated use of dara in AL given its good tolerability and rapid onset of action, regardless of line of therapy. This is especially important in a disease where time is a critical factor in organ recovery. Disclosures Comenzo: Takeda: Consultancy, Research Funding; Caleum: Consultancy; Sanofi: Consultancy; Unum: Consultancy; Prothena: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Amgen: Consultancy; Karyopharm: Consultancy, Research Funding.

scholarly journals Therapeutic Activity of Combining BCL-2 and HMG-CoA Reductase Inhibition in Systemic Light-Chain Amyloidosis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 23-24
Author(s):  
Ping Zhou ◽  
Hashim Mann ◽  
Xun Ma ◽  
Teresa Fogaren ◽  
Yifei Zhang ◽  
...  
Keyword(s):  
Light Chain ◽  
Research Funding ◽  
Plasma Cells ◽  
Response Rate ◽  
Cardiac Response ◽  
Al Amyloidosis ◽  
Light Chain Amyloidosis ◽  
Hematologic Response ◽  
Coa Reductase

Introduction: Overexpression of BCL-2 in association with t(11;14) in multiple myeloma (MM) and systemic light-chain amyloidosis (AL) makes it a therapeutic target for the BCL-2 inhibitor venetoclax; response rates of 60-80% in t(11;14) have been reported in MM (Kumar S, Blood 2017 & Vaxman I, Expert Rev Hematol 2018). Addition of HMG-CoA reductase inhibitors (statins) may augment venetoclax activity (Lee JS, Sci Transl Med 2018). We now report ex-vivo functional activity of venetoclax with AL patient CD138-selected plasma cells and provide clinical outcomes of 8 patients with relapsed/refractory AL who were treated with venetoclax and a statin. Methods: To construct a functional assay NCI-H929 and KMS-12-PE cells were used as controls and incubated with venetoclax to assess the IC50. Cell viability was measured with CellTiter-Glo and caspase activity with Caspase-Glo 3/7 (Promega, Madison, WI). H929 cells were the negative and KMS cells the positive control. From patient marrows CD138+ cells were isolated (Miltenyi Biotec, Auburn, CA) as previously described (Ma X, Gene Ther 2016) and incubated with 100 nM of venetoclax for 18 hours with controls. In AL patients, Venetoclax was started at 200 mg daily and escalated to 400 mg daily after 2 weeks if tolerated. Statin (atorvastatin, 10-40 mg daily or simvastatin 40 mg daily) was started concurrently or for lack of response to venetoclax alone. Bone marrow assessment was performed prior to starting venetoclax and response assessment was performed monthly. Results: Venetoclax induced apoptosis in a dose escalated manner with KMS-12-PE cells (t(11;14) positive) when compared with H929 cells (Figure 1A-B). CD138-selected plasma cells from 20 patients (17 AL, 2 MM, 1 MGUS) were incubated with venetoclax (100 nM) for 18 hours and had a median caspase 3/7 activity level that was significantly higher in patients with t(11;14) (Figure 1C). Eight patients were treated with venetoclax in combination with a statin. Baseline characteristics are provided in Table 1. Median age of the cohort was 70 (range, 59 - 77), of which five (63%) were male, and 6 were λ-type (1-kappa, 1-heavy chain). At diagnosis, four (50%) patients had involvement of two or more organ systems (cardiac, renal, gastrointestinal, vascular, and/or neurological). Cardiac involvement was the most common (88%). Seven patients had t(11;14) and/or positive cyclin D1 staining on pre-treatment marrow studies. The median number of prior therapies was 2 (1 - 5), and all except one had been previously treated with daratumumab. Venetoclax-statin combination was started due to hematologic progression (4), organ progression (1), or suboptimal response to prior therapy (3). At a median follow-up of 8 weeks (5 - 25), overall hematologic response rate is 63% (1 CR, 3 VGPR, 1 PR and 1 progression). Cardiac response was seen in 2 patients. One patient who lacked the t(11;14) mutation had early disease progression. One patient with stage-3 cardiac AL amyloidosis experienced cardiac progression without hematologic response on venetoclax alone but responded promptly with both hematologic and cardiac response to addition of simvastatin, 40 mg daily. Statin dose was reduced in 1 patient due to grade 1 myalgia. All responders continue on treatment at their most recent follow-up. Conclusion: In this cohort of 8 patients with AL amyloidosis treated with a combination of venetoclax and statin, hematologic response rate was 63% and >VGPR was seen in 50%. The combination was well tolerated. Consistent with the preclinical activity of venetoclax in MM, functional activity of venetoclax was similarly higher in plasma cells from AL patients harboring t(11;14). As t(11;14) is the most common cytogenetic abnormality in systemic AL amyloidosis, venetoclax and statin combination may provide a potent therapeutic alternative for relapsed/refractory AL patients and requires validation in clinical trials. Disclosures Chaulagain: Sanofi Genzyme: Honoraria. Comenzo:Takeda: Consultancy, Research Funding; Prothena: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Amgen: Consultancy; Karyopharm: Consultancy, Research Funding; Caleum: Consultancy; Unum: Consultancy; Sanofi: Consultancy. OffLabel Disclosure: Venetoclax is a BCL-2 inhibitor and currently approved for non-Hodgkin's lymphoma and Acute myeloid leukemia. Venetoclax has shown clinical activity in clinical trials with multiple myeloma, especially patients who harbor t(11;14). Given the preclinical and clinical evidence of its efficacy, we treated 8 relapsed/refractory patients with systemic light-chain amyloidosis with a combination of venetoclax and a statin.

Final Results of a Phase 2 Study of Bendamustine in Combination with Dexamethasone in Patients with Previously Treated Systemic Light-Chain (AL) Amyloidosis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4523-4523
Author(s):  
Galina Grigoriev Lagos ◽  
Suzanne Lentzsch ◽  
Raymond L. Comenzo ◽  
Jeffrey Zonder ◽  
Keren Osman ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Response Rate ◽  
Al Amyloidosis ◽  
Event Free Survival ◽  
Advisory Committees ◽  
Free Survival ◽  
Hematologic Response ◽  
Phase 2 Study ◽  
Organ Response

Abstract Background: No established therapies exist for patients who fail or relapse after initial therapy for AL amyloidosis. Bendamustine has shown potential in treating multiple myeloma, chronic lymphocytic leukemia and non-Hodgkins lymphoma but it has not been well studied in AL amyloidosis. We sought to investigate the efficacy and safety of using Bendamustine in combination with dexamethasone (Ben/Dex) in patients with relapsed AL amyloidosis in a multi-center phase 2 study and present the results of the final analysis. Methods: This Phase IIa clinical trial enrolled 31 patients who had persistent or progressive AL amyloidosis after at least 1 prior therapy. An optimal two-stage Simon design approach was used. Of 13 patients initially enrolled, 3 experienced hematologic partial response (PR), and an additional 16 were treated in the second stage. It was pre-determined that if 9 or more of the 29 patients with evaluable response had hematologic PR or better the treatment would be considered worthy of further development. Evaluable response was defined as patients who completed at least 2 treatment cycles. The primary objective was to determine the rate of partial hematologic response (PR). Secondary objectives included the overall hematologic response rate, organ response rate, toxicity profile, event free survival, and overall survival (OS). Patients received treatment in 28 day cycles with Bendamustine given on day 1 and day 2 (100 mg/m2 IV for CrCl≥60 mL/min, 90 mg/m2 IV for CrCl 59-30 mL/min, 70 mg/m2 IV for CrCl 15-30 mL/min) and dexamethasone 20-40 mg given weekly. Treatment was continued until disease progression or for up to 6 courses after complete response (CR). Reasons for discontinuation also included unacceptable toxicity, patient refusal, and non-response. Results :Of the 31 patients enrolled in the trial, 29 had evaluable responses and completed a median of 4 cycles of therapy (range 2-12) with one patient still undergoing treatment as of 7/1/2016. Median age of enrolled patients was 64 (range 42-78). Primarily involved organs included heart (53%), kidney (36%), nerve (7%), and liver (4%); 18 patients had ≥2 major organs involved. The patients received a median of 1.5 prior treatments (range 1-4) and 13 had received prior autologous stem cell transplants. Of evaluable patients (n=29), 41% had hematologic response to Ben/Dex (3% CR, 17% very good partial response, 24% PR). Of these 13 patients, 6 had a response after only 1 cycle of therapy and the median time to best response was 1 cycle (range 1-6 cycles). The median follow up of patients was relatively long, 18.4 months (range 1.5-41.5) and the median OS has not yet been reached (Figure 1). Event free survival defined as time to death, progression of disease or initiation of new therapy was 9.24 months (range 1.8-18.0) (Figure 2). Only 3 patients discontinued treatment due to disease progression while 8 stopped due to an adverse event (AE) although 5 AEs were only grade 1-2 events. There was 1 death during treatment that was unrelated to the study drug and due to underlying cardiac amyloidosis. The most common drug related all grade AEs included anemia (9%), fatigue (8%), and nausea (7%). Organ response was observed in 5 out of 16 patients with renal involvement and 2 out of the 19 patients with cardiac involvement. Conclusions : Bendamustine in combination with dexamethasone is active treatment in patients with AL amyloidosis who had failed multiple prior therapies and results in a significant hematologic response. Treatment was very well tolerated with a low incidence of severe AE in this delicate patient population. Therefore bendamustine is another treatment approach for AL amyloidosis patients who currently have limited therapeutic options. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Lentzsch: Foundation One: Consultancy; BMS: Consultancy; Celgene: Consultancy, Honoraria. Comenzo:Karyopharm: Research Funding; Prothena: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Zonder:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Prothena: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Pharmacyclics: Other: DSMC membership. Pregja:Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Prothena: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Pharmacyclics: Other: data safety monitoring committee. Landau:Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees; Spectrum Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx/Amgen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy.

scholarly journals Hematologic Responses and Cardiac Organ Improvement in Patients with Heavily Pretreated Cardiac Immunoglobulin Light Chain (AL) Amyloidosis Receiving Daratumumab

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4525-4525 ◽  
Author(s):  
Gregory Kaufman ◽  
Ronald Witteles ◽  
Matthew Wheeler ◽  
Patricia Ulloa ◽  
Marie Lugtu ◽  
...  
Keyword(s):  
Light Chain ◽  
Research Funding ◽  
Cardiac Involvement ◽  
Cardiac Response ◽  
Al Amyloidosis ◽  
Immunoglobulin Light Chain ◽  
Prior Therapy ◽  
Hematologic Response ◽  
Heavily Pretreated ◽  
Organ Response

Abstract Introduction: In immunoglobulin light chain (AL) amyloidosis, cardiac involvement is the primary cause of premature death. Light chain suppression, with therapies targeting the underlying plasma cell clone producing amyloidogenic free light chains, has been difficult to achieve in a relapsed/refractory disease setting. Hematologic response is required to obtain a cardiac organ response, which is predictive of survival and is an important, if not primary, therapeutic goal. We have previously reported rapid and favorable hematologic response rates with the monoclonal anti-CD38 antibody daratumumab in a cohort of heavily pretreated relapsed/refractory AL patients. The aim of this study was to evaluate cardiac organ response following light chain suppressive therapy with daratumumab in patients with relapsed/refractory AL. Materials & Methods:Consecutive patients with biopsy-proven AL and cardiac involvement, followed at the Stanford University Amyloid Center, who received daratumumab were retrospectively evaluated for hematologic and cardiac organ response. In accordance with IRB approval, demographic and clinical information was obtained from medical records. Hematologic and cardiac organ response criteria were defined per consensus guidelines in AL (Comenzo et al, Leukemia 2012). Results: Twelve patients with previously treated AL with cardiac involvement received a median of 12 doses (range 5-18) of single agent daratumumab. The antibody was given intravenously at 16 mg/kg weekly for 8 weeks, followed by every other week infusion for 8 doses and then monthly infusions. The median patient age was 67 and 75% of patients were male. The median number of lines of prior therapy was 3; notably, none of the patients had previously achieved a hematologic complete response to prior therapy including high dose melphalan and autologous stem cell transplant in 2 patients. Ten of 12 patients (83%) achieved a partial hematologic response or better with daratumumab (3 complete responses (25%), 3 very good partial responses (25%), and 4 partial responses (33%)). Median NT-pro BNP was 2516 pg/mL prior to daratumumab therapy. Of all 12 treated patients, seven patients were evaluable for cardiac response based on baseline NT-proBNP >650 ng/L. Of these, 3 patients achieved a cardiac organ response by NT-pro BNP criteria (>30% reduction and >300 ng/l decrease). Two patients had cardiac progression by NT-pro BNP criteria (no echocardiographic progression was observed) despite hematologic response with one patient discontinuing therapy to pursue hospice care. Infusion reactions were observed in 8/12 patients with only 1 grade 3 infusion reaction. Conclusions: Daratumumab yielded rapid and significant hematologic responses in our retrospective single institution cohort of heavily pretreated AL patients. At a median daratumumab duration of therapy of only 4 months, evidence of cardiac organ improvement was observed. Daratumumab represents a well tolerated and exceptionally promising new treatment for patients with AL amyloidosis; larger prospective trials to evaluate this agent are warranted. Disclosures Liedtke: Takeda: Consultancy, Research Funding; Prothena: Consultancy, Research Funding; Celgene: Research Funding; Amgen: Consultancy, Research Funding; Novartis: Research Funding; Gilead: Research Funding; Pfizer: Consultancy, Research Funding.

scholarly journals Safety, Tolerability and Response Rates of Daratumumab in Patients with Relapsed Light Chain (AL) Amyloidosis: Results of a Phase II Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2005-2005 ◽  
Author(s):  
Vaishali Sanchorawala ◽  
Shayna Sarosiek ◽  
John Mark Sloan ◽  
Dina Brauneis ◽  
Mary Ellen Migre ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Median Time ◽  
Plasma Cells ◽  
Patient Choice ◽  
Cardiac Response ◽  
Al Amyloidosis ◽  
Prior Therapy ◽  
Hematologic Response ◽  
Organ Systems ◽  
Grade 3

Abstract Daratumumab is a human IgG1k monoclonal antibody targeting the CD38 surface antigen on plasma cells with proven efficacy in multiple myeloma. While biology of clonal plasma cells in AL amyloidosis is distinct from myeloma, clonal plasma cells in AL amyloidosis express surface CD38, providing a rationale for using daratumumab. Infusion-related reactions (IR) of 48% were reported in patients who had daratumumab as monotherapy for relapsed multiple myeloma. Therefore, we designed a clinical trial to study tolerability of daratumumab in those with relapsed AL amyloidosis (clinicaltrials.gov identifier: NCT02841033). The primary objective was to determine the safety and tolerability of infusion of daratumumab, with respect to IR. The secondary objectives were to assess hematologic response, clinical response and time to next treatment. Accrual began in April 2017. Patients with AL amyloidosis after ≥1 prior therapy, and involvement of at least 1 vital organ , eGFR of >20 mL/min, AST/ALT < 3xULN, NT-proBNP ≤8500 pg/mL, LVEF ≥30%, FEV1 ≥50% in patients with COPD or chronic smokers, and ECOG performance status of <3, received daratumumab at 16 mg/kg IV infusion weekly for weeks 1-8, followed by every 2 weeks for weeks 9-24 and every 4 weeks thereafter until progression or unacceptable toxicity, for up to 24 months. The first infusion of daratumumab was given in 1000 mL, the second infusion in 500 mL if no grade 1 or greater reactions occurred, and subsequent doses were administered in 500 mL of saline. All patients received acetaminophen, diphenhydramine, loratadine, famotidine, montelukast and methylprednisolone (100 mg for first 2 infusions and 60 mg thereafter) 30-60 mins prior to infusion. Ondansetron was added after development of grade 1 nausea/vomiting in the first 2 patients. Diphenhydramine, famotidine and methylprednisolone (40 mg) were also administered 2 hrs after start of infusion during the first 2 infusions even if there was no reaction. Methylprednisolone 20 mg (or its equivalent) and montelukast were given 24 and 48 hrs after start of infusion for the first 2 infusions and then it was optional. All patients received prophylaxis with acyclovir. At data cut-off (July 1, 2018) 24 patients were screened and 21 were enrolled. The median age was 65 (range, 42-84), and the median of prior therapies was 2 (range, 1-6): 14 (58.3%) had received SCT, 9 (37.5%) immunomodulatory agents, and 16 (66.6%) proteasome inhibitors. Eleven (52.3%) patients were refractory to prior therapy and the median time from last therapy was 9 months (range, 1-180). The median time from diagnosis to enrollment was 57 months. The median number of organ systems involved was 2 (range, 1-5): 11 (52.3%) had involvement of ≥2 organ systems, 18 (85.7%) had cardiac biomarker stage II or III disease. Median NT-proBNP level was 1346 pg/mL (range, 32-3962) and urine protein excretion was 0.4 g/24 h (range, 0-10.1), while median dFLC was 87.8 mg/L (range, 2.9-328.4). Now, 18 patients are on study and 375 infusions have been completed. The median of infusions received per patient is 19 (range, 3-27). Two patients were removed after developing progression of plasma cell dyscrasia after 2 and 9 cycles and 1 patient was removed by patient choice after 8 cycles. No patient experienced a grade 3-4 IR. Four (19%) patients experienced grade 1 nausea and vomiting during first infusion, which resolved after an antiemetic. The median time of first infusion was 7 hrs and 2nd infusion was 4 hrs 29 mins. Grade 3/4 adverse events were noted in 16 (76%) patients. Respiratory illnesses were experienced by 14 (66.6%), 3 (14%) of these were grade 3 events (Influenza A, Rhino/Enteroviral infection, PCP). Six (28.5%) patients were noted to be iron deficient and required parenteral iron infusion. Hematologic responses were rapid as shown in figure. Hematologic CR and VGPR were achieved by 84.2% (16/19), 85.7% (12/14) and 100% (6/6) patients at 3 months, 6 months and 12 months respectively. Renal response was evident in 37.5% (3/8) and cardiac response was evident in 40% (4/10) at 6 months following initiation of treatment. Daratumumab infusion is well tolerated in patients with relapsed AL amyloidosis when administered with appropriate supportive care. Infusion-related reactions were minimal and not comparable to reported incidence in myeloma. A rapid hematologic response after 1 dose of daratumumab in patients with AL amyloidosis is seen. Figure. Figure. Disclosures Sloan: Stemline Therapeutics: Consultancy.

High Dose Melphalan with Autologous Stem Cell Transplantation Overcomes Poor Prognosis of Primary Amyloidosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1350-1350
Author(s):  
Simrit Parmar ◽  
Mubeen Khan ◽  
Gabriela Rondon ◽  
Nina Shah ◽  
Qaiser Bashir ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Plasma Cells ◽  
High Dose ◽  
Al Amyloidosis ◽  
Hematologic Response ◽  
Bone Marrow Plasma ◽  
Organ Response ◽  
High Dose Melphalan

Abstract Abstract 1350 Background: Systemic Primary AL Amyloidosis is a rare but potentially fatal disease resulting from tissue deposits of amyloid fibrils derived from monoclonal immunoglobulin light chains. High-dose melphalan followed by autologous hematopoietic stem cell transplant (auto HCT) is associated with hematologic and organ responses and improved survival. Methods: In this retrospective analysis we identified 46 patients with primary AL amyloidosis who received auto HCT between 01/1998 to 05/2010 at MDACC. Organ responses were determined using Amyloidosis Consensus Criteria. Results: The median age at auto HSCT was 56 years (34-74) where 61% were males and 35% were older than 60 years of age. 61% had lambda light chain restriction and only 4% had cytogenetic abnormalities. Disease characteristics are summarized in Table 1. The median time from diagnosis to auto HCT was 6.6 months (2.2-29.4 months). 22 pts (47.8%) had one organ, 19 pts (41.3%) had 2 organ and 4 pts (8.7%) had 3 organ involvement. 11 pts (23.9%) had heart and 35 pts (76.1%) had kidney involvement. The median follow up from the time of diagnosis was 22.4 months and from time of auto HCT was 16.7 months. High dose Melphalan dose was 200mg/m2 in 24 pts (52%) and 140mg/m2 in 22 (47.8%). There were 4 early deaths and 4 pts whose follow up was less than 3 months and their response was not assessed. Out of the 38 evaluable patients, the post-transplant organ responses were as follows ≥PR 25(66%), ≥stable disease 35(92%) (Table2). The hematologic responses were: CR=5 (13%), ≥VGPR=10(26%), ≥PR=26 (68%), ≥SD=37(97%). One patient had progressive disease. There was a correlation between organ response and hematologic response (chi square;p<10-3). The day-100 treatment related mortality (TRM) was 8.7% and 1-yr TRM was 13%. The median progression-free (PFS) and overall survival (OS) from auto HCT was 73.8 months and not reached (from transplant). The median PFS and OS from diagnosis were 93 months and 59.8 months respectively. In multivariate analysis, heart involvement (p=0.01), female sex (p=0.011), age ≥60 years (p=0.002), bone marrow plasma cells≥10% (p=0.043) and Beta-2 microglobulin>3.5mg/l (p=0.02) were associated with poor OS. Improved OS correlated with organ response (52.6 vs 11.4 months; p=0.01) and hematologic response (52.6 vs.6.1months; p=0.002). Hemoglobin <10 g/dl (p=0.047), bone marrow plasma cells≥10% (p=0.043) and age≥60 years (p=0.075) were associated with shorter PFS. Hematologc response (p=0.48) and organ response (p=0.12) were not associated with improved PFS. Conclusion: In this analysis the outcome of patients with primary systemic AL amyloidosis was durable with auto HCT with acceptable mortality risk and improved survival. Disclosures: No relevant conflicts of interest to declare.

A Randomized Phase III Trial of Melphalan and Dexamethasone (MDex) Versus Bortezomib, Melphalan and Dexamethasone (BMDex) for Untreated Patients with AL Amyloidosis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 646-646 ◽  
Author(s):  
Efstathios Kastritis ◽  
Xavier Leleu ◽  
Bertrand Arnulf ◽  
Elena Zamagni ◽  
María Teresa Cibeira ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Standard Of Care ◽  
Cardiac Response ◽  
Phase Iii ◽  
Al Amyloidosis ◽  
Advisory Committees ◽  
Phase Iii Trial ◽  
Hematologic Response ◽  
Grade 3

Abstract Background. Current upfront treatment of light chain (AL) amyloidosis is often based on bortezomib in patients. However, data on the safety and efficacy of bortezomib in this setting mostly derive from uncontrolled, retrospective series, that are difficult to compare due to different proportion of patients with advanced disease. Here we report the analysis of a multicenter randomized phase III trial comparing MDex, a current standard of care, and MDex with the addition of bortezomib (BMDex) in newly-diagnosed AL amyloidosis that was performed in Europe and Australia (EMN-03 study, NCT01277016). Patients and Methods. Main eligibility criteria included measurable disease (M-protein >10 g/L or dFLC >50 mg/L), estimated glomerular filtration rate (eGFR) ³30 mL/min, and adequate liver function. Previously treated patients, those who had >30% bone marrow plasma cell or lytic bone lesions, NYHA class >II heart failure, grade 3 sensory or grade 1 painful peripheral neuropathy, or ECOG performance status >2 were excluded. In January 2013 the protocol was amended to include Mayo stage III patients, provided their NT-proBNP was <8500 ng/L (stage IIIa). Patients were randomized to receive either MDex (melphalan at 0.22 mg/kg and dexamethasone at 40 mg daily for 4 consecutive days every 28 days) or BMDex (bortezomib added at 1.3 mg/m2, on days 1, 4, 8, and 11 in cycles 1 and 2, and on days 1, 8, 15, and 22 in the following cycles). The primary endpoint was overall hematologic response at 3 months. Treatment was continued until completion of MDex cycle 9 or BMDex cycle 8, or achievement of CR or of at least partial response (PR) plus organ response after cycle 6, and was discontinued in case PR was not achieved by cycle 3. Enrollment is now completed (110 patients) with the last patient enrolled in February 2016 (database lock: July 25, 2016). Results. Patients' characteristics are reported in the Table. The proportion of patients experiencing at least 1 grade 3-4 severe adverse events (SAE) was similar in the MDex and BMDex arms (49% vs. 60%, P=0.11). The total number of reported adverse events per cycle was lower in the MDex group (10% vs 23%, P<0.01). Most common SAEs (MDex vs. BMDex) were cytopenia (4% vs. 7%, P=0.04), fluid retention (3% vs. 6%, P=0.02), and neuropathy (0 vs. 2%, P<0.01). One patient died within 3 months in the MDex arm and 3 in the BMDex group (P=0.28). Response was evaluated by intent to treat. Hematologic response rates after cycle 3 were 51% and 78% (P=0.001), with 28% and 53% complete response (CR) /very good partial response (VGPR) (P=0.003), in the MDex and BMDex arms, respectively. Overall hematologic response at the end of treatment, after a median of 5 cycles, was 56% and 81% (P=0.001), with 38% and 64% CR/VGPR in the MDex and BMDex arms, respectively (P=0.002). Cardiac response was reached in 8 of 33 evaluable patients treated with MDex (24%) and 10 of 26 (38%) who received BMDex (P=0.119). Renal response was attained in 17 of 35 patients (48%) in both arms. However, there was a higher proportion of cardiac progression in the MDex arm with borderline statistical significance (32% vs. 15%, P=0.054). After a median follow-up of living patients of 25 months, 26 patients (24%) died, 16 in the MDex arm and 10 in the BMDex arm with no significant difference in survival (Figure 1a). Achievement of hematologic and cardiac response at 3 months significantly improved survival (Figures 1b and 1c). Conclusion. This is the first prospective randomized trial of novel agents in AL amyloidosis. The criteria of hematologic and cardiac response are validated in the prospective setting for the first time. The primary endpoint, hematologic response at 3 months has been reached, showing more frequent and more profound hematologic responses with BMDex, preventing progression of cardiac dysfunction, with a modest increase in toxicity. This regimen can be proposed as a new standard of care in AL amyloidosis. We would like to acknowledge the European Myeloma Network, the Australasian Leukaemia and Lymphoma Group and the Leukaemia Foundation of Australia for their ongoing support, and Janssen-Cilag for partially funding the trial and providing the study drug. Disclosures Kastritis: Genesis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Cibeira:Janssen: Honoraria; Celgene: Honoraria. Mollee:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Nilelse: Research Funding. Hajek:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Moreau:Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria. Mateos:Janssen, Celgene, Amgen, Takeda, BMS: Honoraria. Wechalekar:Takeda: Honoraria; Janssen: Honoraria; Glaxo Smith Kline: Honoraria; Celgene: Honoraria. Dimopoulos:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genesis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Palumbo:Janssen Cilag: Honoraria; Takeda: Employment, Honoraria. Sonneveld:Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria, Research Funding. Merlini:Pfizer: Honoraria, Speakers Bureau; Millennium Takeda: Consultancy; Prothena: Honoraria; GlaxoSmithKline: Consultancy. Palladini:Prothena: Honoraria.

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

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e19539-e19539
Author(s):  
Hassan Yameen ◽  
Shayna Sarosiek ◽  
Vaishali Sanchorawala
Keyword(s):  
Plasma Cells ◽  
Response Rate ◽  
Chromosomal Abnormalities ◽  
Complete Response ◽  
High Dose ◽  
Al Amyloidosis ◽  
Response Data ◽  
Hematologic Response ◽  
Number Of Patients ◽  
High Dose Melphalan

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.

Treatment of Light Chain (AL) Amyloidosis and Light Chain Deposition Disease (LCDD) with the Combination of Bortezomib and Dexamethasone.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 191-191 ◽  
Author(s):  
Efstathios Kastritis ◽  
Athanasios Anagnostopoulos ◽  
Maria Roussou ◽  
Savvas Toumanidis ◽  
Constantinos Pamboukas ◽  
...  
Keyword(s):  
Median Time ◽  
Light Chain ◽  
Dose Adjustment ◽  
High Dose ◽  
Al Amyloidosis ◽  
Light Chain Deposition Disease ◽  
Hematologic Response ◽  
Organ Response ◽  
Light Chain Deposition

Abstract Background: Primary (AL) amyloidosis and light chain deposition disease (LCDD) are clonal plasma cells disorders characterized by deposition of either amyloid fibrils (in AL) or amorphous nodular non-congophilic deposits (in LCDD) derived from abnormal light chains, that cause failure of affected organs. Treatment of AL is based on steroids and standard dose or high dose melphalan with ASCT. Data on treatment of LCDD are limited. Bortezomib, a proteasome inhibitor, has significant activity in myeloma, which is enhanced by the addition of dexamethasone (BD) and can be given in myeloma patients with renal impairment. We evaluated this combination in patients with AL and LCDD. Methods: We treated consecutive patients with AL or LCDD with the combination of Bortezomib (1.3 mg/m2 days 1, 4, 8 and 11) and Dexamethasone (40 mg days 1–4), every 21 days, for up to 6 cycles. Dose modifications were made based on toxicity. Organ involvement and hematologic and organ response were assessed following standard criteria (Gertz et al, Am J Hematol 2005). Results: Since September 2005, 21 consecutive AL and 2 LCDD patients started treatment with BD. Eight patients (38%) had at least one prior therapy and 13 (62%) had ≥2 organs involved; kidneys and heart were affected in most patients. The majority had impaired performance status, high BNP values and 7 (33%) patients had creatinine&gt;2 mg/dl. Among the 21 AL patients, 2 are early for evaluation, 4 had non-measurable disease and 15 patients are evaluable: 13 (87%) responded (CR+PR) and 7 (47%) achieved hematologic CR. All 5 patients refractory to high dose DEXA had a hematologic response and 3 had a CR. Two of 3 AL patients with abnormal FLC ratio but involved FLC&lt;100 mg/L achieved normal FLC ratio. Both patients with LCDD responded- the patient who was refractory to VAD had a CR. Median time to hematologic response was 0.93 months; all responses occurred within 2 courses while all patients in hematologic CR maintain CR for a median of 10.5 months (range 4.6–21). So far, 6 (28%) AL patients had organ responses (3 renal and 3 cardiac) while 7 (44%) patients had a sustained &gt;50% reduction in BNP. Median time to organ response in AL patients was 4 months (range 2–8). In both LCDD patients albuminuria was reduced by more than 50%. Median follow-up for all patients and for living patients is 9.5 months (range 1–23) and 12 months (range 4–23) respectively. In an intention to treat basis 8 (38%) patients have progressed, including 3 AL patients (14%) who died while on treatment (with two of them at hematologic PR at the time of their death- one died before she was assessable for response). Five AL patients had either hematologic or organ progression at a median of 6.8 months after treatment initiation. Peripheral neuropathy, fatigue, peripheral edema, constipation and exacerbation of postural hypotension were managed with appropriate dose adjustment; however 10 (47%) patients were not able to receive the planned 6 courses. Conclusions: The combination of BD is feasible for patients with AL amyloidosis and LCDD. Most patients achieve rapid hematologic response and toxicity can be managed with close follow-up and appropriate dose adjustment. This treatment may be a valid option for patients with severe heart or kidney impairment who are not candidates for other therapies.

Updated Results of a Phase 2 Study of Bendamustine in Combination with Dexamethasone (Ben/Dex) in Patients with Previously-Treated Systemic Light-Chain (AL) Amyloidosis

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3041-3041 ◽  
Author(s):  
Suzanne Lentzsch ◽  
Raymond L. Comenzo ◽  
Jeffrey A Zonder ◽  
Keren Osman ◽  
Miao Susanna ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Response Rate ◽  
Nyha Class ◽  
Al Amyloidosis ◽  
Phase 2 ◽  
Cardiac Events ◽  
Advisory Committees ◽  
Hematologic Response ◽  
Phase 2 Study

Abstract Background: Melphalan in combination with dexamethasone is an active and the standard regimen in AL amyloidosis. Unfortunately very often patients relapse and other drugs are needed. Bendamustine is a bifunctional alkylating agent approved for the treatment of CLL, NHL, and MM in Europe and the US. But its safety and efficacy in AL amyloidosis is not known. In an effort to investigate the activity of Ben/Dex and improve the outcome of patients with relapsed AL we conduct a multi-center, Phase 2 study of Ben/Dex in AL (NCT01222260) and report data of an updated unplanned interim analysis. First data were reported at ASH 2014 (Abstr.3480). Methods: All patients had relapsed AL after a median of 2 prior therapies (range 1-4). Patients with very advanced cardiac involvement (NYHA Class IIIB/IV) were excluded. Patients with NYHA Class IIIA, NT-proBNP ≥ 1800 ng/L or BNP ≥ 400 ng/L, abnormal cTnT or cTnI could be included after evaluation by cardiology to determine the risk associated with the treatment. Patients with a CrCl ³ 15 mL/min were considered for the trial if they were not in active renal failure. This Phase IIa clinical trial uses a two-stage optimal Simon design enrolling 13 patients in the first stage. Since at least three patients experienced hematologic PR or better, the trial proceeded to the second stage treating an additional 16 patients. If 9 or more patients out of the total of 29 patients evaluable for response experience a hematologic PR or better, the treatment will be considered worthy of further development. The primary objective is to determine the partial hematologic response rate (PR). Secondary objectives included overall hematologic response (OHR) rate, organ response rate (OrRR) (Palladini et al., JCO 2012), time to failure (TTF), toxicities (adverse events at least possibly related to treatment), overall survival (OS) and the assessment of expression of genes associated with ER stress. Patients were assigned to bendamustine according to CrCl: CrCl ≥ 60 mL/min: 100 mg/m2 IV on day 1 and 2 of each cycle, CrCl 59-15 mL/min: 90 mg/m2 IV on day 1 and 2 of each cycle. The option to dose escalate was available to qualifying subjects including escalating to dose level (+)1: 120 mg/m2 (if CrCl ≥ 60 mL/min at the time of inclusion into the study) and 100 mg/m2 (if CrCl 59 - 15 mL/min at the time of inclusion into the study). Dexamethasone was started at 20-40mg weekly according to the performance status of the patient. The duration of each cycle was 28 days. Results: As of 7/15/15, 26 patients have received treatment and 28 patients have been enrolled. Median age of enrolled patients was 66 (range 44-77). Enrolled patients received a median of 1.5 prior regimens (range 1-4). Twelve of the enrolled patients received prior autologous stem cell transplant. Median number of cycles for treated patients is 3.5 (range is 1-12), with 4 patients still receiving treatment. Of note, only 2 patients discontinued treatment due to disease progression. Only 9 patients discontinued treatment due to AE. Most common drug-related AEs (all grades, >25%) included fatigue (39%), nausea (35%) and Anemia (27%),. No grade ≥3 drug-related AE occured in >20% of patients. Of note, no cardiac events were observed, including any increase in NT-proBNP.Of 24 patients eligible for response evaluation, 11 (46%) have responded hematologically, including (≥PR 42%, CR 4%). The median time to best response of treatment (partial response or better) was 1.57 months (range 0.97 to 15.1 months). The CR occurred in a patient after 5 cycles suggesting that this heavily pretreated patient population needs longer treatment to achieve response. Better responses were especially observed in less heavily treated patients. With a median follow-up of 13.4 months (range 1.5 to 30.3 months) the median OS has not been reached yet (Figure 1). The median PFS is 11.5 months (95% CI,1.5-29.1months) (Figure 2). Conclusions: In our updated unplanned interim analysis we found that Bendamustine in combination with dexamethasone is feasible and effective in pretreated AL amyloidosis with impaired organ function (NYHA IIIB and creatinine clearance of 30-15 mL/min were allowed). Cardiac events related to Bendamustine were not observed. Preliminary hematologic response rates are promising in this pretreated patient population, and organ assessments are ongoing. Further study of this approach is warranted. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Lentzsch: Axiom: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Will discuss the use of Bendamustine and Dexamethasone under clinical trial NCT01222260. Comenzo:Takeda Millennium: Research Funding; Prothena: Research Funding; Takeda Millennium: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Karyopharm: Research Funding. Zonder:Celgene: Membership on an entity's Board of Directors or advisory committees, Other: research support; Prothena: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Osman:Millennium / Takeda: Research Funding.

scholarly journals Firstline Daratumumab Shows High Hematologic and Organ Response Rates in Advanced Cardiac AL Amyloidosis - a Retrospective Case Series

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3123-3123
Author(s):  
Georg Jeryczynski ◽  
Antonia Eder ◽  
Eva-Maria Reitter ◽  
Maria-Theresa Krauth ◽  
Hermine Agis
Keyword(s):  
High Risk ◽  
Median Time ◽  
Al Amyloidosis ◽  
Newly Diagnosed ◽  
Stage Iiia ◽  
Hematologic Response ◽  
Risk Patients ◽  
Organ Response ◽  
Very High

Background AL amyloidosis is a plasma cell dyscrasia and the most common form of amyloidosis. It is associated with deposition of light chain amyloid, which leads to organ dysfunction, most commonly of the heart and kidneys. Treatment focuses on the reduction of the production of the monoclonal light chains and includes the off-label use of antimyeloma drugs. Their use, however, is often limited by the advanced organ dysfunction frequently encountered in these patients. Daratumumab, a monoclonal CD38 antibody has shown efficacy in both newly diagnosed and relapsed AL amyloidosis in several reports. It is usually well tolerated in patients with advanced AL amyloidosis-related heart failure and requires no dose adjustment for impaired kidney function. Aims and Methods The aim of this study was to retrospectively assess the efficacy of daratumumab in a single-center cohort of newly diagnosed AL amyloidosis patients. A chart review was performed on all patients treated with frontline daratumumab as an individual healing attempt at the Department of Oncology at the Medical University of Vienna between April 2017 and May 2019. Results A total of 14 patients (nine male, five female) were evaluable. According to the 2004 Mayo staging system one patient was stage I, four patients were stage II and nine patients were stage III, two of which were in the very high risk group IIIb (NT-proBNP > 8500 ng/L). Twelve patients produced monoclonal lambda light chains. Median number of organs involved was 2 (1-4), with heart (78.6%) and kidneys (64.3%) being the most common. All patients received daratumumab at the dose of 16 mg/m2 for at least 3 cycles (range 3-19). Dexamethasone was reduced to 20 mg per daratumumab infusion to increase tolerability. After a median follow-up of 12.5 months (range 2.17-25.17), eleven patients were still receiving daratumumab at time of analysis. One patient with stage IIIa proceeded to heart transplant after four cycles and later underwent autologous stem cell transplantation, while two patients were lost to follow-up (one patient had to withdraw from treatment due to psychiatric comorbidities; one patient moved to a different center). Seven patients were treated with daratumumab alone, seven patients received either additional proteasome inhibitors, additional IMIDs, or both during the course of their treatment. One patient was also briefly treated with oral cyclophosphamide. Two patients experienced infusion reaction at first administration. There was no severe toxicity leading to discontinuation observed, the most significant toxicity was susceptibility to infections for which six patients received intravenous immunoglobulins. Hematologic and organ response were assessed using previously published criteria (Comenzo et al 2012). All patients showed hematologic response at last follow-up. First hematologic response was classified as PR in 50% and VGPR in 50% after a median time of 44 days (7-252). Best hematologic response was VGPR in 78.6% and CR in 21.4%. The rates remained the same to last follow-up. Median time to best response was 277 days (14-412). In the group of high and very high risk patients 77.8% achieved VGPR and two stage IIIa patients (22.2%) achieved CR at last follow-up. Cardiac response was seen in five out of eleven evaluable patients, all classified as stage IIIa, while kidney response was seen in three out of nine (33.3%) patients with kidney involvement. Median time to heart and kidney response was 281 (88-348) and 196 (62-215) days respectively. Conclusion Daratumumab showed high efficacy as a firstline treatment in newly diagnosed AL amyloidosis yielding a 100% objective hematologic response rate and a significant organ response rate even in high risk patients that usually have a very poor prognosis and limited treatment options. Despite the limitations inherent to any retrospective study, our data underline the role of daratumumab as a safe, effective, and tolerable treatment option in AL amyloidosis both as a monotherapy as well as a combination partner for other agents, in particular in patients with advanced stage AL amyloidosis. Figure OffLabel Disclosure: Off-label use of daratumumab in AL Amyloidosis as an individual healing attempt

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