Response to Bortezomib Based Induction Therapy in Newly Diagnosed Light Chain (AL) Amyloidosis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1867-1867 ◽  
Author(s):  
Veerpal Singh ◽  
Ayman Saad ◽  
Jeanne Palmer ◽  
Jasleen K Randhawa ◽  
Parameswaran N. Hari
Keyword(s):  
Light Chain ◽  
Liver Dysfunction ◽  
Cardiac Involvement ◽  
Response Rate ◽  
Initial Therapy ◽  
Al Amyloidosis ◽  
Karnofsky Performance Score ◽  
Significant Activity ◽  
Newly Diagnosed ◽  
Organ Response

Abstract Abstract 1867 Poster Board I-892 Bortezomib has been shown to have significant activity in the suppression of light chain production and induction of responses in patients with relapsed refractory AL Amyloidosis. We analyzed the outcomes of 16 (9 male) newly diagnosed biopsy proven AL Amyloidosis patients treated with Bortezomib based regimens at our institution. All patients received initial therapy with Bortezomib and dexamethasone (dex). Patients with a Karnofsky performance score ( KPS) >70 received Bortezomib at starting doses of 1.3 mg/m2 along with dexamethasone 40 mg on days 1,4,8, 11 ( with a 10 day rest period). Patients with a lower KPS received Bortezomib/Dex on a weekly schedule as tolerated. Dose adjustments were made based on side effects such as neuropathy, hypotension, GI disturbances or electrolyte imbalances. Patients tolerating Bortezomib/dex with improvement in KPS had cyclophosphamide (4) or lenalidomide (1) added to their initial therapy. Patients: Median age was 64 years (39–88). Nine had kappa light chain involvement. Organ involvement was renal (73%), cardiac (63%), hepatic (25%), tongue or soft tissue (20%), GI (30%). Median KPS was 70 (50 –100). Ten of the 16 patients were treated as in-patients due to multi-organ dysfunction. Five patients required hemodialysis within a month of diagnosis. Cardiac involvement was stage 3 (Mayo risk group) in 25%. Three patients were unevaluable: 2 dying before 2 cycles and 1 discontinued therapy (Grade 3 liver dysfunction). Median follow up was 5 months (range 2–33 mo). Results: Evaluable (receiving at least 2 cycles) patients have all had a free light chain response. The overall hematological response rate was 100% with 55% partial remission (PR) and 45% complete remission (CR). Median cycles to achievement of a light chain response was 2 (range 1–4). Four patients underwent autologous stem cell transplantation with no mortality. Five (40%) of the responders have had an organ response (3 renal, 1 macroglossia, 1 cardiac) with only patients alive for >5 months having any evidence of organ response. Five (40%) of the evaluable patients have died with progressive cardiac involvement (2), relapsed disease (2) or renal failure (1) with refusal of dialysis. In patients receiving at least one dose of bortezomib, non-hematologic toxicity (>grade 2) included -neuropathy (20%), hypotension (20%), severe diarrhea (12%), sepsis (12%), paralytic ileus (6%), liver dysfunction (6%), sudden death (6%). Conclusions: Bortezomib in combination with dexamethasone has a high response rate in newly diagnosed AL amyloidosis. This regimen was well tolerated in a cohort of severe, multisystem amyloidosis patients with low treatment related mortality. Light chain responses were fast whereas organ responses were not seen prior to 5 months of therapy. The regimen also served as a platform for further intensification with the addition of lenalidomide, cyclophosphamide or autologous transplant in responders. Disclosures: Off Label Use: Bortezomib for the therapy of amyloidosis. Hari:Millenium: Honoraria, Research Funding.

Bortezomib with Dexamethasone in Newly Diagnosed Patients with Primary Systemic Light Chain Amyloidosis or Multiple Myeloma-Associated AL Amyloidosis

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 5036-5036 ◽  
Author(s):  
Beihui Huang ◽  
Juan Li ◽  
Junru Liu ◽  
Dong Zheng ◽  
Mei Chen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Side Effects ◽  
Light Chain ◽  
Conflicts Of Interest ◽  
Complete Response ◽  
Al Amyloidosis ◽  
Newly Diagnosed ◽  
Hematologic Response ◽  
Best Response ◽  
Organ Response

Abstract Abstract 5036 Objective: To assess the efficacy and tolerability of bortezomib with dexamethasone for patients with primary systemic light chain (AL) amyloidosis or multiple myeloma-associated AL amyloidosis. Methods: Twelve newly diagnosed patients with primary systemic AL amyloidosis and six patient with multiple myeloma-associated AL amyloidosis were treated with a combination of bortezomib (1. 3 mg/m2 d1, 4, 8, 11) and dexamethasone (20 mg d1–4). Results: Sixteen patients was evaluable. 12/16 had a hematologic response and 6/16 (37. 5%) a hematologic complete response. Median cycles to response was 1 cycle and median cycles to best response was 2 cycles. In patients with primary AL amyloidosis, 8/10 (80. 0%) had a hematologic response and 5/10 (50. 0%) a hematologic complete response. In patients with myeloma-associated AL amyloidosis, 7/10 (70. 0%) had a hematologic response and 1/6 (16. 7%) a hematologic complete response. Twelve patients (75. 0%) had a response in at least one affected organ, in which 7 in patients with primary AL amyloidosis and 5 in myeloma-associated AL amyloidosis. Person correlation between hematologic response and organ response was 0. 667 (p=0. 005). Fatigue, diarrhea and infection were the most frequent side effects. Three patients developed herpes zoster and had to stop chemotherapy. Conclusions: VD produces rapid and high hematological responses in the majority of patients with newly diagnosed AL regardless of primary or associated with myeloma. It is well tolerated with few side effects. This treatment may be a valid option as first-line treatment for newly diagnosed patients with primary systemic AL amyloidosis and multiple myeloma-associated AL amyloidosis. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Phase II Trial of Cyclophosphamide, Lenalidomide and Dexamethasone (CYCLO-LEN-DEX) for Previously Untreated Patients with Light-Chain Amyloidosis (AL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2135-2135
Author(s):  
Joan Blade ◽  
Albert Oriol ◽  
Juan José Lahuerta ◽  
Maria-Victoria Mateos ◽  
Javier de la Rubia ◽  
...  
Keyword(s):  
Partial Response ◽  
Board Of Directors ◽  
Cardiac Involvement ◽  
Al Amyloidosis ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Hematologic Response ◽  
Organ Response ◽  
New Treatment ◽  
Good Partial Response

Abstract Background: Treatment with oral melphalan and dexamethasone has been adopted as the standard of care for newly diagnosed patients with immunoglobulin light chain (AL) amyloidosis not eligible for high-dose melphalan and stem cell transplantation (HDM/SCT). However, new treatment options are still needed for this patient population. Aim: Based on the activity of IMiDs® immunomodulatory drugs in relapsed/refractory AL amyloidosis, we designed a multicenter prospective, phase II trial with lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients not eligible for autologous transplant. Patients and methods: The main inclusion criteria were newly diagnosed AL amyloidosis confirmed by biopsy, significant organ involvement, cardiac ejection fraction over 50%, serum creatinine below 3 mg/dL, and not being eligible for autologous transplant. Treatment schedule consisted of 6 cycles of lenalidomide at 15 mg orally (po) on days 1 to 21, dexamethasone at 20 mg po on days 1 to 4 and 9 to 12, and cyclophosphamide at 300 mg/m2 intravenously (iv) on days 1 and 8 every 28 days, followed by 6 more cycles of lenalidomide at the same dose, dexamethasone at 20 mg po on days 1 to 4 and cyclophosphamide 300 mg/m2 iv on day 1. After these 12 cycles, maintenance with lenalidomide (10 mg po on days 1 to 21) and dexamethasone (20 mg po on days 1 to 4) was planned for three additional years or until discontinuation due to intolerance or disease progression. All patients received prophylaxis of thromboembolic events with oral aspirin (100 mg po daily) or subcutaneous low-molecular-weight heparin. The primary endpoint was hematologic response. Diagnosis of AL amyloidosis, definition of organ involvement and response criteria followed the Consensus Opinion from the Xth International Symposium on Amyloid and Amyloidosis (Gertz et al, Am J Hematol 2005), adding the very good partial response category included in the recently reported criteria (Palladini et al, J Clin Oncol 2012). Assessments of response were performed at the beginning of each cycle during the treatment period and every 3 months during the maintenance phase. Results: From September 2010 to December 2012, 28 patients were enrolled in the study. Twenty-three patients had cardiac involvement, with cardiac stage 3 in 14 of them. The overall hematologic response rate was 46%, including 7 patients (25%) with complete response, 5 patients (18%) with very good partial response and 1 patient (3%) with partial response. The organ response rate was 46% and was only observed among patients who achieved hematologic response. The organ response was reached in 10 (43%) of the 23 patients with renal involvement and 6 (26%) of the 23 patients with cardiac involvement. In 4 patients lenalidomide was reduced or discontinued due to toxicity. A therapy-related serious adverse event was reported in 6 patients. No significant cytopenias and no second primary malignancies (SPM) were observed. So far, 11 patients remain on the study. Seventeen (60%) have been discontinued mostly due to death secondary to cardiac or renal AL-related late events (8 patients), progression or lack of response (4), and toxicity (3). After a median follow up of 24 months, the median PFS and OS have not been reached, being significantly longer in responders. The estimated probability of PFS and OS for responders was 92% at 34 months. In contrast, the median PFS and OS for non-responders were only 1.9 and 2.4 months, respectively. Finally, according to Mayo Clinic risk stratification based on cardiac biomarkers, median OS for patients with stage I-II has not been reached (the 2-year estimate was 100%), and was 2.2 months for stage III (p <0.001; Figure 1). Conclusions: Our results support the efficacy and safety of the combination lenalidomide, dexamethasone and cyclophosphamide as a new treatment option for patients with AL amyloidosis not eligible for ASCT, without the risk of neuropathy associated with bortezomib-based therapies. However, this regimen should be preferably used when the organ function is still preserved since patients with advanced stage disease, particularly those with severe cardiac involvement, are unlikely to benefit. Figure 1. Figure 1. Disclosures Blade: Janssen, Celgene and Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Lenalidomide. First-line therapy in combination for AL amyloidosis.. Oriol:Janssen and Celgene: Honoraria. Lahuerta:Celgene: Honoraria; Janssen: Honoraria. Mateos:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. de la Rubia:Janssen and Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Fernandez de Larrea:Janssen and Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. San Miguel:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cibeira:Janssen and Celgene: Honoraria.

Maintained Hematologic and Organ Responses at Two Years Following Stem Cell Transplant In Systemic Light-Chain Amyloidosis (AL) Using Short-Course Bortezomib and Dexamethasone Consolidation Therapy

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2391-2391 ◽  
Author(s):  
Heather Landau ◽  
Hani Hassoun ◽  
Michael A. Rosenzweig ◽  
Christina Bello ◽  
Elizabeth Hoover ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Plasma Cell ◽  
Cardiac Involvement ◽  
Response Rate ◽  
Al Amyloidosis ◽  
Newly Diagnosed ◽  
Cell Disease ◽  
Advisory Committees ◽  
Hematologic Response

Abstract Abstract 2391 Background: We report two-year follow up results from a phase II trial in which we use bortezomib and dexamethasone (BD) as consolidation following risk-adapted SCT for patients with AL (Blood 2009;114:533a). Methods: Patients with newly diagnosed AL involving <=2 organs were assigned to MEL 100, 140 or 200mg/m2 with SCT, based on age, renal function and cardiac involvement. Responses were assessed at 2–3 mos, 12 mos and 24 mos post-SCT. Patients with persistent clonal plasma cell disease at 2–3 mos post-SCT received consolidation with BD for up to 6 cycles (two 21-day, four 35-day cycles). Organ responses and overall survival (OS) were assessed at 12 and 24 mos post-SCT. Results: Thirty-seven patients were enrolled with kidney (68%), heart (43%), liver/GI (14%) and peripheral nervous system (16%) involvement. Forty-one percent had two organ-involvement. Three patients were removed from study prior to SCT due to ineligibility (N=2) or co-morbid illness (N=1); 1 patient is within 100 days of SCT. Four patients with advanced cardiac disease died within 100 days of SCT, resulting in a TRM of 12% (4/33). With a median follow-up of 29 mos, the OS at 12 mos post-SCT was 86%. At 12 and 24 mos, OS in patients with cardiac involvement was 69% and 49% respectively, versus 100% at both timepoints in those without (P = 0.001). Elevations of brain natruretic peptide (BNP) and troponin-I were significantly associated with worse OS, HR 1.2 (95% CI 1.1–1.4; P = 0.001) and HR 4.2 (95% CI 1.8–9.2; P = 0.001), respectively. Post-SCT, the hematologic response rate was 55% with 24% sCR. Sixty-eight percent (19/28) received consolidation with BD for persistent clonal plasma cell disease. At 12 mos post-SCT, the hematologic response rate in evaluable patients was 95% (20/21) with 62% achieving sCR and 60% having organ improvement. At 24 mos post-SCT, the overall response rate was 82% (14/17) including 53% who maintained a sCR and 88% (15/17) who had organ improvement. Interestingly, 92% (11/12) of patients with kidney involvement had organ responses at 24 mos versus 50% (7/14) at 12 mos. Overall, 87% of patients who received BD improved their hematologic response and all patients responded after 1 cycle. There was no correlation between the number of cycles received (median 6; range 1.25–6) and response. Of the 19 patients who received post-SCT BD, 79% experienced grade III-IV toxicity, which was most often hematologic toxicity with thrombocytopenia in 41%. Grade 2 or greater peripheral neuropathy was seen in 32%. Conclusions: In newly diagnosed patients with systemic AL amyloidosis, consolidation with BD following risk-adapted SCT is safe and effective for eradicating persistent clonal plasma cell disease. Hematologic responses are rapid resulting in high overall and unprecedented sCR rates. Organ function improves in the majority of patients and continues to occur over time. Cardiac involvement is associated with inferior survival and cardiac biomarkers are useful for assigning risk. Relapses are seen following completion of therapy, suggesting that a maintenance regimen following post-SCT consolidation may be worthy of further study. Disclosures: Landau: Millenium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Off Label Use: The presentation will discuss bortezomib for consolidation in AL amyloidosis. Comenzo: Millenium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Upfront Ixazomib Plus Dexamethasone Induce Promptly Hematological Response in Patients with Light-Chain Amyloidosis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1908-1908 ◽  
Author(s):  
Zheng Wei ◽  
Yian Zhang ◽  
Jing Li ◽  
Peng Liu
Keyword(s):  
Light Chain ◽  
Proteasome Inhibitor ◽  
Response Rate ◽  
Stage Iii ◽  
Al Amyloidosis ◽  
Newly Diagnosed ◽  
Light Chain Amyloidosis ◽  
Hematological Response ◽  
Hematological Remission ◽  
Grade Iii

Background: CyBorD (bortezomib, cyclophosphamide, and dexamethasone) is considered as an effective induction regimen in newly diagnosed light chain amyloidosis (AL) patients. Although a full dose of dexamethasone (Dex) leads to a higher response rate, the dose is strictly limited, usually because of fluid retention. Additionally, supervised administration of bortezomib weekly, if applied, increases the cost and inconvenience of treatment for service providers and patients.Ixazomib(IXA), an oral proteasome inhibitor, was reported highly effective as a single agent in relapsed or refractory AL amyloidosis. The objective of this observation is to evaluate the feasibility and efficiency of adding a lower dose of Dex to IXA (Id) as an upfront regimen in AL pts. Patients and Methods: Between 9/29/2018-4/1/2019, twenty-five newly diagnosed (ND) AL pts were sequentially enrolled. All AL pts had positive Congo Red staining in biopsy specimens confirmed by immunoelectron microscopy(IEM). Ixazomib 4mg D1,8,15 and Dexamethasone 10mg D1,8,15,22 were given for a 28-day schedule until disease progression or intolerance. Efficiency and safety profiles were assessed at the beginning of each cycle. Patients who had not achieved PR after 3 cycles received additional oral cyclophosphamide (50mg daily). The patients not achieving PR after 3 more cycles would switch to salvage therapies such as lenalidomide-base regimens or melphalan-based regimens. Upfront Id regimen can be prolonged for 2 cycles after a best hematological response (CR) has been achieved. The primary objective was to determine the response rate of this regimen and to evaluate the safety and tolerability of Upfront Id. Secondary objectives included PFS and OS. Results: Patients(n=25) received a median of 4 cycles (1-8) of Id regimen. Most patients were at late stage (20 pts in MAYO stage III, 4 pts in stage I and 1 pts in stage II). The interphase FISH analysis in BM plasma cells finds translocation t(11,14) in 8 pts.(Table 1) All patients were evaluable for toxicity and twenty-four for the response. The ORR was 66.7%(16/24) post cycle 1 and 70.8%(17/24) post cycle 4. Best hematological response achieved to date of this study is CR in 10pts, VGPR in 5 pts. 5 of the 7 pts did not reach their hematological remission have a t(11,14) translocation. With a median of 197 days (34-281) follow-up, 68%(17/25) of the patients were still alive, and 41.7%(10/24) with their best hematological response. 4 of the patients died of sudden and the rest due to the progression of heart failure. (Figure 1) According to CTC AE 5.0, Grade III/IV AEs (no. of pts) included: diarrhea 16%(4), thrombocytopenia 12%(3), general edema 8%(2), hypokalemia 8%(2), AST increased 4%(1), hyperuricemia 4%(1), and pneumonitis 4%(1). All the 4 patients with serious diarrhea quit therapy because of intolerance. (Table 2) Conclusions: Adding low dose dexamethasone to Ixazomib can induce rapid and profound hematological remission in newly diagnosed AL pts, especially in patients without t(11,14). This entirely oral, chemotherapy-free combination regimen ensures patients' compliance. The relatively low incidence of Grade III/IV AEs also makes the regimen seemingly a broad usage in MAYO stage III pts. However, diarrhea and thrombocytopenia in these patients still need awareness. OffLabel Disclosure: Ixazomib (Ixa) is the first oral proteasome inhibitor that approved for the use in patients with relapsed/refractory multiple myeloma (RRMM) in > 60 countries including US and China. In this single-center real-world study, we present the efficacy and safety profile of Ixazomib-based therapy as frontline therapy in patients with AL amyloidosis.

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.

Bortezomib-Containing Regimens for the Treatment of Newly Diagnosed AL Amyloidosis: Experience of Two Centers in Canada

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2131-2131 ◽  
Author(s):  
Hatem Alahwal ◽  
Kevin W. Song ◽  
Peter Duggan ◽  
Heather J. Sutherland ◽  
Paola Neri ◽  
...  
Keyword(s):  
Overall Survival ◽  
Light Chain ◽  
Cardiac Disease ◽  
Research Funding ◽  
Cardiac Response ◽  
Al Amyloidosis ◽  
Newly Diagnosed ◽  
Dismal Prognosis ◽  
Organ Response ◽  
The Impact

Abstract Introduction Bortezomib is a novel, dipeptide boronic acid molecule that has shown anti-tumor activity against Multiple Myeloma (MM) and more recently has been demonstrated to be efficacious in the treatment of Light-chain Amyloidosis (AL). Bortezomib-based regimens have changed the landscape of the treatment of AL Amyloidosis due to high levels of response as well as the adequate tolerance. Based on the above mentioned, we aimed to assess the role of Bortezomib-containing regimens (BCR) for the treatment of newly diagnosed AL amyloidosis. Methods 80 consecutive patients have been treated with bortezomib-containing regimens at BCCA and TBCC in Calgary, AB and Vancouver, BC, Canada from 01/2010 to 01/2016. Among these cases, 51 (63.8%) have received CyBorD, 19 (23.7%) bortezomib (1.3 mg/m2) and dexamethasone and the rest Bortezomib in different combinations (Table 1). The primary objective of the study was to assess hematological and organ response. Results Clinical characteristics are shown in Table 1. Median age at diagnosis was 66 years and 51.1% of patients were male. At the time of analysis, 56 patients are still alive and 14 patients have already progressed. A HR was seen in 65/72 evaluable patients (ORR, 90%) after a median of 6 cycles (range, 1-24). Fourteen patients (17.5%) did not have measurable disease based on light chain levels. CR (34.7%) and VGPR (26.4%) were seen in 61% of cases. Organ response was achieved in 49% of cases. Cardiac response was observed in 40% of cases. Median OS and PFS have not been reached (Estimate, 67 and 41 months, respectively). (Fig 1a) However, OS was shorter in the group with severe heart involvement (NT-pro-BNP>5000 or BNP>1100) (p=0.03) (Fig 1b). In conclusion, BCR are efficacious for the treatment of newly diagnosed AL Amyloidosis, providing with a high degree of organ and hematological responses. The impact of BCR on advanced heart dysfunction cases remains unclear but it seems that these patients still require a different approach maintaining a dismal prognosis. Overall survival and advanced cardiac disease Overall survival and advanced cardiac disease Figure 1 PFS for the whole AL group treated with BCR Figure 1. PFS for the whole AL group treated with BCR Disclosures Song: Janssen: Honoraria; Otsuka: Honoraria; Celgene: Honoraria, Research Funding. Neri:Celgene and Jannsen: Consultancy, Honoraria. Bahlis:Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; Onyx: Consultancy, Honoraria; BMS: Honoraria. Jimenez-Zepeda:Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene, Janssen, Amgen, Onyx: Honoraria.

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

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 8009-8009 ◽  
Author(s):  
Amandeep Godara ◽  
Nauman Saleem Siddiqui ◽  
Lisa Lee ◽  
Denis Toskic ◽  
Teresa Fogaren ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Cardiac Involvement ◽  
Prognostic Significance ◽  
Antibody Therapy ◽  
Mass Effect ◽  
Initial Therapy ◽  
Al Amyloidosis ◽  
Cardiac Responses ◽  
Number Of Patients ◽  
Organ Response

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

Efficacy and Toxicity of Dose-Reduced Bortezomib/Dexamethasone Chemotherapy In Patients with High Risk Cardiac Light Chain Amyloidosis (Mayo Clinic stage III)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1960-1960 ◽  
Author(s):  
Stefan O Schonland ◽  
Tilmann Bochtler ◽  
Anthony D. Ho ◽  
Ute Hegenbart
Keyword(s):  
Light Chain ◽  
Mayo Clinic ◽  
Cardiac Amyloidosis ◽  
Cardiac Involvement ◽  
Early Death ◽  
Stage Iii ◽  
Al Amyloidosis ◽  
Hematologic Toxicity ◽  
Newly Diagnosed ◽  
Grade 3

Abstract Abstract 1960 Purpose: Severe cardiac involvement is known to confer a poor prognosis in patients with light chain (AL-) amyloidosis. These patients do not qualify for high-dose chemotherapy regimens. In a recent analysis we could show that melphalan/dexamethasone therapy was not able to overcome this poor prognosis (Dietrich et al, 2010). Since bortezomib is known to rapidly lower the involved light chain levels (iFLC), it appears a promising alternative regimen. There is only one prospective phase I/II trial in AL amyloidosis using single agent bortezomib (Reece et al., 2009). However, patients with advanced cardiac amyloidosis had been excluded. We therefore assessed the feasibility of bortezomib/dexamethasone (Bd) in patients with high-risk cardiac amyloidosis as defined by Mayo Clinic stage III (median overall survival (OS) 3.5 months (mo), Dispenzieri et al, 2004). Patients and Method: We retrospectively evaluated 38 consecutive patients with systemic AL amyloidosis, who were classified as Mayo Clinic stage III cardiac amyloidosis based on their elevated cardiac biomarkers NT-proBNP, TNT and hsTNT values (patient characteristics table 1). 14 patients were untreated. For the sake of tolerability Bd was administered twice weekly with a reduced bortezomib dosage of 4 × 1.0 mg/m2 and dexamethasone 8 × 8 mg in a 3 week schedule. Result: Median observation of living patients is 5 mo after start of Bd. Median OS is 9 mo (Figure 1a). 18 patients died; among them 11 (29%) during ongoing bd. Median OS of the first line therapy group was 7 mo versus 13 mo in the relapsed group (p=0.056, Figure 1b). 21 patients achieved a hematological remission (HR) after a median of 3 cycles (64% out of 33 evaluable patients, 2 CRs and 19 PRs), whereas 3 patients died during the first Bd cycle and further 2 just started with Bd. Hematologic toxicity grade 3 or 4 according to NCI criteria was observed in 9 patients (24%) (toxicities are listed in table 1). Apart from the 11 early deaths we observed non-hematologic toxicity grade 3 in 8 patients and grade 4 in 6 patients. In 3 patients, the bortezomib dose had to be reduced due to toxicity. Therapy was stopped before the planned 6 – 8 cycles in 11 patients, in 4 cases due to toxicity, in 5 cases due to lacking HR and in 2 cases due to patient‘s choice. 9 patients completed their therapy regularly in HR while therapy is still ongoing in 5 patients. It is planned to update these data in November 2010. Discussion: The goal of this study was to assess whether patients with severe cardiac amyloidosis as defined by Mayo Clinic stage III benefit from Bd therapy. As already known from other studies, we observed a fast reduction of iFLC within 3 months from 203 to 81 mg/l (of evaluable patients) in median. Overall, HR rate was 64%, which is comparable to 71% previously reported by Kastritis et al, 2010. However, toxicity and early death rate were considerable. Main problem of the newly diagnosed patients was the severity of cardiac involvement (median NTpro BNP 11.346 ng/l) leading to a high early mortality. Main problem of the pretreated patients was the lower HR rate of 52% versus 83% of the newly diagnosed patients. Though we observed substantial toxicities in spite of the reduced Bd dosages, the rather poor OS does not appear to be largely due to toxicity. Conclusion: Dose-reduced Bd might be an important treatment option for patients with severe cardiac AL amyloidosis Mayo Clinic stage III because of its high efficacy. However, the toxicity is still significant. Inpatient care for the first cycle of Bd might lead to a reduction of the early death rate. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Efficacy and Tolerability of Daratumumab in Heavily Pretreated AL Amyloidosis: A Systematic Review

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2025-2025 ◽  
Author(s):  
Muhammad Aadil Rahman ◽  
Ali Younas Khan ◽  
Awais Ijaz ◽  
Muhammad Junaid Tariq ◽  
Muhammad Usman ◽  
...  
Keyword(s):  
Heart Failure ◽  
Partial Response ◽  
Light Chain ◽  
Cardiac Amyloidosis ◽  
Cardiac Involvement ◽  
Renal Involvement ◽  
Renal Amyloidosis ◽  
Al Amyloidosis ◽  
Heavily Pretreated ◽  
Organ Response

Abstract Introduction Light chain (AL) amyloidosis is a low burden plasma cell disorder, characterized by deposition of misfolded lambda or kappa light chains. Kidney dysfunction is present in almost two-thirds of patients at the time of initial presentation, followed by diastolic heart failure in about 50% of cases, which is responsible for 75% of deaths in these patients. Autologous stem cell transplant (auto-SCT) remains the gold standard for the management of AL amyloidosis but is often impractical to perform by virtue of patients' age, medical comorbidities including cardiac involvement. Methods We conducted a literature search using three databases (PubMed, Embase,Web of Science). Our search strategy included MeSH terms and key words such as AL amyloidosis, daratumumab and darzalex from date of inception to March 2018. After excluding duplicates, reviews and non-relevant articles, we selected eight studies, including two case reports, two phase II prospective trials and four retrospective trials. Results Data on 129 patients was included, there ages ranged from 43-83 years. Median number of prior therapies were 3 (range: 2-6), 106 (82%) received proteasome inhibitor (bortezomib) based therapy, and 69 (53.5%) received immunomodulatory (lenalidomide) based therapy. Another 41 (32%) received high dose melphalan (HDM) followed by auto-SCT. The time from the diagnosis of AL to the start of daratumumab therapy varied from 0.7-150 months. Eighty-nine (69%) patients had cardiac and 64 (49.6%) patients had renal involvement. A total of 114 (88%) patients received a daratumumab dose of 16 mg/kg weekly for 8 weeks followed by every 2 weeks for the next 8 weeks. A total of 104 patients were evaluable for hematological response, assessed by improvement in free light chain (FLC) levels. Daratumamab achieved an impressive overall response rate (ORR) of 72% (n=75). Complete remission (CR) in 15 (14%) of patients, very good partial response (VGPR) in 44 (42%) and a partial response (PR) in 16 (15%) of patients was noted. Thirty-four patients with cardiac involvement and 26 patients with renal amyloidosis were assessed for organ response across four studies. Thirteen (38%) patients with cardiac amyloidosis demonstrated an improvement in N-terminal pro brain natriuretic peptide (NT-proBNP) levels. Ten (38%) patients with renal involvement responded according to consensus criteria [Palladini et al 2014] for organ response. Another two had improvement in serum creatinine levels. Among the 129 patients treated with daratumumab for AL amyloidosis, 36 (32%) reported infusion related reactions (IRR). Most were mild (grade 1-2). Daratumumab infusion was well tolerated in patients with cardiac (n=54) and renal involvement (n=48). Only one patient needed adjustment in his diuretic dose, another one developed decompensated heart failure and one died due to progression of cardiac disease. Seven patients had worsening of their NT-proBNP levels. Similarly, no dose adjustments were required for patients with renal amyloidosis and one patient tolerated daratumumab infusion at a GFR<20 mL/min without any complications. Conclusion Daratumumab monotherapy is associated with deep and prompt hematological responses in patients with heavily pretreated AL amyloidosis, at the standard dosing regimens used for multiple myeloma, with a favorable safety profile. Furthermore, daratumumab performed well in patients with cardiac amyloidosis even though there is an increased risk of volume overload and infusion related morbidity. Given the high incidence of peripheral neuropathy with bortezomib, cardiotoxicity with carfilzomib based regimens in amyloidosis patients, daratumumab appears to be a suitable alternative. It has already been approved for relapsed amyloidosis (AL) patients in the European Union. Currently, it is being investigated as monotherapy for AL amyloidosis in phase 2 trials (NCT02841033 and NCT02816476) and in combination with bortezomib, cytoxin and dexamethasone (VCd) in a phase III trial (NCT03201965). Disclosures No relevant conflicts of interest to declare.

Outcomes By Cardiac Stage in Newly Diagnosed AL Amyloidosis: Results from Andromeda

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 44-45
Author(s):  
Monique C. Minnema ◽  
Angela Dispenzieri ◽  
Giampaolo Merlini ◽  
Raymond L. Comenzo ◽  
Efstathios Kastritis ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Cardiac Involvement ◽  
Cardiac Response ◽  
Al Amyloidosis ◽  
Newly Diagnosed ◽  
Publicly Traded ◽  
Advisory Committees ◽  
Hazard Ratios ◽  
Organ Response

Background: The extent of cardiac involvement has a major impact on clinical outcomes in patients with newly diagnosed light chain (AL) amyloidosis. Here, we present the hematologic responses, major organ deterioration progression-free survival (MOD-PFS) and event-free survival (MOD-EFS), and organ responses by cardiac stage in patients with newly diagnosed AL amyloidosis treated with cyclophosphamide, bortezomib, and dexamethasone (VCd) with or without daratumumab subcutaneous (DARA SC) in the ANDROMEDA trial (NCT03201965). Methods: Key eligibility criteria included newly diagnosed AL amyloidosis with measurable hematologic disease, ≥1 involved organ, cardiac stage I-IIIA (based on the European Modification of the Mayo staging system), eGFR ≥20 mL/min, and absence of symptomatic multiple myeloma. Patients were randomized (1:1) to receive DARA-VCd or VCd alone. All patients received bortezomib (1.3 mg/m2 SC weekly), cyclophosphamide (300 mg/m2 oral [PO] or intravenous [IV] weekly [500 mg maximum]), and dexamethasone (20-40 mg PO or IV weekly) for six 28-day cycles. DARA SC (1800 mg, co-formulated with recombinant human hyaluronidase PH20 in 15 mL) was administered by injection weekly in Cycles 1-2, every 2 weeks in Cycles 3-6, and every 4 weeks thereafter for up to 24 cycles. Disease evaluations occurred every 4 weeks (Cycles 1-6) and every 8 weeks (after Cycle 7) until major organ deterioration, hematologic progression, death, end of study, or withdrawal. The primary endpoint was overall (ie, at any time) hematologic complete response (CR) rate. Secondary endpoints included MOD-PFS, MOD-EFS, organ response rate, time to hematologic response, survival, and safety. Analyses of hematologic CR and MOD-PFS were performed on the intent-to-treat analysis set; cardiac response analyses were based on patients who were evaluable for cardiac response, defined as patients with baseline NT-ProNBP value ≥650 ng/L or baseline NYHA class 3 or 4 and received at least 1 administration of study treatment. Patients without a baseline assessment or post-baseline assessment were censored at randomization for the MOD-PFS analysis. Descriptive statistics were used to summarize overall CR rate and organ response rate. Hazard ratios and corresponding 95% confidence intervals were estimated based on Cox proportional hazard model. Results: A total of 388 patients were randomized to receive DARA-VCd (n=195) or VCd alone (n=193). Baseline characteristics were well balanced between treatment groups. The median age was 64 years and the proportions of patients with cardiac stage I, II, and III were 23%, 40%, and 37%, respectively. The median duration of treatment was 9.6 months for DARA-VCd and 5.3 months for VCd. Median follow-up was 11.4 months (range, 0.03-21.3+). Baseline characteristics were generally balanced across cardiac stages, except increasing cardiac stage was associated with older age (≥65 years), worse Eastern Cooperative Oncology Group performance status, more advanced renal failure (CrCl ≤30), and functionally worse heart failure (NYHA IIIA). Hematologic CR rates were higher in the DARA-VCd group than in the VCd group in patients with cardiac stages I, II, and III at baseline (Table). Cardiac and renal response rates at 6 months were also higher in the DARA-VCd group regardless of cardiac stage at baseline (Table). The hazard ratios (HRs) for MOD-PFS were 0.33, 0.55 and 0.66 for cardiac stages I, II and III, respectively, favoring DARA-VCd. Corresponding HRs for MOD-EFS were 0.24, 0.39, and 0.48, respectively. Rates of any grade adverse events (AEs) were similar in patients with and without cardiac involvement at baseline. Across both treatment arms, rates of serious treatment-emergent AEs were higher in patients with cardiac involvement at baseline than in those without. Conclusions: The benefit of DARA-VCd was retained over VCd alone across cardiac stages for hematologic CR, MOD-PFS, MOD-EFS, and organ responses. Disclosures Minnema: Kite, a Gilead Company: Speakers Bureau; Celgene: Other: travel support, Research Funding; Amgen: Consultancy; Servier: Consultancy. Dispenzieri:Alnylam: Research Funding; Intellia: Research Funding; Janssen: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Celgene: Research Funding. Comenzo:Unum: Consultancy; Prothena: Consultancy, Research Funding; Amgen: Consultancy; Sanofi: Consultancy; Caleum: Consultancy; Janssen: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Kastritis:Janssen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Wechalekar:Takeda: Honoraria, Other: Travel; Celgene: Honoraria; Janssen: Honoraria, Other: Advisory; Caelum: Other: Advisory. Witteles:Pfizer: Membership on an entity's Board of Directors or advisory committees; Alnylam Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Maurer:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Alnylam: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ionis: Research Funding; Eidos: Research Funding; Akcea: Research Funding. Tran:Janssen: Current Employment, Current equity holder in publicly-traded company. Qin:Janssen: Current Employment. Vasey:Janssen Research & Development: Current Employment, Current equity holder in publicly-traded company. Tromp:Janssen: Current Employment, Current equity holder in publicly-traded company. Weiss:Janssen: Current Employment, Current equity holder in publicly-traded company. Vermeulen:Janssen: Current Employment, Current equity holder in publicly-traded company. Jaccard:Janssen: Consultancy, Honoraria, Other: A.J. has served in a consulting or advisory role for Janssen and has received honoraria from, received research funding from, and had travel, accommodations, or other expenses paid for or reimbursed by Janssen., Research Funding; Celgene: Honoraria, Other: A.J. has served in a consulting or advisory role for Janssen and has received honoraria from, received research funding from, and had travel, accommodations, or other expenses paid for or reimbursed by Celgene., Research Funding.

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