Dartumumab in Pretreated AL Amyloidosis: A Systematic Review

Background: Amyloidosis is characterized by the deposition of misfolded lambda or kappa light chain (AL) proteins in tissue. It commonly affects the heart, which correlates with poor prognosis. Disease-modifying therapies aim to suppress the production of abnormal light chains. Daratumumab (Dara) use is associated with a reduction in light chain protein production. Dara is a human anti-CD38 monoclonal antibody approved for the treatment of newly diagnosed and Relapsed & Refractory Multiple Myeloma. AL amyloidosis plasma cells express CD38, and therefore, Dara is an attractive alternative in this setting. This review aims to assess the efficacy and safety of daratumumab in pre-treated AL amyloidosis patients. Methods: We conducted a comprehensive literature search in PubMed, Embase, Medline using MeSH terms and keywords "AL amyloidosis," "daratumumab", and "darzalex" to incorporate the studies published up to July 2020. We included studies assessing the efficacy and safety of daratumumab alone or in combination with other therapies in pretreated AL amyloidosis. After excluding duplicates, non-relevant, and review articles, we selected four prospective and twelve retrospective studies. RESULTS: In our review, data on 482 patients were included. The ages ranged from 35-88 years. The median number of prior therapies was 3 (ranges:2-6), and the most common therapy was bortezomib in 90% of patients followed by immunomodulators in 55% and stem cell transplant in 35%. A total of 260 (54%) patients received Dara monotherapy, 126 (26%) received Dara plus Dexamethasone (d), and 96 (20%) patients received other Dara containing two or three-drug regimens. The time from the diagnosis to the start of Dara therapy varied from 1 to 137 months. 71 % of patients had cardiac, and 62 % had renal involvement. There was a greater than 30 % reduction of N-terminal pro-brain natriuretic peptide (NT-proBNP) in cardiac patients responsive to therapy. 1. Daratumumab monotherapy: Dara monotherapy achieved an overall response rate (ORR) of 76% (191/249), complete response (CR) of 30% (69/224), very good partial response (VGPR) of 41% (79/192) and partial response (PR) of 14% (19/140). The overall survival (OS) ranges from 59-100% at 10-12 months were noted. Table 1. 2. Daratumumab+ Dexamethasone: Dara plus d achieved ORR of 81% (86/106), CR of 51% (53/102), VGPR of 29% (18/62), PR of 15% (15/102), and OS of 87% at 24 months. Table 1. 3. Daratumumab with combination regimens: The use of Dara based combination regimens of Dara+pomalidomide (P)+d (36% of patients), Dara+lenalidomide (R)+d (32%) and Dara+bortezomib (V)+d (18%), reported by Abeykoon et al., showed an ORR of 88% (14/16), CR of 19 % (3/16), VGPR of 63% (10/16), PR of 6 %(1/16), OS of 89 % at 10 months and progression-free survival (PFS) of 83% at 10 months. Godara et al. reported an ORR of 100% (9/9) using a combination of Dara and birtamimab. The combination of D+cyclophosphamide (c)+V+d reported by Palladini et al. achieved an ORR of 96 % (27/28), CR of 36 % (11/28), VGPR of 29 % (8/28) and PR of 14 % (4/28).Table 1. The most reported adverse event was infusion-related reactions; grade 3-4 adverse were less than 10 % and mostly related to the heart (heart failure & atrial fibrillation). The most-reported hematological adverse effects were anemia, thrombocytopenia, neutropenia, infections, and sepsis. The most common non-hematological adverse events were heart failure, bronchitis, pneumonia, fatigue, nausea, and diarrhea. Table 2. Conclusion: Dara therapy is associated with promising efficacy with a response rate of more than 70% when used alone and more than 80% when used in combination. These regimens are well tolerated in advanced cardiac disease patients with a tolerable risk of volume overload and infusion-related complications. Additional multicenter randomized, double-blind clinical trials are needed to confirm these results. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

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

Blood ◽

10.1182/blood-2018-99-115214 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2025-2025 ◽

Cited By ~ 1

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.

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Sequential Heart and Autologous Stem Cell Transplantation for AL Amyloidosis.

Blood ◽

10.1182/blood.v108.11.3092.3092 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3092-3092

Author(s):

Martha Lacy ◽

Angela Dispenzieri ◽

Suzanne R. Hayman ◽

Shaji Kumar ◽

Robert Kyle ◽

...

Keyword(s):

Heart Failure ◽

Stem Cell ◽

Peripheral Nerve ◽

Median Time ◽

Median Survival ◽

Heart Transplant ◽

Renal Involvement ◽

Al Amyloidosis ◽

Cell Transplant ◽

Peripheral Nerve Involvement

Abstract Background: Patients with AL and congestive heart failure have a median survival of less than one year. Methods: Between 1994 and 2005, 11 patients underwent sequential heart transplant followed by autologous peripheral blood stem cell transplant (SCT) for treatment of AL. Patients had heart dominant AL with minimal/no other organ impairment and no evidence of multiple myeloma. Results: Patients ranged in age from 35 to 63 years (median 54). All had biopsy proven amyloidosis and monoclonal protein detectable in serum (73%) or urine (100%). Free light chain assay was available prior to SCT in 6 and was abnormal in all. All patients presented with NYHA Class III or IV heart failure. All but two patients had no other organ involved at the time of heart transplant. One patient had his heart transplant at another facility and had renal involvement at the time of heart transplant. One patient had peripheral nerve involvement documented prior to heart transplant. Five patients had progression of amyloid to involve other organs by the time of SCT. These included: renal (6), peripheral nerve (2), macroglossia (3), gastrointestinal (2). The median time from diagnosis to heart transplant was 3 months (range 1 to 5). The median time from heart transplant to SCT was 8 months, (range 3 to 24). Conditioning chemotherapy consisted of melphalan 200 mg /m2 (6 patients) or melphalan 140 mg/m2 (5 patients). Two patients died of complications before day +100, (TRM of 18%). Hematologic remissions were seen in 8 and organ responses in 3. Five were unable to be evaluated for organ response due to the heart transplant. Three died from progressive amyloidosis at 66, 56.7, and 55 months following SCT. The median survival is 56.7 months from SCT. Six are alive with a median follow-up of 24 months, range 9 to 90 months. Among the 6 surviving patients, one patient relapsed and one patient has failed to improve, but 4 patients are in continued remission. One patient developed secondary myelodysplastic syndrome. Conclusions: Heart transplant followed by SCT is feasible and offers durable remissions for carefully selected patients with cardiac AL. Figure Figure

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Depth of response prior to autologous stem cell transplantation to predict survival in light chain amyloidosis.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.8516 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 8516-8516

Author(s):

Iuliana Vaxman ◽

M Hasib Sidiqi ◽

Abdullah S. Al Saleh ◽

Shaji Kumar ◽

Eli Muchtar ◽

...

Keyword(s):

Stem Cell ◽

Partial Response ◽

Induction Therapy ◽

Light Chain ◽

Multivariable Analysis ◽

Al Amyloidosis ◽

Prognostic Impact ◽

Cell Transplant ◽

Depth Of Response ◽

The Impact

8516 Background: The role of induction therapy prior to autologous stem cell transplant (ASCT) in immunoglobulin light chain (AL) amyloidosis remains controversial. Data on the prognostic impact of response to induction in a transplanted cohort are lacking. The aim of this study was to assess the impact of response to induction therapy on survival in patients undergoing ASCT for AL amyloidosis. Methods: We conducted a retrospective study of all newly diagnosed AL amyloidosis patients who received induction prior to ASCT between January 2007 and August 2017 at Mayo Clinic, Rochester, Minnesota. Patients receiving only corticosteroids prior to transplant were excluded as were those with an involved light chain of less than 5 mg/dL (not measurable for response). Results: 134 patients met inclusion criteria. The median age at diagnosis was 60 (range 36-74) and 85 (63%) were men. The most commonly used induction regimen was proteasome inhibitor-based (73.1%, n=98). The overall response rate to induction was 83% (complete response 17%, very good partial response 30% and partial response 36%). With a median follow up of 56.5 months, the median PFS and OS was 48.5 months and not reached, respectively. Response depth to induction therapy was associated with improved PFS and OS and was independent of the bone marrow plasma cell percentage. The median PFS was not reached for patients achieving ≥VGPR prior to ASCT and 33.8 months for patient achieving PR or less (P=0.001). The median OS was longer in patients with deeper responses (not reached for patients achieving ≥VGPR vs. 128 months for patients achieving PR or less (P=0.02). On multivariable analysis, independent predictors of OS were melphalan conditioning dose (RR= 0.38; P=0.018) and depth of response prior to transplant (RR 2.52; P=0.039). Conclusions: Hematologic response prior to transplant predicts post-transplant outcomes in patients with AL amyloidosis. [Table: see text]

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Light chain amyloidosis

Mediterranean Journal of Hematology and Infectious Diseases ◽

10.4084/mjhid.2018.022 ◽

2018 ◽

Vol 10 (1) ◽

pp. e2018022 ◽

Cited By ~ 17

Author(s):

Paolo Milani ◽

Giampaolo Merlini ◽

Giovanni Palladini

Keyword(s):

Plasma Cell ◽

Light Chain ◽

Molecular Mechanisms ◽

Cell Clone ◽

Renal Involvement ◽

Response To Therapy ◽

Al Amyloidosis ◽

Cell Transplant ◽

Cardiac Damage ◽

Risk Patients

Light chain (AL) amyloidosis is caused by a usually small plasma-cell clone that is able to produce the amyloidogenic lights chains. They are able to misfold and aggregate, deposit in tissues in the form of amyloid fibrils and lead to irreversible organ dysfunction and eventually death if treatment is late or ineffective. Cardiac damage is the most important prognostic determinant. The risk of dialysis is predicted by the severity of renal involvement, defined by the baseline proteinuria and glomerular filtration rate, and by response to therapy. The specific treatment is chemotherapy targeting the underlying plasma-cell clone. This needs be risk adapted, according to the severity of cardiac and/or multi-organ involvement. Autologous stem cell transplant (preceded by induction and/or followed by consolidation with bortezomib-based regimens) can be considered for low-risk patients (~20%). Bortezomib combined with alkylators is used in the majority of intermediate-risk patients, and with possible dose escalation in high-risk subjects. Novel, powerful anti-plasma cell agents were investigated in the relapsed/refractory setting, and are being moved to upfront therapy in clinical trials. In addition, the use of novel approaches based on antibodies targeting the amyloid deposits or small molecules interfering with the amyloidogenic process gave promising results in preliminary studies. Some of them are under evaluation in controlled trials. These molecules will probably add powerful complements to standard chemotherapy. The understanding of the specific molecular mechanisms of cardiac damage and the characteristics of the amyloidogenic clone are unveiling novel potential treatment approaches, moving towards a cure for this dreadful disease.

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Efficacy and Safety Profile of Bortezomib Based Regimens for Treatment of Newly Diagnosed Amyloidosis: A Systematic Review of Literature

Blood ◽

10.1182/blood-2019-127190 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5583-5583

Author(s):

Muhammad Abdullah Yousaf ◽

Muhaddis Ejaz Ahmad ◽

Maaz Ahmed Yusufi ◽

Hamza Hassan ◽

Adeela Mushtaq ◽

...

Keyword(s):

Clinical Trial ◽

Overall Survival ◽

Retrospective Study ◽

Partial Response ◽

Induction Therapy ◽

Cochrane Library ◽

Al Amyloidosis ◽

Cell Transplant ◽

Newly Diagnosed ◽

Efficacy And Safety

Introduction: For more than a decade, bortezomib (V) has become an integral part of initial treatment of AL amyloidosis It is cytotoxic to plasma cells. We report published literature on efficacy and safety of bortezomib based regimens in patients (pts) with newly diagnosed amyloidosis (ND-AL). Methods: Following PRISMA guidelines, we performed a comprehensive literature search for articles published after 2007 using Pubmed, Embase, Clinical Trials.gov, Cochrane Library and Web of Science. Initially, 649 articles were identified and after a thorough screening, we finalized 9 studies involving 213 ND-AL patients. Prospective (n=91) and retrospective (n=122) studies were included. MeSH terms and keywords were bortezomib and newly diagnosed AL amyloidosis. Results: Chemotherapy followed by HDCT versus frontline HDCT / ASCT: In a retrospective study involving 31 pts by Scott et al., with induction chemotherapy with V-based regimens (n=12), with non-V-based regimens (n=6) and frontline (n=13) high dose melphalan (HDM) therapy followed by autologous stem cell transplant (ASCT). Overall hematological response (OHR) and organ response (OR) rates in the entire cohort after ASCT were 77% and 58% respectively. OHR and OR were 92% & 75% in V-pretreated group and 69% & 54% in pts who received no treatment. The trend was similar for other responses (Table 1). In a clinical trial by Huang, X., et al., induction therapy with Vd (V in combination with dexamethasone) prior to HDM/SCT was compared with frontline HDM/SCT in 58 patients. The OHR, and complete response (CR) between Vd+HDM/SCT (20 evaluable pts) and frontline HDM/SCT (23 evaluable pts) groups were 85.7% versus 53.5% and 67.9% versus 35.7% respectively. All organs showed better response in Vd+HDM/SCT group (Table 1). Vd/CyBorD (Cyclophosphamide, bortezomib, dexamethasone) prior to ASCT: In a prospective clinical trial by Sanchorawala et al., 35 pts were given induction with Vd before HDM and ASCT. Among 27 evaluable pts, OHR was 100% with CR in 76.9% and very good partial response (VGPR) in 23% pts. In a study by Hong et al., 20 patients received induction with Vd or CyBorD prior to ASCT. OHR was 89% with CR in 55%, partial response (PR) in 10% and VGPR in 33%. 5-year overall survival (OS) was 80% and 5-year progression free survival (PFS) was 69%. Vd/CyBorD without ASCT: In a retrospective study by Zhao et al., 23 pts received Vd. OHR was 100% with CR in 44% and PR in 38.9% pts. Median overall survival (mOS) was 38 months and 3-year OS was 41-72%. OR was 25% with kidney being the organ showing response in maximum pts (84%). Kikukawa et al., reported 8 pts who received CyBorD, OHR was 100% with CR in 50%, PR in 25% and VGPR in 25% pts. 63% pts showed OR in heart and/or kidney. In a study by Huang, B., et al., Vd was given to 12 renal ND-AL pts and among 10 evaluable pts, OHR was 80% with CR in 50% and PR in 10%. mOS was 8.2 months and OR was 50%. Other Regimens: In a study by Lee et al., involving 19 pts, VMP (bortezomib, melphalan, prednisone) was given as induction therapy. OHR was 84% with CR in 37%, PR in 26% and VGPR in 21% pts. OS was 39% at 2 years and PFS was 8 months. OR was 53% with heart (50%) and kidney (40%). In a retrospective review by Chari et al., 9 pts were treated with a triplet regimen (V, cyclophosphamide or lenalidomide/thalidomide and d). OHR was 88% with CR in 22% and PR in 66% pts. OR was 77% with heart and kidney both at 44%. Conclusion: In ND-AL pts, V-based combination regimens are very effective and well tolerated as induction therapy, or when used as therapy prior to HDM/ASCT and this approach resulted in better outcomes when compared to frontline HDM/ASCT. Three drug combination therapy with V is effective. Kidney and heart were the major organs to show improvement with therapy. Novel combinations need to be studied in randomized prospective clinical trials. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

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A Systematic Review on Efficacy and Safety of Lenalidomide Based Regimens for Treatment of Newly Diagnosed Amyloidosis

Blood ◽

10.1182/blood-2019-127236 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5584-5584

Author(s):

Muhaddis Ejaz Ahmad ◽

Muhammad Abdullah Yousaf ◽

Mustafa Nadeem Malik ◽

Abdul Rafae ◽

Tariq Iqtidar Sadiq Syed ◽

...

Keyword(s):

Partial Response ◽

Plasma Cells ◽

Nk Cell ◽

Induction Agent ◽

High Dose ◽

Al Amyloidosis ◽

Cell Transplant ◽

Newly Diagnosed ◽

Efficacy And Safety ◽

Front Line

Introduction: Lenalidomide (L), a commonly used drug for the treatment of Multiple Myeloma, but currently it is not being not used as front line agent for the treatment of AL amyloidosis. It works through various mechanism, can cause direct toxicity to plasma cells, inhibits angiogenesis, and promotes tumor apoptosis. Cyclophosphamide (Cy), causes cross links between DNA which leads to cell apoptosis. For last decade, Cy is being used in combination with agents like Velcade for more than and decade, there is paucity of literature about its use in combination with L. L based regimen may be necessary in patients who have contraindications to bortezomib use, additionally targeted immunotherapy based combinations with daratumumab, through NK cell mediated cytotoxicity, may be more effective in the presence of immunomodulatory drugs. Our main objective is to analyze the published literature for the efficacy and toxicity of L based regimens for the treatment of newly diagnosed Amyloidosis (ND-AL). Methods: A systematic search of databases using (per PRISMA guidelines) PubMed, Embase, Web of science, Cochrane database and Clinicaltrials.gov was performed from January 2012 onward, with no restrictions of publication language. A total of 649 articles were identified initially and after a detailed screening, we finalized 9 studies involving 223 ND-AL patients. Results: Lenalidomide, dexamethasone, Cyclophosphamide (LCyD): In a phase II trial by Ciberia et al, (n=28) ND-AL patients (pts) were treated with LCyD. Overall hematological response (OHR) was 46% with complete response (CR) in 25%, very good partial response (VGPR) in 18% and partial response (PR) in 3% pts. Organ response (OR) was 46% with maximum pts. showing response in kidney (43%) and heart (26%). In a study by Kastritis et al., involving 24 pts, LCyD induced, OHR was observed in 55% pts with CR in 8 % (Table 1). For comparison with regimens like Cy, Bortezomib and Dexamethasone (CyBorD), in a retrospective study by Hong et al., 24 pts were given CyBorD. OHR was 89% with CR, VGPR and PR demonstrated in 55%, 33% and 10% pts respectively. 5-yr OS was 80% and 5-yr PFS was 69% (Table 1). Mikhael et al., reported 17 pts given CyBorD. OHR was 94% with CR in 71% and PR in 24% pts. Venner et al., et al. (n=43) reported 20 patients of ND-AL treated with CyBorD showed OHR of 81.4%, with CR in 41.9% and PR in 39.5%. 46% pts showed OR. Chari et al. reported 9 pts. who were given extensive combinations of Cyc and L. OHR was 88%, with CR in 22% and PR in 66% pts. 77% pts showed an OR (Table 1). Induction with L prior to High dose Melphalan (HDM) and stem cell transplant (SCT) vs front line HDM/SCT: In a study by Cowan et al., (n=45) pts in group A (n=21) received induction therapy using novel agent induction using agents like Bortezomib and Lenalidomide prior to HDM/SCT. CR was observed in 50%, VGPR in 7% and PR in 7% pts. Group B (n=24) pts were given HDM/SCT upfront. CR was observed in 28%, VGPR in 14% and PR in 14% pts. Similarly study by Scott et. al., 31 pts who received HDM consolidation were categorized in 3 groups i.e no induction, induction with V-based regimen and induction with other regimens including L. In pts with len/dex (n=2) OHR was 100%, with CR observed in 100% pts (Table 1). Melphalan (M), Lenalidomide (L) and Dexamethasone (d): In a clinical trial (NCT00890552), 25 pts who were given L, M and d, showed a CR of 8%, VGPR of 16% and PR of 33% pts. mOS was 12 mo (Table 1). Conclusion: There is paucity of literature about the use of Lenalidomide for the treatment of newly diagnosed AL patients. In ND-AL pts, CyBorD and as well as Lenalidomide/dexamethasone-based regimens has shown excellent overall hematological responses (up to 100%). Major adverse effects were anemia, thrombocytopenia, neutropenia and rash. We recommend, with adequate sample size, prospective studies need to be conducted for better understanding of efficacy and safety of L based therapies in newer combinations for the treatment of AL Amyloidosis. With good efficacy and tolerance data to support its use, Lenalidomide may have a potential role for its use as an induction agent, salvage therapy as well as post induction long term term maintenance therapy for select AL amyloidosis cases who cant achieve complete remission with induction and / or consolidation regimens. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

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Quantitative Immunoprecipitation Free Light Chain Mass Spectrometry (QIP-FLC-MS) Simplifies Monoclonal Protein Assessment and Provides Added Clinical Value in Systemic AL Amyloidosis

Blood ◽

10.1182/blood-2019-128175 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4375-4375 ◽

Cited By ~ 1

Author(s):

Faye Amelia Sharpley ◽

Hannah Victoria Giles ◽

Richa Manwani ◽

Shameem Mahmood ◽

Sajitha Sachchithanantham ◽

...

Keyword(s):

Mass Spectrometry ◽

Light Chain ◽

Residual Disease ◽

Renal Involvement ◽

Light Chains ◽

Al Amyloidosis ◽

Free Light Chains ◽

Accurate Identification ◽

Monoclonal Protein ◽

Serum And Urine

Introduction Early diagnosis, effective therapy and precise monitoring are central for improving clinical outcomes in systemic light chain (AL) amyloidosis. Diagnosis and disease response assessment is primarily based on the presence of monoclonal immunoglobulins and free light chains (FLC). The ideal goal of therapy associated with best outcomes is a complete responses (CR), defined by the absence of serological clonal markers. In both instances, detection of the monoclonal component (M-component) is based on serum FLC assessment together with traditional serum and urine electrophoretic approaches, which present inherent limitations and lack sensitivity particularly in AL where the levels are typically low. Novel mass spectrometry methods provide sensitive, accurate identification of the M-component and may prove instrumental in the timely management of patients with low-level amyloidogenic light chain production. Here we assess the performance of quantitative immunoprecipitation FLC mass spectrometry (QIP-FLC-MS) at diagnosis and during monitoring of AL amyloidosis patients treated with bortezomib-based regimens. Methods We included 46 serial patients with systemic AL amyloidosis diagnosed and treated at the UK National Amyloidosis Centre (UK-NAC). All patients had detailed baseline assessments of organ function and serum FLC measurements. Baseline, +6- and +12-month serum samples were retrospectively analysed by QIP-FLC-MS. Briefly, magnetic microparticles were covalently coated with modified polyclonal sheep antibodies monospecific for free kappa light chains (anti-free κ) and free lambda light chains (anti-free λ). The microparticles were incubated with patient sera, washed and treated with acetic acid (5% v/v) containing TCEP (20 mM) in order to elute FLC in monomeric form. Mass spectra were acquired on a MALDI-TOF-MS system (Bruker, GmbH). Results were compared to serum FLC measurements (Freelite®, The Binding Site Group Ltd), as well as electrophoretic assessment of serum and urine proteins (SPE, sIFE, UPE and uIFE). Results Cardiac (37(80%) patients) and renal (31(67%) patients) involvement were most common; 25(54%) patients presented with both. Other organs involved included liver (n=12), soft tissue (n=4), gastrointestinal tract (n=3) and peripheral nervous system (n=2). Baseline Freelite, SPE, sIFE and uIFE measurements identified a monoclonal protein in 42(91%), 22(48%), 34(74%) and 21(46%) patients, respectively. A panel consisting of Freelite + sIFE identified the M-component in 100% of the samples. QIP-FLC-MS alone also identified an M-component in 100% of the samples and was 100% concordant with Freelite for typing the monoclonal FLC (8 kappa, 34 lambda). In 4 patients, QIP-FLC-MS identified an additional M-protein that was not detected by the other techniques. In addition, 4/8(50%) kappa and 4/38(11%) lambda patients showed a glycosylation pattern of monoclonal FLCs at baseline by mass spectrometry. Interestingly, the frequency of renal involvement was significantly lower for patients with non-glycosylated forms (25% vs 76%, p=0.01), while no similar relationship was found for any other organs. During the 1-year follow-up period, 17 patients achieved a CR; QIP-FLC-MS identified serum residual disease in 13(76%) of these patients. Conclusion In our series, QIP-FLC-MS was concordant with current serum methods for identifying the amyloidogenic light chain type and provided, against all other individual tests, improved sensitivity for the detection of the monoclonal protein at diagnosis and during monitoring. The ability to measure the unique molecular mass of each monoclonal protein offers clone-specific tracking over time. Glycosylation of free light chains is over-represented in AL patients which may allow earlier diagnosis and better risk-assessment of organ involvement. Persistence of QIP-FLC-MS positive M component in patients otherwise in CR may allow targeted therapy. Overall, QIP-FLC-MS demonstrates potential to be exploited as a single serum test for precise serial assessment of monoclonal proteins in patients with AL amyloidosis. Disclosures Wechalekar: GSK: Honoraria; Janssen-Cilag: Honoraria; Amgen: Research Funding; Takeda: Honoraria; Celgene: Honoraria.

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Conventional Therapy for Amyloid Light-Chain Amyloidosis

Acta Haematologica ◽

10.1159/000507072 ◽

2020 ◽

Vol 143 (4) ◽

pp. 365-372

Author(s):

Paolo Milani ◽

Giovanni Palladini

Keyword(s):

Stem Cell ◽

Plasma Cell ◽

Light Chain ◽

Cell Clone ◽

Alkylating Agents ◽

Proteasome Inhibitors ◽

Response Rates ◽

Al Amyloidosis ◽

Cell Transplant ◽

Conventional Chemotherapy

The vast majority of patients with light-chain (AL) amyloidosis are not eligible for stem cell transplant and are treated with conventional chemotherapy. Conventional regimens are based on various combinations of dexamethasone, alkylating agents, proteasome inhibitors, and immunomodulatory drugs. The choice of these regimens requires a careful risk stratification, based on the extent of amyloid organ involvement, comorbidities, and the characteristics of the amyloidogenic plasma cell clone. Most patients are treated upfront with bortezomib and dexamethasone combined with cyclophosphamide or melphalan. Cyclophosphamide does not compromise stem cell mobilization and harvest and is more manageable in renal failure. Melphalan can overcome the effect of t(11;14), which is associated with lower response rates and shorter survival in subjects treated with bortezomib and dexamethasone, or in combination with cyclophosphamide. Lenalidomide and pomalidomide are the mainstay of rescue treatment. They are effective in patients exposed to bortezomib, dexamethasone, and alkylators, but deep hematologic responses are rare. Ixazomib, alone or in combination with lenalidomide, increases the rate of complete responses in relapsed/refractory patients. Conventional chemotherapy regimens will represent the backbone for future combinations, particularly with anti-plasma-cell immunotherapy, that will further improve response rates and outcomes.

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Sequential response-driven bortezomib-based therapy followed by autologous stem cell transplant in AL amyloidosis

Blood Advances ◽

10.1182/bloodadvances.2020002219 ◽

2020 ◽

Vol 4 (17) ◽

pp. 4175-4179

Author(s):

Marco Basset ◽

Paolo Milani ◽

Mario Nuvolone ◽

Francesca Benigna ◽

Lara Rodigari ◽

...

Keyword(s):

Stem Cell ◽

Partial Response ◽

Stem Cell Transplant ◽

Complete Response ◽

Autologous Stem Cell Transplant ◽

Survival Duration ◽

Al Amyloidosis ◽

Cell Transplant ◽

Duration Of Response ◽

Landmark Analyses

Abstract Autologous stem cell transplant (ASCT) is highly effective in selected patients with light chain (AL) amyloidosis. Bortezomib, preceding or following ASCT, improves responses. Satisfactory responses, including at least a partial response, very good partial response (VGPR) with organ response, or complete response, can be observed after induction therapy alone. We report 139 patients treated upfront with cyclophosphamide/bortezomib/dexamethasone (CyBorD), followed by ASCT only if response was unsatisfactory. Only 1 treatment-related death was observed. After CyBorD, hematologic response (HR) rate was 68% (VGPR or better, 51%), with 45% satisfactory responses. Transplant was performed in 55 (40%) subjects and resulted in an 80% HR rate (65% ≥ VGPR). Five-year survival was 86% and 84% in patients treated with ASCT or CyBorD alone, respectively (P = .438). Also, 6- and 12- month landmark analyses did not show differences in survival. Duration of response was not different in the 2 groups (60 vs 49 months; P = .670). Twenty-one (15%) patients with an unsatisfactory response to CyBorD could not undergo ASCT because of ineligibility or refusal; instead, they received rescue chemotherapy, with HR in 38% of cases and 51% 5-year survival. This sequential response-driven approach, offering ASCT to patients who do not attain satisfactory response to upfront CyBorD, is very safe and effective in AL amyloidosis.

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Seeking Diagnostic Confidence in Typing Amyloidosis: Prospective Results with an Algorithm To Minimize Misdiagnosis of Immunoglobulin Light-Chain (AL) Amyloidosis.

Blood ◽

10.1182/blood.v106.11.5099.5099 ◽

2005 ◽

Vol 106 (11) ◽

pp. 5099-5099

Author(s):

Raymond L. Comenzo ◽

Ping Zhou ◽

Limin Wang ◽

Bradly D. Clark ◽

Martin Fleisher ◽

...

Keyword(s):

African American ◽

Peripheral Neuropathy ◽

African Americans ◽

Light Chain ◽

Monoclonal Gammopathy ◽

Al Amyloidosis ◽

Cell Transplant ◽

Cardiac Amyloid ◽

Hereditary Amyloidosis ◽

The Usa

Abstract In order to treat patients with symptomatic amyloidosis, the amyloidosis must be typed with confidence. Immunohistochemical techniques for light-chain isotype identification of amyloid are not reliable, and techniques to type fibrils extracted from clinical specimens are neither widely available nor validated. Retrospectively, investigators in the United Kingdom have shown that hereditary amyloidosis can be misdiagnosed as AL in 10% of cases because family history is often not relevant and because a monoclonal gammopathy (MG) and an hereditary variant can be present in the same patient (NEJM2002;346). The most common types of amyloidosis in the USA are AL and hereditary, the latter due to mutations in proteins such as transthyretin (TTR), fibrinogen A α-chain (FnAα), apolipoprotein AI or AII, and lysozyme. The genes for these proteins are not routinely examined in all cases of likely AL amyloidosis, and clinical genetics laboratories do not offer screening for all of them. The most common hereditary variant in the USA is the V122I transthyretin mutation found in 4% of African-Americans. In addition, a common presentation of both AL and hereditary amyloidosis is peripheral neuropathy. Furthermore, in the case of FnAα nephropathy, patients usually have isolated renal amyloid without marrow involvement. To minimize the risk of misdiagnosis of AL at our center, we prospectively tested four categories of patients with a tissue diagnosis of amyloidosis for hereditary variants whether or not MG was present: African-Americans, patients with dominant peripheral neuropathy (PN), patients with isolated renal amyloidosis (RA) without marrow involvement, and patients referred for hereditary testing or lack of MG. Testing was by PCR amplification and sequencing of genomic DNA. From 6/1/02 to 8/1/05, we evaluated 178 patients referred for amyloidosis, and 30% (n=54) were screened according to this algorithm: 20 African-Americans (16 with MG), 16 with PN (11 with MG), 7 with RA without marrow amyloid (all with MG), 7 referred for hereditary testing and 4 without MG. Of those with amyloidosis and monoclonal gammopathies, 6% (2/34) had both a monoclonal gammopathy and heterozygosity for a mutant TTR: a 45 year-old African-American man (V122I) with cardiac amyloid and a 59 year-old man (F64L) with polyneuropathy. Of the 9 African-American and PN patients without MG, 4 had mutant TTR. Of 7 sent for hereditary testing, 6 had mutant TTR, one of whom also was found to have undiagnosed stage I lambda light-chain myeloma. Of 4 without MG, 2 had senile cardiac amyloid, 1 AA and 1 had amyloid that could not be typed. For those with mutant TTR and MG, TTR tissue-staining resolved the type of amyloid. These results justify further study of screening for hereditary variants in patients with apparent AL, including those with AL associated with multiple myeloma. Myelotoxic therapies such as stem cell transplant are not appropriate treatments for patients with hereditary amyloidosis. These results also highlight the need for the development, validation and dissemination of reliable techniques for identifying fibrils extracted from tissue, and raise the question as to whether or not hereditary amyloid proteins increase the risk of developing MG.

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