Droxidopa for Treatment of Refractory Orthostatic Hypotension in Patients with AL Amyloidosis: A Case Series

Abstract Background Orthostatic hypotension due to autonomic dysfunction is a well-known complication of light chain (AL) amyloidosis, which can become progressively debilitating and difficult to manage. Treatment of the underlying plasma cell dyscrasia will eventually decrease further amyloid deposition. Management of orthostatic hypotension secondary to AL amyloidosis improves quality of life and facilitates delivery of plasma cell therapy. Pharmacologic interventions include fludrocortisone, sympathomimetic agents such as midodrine, droxidopa, the acetylcholinesterase inhibitor pyridostigmine or the norepinephrine transporter (NET) inhibitor atomoxetine. Fludrocortisone is often poorly tolerated in amyloid patients because it may exacerbate edema. Droxidopa is a synthetic amino acid analog that is directly metabolized to norepinephrine by dopa-decarboxylase, which increases blood pressure (BP) by inducing peripheral arterial and venous vasoconstriction. Aims To assess the effectiveness of droxidopa in patients with AL amyloidosis with severe orthostatic hypotension refractory to midodrine. Also, to describe effective dose of droxidopa, duration of therapy, adverse effects and reasons for discontinuation. Methods A regional retrospective study was done in patients with AL amyloidosis with severe, refractory orthostatic hypotension who received droxidopa. Retrospective data was reviewed from 2018 to 2021 at a single academic center in the United States. Results Five patients with AL amyloidosis were included in the study; three patients had lambda-restricted plasma cell dyscrasia and two had multiple myeloma (MM) associated AL amyloidosis (both kappa light chain restricted). Of the five patients, all had cardiac, renal, autonomic nervous system and peripheral nervous system involvement and two of the five had gastrointestinal involvement as well. Given their poor performance status and advanced organ involvement, none of the patients were eligible for high-dose intravenous melphalan with autologous peripheral blood stem cell transplantation (HDM/SCT), and thus were treated with cyclophosphamide, bortezomib and dexamethasone (CyBorD). All patients achieved very good partial response to complete hematologic response. The main findings are summarized in table 1. All patients had severe, symptomatic orthostatic hypotension that was objectively defined as a decrease in systolic blood pressure by 20 millimeters of mercury (mmHg) or a decrease in diastolic blood pressure of 10 mmHg from supine to either sitting or standing in the clinic or at home (Freeman R consensus statement on the definition of orthostatic hypotension, 2011). Initial treatment for all patients included midodrine, ranging from 5 to 30mg TID based on individual tolerance. Three of the patients also were initially treated with fludrocortisone 0.05 to 0.2mg daily (use limited by fluid retention). Only one patient was on pyridostigmine 30mg TID (case 5). Given persistence of symptoms despite therapy, droxidopa was started at 100mg TID in all patients, and the dose was titrated as tolerated. None required the maximal approved dose of 600mg TID. The indication to start droxidopa was based on refractory, symptomatic orthostatic hypotension in all five patients. After initiation of droxidopa, all except for one patient reported improvement both in symptoms of lightheadedness as well as measurements of orthostatic blood pressure values. By the end of this study, three patients continued treatment with droxidopa (cases 1-3); one was weaned-off after resolution of symptoms (case 5) and one was discontinued due to supine hypertension (case 4). Conclusion Data shows that droxidopa is an effective treatment of orthostatic hypotension refractory to midodrine in patients with AL amyloidosis. Slow titration may be important to minimize rapid changes in blood pressure. Further studies are warranted to assess droxidopa's safety and compare with other treatments for orthostatic hypotension. Figure 1 Figure 1. Disclosures Hughes: Amgen: Speakers Bureau; Rigel: Other: Advisory Board, Research Funding; Abbvie: Speakers Bureau; Karyopharm: Other: Advisory Board, Speakers Bureau. Sanchorawala: Celgene: Research Funding; Takeda: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron: Membership on an entity's Board of Directors or advisory committees; Proclara: Membership on an entity's Board of Directors or advisory committees; Oncopeptide: Research Funding; Karyopharm: Research Funding; Sorrento: Research Funding; Pfizer: Honoraria. Sloan: Nuvectis: Consultancy; Abbvie: Consultancy; Stemline: Consultancy; Astrazeneca: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Pharmacosmos: Membership on an entity's Board of Directors or advisory committees.

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A Phase II Trial of Nivolumab and Ibrutinib for Patients with Relapsed or Refractory Central Nervous System Lymphoma

Blood ◽

10.1182/blood-2019-131463 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4086-4086

Author(s):

Jason R. Westin ◽

Nathan H. Fowler ◽

Loretta J. Nastoupil ◽

Sattva S Neelapu ◽

Hun Ju Lee ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Response Rate ◽

Single Agent ◽

Advisory Board ◽

Cns Lymphoma ◽

Advisory Committees

Background: Central Nervous System (CNS) lymphoma is a rare and distinct subtype of diffuse large B-cell lymphoma (DLBCL). CNS lymphoma has a unique genomic profile which has similarities to the activated B-cell (ABC) subtype of DLBCL, which may speak to potential targets for therapy. These aberrancies include near uniform reliance on Toll-Like Receptor signaling, mutations of MYD88, and frequent translocation or copy number alterations of 9p24 which codes for programmed death receptor ligand 1 (PD-L1). Mutations of MYD88 may predict for response to Bruton's tyrosine kinase (BTK) inhibitors in patients with systemic DLBCL. Expression of PD1 or PD-L1, which corresponds to response with PD-targeted therapy in solid tumors, has been found on up to 90% of CNS lymphoma cases, and 60% of specimens had tumor infiltrating lymphocytes which were PD1+ (Berghoff, Clin Neuropath 2014). In addition, the majority of CNS lymphoma cases have a copy gain of 9p24.1, associated with increased expression of PD-L1 (Chapuy, Blood 2016). This suggests a potential ongoing immune reaction against CNS lymphoma, but the microenvironment and tumor conspire to render the immune response ineffective. Ibrutinib is a BTK inhibitor which is FDA approved for multiple B-cell malignancies and is known to achieve therapeutic concentration in the cerebral spinal fluid (CSF), with activity in CNS lymphoma as a single agent and in combination with other agents. Nivolumab is a PD1 inhibitor which is FDA approved for multiple malignancies, with impressive anecdotal evidence of single agent activity in CNS lymphoma. Ibrutinib and nivolumab have been combined in other studies with modest toxicities. Study Design and Methods: We are conducting a phase II, open label, single center clinical trial combining ibrutinib with nivolumab to treat patients with relapsed CNS lymphoma (NCT03770416). Patients are eligible if they have CNS lymphoma relapsed after or were refractory to at least 1 prior line of therapy with adequate organ and bone marrow function, are aged 18y or greater, have not received prior ibrutinib or PD1 inhibitor, and do not require persistent high dose steroids. The trial has two cohorts which will be sequentially enrolled. Cohort A begins with ibrutinib 560mg oral daily for a single 28-day cycle, followed by ibrutinib combined with nivolumab 240mg IV every 14 days. Cohort B begins with the ibrutinib and nivolumab combination during the first cycle. Patients who have at least a partial response at the conclusion of the planned 6 cycles of combined ibrutinib and nivolumab may continue therapy for up to 2 years total or until progression of disease or unacceptable toxicity occurs. Neurocognitive assays and patient reported outcome instruments are being utilized. The primary objective is to determine the best overall response rate during the first 24 weeks of therapy. Secondary objectives will include the response rate of ibrutinib as a lead in prior to the combination, the complete response rate, landmark survival outcomes, and the safety of the combination. Exploratory analyses include assays of the blood and CSF for ctDNA and immune profiling. The first patient was treated in February 2019, with a planned total of 40 patients to be enrolled. Disclosures Westin: MorphoSys: Other: Advisory Board; Juno: Other: Advisory Board; Novartis: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board, Research Funding; 47 Inc: Research Funding; Genentech: Other: Advisory Board, Research Funding; Curis: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; Unum: Research Funding. Fowler:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: 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; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nastoupil:TG Therapeutics: Honoraria, Research Funding; Novartis: Honoraria; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Celgene: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding; Spectrum: Honoraria; Bayer: Honoraria. Neelapu:Allogene: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Novartis: Consultancy; Karus: Research Funding; Celgene: Consultancy, Research Funding; Precision Biosciences: Consultancy; Cell Medica: Consultancy; Incyte: Consultancy; Acerta: Research Funding; Unum Therapeutics: Consultancy, Research Funding; Pfizer: Consultancy; BMS: Research Funding; Poseida: Research Funding; Merck: Consultancy, Research Funding; Cellectis: Research Funding. Parmar:Cellenkos Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: ibrutinib and nivolumab are not yet indicated for CNS lymphoma

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In Vitro and inVivo Activity of Melflufen in Amyloidosis

Blood ◽

10.1182/blood-2019-125952 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3100-3100 ◽

Cited By ~ 2

Author(s):

Ken Flanagan ◽

Muntasir M Majumder ◽

Romika Kumari ◽

Juho Miettinen ◽

Ana Slipicevic ◽

...

Keyword(s):

Board Of Directors ◽

Cell Lines ◽

Plasma Cell ◽

Light Chain ◽

Research Funding ◽

Plasma Cells ◽

Al Amyloidosis ◽

Advisory Committees

Background: Immunoglobulin light-chain (AL) amyloidosis is a rare disease caused by plasma cell secretion of misfolded light chains that assemble as amyloid fibrils and deposit on vital organs including the heart and kidneys, causing organ dysfunction. Plasma cell directed therapeutics, aimed at preferentially eliminating the clonal population of amyloidogenic cells in bone marrow are expected to reduce production of toxic light chain and alleviate deposition of amyloid thereby restoring healthy organ function. Melphalan flufenamide ethyl ester, melflufen, is a peptidase potentiated alkylating agent with potent toxicity in myeloma cells. Melflufen is highly lipophilic, permitting rapid cellular uptake, and is subsequently enzymatically cleaved by aminopeptidases within cells resulting in augmented intracellular concentrations of toxic molecules, providing a more targeted and localized treatment. Previous data demonstrating multiple myeloma plasma cell sensitivity for melflufen suggests that the drug might be useful to directly eliminate amyloidogenic plasma cells, thereby reducing the amyloid load in patients. Furthermore, the increased intracellular concentrations of melflufen in myeloma cells indicates a potential reduction in systemic toxicity in patients, an important factor in the fragile amyloidosis patient population. To assess potential efficacy in amyloidosis patients and to explore the mechanism of action, we examined effects of melflufen on amyloidogenic plasma cells invitro and invivo. Methods: Cellular toxicity and apoptosis were measured in response to either melflufen or melphalan in multiple malignant human plasma cell lines, including the amyloidosis patient derived light chain secreting ALMC-1 and ALMC-2 cells, as well as primary bone marrow cells from AL amyloidosis patients, using annexin V and live/dead cell staining by multicolor flow cytometry, and measurement of cleaved caspases. Lambda light chain was measured in supernatant by ELISA, and intracellular levels were detected by flow cytometry. To assess efficacy of melflufen in vivo, the light chain secreting human myeloma cell line, JJN3, was transduced with luciferase and adoptively transferred into NSG mice. Cell death in response to melflufen or melphalan was measured by in vivo bioluminescence, and serum light chain was monitored. Results: Melflufen demonstrated increased potency against multiple myeloma cell lines compared to melphalan, inducing malignant plasma cell death at lower doses on established light chain secreting plasma cell lines. While ALMC-1 cells were sensitive to both melphalan and melflufen, the IC50 for melphalan at 960 nM was approximately 3-fold higher than melflufen (334 nM). However, ALMC-2 cells were relatively insensitive to melphalan (12600 nM), but maintained a 100-fold increase in sensitivity to melflufen (121 nM). Furthermore, while 40% of primary CD138+ plasma cells from patients with diagnosed AL amyloidosis responded to melflufen treatment in vitro, only 20% responded to melphalan with consistently superior IC50 values for melflufen (Figure 1). Light chain secreting cell lines and AL amyloidosis patient samples were further analyzed by single cell sequencing. We further examined differential effects on apoptosis and the unfolded protein response in vitro in response to either melflufen or melphalan. This is of particular interest in amyloidosis, where malignant antibody producing plasma cells possess an increased requirement for mechanisms to cope with the amplified load of unfolded protein and associated ER stress. As AL amyloidosis is ultimately a disease mediated by secretion of toxic immunoglobulin, we assessed the effects of melflufen on the production of light chain invitro, measuring a decrease in production of light chain in response to melflufen treatment. Finally, we took advantage of a recently described adoptive transfer mouse model of amyloidosis to assess the efficacy of melflufen and melphalan in eliminating amyloidogenic clones and reducing the levels of toxic serum light chain in vivo. Conclusions: These findings provide evidence that melflufen mediated toxicity, previously described in myeloma cells, extends to amyloidogenic plasma cells and further affects the ability of these cells to produce and secrete toxic light chain. This data supports the rationale for the evaluation of melflufen in patients with AL amyloidosis. Figure 1 Disclosures Flanagan: Oncopeptides AB: Employment. Slipicevic:Oncopeptides AB: Employment. Holstein:Celgene: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; Genentech: Membership on an entity's Board of Directors or advisory committees; Sorrento: Consultancy. Lehmann:Oncopeptides AB: Employment. Nupponen:Oncopeptides AB: Employment. Heckman:Celgene: Research Funding; Novartis: Research Funding; Oncopeptides: Research Funding; Orion Pharma: Research Funding.

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Safety and Tolerability of Cael-101 in Combination with Anti-Plasma Cell Dyscrasia Therapy in Patients with AL Amyloidosis: 1-Year Results from an Open-Label Phase 2 Trial

Blood ◽

10.1182/blood-2021-153636 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 468-468

Author(s):

Jason Valent ◽

Jeffrey A. Zonder ◽

Michaela Liedtke ◽

John Silowsky ◽

Michael R. Kurman ◽

...

Keyword(s):

Board Of Directors ◽

Plasma Cell ◽

Amyloid Fibrils ◽

Renal Involvement ◽

Plasma Cell Dyscrasia ◽

Al Amyloidosis ◽

Phase 2 ◽

Open Label ◽

Advisory Committees ◽

Phase 2 Trial

Abstract Background: AL amyloidosis, a rare, severe, progressive, systemic disorder caused by plasma cell dyscrasia (PCD), results in insoluble immunoglobulin light chain amyloid fibrils depositing in organs and causing significant dysfunction, morbidity, and mortality. Most patients receive anti-PCD therapy as standard of care (SOC) to suppress plasma cell proliferation and arrest the generation and deposition of new amyloid fibrils. At present, no approved therapies exist that target fibrils already deposited. CAEL-101, a monoclonal antibody, binds to amyloid light chain fibrils and promotes removal from tissues. In this Phase 2 trial, patients were treated with doses up to 1000 mg/m 2, combined with SOC, demonstrating this dose was well tolerated and appropriate for Phase 3. Aim: Evaluate long-term safety and tolerability of CAEL-101, administered with SOC in AL amyloidosis. Methods: Adult patients with confirmed AL amyloidosis diagnosis (Mayo Stages I, II, IIIa), 6-month minimum life expectancy, and measurable hematologic disease were eligible for this ongoing, open-label, phase 2 study (NCT04304144). Patients with other forms of amyloidosis, multiple myeloma, supine systolic blood pressure <90 mm Hg, or symptomatic orthostatic hypotension were excluded. All patients received CAEL-101 1000mg/m 2 every other week with SOC anti-PCD therapy until investigator decided anti-PCD was no longer needed (Figure). Safety assessments included treatment-emergent adverse events (TEAEs), clinical laboratory tests, electrocardiograms, vital signs, and physical examinations. Pharmacokinetic endpoints included maximum serum concentration (C max) and minimum serum concentration of CAEL-101 prior to next dose (C trough). Exploratory endpoints included biomarkers for cardiac function (cardiac troponin T [cTnT] and N-terminal pro-brain natriuretic peptide [NT-proBNP]), and renal function (estimated glomerular filtration rate and proteinuria). Results: The 25 patients averaged 65.2 years (range 47 to 80), with the majority male (72.0%). Mayo Stages I (8.0%), II (76.0%), and IIIa (16.0%) reflected the wide range of disease severity in enrolled patients ; 19 (76.0%) presented with cardiac involvement, 8 (32.0%) with renal involvement, and 20 (80.0%) had received prior anti-PCD therapy. Twenty-four (96.0%) patients experienced TEAEs, but only 6 (24.0%) experienced a possibly treatment related TEAE (Table). Eight (32.0%) patients experienced at least 1 Grade ≥3 TEAE and 7 (28.0%) experienced at least 1 serious adverse event. There were 3 (12.0%) discontinuations; 1 death due to septic pneumonia (investigator determined not related to CAEL-101), one heart transplant, and one patient who withdrew consent. Most common TEAEs included nausea (9 [36.0%]], constipation (8 [32.0%]), and diarrhea, fatigue, or rash (7 [28.0%] each). Addition of daratumumab (n = 12) to the anti-PCD combination treatment of cyclophosphamide-bortezomib-dexamethasone (CyBorD) did not alter the pharmacokinetic or tolerability profile of CAEL-101. Of the 19 current cardiac evaluable patients (baseline NT-proBNP ≥332 ng/L and ≥1 post-first-dose NT-proBNP value), 15 (78.9%) have responded (≥ 30% NT-proBNP decrease from baseline) or are stable on CAEL-101 therapy. Renal evaluable patients, as determined by Investigator at a single site, showed a similar proteinuria response. Discussion: This ongoing trial is evaluating the long-term safety and tolerability of CAEL-101 administered with anti-PCD SOC as a treatment to reduce amyloid burden in patients with cardiac AL amyloidosis. CAEL-101 was well tolerated when administered with anti-PCD therapy. Most TEAEs observed were mild to moderate in severity and did not require intervention. There were no meaningful differences in tolerability or exposure to CAEL-101 when daratumumab was added to the anti-PCD regimen. Improvements in cardiac and renal response biomarkers were observed in most patients presenting with cardiac or renal involvement, respectively, at study entry. Conclusion: After approximately 1-year, CAEL-101, as part of an AL amyloidosis treatment strategy, demonstrates to be well tolerated. This updated report confirms previous findings for the use of CAEL-101 in combination with anti-PCD. A Phase 3 clinical program is ongoing to further elucidate the efficacy and safety of CAEL-101. Figure 1 Figure 1. Disclosures Valent: Takeda Pharmaceuticals: Speakers Bureau; Amgen: Speakers Bureau; Caelum Biosciences: Other: Clinical Trial Funding; Celgene Corporation: Speakers Bureau. Zonder: Caelum Biosciences: Consultancy; Regeneron: Consultancy; Intellia: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alnylam: Consultancy; BMS: Consultancy, Research Funding. Liedtke: Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Alnylam: Membership on an entity's Board of Directors or advisory committees. Silowsky: Caelum Biosciences: Current Employment. Kurman: Caelum Biosciences: Other: Medical Monitor. Daniel: Caelum Biosciences: Current Employment. Jobes: Caelum Biosciences: Current Employment. Harnett: Caelum Biosciences: Current Employment. Raviwong: Caelum Biosciences: Current Employment. Spector: Caelum Biosciences: Current Employment. Sobolov: Caelum Biosciences: Current Employment.

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Sars-Cov-2 Infection and Systemic Light Chain Amyloidosis: The International Society of Amyloidosis' Survey

Blood ◽

10.1182/blood-2020-141569 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 11-11

Author(s):

Paolo Milani ◽

Vaishali Sanchorawala ◽

Ramon Lecumberri ◽

Sunil Saith ◽

Mathew S. Maurer ◽

...

Keyword(s):

Mechanical Ventilation ◽

Data Collection ◽

Board Of Directors ◽

International Society ◽

Light Chain ◽

Research Funding ◽

Advisory Board ◽

Al Amyloidosis ◽

Advisory Committees ◽

Heart Involvement

Introduction: The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has become a global health crisis since it was first reported in December 2019. In a subset of infected subjects, pneumonia, multi-organ failure, and eventually death can occur. Frail patients and those with comorbidities are believed to be at increased risk of severe manifestations of SARS-CoV-2 infection. Patients with light chain (AL) amyloidosis have a hematologic malignancy that causes multi-organ dysfunction and can be at higher risk of complications and death. The International Society of Amyloidosis (ISA) has issued a guidance (Kastritis et al. BJH 2020, https://cms.cws.net/content/isaamyloidosis.org/files/ISA%20recommendations%20Covid-19%20v_%203_3.pdf) for patients with amyloidosis during the pandemic and called for an international data collection in April 2020. Aim of this study is to report the preliminary data of the ongoing international survey regarding systemic AL amyloidosis and COVID-19. Methods: The survey was proposed by the ISA Board and approved by the coordinating institution's Ethics Committee. All members of the ISA were invited to participate by email and a link for participation is online on ISA website. RedCap software was used for the data collection. Results: Twelve Institutions requested the access to the data collection system from 7 countries. At the data lock of July 26, 2020, 29 patients with systemic amyloidoses were collected from 7 different Institutions. Systemic AL amyloidosis patients reported so far were 19: 12 from the Pavia Amyloidosis Research and Treatment Center (Italy), 3 from the Boston Medical Center (USA), and 1 patient each from the Columbia University Hospital (New York, USA), Hospital Clinic (Barcelona, Spain), Clinica Universitaria de Navarra (Navarra, Spain) and Amyloidosis Centrum (Heidelberg, Germany). Eleven (58%) had heart involvement, 8 (42%) had kidney and two or more organs were involved in 9 patients (47%). The most frequent comorbidities reported were history of hypertension in 7 (37%) and cardiovascular diseases in 3 (16%). Four (21%) patients were newly diagnosed and treatment-naïve at the time SARS-CoV-2 infection was documented. The remaining 15 patients had received a median number of 2 previous lines of therapy (range 1-3). Nine (47%) patients were on active chemotherapy at the time of COVID-19 infection. Five were receiving daratumumab combinations, and the 4 remaining patients were on cyclophosphamide, bortezomib and dexamethasone, oral melphalan and dexamethasone, lenalidomide and ixazomib. Relevant concomitant medications were anti-hypertensive drugs in 26% of cases and diuretics in 21%. One patient was on dialysis. COVID-19-related symptoms were fever 11 (58%), cough 8 (42%), anosmia and ageusia. Pneumonia was documented in 10 (53%) patients, 5 of whom had acute respiratory distress syndrome (ARDS) (26%). Four of them were treated with non-mechanical ventilation and one accessed intensive care support. Three of the 5 patients with severe COVID-19 had heart involvement, 2/5 had concomitant heart and kidney involved and 3 was infected while on active chemotherapy. Azytromicin was used in 6 (26%) cases, which was in combination with hydroxycloroquine in 4 of them. Three patients received steroids as treatment for SARS-CoV-2 infection, while anticoagulant therapy was used only in two cases. Lopinavir, tocilizumab and sarilumab were used in one patient each. Four patients (21%) died in the whole cohort. Three had ARDS and one patient died few weeks after the recovery of COVID-19 infection. All deceased patients had heart involvement, 2 were on active therapy (daratumumab plus bortezomib and ixazomib plus dexamethasone). Two patients with kidney involvement at diagnosis, one with ARDS and one with a radiological documented pneumonia treated with non-mechanical ventilation recovered from COVID-19 but developed subsequent worsening of renal function, requiring dialysis in one case. Conclusions: The fatality rate and the proportion of patients with severe COVID-19 in this series is in the higher range of reports from the general population. Severe SARS-CoV-2 infection can result in renal failure in patients with renal AL amyloidosis. Disclosures Milani: Janssen: Other: Speaker honoraria; Pfizer: Other: Speaker honoraria; Celgene: Other: Travel support. Sanchorawala:Oncopeptide: Research Funding; Abbvie: Other: advisory board; Proclara: Other: advisory board; Caleum: Other: advisory board; Regeneron: Other: advisory board; Prothena: Research Funding; Takeda: Research Funding; Janssen: Research Funding; UpToDate: Patents & Royalties; Caelum: Research Funding; Celgene: Research Funding. Cibeira:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational lectures; Akcea Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Other: Educational lectures; Amgen: Honoraria, Other: Educational lectures. Schönland:Janssen, Prothena, Takeda: Honoraria, Other: travel support to meetings, Research Funding. Palladini:Celgene: Other: Travel support; Jannsen Cilag: Honoraria, Other.

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Efficacy and Long-Term Outcomes of Autologous Stem Cell Transplant (ASCT) for Patients with POEMS Syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal Protein, Skin Changes): A CIBMTR Analysis

Blood ◽

10.1182/blood-2021-151325 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 120-120

Author(s):

Ankit Kansagra ◽

Angela Dispenzieri ◽

Raphael Fraser ◽

Noel Estrada-Merly ◽

Shaji Kumar ◽

...

Keyword(s):

Multivariate Analysis ◽

Rare Disease ◽

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

Poems Syndrome ◽

Plasma Cell Dyscrasia ◽

Cell Transplant ◽

Advisory Committees

Abstract Introduction POEMS syndrome is a rare disease associated with a plasma cell dyscrasia with limited information regarding the role of ASCT. Small single institution series have demonstrated deep and durable responses after ASCT along with neurological improvement. Despite these benefits, ASCT is thought to have higher treatment related morbidity and mortality, limiting its use. We describe the outcomes from an international multicenter database of patients with POEMS syndrome undergoing ASCT. Methods We performed a retrospective analysis using the Center for International Blood and Marrow Transplant Research (CIBMTR) database to evaluate the outcomes of patients undergoing ASCT for POEMS syndrome. Standard descriptive methods were used to report patient characteristics. Univariate and multivariate analysis were performed to identify predicators for non-relapse mortality (NRM), relapse, progression-free and overall survival (PFS, OS). NRM was compared between POEMS and multiple myeloma (MM) patients who underwent ASCT during the same time period. Results Between 2008-2018, 331 pts with POEMS syndrome who underwent ASCT were identified. The median age was 51 years, with 66% males. Racial distribution was 65% Caucasians, 19% African American, 5% other, and 10% missing. Pre-transplant characteristics included 70% patients had Karnofsky score <90, and 50% had HCT-CI ≥ 3, reflecting underlying disease severity and symptoms. The most common comorbidity was pulmonary (52%). Only 14% of patients were in very good partial response or better at the time of ASCT and 72 (22%) patients underwent ASCT without prior treatment. The median time from diagnosis to ASCT was 7 months and 74% underwent ASCT within 12 months of diagnosis. The most common mobilization strategy was GCSF +/- plerixafor in 50% of pts and 87% of pts received conditioning with 200mg/m2 of Melphalan. The median follow up was 48 (range 3-137) months. At day 100, NRM was 0.9 % (95% CI: 0.2-2.2%). At 4 years, NRM was 4.9% (95% CI: 2.6-7.9%), relapse 15.4% (95% CI 11.3-20.1%), PFS 79.7% (95% CI 74.5-84.3%) and OS 92% (95% CI 89.2-95.6%). Subsequent neoplasms were seen in 16 (5%) with 4 myeloid malignancy and 12 solid tumors. On multivariate analysis, age ≥ 60 years was associated with greater hazards of mortality, HR 2.6 (95% CI 1.2-5.6), p 0.01. The figure shows the comparable NRM between POEMS and MM (p 0.31). Conclusions: We report outcomes of the largest ASCT series of POEMS patients. Despite a high HCT-CI and low functional status among patients with POEMS syndrome, no difference in NRM was seen when compared to MM. Post-transplant outcomes were excellent and support single center data on the role of ASCT in this rare disease. Figure 1 Figure 1. Disclosures Kansagra: Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Alynylam: Membership on an entity's Board of Directors or advisory committees; Cota Health: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Dispenzieri: Alnylam: Research Funding; Pfizer: Research Funding; Sorrento Therapeutics: Consultancy; Takeda: Research Funding; Oncopeptides: Consultancy; Janssen: Consultancy, Research Funding. Kumar: Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; BMS: Consultancy, Research Funding; Oncopeptides: Consultancy; Beigene: Consultancy; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche-Genentech: Consultancy, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Honoraria; Novartis: Research Funding; Bluebird Bio: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Carsgen: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tenebio: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Qazilbash: Bristol-Myers Squibb: Other: Advisory Board; NexImmune: Research Funding; Janssen: Research Funding; Biolline: Research Funding; Oncopeptides: Other: Advisory Board; Angiocrine: Research Funding; Amgen: Research Funding. Shah: GSK: Consultancy; Karyopharm: Consultancy; Oncopeptides: Consultancy; Indapta Therapeutics: Consultancy; Janssen: Research Funding; Nektar: Research Funding; Bluebird Bio: Research Funding; Teneobio: Research Funding; CareDx: Consultancy; BMS/Celgene: Research Funding; Sanofi: Consultancy; Sutro Biopharma: Research Funding; CSL Behring: Consultancy; Poseida: Research Funding; Precision Biosciences: Research Funding; Amgen: Consultancy; Kite: Consultancy. D'Souza: Sanofi, Takeda, Teneobio, CAELUM, Prothena: Research Funding; Imbrium, Pfizer, BMS: Membership on an entity's Board of Directors or advisory committees; Janssen, Prothena: Consultancy.

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Neutralizing Antibody Responses Against Sars-Cov-2 in Patients with Plasma Cell Disorders Who Are on Active Treatment after Two Doses of mRNA Vaccination

Blood ◽

10.1182/blood-2021-152954 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3804-3804

Author(s):

Al-Ola Abdallah ◽

Zahra Mahmoudjafari ◽

Meera Mohan ◽

Joseph P. McGuirk ◽

Cassie Remker ◽

...

Keyword(s):

Partial Response ◽

Board Of Directors ◽

Plasma Cell ◽

Active Treatment ◽

Research Funding ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Al Amyloidosis ◽

Advisory Committees ◽

Plasma Cell Disorders

Abstract Background Patients (Pts) with multiple myeloma (MM) experience prolonged immunosuppression due to the incurable nature of the disease and corresponding treatment modalities. Due to this many MM pts with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) require hospitalization, with an increased mortality rate over healthy adults. Two mRNA vaccines against (SARS-CoV-2): BNT162b2 & mRNA-1273 were approved under an emergency use authorization (EUA) by the Food and Drug Administration (FDA) due to the high efficacy in preventing SARS-CoV-2. The aim of this study was to analyze the antibody (Abs) response in all pts with plasma cell disorders (PCD) including MM, AL-Amyloidosis, and smoldering myeloma (SMM) who are on active treatment. Patients & Methods All pts (MM, AL-Amyloidosis, and SMM) on active treatment who received SARS-CoV-2 mRNA vaccine were identified at the University of Kansas Health System between January 2021 to July 2021and reviewed retrospectively. Descriptive analyses were performed on available data for patient characteristics. Abs against SARS-CoV-2 were measured using methodology approved by the FDA (enzyme-linked immunosorbent assay; cPass SARS-CoV-2 Neutralizing Antibody Detection Kit; GenScript, Piscataway, NJ). We stratified pts into clinically relevant responders (>250 IU/mL), partial responders (50-250 IU/mL), and non-responders (<50 IU/mL) Results A total of 118 pts were identified in our analysis and are described in Table 1. Of the total pts, 102 (86%) had MM, 13 (11%) pts had AL-Amyloidosis, and 3 (3%) pts had SMM. Median age was 69 years (45-95), 96 pts (81%) were Caucasian, and 57 (48%) were male. Median lines of prior treatment was 2 (1-13). Active PCD patients were treated with single-agent therapy in 60 pts (51%), doublet-based therapy in 5 pts (4%), and triplet-based therapy in 51 pts (43%). Daratumumab based therapy was utilized in 59 pts (50%). All pts included received two doses of either BNT162b2 or mRNA-1273. At the time of abs testing 82 patients (69%) were in a very good partial response (VGPR) or better, 29 pts (25%) were in partial response, while 7 pts (6%) had stable disease. Five pts (4%) had COVID-19 infection prior to the vaccine. The median time between thesecond dose of the vaccine and testing for Abs was 100 days (34-190). Only 46 pts (39%) developed an adequate response, 36 pts (30.5%) had a partial response, while 36 (30.5%) did not respond to the vaccine. Low Ab levels were seen in all PCD subtypes with the following mean levels: SMM :25.4 (5.4- 36.9) IU/mL, MM 148 (0- >250) IU/mL, and AL- Amyloidosis 92.35 (range 0- >250) IU/mL. Among the 5 pts with COVID-19 infection prior to the vaccination, full Abs response was observed in 4 pts, and 1 patient had no Abs response. Type of treatment did not affect the response to treatment in any clinically meaningful way. The odds ratio of achieving a clinically relevant Abs response was higher in pts with absolute lymphocyte counts>0.5 K/uL (p=0.01) and IgG levels> 400 mg/dL (p=0.04) and lower in pts receiving treatments with daratumumab combinations or anti-BCMA therapy (p<0.0001). Higher levels of anti-SARS-CoV-2 Abs were observed in pts with ≥ VGPR (mean≈147 IU/mL) compared to <VGPR (mean≈ 119 IU/mL). However, in this dataset, this difference was not statistically significant (p=0.17). Conclusion mRNA vaccine Ab response is lower in PCD pts getting active treatment compared with the general population. For PCD patients on active treatment, mRNA vaccine produced full antibody responses and partial responses in 39% and 30.5% of pts, respectively. anti-SARS-CoV-2 abs are especially low for patients on daratumumab combinations or anti-BCMA therapy, low lymphocytes, and low IgG levels at the time of vaccination. Some PCD may not develop anti-SARS-CoV-2 abs despite vaccination and/or previous COVID-19 infection. Therefore, checking anti-SARS-CoV-2 abs may be clinically useful in identifying patient's response. Further prospective studies should ascertain the value of a 3 rd vaccine dose in this population. Figure 1 Figure 1. Disclosures Mahmoudjafari: Omeros: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. McGuirk: Astelllas Pharma: Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; EcoR1 Capital: Consultancy; Gamida Cell: Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Fresenius Biotech: Research Funding; Bellicum Pharmaceuticals: Research Funding; Novartis: Research Funding; Pluristem Therapeutics: Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Novartis: Research Funding. Atrash: Jansen: Research Funding, Speakers Bureau; AMGEN: Research Funding; GSK: Research Funding.

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Successful Conversion and Implementation to Subcutaneous Daratumumab in Patients with Multiple Myeloma (MM) and Light Chain (AL) Amyloidosis

Blood ◽

10.1182/blood-2021-147518 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1975-1975

Author(s):

David Hughes ◽

Lynnette Henshaw ◽

Frances Blevins ◽

Camille V Edwards ◽

Adam Lerner ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Medical Center ◽

Advisory Board ◽

Fixed Dose ◽

Al Amyloidosis ◽

Post Injection ◽

Advisory Committees ◽

Oral Agents ◽

Clinic Efficiency

Abstract Introduction Intravenous (IV) daratumumab has become a standard in the treatment of MM and AL amyloidosis largely due to its significant clinical benefit. Due to the high risk of infusion-related reactions (IRRs) prolonged infusion times are required at time of treatment initiation. These lengthy administrations can limit clinic capacity, require split dose infusions, increase chair time, and decrease patient satisfaction. Fixed-dose subcutaneous (SC) formulation of daratumumab (daratumumab and hyaluronidase-fihj) was approved in 2020 for the treatment of MM and subsequently, AL amyloidosis in 2021. While landmark trials have demonstrated its efficacy, there is lack of consensus around the standardized pre-medications and post-injection monitoring times for SC daratumumab. We present real world evidence from a large academic center with adoption and standardization of SC formulation of daratumumab into clinical practice. Methods We evaluated all patients that received SC daratumumab for MM and/or AL amyloidosis at Boston Medical Center from June 1, 2020 to February 28, 2021. Baseline demographics were collected, including patient diagnosis, chemotherapy regimen, prior daratumumab administration details, and total doses of daratumumab received. Patients that were naïve to daratumumab, started their first dose as a SC injection. Patients were monitored for 30 minutes following the first SC dose and were pre-medicated with all oral agents: acetaminophen, dexamethasone, and diphenhydramine. Infusion chair time, improvement in clinic efficiency (using our standard infusion time of 90 minutes for IV daratumumab infusions after the 2nd dose), and safety were evaluated. Results A total of 41 patients were treated with SC daratumumab. Eighteen patients (44%) were switched from IV daratumumab to SC daratumumab. All other patients were naïve to SC daratumumab (n=23). All patients were monitored for 30 minutes after their first SC daratumumab dose only. In the absence of an ARR (administration-related reactions), patients were not monitored after subsequent injections. One patient had facial and neck swelling 2 days after administration of SC daratumumab (with no other symptoms) but resolved within 24 hours of an additional dose of dexamethasone and did not recur upon re-challenge of SC daratumumab. One patient experienced nausea following her first dose of SC daratumumab but it resolved without intervention. All patients received dexamethasone 20-40 mg (as anti-myeloma dose), acetaminophen 650 mg, and diphenhydramine 25-50 mg prior to the dose of SC daratumumab. Fourteen patients (24%) received montelukast 10 mg and 19 patients (46%) received famotidine 20-40 mg prior to the dose of SC daratumumab at provider discretion. Dexamethasone 4 mg daily for two days post-injection was not administered with SC formulation as was previously routine with the IV formulation. When analyzing the chair time saved by this standard monitoring protocol, a total of 478.8 hours of chair time were saved that were used for other patients in our practice (average of 11.7 hours saved per patient). Conclusion We report a successful conversion and adoption of SC daratumumab at our ambulatory hematology/oncology clinic. A standard 30-minute monitoring parameter can safely be implemented following the first SC daratumumab dose. Furthermore, less aggressive supportive medications can also be used. Integration of the SC formulation yielded significant chair time savings and may have the ability to create a more efficient clinic workflow. Figure 1 Figure 1. Disclosures Hughes: Rigel: Other: Advisory Board, Research Funding; Amgen: Speakers Bureau; Karyopharm: Other: Advisory Board, Speakers Bureau; Abbvie: Speakers Bureau. Sloan: Pharmacosmos: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria; Stemline: Honoraria. Sanchorawala: Abbvie: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron: Membership on an entity's Board of Directors or advisory committees; Proclara: Membership on an entity's Board of Directors or advisory committees; Oncopeptide: Research Funding; Karyopharm: Research Funding; Sorrento: Research Funding; Pfizer: Honoraria.

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Addition of Cyclophosphamide and Higher Doses of Dexamethasone Do Not Improve Outcomes of Patients with AL Amyloidosis Treated with Bortezomib

Blood ◽

10.1182/blood.v128.22.4500.4500 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4500-4500

Author(s):

Efstathios Kastritis ◽

Maria Gavriatopoulou ◽

Maria Roussou ◽

Despina Fotiou ◽

Dimitrios Ziogas ◽

...

Keyword(s):

Board Of Directors ◽

Plasma Cell ◽

Research Funding ◽

Response Rate ◽

Cell Clone ◽

Cardiac Response ◽

Al Amyloidosis ◽

Advisory Committees ◽

Renal Response ◽

Higher Doses

Abstract Treatment of AL amyloidosis is based on the elimination of the plasma cell clone that produces the amyloidogenic light chains. Typically, these are indolent clones and plasma cell burden is low, thus, even low dose, low toxicity, regimens may be very effective. Bortezomib is effective in targeting plasma cells. Several series have also shown that bortezomib either as single agent or in combinations, such as bortezomib with dexamethasone (VD) or with the addition of cyclophosphamide (VCD) induce high rates of hematologic CRs and organ responses. Patients with AL are frail due to multisystemic involvement and data from the treatment of frail patients with myeloma, usually elderly ones, have shown that addition of a third agent to VD does not improve outcomes and may increase toxicity. However, VCD is considered as a "standard" regimen for primary therapy of patients with AL, in most centers, but, it is not clear whether the addition of a third drug (cyclophosphamide) to bortezomib/dexamethasone (VD) further and significantly improves efficacy, given the substantial activity of bortezomib itself. Thus, we compared the outcomes of patients with AL amyloidosis who received (VD) or with VD plus a third agent (VCD). The analysis included 101 consecutive patients with biopsy confirmed AL amyloidosis, all diagnosed and treated in the Department of Clinical Therapeutics, Athens, Greece. All patients received similar supportive care and were treated in two consecutive periods (up to 2010 received VD and after 2011 received VCD). Median age was 65 years, 70% had cardiac and 71% renal involvement; Mayo stage was -1, -2 & -3 in 20%, 47% & 33% while renal stage was -1, -2 and -3 in 22%, 56% & 22% of the patients respectively. Treatment was VD in 59 (58%) and VCD in 42 (42%) patients. Compared to patients who received VCD, patients who received VD were older (median age 67 vs 60.5 years, p=0.024), were more often Mayo stage 3 (42% vs 29%, p=0.03), had lower eGFR (median 54 vs 86 ml/min/1.73 m2) but had similar distribution in renal stages. Heart, renal and nerve involvement were similar between those who received VD vs VCD (p>0.5 for all). According to our institutional guidelines for patients with AL amyloidosis schedule of bortezomib (twice per week vs weekly) and dexamethasone are adjusted to cardiac risk and presence of neuropathy. Weekly bortezomib was given in 41% of patients who received VD and vs 40% with VCD and the starting dose was 1.3 mg/m2 in 90% and 92.5% respectively. The median dose of dexamethasone for all patients was 160 mg/month, but for patients treated with VD was 240 mg/month and was 144 mg/month for those treated with VCD (p=0.01). Early mortality (<3 months from start of therapy) was 22% for patients treated with VD and 8% for patients treated with VCD, but after adjustment for Mayo stage there was no difference, and was 36% vs 29% in patients with Mayo stage 3 disease. On intent to treat a hematologic response was achieved by 72% (CR:25%, VGPR:17% , PR: 30%) and was 68% for patients treated with VD and 78% for VCD (p=0.26); after adjustment for Mayo stage there was still no difference in response rates. Regarding CR+VGPR, it was 47.5% with VD and 35% with VCD. Notably higher doses of dexamethasone or twice-weekly bortezomib schedule were not associated with significantly higher hematologic response rates or CR+VGPR rates. Organ responses occurred in 35% of patients (cardiac in 26%, renal in 42%). For VD, cardiac response rate was 29% and renal response rate was 43%, while for VCD cardiac response was 21% and renal response was 41% (p>0.5 for all comparisons). Median follow up is 3 years and median overall survival (OS) is 34 months. Median OS of patients treated with VD vs VCD was similar (33 vs 36 months, p=0.45). After adjustment for the dose and schedule of bortezomib and dexamethasone, and Mayo stage, still there was no difference in the OS between patients treated with VD vs VCD and no prognostic effect of higher doses of dexamethasone and twice weekly bortezomib was found. In conclusion, our data indicate that bortezomib even with low doses of dexamethasone is effective for the treatment of AL amyloidosis; higher doses of dexamethasone and addition of a third agent (cyclophosphamide) does not seem to have a profound effect on efficacy and survival. Our data also indicate the limits of bortezomib-based therapies, and new agents either targeting the plasma cell clone (like monoclonal antiCD38) or targeting the amyloid deposits are needed. Disclosures Kastritis: Genesis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Terpos:Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Genesis: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Celgene: Honoraria. Dimopoulos:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: 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; Genesis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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A Phase II Study of Isatuximab (SAR650984) (NSC-795145) for Patients with Previously Treated AL Amyloidosis (SWOG S1702; NCT#03499808)

Blood ◽

10.1182/blood-2020-143180 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 20-21

Author(s):

Terri L. Parker ◽

Adam Rosenthal ◽

Vaishali Sanchorawala ◽

Heather J Landau ◽

Erica Campagnaro ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Cardiac Involvement ◽

Phase Ii Study ◽

Advisory Board ◽

Al Amyloidosis ◽

Advisory Committees ◽

Serum Free Light Chain ◽

Previously Treated Patients ◽

Previously Treated

Background: Isatuximab (SAR650984) is an IgG1k monoclonal antibody that binds with high affinity to CD38 expressed on plasma cells in AL amyloidosis. It has been shown to be efficacious and well tolerated in relapsed and refractory multiple myeloma as a single agent and in combination. Here we report on the preliminary results of a prospective multi-center, phase II study of isatuximab in previously treated patients with AL amyloidosis (NCT03499808). Methods: Eligibility included age ≥ 18 years, relapsed or refractory systemic AL amyloidosis, ≥ 1 prior line of therapy, measurable disease (defined as a positive monoclonal serum immunofixation electrophoresis (IFE) or urine IFE, a serum free light chain ratio outside of the normal range (0.25-1.65), and a difference in the involved versus the uninvolved serum free light chain of ≥ 4.5 mg/dL), at least one organ involved, not refractory to daratumumab, ECOG performance status 0-2, creatinine clearance ≥25 mL/min as measured by 24-hour urine collection or as estimated by Cockcroft and Gault formula, and NT-proBNP ≤8500 pg/mL. Patients received isatuximab intravenously 20 mg/kg weekly during the first 28 day cycle and every other week during cycles 2 through 24 for a maximum of 24 cycles. The primary objective was hematologic response with secondary objectives of organ response, safety, progression free survival, and overall survival. Results: At data cut-off (July 24, 2020), 43 patients were registered from March 2018 to September 2019 at 14 institutions. Thirty six patients were eligible with 35 patients receiving at least one dose of isatuximab. Of the eligible patients, the median age was 70 (range 40-81). Prior therapies included proteasome inhibitors in 32 patients (89%), high dose therapy followed by autologous stem cell transplant in 17 patients (47%), immunomodulatory therapy in 9 patients (25%), and anti-CD38 monoclonal antibody therapy in 2 patients (6%). Single organ system involvement was seen in 19 patients (53%), ≥ 2 organ systems in 17 patients (47%), 16 patients (44%) had renal involvement, and 24 (67%) had cardiac involvement. For those with cardiac involvement, 7 patients (29%) had cardiac biomarker stage II and 9 patients (38%) had stage III disease using the Revised Mayo Staging (Kumar S et al., J Clin Oncol, 2012). A total of 17 patients remain on therapy. The median duration on treatment for eligible patients is currently 11.8 months (current range, 0.3-22.1). Of the 19 patients who discontinued treatment, the most common reasons included adverse events in 5 patients (26%), disease progression in 4 patients (21%), sub-optimal response in 2 patients (11%), and concerns related to COVID-19 in 2 patients (11%). The current median follow up is 16.3 months. The most common drug-related AEs were infusion related reactions in 18 patients (50%) with the majority (16/18) being grade I or II, anemia in 9 patients (25%) with the majority (8/9) being grade I, and lymphopenia in 8 patients (22%). Patient characteristics and preliminary safety data were previously presented at the International Symposium on Amyloidosis. The overall hematologic response rate was 77%. Hematological complete response (CR) was observed in 1 of 35 evaluable (completing at least 1 dose) patients (3%), very-good-partial response (VGPR) in 19 patients (54%), and partial response (PR) in 7 patients (20%). Conclusions: Isatuximab demonstrates encouraging efficacy in previously treated patients with AL amyloidosis. The administration of isatuximab in these patients is associated with a good safety profile similar to other monoclonal antibodies against CD38. The data will be updated at the meeting. Disclosures Sanchorawala: Prothena: Research Funding; Caelum: Research Funding; Oncopeptide: Research Funding; Janssen: Research Funding; Regeneron: Other: advisory board; Caleum: Other: advisory board; Proclara: Other: advisory board; Abbvie: Other: advisory board; UpToDate: Patents & Royalties; Takeda: Research Funding; Celgene: Research Funding. Kapoor:Sanofi: Consultancy, Research Funding; Celgene: Honoraria; Cellectar: Consultancy; Janssen: Research Funding; Amgen: Research Funding; GlaxoSmithKline: Research Funding; Takeda: Honoraria, Research Funding. Neparidze:GlaxoSmithKline: Research Funding; Janssen: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Eidos Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Diagnostic committee member . Sarosiek:Spectrum: Research Funding. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy. Usmani:Incyte: Research Funding; Takeda: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; SkylineDX: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Array Biopharma: Research Funding; Pharmacyclics: Research Funding; Celgene: Other; Seattle Genetics: Consultancy, Research Funding; GSK: Consultancy, Research Funding; BMS, Celgene: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Amgen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Abbvie: Consultancy. Orlowski:Laboratory research funding from BioTheryX, and clinical research funding from CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding; STATinMED Research: Consultancy; Founder of Asylia Therapeutics, Inc., with associated patents and an equity interest, though this technology does not bear on the current submission.: Current equity holder in private company, Patents & Royalties; Sanofi-Aventis, Servier, Takeda Pharmaceuticals North America, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen, Inc., AstraZeneca, BMS, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Regeneron Pharmaceuticals, Inc.,: Honoraria, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Isatuximab is FDA approved for relapsed refractory myeloma in combination with pomalidomide and dexamethasone. Isatuximab is not FDA approved for AL amyloidosis.

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Phase 2 Trial of Ixazomib, Cyclophosphamide and Dexamethasone for Treatment of Previously Untreated Light Chain Amyloidosis

Blood ◽

10.1182/blood-2020-138814 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 52-53

Author(s):

Eli Muchtar ◽

Morie A Gertz ◽

Betsy Laplant ◽

Francis K. Buadi ◽

Nelson Leung ◽

...

Keyword(s):

Clinical Trials ◽

Board Of Directors ◽

Light Chain ◽

Research Funding ◽

Advisory Board ◽

Organ Involvement ◽

Al Amyloidosis ◽

Advisory Committees ◽

Hematologic Response ◽

Phase 2 Trial

Background: Bortezomib, a proteasome inhibitor, has shown efficacy in the treatment of newly diagnosed and relapsed light chain (AL) amyloidosis, and the combination of bortezomib, cyclophosphamide and dexamethasone is a commonly used regimen in AL. Ixazomib is the first oral proteasome inhibitor to be approved, and the combination of ixazomib with cyclophosphamide and dexamethasone is an all oral effective regimen for the treatment of multiple myeloma. This phase 2 trial was designed to evaluate the efficacy of this regimen in patients with AL, who have not received any therapy. Patients and methods: Newly diagnosed patients with biopsy proven AL amyloidosis, with organ involvement requiring therapy, were enrolled if they had measurable disease (Serum immunoglobulin free light chain ≥5 mg/dL AND abnormal serum free light chain ratio) and adequate organ function. Patients with severe organ involvement were excluded (Alkaline phosphatase >750 U/L, creatinine clearance <30 mL/min or NT-ProBNP ≥ 7500 ng/dL). Treatment consisted of ixazomib 4 mg days 1, 8, 15; cyclophosphamide 500 mg PO weekly and dexamethasone 40 mg, weekly for twelve 28-day cycles, followed by ixazomib maintenance (days 1, 8, 15) at the last tolerated dose till progression. The primary objective was to determine the hematologic response rate of ixazomib, used in combination with cyclophosphamide and dexamethasone in patients with previously untreated AL. A one-stage binomial design was utilized to test the null hypothesis that the hematologic response rate is at most 30% against the alternative hypothesis that it is at least 50%, with 85% power and 9% type I error. Results: Thirty-five patients were enrolled, median age was 67 (range 38-78) years; 69% were male. Organ involvement included cardiac in 23 (65.7%), renal in 19 (54.3%), and nervous system involvement in 5 (14.3%). At data cutoff 8 patients still remain on study with a median follow up of 4.4 months for those who are alive. Across the trial a median of 4 cycles (range 0-23) of treatment have been completed; the most common reason for going off study was institution of alternate therapy in 17 patients (63%). The overall hematologic response was 57% (20/35) and included amyloid CR in 5 (14%), VGPR in 9 (26%) and a PR in 6 (17%) patients. Confirmed organ responses have been observed in 5 patients so far, 2 each for cardiac and renal and 1 hepatic. The median PFS and OS have not been reached; 4 patients had hematological progression; 6 patients (17%) have died. Across 193 cycles of treatment administered, dose modification was required in 5, 3, and 10 patients, respectively, for ixazomib, cyclophosphamide and dexamethasone. A grade 3 or higher adverse event (AE), at least possibly attributed to the study drugs, was observed in 41% of patients. The figure shows the maximum grade of adverse events for individual patients seen in more than one patient across the study. Conclusions: The all-oral regimen of ixazomib, cyclophosphamide, and dexamethasone is active in patients with previously untreated AL amyloidosis with hematologic responses observed in 57% of patients, including complete responses. Organ response has been observed but will likely need longer follow up for accurate assessment, given the delay in organ responses in this disease. Further evaluation of this combination is warranted. Disclosures Gertz: Alnylam: Consultancy; Ionis/Akcea: Consultancy; Amgen: Consultancy; Medscape: Consultancy, Speakers Bureau; Physicians Education Resource: Consultancy; Data Safety Monitoring board from Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Johnson and Johnson: Speakers Bureau; DAVA oncology: Speakers Bureau; Advisory Board for Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Advisory Board for Proclara: Membership on an entity's Board of Directors or advisory committees; i3Health: Consultancy; Springer Publishing: Patents & Royalties; Amyloidosis Foundation: Research Funding; International Waldenstrom Foundation: Research Funding; NCI SPORE MM: Research Funding; Prothena: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Spectrum: Consultancy, Research Funding; Annexon: Consultancy; Appellis: Consultancy. Kapoor:Celgene: Honoraria; GlaxoSmithKline: Research Funding; Takeda: Honoraria, Research Funding; Amgen: Research Funding; Sanofi: Consultancy, Research Funding; Janssen: Research Funding; Cellectar: Consultancy. Larsen:Janssen Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dingli:Apellis: Consultancy; Janssen: Consultancy; Sanofi-Genzyme: Consultancy; Rigel: Consultancy; Bristol Myers Squibb: Research Funding; Karyopharm Therapeutics: Research Funding; Alexion: Consultancy; Millenium: Consultancy. Dispenzieri:Janssen: Research Funding; Intellia: Research Funding; Alnylam: Research Funding; Celgene: Research Funding; Pfizer: Research Funding; Takeda: Research Funding. Kumar:Adaptive Biotechnologies: Consultancy; Carsgen: Other, Research Funding; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Genecentrix: Consultancy; Dr. Reddy's Laboratories: Honoraria; Tenebio: Other, Research Funding; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; BMS: Consultancy, Research Funding; Sanofi: Research Funding; Novartis: Research Funding; Kite Pharma: Consultancy, Research Funding; Karyopharm: Consultancy; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Merck: Consultancy, Research Funding; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Cellectar: Other; MedImmune: Research Funding.

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