541 Prevalence of amyloid transthyretin cardiomyopathy in elderly subjects from the general population: first results from the catch study

Aims Amyloid transthyretin cardiomyopathy (ATTR-CM) has become treatable. Wild-type ATTR-CM is an age-related disorder. Establishing the exact prevalence of ATTR-CM in elderly subjects from the general population may be useful for healthcare providers and policy makers alike. Methods and results The characterizing the burden of Amyloid Transthyretin CardiomyopatHy in the elderly (CATCH) study is a population screening on all subjects aged ≥65 years followed by general practitioners working at the Casa della Salute in Terricciola, in an area of Tuscany where there is no cluster of variant ATTR. The study started on 12 March 2021 and is ongoing. The first step of the evaluation includes clinical history and physical examination, electrocardiogram, transthoracic echocardiogram, and blood sampling with measurement of N-terminal pro-B-type natriuretic peptide and high-sensitivity (hs) troponin T. The following elements are searched: (i) any clinical red flag of amyloidosis (history of carpal tunnel syndrome, lumbar spine stenosis, etc.), (ii) interventricular septal thickness ≥12 mm or other echocardiographic red flags, and (iii) hs-troponin T higher than the upper reference limit (14 ng/l). Patients with any of these elements are referred to a second step including diphosphonate scintigraphy and the search for a monoclonal protein in the serum and urine. The standard diagnostic workup for CA is then followed until the diagnosis is confirmed or discarded. As of 31 October 2021, 514 subjects ≥65 years have been evaluated for possible participation. Among them, 135 (26%) could not be contacted, were reluctant to enter the study, died before being contacted, or were bedridden. Out of the other 379 subjects, 329 (87%) have already undergone the first step. Forty percent of individuals (n = 132) have been referred to the second step. Thirteen subjects have declined (10%); 69 patients have undergone diphosphonate scintigraphy, and the search for a monoclonal protein (while the other 50 are awaiting these exams). Two subjects showed an intense myocardial uptake of the diphosphonate tracer (Perugini score 2–3) and no monoclonal protein, and were then diagnosed with ATTR-CM. They were both women, aged 83 and 78 years, both mildly symptomatic for dyspnoea (New York Heart Association II) and with unexplained hypertrophy. The search for TTR gene mutation was negative in the first case and is still ongoing in the second. Based on these preliminary data, the prevalence of ATTR-CM in the elderly population can be calculated as 2/266 = 0.8% (Figure). Conclusions The CATCH study is expected to enroll at least 1000 subjects and will provide the first data on the epidemiology of ATTR-CM in elderly subjects. Based on an interim analysis, almost 1 in 100 individuals ≥65 years has ATTR-CM.

Multiple Myeloma Oligosecretory Relapse, a Non-Negligible Phenomenon. Frequency, Clinical Characteristics and Outcomes in a Single Center

Introduction: Multiple myeloma (MM) is malignancy of plasma cells, which secrete monoclonal antibodies that are detectable in the patient's (pt) serum and/or urine. Infrequently, MM may present as an oligosecretory disease, where monoclonal protein (M-protein) and involved free light chain (iFLC) are either not detected (=non-secretory) or are both below the threshold for measurable disease (=oligosecretory) as defined by International Myeloma Working Group (IMWG). The incidence of non-secretory MM at presentation has been estimated at 1-2% [Chawla, Eur J Haematol 2015], yet data regarding the frequency and clinical phenotype of oligosecretory relapse is lacking. These pts are typically excluded from most clinical trials. Methods: Pt's MM was classified as oligo-secretory, in the absence of measurable disease according to the IMWG criteria (M-protein≥1 gr/dL, or U-PEP > 200 mg/24 hrs or involved free light chain≥ 100 mg/L). Relapse was defined according to IMWG criteria, based on changes in monoclonal protein in the serum or urine, bone or extramedullary lesions on imaging, bone-marrow plasmacytosis, serum hemoglobin, creatinine and calcium levels. Pts treated at our center for MM, who had secretory (i.e., measurable disease) MM at diagnosis, and relapsed (secretory or non-secretory relapse) between January 2016 to July 2020, were included. MM baseline pt and disease characteristics, disease characteristics at relapse, treatment regimens and outcomes were documented. The first oligosecretory relapse (OSR) that any given pt experienced was defined as the index OSR for that pt. For each pt with an OSR, we identified the first 4 pts with a secretory relapse (SR) in the dataset, who matched the pt by the relapse index number and calendar year of relapse, to form a SR comparator group. We compared pt and disease characteristics, therapy patterns and outcomes between the OSR and SR groups. Results: One hundred and seventy-seven pts with relapse were identified; 8 (4.5%) had oligo-secretory disease at MM diagnosis and were excluded; 152 of the 169 pts who were secretory at presentation (89.9%) had secretory MM at all relapses; 17 (10.0%) had an OSR (4 non-secretory and 13 oligosecretory), the SR comparator group included 67 pts. Pts with OSR had similar characteristics compared to SR pts at MM presentation, in terms of demographics, FISH cytogenetics, ISS, levels of M-protein and involved FLC, frequency of extramedullary disease, target organ involvement; Treatment pattern and response to upfront therapy were comparable (Fig1 A). Oligosecretory disease was more frequent at relapse compared to newly diagnosed MM (10% vs 4.5%), proportion of OSR among pts with previously secretory MM increased in later relapses. The proportion of OSR from total 3 rd or 4 th relapses, was high as 20% and 17.6%, respectively (Fig 1B). OSR pts had a higher rate of new plasmacytoma (53% vs 9%, p<0.001) as the criteria for relapse, and a trended towards increase in LDH, and higher rate of extramedullary disease (17% vs 4.4%, p=0.09) whereas increase in monoclonal protein was more frequent in the SR group as a criterion for relapse. Overall response rate to therapy of the index relapse was similar between groups among evaluable pts (58% vs 64%), however, in 5/17 (29%) of the OSR, response was non evaluable from available documentation. Median follow up was 10.2 months [Q1 4.1- Q3 16.7]. Twelve-months progression free survival was 82.4% vs 73.8% (p=0.76), and 12-months overall survival was 60.2% vs 64.75% (p=0.60) in RS and OSR, respectively. Conclusions: Oligosecretory disease was more frequent in relapsed MM, compared to its rate at MM presentation, reaching 10% of the pts with relapsed MM and increasing in more advanced relapses. Pts with OSR and those with SR had similar clinical characteristics of their MM at presentation as well as comparable outcomes, but pts with OSR had higher rates of new skeletal and extramedullary lesions. As identification of the OSR may be challenging in the absence of serum and urine biomarkers, awareness and clinical alertness are warranted to avoid end organ damage. We suggest inclusion of OSR pts in clinical trials should be considered, despite some challenges in following their therapy response, as they comprise a non-negligible proportion of pts, in particular in the advanced relapse setting. Figure 1 Figure 1. Disclosures Avivi: Kite, a Gilead Company: Speakers Bureau; Novartis: Speakers Bureau. Cohen: Neopharm / promedico: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karophram: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: 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.

CD19-Targeted CAR T Cell Therapy for Concomitant Diffuse Large B Cell Lymphoma and Myeloma

While DLBCL and myeloma comprise a large fraction of annual hematologic malignancies, the co-occurrence of these malignancies is particularly rare. The FDA has approved three CD19-targeted CAR T cell therapies for B-cell lymphoma (Kymriah, Yescarta, and Brenyazi) and more recently a single CAR T cell therapy for myeloma (Abecma). We present a case of concurrent multiply r/r DLBCL and non-r/r myeloma treated exclusively with CD19-targeted CAR T cell therapy. A 77-year-old female was admitted to an outside hospital with a chief complaint of one week of constipation, incidental labs demonstrating hypercalcemia and AKI, and a bone marrow biopsy consistent with myeloma (phenotype lamda, CD138-, MUM01+, CD56- and CD117, KITE-). There were 20% lambda-restricted plasma cells with no evidence of lymphoma. She also had concomitant anemia with a hemoglobin of 9.6 g/dL best attributed to the plasma cell dyscrasia, thus fulfilling criteria from the International Myeloma Working Group.Beta-2-microglobulin was 6.8 mg/L, consistent with stage 3 disease. She demonstrated two M proteins at time of diagnosis; each was 0.40 g/dL. Interestingly these monoclonal proteins were IgG-Kappa and an IgM protein. The patient was transferred to our institution for management after receiving a single cycle of bortezomib, cyclophosphamide and dexamethasone. A right inguinal lymph node biopsy of an existing right thigh mass revealed atypical cells with findings consistent with non-GC DLBCL [CD20+, PAX5+ (weak), MUM1+, BCL2+, CD10-, CD5-, BCL6-, BCL1-, cMYC-; R-IPI 4, CNS-IPI 4, Stage IV]. Chemotherapy with R-CHOP for four cycles resulted in a mixed response. Upon subsequent hospitalization, a second right inguinal lymph node biopsy was consistent with refractory DLBCL [positive for CD79a, CD20 (weak), MUM1, BCL2, BCL6, MIB1 Ki67 60-70% proliferative fraction, CD30 (1-2%), negative for CD10, CD3, CD5, BCL1, MYC]. Radiation followed by RICE given as second line therapy had no meaningful response on imaging. However, monoclonal protein resolved after a second cycle of RICE. Pathology indicated a CD19+ specimen on review. Polatuzumab vedotin was given as bridging therapy, followed by lymphodepletion regimen and ultimately CD19-targeted CAR T cell infusion. A partial response for lymphoma was seen at 90-day evaluation (Deauville 3). Immunofixation was positive as late as 16 days post infusion with no abnormality detected at subsequent testing 32 days post infusion. At three months, the M protein level was 0.00 g/dL with no detectable monoclonal protein on immunofixation or electrophoresis testing. Flow cytometry peripheral blood smear was negative for plasma cells by CD38 and CD138 labeling seven months post CAR T infusion. CD19-targeted CAR T cell therapy is established as an accepted standard of care for multiply r/r DLBCL when it is available. However, the role of HSCT in r/r DLBCL is standard of care after second line salvage. In our patient, however, she failed to adequately respond to salvage chemotherapy. Though there is data supporting the use of HSCT in chemorefractory patients, it is not as successful as in chemosensitive disease. Several trials have investigated BCMA-targeted CAR T cell therapy in r/r myeloma and have reported high response rates, however there is a lack of data supporting these immunologic therapies in non-r/r myeloma. Data regarding CD19 CAR T cell's effect on myeloma is limited as secondary malignancies typically exclude subjects from enrollment; however, CD19-mediated responses have been reported in vitro and CD19-targeted clinical trials are underway in r/r myeloma. Based on emerging data regarding the effectiveness of CAR T, our team elected to pursue CD19 CAR T cell therapy. One critique is that the monoclonal protein detected in the blood was different from the lambda-restricted plasma cell population that was noted in the initial bone marrow biopsy. However, given the lack of detectable myeloma based on labs and imaging, we have elected to defer a bone marrow biopsy at this time. Our patient case shows that directing toward the more aggressive malignancy, typically the lymphoma with CAR T cell therapy, can target the myeloma as well. This has significant implications on guiding treatment decisions in future patients presenting with concomitant malignancies. Furthermore, new data from studies investigating CD19-targeted therapies' effect on myeloma will have amplified clinical relevance. Disclosures Ciccolini: Currant Insights, LLC: Consultancy; Techspert.io.: Consultancy; Guidepoint: Consultancy; Atheneum: Consultancy; First Thought: Consultancy; GLG: Consultancy; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; JADPRO: Honoraria. Kalac: Astra Zeneca: Consultancy; Kyowa Kirin: Consultancy; Gilead: Consultancy; Jannsen: Research Funding; Guidepoint: Consultancy; GLG: Consultancy.

Semi-quantitative measurements of chemokine receptor 4-targeted 68Ga-pentixafor PET/CT in response assessment of Waldenström macroglobulinemia/lymphoplasmacytic lymphoma

Purpose 68Ga-pentixafor PET/CT was reported to have a high sensitivity in detecting tumor involvement of Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) in our previous study. We aimed to further investigate the semi-quantitative measurements of 68Ga-pentixafor PET/CT in response assessment in WM/LPL. Methods Fifteen patients with WM/LPL were recruited in a prospective cohort study and underwent both 68Ga-pentixafor and 18F-FDG PET/CT at baseline and post-treatment. PET/CT-based responses were analyzed with semi-quantitative assessments of metabolic tumor volume (MTV) and total lesions glycolysis/uptake (TLGFDG and TLUCXCR4), and the correlation between PET/CT-based response and clinical response, monoclonal protein and IgM response was analyzed. Results After chemotherapy, 5 patients had complete response or very good partial response, 8 had partial response or minimal response and 2 had progressive disease. In quantitative analysis, 68Ga-pentixafor PET/CT-based response (measured in ∆TLUCXCR4%, ∆MTVCXCR4%, ∆SUVpeak%) showed a significant direct correlation with clinical response, monoclonal protein and IgM response (p < 0.01). However, 18F-FDG PET/CT-based response was independent from clinical response (p > 0.05). Conclusions The semi-quantitative measurements of 68Ga-pentixafor PET/CT outperformed 18F-FDG PET/CT in response assessment of WM/LPL.

The efficiency of hypogammaglobulinemia reflex immunofixation electrophoresis in identifying monoclonal proteins

Introduction/Objective Hypogammaglobulinemia can be a common occurrence in disorders with monoclonal gammopathies. Because hypogammaglobulinemia may mask a monoclonal protein on serum protein electrophoresis (sPEP), its presence in the absence of a discernible M-spike is often the basis of reflexive testing by immunofixation electrophoresis (IFE). At our Institution, reflex IFE has historically been performed in cases where the gamma fraction on sPEP is &lt;0.6 g/dL. The aim of this study was to test the predictive performance of hypogammaglobulinemia in identifying abnormal bands on IFE in newly screened patients. Methods/Case Report All patients that underwent sPEP testing from November 2020 to May 2021 at our Institution were identified. Among them, patients with gamma fraction &lt;0.6 g/dL and no previous sPEP testing were included for analysis. Reflex IFE results were reviewed for identification of abnormal bands. Results (if a Case Study enter NA) Out of a total number of 1,374 patients tested for sPEP in the study period, 72 had serum gamma fraction &lt;0.6 g/dL (5.2%). Among them, 36 patients had no previous sPEP testing, and their reflex IFE were reviewed. In 38.8% of the cases, the IFE showed one or more abnormal (monoclonal) bands. When considering a new threshold for hypogammaglobulinemia IFE reflex of &lt;0.4 g/dL, the diagnostic yield for finding abnormal bands increased to 62.5%. Moreover, a percentage reduction of 64.2% was observed in the number of reflex IFE performed. Conclusion Although these data must be confirmed using a larger sample population, a lower threshold for hypogammaglobulinemia may be proposed at our Institution to reduce labor and costs and to improve efficiency of monoclonal protein detection.

Waldenstrom Macroglobulinemia and the Eye: A case report and review

Waldenstrom macroglobulinemia (WM) is a rare, malignant lymphoproliferative B-cell disorder causing an excessive buildup of monoclonal protein. WM is associated with excessive buildup of IgM, which can cause blood hyperviscosity and damage many organ systems. This case report describes a patient who was followed annually but rapidly developed posterior pole and significant midperipheral hemorrhages secondary to a hyperviscosity condition of the retina. Management of this condition is dependent on macular involvement and must be co-managed with an oncologist.

Grade 3 myocardial uptake in 99mtechnetium-pyrophosphate scintigraphy in light chain cardiac amyloidosis

We report grade 3 myocardial uptake in 99mtechnetium-pyrophosphate (99mTc-PYP) scintigraphy in a case of light-chain cardiac amyloidosis (CA), which emphasizes the importance of screening for monoclonal protein even in typical 99mTc-PYP findings of transthyretin CA.