Citations

Abstract Background Transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasingly recognized cause of heart failure (1,2). 99mTc- pyrophosphate cardiac scintigraphy (PYP) enables accurate, noninvasive diagnosis of ATTR-CM when coupled with appropriate clinical and laboratory evaluations to rule out light chain amyloidosis (3,4). High sensitivity cardiac troponin T (hs-cTnT) is routinely assessed for diagnostic purposes when ATTR-CM is suspected in clinical practice. Purpose To investigate the diagnostic performance of hs-cTnT in patients undergoing PYP for suspected ATTR-CM. Methods Observational study of patients undergoing PYP at a United States (US) cardiac amyloidosis referral center from 2013 to September 2022 and with at least one hs-cTnT value available within 1 year. 3-hour planar imaging followed by single photon-emission computed tomography with computed tomography was performed. Final diagnoses of ATTR-CM were validated using all clinical information. The lowest reportable clinical value for hs-cTnT in the US is <6 ng/L (limit of quantitation). Results A total of 1572 patients underwent PYP and had a hs-cTnT value available within the study period. Of these, ATTR-CM was diagnosed in 475 patients (30%). Median (IQR) hs-cTnT was 48 (31-67) ng/L in patients with ATTR-CM and 26 (13-48) ng/L in those without. The area under the curve of hs-cTnT for the diagnosis of ATTR-CM was 0.69 (0.67-0.72). Among patients with a very low hs-cTnT value, i.e. <6 ng/L (n=100, 6.4% of the overall cohort), 7 (7%) patients had a final ATTR-CM diagnosis while 93 (93%) did not. Therefore, a threshold of <6 ng/L demonstrated a negative predictive value (NPV) of 93% (IQR 88, 98) and a sensitivity of 99% (97, 100) for ruling out ATTR-CM. The highest NPV was achieved with a threshold of 12 ng/L; 269 (17%) patients had hs-cTnT below this value and, of those, only 16 (6%) had a final diagnosis of ATTR-CM. This resulted in a NPV of 94% (91, 97) and a sensitivity of 97% (95, 98) for ruling out ATTR-CM. When considering progressively increasing hs-cTnT values as potential thresholds to aid in the prediction of ATTR-CM (Figure), we observed a progressive increase in specificity (above 90% for hs-cTnT values > 95 ng/L), but the positive predictive value (PPV) remained low (below 50%). Conclusions Among patients undergoing PYP for suspected ATTR-CM at a US referral center, a very low hs-cTnT value was present in a minority of patients but demonstrated good performance in ruling out ATTR-CM. The highest NPV (94%) was achieved with a threshold of < 12 ng/L. Higher hs-cTnT values showed a good specificity, but PPV remained low. Therefore, while a very low hs-cTnT might be of help in identifying those at low risk of ATTR-CM, the ubiquitous presence of increased hs-cTnT in many of these patients suggests the need for a multiparametric diagnostic approach to make the diagnosis.hs-cTnT in patients undergoing PYP scan

Abstract The approach to patients with high-risk smoldering multiple myeloma (SMM) varies among clinicians; while some advocate early intervention, others reserve treatment at progression to multiple myeloma (MM). We aimed to describe the myeloma-defining events (MDEs) and clinical presentations leading to MM diagnosis among SMM patients seen at our institution. We included 406 patients diagnosed with SMM between 2013-2022, seen at Mayo Clinic, Rochester, MN. The 2018 Mayo 20/2/20 criteria were used for risk stratification. Median follow-up was 3.9 years. Among high-risk patients who did not receive treatment in the SMM phase (n=71), 51 progressed by last follow-up; the MDEs included: bone lesions(37%), anemia(35%), hypercalcemia(8%), and renal failure(6%); 24% met MM criteria based on marrow plasmacytosis (≥60%) and/or free light chain ratio (>100); 45% had clinically significant MDEs (hypercalcemia, renal insufficiency, and/or bone lesions). MM diagnosis was made based on surveillance labs/imaging(45%), testing obtained due to provider suspicion for progression(14%), bone pain(20%), and hospitalization/ED presentations due to MM complications/symptoms(4%). The presentation was undocumented in 14%. A high proportion (45%) of patients with high-risk SMM on active surveillance develop end-organ damage at progression. About a quarter of patients who progress to MM are not diagnosed based on routine interval surveillance testing.

Abstract Objectives Diagnosis of light chain amyloidosis (AL) requires demonstration of amyloid deposits in a tissue biopsy followed by appropriate typing. Previous studies demonstrated increased dimerization of monoclonal serum free light chains (FLCs) as a pathological feature of AL. To further examine the pathogenicity of FLC, we aimed at testing amino acid sequence homology between circulating and deposited light chains (LCs). Methods Matched tissue biopsy and serum of 10 AL patients were subjected to tissue proteomic amyloid typing and nephelometric FLC assay, respectively. Serum FLC monomers (M) and dimers (D) were analyzed by Western blotting (WB) and mass spectrometry (MS). Results WB of serum FLCs showed predominance of either κ or λ type, in agreement with the nephelometric assay data. Abnormal FLC M–D patterns typical of AL amyloidosis were demonstrated in 8 AL-λ patients and in one of two AL-κ patients: increased levels of monoclonal FLC dimers, high D/M ratio values of involved FLCs, and high ratios of involved to uninvolved dimeric FLCs. MS of serum FLC dimers showed predominant constant domain sequences, in concordance with the tissue proteomic amyloid typing. Most importantly, variable domain sequence homology between circulating and deposited LC species was demonstrated, mainly in AL-λ cases. Conclusions This is the first study to demonstrate homology between circulating FLCs and tissue-deposited LCs in AL-λ amyloidosis. The applied methodology can facilitate studying the pathogenicity of circulating FLC dimers in AL amyloidosis. The study also highlights the potential of FLC monomer and dimer analysis as a non-invasive screening tool for this disease.

Abstract Disease Overview POEMS syndrome is a life‐threatening condition due to an underlying plasma cell neoplasm. The major criteria for the syndrome are polyradiculoneuropathy, clonal plasma cell disorder, sclerotic bone lesions, elevated vascular endothelial growth factor, and the presence of Castleman disease. Minor features include organomegaly, endocrinopathy, characteristic skin changes, papilledema, extravascular volume overload, and thrombocytosis. Diagnosis The diagnosis of POEMS syndrome is made with three of the major criteria, two of which must include polyradiculoneuropathy and clonal plasma cell disorder, and at least one of the minor criteria. Risk Stratification Because the pathogenesis of the syndrome is not well understood, risk stratification is limited to clinical phenotype rather than specific molecular markers. Risk factors include low serum albumin, age, pleural effusion, pulmonary hypertension, and reduced estimated glomerular filtration rate. Risk‐Adapted Therapy For those patients with a dominant plasmacytoma, first‐line therapy is irradiation. Patients with diffuse sclerotic lesions or disseminated bone marrow involvement should receive systemic therapy. Corticosteroids are temporizing, but alkylators and lenalidomide are the mainstays of treatment, the former either in the form of low‐dose conventional therapy or as high‐dose conditioning for stem cell transplantation. Thalidomide and bortezomib also have activity, but their benefit needs to be weighed against their risk of exacerbating the peripheral neuropathy. Daratumumab combinations also appear promising based on case series. Prompt recognition and institution of both supportive care measures and therapy directed against the plasma cell result in the best outcomes.

Abstract Most patients with solitary bone plasmacytomas (SBP) progress to multiple myeloma (MM) after definitive radiation therapy as their primary treatment. Whether the presence of high-risk (HR) cytogenetic abnormalities by fluorescence in situ hybridization (FISH) in the clonal plasma cells, obtained either directly from the diagnostic SBP tissue or the corresponding bone marrow examination at the time of diagnosis, is associated with a shorter time to progression (TTP) to MM is unknown. This study evaluated all patients diagnosed with SBP at the Mayo Clinic from January 2012 to July 2022. The presence of del(17p), t(14;16), t(4;14), or +1q (gain or amplification) by FISH in clonal plasma cells was defined as HR. A total of 114 patients were included in this cohort, and baseline FISH was available for 55 patients (48%), of which 22 were classified as HR (40%). The median TTP to MM for patients with SBP and HR FISH was 8 months (95% confidence interval [CI], 6.3-26) compared with 42 months (95% CI, 25-not reached [NR]) in patients with SBP without HR FISH (P < .001). In a multivariate analysis, only HR FISH was a significant predictor for shorter TTP to MM, independent of minimal marrow involvement and an abnormal serum free light chain ratio at diagnosis. Deletion (17p) and gain 1q abnormalities were the most common FISH abnormalities responsible for the short TTP to MM. Thus, assessing for HR FISH abnormalities in clonal plasma cells derived from either the diagnostic SBP tissue or the staging bone marrow examination of patients with newly diagnosed SBP is feasible and prognostic for a shorter TTP to MM.