Systemic AL amyloidosis with an undetectable plasma cell dyscrasia: A zebra without stripes
Authors: Andrew Staron, Yachana Kataria, David L. Murray, J. Mark Sloan, Vaishali Sanchorawala
Journal: American Journal of Hematology (2019)

The hallmark of systemic AL amyloidosis is an underlying plasma cell dyscrasia, measured as a monoclonal gammopathy, either by serum/urine immunofixation electrophoresis (IFE) or abnormal serum free light chain (sFLC) concentrations. Unlike in multiple myeloma, the plasma cell dyscrasia in AL amyloidosis is often subtle. Limitations of individual IFE and sFLC assays necessitate a combination of tests when evaluating patients with AL amyloidosis.1 Novel modalities with higher sensitivity are emerging, such as a mass-spectrometry-based assay (MASS-FIX).2 However, for some patients a plasma cell dyscrasia cannot be detected, imparting a diagnostic and management dilemma. Standard criteria for assessing hematologic treatment response, for example, are dependent on the normalization of plasma cell dyscrasia markers. In a retrospective review, we identified six patients with systemic AL amyloidosis confirmed by liquid chromatography and tandem mass spectrometry (LC-MS/MS), who had no evidence of an underlying plasma cell dyscrasia. Their clinical characteristics and outcomes are described. Clinical data were collected with approval by the IRB from a database of consented patients at the Amyloidosis Center at Boston University School of Medicine. Systemic AL amyloidosis was defined as Congophilic amyloid deposits in at least one vital organ (ie, heart, kidney, liver or nervous system). Isolated non-vital organ involvement was considered localized disease and excluded. For all patients, serum/urine IFE were executed using a Hydrasys analyzer with Hydragel 4IF/9IF, and sFLC levels quantified by a Binding Site Optilite analyzer using Freelite reagent sets (reference interval for normal sFLC ratio was 0.26 to 1.65). Of 673 patients with AL amyloidosis who presented between 2010 and 2019, serum and urine IFE were positive in 526 (78%) and 528 (78%) patients, respectively; 614 (91%) had at least one positive IFE. Additionally, sFLC ratio was abnormal in 517 (77%) patients. When these monoclonal gammopathy studies were combined, only 11 (1.6%) had all normal results. Bone marrow examination identified monotypic plasma cells in five of these 11 cases. The remaining six (0.9%) treatment-naïve patients had no detection of a plasma cell dyscrasia by all conventional measures. The variety of clinical presentations are described in Table 1, including more rapidly progressive symptoms for some patients vs slower evolving or a paucity of symptoms among others. All but one patient had multiple organs affected. Kidney involvement was most common, followed by bone involvement (over 50% marrow amyloid infiltration) seen in four patients. Case 2 had an elevated NT-proBNP of 590 pg/mL and findings on cardiac MRI, as well as 18F-Florbetapir imaging, consistent with cardiac involvement. A negative 99 m-technetium pyrophosphate scan made concurrent transthyretin-related (ATTR) amyloid cardiomyopathy unlikely. In all six cases, amyloid precursor protein was determined by LC-MS/MS to be immunoglobulin lambda light chain. Typing of subcutaneous fat or a second organ was confirmatory in three patients. Scrutiny of the mass spectrometry proteomes did not reveal another protein that might play a role in amyloidosis, and genetic testing for familial forms of amyloidosis (ie, variant TTR, lysozyme, apo-A1, apo-A2, fibrinogen-alpha) was also negative. Five patients underwent plasma cell-directed treatments; their outcomes are shown in Table 1. Two died during treatment and another two achieved improvement in the difference between involved and uninvolved light chains (dFLC). Improvements in end-organ function, however, were modest and no patient met organ response per standard criteria. Although case 4 demonstrated improvement in macroglossia and neuropathy with lenalidomide, pulmonary testing indicated progression, requiring therapy change to ixazomib. Case 1 never underwent plasma cell-targeted therapy and was lost to follow-up. He re-presented 12-years later with increased proteinuria (1.6 g/24-hours) despite no measurable plasma cell dyscrasia, and repeat kidney biopsy demonstrated persistence of AL-lambda amyloid deposition. Most recently, his proteinuria has improved (350 mg/24-hours) while on an ACE inhibitor only. Systemic AL amyloidosis with an undetectable plasma cell dyscrasia is a rare entity, described here in 6 of 673 patients. These perplexing cases challenge our notion of amyloid pathogenesis. Conceivably, the underlying plasma cell dyscrasia is so subtle that it evades detection by conventional techniques, or has spontaneously remitted altogether. Splenic plasma cells could also serve as the source of amyloidogenic light chains,3 thus explaining an absence of monoclonal plasma cells on bone marrow examination. Light chains with especially unstable kinetics could be driving amyloid formation, even at very low concentrations. Alternatively, the light chains could be so organ-avid that immediate absorption precludes serum accumulation or detection. Note, MASS-FIX is a method with higher analytical sensitivity previously shown to detect a monoclonal protein in a newly diagnosed patient with AL amyloidosis, that only had evidence of clonal disease by bone marrow biopsy.2 Serum and urine were analyzed by MASS-FIX in cases 1 and 2; however, a monoclonal gammopathy was not detected. Rather than the quantity of circulating monoclonal protein being too small, perhaps a unique quality of the light chains accounts being undetectable by IFE or MASS-FIX. Post-translational modifications such as N-glycosylation, for example, are commonly present in the monoclonal light chains of patients with AL amyloidosis.4 Glycosylation could interfere with targeted antibody binding and influence light chain mass and charge. Heterogeneity of N-glycosylation due to various glycoforms perhaps causes monoclonal proteins to appear dissimilar and evade detection. Another possibility is that these patients are in an early precursor disease state, and a quantifiable monotypic plasma cell population might not emerge until years later. The existence of a precursor disease state was previously suggested in a study identifying glycosylation patterns associated with AL amyloidosis before diagnosis and symptom onset.5 Interestingly case 3 in our report presented with an incidental femur amyloidoma in 2001, but had no other site of amyloid involvement on extensive evaluation. Fifteen-years later, he developed progression of amyloidosis to the kidneys, along with new soft tissue retroperitoneal amyloidomas. However, emergence of a monoclonal gammopathy did not occur. An alternative explanation is that the underlying plasma cell dyscrasia spontaneously resolved prior to diagnosis. Spontaneous remissions have been documented in other plasma cell dyscrasias such as light chain monoclonal gammopathy of undetermined significance (LC-MGUS) and multiple myeloma,6, 7 but are not yet recognized in AL amyloidosis. Due to ineffective clearance from tissues, amyloid deposits can remain in organs for many years, even in successfully treated patients with achievement of hematologic complete response. A patient could conceivably be diagnosed with AL amyloidosis by histopathology after the underlying plasma cell dyscrasia is no longer active. This might account for case 1, who demonstrated organ stability over time despite no targeted treatment. Recent assessment for minimal residual disease by multiparametric flow method (10−5 level of detection) did not identify an aberrant clonal plasma cell population in this patient. We conclude that for select patients with clinical features of systemic AL amyloidosis (ie, heart failure with preserved ejection fraction, proteinuria, unexplained hepatomegaly, and axonal demyelinating peripheral neuropathy), the absence of monoclonal gammopathy should not deter aspiration of subcutaneous fat and/or tissue biopsy of the affected organ. Only histopathological analysis for Congophilia and accurate precursor protein typing can lead to diagnosis in some cases. Moreover, it is important to distinguish these systemic cases from localized AL amyloidosis, which does not require systemic chemotherapy. The Amyloidosis Center database and repository is supported by Amyloid Research Fund of School of Medicine, Boston University. The authors declare no competing conflicts of interest. AS collected and analyzed data, and wrote the manuscript in consultation with YK, DJM and JMS; VS edited and revised the final version.