Monoclonal gammopathy plus positive amyloid biopsy does not always equal AL amyloidosis
Authors: M Hasib Sidiqi, Surendra Dasari, Ellen D. McPhail, Francis K. Buadi, Rahma Warsame, Martha Q. Lacy, David Dingli, Wilson I. Gonsalves, Prashant Kapoor, Taxiarchis Kourelis, Nelson Leung, Eli Muchtar, Martha Grogan, John A. Lust, Shaji Kumar, Robert A. Kyle, Vincent S. Rajkumar, Morie Gertz, Angela Dispenzieri
Journal: American Journal of Hematology (2019)

Amyloidosis is a disease in which misfolded proteins aggregate and deposit in tissues leading to organ damage and dysfunction. The two most common forms are immunoglobulin light chain (AL) amyloidosis and wild type transthyretin (ATTRwt) amyloidosis. The former is related to a neoplastic B cell or plasma cell clone while the latter is thought to be related to aging and has been reported primarily in older men. The prevalence of both ATTRwt amyloidosis and plasma cell disorders (PCDs) increases with age.1, 2 Previous reports have suggested an increased prevalence of monoclonal gammopathy of undetermined significance (MGUS) in patients with ATTRwt.3 Little data exist on the prevalence of other PCDs in this cohort. Herein, we report on the prevalence of PCDs in patients with ATTRwt seen at the Mayo Clinic. After approval by the Mayo Clinic Institutional review board, we retrospectively reviewed all patients diagnosed with ATTRwt at our institution between 1 January 2009 and 31 of December 2017. The start date of the study was chosen to coincide with routine clinical availability of laser microdissection mass spectrometry (LCMS) for subtyping of amyloidosis. Four hundred and ninety five patients with ATTRwt were evaluated during the study period. Of the 495 ATTRwt seen during this period, 142 (29%) were diagnosed with a PCD and formed our study cohort. Baseline characteristics are listed in Table 1. Monoclonal protein testing included SIFE, UIFE and FLC in 96% (n = 136), 72% (n = 102) and 98% (n = 139) of patients, respectively. Abnormalities were detected on SIFE, UIFE and FLC in 56% (n = 79), 27% (n = 39) and 72% (n = 102) of patients, respectively. The vast majority (90%, n = 128) of patients had MGUS (47% of whom were light chain MGUS [LC-MGUS]). The non-MGUS diagnoses included smoldering myeloma (SMM) in <1% (n = 2), multiple myeloma (MM) in 6% (n = 9), AL amyloidosis in 4% (n = 6), and lymphoplasmacytic lymphoma (LPL) in 4% (n = 6). MM and LPL developed after progression from documented MGUS in two and three patients, respectively. The plasma cell diagnosis was concurrent (within 6 months) with the diagnosis of ATTRwt in 86% (n = 122). In the remainder of patients, ATTRwt was diagnosed after the PCD (median time 4.6 years, range 0.5-26.3). The most common monoclonal protein isotypes were light chain only (44%) and IgG kappa (16%). Light chain subtype was kappa in the majority of patients (78%), driven primarily by the LC-MGUS cohort all of whom were kappa. In 31% (n = 44) of patients ATTRwt was diagnosed in patients presenting initially with a clinical history and preliminary workup suggestive of AL amyloidosis. The organ biopsied for the diagnosis of ATTRwt was heart in 43% (n = 61), bone marrow in 25% (n = 35), fat in 8% (n = 12) and other sites in 6% (n = 8, three lung, two lip, two bladder and one small bowel). LCMS confirmed ATTRwt amyloidosis in all patients with a biopsy positive for amyloid by Congo red staining. Twenty-six (18%) patients were diagnosed with ATTRwt based on clinical features and a strongly positive Technetium-99m pyrophosphate (PYP) scan. PYP scan was positive for ATTR in 55/56 patients (median heart to contralateral [H/CL] ratio 1.6, range 1.1-2.4). Among the 26 patients with a PCD who did not have tissue biopsy confirmation of ATTRwt, 25 had H/CL ratio reported on PYP (median H/Cl ratio 1.6, range 1.2-2.4). One patient with a PYP scan positive for ATTR did not have an H/CL ratio reported. We noted a disproportionate number of patients with LC-MGUS and performed a subgroup analysis of this cohort (see Supporting Information Table 1). All 60 patients with LC-MGUS were kappa light chain type. SIFE, UIFE and FLC was performed in 90% (n = 54), 53% (n = 32) and 100% of patients, respectively. In this cohort, no patient had a positive SIFE, 5% (n = 3) had positive UIFE and 97% (n = 58) had an elevated FLC ratio. Two patients were diagnosed with LC-MGUS based on a positive UIFE only. The majority of these patients had borderline FLC testing (FLCr ≤3 in 93%, n = 56). The involved FLC was <5 mg/dL in 70% (n = 42). At last follow up, 43/142 (30%) patients have died. Median overall survival for the cohort was 67 months (95% CI, 41-73 months). Overall survival (OS) was not affected by the presence of MGUS (median OS 41 months for ATTRwt without MGUS vs. 67 months for ATTRwt with MGUS, P = 0.59). Our study shows that a spectrum of PCDs can occur in patients with ATTRwt. Unsurprisingly, given the shared demographic of peak incidence, the most common coexisting PCD was MGUS, occurring in 26% of patients with ATTRwt. This is congruent with previous reports of prevalence of MGUS in patients with ATTRwt ranging from 10% to 39%. (3) However, it should be noted that 47% of the MGUS cohort had LC-MGUS, exclusively kappa type, with the majority having minimally elevated involved FLC's and FLC ratios. The serum FLC assay is a highly sensitive and specific test recommended as a standard investigation in patients with newly diagnosed PCDs.4 However, false positives may occur in patients with polyclonal hypergammaglobulinemia or patients with renal failure.5 Borderline elevations in the FLC level and ratio need to be interpreted with caution particularly in selected populations such as our cohort with ATTRwt. This admonition should be counterbalanced by the fact that up to 20% of AL amyloidosis cases have a dFLC of <5 mg/dL and 40% of <20 mg/dL. The development of mass spectrometry based techniques, such as monoclonal immunoglobulin rapid accurate mass measurement (miRAMM), to assess for serum monoclonal proteins, however, may have a significant impact in this setting. Given the increased sensitivity of these tests we may detect a higher prevalence of MGUS in these patients than already reported.6 In addition, these assays may provide more definitive evidence for monoclonality in patients with borderline elevated FLC ratios. The prevalence of other PCDs in patients with ATTRwt was 4% (n = 20) with six patients having progressed from a documented previous MGUS. These patients were all diagnosed ATTRwt concurrently or after the diagnosis of the PCD. Given the presence of a monoclonal disorder, the clinician would typically suspect AL amyloidosis if amyloid is detected. Our study highlights the importance of accurate subtyping in patients with amyloidosis, irrespective of the presence of a PCD. A potential limitation of our study was the inclusion of 26 patients (18%) without a tissue diagnosis of ATTRwt. Although all of these patients had a clinical syndrome suggestive of amyloidosis and a PYP scan consistent with ATTR, due to the presence of MGUS, they do not meet strict international consensus criteria for a diagnosis of ATTR. In our study, of the 30 patients with a tissue diagnosis that also had a PYP scan performed, 29 were positive, a sensitivity of 97%. While this does not negate the necessity of trying to obtain tissue confirmation for patients, it is a scenario that is increasingly likely to be encountered by physicians. The median age of our cohort was 78, a demographic of patients that typically have other comorbidities and may not tolerate endomyocardial biopsy, a procedure with potential complications albeit rare. In conclusion, our study confirms the high rate of MGUS in patients with ATTRwt, sheds light on the prevalence of other PCDs in these patients, and serves as a cautionary reminder that a diagnosis of a PCD and amyloidosis does not always equate AL amyloidosis. M.H.S. designed the study, analyzed the data, wrote the first draft, and approved the final version of the manuscript. M.G., M.A.G., J.A.L., R.A.K., S.V.R., E.M., F.K.B., R.W., M.Q.L., D.D., N.L., W.I.G., S.K.K., P.K., and T.V.K., performed patient management, revised the manuscript critically, and approved the final version of the manuscript; S.D., E.M. analyzed the data, revised the manuscript critically, and approved the final version of the manuscript and A.D. designed the study, analyzed the data, wrote the first draft, approved the final version of the manuscript, and performed patient management. M.A.G. received consultancy from Millenium and honoraria from Celgene, Millenium, Onyx, Novartis, SmithKline, Prothena, Ionis, and Amgen. S.K.K. received consultancy from Celgene, Millennium, Onyx, Janssen, and BMS and research funding from Celgene, Millennium, Novartis, Onyx AbbVie, Janssen, and BMS. M.Q.L. received research funding from Celgene. D.D. received research funding from Karyopharm Therapeutics, and Millenium Pharmaceuticals. P.K. received research funding from Takeda, Celgene, and Amgen. A.D. received research funding from Celgene, Millennium, Pfizer, and Janssen and travel grant from Pfizer. The remaining authors declare no competing financial interests. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.