Objective: To identify the prevalence of monoclonal gammopathy of undetermined significance (MGUS) in patients with transthyretin (ATTR) amyloidosis.
Patients and methods: We performed a ...retrospective analysis of patients with biopsy-proven ATTRwt (wild-type transthyretin amyloid protein) and genopositive ATTR V122I (valine-to-isoleucine substitution at position 122 of the TTR gene) amyloidosis evaluated at the Amyloidosis Center at Boston University and Boston Medical Center between 1 January 2003 and 31 December 2016.
Results: There were a total of 226 patients with ATTRwt and ATTR V122I amyloidosis evaluated during the specified time frame with 155 and 71 patients in each cohort, respectively. Those with complete medical records, 140 patients with ATTRwt and 57 V1221 ATTRm subjects, were included in the analyses. Fifty-five patients (39%) in the ATTRwt cohort and 28 patients (49%) in the ATTR V122I cohort had an MGUS, as indicated by an abnormality in the serum-free light-chain ratio and/or serum immunofixation electrophoresis.
Conclusion: These data confirm the high prevalence of coexistent MGUS with ATTR amyloidosis in this patient population, with an MGUS rate that is higher than the general population. These findings also highlight the importance of a thorough diagnostic evaluation in patients with amyloidosis to determine the precursor protein, as the clinical course and treatment of AL (light-chain amyloid protein) and ATTR amyloidosis are distinct.
In marked contrast to multiple myeloma, racial/ethnic minorities are underrepresented in publications of systemic light-chain (AL) amyloidosis. The impact of race/ethnicity is therefore lacking in ...the narrative of this disease. To address this gap, we compared disease characteristics, treatments, and outcomes across racial/ethnic groups in a referred cohort of patients with AL amyloidosis from 1990 to 2020. Among 2416 patients, 14% were minorities. Non-Hispanic Blacks (NHBs) comprised 8% and had higher-risk sociodemographic factors. Hispanics comprised 4% and presented with disproportionately more BU stage IIIb cardiac involvement (27% vs. 4-17%). At onset, minority groups were younger in age by 4-6 years. There was indication of more aggressive disease phenotype among NHBs with higher prevalence of difference between involved and uninvolved free light chains >180 mg/L (39% vs. 22-33%, P = 0.044). Receipt of stem cell transplantation was 30% lower in Hispanics compared to non-Hispanic White (NHWs) on account of sociodemographic and physiologic factors. Although the age/sex-adjusted hazard for death among NHBs was 24% higher relative to NHWs (P = 0.020), race/ethnicity itself did not impact survival after controlling for disease severity and treatment variables. These findings highlight the complexities of racial/ethnic disparities in AL amyloidosis. Directed efforts by providers and advocacy groups are needed to expand access to testing and effective treatments within underprivileged communities.
Monoclonal antibody light chain proteins secreted by clonal plasma cells cause tissue damage due to amyloid deposition and other mechanisms. The unique protein sequence associated with each case ...contributes to the diversity of clinical features observed in patients. Extensive work has characterized many light chains associated with multiple myeloma, light chain amyloidosis and other disorders, which we have collected in the publicly accessible database, AL-Base. However, light chain sequence diversity makes it difficult to determine the contribution of specific amino acid changes to pathology. Sequences of light chains associated with multiple myeloma provide a useful comparison to study mechanisms of light chain aggregation, but relatively few monoclonal sequences have been determined. Therefore, we sought to identify complete light chain sequences from existing high throughput sequencing data.
We developed a computational approach using the MiXCR suite of tools to extract complete rearranged
sequences from untargeted RNA sequencing data. This method was applied to whole-transcriptome RNA sequencing data from 766 newly diagnosed patients in the Multiple Myeloma Research Foundation CoMMpass study.
Monoclonal
sequences were defined as those where >50% of assigned
or
reads from each sample mapped to a unique sequence. Clonal light chain sequences were identified in 705/766 samples from the CoMMpass study. Of these, 685 sequences covered the complete
region. The identity of the assigned sequences is consistent with their associated clinical data and with partial sequences previously determined from the same cohort of samples. Sequences have been deposited in AL-Base.
Our method allows routine identification of clonal antibody sequences from RNA sequencing data collected for gene expression studies. The sequences identified represent, to our knowledge, the largest collection of multiple myeloma-associated light chains reported to date. This work substantially increases the number of monoclonal light chains known to be associated with non-amyloid plasma cell disorders and will facilitate studies of light chain pathology.
AL amyloidosis is the most common form of systemic amyloidosis and is associated with an underlying plasma cell dyscrasia. It is often difficult to recognize because of its many manifestations. ...Recent diagnostic and prognostic advances include the serum-free light chain assay, cardiac MRI, and serologic cardiac biomarkers. Treatment strategies that have evolved during the past decade are prolonging survival and preserving organ function. This article outlines the role of high-dose melphalan and stem cell transplantation. This year marks the 20th anniversary for the first patient who underwent successful stem cell transplantation for this disease at Boston Medical Center.
Previous studies have suggested that, in patients with AL amyloidosis treated with high-dose melphalan and autologous stem-cell transplantation (HDM/SCT), the greatest benefit is seen in those ...patients achieving a hematologic complete response (CR). We analyzed a series of 421 consecutive patients treated with HDM/SCT at a single referral center and compared outcomes for patients with and without CR. Treatment-related mortality was 11.4% overall (5.6% in the last 5 years). By intention-to-treat analysis, the CR rate was 34% and the median event-free survival (EFS) and overall survival (OS) were 2.6 and 6.3 years, respectively. Eighty-one patients died within the first year after HDM/SCT and were not evaluable for hematologic and organ response. Of 340 evaluable patients, 43% achieved CR and 78% of them experienced an organ response. For CR patients, median EFS and OS were 8.3 and 13.2 years, respectively. Among the 195 patients who did not obtain CR, 52% achieved an organ response, and their median EFS and OS were 2 and 5.9 years, respectively. Thus, treatment of selected AL patients with HDM/SCT resulted in a high organ response rate and long OS, even for those patients who did not achieve CR.
The survivorship needs of patients with light-chain (AL) amyloidosis are complex, as is the diagnosis and treatment itself. Early diagnosis is critical in improving patient outcomes; however, given ...the nonspecific nature of the symptoms, most patients with AL amyloidosis require evaluation by multiple specialists, resulting in significant delays in diagnosis of up to 3 years. An early and accurate diagnosis can help reduce the psychological toll of the patient’s journey to diagnosis. Given the high symptom burden and complex process of diagnosis, it is not surprising that patients with AL amyloidosis report worse health-related quality of life than the general population. Organ dysfunction associated with AL amyloidosis also may make the treatment directed towards plasma cell clone difficult to tolerate, leading to morbidity and mortality. Furthermore, supportive care requires an integrated, multidimensional and patient-centered approach to improve survival and feelings of well-being, as organ responses lag behind hematologic responses. The impact of AL amyloidosis is often devastating for the patient and may last beyond the effects of treatment. Future research is needed to study and assess the needs of survivors of AL amyloidosis utilizing valid, reliable and standardized measures.
Amyloidosis of the gastrointestinal tract, with biopsy-proven disease, is rare. We reviewed a series of patients who presented with biopsy-proven gastrointestinal amyloidosis and report their ...clinical characteristics, treatments, and survival. This is a retrospective review of data prospectively collected from January 1998 to December 2011 in a tertiary referral center; 2,334 patients with all types of amyloidosis were evaluated during this period. Seventy-six patients (3.2%) had biopsy-proven amyloid involvement of the gastrointestinal tract. Their median age was 61 years (range, 34-79). Systemic amyloidosis with dominant gastrointestinal involvement was present in 60 (79%) patients, whereas the other 16 (21%) patients had amyloidosis localized to the gastrointestinal tract without evidence of an associated plasma cell dyscrasia or other organ involvement. Of the 60 systemic cases, 50 (83%) had immunoglobulin light-chain, five (8%) had familial lysozyme, three (5%) had wild-type transthyretin, and two (3%) had mutant transthyretin amyloidosis. The most frequent symptoms for all patients were weight loss in 33 (45%) and gastrointestinal bleeding in 27 (36%). Incidental identification of amyloidosis on routine endoscopic surveillance played a role in the diagnosis of seven patients with systemic immunoglobulin light-chain, and four patients with immunoglobulin light-chain localized to the gastrointestinal tract. Amyloid protein subtyping was performed in 12 of the cases of localized disease, and all had lambda light chain disease. Of the 50 patients with systemic immunoglobulin light-chain amyloidosis, 45 were treated with anti-plasma cell therapy. The median survival has not been reached for this group. For the 16 patients with localized gastrointestinal amyloidosis, supportive care was the mainstay of treatment; none received anti-plasma cell therapy. All 16 are alive at a median follow-up of 36 months (range, 1-143). Patients with biopsy-proven gastrointestinal amyloidosis often present with weight loss and bleeding. In localized cases, all that underwent typing were due to lambda light chain amyloidosis and none progressed to systemic disease during the period of follow-up. Most patients with systemic disease had immunoglobulin light-chain, and their tolerance of therapy and median survival were excellent. Although a rare manifestation of amyloidosis, staining for amyloid should be considered in patients undergoing gastrointestinal biopsy who have unexplained chronic gastrointestinal symptoms.
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