Dispenzieri, Angela

Key PointsRadiation is appropriate primary therapy in approximately 25% of cases. Radiation provides long-term remissions in more than 50% of patients.

Amyloidosis affecting lymph nodes (LN) may occur in the setting of systemic amyloidosis or as an entity localized to the site of production (peritumoral). Why some LN amyloid remains peritumoral is unknown. We speculated that the composition of amyloid in these two presentations differs. We analyzed the amyloid proteome in LN amyloid samples to identify differences between the systemic and peritumoral subtypes. In immunoglobulin‐derived LN amyloidosis (N = 26), 70% had heavy chain amyloid (AH or mixed AH/AL). True localized LN amyloidosis was rare, with only 2 patients without a monoclonal protein component. Nineteen patients (73%) had typical amyloid syndromes (100% of AL vs 67% of AH/AL, P = 0.02). A trend to improved survival for the AH/AL group in comparison to AL (median 5‐year survival 48 vs. 19 months, P = 0.06) was seen. Mass spectrometric amyloid analysis is a powerful tool for characterizing amyloid and may provide additional prognostic information. Am. J. Hematol. 88:577–580, 2013. © 2013 Wiley Periodicals, Inc.

ICD in Cardiac AmyloidosisBackgroundCardiac amyloidosis (CA) is associated with increased risk of sudden cardiac arrest. Although ICD therapy improves survival in patients with cardiomyopathy due to other etiologies, the benefit of ICD therapy in patients with CA is unclear in large part due to limited data on the precise mechanism of sudden cardiac arrest and selection of patients with cardiac amyloidosis for ICD therapy.ObjectiveThe objective was to determine the benefit of ICD therapy in cardiac amyloidosis.MethodsWe reviewed all ICD implant indications, procedures, and therapies, of CA patients evaluated at Mayo Clinic between 2000 and 2009.ResultsA total of 53 patients with CA (33 AL, 10 senile, 9 familial, and 1 AA) who underwent ICD implantation were included. Indication for ICD implantation was for primary prevention of sudden cardiac arrest in 41 (77%) patients and secondary prevention in 12 (23%) patients. The rate of appropriate ICD shocks was 32% in the first year and was observed almost exclusively in AL amyloidosis patients, occurring in 15 patients (12 AL amyloidosis, 2 senile, 1 AA). Appropriate ICD shocks were more frequent in patients with prior sudden cardiac arrest or sustained ventricular arrhythmias (secondary prevention indication), and less frequent in patients who presented with decreased ejection fraction or syncope.ConclusionsA high rate of appropriate ICD shocks was observed especially in patients with AL‐type amyloidosis. However, appropriate ICD therapy did not translate into overall survival benefit, suggesting that selection of patients with CA who might be candidates for ICD is imprecise.

Key PointsIn this study, African American MM patients have a significantly lower frequency of IgH translocations than European American patients.

To clarify the presentation and course of patients with chronic lymphocytic leukemia (CLL) and amyloidosis. Mayo databases were interrogated for patients who carried a diagnosis of amyloidosis and CLL evaluated at Mayo Clinic, Rochester from January 1974 to October 2012. Charts were abstracted and data analyzed. Of the 33 patients identified, 20 (61%) were diagnosed with AL and 13 (39%) with non‐AL. Only four patients had immunoglobulin light chain amyloidosis (AL) that could be solely attributed to the CLL clone; another six had both a plasma cell clone and a CLL clone that shared the same light chain. Median overall survival was 15.6 months for patients with AL and 58.1 months for patients with non‐AL. For patients with AL management involved chemotherapy targeted toward monoclonal plasma cells, lymphocytes or both, and for patients with non‐AL no specific amyloid treatment was administered. AL is a rare complication of CLL, but in this elderly population of patients non‐AL is nearly as common. Distinguishing between these two groups is essential since patients with non‐AL amyloidosis have better outcomes and they do not require cytotoxic chemotherapy to treat their amyloidosis. Am. J. Hematol. 88:375–378, 2013. © 2013 Wiley Periodicals, Inc.

Purpose To identify the criteria for hematologic and cardiac response to treatment in immunoglobulin light chain (AL) amyloidosis based on survival analysis of a large patient population. Patients and Methods We gathered for analysis 816 patients with AL amyloidosis from seven referral centers in the European Union and the United States. A different cohort of 374 patients prospectively evaluated at the Pavia Amyloidosis Research and Treatment Center was used for validation. Data was available for all patients before and 3 and/or 6 months after initiation of first-line therapy. The prognostic relevance of different criteria for hematologic and cardiac response was assessed. Results There was a strong correlation between the extent of reduction of amyloidogenic free light chains (FLCs) and improvement in survival. This allowed the identification of four levels of response: amyloid complete response (normal FLC ratio and negative serum and urine immunofixation), very good partial response (difference between involved and uninvolved FLCs [dFLC] < 40 mg/L), partial response (dFLC decrease > 50%), and no response. Cardiac involvement is the major determinant of survival, and changes in cardiac function after therapy can be reliably assessed using the cardiac biomarker N-terminal natriuretic peptide type B (NT-proBNP). Changes in FLC and NT-proBNP predicted survival as early as 3 months after treatment initiation. Conclusion This study identifies and validates new criteria for response to first-line treatment in AL amyloidosis, based on their association with survival in large patient populations, and offers surrogate end points for clinical trials.

AbstractMultiple myeloma is the most frequent monoclonal gammopathy to involve the kidney; however, a growing number of kidney diseases associated with other monoclonal gammopathies are being recognized. Although many histopathologic patterns exist, they are all distinguished by the monoclonal immunoglobulin (or component) deposits. The hematologic disorder in these patients is more consistent with monoclonal gammopathy of undetermined significance (MGUS) than with multiple myeloma. Unfortunately, due to the limitations of the current diagnostic schema, they are frequently diagnosed as MGUS. Because treatment is not recommended for MGUS, appropriate therapy is commonly withheld. In addition to end-stage renal disease, the persistence of the monoclonal gammopathy is associated with high rates of recurrence after kidney transplantation. Preservation and restoration of kidney function are possible with successful treatment targeting the responsible clone. Achievement of hematologic complete response has been shown to prevent recurrence after kidney transplantation. There is a need for a term that properly conveys the pathologic nature of these diseases. We think the term monoclonal gammopathy of renal significance is most helpful to indicate a causal relationship between the monoclonal gammopathy and the renal damage and because the significance of the monoclonal gammopathy is no longer undetermined.

Abstract Monoclonal gammopathy of undetermined significance (MGUS) is a precursor to multiple myeloma and related diseases. The majority of MGUS cases are characterized by the expression of immunoglobulin heavy chain (IgH); however, approximately one-fifth of MGUS cases do not present with IgH expression. These individuals have light chain MGUS (LC-MGUS), a precursor to light-chain MM (LC-MM). LC-MGUS is characterized by an absence of IgH and an abnormal free light chain ratio (FLC-R), indicating excessive expression of either κ or ≤ free light chains. LC-MGUS has a prevalence of 0.8% in the general population over the age of 50, as compared with a prevalence of 3.2% for heavy-chain MGUS (HC-MGUS) (Dispenzieri, 2010). There is currently little understanding of the association between family history of HC-MGUS or multiple myeloma (MM) and LC-MGUS. We investigated whether the prevalence of LC-MGUS is elevated in first-degree relatives of patients with either HC-MGUS or MM. HC-MGUS probands expressed IgH and were recruited through a population-based study of Olmsted County residents; MM probands consisted of both HC-MM and LC-MM and were recruited through the Mayo Clinic Hematology practice. Serum samples were collected from first-degree relatives of probands older than 40 years of age and subjected to electrophoresis, immunofixation, and free light chain assay. Prevalence of LC-MGUS was calculated in all first-degree relatives combined, and in relatives from both HC-MGUS and MM families separately. We compared the prevalence in family members to that in a well-defined Olmsted County, MN cohort (Dispenzieri, 2010) of patients aged 50 and over. A total 911 relatives of 232 MM and 97 MGUS patients were studied. LC-MGUS was detected in 17/911 (1.9%) relatives, for an age- and sex-adjusted prevalence of 1.7% (95% CI, 0.9% to 2.6%). Prevalence among relatives of MM probands (age- and sex- adjusted rate 2.1%; 95% CI, 1.0% to 3.2%) was higher than among relatives of MGUS probands (age- and sex- adjusted rate 0.6%; 95% CI, 0.0%-1.6%). There was an increased risk of LC-MGUS in relatives compared to the reference population which was predominantly due to the increased risk among relatives of MM probands (risk ratio=3.4, 95% CI 2.0, 5.51) as opposed to relatives of MGUS probands (risk ratio=1.1, 95% CI, 0.3 to 4.5). Among MM probands, there was no significant difference between the prevalence increase in relatives of the 32 probands with LC-MM and that of the relatives of the 200 probands with HC-MM (3.8 vs 3.3, ratio=1.2, 95% CI: 0.3-5.1, p=0.85). We conclude that the prevalence of LC-MGUS is significantly higher among first degree family members of all MM probands compared to the general population. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5485. doi:1538-7445.AM2012-5485