Free Light-Chain Levels in Patients with Transthyretin Amyloid Cardiomyopathy in Attr-ACT

Abstract Introduction: In cardiac amyloidosis (CA), immunoglobulin-derived light chains (AL) and transthyretin (TTR) are the most common amyloidogenic proteins infiltrating the heart. 1 Identification of the specific precursor protein leading to amyloid deposition is needed to establish the correct therapeutic approach. 2 In both AL- and TTR-related CA, an early and accurate diagnosis is critical to achieving the best treatment outcomes. TTR amyloid cardiomyopathy (ATTR-CM) is often misdiagnosed as other causes of heart failure (HF), including AL CA. 3 While almost all patients with AL amyloidosis have elevated serum free light-chain (sFLC) levels and abnormal free kappa:lambda (κ:λ) ratios, 4 patients with ATTR-CM can also have abnormal sFLC levels due to either an unrelated monoclonal gammopathy or relative κ-predominance in renal dysfunction. 2,5 Because ATTR-CM most often occurs in elderly adults and is commonly accompanied by renal comorbidity, we theorized that patients with ATTR-CM may have κ:λ ratios that approach, or exceed, the upper limit of the normal reference range (0.26-1.65 6). High light-chain ratios in these patients have the potential to increase the likelihood of misdiagnosis of a monoclonal plasma cell disorder and may lead to unnecessary referrals to hematologists and/or inappropriate treatments. To explore this theory, we evaluated κ:λ ratios in patients with biopsy-proven ATTR-CM who were enrolled in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT). 7 Methods: In ATTR-ACT, a double-blind, placebo-controlled, randomized study, patients with biopsy-proven ATTR-CM, and without light-chain amyloidosis, received tafamidis or placebo for 30 months. In the current analysis, sFLC levels and κ:λ ratios were assessed in the intent-to-treat population (N=441), excluding patients with a prior diagnosis of monoclonal gammopathies (n=13; defined by MedDRA preferred terms: 'monoclonal gammopathy', 'plasma cell myeloma', 'plasma cell disorder', and 'hypergammaglobulinemia benign monoclonal'). Subgroup analyses were performed by estimated glomerular filtration rate (eGFR) category (≥60 vs ≥40 to <60 vs <40 mL/min/1.73 m 2). Findings were summarized using descriptive statistics (min/max, mean, median, and interquartile range [IQR]). Results: In 422 patients with ATTR-CM and available sFLC data, and without a prior diagnosis of monoclonal gammopathies, the mean κ:λ ratio was 1.45 (median, 1.20 [IQR, 0.98, 1.47]) (Figure). The ratio increased with declining renal function: eGFR ≥60 mL/min/1.73 m 2, mean, 1.25 (median [IQR], 1.11 [0.94, 1.38]); ≥40 to <60 mL/min/1.73 m 2, 1.52 (1.22 [0.99, 1.49]); and <40 mL/min/1.73 m 2, 1.62 (1.30 [1.05, 1.68)]. Conclusions: In patients with biopsy-proven ATTR-CM without known monoclonal gammopathies who were enrolled in ATTR-ACT, the mean κ:λ ratio showed a κ-predominance, often exceeding the upper range of normal in patients with more advanced kidney dysfunction. The findings suggest that individuals with ATTR-CM can have higher sFLC levels than those normally seen in the general population, and such elevations do not necessarily indicate the presence of monoclonal gammopathy of undetermined significance or AL CA. In an era when most patients with ATTR-CM and without monoclonal gammopathies are diagnosed noninvasively using bone scintigraphy, age- and renal-function-based sFLC norms are critical to ensure appropriate use of diagnostic testing modalities. References: 1. Maleszewski JJ. Cardiovasc Pathol. 2015;24:343-50. 2. Donnelly JP, et al. Cleve Clin J Med. 2017;84:12-26. 3. Witteles RM, et al. JACC Heart Fail. 2019;7:709-716. 4. Falk RH, et al. J Am Coll Cardiol. 2016;68:1323-41. 5. Geller HI, et al. Mayo Clin Proc. 2017;92:1800-5. 6. Katzmann JA, et al. Clin Chem. 2002;48:1437-44. 7. Maurer MS, et al. N Engl J Med. 2018;379:1007-16. Figure 1 Figure 1. Disclosures Hoffman: BMS, Celgene: Honoraria. Sultan: Pfizer: Current Employment, Current equity holder in publicly-traded company. Gundapaneni: Pfizer: Current Employment, Current equity holder in publicly-traded company. Witteles: Pfizer: Honoraria, Research Funding; Alnylam: Honoraria, Research Funding; Eidos: Research Funding.

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Monoclonal Gammopathy in An African American Cohort From a VA Medical Center.

Blood ◽

10.1182/blood.v114.22.4869.4869 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4869-4869

Author(s):

Avni M Desai ◽

Richard L Amdur ◽

Min-Ling L Liu ◽

Joao Ascensao ◽

Dalia Mobarek ◽

...

Keyword(s):

African American ◽

Plasma Cell ◽

Light Chain ◽

Monoclonal Gammopathy ◽

Medical Center ◽

Kaplan Meier ◽

Plasma Cell Disorder ◽

Actuarial Risk ◽

Cell Disorder ◽

Bence Jones Proteinuria

Abstract Abstract 4869 The information regarding monoclonal gammopathy of unknown significance (MGUS) derives mainly from studies of Caucasian individuals. In contrast, this study describes the characteristics of 492 African American (AA) male patients identified with MGUS from the electronic database at the Washington VAMC. Review of their individual electronic records showed that none of the patients initially had evidence of myeloma or other symptomatic plasma cell or lymphoproliferative disorder. The median age at diagnosis of MGUS was 68 years old (range 28.5 to 95.6 years). The distribution of monoclonal immunoglobulin (M Ig) subtypes were IgG 78.1%, IgA 14.8%, IgM 6.9%; light chain only in the urine 2.9% or in the serum 1.0%, The light chain distribution of the M Igs was 60% kappa, 40% lambda. Fifty-nine patients (12%) had diclonal and 4 (0.8%) had triclonal M Igs. The median amount of M Ig was 0.26 g/dL; 47.8% were too small to quantitate. Ninety-four (25.5%) of 368 tested had Bence-Jones proteinuria, with a similar kappa:lambda distribution and 4 patients showed both light chains. Clinical characteristics were as follows: hepatitis C 15.5%, HIV 5.1%, other significant infections 26.8%, and chronic autoimmune or inflammatory disorders 10.3%. The patients were followed clinically for a median of 4.1 years (range 0.35 to 21.02 years), and the median interval between the first and last electrophoresis was 1.41 years (range 0 to 19.97 years). During this period 21 patients (4.3%) progressed to a malignant plasma cell disorder (myeloma 20, solitary plasmacytoma 1). 133 patients (27.0%) died of other causes, and in 26 (5.3%) the M protein had resolved. The actuarial risk determined by a Kaplan Meier plot of progression to a symptomatic plasma cell disorder was 13.5 % at 11 years. The initial M Ig in the patients who progressed was IgG in 15, IgA in 4, and isolated BJ proteinuria in 2. The only recognized predicting characteristic for progression was the detection of Bence-Jones proteinuria at diagnosis of MGUS: Thirteen of 20 (65%) progressing patients tested were positive as compared to 81 of 348 (23.0%) of the non-progressors (p = .0003) A number of features distinguish this AA MGUS cohort from previous series of Caucasian patients. MGUS was detected at an earlier age: 8.9% (5.2% excluding HCV and HIV patients) were under the age of 50. The percentage of AA patients with very low level M proteins was more than threefold that previously reported. The percentage of patients with IgM M Ig was less than one-half noted in previous studies. The actuarial risk of progression to a symptomatic plasma cell disorder as calculated from a Kaplan Meier plot appears to be comparable to previous reports in predominantly Caucasian series. Dr. Desai worked on this project following completion of her internal medicine residency. She is now a Hematology Oncology fellow at Montefiore Medical Center, New York NY. Disclosures No relevant conflicts of interest to declare.

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Natural History of Amyloidosis Isolated to Fat and Bone Marrow Aspirate

Blood ◽

10.1182/blood.v126.23.5303.5303 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5303-5303

Author(s):

Rajshekhar Chakraborty ◽

Morie A. Gertz ◽

Angela Dispenzieri ◽

Wilson I. Gonsalves ◽

Ronald S. Go ◽

...

Keyword(s):

Bone Marrow ◽

Natural History ◽

Plasma Cell ◽

Light Chain ◽

Research Funding ◽

Bone Marrow Aspirate ◽

Systemic Amyloidosis ◽

Plasma Cell Disorder ◽

Cell Disorder

Abstract Background: Light chain Amyloidosis (AL) is characterized by deposition of light chain derived amyloid fibrils in major organs and/or soft tissue. An observational study on natural history and outcome of localized immunoglobulin light-chain amyloidosis without vital organ (liver, heart, kidney, peripheral and autonomic nervous system) involvement has shown extremely low rate of progression (1%) to systemic amyloidosis at a median follow-up of 74.4 months (Mahmood S et al. The Lancet Haematology; 2015; 6:e241-e250). There is, however, limited evidence in published literature on natural history of AL amyloidosis confined to fat and/or bone marrow biopsy, without involvement of vital organs or other soft tissues. Methods: We retrospectively identified patients with AL amyloidosis limited to fat and/or bone marrow aspirate in a single-institution database. Patients were evaluated for progression to systemic amyloidosis. Statistical analysis was done using JMP 10.0.0 (SAS Institute Inc.). Results: We identified 117 patients, with a median age of 70 years, who had light chain amyloidosis detected in abdominal fat aspirate and/or bone marrow biopsy, without systemic involvement. Amyloid was seen in fat only in 39%, marrow only in 54% and in both sites in 7%. The median follow up was 45.6 months (95% CI-38.1-57.7) from detection of amyloid. Of these, 64% were alive at the time of analysis. Among 117 patients, 65 were treated for a diagnosis of another plasma cell disorder made prior to or concurrent with detection of amyloid. The remaining 52 patients only had isolated fat or marrow amyloid. Among 65 patients with another diagnosis of plasma cell disorder requiring treatment, 3 progressed to systemic amyloidosis, one each with cardiac, renal and lymph node (LN) involvement detected at 32, 42 and 65 months respectively from the detection of amyloid. The first 2 patients had underlying multiple myeloma, and the third patient with LN involvement had underlying Waldenström macroglobulinemia. Among 52 patients without another diagnosis of a plasma cell disorder requiring treatment, at a median follow up of 32 months, no progression to systemic amyloidosis was observed. Median overall survival (OS) in 117 patients from detection of amyloid, using Kaplan-Meier survival estimates, was 60.2 months (95% CI-48.9-146.1). Conclusion: Our study highlights the fact that isolated amyloidosis detected in fat and/or bone marrow aspirate, in the absence of another plasma cell dyscrasias that require therapy, is unlikely to progress to systemic amyloidosis. Watchful waiting might be considered in such patients after a thorough evaluation to rule out systemic involvement. Disclosures Gertz: Smith Kline: Honoraria; Novartis: Honoraria; Onyx: Honoraria; millenium: Consultancy, Honoraria; Celgene: Honoraria. Kumar:Celgene: Consultancy, Research Funding; Abbvie: Research Funding; Millenium: Consultancy, Research Funding; Novartis: Research Funding; Onyx: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; BMS: Consultancy, Research Funding.

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Incidentally Detected Amyloid Light-Chain Amyloidosis Caused by Monoclonal Gammopathy of Undetermined Significance: Possible Time-Dependent Change in Colonic Findings

Case Reports in Gastroenterology ◽

10.1159/000494919 ◽

2018 ◽

Vol 12 (3) ◽

pp. 737-746

Author(s):

Toshiro Fukui ◽

Yuji Tanimura ◽

Yasushi Matsumoto ◽

Shunsuke Horitani ◽

Takashi Tomiyama ◽

...

Keyword(s):

Plasma Cell ◽

Light Chain ◽

Monoclonal Gammopathy ◽

Amyloid Deposition ◽

Fecal Occult Blood ◽

Al Amyloidosis ◽

Plasma Cell Disorder ◽

Amyloid Light Chain ◽

Cell Disorder ◽

Undetermined Significance

Amyloid light-chain (AL) amyloidosis is associated with plasma cell disorder and monoclonal light chains. This type of amyloidosis is the prominent type involving the gastrointestinal tract. Monoclonal gammopathy of undetermined significance (MGUS) is the most common plasma cell disorder and a known precursor of more serious diseases. A 72-year-old male was treated for high blood pressure, diabetes, and gout at the clinic of a private physician. Due to a positive fecal occult blood test discovered during colon cancer screening, he underwent colonoscopy and was diagnosed with adenomatous polyps by biopsies. Two months later, he was referred to our hospital for endoscopic resection of the polyps. Although the polyps were successfully removed, a colonoscopy revealed two types of ulcerative lesions. Immunohistopathological evaluations obtained from these lesions and polyps confirmed amyloid deposition. Although esophagogastroduodenoscopy results were normal, a biopsy specimen from the patient’s stomach showed the same type of amyloid deposition. Immunoelectrophoresis showed M-proteins for anti-IgG-λ in the serum and λ type Bence-Jones protein in the urine. His blood, bone marrow, and urine test results led to a diagnosis of MGUS. A coronary angiography revealed multivessel stenosis, and the patient’s cardiac function improved after coronary artery stenting. Hereafter, a combination therapy with bortezomib, lenalidomide, and dexamethasone is planned. This is a case report of systemic AL amyloidosis caused by MGUS, which was incidentally detected by colonoscopy.

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T Cell Large Granular Lymphocytic Leukemia and Co-Existing Plasma Cell Disorders

Blood ◽

10.1182/blood-2018-99-114953 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5368-5368

Author(s):

M Hasib Sidiqi ◽

Mohammed A Aljama ◽

David S. Viswanatha ◽

David Dingli

Keyword(s):

Multiple Myeloma ◽

Plasma Cell ◽

Mayo Clinic ◽

Monoclonal Gammopathy ◽

Specific Therapy ◽

Plasma Cell Disorders ◽

Plasma Cell Disorder ◽

Cell Disorder ◽

Lgl Leukemia

Abstract T cell large granular lymphocytic (T-LGL) leukemia has been reported to occur in patients with plasma cell disorders (PCD). We conducted a retrospective review of patients diagnosed with T-LGL leukemia and a PCD at the Mayo Clinic. 22 patients were identified with T-LGL leukemia and a plasma cell disorder. The T-LGL leukemia preceded the PCD in 18% (n=4), was synchronous in 50% (n=11) and diagnosed post plasma cell disorder in 32% (n=7) of patients. The PCD diagnosis varied and included monoclonal gammopathy of undetermined significance (MGUS, n=13), multiple myeloma (MM, n=5), smoldering multiple myeloma (SMM. N=2), lymphoplasmacytic lymphoma (LPL, n=1) and monoclonal gammopathy of renal significance (MGRS, n=1). 5 patients developed T-LGL leukemia after treatment for a PCD (4 with MM and 1 with LPL). 4 patients with MGUS progressed to a more aggressive disease, 3 to MM and 1 to LPL. Neutropenia (76%) and anemia (70%) were the most common clinical presentation. None of the patients had rheumatoid arthritis. Treatment for the TLGL was variable with a number of different agents used listed in Table 1. 45% (n=10) of patients had an indolent course and did not receive specific therapy for TLGL. 6 patients responded to a single line of therapy, all of whom received either cyclophosphamide or methotrexate based regimens. The remainder had a relapsing course with multiple lines of therapy including 2 patients that received splenectomy. Nine patients were identified as having symptomatic multiple myeloma and TLGL, Table 2. Four patients had progressed from a preexisting plasma cell disorder, 3 with MGUS and 1 with SMM. The diagnosis of TLGL preceded myeloma in 1 patient was concurrent in 4 and post myeloma diagnosis in 4 patients. Time to diagnosis of TLGL post myeloma ranged from 10 to 63 months. At time of LGL diagnosis neutropenia was present in 7/9 patients and anemia in 6/8 (data unavailable for 1 patient). Cytogenetics data was available in 7 patients. Hyperdiploidy was the most common abnormality (3/7) followed by deletion 13q (2/7), t(14;16) in 1 patient and 1q amplification in 1 patient. The majority of patients were treated with novel agents with 7 receiving bortezomib based therapy. 3 patients underwent autologous stem cell transplantation. Therapy directed at the TLGL was given to 4/9 patients. This consisted of a combination of cyclophosphamide and prednisone in 3/4 patients all of whom responded to therapy with resolution of cytopenias. One patient had TLGL with multiple relapses and required multiple lines of therapy including eventual splenectomy. 3 patients with TLGL diagnosed after the diagnosis of myeloma did not receive specific therapy directed at the TLGL. The clinical course of the TLGL in these 3 patients was indolent and did not appear to be affected by therapy for multiple myeloma. At last follow up 5 patients have died. After a median follow up of 76 months post TLGL diagnosis the median overall survival (OS) post TLGL diagnosis was not reached for the entire cohort. In the cohort of patients with multiple myeloma, median OS from time of myeloma diagnosis was 71 months. Median OS from time of TLGL diagnosis was not reached. T-LGL leukemia can present in patients with a variety of plasma cell disorders and occur at any stage of the disease process. It is an important differential to consider in patients with unexplained cytopenias that are incongruent with the activity of the plasma cell disorder. Disclosures Dingli: Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding.

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Expression of CD126 (IL-R alpha) on Plasma Cells in Monoclonal Gammopathies.

Blood ◽

10.1182/blood.v108.11.5066.5066 ◽

2006 ◽

Vol 108 (11) ◽

pp. 5066-5066

Author(s):

Syed T. Mahmood ◽

Shaji Kumar ◽

Teresa K. Kimlinger ◽

Jessica L. Haug ◽

Michael Timm ◽

...

Keyword(s):

Plasma Cell ◽

Monoclonal Gammopathy ◽

Plasma Cells ◽

Cell Subset ◽

Primary Amyloidosis ◽

Normal Plasma ◽

Plasma Cell Disorders ◽

Plasma Cell Disorder ◽

Cell Disorder

Abstract Background: IL-6 is important for proliferation and inhibition of apoptosis in malignant plasma cells. Understanding the role of IL-6 receptor alpha chain (CD126) in the pathogenesis of plasma cell disorders may help in developing future treatment therapies for these diseases. A previous study has shown that CD126 (alpha subunit of IL-6 receptor) is expressed distinctly in myeloma, monoclonal gammopathy of unknown significance (MGUS), and plasmacytomas when compared to normal. We performed this study in order to confirm and describe the expression of CD126 in different plasma cell disorders. Design and Methods: Using flow cytometry we assessed CD126 expression on clonal plasma cells from patients with Primary Amyloidosis (n=7), monoclonal gammopathy of undetermined significance (MGUS) (n=13), smoldering Myeloma (SMM) (n=19) and active Myeloma (n=22), as well as normal plasma cells (n=9). Plasma cells were identified by their characteristic CD38/45 expression. The expression of CD126 was separately analyzed on the CD45 positive and negative plasma cells. CD 126 expression was considered significant when more than 20% of the cells had expression. Results: CD126 expression was seen distinctly in plasma cell disorder plasma cells and not in normal plasma cells when all plasma cells were studied together. The highest expression percentages were found in Amyloid (28%) followed closely by MGUS 29(%), then SMM (23%), and Myeloma (12%) cells. The CD45 neg subset was similarly positive in the plasma cell disorder group. In this group, MGUS showed the highest expression percentage followed distantly by Amyloid, Myeloma, and SMM. The CD45 pos subset was uniformly positive in expression of CD126. If was found that this subset expressed higher levels of CD126 in all the studied plasma cell disorders and normal plasma cells when compared to the CD45 neg subset. Conclusion: The findings of this study confirm the increased expression of CD126 in plasma cell disorders when compared to normal plasma cells. The higher expression of CD126 in the CD45 pos plasma cell subset has not been previously described. In addition, the CD45 pos subset expressed higher levels of CD126 in all study groups when compared to the CD45 pos subset. This data contributes to the understanding of IL-6 receptor physiology and confirms the important role of the CD45 pos subset in the proliferation of neoplastic plasma cells. The findings are in accordance with the increased proliferative rates seen in the CD45 fraction of malignant plasma cells.

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A Pre-Existing Plasma Cell Disorder Occurs in Most Patients with Multiple Myeloma.

Blood ◽

10.1182/blood.v112.11.1693.1693 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1693-1693 ◽

Cited By ~ 2

Author(s):

Brendan M Weiss ◽

Pramvir Verma ◽

Jude Abadie ◽

Robin Howard ◽

Michael Kuehl

Keyword(s):

Multiple Myeloma ◽

Plasma Cell ◽

Light Chain ◽

Medical Center ◽

Walter Reed Army Medical ◽

Cell Transplant ◽

Serum Samples ◽

Published Evidence ◽

Plasma Cell Disorder ◽

Cell Disorder

Abstract Background. A pre-existing plasma cell disorder (PPCD), such as monoclonal gammopathy of undetermined significance (MGUS), is thought to be present in at least one-third of patients presenting with symptomatic multiple myeloma (MM). However, no study has comprehensively evaluated the proportion of patients with MM that had a PPCD by laboratory testing on pre-diagnostic sera. Methods. The Walter Reed Army Medical Center autologous stem cell transplant database was cross-referenced with the Department of Defense Serum Repository (DoDSR) database, which catalogs serum samples collected every 2 years on over 4 million active-duty service members. All samples 32 years prior to the diagnosis of MM were retrieved. Serum protein electrophoresis (SPEP), immunofixation electrophoresis (IFE) and serum free light chain analysis (sFLC) (The Binding Site, San Diego, CA) were performed on all samples. A PPCD was defined as a positive SPEP, IFE or abnormal sFLC ratio. Results. Serum samples prior to the diagnosis of MM were available for 30/90 patients, and the median number of samples per patient was 3.5 (range, 1–14). The median age at diagnosis of MM was 48.1 yrs (29–67), with 96% male, 53% Caucasian, and 47% African-American. The Ig isotype of MM was IgG 76%, IgD 10%, light-chain 7%, and non-secretory 7%. A PPCD was detected in 27/30 patients (90%, 95% CI 74–97%). The initial PPCD was detected by sFLC alone in 6/27 (22.2%), IFE alone 2/27 (7.4%), SPEP+IFE 5/27 (18.5%), SPEP+IFE+sFLC 13/27 (48.1%) and IFE+sFLC 1/27 (3.7%). There were 4 patients whose only positive sera was 2.5–3.5 years prior to diagnosis, with all preceding sera negative. Conclusions. First, a pre-existing plasma cell disorder is present in most MM patients at least 2.5 years prior to diagnosis. Second, consistent with published evidence for a small fraction of patients with high risk MGUS, 4/30 patients were documented to progress rapidly through an MGUS phase to MM. Third, 4/4 patients with light chain only or non-secretory MM had a PPCD that was detected only by sFLC, thereby indicating that all these tumors are preceded by a light chain only or non-secretory PPCD.

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IgM Multiple Myeloma: Disease Definition, Prognosis, and Differentiation From Waldenstrom's Macroglobulinemia.

Blood ◽

10.1182/blood.v114.22.1828.1828 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1828-1828 ◽

Cited By ~ 2

Author(s):

Steven Schuster ◽

Angela Dispenzieri ◽

S. Vincent Rajkumar ◽

Alvaro Moreno Aspitia ◽

Robert Kyle ◽

...

Keyword(s):

Multiple Myeloma ◽

Plasma Cell ◽

Monoclonal Gammopathy ◽

Median Overall Survival ◽

Bone Lesions ◽

Lytic Lesions ◽

Lytic Bone Lesions ◽

Plasma Cell Disorder ◽

Definition Of ◽

Cell Disorder

Abstract Abstract 1828 Poster Board I-854 Background IgM Multiple Myeloma (MM) and Waldenstrom's Macroglobulinemia (WM) are two hematologic diagnoses with the common variable of an IgM monoclonal gammopathy. Distinguishing these two diagnoses is critical as the approach to therapy is different. A study by Avet-Loiseau et al demonstrated the presence of t(11;14) translocations in 7 of 8 patients with IgM MM that was absent in all of a series of 17 cases of WM (Semin Oncol 2003 30:2;153). However, 6 of the 8 IgM MM cases lacked classic lytic lesions. Method A priori, based on the literature and the natural history of MM, we defined IgM MM as a symptomatic clonal plasma cell proliferative disorder characterized by a serum IgM monoclonal protein (regardless of size) plus presence of t(11;14) on fluorescent in situ hybridization (FISH) and/or lytic bone lesions felt to be related to the underlying plasma cell disorder. The cases for the study were screened by a computerized database search for ‘IgM’ and ‘Myeloma’ of all patients seen at Mayo Clinic in the last 30 years at all three sites (Rochester, Arizona and Florida). Patients identified on the computerized screen were then audited by chart review to identify the study cohort. Results 38 cases were identified on initial screen of the computerized database as potential patients with IgM MM. Of these, a total of 22 cases met our specific definition of IgM myeloma (t(11;14 and/or lytic lesions). Of the remaining 16 cases, 8 were IgM MGUS, 5 were WM based on clinical presentation (hyperviscosity, lymphadenopathy and organomegaly) and biopsy findings of lymphoplasmacytic lymphoma, 1 was excluded due to lack of information, and the remaining 2 patients were indeed considered to have clinical IgM MM. Interestingly, these two patients did not have either the t(11;14) or lytic lesions, but rather had immunophenotypic features suggestive of MM and not WM (CD138+, CD20-). Table 1 summarizes the clinical characteristics of the 22 patients who met our criteria for IgM MM. All 22 patients had lytic bone lesions. Of the 17 evaluated with FISH, 6 (35%) demonstrated the t(11;14) abnormality. Median overall survival by Kaplan-Meier analysis was 37 months represented in Figure 1. Conclusion IgM MM is a discrete clinical entity that can and should be distinguished from WM. Our definition of IgM MM is designed to be specific and requires the presence of a symptomatic IgM secreting plasma cell proliferative disorder plus presence of t(11;14) and/or lytic bone lesions felt related to the underlying plasma cell disorder. In this, the largest series of patients with IgM MM, the t(11;14) abnormality is very specific for IgM MM, but may not be sensitive, being present in approximately 1/3 of patients. The median overall survival is similar to non-IgM myeloma patients treated during this period, and much shorter than what would be expected for WM. The minority of symptomatic patients with IgM monoclonal gammopathy who do not meet this criteria, but have immunophenotypic features more suggestive of MM rather than WM need further study. Disclosures No relevant conflicts of interest to declare.

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High Serum Free Kappa Chains Are Frequently Missed By Serum Immunofixation

Blood ◽

10.1182/blood.v124.21.5708.5708 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5708-5708 ◽

Cited By ~ 1

Author(s):

Surbhi Sidana ◽

Lisa Rybicki ◽

Frederic J. Reu ◽

Thomas Daly

Keyword(s):

Plasma Cell ◽

Light Chain ◽

Conflicts Of Interest ◽

High Serum ◽

Serum Free ◽

Bone Marrow Plasma ◽

Plasma Cell Disorder ◽

Serum Free Light Chains ◽

Monoclonal Proteins ◽

Cell Disorder

Abstract Background: Serum free light chains (sFLC) and immunofixation (IFE) analysis are used to detect monoclonal proteins. We noticed that some multiple myeloma (MM) patients (pts) had negative IFE results despite very high sFLC levels. This analysis was done to determine the frequency of this finding in a large cohort. Methods: Following IRB approval, samples with simultaneous sIFE and sFLCs ordered from 1/2013 to 9/2013 were identified by querying our lab electronic database. Freelite (R) Human Kappa & Lambda Free kit (The Binding Site, Birmingham, UK) was used for sFLC and SPIFE® ImmunoFix-15 gels (Helena Laboratories, Beaumont, TX) for IFE. Clinical review was performed for a subset of patients with discrepant results between the two assays. Results: 4404 samples from 2200 pts were identified with simultaneous sFLC and sIFE results. Overall 348 of 4404 (7.9%) samples had an abnormal sFLC ratio but a negative sIFE. Of 205 pts (457 samples) with involved serum free kappa above the expected IFE threshold (200 mg/L), 42 pts (103 samples) had negative sIFEs (20.5% pts; 22.5% samples) despite median free kappa of 556.6 mg/L (range 208.1 to 4954.4). This was much less common for involved free lambda. Only 4 of 107 pts with free lambda above 200mg/L had negative sIFEs (3.7%). Information of the nature of the plasma cell disorder was available on 40 of the 42 patients with free kappa > 200mg/L and negative IFE. In this group, 62.5% (n=25) had symptomatic MM, 12.5% (n=5) had asymptomatic MM, 5% (n=2) had light chain amyloidosis, 5% (n=2) had both amyloidosis and MM, and 15% (n=6) had MGUS or a not yet fully worked up plasma cell disorder. Conclusions: Serum IFE, with a commonly used kit, missed about 20% of patients with free kappa above the expected IFE threshold, while free lambda was detected more reliably. Results suggest current criteria for complete remission which rely on immunofixation and bone marrow plasma cell infiltration may need to be revised for kappa light chain myeloma. Disclosures No relevant conflicts of interest to declare.

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Diagnosis and Management of Monoclonal Gammopathy and Smoldering Multiple Myeloma

Journal of the National Comprehensive Cancer Network ◽

10.6004/jnccn.2020.7660 ◽

2020 ◽

Vol 18 (12) ◽

pp. 1720-1729

Author(s):

Timothy M. Schmidt ◽

Natalie S. Callander

Keyword(s):

Multiple Myeloma ◽

Plasma Cell ◽

Monoclonal Gammopathy ◽

Treatment Guidelines ◽

The United States ◽

Smoldering Multiple Myeloma ◽

Risk Of Progression ◽

Plasma Cell Disorder ◽

Monoclonal Proteins ◽

Cell Disorder

The presence of monoclonal proteins is common, with a prevalence in the United States around 5% that increases with age. Although most patients are asymptomatic, most cases are caused by a clonal plasma cell disorder. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic precursor conditions with variable risk of progression to multiple myeloma. In recent years, significant progress has been made to better understand the factors that lead to the development of symptoms and progression to myeloma. This review summarizes the current diagnosis treatment guidelines for MGUS and SMM and highlights recent advances that underscore a shifting paradigm in the evaluation and management of plasma cell precursor conditions.

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Lenalidomide/Melphalan / Dexamethasone Chemotherapy In 50 Patients With Newly Diagnosed Amyloid Light Chain Amyloidosis: First Results Of a Prospective Single Center Phase 2 Study (Leomex)

Blood ◽

10.1182/blood.v122.21.1993.1993 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1993-1993

Author(s):

Stefan O Schonland ◽

Tilmann Bochtler ◽

Axel Benner ◽

Marianne Gawlik ◽

Christoph Kimmich ◽

...

Keyword(s):

Plasma Cell ◽

Light Chain ◽

Cardiac Amyloidosis ◽

High Dose ◽

Al Amyloidosis ◽

Newly Diagnosed ◽

Number Of Patients ◽

Plasma Cell Disorder ◽

Amyloid Light Chain ◽

Cell Disorder

Abstract Introduction Amyloid light chain (AL) amyloidosis is a rare and life-threatening protein-misfolding disorder that is causedin most cases by a monoclonal plasma cell disorder. The goal of chemotherapy is to normalize the involved free light chain in serum which leads to an improvement or at least stabilization of organ function in most of these patients. A major challenge is the high treatment-related mortalityand toxicity in patients with advanced cardiac amyloidosis. Study design We performed a prospective single centerphase 2 trial with50 patients not eligible for high-dose treatment.Main inclusion criteria were: newly diagnosed and biopsy proven AL amyloidosis, significant organ involvement, age < 75 yrs and creatinine clearance > 40 ml/min. Treatment schedule was 6 cycles of an oral treatment with lenalidomide 10 mg day 1-21, melphalan 0.15 mg/kg day 1-4 and dexamethasone 20 mg day 1-4 every 4 weeks (L-M-dex). Primary endpoint was the rate of complete remissions (CR) of the underlying plasma cell disorder after 6 treatment cycles. Patients who received at least 3 cycles were eligible for hematologic remission (HR=CR+PR) analysis (At the time of study initiation “very good partial remission”in AL amyloidosis was not yet defined). The study was financially supported by Celgene. Patients and Methods Fiftypatients were included between 2009 and 2012. The median age was 67 years. 74% of patients had cardiac involvement. Outcome was compared with a historical group of 53 AL patients who received M-dex between 2004 and 2009 and fulfilled the same in- and exclusion criteria (patient characteristics see table). Results Forty-five patients (90%) completed 3 cycles and 35 patients (70%) completed 6 treatment cycles; overall 253 cycles could be administered. Reasons of discontinuation were toxicity in 6 patients (including one treatment-related death in the first cycle) or AL progression (9 patients). Ninety adverse events (AE) ≥ CTC grade 3 were recorded including 16 severe AEs. Seventeen hematologic AEs were observed (neutropenia 76%, CTC grade 4 in 2 patients). Most common non-hematologic AE was worsening of cardiac function or symptoms of autonomic neuropathy (14 patients). Furthermore 8 patients suffered from an infection, one patient developed acute renal failure and one patient a deep vein thrombosis. HR was achieved in 78% of patients: CR in 9 (20%)and PR in 26 (58%) of45 evaluable patients, respectively. Organ response was observed in 5 patients at the end of the study (6 months after the end of treatment). In the historical M-dex group HR rate was lower (58%, p=0.06): CR in 6 (15%)andPR in 17(43%) of 40 evaluable patients. OS was significantly improved using L-M-dex (see figure 1, median OS not reached vs. 26 mo., p=0.03). There was also a trend for a better EFS in the L-M-dex group (see figure 2, median EFS 23 vs. 16 mo., p=0.06). Of note, 3 L-M-dex patients (6%) died within 3 months after start of chemotherapy compared to 10 patients (19%) in the M-dex-group. Conclusion This is the largest phase II trial usinglenalidomide, melphalan and dexamethason in newly diagnosed AL amyloidosis patients. Treatment was effective and feasible in this cohort of mostly elderlypatients. 78% of evaluable patients achieved a hematologic remission. The early death rate was low with 6% despite of inclusion of a high number of patients with advanced cardiac amyloidosis. Overall, toxicity was manageable in most patients. Further improvement of these results might be achieved by prolongation of therapy in patients who have responded to and tolerate this combination therapy well. Disclosures: Schonland: Celgene: Honoraria; Janssen: Honoraria. Off Label Use: lenalidomide in amyloidosis. Hegenbart:Janssen: Honoraria.

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