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Clinical Analysis of Cardiac Involvement in 53 Patients With Multiple Myeloma Coexistent With Light Chain Amyloidosis
Journal Pre-proof Clinical analysis of cardiac involvement in 53 patients with multiple myeloma coexistent with light chain amyloidosis Yuanyuan Yu, Zhongxia Huang, Wanli Hu, Xin Li, Man Shen, Jiajia Zhang, Ran Tang, Shilun Chen, Wenming Chen PII:
S2152-2650(20)30038-0
DOI:
https://doi.org/10.1016/j.clml.2020.01.002
Reference:
CLML 1512
To appear in:
Clinical Lymphoma, Myeloma and Leukemia
Received Date: 29 July 2019 Revised Date:
30 December 2019
Accepted Date: 2 January 2020
Please cite this article as: Yu Y, Huang Z, Hu W, Li X, Shen M, Zhang J, Tang R, Chen S, Chen W, Clinical analysis of cardiac involvement in 53 patients with multiple myeloma coexistent with light chain amyloidosis, Clinical Lymphoma, Myeloma and Leukemia (2020), doi: https://doi.org/10.1016/ j.clml.2020.01.002. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 The Author(s). Published by Elsevier Inc.
Micro-Abstract
We analyzed 53 patients with multiple myeloma (MM) coexistent with light chain amyloidosis (AL) to evaluate the influence on survival. Of them, 22 patients were treated with a bortezomib-based regimen, and the response rate was more effective than the other. The median OS for the total cohort was 12 months. Cardiac involvement significantly adversely affected survival (6 vs. 40 months), as did systolic blood pressure (SBP< 90 mmHg, 3 vs. 8.5 months). Cardiovascular dysfunction caused by AL is a major determinant of shortening survival for the total cohort.
Manuscript Number: CLML-D-19-00021 Revised manuscript 20191230
Clinical analysis of cardiac involvement in 53 patients with multiple myeloma coexistent with light chain amyloidosis Yuanyuan YU†, Zhongxia HUANG†*,Wanli HU, Xin LI, Man SHEN, Jiajia ZHANG, Ran TANG, Shilun CHEN, Wenming CHEN Address for correspondence: Zhongxia HUAN, MD, Multiple Myeloma Medical Center of Beijing, Department of Hematology, Beijing Chao-yang Hospital, Capital Medical University, 5 Jingyuan Road, Shijingshan District, Beijing 100043, CHINA Fax: +86-10-51718951; e-mail contact: [email protected] † Y.Y. and Z.H. contributed equally to this article, and both should be considered first author.
Abstract Background: We identified 53 patients with multiple myeloma (MM) who had biopsy evidence of light chain amyloidosis (AL), and studied their cardiac involvement and outcomes. Patients and Methods: 53 patients in whom MM and AL were initially diagnosed from July 1, 2006 to June 30, 2016.The diagnosis of MM required >10% of clonal plasma cells in bone marrow and one of the CRAB symptoms, meanwhile, the diagnosis of AL must meet pathological diagnostic criteria and monoclonal immunoglobulin light chain. Echocardiograms and cardiac biomarker such as N terminal pro B-type natriuretic peptide (NT-proBNP) was used for evaluation of cardiac damage on the baseline and before every
cycle of regiment. Results: There were 36 men and 17 women with a median age of 59 years, their main organ involvement was kidney(72%) and heart(62%).Of them, twenty-two patients were treated with a bortezomib-based regimen, and the response rate was more effective than the other 21 patients who receiving non-bortezomib-based regimens (64% vs. 29%). The median OS for the total cohort was 12 months (P<0.05). The median OS of MM cohort with ISS stage I and II together was 34 months, which was longer than that of patients with stage III of 8 months. The median OS in Mayo stages I, II and III was 38, 8 and 1 months (P < 0.05). Cardiac involvement significantly adversely affected survival (6 vs. 40 months), as did systolic blood pressure (SBP< 90 mmHg, 3 vs. 8.5 months). Conclusions: Patients coexistent with MM and AL is rare, AL has a negative impact on survival for the total cohort. Especially, cardiovascular dysfunction caused by AL maybe a major determinant of shortening survival. Keyword: Multiple myeloma, Amyloidosis, Cardiac involvement, Bortezomib, Survival Abbreviations MM: multiple myeloma; AL: light chain amyloidosis; CRAB: Initial letter abbreviation of hypercalcemia, renal insufficiency, anemia, osteolytic lesions :SBP: systolic blood pressure; IMWG: International Myeloma Working Group; AEs: adverse events; CR/nCR: complete remission/near-complete remission; PR: partial remission; VGPR: very good partial remission; CT: computed tomography; FISH: fluorescence in situ hybridization; Ig: immunoglobulin; ISS: International Staging System; MRI: magnetic resonance imaging; ORR: overall response rate; OS: overall survival. Nt-proBNP: N-terminal probrain natriuretic peptide
Introduction Multiple myeloma (MM) is a malignant plasma cell disease characterized by clonal proliferation of malignant plasma cells in the bone marrow, and elevation of monoclonal immunoglobulin in blood or urine, causing hypercalcemia, renal insufficiency, anemia, osteolytic lesions (CRAB symptoms) and a series of clinical manifestations1. In some cases these monoclonal immunoglobulin light chains or their fragments are folded to form insoluble fibers that deposit in tissues, resulting in kidney, heart or other organ dysfunction2,3,which caused Light chain amyloidosis(AL). MM and AL have a concent pathological basis, the incidence of both plasma cell disorders in European and American countries is reported to be urr10–26%3-5.Cardiac amyloidosis typically causes a restrictive cardiomyopathy, in which the deposition of misfolded amyloid proteins in the myocardium causes structural alterations, eventually leading to heart failure. Heart involvement is present in almost two-thirds of AL patients, representing the most common cause of death6. Given the heterogeneity of the two diseases, it is essential to understanding the characteristics and outcomes of cardiac involvement in MM coexistent with AL.
Patients and Method Diagnostic and therapeutic criteria of patients In his study, 53 patients with newly diagnosed MM with AL were identified from a clinical database in Beijing Chao-yang Hospital. The records were reviewed for all patients in whom MM and AL were initially diagnosed at the hospital from January 1, 2006, to June 30, 2016. Diagnostic and staging criteria were defined as in the International Myeloma Working Group
(IMWG) 7,8, and amyloid protein was demonstrated with Congo red staining and immunohistochemistry9. All patients experienced biopsy such as bone marrow biopsy, abdominal fat and renal biopsy, and no serious bleeding or other adverse events during biopsy. To assess cardiac function of the patients, echocardiograms and cardiac biomarkers such as N terminal pro B-type natriuretic peptide (NT-proBNP) or troponin T (TnT) were estimated on the baseline and before every cycle of treatment. On the basis of pathological diagnosis of AL, if the level of NT-proBNP was more than 328 pg/ml,ventricular septal thickness > 12 mm and urine protein was greater than 0.5g/24h, and there is no other reason to explain, it is defined as cadiac and renal involvement by AL 9-12. AL was staged using the Mayo system based on the high level of NT-proBNP and TnT 13. According to international criteria for MM14 and AL15, response to therapy and organ function were determined after treatment. Patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering MM, solitary plasmacytoma and plasma cell leukemia were excluded. Follow-up letters or telephone contact was made with all patients if they had not been seen or heard from for the previous year. Death certificates were requested when needed. In our study, 43 patients (10 patients discontinued treatment) received initial therapy with bortezomib-based or non-bortezomib-based regimens for 1–8 cycles (average 4–6), and then began consolidation or maintenance treatment. Treatment and groups Treatment related data were available for 43 patients. Twenty-two (51%) patients received bortezomib-based regimens as follows: bortezomib (Velcade, V) and dexamethasone (D)
(VD, n=6) or VD with cyclophosphamide (C) (VCD, n=16), the other 21 (49%) patients received non-bortezomib-based regimens as follows: CD (n=7) or CD with doxorubicin (Adriamycin, A) ( CAD, n=9), or CD with thalidomide (T) (CTD, n=5). Among the above regimens, bortezomib (1.0–1.3 mg/m2) was given intravenously or subcutaneously on days 1, 4, 8 and 11 of a 21-day cycle or weekly, and dexamethasone 15–20 mg/day on days 1, 4, 8 and 11 cycle or weekly, cyclophosphamide (200 mg/m2) and doxorubicin (9 mg/m2). For the CTD regimen, cyclophosphamide was given on days 1–4/15–18 intravenously and dexamethasone 15–20 mg/day on days 1–4/15–18, orally, and thalidomide (100 mg) was administered orally each day. Between the two treatment groups, treatment regimens were heterogeneous, but VCD and CD with or without doxorubicin were the most commonly used. In patients achieving a complete response (CR) or very good partial response (VGPR), the regimen was repeated for two to four cycles as consolidation therapy. Maintenance therapy mainly comprised thalidomide 100 mg/day, and other regimen included small doses of prednisone of 30 mg/day. Patients who were unable to tolerate the adverse events (AEs), were in poor physical condition, or had serious arrhythmia did not receive maintenance therapy. Aspirin or low molecular weight heparin was routinely used to prevent venous thrombosis in patients who had no contraindications. Herpes zoster prophylaxis was routinely given to patients who received bortezomib-based regimens. The patients were assessed after the completion of two cycles of chemotherapy. Bisphosphonates were used intravenously monthly for myeloma bone disease. Ethics statement
The study was approved by the Ethics Committee of Beijing Chao-yang Hospital, Capital Medical University, and follow-up information was obtained with consent of patients. All aspects of the study were conducted in accordance with the principles of the Declaration of Helsinki. Written informed consent was obtained from the patients for review of images and publication of this report. Statistical analysis We used SPSS version 22.0 (SPSS Inc., Chicago, IL, USA) for data analysis. The Kaplan–Meier method was used to assess overall survival (OS) and progression-free survival (PFS). P < 0.05 (log-rank test) was considered statistically significant.
Results Baseline clinical features Fifty-three patients with MM and AL were included, all had biopsy evidence of AL (Supplemental Table). The median age at diagnosis of all patients was 60 years. There were 36 (68%) male and 17 (32%) female patients. The diagnosis of AL requires a pathological biopsy. According to positive staining for Congo red in pathological tissues, 72% (38/53) of the patients had renal involvement and 62% (33/53) had cardiac involvement. The former showed median 24-hour urinary protein concentration of 4.4 g/L and median serum creatinine value of 484.3μmol/L, the latter showed different symptoms, such as dyspnea (67%, 22/53 cases), palpitations (18%, 6/53 cases), chest pain (12 %, 4/53 cases), and syncope (6%, 2/53 cases).Other prominent features were congestive heart failure ( 67% , 22/53 cases) and systolic hypotension below 90mmHg (33%, 11/53 cases) .In terms of International Staging (ISS) for MM, 4% (2/53), 32% (17/53) and 64% (34/53) of cases were
stage I, II and III, respectively. For Mayo staging for AL, 28% (15/53), 66% (35/53) and 6% (3/53) of cases were stage I, II and III, respectively. The general clinical characteristics were shown in Table 1. Forty-seven percent of patients (25/53 cases) underwent CD138 magnetic bead sorting for fluorescence in situ hybridization (FISH) bone marrow testing and 34% (18/53) had abnormalities. Among them, the high-risk abnormal gene such as 17p- ,t(4;14),t(14;16) and amplification of 1q21 were in 8 % (2/25) , 8 % (2/25),8 % (2/25) and 24% (6/25) cases respectively (Table 1).
Characteristics of patients with cardiac involvement In 33 patients with cardiac involvement, the median concentration of NT-proBNP was 14,213 (range 333–27 253) pg/mL. In electrocardiography, there were low-voltage leads and premature beat in 49% (16/33) and 73% (24/33) of patients, respectively. Echocardiography is a noninvasive, a widely used tool for monitoring heart function. All of 33 patients had atrial or ventricular enlargement. There were decreased diastolic function and left ventricular wall thickening in 42% (14/33) and 52% (17/33) of patients, respectively. Forty-seven percent (25/33) of patients had ventricular septal thickness > 12 mm, with a median thickness of 14.9 mm (Table 2).
Treatment response For bortezomib-based regimens, CR was 27% (6/22), VGPR was 9% (2/22), PR was 27% (6/22), and overall response rate (ORR; CR+PR+VGPR) was 64% (14/22). For non-bortezomib-based regimens, CR was 14% (3/21), VGPR was 5% (1/21), PR was 10% (2/21), and ORR was 29% (6/21). Of the 6 patients who received the treatment response, 3
cases of AL improved, 2 cases were stable, and 1case showed progression. Bortezomib-based regimens were more effective than non-bortezomib-based regimens in relation to ORR (64% vs. 29%, P < 0.05). Some organ function such as kidney, heart and tongue improved after treatment, but no difference was found between the two treatment groups (Supplemental Data).
Survival outcomes The median OS for the total cohort was 12 months (P < 0.05). For the MM cohort, OS of patients with ISS stage I and II together was 34 months, which was longer than that of patients at ISS stage III with 8 months (P < 0.05) (Figure 1). For the AL cohort, the OS of patients with only one organ involved was 37 months, which was longer than in patients with two organs involved (12 months) and three or more organs involved (5.5 months) (P < 0.05) (Figure 2). OS was 13 and 8 months in patients with and without renal insufficiency, respectively, but this difference was not significant (Supplemental Data). OS was 6 months for patients with cardiac involvement by AL (Supplemental Table 2), which was shorter than the 40 months in other patients (Figure 3). For stage of AL, OS was 38, 8 and 1 months in the patients with Mayo stage I, II and III , respectively (P < 0.05, Figure 4). OS was 3 months in patients with systolic blood pressure (SBP) <90 mmHg, which was shorter than in patients without hypotension (8.5 months) (P < 0.05) (Figure 5). For patients with a septal thickness greater than or less than 15 mm, the median OS was 5 and 14 months, respectively, and the former was significantly shorter than the latter. (P < 0.05) (Figure 6).
Forty-one percent of patients (25/53) underwent FISH test, and 72% of these (18/25) had abnormalities. Of them, 48%(12/25) had high-risk genetic abnormalities of TP53 deletion, t (14; 16) and 1q21 amplification, and their OS was 8 months, which was shorter than 27 months in other patients (P < 0.05) (Figure 7). The independent prognostic factors were not found among the influencing factors for survival. However, it can be seen from Figure 8 that patients with SBP < 90 mmHg, NT-proBNP ≥ 8000 pg/ml and septal thickness ≥ 15 mm all had a poor prognosis(Figure 8). It should be noted that only 3 patients underwent autologous hematopoietic stem cell transplantation of all 43 patients who received chemotherapy, and their previous initial induction therapy was 4-6 cycles of VCD regimens. All three patients reached CR after transplantation and PFS was 48, 36 and 16 months, but OS was not reached.
Discussion Compared to most case reports, this is a clinical study of a certain number of MM patients coexisting with AL. Fifty-three patients were analyzed and our data showed that the incidence rate was 0.6%, according to the total of 8833 MM patients in the past 10 years. This is less than the current reported incidence 3,5 . Among them, 62% of patients contained lambda light chain in their M protein, and the kidneys and heart were the two most commonly affected organs, which is similar to the literature 3,16-19. More than 10% of clonal plasma cells and high levels of M protein, especially immunoglobulin light chain levels, can be present in both MM and AL, and CRAB symptoms caused by malignant plasma cell disease are unique to MM. Therefore, while
MM and AL the two diseases were combined exist, refer to the method of Mayo Clinic, CRAB symptoms were the key points for diagnosing MM 12. Among the 43 patients who underwent treatment, their organ function was improved after receive with bortezomib-based regimens. Currently the OS of the entire cohort is 12 months, which is similar to the results of other studies 2, 20. Using Mayo staging to further compare patients in different stages of the AL cohort, it was found that both AL staging and increased number of affected organs can shorten OS. These data shows that occurrence of AL and its severity significantly affect the survival of MM patients, even in the current new drug era 2,12,,16-26. Although high level of baseline 24-hou proteinuria has been proposed as a marker of renal involvement and progression of renal dysfunction, our current research data showed that kidney involvement does not have a major impact on survival, similar to existing research results2,21.Forty-eight percent of patients who showed abnormal genes of TP53 deletion, t(14; 16), and 1q21 amplification had shorter OS than other patients (8 vs. 26.5 months), favoring the adverse effects of these high-risk genes on survival 22. The incidence of cardiac involvement in our study was slightly lower，this may be related to the fact that patients were reluctant to undergo such detection means because of its more invasive than the other biopsies.Echocardiography is a cornerstone for the diagnosis for heart involvement6. NT-proBNP elevation is still widely used clinically for diagnostic and prognostic indicators of cardiac insufficiency and myocardial involvement in cases where pathological evidence is confirmed in the kidney or other tissues to be diagnosed as AL2,12,also our data clearly confirmed that cardiac involvement was a major prognostic
factor for AL 3,12,18,20. In our study, patients had the following clinical features of cardiac AL, such as progressive refractory heart failure,uniform left ventricular hypertrophy with low voltage of ECG, diffuse reduction of left ventricular wall activity and progressive blood pressure reducing. These patients had more severe heart involvement than the literature 24such as 42% of patients with NT-proBNP concentration >8000 pg/mL and 33% with SBP <90 mmHg, so maybe these factors hindered the high remission rate of bortezomib-based regimens convert into a survival advantage. NT-proBNP, with 100% diagnostic sensitivity to presymptomatic organ damage 2, prompted us to advocate biomarker-based screening in patients with MM who are at higher risk of developing AL, especially for the patients with high levels of immunoglobulin light chain. The pathogenesis of MM with AL is unclear, and it is currently believed to be mainly associated with aberrant evolution and dysfunction of monoclonal plasma cells. In the treatment of AL, it is not enough to use only the current anti-myeloma therapy2,9,10, and the combination of anti-amyloid regimens in the future will be reasonable. In short, although MM concurrent AL is rare, AL has a negative impact on survival. This study determined that cardiovascular dysfunction caused by AL is the main determinant of shortening survival in patients with MM complicated with AL and the necessary interventions should be taken to prevent cardiovascular risk. Authors’ Contributions Zhongxia Huang designed the study, conducted the study, and wrote the paper. Yuanyuan Yu performed data collection and analysis.
Acknowledgements The work was supported in part by Scientific and Technological Achievements and Appropriate Technology Promotion Projects of Beijing Municipal Health Commission (2018-TG-07) and Key Medical Support for Specialist Construction Project of Shijingshan District, Beijing (20170006).Thanks to Prof. Kyle with constructive comments and detailed textual amendments. We also thank International Science Editing (http://www.internationalscienceediting.com) for providing language editing assistance. Disclosure The authors have stated that they have no conflict of interest.
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6. Milani P, Dispenzieri A, Scott CG, et al. Independent prognostic value of stroke volume index in patients with immunoglobulin light chain amyloidosis.Circ Cardiovasc Imaging, 2018 May,11(5):e006588. 7. Rajkumar S V, Dimopoulos M A, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncology 2014, 15(12):538-548. 8. Palumbo A, Avet-Loiseau H, Oliva S，et al. Revised International Staging System for Multiple Myeloma: A Report From International MyelomaWorking Group. J Clin Oncol. 2015 Sep 10;33(26):2863-2869. doi: 10.1200/JCO.2015.61.2267. Epub 2015 Aug 3. 9. Omar K. Siddiqi, Frederick L. Ruberg. Cardiac Amyloidosis: An Update on Pathophysiology, Diagnosis, and Treatment. Trends Cardiovasc Med 2018 Jan; 28(1): 10– 21. 10. Desport E, Bridoux F, Sirac C, et al. Al amyloidosis. Orphanet Journal of Rare Diseases 2012;7(1):1-13. 11. Pepys M B. Amyloidosis. Annu Rev Med 2006; 57(57):223-241. 12. Kourelis TV, Kumar SK, Gertz MA,et al. Coexistent multiple myeloma or increased bone marrow plasma cells define equally high-riskpopulations in patients with immunoglobulin light chain amyloidosis. J Clin Oncol 2013 Dec 1;31(34):4319-4324. 13.Dispenzieri A, Gertz M A, Kyle R A, et al. Serum Cardiac Troponins and N-Terminal Pro-Brain Natriuretic Peptide: A Staging System for Primary Systemic Amyloidosis. J Clin Oncol 2004; 22(18):3751-3757.
14. Palumbo A, Rajkumar S V, San Miguel J F, et al. International Myeloma Working Group consensus statement for the management, treatment, and supportive care of patients with myeloma not eligible for standard autologous stem-cell transplantation. J Clin Oncol 2014 Feb 20;32(6):587-600. 15. Palladini, G., Dispenzieri, A., Gertz, M.A. et al.New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes. J Clin Oncol 2012;30:4541–4549. 16. Maleszewski JJ. Cardiac amyloidosis: pathology, nomenclature, and typing. Cardiovasc Pathol 2015; 24(6):343-350. 17. Kastritis E, Dimopoulos M A. Prognosis and risk assessment in AL amyloidosis--state of the art. Amyloid 2011 Jun;18 Suppl 1:89-91. 18. Falk R H. Cardiac Amyloidosis A Treatable Disease, Often Overlooked. Circulation 2011; 124(9):1079-1085. 19. Kozlowski P, Montgomery S, Befekadu R, et al.The risk of renal disease is increased in lambda myeloma with bone marrow amyloid deposits.J Blood Med 2017 Mar 6;8:29-34. 20. Petruzziello F, Zeppa P, Catalano L, et al. Amyloid in bone marrow smears of patients affected by multiple myeloma. Ann Hematol 2010 May;89(5):469-474. 21..Plummer C, Driessen C, Szabo Z, Mateos MV.Management of cardiovascular risk in patients with multiple myeloma.Blood Cancer J. 2019 Feb 26;9(3):26. 22. Ohashi T, Kikuchi N, Yamamoto T. Unusual milia amyloidosis as initial signs of multiple myeloma-associated systemic amyloidosis. Int J Dermatol 2013 Aug; 52(8):981-982. 23. Palumbo A. Multiple myeloma.. N Engl J Med 2011; 364(11):1046-1060.
24. Dispenzieri A, Buadi F, Kumar SK, et al. Treatment of Immunoglobulin Light Chain Amyloidosis: Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) Consensus Statement. Mayo Clin Proc 2015 Aug;90(8):1054-1081. 25. Wechalekar AD, Schonland SO, Kastritis E, et al. A European collaborative study of treatment outcomes in 346 patients with cardiac stage III AL amyloidosis. Blood 2013; 121(17):3420-3427. 26. Kyriakou P,Mouselimis D,Tsarouchas A,et al. Diagnosis of cardiac amyloidosis: a systematic review on the role of imaging and biomarkers. BMC Cardiovasc Disord 2018; 18: 221.
Illustrations and figures Table 1 General Clinical Characteristics Table 2 Clinical Features of Cardiac Involvement Figure 1 Effects of Stages and Organ Involvement on Survival A. Survival comparison of ISS stages. B. Influence of extent of involvement organs by AL on survival. C. Influence of cardiac involved on survival.
D. Impact of Mayo stage on survival. In the Figure A,B,C
and D , P < 0.05,respectively, which is statistically significant. Note: ISS: International Staging System; OS: overall survival.
Figure 2 Effects of Cardiovascular Factors and Genetics on Survival
E. Impact of hypotension on survival.
F. Survival comparison of septal thickness. G. Impact of high
risk in FISH on survival.H. Impact on survival of cardiac factors. In the Figure E,F,G and H , P < 0.05,respectively, which is statistically significant. Notes: SBP: systolic blood pressure; FISH: fluorescence in situ hybridization; OS: overall survival;Nt-proBNP: N-terminal probrain natriuretic peptide.
Supplemental Data Supplemental Table Congo red staining of the biopsy site Supplemental Table Biopsy site
Congo red staining of the biopsy site Cases
Positive cases
Positive rate (%)
Abdominal fat
22
17
77.3
Bone marrow
32
12
37.5
Kidney
15
12
80
Tongue
6
4
66.7
Intestinal mucosa
9
8
88.9
Gastric mucosa
8
4
50
Mass in the groin
1
1
100
Mass in the buttocks
1
1
100
Bronchial mucosa in the lungs
1
1
100
CLML 1512
Illustrations and figures Table 1 General Clinical Characteristics Table 2 Clinical Features of Cardiac Involvement Figure 1 Effects of Stages and Organ Involvement on Survival A. Survival comparison of ISS stages. B. Influence of extent of involvement organs by AL on survival. C. Influence of cardiac involved on survival.
D. Impact of Mayo stage on survival. In the Figure A,B,C and D , P < 0.05,respectively, which
is statistically significant. Note: ISS: International Staging System; OS: overall survival.
Figure 2 Effects of Cardiovascular Factors and Genetics on Survival E. Impact of hypotension on survival.
F. Survival comparison of septal thickness. G. Impact of high risk in FISH on
survival.H. Impact on survival of cardiac factors. In the Figure E,F,G and H , P < 0.05,respectively, which is statistically significant. Notes: SBP: systolic blood pressure; FISH: fluorescence in situ hybridization; OS: overall survival;Nt-proBNP: N-terminal probrain natriuretic peptide.
Supplemental Data Supplemental Table 1 Efficacy of Bortezomib-based Regimens Supplemental Table 2 Impact on Survival of Cardiac Factors Supplemental Table Congo red staining of the biopsy site
Table 1 General clinical characteristic Cases（ （%） ）
Clinical features Age (years)
60
Gender: Male/ Female（Cases） Clonal plasma cell in Bone marrow <10%/ 10-19%/≥20% Serum M- protein（g/L） <30/30-50/51-69/ ≥70 Calcium >11 mg/dl
36/17 0/39(74)/ 14(26) 0/5(9.4)/ 16(30.2)/ 32(60.4) 2(3.7)
Creatinine >176.8μmol/L(median, 484.3±211.5)
12(22.6)
Hemoglobin <10 g//L
45(84.9)
Bone lesions, lytic or pathologic fractures
47(88.7)
M component at diagnosis λ/ IgG-λ/ IgA-λ/ IgD-λ/ k/ IgG-k/ IgA-k Stage of ISS for MM Type of AL
I/Ⅱ/Ⅲ
λ/κ
15(28/11(21)/5(9)/ 2(4）/10(19)/ 9(17)/ 1(2） 2(3.8)/ 17(32.1）/34(64.2） 33(62）/20(38）
Kidney involved by AL
proteinuria >0.5g/24h/L
38(71.7)
Cardiac involved by AL
NT-proBNP >332 (pg/ml)
33(62.3)
Mayo staging for AL
I/Ⅱ/Ⅲ
Abnormal gene
15(28.3/35(66/3(5.7） 18(34)
High risk 17p- / t(4;14)/t(14;16)/ Amplification of 1q21
2(8)/2(8)/ 2(8)/6(24)
Non-high risk t(11;14)/ 13q-
5(20)/ 1(4)
Table 2 Clinical features of cardiac involvement by AL in 33 patients Factors
Cases（ （%)
Symptoms Dyspnea/ Palpitation/ Chest pain/ Syncope
22(67)/ 6(18)/ 4(12)/ 2(6)
Signs SBP (mm/Hg) < 90, Median, 86±5
11(33)
Congestive cardiac failure
22(67)
NYHA level Ⅱ/Ⅲ/Ⅳ
4(12)/10(30)/ 8(24)
Laboratory tests NT-proBNP >332 (pg/ml) Range <332/333 -2000/2001-5000/5001-7999/≥8000 cTnI＞0.01(ng/ml)
33(62) 0/4(12)/ 7(21)/ 8(24)/ 14(42) 24(73)
Electrocardiogram Low voltage in the limbs leads
16(49)
Atrioventricular block
3(9)
Others such as premature beat
24(73)
Echocardiography Decreased diastolic function
14(42）
Left ventricular wall thickening (mm)
17(52）
Septal thickness in Ventricular (SEP)>12(mm) Median, 14.9±2.0 12.1-14.9/≥ 15 Others such as atrial or ventricular enlargement
25(76) 21(64)/4(12) 33(100）
Note: SBP :Systolic blood pressure; NYHA: New York Cardiac Association NT-proBNP: N-terminal proBNP; TnI: troponin.
Three Supplemental Tables Supplemental Table 1 Efficacy of Bortezomib-based Regimens Regimens Bortezomib-based regimens
Cases
ORR(%)
Organ function(%)
22
63.6
Improved(31.8) Stable(18.2) Disease progression(13.6)
Non bortezomib-based regimens
21
28.6
Improved(14.3) Stable(9.5) Disease progression(4.8)
Note: CR/nCR: complete remission/near-complete remission; PR: partial remission; VGPR: very good partial remission; ORR:overall response rate (CR+PR+VGPR).
Supplemental Table 2 Impact on Survival of Cardiac Factors Factors
Months (ranges)
Total OS
12(1-102）
Cardiac involvement
6(1-36)
Mayo stage III
1(1-2)
Septal thickness ≥15 mm
5(1-28）
Systolic hypotension
3(1-8)
Note: OS: overall survival.
Supplemental Table Congo red staining of the biopsy site Biopsy site
Cases
Positive cases
Positive rate (%)
Abdominal fat
22
17
77.3
Bone marrow
32
12
37.5
Kidney
15
12
80
Tongue
6
4
66.7
Intestinal mucosa
9
8
88.9
Gastric mucosa
8
4
50
Mass in the groin
1
1
100
Mass in the buttocks
1
1
100
Bronchial mucosa in the lungs
1
1
100
A
Figure 1 Survival comparison of ISS stages.
B
Figure 2 Influence of extent of involvement organs on survival
C
Figure 3 Influence of cardiac involved on survival.
D
Figure 4 Impact of Mayo stage on survival
E
Figure 5 Impact of hypotension on survival
F
Figure 6. Survival comparison of septal thickness.
G
Figure 7 Impact of high risk in FISH on survival.
H
Figure 8 Impact on survival of cardiac factors
Clinical Practice Points
.The clinical diagnostic concept of MM combined with AL is ambiguous, and this study further clarifies the boundaries of diagnosis. The diagnosis of MM with AL needs to meet the international diagnostic criteria for symptomatic MM and AL at the same time, and CRAB symptoms are the key point to diagnosing MM.
.Our results show the characteristics of cardiac involvement and negative impact on survival. The study also determined that cardiovascular dysfunction caused by AL is the main determinant of shortening survival of patients with MM concurrent AL.
S2152-2650(20)30038-0
DOI:
https://doi.org/10.1016/j.clml.2020.01.002
Reference:
CLML 1512
To appear in:
Clinical Lymphoma, Myeloma and Leukemia
Received Date: 29 July 2019 Revised Date:
30 December 2019
Accepted Date: 2 January 2020
Please cite this article as: Yu Y, Huang Z, Hu W, Li X, Shen M, Zhang J, Tang R, Chen S, Chen W, Clinical analysis of cardiac involvement in 53 patients with multiple myeloma coexistent with light chain amyloidosis, Clinical Lymphoma, Myeloma and Leukemia (2020), doi: https://doi.org/10.1016/ j.clml.2020.01.002. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 The Author(s). Published by Elsevier Inc.
Micro-Abstract
We analyzed 53 patients with multiple myeloma (MM) coexistent with light chain amyloidosis (AL) to evaluate the influence on survival. Of them, 22 patients were treated with a bortezomib-based regimen, and the response rate was more effective than the other. The median OS for the total cohort was 12 months. Cardiac involvement significantly adversely affected survival (6 vs. 40 months), as did systolic blood pressure (SBP< 90 mmHg, 3 vs. 8.5 months). Cardiovascular dysfunction caused by AL is a major determinant of shortening survival for the total cohort.
Manuscript Number: CLML-D-19-00021 Revised manuscript 20191230
Clinical analysis of cardiac involvement in 53 patients with multiple myeloma coexistent with light chain amyloidosis Yuanyuan YU†, Zhongxia HUANG†*,Wanli HU, Xin LI, Man SHEN, Jiajia ZHANG, Ran TANG, Shilun CHEN, Wenming CHEN Address for correspondence: Zhongxia HUAN, MD, Multiple Myeloma Medical Center of Beijing, Department of Hematology, Beijing Chao-yang Hospital, Capital Medical University, 5 Jingyuan Road, Shijingshan District, Beijing 100043, CHINA Fax: +86-10-51718951; e-mail contact: [email protected] † Y.Y. and Z.H. contributed equally to this article, and both should be considered first author.
Abstract Background: We identified 53 patients with multiple myeloma (MM) who had biopsy evidence of light chain amyloidosis (AL), and studied their cardiac involvement and outcomes. Patients and Methods: 53 patients in whom MM and AL were initially diagnosed from July 1, 2006 to June 30, 2016.The diagnosis of MM required >10% of clonal plasma cells in bone marrow and one of the CRAB symptoms, meanwhile, the diagnosis of AL must meet pathological diagnostic criteria and monoclonal immunoglobulin light chain. Echocardiograms and cardiac biomarker such as N terminal pro B-type natriuretic peptide (NT-proBNP) was used for evaluation of cardiac damage on the baseline and before every
cycle of regiment. Results: There were 36 men and 17 women with a median age of 59 years, their main organ involvement was kidney(72%) and heart(62%).Of them, twenty-two patients were treated with a bortezomib-based regimen, and the response rate was more effective than the other 21 patients who receiving non-bortezomib-based regimens (64% vs. 29%). The median OS for the total cohort was 12 months (P<0.05). The median OS of MM cohort with ISS stage I and II together was 34 months, which was longer than that of patients with stage III of 8 months. The median OS in Mayo stages I, II and III was 38, 8 and 1 months (P < 0.05). Cardiac involvement significantly adversely affected survival (6 vs. 40 months), as did systolic blood pressure (SBP< 90 mmHg, 3 vs. 8.5 months). Conclusions: Patients coexistent with MM and AL is rare, AL has a negative impact on survival for the total cohort. Especially, cardiovascular dysfunction caused by AL maybe a major determinant of shortening survival. Keyword: Multiple myeloma, Amyloidosis, Cardiac involvement, Bortezomib, Survival Abbreviations MM: multiple myeloma; AL: light chain amyloidosis; CRAB: Initial letter abbreviation of hypercalcemia, renal insufficiency, anemia, osteolytic lesions :SBP: systolic blood pressure; IMWG: International Myeloma Working Group; AEs: adverse events; CR/nCR: complete remission/near-complete remission; PR: partial remission; VGPR: very good partial remission; CT: computed tomography; FISH: fluorescence in situ hybridization; Ig: immunoglobulin; ISS: International Staging System; MRI: magnetic resonance imaging; ORR: overall response rate; OS: overall survival. Nt-proBNP: N-terminal probrain natriuretic peptide
Introduction Multiple myeloma (MM) is a malignant plasma cell disease characterized by clonal proliferation of malignant plasma cells in the bone marrow, and elevation of monoclonal immunoglobulin in blood or urine, causing hypercalcemia, renal insufficiency, anemia, osteolytic lesions (CRAB symptoms) and a series of clinical manifestations1. In some cases these monoclonal immunoglobulin light chains or their fragments are folded to form insoluble fibers that deposit in tissues, resulting in kidney, heart or other organ dysfunction2,3,which caused Light chain amyloidosis(AL). MM and AL have a concent pathological basis, the incidence of both plasma cell disorders in European and American countries is reported to be urr10–26%3-5.Cardiac amyloidosis typically causes a restrictive cardiomyopathy, in which the deposition of misfolded amyloid proteins in the myocardium causes structural alterations, eventually leading to heart failure. Heart involvement is present in almost two-thirds of AL patients, representing the most common cause of death6. Given the heterogeneity of the two diseases, it is essential to understanding the characteristics and outcomes of cardiac involvement in MM coexistent with AL.
Patients and Method Diagnostic and therapeutic criteria of patients In his study, 53 patients with newly diagnosed MM with AL were identified from a clinical database in Beijing Chao-yang Hospital. The records were reviewed for all patients in whom MM and AL were initially diagnosed at the hospital from January 1, 2006, to June 30, 2016. Diagnostic and staging criteria were defined as in the International Myeloma Working Group
(IMWG) 7,8, and amyloid protein was demonstrated with Congo red staining and immunohistochemistry9. All patients experienced biopsy such as bone marrow biopsy, abdominal fat and renal biopsy, and no serious bleeding or other adverse events during biopsy. To assess cardiac function of the patients, echocardiograms and cardiac biomarkers such as N terminal pro B-type natriuretic peptide (NT-proBNP) or troponin T (TnT) were estimated on the baseline and before every cycle of treatment. On the basis of pathological diagnosis of AL, if the level of NT-proBNP was more than 328 pg/ml,ventricular septal thickness > 12 mm and urine protein was greater than 0.5g/24h, and there is no other reason to explain, it is defined as cadiac and renal involvement by AL 9-12. AL was staged using the Mayo system based on the high level of NT-proBNP and TnT 13. According to international criteria for MM14 and AL15, response to therapy and organ function were determined after treatment. Patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering MM, solitary plasmacytoma and plasma cell leukemia were excluded. Follow-up letters or telephone contact was made with all patients if they had not been seen or heard from for the previous year. Death certificates were requested when needed. In our study, 43 patients (10 patients discontinued treatment) received initial therapy with bortezomib-based or non-bortezomib-based regimens for 1–8 cycles (average 4–6), and then began consolidation or maintenance treatment. Treatment and groups Treatment related data were available for 43 patients. Twenty-two (51%) patients received bortezomib-based regimens as follows: bortezomib (Velcade, V) and dexamethasone (D)
(VD, n=6) or VD with cyclophosphamide (C) (VCD, n=16), the other 21 (49%) patients received non-bortezomib-based regimens as follows: CD (n=7) or CD with doxorubicin (Adriamycin, A) ( CAD, n=9), or CD with thalidomide (T) (CTD, n=5). Among the above regimens, bortezomib (1.0–1.3 mg/m2) was given intravenously or subcutaneously on days 1, 4, 8 and 11 of a 21-day cycle or weekly, and dexamethasone 15–20 mg/day on days 1, 4, 8 and 11 cycle or weekly, cyclophosphamide (200 mg/m2) and doxorubicin (9 mg/m2). For the CTD regimen, cyclophosphamide was given on days 1–4/15–18 intravenously and dexamethasone 15–20 mg/day on days 1–4/15–18, orally, and thalidomide (100 mg) was administered orally each day. Between the two treatment groups, treatment regimens were heterogeneous, but VCD and CD with or without doxorubicin were the most commonly used. In patients achieving a complete response (CR) or very good partial response (VGPR), the regimen was repeated for two to four cycles as consolidation therapy. Maintenance therapy mainly comprised thalidomide 100 mg/day, and other regimen included small doses of prednisone of 30 mg/day. Patients who were unable to tolerate the adverse events (AEs), were in poor physical condition, or had serious arrhythmia did not receive maintenance therapy. Aspirin or low molecular weight heparin was routinely used to prevent venous thrombosis in patients who had no contraindications. Herpes zoster prophylaxis was routinely given to patients who received bortezomib-based regimens. The patients were assessed after the completion of two cycles of chemotherapy. Bisphosphonates were used intravenously monthly for myeloma bone disease. Ethics statement
The study was approved by the Ethics Committee of Beijing Chao-yang Hospital, Capital Medical University, and follow-up information was obtained with consent of patients. All aspects of the study were conducted in accordance with the principles of the Declaration of Helsinki. Written informed consent was obtained from the patients for review of images and publication of this report. Statistical analysis We used SPSS version 22.0 (SPSS Inc., Chicago, IL, USA) for data analysis. The Kaplan–Meier method was used to assess overall survival (OS) and progression-free survival (PFS). P < 0.05 (log-rank test) was considered statistically significant.
Results Baseline clinical features Fifty-three patients with MM and AL were included, all had biopsy evidence of AL (Supplemental Table). The median age at diagnosis of all patients was 60 years. There were 36 (68%) male and 17 (32%) female patients. The diagnosis of AL requires a pathological biopsy. According to positive staining for Congo red in pathological tissues, 72% (38/53) of the patients had renal involvement and 62% (33/53) had cardiac involvement. The former showed median 24-hour urinary protein concentration of 4.4 g/L and median serum creatinine value of 484.3μmol/L, the latter showed different symptoms, such as dyspnea (67%, 22/53 cases), palpitations (18%, 6/53 cases), chest pain (12 %, 4/53 cases), and syncope (6%, 2/53 cases).Other prominent features were congestive heart failure ( 67% , 22/53 cases) and systolic hypotension below 90mmHg (33%, 11/53 cases) .In terms of International Staging (ISS) for MM, 4% (2/53), 32% (17/53) and 64% (34/53) of cases were
stage I, II and III, respectively. For Mayo staging for AL, 28% (15/53), 66% (35/53) and 6% (3/53) of cases were stage I, II and III, respectively. The general clinical characteristics were shown in Table 1. Forty-seven percent of patients (25/53 cases) underwent CD138 magnetic bead sorting for fluorescence in situ hybridization (FISH) bone marrow testing and 34% (18/53) had abnormalities. Among them, the high-risk abnormal gene such as 17p- ,t(4;14),t(14;16) and amplification of 1q21 were in 8 % (2/25) , 8 % (2/25),8 % (2/25) and 24% (6/25) cases respectively (Table 1).
Characteristics of patients with cardiac involvement In 33 patients with cardiac involvement, the median concentration of NT-proBNP was 14,213 (range 333–27 253) pg/mL. In electrocardiography, there were low-voltage leads and premature beat in 49% (16/33) and 73% (24/33) of patients, respectively. Echocardiography is a noninvasive, a widely used tool for monitoring heart function. All of 33 patients had atrial or ventricular enlargement. There were decreased diastolic function and left ventricular wall thickening in 42% (14/33) and 52% (17/33) of patients, respectively. Forty-seven percent (25/33) of patients had ventricular septal thickness > 12 mm, with a median thickness of 14.9 mm (Table 2).
Treatment response For bortezomib-based regimens, CR was 27% (6/22), VGPR was 9% (2/22), PR was 27% (6/22), and overall response rate (ORR; CR+PR+VGPR) was 64% (14/22). For non-bortezomib-based regimens, CR was 14% (3/21), VGPR was 5% (1/21), PR was 10% (2/21), and ORR was 29% (6/21). Of the 6 patients who received the treatment response, 3
cases of AL improved, 2 cases were stable, and 1case showed progression. Bortezomib-based regimens were more effective than non-bortezomib-based regimens in relation to ORR (64% vs. 29%, P < 0.05). Some organ function such as kidney, heart and tongue improved after treatment, but no difference was found between the two treatment groups (Supplemental Data).
Survival outcomes The median OS for the total cohort was 12 months (P < 0.05). For the MM cohort, OS of patients with ISS stage I and II together was 34 months, which was longer than that of patients at ISS stage III with 8 months (P < 0.05) (Figure 1). For the AL cohort, the OS of patients with only one organ involved was 37 months, which was longer than in patients with two organs involved (12 months) and three or more organs involved (5.5 months) (P < 0.05) (Figure 2). OS was 13 and 8 months in patients with and without renal insufficiency, respectively, but this difference was not significant (Supplemental Data). OS was 6 months for patients with cardiac involvement by AL (Supplemental Table 2), which was shorter than the 40 months in other patients (Figure 3). For stage of AL, OS was 38, 8 and 1 months in the patients with Mayo stage I, II and III , respectively (P < 0.05, Figure 4). OS was 3 months in patients with systolic blood pressure (SBP) <90 mmHg, which was shorter than in patients without hypotension (8.5 months) (P < 0.05) (Figure 5). For patients with a septal thickness greater than or less than 15 mm, the median OS was 5 and 14 months, respectively, and the former was significantly shorter than the latter. (P < 0.05) (Figure 6).
Forty-one percent of patients (25/53) underwent FISH test, and 72% of these (18/25) had abnormalities. Of them, 48%(12/25) had high-risk genetic abnormalities of TP53 deletion, t (14; 16) and 1q21 amplification, and their OS was 8 months, which was shorter than 27 months in other patients (P < 0.05) (Figure 7). The independent prognostic factors were not found among the influencing factors for survival. However, it can be seen from Figure 8 that patients with SBP < 90 mmHg, NT-proBNP ≥ 8000 pg/ml and septal thickness ≥ 15 mm all had a poor prognosis(Figure 8). It should be noted that only 3 patients underwent autologous hematopoietic stem cell transplantation of all 43 patients who received chemotherapy, and their previous initial induction therapy was 4-6 cycles of VCD regimens. All three patients reached CR after transplantation and PFS was 48, 36 and 16 months, but OS was not reached.
Discussion Compared to most case reports, this is a clinical study of a certain number of MM patients coexisting with AL. Fifty-three patients were analyzed and our data showed that the incidence rate was 0.6%, according to the total of 8833 MM patients in the past 10 years. This is less than the current reported incidence 3,5 . Among them, 62% of patients contained lambda light chain in their M protein, and the kidneys and heart were the two most commonly affected organs, which is similar to the literature 3,16-19. More than 10% of clonal plasma cells and high levels of M protein, especially immunoglobulin light chain levels, can be present in both MM and AL, and CRAB symptoms caused by malignant plasma cell disease are unique to MM. Therefore, while
MM and AL the two diseases were combined exist, refer to the method of Mayo Clinic, CRAB symptoms were the key points for diagnosing MM 12. Among the 43 patients who underwent treatment, their organ function was improved after receive with bortezomib-based regimens. Currently the OS of the entire cohort is 12 months, which is similar to the results of other studies 2, 20. Using Mayo staging to further compare patients in different stages of the AL cohort, it was found that both AL staging and increased number of affected organs can shorten OS. These data shows that occurrence of AL and its severity significantly affect the survival of MM patients, even in the current new drug era 2,12,,16-26. Although high level of baseline 24-hou proteinuria has been proposed as a marker of renal involvement and progression of renal dysfunction, our current research data showed that kidney involvement does not have a major impact on survival, similar to existing research results2,21.Forty-eight percent of patients who showed abnormal genes of TP53 deletion, t(14; 16), and 1q21 amplification had shorter OS than other patients (8 vs. 26.5 months), favoring the adverse effects of these high-risk genes on survival 22. The incidence of cardiac involvement in our study was slightly lower，this may be related to the fact that patients were reluctant to undergo such detection means because of its more invasive than the other biopsies.Echocardiography is a cornerstone for the diagnosis for heart involvement6. NT-proBNP elevation is still widely used clinically for diagnostic and prognostic indicators of cardiac insufficiency and myocardial involvement in cases where pathological evidence is confirmed in the kidney or other tissues to be diagnosed as AL2,12,also our data clearly confirmed that cardiac involvement was a major prognostic
factor for AL 3,12,18,20. In our study, patients had the following clinical features of cardiac AL, such as progressive refractory heart failure,uniform left ventricular hypertrophy with low voltage of ECG, diffuse reduction of left ventricular wall activity and progressive blood pressure reducing. These patients had more severe heart involvement than the literature 24such as 42% of patients with NT-proBNP concentration >8000 pg/mL and 33% with SBP <90 mmHg, so maybe these factors hindered the high remission rate of bortezomib-based regimens convert into a survival advantage. NT-proBNP, with 100% diagnostic sensitivity to presymptomatic organ damage 2, prompted us to advocate biomarker-based screening in patients with MM who are at higher risk of developing AL, especially for the patients with high levels of immunoglobulin light chain. The pathogenesis of MM with AL is unclear, and it is currently believed to be mainly associated with aberrant evolution and dysfunction of monoclonal plasma cells. In the treatment of AL, it is not enough to use only the current anti-myeloma therapy2,9,10, and the combination of anti-amyloid regimens in the future will be reasonable. In short, although MM concurrent AL is rare, AL has a negative impact on survival. This study determined that cardiovascular dysfunction caused by AL is the main determinant of shortening survival in patients with MM complicated with AL and the necessary interventions should be taken to prevent cardiovascular risk. Authors’ Contributions Zhongxia Huang designed the study, conducted the study, and wrote the paper. Yuanyuan Yu performed data collection and analysis.
Acknowledgements The work was supported in part by Scientific and Technological Achievements and Appropriate Technology Promotion Projects of Beijing Municipal Health Commission (2018-TG-07) and Key Medical Support for Specialist Construction Project of Shijingshan District, Beijing (20170006).Thanks to Prof. Kyle with constructive comments and detailed textual amendments. We also thank International Science Editing (http://www.internationalscienceediting.com) for providing language editing assistance. Disclosure The authors have stated that they have no conflict of interest.
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6. Milani P, Dispenzieri A, Scott CG, et al. Independent prognostic value of stroke volume index in patients with immunoglobulin light chain amyloidosis.Circ Cardiovasc Imaging, 2018 May,11(5):e006588. 7. Rajkumar S V, Dimopoulos M A, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncology 2014, 15(12):538-548. 8. Palumbo A, Avet-Loiseau H, Oliva S，et al. Revised International Staging System for Multiple Myeloma: A Report From International MyelomaWorking Group. J Clin Oncol. 2015 Sep 10;33(26):2863-2869. doi: 10.1200/JCO.2015.61.2267. Epub 2015 Aug 3. 9. Omar K. Siddiqi, Frederick L. Ruberg. Cardiac Amyloidosis: An Update on Pathophysiology, Diagnosis, and Treatment. Trends Cardiovasc Med 2018 Jan; 28(1): 10– 21. 10. Desport E, Bridoux F, Sirac C, et al. Al amyloidosis. Orphanet Journal of Rare Diseases 2012;7(1):1-13. 11. Pepys M B. Amyloidosis. Annu Rev Med 2006; 57(57):223-241. 12. Kourelis TV, Kumar SK, Gertz MA,et al. Coexistent multiple myeloma or increased bone marrow plasma cells define equally high-riskpopulations in patients with immunoglobulin light chain amyloidosis. J Clin Oncol 2013 Dec 1;31(34):4319-4324. 13.Dispenzieri A, Gertz M A, Kyle R A, et al. Serum Cardiac Troponins and N-Terminal Pro-Brain Natriuretic Peptide: A Staging System for Primary Systemic Amyloidosis. J Clin Oncol 2004; 22(18):3751-3757.
14. Palumbo A, Rajkumar S V, San Miguel J F, et al. International Myeloma Working Group consensus statement for the management, treatment, and supportive care of patients with myeloma not eligible for standard autologous stem-cell transplantation. J Clin Oncol 2014 Feb 20;32(6):587-600. 15. Palladini, G., Dispenzieri, A., Gertz, M.A. et al.New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes. J Clin Oncol 2012;30:4541–4549. 16. Maleszewski JJ. Cardiac amyloidosis: pathology, nomenclature, and typing. Cardiovasc Pathol 2015; 24(6):343-350. 17. Kastritis E, Dimopoulos M A. Prognosis and risk assessment in AL amyloidosis--state of the art. Amyloid 2011 Jun;18 Suppl 1:89-91. 18. Falk R H. Cardiac Amyloidosis A Treatable Disease, Often Overlooked. Circulation 2011; 124(9):1079-1085. 19. Kozlowski P, Montgomery S, Befekadu R, et al.The risk of renal disease is increased in lambda myeloma with bone marrow amyloid deposits.J Blood Med 2017 Mar 6;8:29-34. 20. Petruzziello F, Zeppa P, Catalano L, et al. Amyloid in bone marrow smears of patients affected by multiple myeloma. Ann Hematol 2010 May;89(5):469-474. 21..Plummer C, Driessen C, Szabo Z, Mateos MV.Management of cardiovascular risk in patients with multiple myeloma.Blood Cancer J. 2019 Feb 26;9(3):26. 22. Ohashi T, Kikuchi N, Yamamoto T. Unusual milia amyloidosis as initial signs of multiple myeloma-associated systemic amyloidosis. Int J Dermatol 2013 Aug; 52(8):981-982. 23. Palumbo A. Multiple myeloma.. N Engl J Med 2011; 364(11):1046-1060.
24. Dispenzieri A, Buadi F, Kumar SK, et al. Treatment of Immunoglobulin Light Chain Amyloidosis: Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) Consensus Statement. Mayo Clin Proc 2015 Aug;90(8):1054-1081. 25. Wechalekar AD, Schonland SO, Kastritis E, et al. A European collaborative study of treatment outcomes in 346 patients with cardiac stage III AL amyloidosis. Blood 2013; 121(17):3420-3427. 26. Kyriakou P,Mouselimis D,Tsarouchas A,et al. Diagnosis of cardiac amyloidosis: a systematic review on the role of imaging and biomarkers. BMC Cardiovasc Disord 2018; 18: 221.
Illustrations and figures Table 1 General Clinical Characteristics Table 2 Clinical Features of Cardiac Involvement Figure 1 Effects of Stages and Organ Involvement on Survival A. Survival comparison of ISS stages. B. Influence of extent of involvement organs by AL on survival. C. Influence of cardiac involved on survival.
D. Impact of Mayo stage on survival. In the Figure A,B,C
and D , P < 0.05,respectively, which is statistically significant. Note: ISS: International Staging System; OS: overall survival.
Figure 2 Effects of Cardiovascular Factors and Genetics on Survival
E. Impact of hypotension on survival.
F. Survival comparison of septal thickness. G. Impact of high
risk in FISH on survival.H. Impact on survival of cardiac factors. In the Figure E,F,G and H , P < 0.05,respectively, which is statistically significant. Notes: SBP: systolic blood pressure; FISH: fluorescence in situ hybridization; OS: overall survival;Nt-proBNP: N-terminal probrain natriuretic peptide.
Supplemental Data Supplemental Table Congo red staining of the biopsy site Supplemental Table Biopsy site
Congo red staining of the biopsy site Cases
Positive cases
Positive rate (%)
Abdominal fat
22
17
77.3
Bone marrow
32
12
37.5
Kidney
15
12
80
Tongue
6
4
66.7
Intestinal mucosa
9
8
88.9
Gastric mucosa
8
4
50
Mass in the groin
1
1
100
Mass in the buttocks
1
1
100
Bronchial mucosa in the lungs
1
1
100
CLML 1512
Illustrations and figures Table 1 General Clinical Characteristics Table 2 Clinical Features of Cardiac Involvement Figure 1 Effects of Stages and Organ Involvement on Survival A. Survival comparison of ISS stages. B. Influence of extent of involvement organs by AL on survival. C. Influence of cardiac involved on survival.
D. Impact of Mayo stage on survival. In the Figure A,B,C and D , P < 0.05,respectively, which
is statistically significant. Note: ISS: International Staging System; OS: overall survival.
Figure 2 Effects of Cardiovascular Factors and Genetics on Survival E. Impact of hypotension on survival.
F. Survival comparison of septal thickness. G. Impact of high risk in FISH on
survival.H. Impact on survival of cardiac factors. In the Figure E,F,G and H , P < 0.05,respectively, which is statistically significant. Notes: SBP: systolic blood pressure; FISH: fluorescence in situ hybridization; OS: overall survival;Nt-proBNP: N-terminal probrain natriuretic peptide.
Supplemental Data Supplemental Table 1 Efficacy of Bortezomib-based Regimens Supplemental Table 2 Impact on Survival of Cardiac Factors Supplemental Table Congo red staining of the biopsy site
Table 1 General clinical characteristic Cases（ （%） ）
Clinical features Age (years)
60
Gender: Male/ Female（Cases） Clonal plasma cell in Bone marrow <10%/ 10-19%/≥20% Serum M- protein（g/L） <30/30-50/51-69/ ≥70 Calcium >11 mg/dl
36/17 0/39(74)/ 14(26) 0/5(9.4)/ 16(30.2)/ 32(60.4) 2(3.7)
Creatinine >176.8μmol/L(median, 484.3±211.5)
12(22.6)
Hemoglobin <10 g//L
45(84.9)
Bone lesions, lytic or pathologic fractures
47(88.7)
M component at diagnosis λ/ IgG-λ/ IgA-λ/ IgD-λ/ k/ IgG-k/ IgA-k Stage of ISS for MM Type of AL
I/Ⅱ/Ⅲ
λ/κ
15(28/11(21)/5(9)/ 2(4）/10(19)/ 9(17)/ 1(2） 2(3.8)/ 17(32.1）/34(64.2） 33(62）/20(38）
Kidney involved by AL
proteinuria >0.5g/24h/L
38(71.7)
Cardiac involved by AL
NT-proBNP >332 (pg/ml)
33(62.3)
Mayo staging for AL
I/Ⅱ/Ⅲ
Abnormal gene
15(28.3/35(66/3(5.7） 18(34)
High risk 17p- / t(4;14)/t(14;16)/ Amplification of 1q21
2(8)/2(8)/ 2(8)/6(24)
Non-high risk t(11;14)/ 13q-
5(20)/ 1(4)
Table 2 Clinical features of cardiac involvement by AL in 33 patients Factors
Cases（ （%)
Symptoms Dyspnea/ Palpitation/ Chest pain/ Syncope
22(67)/ 6(18)/ 4(12)/ 2(6)
Signs SBP (mm/Hg) < 90, Median, 86±5
11(33)
Congestive cardiac failure
22(67)
NYHA level Ⅱ/Ⅲ/Ⅳ
4(12)/10(30)/ 8(24)
Laboratory tests NT-proBNP >332 (pg/ml) Range <332/333 -2000/2001-5000/5001-7999/≥8000 cTnI＞0.01(ng/ml)
33(62) 0/4(12)/ 7(21)/ 8(24)/ 14(42) 24(73)
Electrocardiogram Low voltage in the limbs leads
16(49)
Atrioventricular block
3(9)
Others such as premature beat
24(73)
Echocardiography Decreased diastolic function
14(42）
Left ventricular wall thickening (mm)
17(52）
Septal thickness in Ventricular (SEP)>12(mm) Median, 14.9±2.0 12.1-14.9/≥ 15 Others such as atrial or ventricular enlargement
25(76) 21(64)/4(12) 33(100）
Note: SBP :Systolic blood pressure; NYHA: New York Cardiac Association NT-proBNP: N-terminal proBNP; TnI: troponin.
Three Supplemental Tables Supplemental Table 1 Efficacy of Bortezomib-based Regimens Regimens Bortezomib-based regimens
Cases
ORR(%)
Organ function(%)
22
63.6
Improved(31.8) Stable(18.2) Disease progression(13.6)
Non bortezomib-based regimens
21
28.6
Improved(14.3) Stable(9.5) Disease progression(4.8)
Note: CR/nCR: complete remission/near-complete remission; PR: partial remission; VGPR: very good partial remission; ORR:overall response rate (CR+PR+VGPR).
Supplemental Table 2 Impact on Survival of Cardiac Factors Factors
Months (ranges)
Total OS
12(1-102）
Cardiac involvement
6(1-36)
Mayo stage III
1(1-2)
Septal thickness ≥15 mm
5(1-28）
Systolic hypotension
3(1-8)
Note: OS: overall survival.
Supplemental Table Congo red staining of the biopsy site Biopsy site
Cases
Positive cases
Positive rate (%)
Abdominal fat
22
17
77.3
Bone marrow
32
12
37.5
Kidney
15
12
80
Tongue
6
4
66.7
Intestinal mucosa
9
8
88.9
Gastric mucosa
8
4
50
Mass in the groin
1
1
100
Mass in the buttocks
1
1
100
Bronchial mucosa in the lungs
1
1
100
A
Figure 1 Survival comparison of ISS stages.
B
Figure 2 Influence of extent of involvement organs on survival
C
Figure 3 Influence of cardiac involved on survival.
D
Figure 4 Impact of Mayo stage on survival
E
Figure 5 Impact of hypotension on survival
F
Figure 6. Survival comparison of septal thickness.
G
Figure 7 Impact of high risk in FISH on survival.
H
Figure 8 Impact on survival of cardiac factors
Clinical Practice Points
.The clinical diagnostic concept of MM combined with AL is ambiguous, and this study further clarifies the boundaries of diagnosis. The diagnosis of MM with AL needs to meet the international diagnostic criteria for symptomatic MM and AL at the same time, and CRAB symptoms are the key point to diagnosing MM.
.Our results show the characteristics of cardiac involvement and negative impact on survival. The study also determined that cardiovascular dysfunction caused by AL is the main determinant of shortening survival of patients with MM concurrent AL.