Cardiac light chain amyloidosis secondary to Waldenström's macroglobulinemia: A case report and review

Introduction

Waldenström's macroglobulinemia (WM), also recognized as lymphoplasmacytic lymphoma (LPL), represents a rare mature B-cell proliferative disorder, accounting for <2% of all non-Hodgkin lymphomas (1,2). WM is composed of small B lymphocytes, plasma cell-like lymphocytes and plasma cells, which produce a large amount of monoclonal immunoglobulin M (IgM) in the bone marrow, leading to increased blood viscosity and potentially causing various symptoms and complications (3,4). The diagnosis of WM usually requires a combination of clinical symptoms, hematological tests and bone marrow biochemical analysis (5,6). The common symptoms of WM are anemia, thrombocytopenia, elevated serum IgM levels and increased blood viscosity. The treatment options for WM include chimeric antigen receptor-T cell therapy, chemotherapy, targeted therapy [such as Bruton's tyrosine kinase (BTK) inhibitors, BCL-2 inhibitors], immunomodulators and monoclonal antibodies (7-9). The common therapeutic drugs for WM are chemotherapy drugs (such as bortezomib, cyclophosphamide), immunomodulators (such as rituximab) and proteasome inhibitors (such as thalidomide) (10). The median age at diagnosis for WM is ~71 years with the median survival associated with this disease being >10 years (11,12). Patients diagnosed with WM have a heightened risk of developing amyloidosis, including the light chain amyloidosis (AL) type driven by light chain proteins and the transthyretin amyloidosis (ATTR) type precipitated by abnormal transthyretin protein synthesis (13,14). Notably, 10% of amyloidosis cases associated with WM present as the AL type, implicating multiple organ systems and leading to significant morbidity (13). This comprehensive study explores and reviews the diagnosis and treatment methods for a patient with cardiac AL amyloidosis secondary to WM.

Case report

Basic information

A 67-year-old male patient presented to Luohu People's Hospital of Shenzhen (Shenzhen, China) in August 2021 with the chief complaints of chest tightness, nocturnal dyspnea and a paroxysmal cough persisting for half a month. The patient had no family history of hematologic disorders or amyloidosis. Past medical history included hypertension (controlled) and no psychosocial risk factors. Between January 2019 and July 2021, the patient had sought medical attention at an external hospital (Shenzhen People's Hospital, Shenzhen, China) due to chest tightness and nocturnal dyspnea and was diagnosed with ‘chronic heart failure’. Prior interventions for heart failure in 2019 included diuretics, spironolactone tablets, furosemide tablets and sacubitril valsartan sodium tablets for 2 years, which provided transient symptom relief but no improvement in cardiac function. The patient suffered from the symptoms of chest tightness and orthopnoea at night, accompanied by paroxysmal cough, as well as numbness in the toes.

The patient also had symptoms such as difficulty breathing, edema, fatigue and atrial fibrillation in chronic heart failure. However, the patient's symptoms of chronic heart failure were different from those caused by traditional coronary heart disease and hypertension. The patient presented with the following: i) Postural hypotension and diastolic dysfunction; ii) special cardiac signs: a) Thickened ventricular wall but relatively preserved systolic function (ultrasound showed ‘granular’ myocardial echoes); b) low voltage on electrocardiogram (related to myocardial amyloid infiltration); iii) multiple systemic involvement manifestations (systemic deposition of amyloid protein): Peripheral neuropathy; numbness and pain in hands and feet; renal dysfunction and elevated creatinine levels; iv) poor response to traditional heart failure treatment: According to disease feedback, diuretics have limited efficacy in treating current patients Beta blockers and angiotensin-converting enzyme inhibitors are also not suitable as they can exacerbate hypotension. The main pathological manifestation of traditional chronic heart failure is myocardial systolic and diastolic dysfunction (13). Cardiac amyloidosis is an infiltrative cardiomyopathy and mainly characterized by amyloid deposition leading to myocardial stiffness and affecting diastolic function (14). Therefore, examinations for cardiac amyloidosis were necessary.

Laboratory tests

The blood routine examination indicated a white blood cell count of 5.68x109/l, platelet count of 184x109/l and hemoglobin concentration of 136 g/l, all within normal ranges. Cardiac enzyme tests revealed cardiac stress with a creatine kinase level of 48 U/l and an N-terminal pro-brain natriuretic peptide II level of 8,288 pg/ml. Cardiac infarction markers indicated myocardial injury with a troponin T level of 0.154 ng/ml and a myoglobin level of 96 ng/ml. The renal function panel showed a creatinine level of 256 µmol/l, a uric acid level of 521 µmol/l and a β2-microglobulin concentration of 14.7 mg/l, indicating impaired renal function. The Ig profile showed abnormal levels with results of IgG 19.5 g/l, IgA 0.60 g/l and IgM 9.98 g/l (Table I). Serum protein electrophoresis (Fig. S1; Data SI; Table SI) revealed albumin (ALB) at 49.2%, β1 globulin (β1G) decreased to 4.5% and β2G at 19.2%. Immunofixation electrophoresis (Data SI; Table SII) showed positive IgM-λ type M protein, an erythrocyte sedimentation rate of 59.0 mm/h, negative Bence Jones protein and a free light chain ratio (κ/λ ratio) of 0.26, with free κ and λ light chains at 132 and 507 mg/l, respectively. The urine analysis showed no protein and the 24-h urine protein measurement was 93.6 mg, which was within the normal range. The electrocardiogram showed low voltage in the limb leads, suggesting cardiac abnormalities (Fig. S2). Genetic mutation detection (Fig. S3; Data S1; Table SIII) was tested by droplet digital polymerase chain reaction based on droplet separation and single-molecule amplification techniques, which identified the presence of MYD88 innate immune signal transduction adaptor (MYD88) with positive L265P mutation with a mutation frequency of 2.89%. Noteworthy abnormalities included cardiac stress, myocardial injury, impaired renal function, abnormal Ig levels, positive IgM-λ type M protein, significant proteinuria and low voltage in the limb leads.

Table I Laboratory test results of the patient.

Table I

Laboratory test results of the patient.

Examination items	Test values	Normal range
Blood cell count, x109/l	5.68	3.5-9.5
Platelet count, x109/l	184	125-350
Hemoglobin concentration, g/l	136	130-175
N-terminal pro-brain natriuretic peptide II, pg/ml	8,288	<125
Troponin T level, ng/ml	0.154	<0.014
Myoglobin level, ng/ml	96	28-72
Creatinine level, µmol/l	256	57-111
Uric acid level, µmol/l	521	208-428
Creatine kinase level, U/l	48	50-310
β2-microglobulin concentration, mg/l	14.7	0.8-2.2
Immunoglobulin IgG, g/l	19.5	8.6-17.4
Immunoglobulin IgA, g/l	0.60	1.0-4.2
Immunoglobulin IgM, g/l	9.98	0.3-2.2
Erythrocyte sedimentation rate, mm/h	59.0	<43.5
Serum light chain ratio (κ/λ)	0.26	0.31-1.56
Serum light chains κ, mg/l	132	6.7-22.4
Serum light chains λ, mg/l	507	8.3-27.0
24-h urine protein, mg	93.6	<150

Pathological examination

The echocardiography images (Fig. 1A and B) revealed left ventricular posterior wall hypertrophy with a thickness of 15.6 mm and interventricular septum of bilateral atrial enlargement with a thickness of 13.3 mm, which were both higher than normal values (both <12 mm). The thickened myocardium exhibited scattered sparkling granular echoes and a small amount of pericardial effusion. The heart valves were thick and rough and regurgitated. Fig. 1B shows that the left ventricular fractional shortening ratio was 22%, which is lower than the normal value (25-35%). The broadened main pulmonary artery diameter resulted in high pulmonary artery pressure. Fig. 1C shows that the left ventricular ejection fraction value of cardiac function was 44.3%, which is lower than the normal value (>50%). Fig. 1D shows that the left ventricular wall motion amplitude was slightly lower than normal, with a peak value of 61.6 cm/sec (normal range, 67-109 cm/sec). The aforementioned findings suggested that the left ventricular diastolic and systolic function were reduced, resulting in mild heart failure.

Figure 1 Echocardiography images. (A) LV (left ventricular) posterior wall hypertrophy and thickened bilateral atrial. (B) Various cardiac parameters with ultrasonography measurements. (C) Low LV ejection fraction value with decreasing blood-pumping function. (D) Decrease of LV systolic function. Cardiac echocardiography demonstrating LV hypertrophy (16 mm), sparkling granular echoes (amyloid deposition) and pericardial effusion. LV, left ventricle; IVSd, interventricular septum thickness in diastole; LVIDd, left ventricular internal diameter in diastole; LVPWd, left ventricular posterior wall thickness in diastole; IVSs, interventricular septum thickness in systole; LVIDs, left ventricular internal diameter in systole; LVPWs, left ventricular posterior wall thickness in systole; EDV, end-diastolic volume; MM-Teich, M-mode Teichholz formula; IVS, interventricular septum thickness; LVPW, left ventricular posterior wall thickness; FS, fractional shortening; ESV, end-systolic volume; EF, ejection fraction; LV, left ventricular; A4C, apical four-chamber view; A4Cd/A4Cs, apical four-chamber view in diastole/systole; Vol, volume; TIS, thermal index for soft tissue; MI, mechanical index; Dist, distance.

The bone marrow morphology (Data SI; Table SIV) revealed active proliferation with an increased proportion of lymphocytes, as shown in Fig. 2. Certain lymphocytes exhibited plasma-like differentiation, while lymphocytes and plasma-like lymphocytes exhibited focal aggregation. The lymphocytes were predominantly mature, with ~10% identified as abnormal lymphocytes. The abnormal lymphocytes had a small size, dense nuclear chromatin and a small cell mass, and part of the cell cytoplasm exhibited blue, foam-like, plasma cell-like changes or irregular cytoplasm edges with burrs. The proportion and morphology of erythrocytes were normal. Platelets were distributed in single or small clusters and were easily visible with a small number of abnormal platelets. The proportion of plasma cells was about 4%, which were mature plasma cells.

Figure 2 Bone marrow cell morphology with Wright Giemsa staining. The morphology of the bone marrow shows that certain lymphocytes exhibit plasma-like differentiation, while others show focal aggregation of lymphocytes and plasma-like lymphocytes (magnification, x1,000) Certain lymphocytes exhibited plasma-like differentiation and focal aggregation (red arrow). The abnormal lymphocytes (purple colour) have plasma cell-like changes or irregular cytoplasm edges with burrs (blue arrow).

The flow cytometry of bone marrow (Data SI; Table SV) results showed that lymphocytes constituted 13.72% of nucleated cells (normal range, 10-20%), with T lymphocytes comprising 49.69% (normal range, 60-80%). The CD4+/CD8+ ratio was 0.37 (normal range, 1.4-2.0), reflecting a decreased ratio, yet no discernible phenotypic abnormalities were apparent. Among the lymphocytes, the proportion of CD19+ B cells was 32.78% (normal range, 5-15%; Fig. S4), exhibiting a phenotype characterized by CD19+, CD20+, Lambda++, Kappa-, CD5-, CD10-, CD3-, GD4-, CD8-, CD2- and CD7-. Granulocytes accounted for 68.96% (normal range, 50-60%), with a proportion within the normal range, and no notable abnormalities were observed in the proportion and phenotype of granulocytes at various stages. The CD34+ and CD117+ marrow cells had a low proportion of 0.47% (normal value, <1%), and no apparent phenotypic abnormalities were observed. Notably, abnormal mature B cells, displaying immunophenotypic abnormalities, made up ~4.94% (normal value, 0%) of nucleated cells. B-cell lymphoma excluding CD5- and CD10-could not be conclusively ruled out, necessitating further investigation to establish a definitive diagnosis.

Fig. 3A shows the bone marrow biopsy with immunohistochemistry and Congo red staining (Data S1), which was completed through biopsy of the posterior superior iliac spine. The results indicate that the proportion of red bone marrow decreased, the proportion of granulocytes, red cells and megakaryocytes in the red pulp was normal, and the morphology of each cell was relatively mature, with a few scattered plasma cells. In typical amyloidosis cases, amyloid substance is an amorphous extracellular eosinophilic substance, which is commonly identified by the normal Congo red staining method because with other staining, it is difficult to distinguish colors. The Congo red staining was positive, displaying in orange red, which indicated the existence of amyloid substance. Amyloid protein mass spectrometry was performed on abdominal fat biopsy (Congo red-positive) with 84% sensitivity (15), which is a recommendation surrogate biopsy tissue for most patients, and confirming AL type with predominant Ig λ C2 spectra (12%). Cardiac tissue biopsy was not feasible due to the patient's unstable condition. Fig. 3B shows the biopsy of abdominal wall fat tissue with Congo red staining; an apple green color originating from amyloid substance with double refraction was visible under a polarized light microscope, which was transformed through the amyloid substance. Therefore, the Congo red staining with orange red and apple green color transformation both confirmed cardiac amyloidosis in this case.

Figure 3 Bone marrow and adipose tissue biopsy with Congo red staining for verifying amyloidosis. (A) Bone marrow biopsy analysis with immunohistochemistry and Congo red staining. Congo red stain positive (scale bar, 50 µm). (B) Biopsy of abdominal wall fat tissue with Congo red staining; amyloid proteins display in orange red and form apple green birefringence under a polarized fiber microscope (magnification, x400).

The amyloid protein mass spectrometry spectrum of abdominal adipose tissue was used to determine the amyloidosis type (Data S1), as shown in Fig. 4. Fibrinogen α chain (Fibα), the Ig light chain constant (Igλ C2), the Ig heavy chains Igµ, Igγ1 and Igα C1, Ig light chain κ C, lysozyme (lys) and gelsolin (gel) were detected. Among the currently known sub-typing proteins in Fig. 4, Fibα has the highest relative abundance in spectra, but Fibα<β+γ indicates that Fibα comes from blood contamination (α 218, β 294, γ 188) and is not a sedimentary protein (16). Compared with heavy chains, light chains (especially λ type) are more likely to form amyloid fibrils due to their genetic sequence and high secretion characteristics (13). Thus, light chains are more prone to deposit in the cardiac position, leading to cardiac amyloidosis. Excluding Fibα, among other typing proteins, Igλ C2 had the highest relative abundance in the spectrum, κ and λ values are significantly higher than the normal range (Table I), indicating that the main type is AL amyloidosis. Therefore, based on the positive Congo red staining and abdominal adipose tissue mass spectrometry analysis, the diagnosis was cardiac amyloidosis of the AL type.

Figure 4 Amyloid protein mass spectrometry-Ig light chain type (AL type). Mass spectrometry peaks identify Igλ C2 and µ heavy chain as the dominant amyloid protein. Ig, immunoglobulin; Fibα, fibrinogen α chain; Gel, gelsolin.

Diagnosis and treatment process

Based on the comprehensive characteristics of the case and auxiliary examination results, the diagnosis aligns with the criteria for LPL/WM, IgM-λ type, high-risk, accompanied by cardiac AL amyloidosis. The patient's prior diagnosis of chronic heart failure made in 2019 was attributed to non-specific causes, and no amyloidosis or hematologic malignancy was suspected until 2021, which highlights the importance of considering amyloidosis in refractory heart failure. The diagnosis of WM was confirmed through abnormal IgM (9.98 g/l) levels, λ-free light chains (507 mg/l), the existence of small B lymphocytes, plasma cell-like lymphocytes, plasma cells, M protein and MYD88 with L265P mutation. The cardiac amyloidosis was identified through cardiac biomarkers (N-terminal pro-B-type natriuretic peptide: 8,288 pg/ml), cardiac echocardiography (sparkling echoes), positive Congo red staining of bone marrow and apple green color transformation of abdominal fat biopsy, and mass spectrometry peaks of Ig λ C2 and µ heavy chain as the dominant amyloid protein with AL type.

In August 2021, the patient initiated the BR regimen, which consisted of Bendamustine (0.15 g intravenously on days 2-3) and Rituximab (0.6 g intravenously on day 1), following a 28-day chemotherapy cycle. A second course of the BR regimen was administered in September 2021, maintaining the same regimen and dosage as the initial course. The disease was subsequently evaluated as stable disease. In October 2021, the patient underwent a third-line treatment with the BRD regimen. This regimen included subcutaneous injections of 2 mg bortezomib on days 1, 8, 15 and 22, intravenous infusion of 0.5 g rituximab on the same days, and intravenous infusion of 10 mg dexamethasone on days 1, 8, 15 and 22, with treatments administered once a week within a 28-day chemotherapy cycle. After the treatment, the patient was determined to show a partial response (PR). The patient adhered to treatment with no adverse events and at the six-month follow-up, the patient showed sustained hematological PR but progressive diastolic dysfunction on echocardiography. The patient voluntarily left the hospital due to economic difficulties. The PR was mainly based on hematological criteria: >50% reduction in serum IgM (from 9.98 to 4.79 g/l), >50% reduction in the difference of serum free light chain (dFLC) and a decrease of cardiac injury markers (troponin T: 0.119 ng/ml). Cardiac function (ejection faction: 50%) remained stable but did not improve due to irreversible amyloid deposition. The follow-up was terminated as the patient did not return to the hospital for treatment after discharge.

Discussion

Cardiac AL amyloidosis secondary to WM presents diverse clinical manifestations and treatment complexities. According to the Chinese Society of Clinical Oncology, the ‘Diagnosis and Treatment of LPL/WM Chinese Expert Consensus (2022 version)’ outlines the diagnostic criteria for WM (17). The diagnostic markers of WM are small B lymphocytes, plasma cell-like lymphocytes and plasma cells, as well as high concentrations of IgM. The diagnostic markers of amyloidosis are positive Congo red staining of the fat tissue biopsy and apple green color transformation. The diagnosis requires exclusion of other lymphomas and the presence of the MYD88 with L265P mutation, found in >90% of WM cases (18). Herein, the genetic mutation detection of this case identified the presence of MYD88 with positive L265P mutation type.

At present, the specific mechanisms of WM are not fully understood, but studies have confirmed that genetic alterations may occur. García-Sanz et al (19) studied the clonality of tumor populations in WM and how clonal complexity can evolve and impact disease progression. Single-cell transcriptomics analysis also indicated that MYD88 could be an early event in tumorigenesis (20). In addition, X-box binding protein 1 (XBP1)-endoplasmic reticulum to nucleus signaling 1α (ERN1α) may play a role in the pathogenesis of WM because about 80% of patients have high XBP1 splicing mRNA expression, with 80% showing high mRNA ERN1α expression (21). The WM tumor progression is closely related to the bone marrow microenvironment and cytokines (22).

A study that included 20 years of data (1988 to 2007) from the Surveillance, Epidemiology and End Results (SEER) program showed that the median age at diagnosis for WM was 73 years, with an overall age-adjusted incidence rate of 0.38/100,000 per year, increasing to 2.85 among patients older than 80 years (23). Risk factors for WM prognosis include age (>65 years), elevated β-2 microglobulin, organomegaly, anemia, thrombocytopenia, low ALB, high serum monoclonal protein and high serum free light chain concentration. Recent research indicates that the median age at diagnosis for WM is ~71 years (12). Previous studies indicated that the median survival of patients with WM under the age of 70 is in excess of 10 years, that of patients aged 70-79 years is ~7 years and the median survival of patients aged 80 years or above is nearly 4 years (8,12). The incidence rate of WM is ~24,000 individuals every year globally, and the male-to-female ratio is 3.2:1. One study based on 5,784 patients with WM in the SEER database indicated that the median overall survival (OS) improved from 6 to 8 years from 1991 to 2010(24). Another study determined that the median survival after treatment initiation was 87 months among 587 patients with WM (25).

The median diagnostic age of cardiac amyloidosis was determined to be >60 years (26). The median survival of cardiac ATTR and AL amyloidosis was determined to be 2-5 years and the OS at 2 years was 63% for AL and 98% for ATTR from diagnosis, indicating that the prognosis of cardiac ATTR amyloidosis is better than that of cardiac AL amyloidosis (27). The median survival of patients with AL amyloidosis associated with WM was reported to be in the range of 49-78 months, which was not significantly different compared with patients without IgM, as survival is independently affected by cardiac involvement (28-30).

WM may lead to various complications, including cardiac amyloidosis, and the heart is easily affected by amyloidosis secondary to WM. Among patients with WM in SEER database, most subjects were found to present with symptoms related to tumor burden, while only ~10% of patients concurrently suffer from AL amyloidosis (12,13). Cardiac amyloidosis is an uncommon cardiopathy and characterized by the deposition of insoluble amyloid proteins within cardiac tissues. The mechanism of amyloidosis secondary to WM is that abnormal production and deposition of monoclonal IgM may cause cardiac amyloidosis, affecting cardiac structure and function and resulting in heart failure (13). The definition, the diagnostic criteria, criteria for initiation of therapy and a new classification scheme of amyloidosis and WM were established in 2004(31). A study of 50 patients with serum IgM monoclonal gammopathy showed that 53% of the patients died of cardiac amyloidosis, while 32, 14 and 10% of patients also had renal, liver and lung amyloidosis, respectively (32). IgM-related amyloidosis accounts for only 6-10% in patients with various Ig-related amyloidoses, and 54% of cases among them were associated with underlying non-Hodgkin's lymphoma, including WM (33,34). A test of the MYD88 mutation status is necessary for the evaluation of IgM-related AL, as these mutations are distinct features of WM (35). Gustine et al (36) studied consecutive patients from 2006 to 2022; all patients were diagnosed with WM-AL amyloidosis through the criteria of the presence of IgM paraprotein, bone marrow infiltration by lymphoplasmacytic lymphoma and positive Congo red staining of a biopsy specimen. The median OS was 7.3 years in 49 patients with WM-AL amyloidosis. Patients with WM with cardiac amyloidosis may be misdiagnosed as either AL or ATTR amyloidosis by immunohistochemistry and can be correctly identified by mass spectrometry (37). The reported patients with WM-ATTR amyloidosis had a lower dFLC than patients with AL. In the case of the present study, a delay in diagnosis occurred due to overlapping symptoms with heart failure and the rarity of WM-associated AL amyloidosis.

WM secondary to cardiac amyloidosis is controlled and treated through chemotherapy, immunotherapy and targeted therapy, and a high level of autologous stem cell transplantation. The management of cardiac symptoms requires specific interventions for heart failure, arrhythmias and conduction abnormalities. First-line treatment options for symptomatic patients with WM include Rituximab-chemotherapy and BTK inhibitors, such as ibrutinib, either alone or combined with rituximab and zanubrutinib (13,36). For patients with WM-AL amyloidosis, the most common salvage therapy method is a bortezomib- and/or bendamustine-based regimen (36). BR is preferred for rapid tumor reduction or high tumor burden, showing potential for longer progression-free survival. The choice of BTK inhibitors should consider the MYD88 L265P mutation, as the wild-type shows the best response and the mutated type has a poor response and may benefit from added rituximab (38). The patient of the present study carried the MYD88 L265P mutation, which was treated with the BR and BRD regimen rather than BTK inhibitors. Compared with Bendamustine, proteasome inhibitors such as bortezomib are not first-line medications but may be used in resistant cases to target and kill tumor cells. The Bendamustine is more expensive than bortezomib, and thus, the patient preferred the BRD regimen; however, both the BR and BRD regimens failed to achieve the expected effect with only a PR. AL amyloidosis is one of the most dangerous disorders related to the M protein, which is better treated before irreversible organ impairment has occurred (28,39). In the present study, the patient with WM-AL amyloidosis failed to respond to the BR and BRD regimens, presumably because he was diagnosed with chronic heart failure at an external hospital in 2019, but was diagnosed as WM accompanied by cardiac AL amyloidosis in 2021. The irreversible organ impairment caused by WM-AL amyloidosis may have occurred before therapy at our hospital.

Numerous specific cases of WM accompanied by cardiac amyloidosis have been reported in the literature. A 70-year-old male was diagnosed as WM with AL amyloidosis, was then started on bortezomib, cyclophosphamide, dexamethasone and rituximab, and after three cycles of therapy, IgM had decreased to 1,500 mg/dl with improved performance status (13). A 52-year-old male was diagnosed with WM accompanied by AL amyloidosis and the rituximab and bortezomib-based chemotherapy was ineffective (40). A 76-year-old African American male with chronic kidney disease was diagnosed with WM accompanied by ATTR amyloidosis, and after 12 months of tafamidis-based chemotherapy, cardiac and hematological conditions were stable (41). An 80-year-old female hospitalized for chronic dyspnea and cough was diagnosed with λ light chain and µ heavy chain type amyloidosis; the patient was not suited for chemotherapy or immunotherapy due to severe heart failure and hypotension (42). The previous study demonstrated that WM-AL amyloidosis can also be treated with the standard WM regimens, such as bortezomib, dexamethasone and rituximab or bendamustine and rituximab (36). High-dose melphalan and stem cell transplantation (HDM/SCT) should be a new option for patients with WM-AL amyloidosis, as HDM/SCT-based therapy can prolong survival to >20 years in typical AL amyloidosis (43).

In conclusion, a case was diagnosed with WM accompanied by cardiac AL amyloidosis based on the presence of abnormal IgM paraprotein levels and the high Ig λ C2 spectrum in the amyloid protein mass spectrometry. The novelty of this case lies in the rare cardiac AL amyloidosis secondary to WM, particularly the diagnostic challenges and the limited treatment response due to irreversible cardiac damage. The BR and BRD-based therapy only yielded a PR and the symptom of chronic heart failure due to irreversible organ impairment had occurred before treatment at our hospital. This result indicates that WM secondary to cardiac amyloidosis needs to be diagnosed and treated as early as possible by inspecting IgM levels, amyloid protein mass spectrometry, genetic mutation analysis and pathological examination of tissues before the irreversible organ impairment at the site of the heart. In addition, the mechanisms, treatment methods and survival of WM, ATTR or AL amyloidosis and WM-AL amyloidosis were reviewed in this paper. The complexities of WM and its secondary complications such as cardiac amyloidosis highlight the need for ongoing research and collaboration. Integrating advanced diagnostic techniques and personalized treatment strategies will improve the management of this disease and increase patient quality of life.

Supplementary Material

Supplementary methods

Test result of serum protein electrophoresis. The peak on the left represents ALB protein and the peak on the right represents γ globulin. The appearance of steep ‘peaks’ in the right elecrophoretic bands indicates the presence of abnormally increased immunoglobulin. Ref. Conc., reference concentration΄ ALB, albumin.

Low voltage in the limb leads in the electrocardiogram.

Gene mutation detection by droplet digital polymerase chain reaction. The blue dots represent the MYD88 mutant type. The green dots represent MYD88 wild-type (no mutation). Orange dots represent a mixed state of mutant and wild-type (such as chimeric mutations or low abundance mutations). The black dots represent the background noise.

Flow cytometry results. The antibody labeling method is the five color method. The antibodies include CD19-PC5.5 for recognizing B cells, and CD20-APC for recognizing mature B cells. The gated area includes CD19+ and CD20+ cells (pink area), representing a subset of B cells that simultaneously express CD19 and CD20. The green area on the left represents CD19 low expression or negative cells. The 4.94% is the proportion of CD19+ and CD20+ in the total lymphocytes based on upstream lymphocyte gating. The 32.78% represents the proportion of CD19+ and CD20+ in CD19+ cells in this case.

Test results of serum protein electrophoresis.

Test results of immunofixation electrophoresis.

Test results of genetic mutation detection.

Test results of bone marrow histology morphology.

Test results of bone marrow histology morphology.

Acknowledgements

The authors thank Miss Shuaiyang Wang (technologist-in-charge) and Miss Hongmei Mo (associate senior technologist) of the Clinical Laboratory of Luohu People's Hospital of Shenzhen (Shenzhen, China), and Miss Huizhi Guo (attending physician) of the Department of Ultrasound of Luohu People's Hospital of Shenzhen for providing the examination reports of the current patient.

Funding

Funding: This research was funded by Sanming Project of Medicine in Shenzhen (grant no. SZSM202301035).

Availability of data and materials

The data generated in the present study may be requested from the corresponding author.

Authors' contributions

FD was responsible for the case diagnosis and treatment, as well as writing and analysis of the manuscript. AG contributed to the data analysis and collection. LZ analyzed patient data, DL provided treatment advice, JC collected image data, HX collected pathological data, WL collected ultrasound data, JL collected flow cytometry of bone marrow data and YL collected the amyloid protein mass spectrometry spectrum data. HC was responsible for study conception and revisions to the manuscript. All authors have read and approved the final manuscript. FD and HC confirm the authenticity of all the raw data.

Ethics approval and consent to participate

This study received approval from the Shenzhen Luohu People's Hospital Research Ethics Committee (grant no. 2024-LHQRMYY-KYLL-26). The protocol and informed consent form were reviewed and approved on May 12, 2024, with a subsequent simplified review conducted on May 23, 2024. The study adheres to ethical standards as outlined by the committee. The patient provided written informed consent for participation.

Patient consent for publication

The patient provided written informed consent for publication of their data, including case information and images.

Competing interests

The authors declare that they have no competing interests.

References