Abstract
Daratumumab, an anti-human CD38 monoclonal antibody, has become the standard of care in patients with systemic light-chain (AL) amyloidosis and multiple myeloma (MM). Herein, we report two cases of AL cardiac amyloidosis with MM who were treated with daratumumab, lenalidomide, and dexamethasone (DRd). Serial evaluation of cardiac biomarkers, echocardiography, and cardiac magnetic resonance imaging (CMR) were performed during 12 months of DRd treatment. A complete hematologic response was achieved three months after treatment initiation and sustained during the observation period. Twelve months after DRd treatment, we found improvements in levels (values for case 1 and case 2, respectively) of B-type natriuretic peptide (593.2 → 312.2 pg/mL and 202.4 → 104.3 pg/mL), N-terminal pro-brain natriuretic peptide (4005 → 1800 pg/mL and 2576 → 1170 pg/mL), high-sensitivity cardiac troponin T (0.156 → 0.072 ng/mL and 0.0678 → 0.0467 ng/mL), and global longitudinal strain (−6.8 → −10.4 % and −11.8 → −14.8 %). CMR revealed no noticeable changes in native T1 value or extracellular volume fraction. However, one case showed decreased native T2 value (61 → 55 ms). In conclusion, DRd treatment improved heart failure and cardiac function, relieved myocardial damage, and prevented amyloid deposition progression in the patients with AL cardiac amyloidosis. Cardiac biomarkers and imaging findings may be useful for monitoring the therapeutic effects of daratumumab-containing regimens.
Learning objective
Daratumumab-containing regimens led to a rapid complete hematologic response, improvements in heart failure symptoms, cardiac function, and regression of myocardial damage in light-chain cardiac amyloidosis. This treatment prevents additional amyloid deposition and suppresses the direct cardiotoxic effects of amyloidogenic immunoglobulin light-chains. Serial assessments of cardiac biomarkers and imaging findings are useful for evaluating the therapeutic effect of daratumumab-containing regimens.
Keywords: Light-chain amyloid, Daratumumab, Biomarkers, Imaging
Introduction
Immunoglobulin light-chain (AL) amyloidosis is a lethal condition resulting from misfolded immunoglobulin ALs produced by clonal CD38-positive plasma cells. AL cardiac amyloidosis is characterized by cardiac toxicity due to extracellular deposition of amyloid fibrils and immunoglobulin ALs, causing cardiac hypertrophy and leading to fatal heart failure, thromboembolism, and arrhythmia [1].
Proteasome inhibitors (bortezomib and ixazomib), alkylating agents (cyclophosphamide and melphalan), and steroids (dexamethasone and prednisolone), commonly used for multiple myeloma (MM) have been repurposed for treatment of AL amyloidosis. A recent phase 3 trial showed that addition of daratumumab, a human CD38 monoclonal antibody, to cyclophosphamide, bortezomib, and dexamethasone (CyBorD) led to higher frequencies of complete hematologic responses and better clinical outcomes compared with using CyBorD alone for AL amyloidosis treatment [2]. Therefore, a daratumumab-containing regimen is expected to be the mainstay treatment of AL amyloidosis.
The diagnostic and prognostic utilities of cardiac biomarkers, echocardiography, and cardiac magnetic resonance imaging (CMR) have been widely reported [3]. Evaluation of disease progression and therapeutic effects in cardiac amyloidosis using these modalities has received much attention.
Herein, we report two cases of AL cardiac amyloidosis achieving complete hematologic response 12 months after treatment with a daratumumab-containing regimen. Serial measurements of cardiac biomarkers and imaging parameters helped evaluate the therapeutic effect of the daratumumab-containing regimen on cardiac amyloidosis.
Case report
Case 1
A76-year-old man who underwent surgery for bilateral carpal tunnel syndrome at age 74 years had no history of cardiovascular disease. He experienced dyspnea five days prior to admission to a nearby hospital and was diagnosed with heart failure. He was referred to our hospital for further examination. Electrocardiography showed prolonged PQ interval, low voltage in limb leads, and poor R-wave progression in leads V2–V3. Chest X-ray indicated cardiac enlargement (Online Fig. 1A). Laboratory test results showed increased levels of B-type natriuretic peptide (BNP) (593.2 pg/mL; normal range: <18.4 pg/mL), N-terminal pro-brain natriuretic peptide (NT-proBNP) (4005 pg/mL; normal range: <125 pg/mL), and high-sensitivity cardiac troponin T (hs-cTnT) (0.156 ng/mL; normal range: <0.014 ng/mL). Transthoracic echocardiography (TTE) revealed left ventricular (LV) hypertrophy (interventricular septum: 16.1 mm), diffuse hypokinesis with reduced LV ejection fraction (LVEF) (46.9 %), and impaired global longitudinal strain (GLS) (−6.8 %) with apical sparing. Serum free light chain (FLC) concentrations were 20.2 mg/L and 869 mg/L for κ and λ (κ/λ ratio: 0.02), respectively. Serum and urine immunofixation electrophoresis revealed presence of IgG-λ type monoclonal proteins. Contrast-enhanced CMR showed elevated native T1 value (1519 ms; reference: <1250 ms), native T2 value (61 ms; reference: 40–45 ms), and extracellular volume fraction (ECV) (65.1 %). Late gadolinium enhancement (LGE) was observed in the global subendocardium. Immunohistochemical staining of a gastrointestinal biopsy revealed AL amyloid deposition. Based on hematological findings, including increases in monoclonal plasma cells of up to 16 % within the bone marrow, the patient was diagnosed with AL cardiac amyloidosis with MM. Subsequently, DRd treatment (daratumumab, lenalidomide, and dexamethasone), a standard regimen for newly diagnosed transplant-ineligible patients with MM, was initiated. Three months after treatment, complete hematologic response was achieved. After 12 months, the levels of BNP (312.2 pg/mL), NT-proBNP (1800 pg/mL), and hs-cTnT (0.0720 ng/mL) also improved (Fig. 1). Electrocardiography revealed no remarkable changes. Chest X-ray showed improvements in cardiac enlargement (Online Fig. 1B). CMR showed no changes in native T1 value (1516 ms), ECV (66.7 %), or localization of LGE. However, decreases in T2 value (55 ms) were observed (Fig. 3A). Among echocardiographic parameters, improvements in LV hypertrophy (interventricular septum: 15.1 mm) and GLS (−10.4 %) were observed (Fig. 1 and Online Fig. 2A).
Fig. 1.
Serial biomarkers and echocardiographic findings over 12 months of DRd treatment in case 1. The κ/λ ratio normalizes after 3 months. Cardiac biomarkers left ventricular hypertrophy and GLS are improved.
BNP, B-type natriuretic peptide; BP, blood pressure; dFLC, difference between involved and uninvolved serum free light chain levels; DRd, daratumumab, lenalidomide, dexamethasone; HR, heart rate; hs-cTnT, high-sensitivity cardiac troponin T; IVSTd, interventricular septum diameter; LVDd, left ventricular diastolic diameter; LVDs, left ventricular systolic diameter; LVEF, left ventricular ejection fraction; LV-GLS, left ventricular global longitudinal strain, NT-proBNP, N-terminal pro-brain natriuretic peptide; NYHA, New York Heart Association; PLVWd, left ventricular posterior wall diameter; TRPG, tricuspid regurgitation peak gradient.
Fig. 3.
CMR findings (native T1, ECV, and native T2) at baseline and after 12 months of DRd therapy in (A) case 1 and (B) case 2.
CMR, cardiac magnetic resonance imaging; DRd, daratumumab, lenalidomide, dexamethasone; ECV, extracellular volume fraction.
Case 2
A 67-year-old woman was admitted to a regional hospital for fatigue and dyspnea on exertion in the previous 3 months. She had a history of proteinuria. However, no further examination was performed. TTE revealed LV hypertrophy. Bence-Jones proteins were detected in the urine. Therefore, she was suspected to have AL cardiac amyloidosis. Myocardial biopsy revealed amyloid deposition. The patient was referred to our hospital for further examination. Electrocardiography showed low voltage of limb leads, poor R-wave progression in leads V2–V4. Chest X-ray showed cardiac enlargement and left-dominant pleural effusion (Online Fig. 1C). Laboratory test results demonstrated elevated levels of BNP (202.4 pg/mL), NT-proBNP (2576 pg/mL), and hs-cTnT (0.0678 ng/mL). Serum FLC concentrations were 14.9 mg/L and 656 mg/L for κ and λ (κ/λ ratio: 0.02). TTE revealed that the patient's LV was hypertrophied (interventricular septum: 13.9 mm), and impaired GLS (−11.8 %). Contrast-enhanced CMR showed increased native T1 value (1472 ms), native T2 value (52.7 ms), and ECV (53.8 %). LGE was observed in the subendocardium. Similar to case 1, based on hematological findings, including an increase in monoclonal plasma cells of up to 26 % within the bone marrow and immunoglobulin AL positivity for myocardial amyloid deposits, the patient was diagnosed with AL cardiac amyloidosis with MM. Therefore, DRd treatment was initiated. Three months post-treatment, complete hematological response was achieved. Twelve months after treatment, laboratory test results showed improved BNP (104.3 pg/mL), NT-proBNP (1170 pg/mL), and hs-cTnT (0.0467 ng/mL) levels (Fig. 2). Electrocardiography revealed no changes and chest X-ray showed reduction in left-dominant pleural effusion (Online Fig. 1D). CMR did not show noticeable changes in native T1 value (1484 ms), T2 value (54.3 ms), ECV (57.3 %) (Fig. 3B), or localization of LGE. Among echocardiographic parameters, an improvement in LV hypertrophy (interventricular septum: 13.2 mm) and GLS (−14.8 %) were observed (Fig. 2 and Online Fig. 2B).
Fig. 2.
Serial biomarkers and echocardiographic findings over 12 months of DRd treatment in case 2. The κ/λ ratio normalizes after 3 months. Cardiac biomarkers left ventricular hypertrophy and GLS are improved.
BNP, B-type natriuretic peptide; BP, blood pressure; dFLC, difference between involved and uninvolved serum free light chain levels; DRd, daratumumab, lenalidomide, dexamethasone; HR, heart rate; hs-cTnT, high-sensitivity cardiac troponin T; IVSTd, interventricular septum diameter; LVDd, left ventricular diastolic diameter; LVDs, left ventricular systolic diameter; LVEF, left ventricular ejection fraction; LV-GLS, left ventricular global longitudinal strain, NT-proBNP, N-terminal pro-brain natriuretic peptide; NYHA, New York Heart Association; PLVWd, left ventricular posterior wall diameter; TRPG, tricuspid regurgitation peak gradient.
Discussion
The current report describes two AL cardiac amyloidosis cases with MM treated with a daratumumab-containing regimen, evaluated by serial measurements of cardiac biomarkers and imaging parameters. Complete hematologic response was achieved within approximately three months and maintained without severe adverse events or worsening heart failure.
Improvements in cardiac biomarker levels were observed during DRd treatment. Decreased natriuretic peptide levels reflected improvement in heart failure symptoms. Moreover, reduced hs-cTnT levels indicated improvements in cardiac injury. Cardiac injury in AL cardiac amyloidosis is associated with multiple factors, including heart failure, coronary microvascular dysfunction, and secondary myocardial ischemia [1]. Additionally, circulating amyloidogenic ALs appear to have direct cardiotoxic effects independent of extracellular fibril deposition. We speculate that improvements in cardiac injury may partly be due to reductions in toxic amyloidogenic ALs by DRd treatment and hs-cTnT can be a sensitive biomarker of treatment effects on AL cardiac manifestation.
CMR is a useful imaging modality for evaluating myocardial tissue composition in cardiac amyloidosis. Native T1 and ECV have been recognized to reflect fibrosis and cardiac amyloid burden in addition to edema, inflammation, and vasodilatation, whereas T2 more specifically reflects edema and inflammation [4]. Several reports have confirmed the significance of serial CMR in evaluating the therapeutic effect of disease-modifying treatment on myocardial tissue composition in cardiac amyloidosis. Rettl et al. [5] reported no significant changes in serial measurements of native T1 and ECV in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) treated with tafamidis, a transthyretin stabilizer. However, treatment-naïve ATTR-CM patients with clear signs of disease progression have increased ECV. Compared with that in treatment-naïve patients, ECV increase was inhibited in patients with hereditary ATTR-CM treated with patisiran, a transthyretin-specific small interfering RNA, for 12 months [6]. Similar to previous reports, our two cases showed no significant changes in native T1 or ECV after DRd treatment, suggesting that additional amyloid accumulation and myocardial fibrosis was suppressed, whereas a removal of amyloid deposits was not achieved.
Kotecha et al. [7] observed higher native T2 value in untreated than in treated AL amyloidosis that were associated with poor clinical outcomes after adjustment for known prognostic factors. In AL amyloidosis, native T2 reflects myocardial inflammation and cellular edema caused by toxic effects due to extracellular AL accumulation. In one of our cases, we found decreased native T2 value after 12 months of treatment. However, we observed no changes in the second case, despite achieving complete hematologic response and improvements in cardiac biomarkers. Longer follow-up and further research are warranted to determine the mechanism of native T2 elevation and feasibility of serial CMR measurements in evaluating therapeutic effects in AL cardiac amyloidosis.
Reduced LV GLS in systemic AL amyloidosis indicates progression of cardiac involvement and can be an independent predictor of survival [8]. Improvement in LV hypertrophy is a conventional index of therapeutic response in cardiac amyloidosis. Post-treatment, LV hypertrophy and GLS were improved in both cases. Therefore, these parameters may be suitable indicators of the therapeutic effect in AL cardiac amyloidosis.
Hematologic response to chemotherapy is key to improvements in cardiac function and cardiac biomarkers in AL amyloidosis [9], [10]. A daratumumab-containing regimen was associated with higher frequencies of complete hematologic responses and better clinical outcomes compared with using CyBorD alone [2]. Therefore, daratumumab-containing regimens could achieve improvement in cardiac function and biomarkers due to higher frequency of complete hematologic response compared with conventional treatment.
In conclusion, our cases suggest that DRd treatment might improve heart failure, cardiac function, and myocardial damage. DRd treatment could prevent additional amyloid deposition in the myocardium and suppress the direct cardiotoxic effects of amyloidogenic immunoglobulin ALs. Serial assessments of biomarkers and imaging findings might be useful for evaluating therapeutic effects in patients with AL cardiac amyloidosis during daratumumab administration.
Declaration of competing interest
None.
Acknowledgments
This research was supported by Japan Intractable Diseases (Nanbyo) Research Foundation.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.jccase.2022.06.008.
Appendix A. Supplementary data
Online Fig. 1. Serial evaluation of electrocardiography and chest X-ray images at baseline and after 12 months of DRd therapy in (A, B) case 1 and (C, D) case 2.
CTR, cardiothoracic ratio; DRd, daratumumab, lenalidomide, dexamethasone.
Online Fig. 2. Serial measurement of GLS at baseline, 6 months, and after 12 months of DRd therapy in (A) case 1 and (B) case 2.
DRd, daratumumab, lenalidomide, dexamethasone, GLS: global longitudinal strain, LS: longitudinal strain.
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Associated Data
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Supplementary Materials
Online Fig. 1. Serial evaluation of electrocardiography and chest X-ray images at baseline and after 12 months of DRd therapy in (A, B) case 1 and (C, D) case 2.
CTR, cardiothoracic ratio; DRd, daratumumab, lenalidomide, dexamethasone.
Online Fig. 2. Serial measurement of GLS at baseline, 6 months, and after 12 months of DRd therapy in (A) case 1 and (B) case 2.
DRd, daratumumab, lenalidomide, dexamethasone, GLS: global longitudinal strain, LS: longitudinal strain.