Improvement in global longitudinal strain following plasma cell-directed therapy is associated with long-term survival among patients with AL amyloidosis

Abstract

Aims

Cardiac impairment in AL amyloidosis is the major determinant of survival. Treatment goals include reducing circulating light chains to improve organ function. Global longitudinal strain (GLS) is an independent predictor of survival and useful for assessing cardiac function before and after therapy. This study aimed to describe GLS change from baseline to one year post-treatment, identify factors associated with GLS improvement (GLS+), and evaluate its prognostic significance.

Methods and results

Ninety-seven patients with AL amyloidosis and cardiac stage II/III disease who underwent echocardiogram and haematologic evaluation at baseline and one year were included. GLS+ was defined as a 2.0%-point increase. A cardiac or B-type natriuretic peptide (BNP+) response was defined as a 30% reduction from baseline. Overall survival was measured from baseline echocardiogram to death. Of 97 patients, 62% had Stage II, 29% Stage IIIa, and 9% Stage IIIb disease. Baseline median left ventricular ejection fraction, GLS, and septal thickness were 65%, −14.9%, and 1.3 cm, respectively. GLS+ was observed in 36% of patients and BNP+ in 51%. Median overall survival was 113.4 months. The hazard ratio for survival was 0.42 in the GLS+ group and 0.46 in the BNP+ group, after adjusting for haematologic response.

Conclusion

GLS improvement post-treatment confers a significant survival benefit. This study supports GLS as an important marker for risk stratification and cardiac response.

Graphical Abstract

Graphical Abstract.

Introduction

The goals of treatment in AL amyloidosis are to block the production of monoclonal light chains, prevent organ damage, and, if possible, reverse existing damage. Cardiac involvement, occurring in more than 50% of AL amyloid cases, is the major determinant of survival.¹ As more therapeutic options become available, accurate monitoring and assessment tools to detect and quantify cardiac involvement are essential to evaluate their effectiveness and guide treatment decisions.

The current standard for assessing cardiac response post-treatment relies on a reduction in N-terminal pro-brain natriuretic peptide (NT-proBNP), a serum biomarker of myocardial stress.² However, natriuretic peptide levels may not directly reflect myocardial function, as they can be influenced by factors such as intravascular volume overload or changes in renal function. Global longitudinal strain (GLS), an index of myocardial deformation, is a sensitive marker of myocardial function that has been shown to provide incremental prognostic value beyond circulating cardiac biomarkers in patients with AL amyloidosis.^3–5 Previously, Cohen et al. from the UK National Amyloidosis Center⁶ demonstrated that improvement in GLS provided independent and additional prognostic value compared to improvements in NT-proBNP levels following plasma-directed therapy in patients with cardiac involvement. Their work was pivotal in identifying additional markers of cardiac response and predictors of survival. Given the importance of assessing cardiac improvement—a key factor in treatment decisions—it would be worthwhile to validate this finding in other populations of patients with AL amyloidosis to determine its broader applicability.

Thus, the current study aimed to examine the change in GLS from pre-treatment to 1 year after plasma-directed therapy in patients with baseline cardiac stage II, IIIa, or IIIb disease, as defined by the Boston University (BU) staging system. This system, which relies on B-type natriuretic peptide (BNP), is applicable in centres where NT-proBNP is unavailable and has proven to be highly informative and predictive of prognosis.^7,8 The study also sought to identify clinical factors associated with GLS improvement and assess its prognostic significance.

Methods

Study design and patient selection

Two-hundred and eighteen consecutive patients with newly diagnosed biopsy-proven systemic AL amyloidosis, with positive troponin I and/or BNP classified as BU stage II, IIIa, or IIIb disease, evaluated at Memorial Sloan Kettering Cancer Center between May 2007 and January 2020, were identified, and included in the study. Patients with Stage I disease were not included due to the absence of elevated cardiac biomarkers, indicating a low likelihood of prognostically significant cardiac involvement. The BU staging system, based on the cut-off of troponin I (TnI) 0.1ng/mL and BNP 81 pg/L, consisted of the following definitions: Stage I—both Tn and BNP below the cut-offs; Stage II—either Tn or BNP above the cut-off; Stage IIIa—both Tn and BNP above the cut-offs with BNP < 700 pg/L; Stage IIIb—both Tn and BNP above the cut-offs with BNP ≥ 700 pg/L.⁸ Patients who were alive and had a 1 year follow-up echo and haematologic evaluation available were included in this analysis.

Baseline clinical, echocardiographic, and laboratory test results were collected prior to or within one month of the start of plasma cell-directed therapy. Clinical and treatment data were extracted from a prospectively maintained database of an ongoing Memorial Sloan Kettering Cancer Center Institutional Review Board approved protocol that collects clinical characteristics and outcomes of patients with systemic AL amyloidosis. Ethical approval was granted for this protocol.

Echocardiography

The conventional two-dimensional (2D) and Doppler echocardiography protocols have been previously described.⁴ Briefly, the studies were performed using commercially available standard ultrasound scanners (Vivid E9, General Electric Medical Systems and iE33, Philips Medical Systems), according to the standardized American Society Echocardiography (ASE) protocol.⁹ Left ventricular ejection fraction (LVEF) was calculated using the modified Simpson’s method. Mitral inflow velocity pattern was recorded from the apical four-chamber view with the pulsed-wave Doppler sample volume positioned at the tips of the leaflets during diastole. Peak early filling (E-wave) and late diastolic filling (A-wave) velocities were measured, and their ratio (mitral E/A) derived. Doppler tissue imaging of the mitral annulus was performed with measurement of the early (e′) diastolic velocity at the lateral and medial annulus.

Strain measurement

The methods of image acquisition and post-processing of strain measurements have been previously described.⁴ Briefly, GLS measurements were performed offline using vendor independent 2D Cardiac Performance Analysis software (Tom Tec Imaging Systems, Unterschleissheim, Germany). All echocardiographic measurements were made with the operator blinded to the clinical and outcome data. The endocardial border was traced in end-diastole in the three standard apical views, which allowed the software to track myocardial movement throughout the cardiac cycle.¹⁰ After careful inspection, manual correction was performed if the myocardial tracking was suboptimal. Each view was divided into six segments, for a total of 18 segments representing the entire LV. Longitudinal strain curves were generated for each segment. GLS was calculated as the average value of the peak negative systolic strain values for all the segments within the three standard apical views.

Repeatability and reproducibility

Echocardiograms were analysed by a single experienced echocardiographer. To assess reproducibility, GLS measurements in 25 randomly selected patients were repeated on two occasions by the original reader to determine intra-observer variability and by a second experienced reader blinded to prior measurements to determine inter-observer variability. The mean difference in calculated GLS was −0.052 (95% CI −1.09 to +0.98) and −0.028% (95% CI −1.74% to +1.69%) for intra and inter-observer variabilities, respectively (see Supplementary material online, Figure S1).

Criteria for haematologic and cardiac response

The haematologic response at 1 year following plasma cell-directed therapy was defined according to the following published criteria¹¹: (i) complete response (CR): normalization of the involved free light chain (FLC) to below the upper limit of normal, and negative serum and urine immunofixation; (ii) very good partial response (VGPR): a difference between involved and uninvolved light chains (dFLC) of <40 mg/L; (iii) partial response (PR): a dFLC decrease > 50%; and (iv) no response (NR): no significant dFLC change. A deeper light chain response (DR) has been defined as a difference between involved and uninvolved light chains (dFLC) < 10 mg/L. Cardiac or BNP response (BNP+) was defined based on a 30% reduction from pre-treatment as per definition of cardiac improvement.^2,7 The absolute value of GLS was reported. Similar to the previously published study,⁶ GLS improvement (GLS+) was defined as an absolute 2.0%-point increase from baseline, a cut-off representing a meaningful change beyond measurement variability (see Supplementary material online, Figure S1).

Statistical analysis

Overall survival (OS) was defined as time from the baseline echocardiogram obtained within one month of treatment to death from any cause. Continuous variables are presented as median [interquartile range (IQR)] and categorical variables as number (percentage). Clinical characteristics and echocardiographic parameters were compared by group using the Wilcoxon signed rank or Kruskal–Wallis test for continuous variables and χ² test or Fisher’s exact test for categorical variables. Correlation between BNP response and GLS response was calculated by Pearson correlation coefficients. Survival analysis was performed using the Kaplan–Meier method and a log-rank test was used to compare overall survival between groups of interest. Multivariable Cox proportional hazards models evaluated associations between overall survival with GLS improvement, BNP response, and GLS improvement or BNP response, adjusting for haematologic response and age. To compare the goodness-of-fit of the models, the Likelihood-Ratio test was performed between models. Statistical significance was defined as a two-sided P-value of <0.05. Bland–Altman plots were used to display inter-and intra-observe variabilities in GLS measurements. Statistical analyses were performed in R, version 3.5.2 (R Foundation for Statistical Computing), Stata, version 15.1 (StataCorp, LLC), and SAS Version 9.4 (SAS Institute, Inc., Cary, NC).

Results

Patient characteristics

Two-hundred and eighteen AL amyloidosis patients with BU cardiac stage II-IIIb were identified. The clinical and echocardiographic characteristics of this baseline group are shown in Supplementary Tables. Fifty-seven patients died before reaching one year after starting treatment, and an additional 64 patients were lost to follow-up or had missing 1-year echo/GLS data. This resulted in a study group of 97 patients who fulfilled the criteria. Patients in the study group were similar to the patients lost to follow-up or missing 1 year echo with respect to the baseline clinical and echocardiographic characteristics. As expected, patients who died before reaching one year had more advanced disease with higher levels of TnI and BNP, and dFLC, as well as more impaired cardiac structure and function. The baseline clinical characteristics of the study group are shown in Table 1. Of 97 patients, 62% (60) had BU Stage II, 29% (28) had BU Stage IIIa, and 9% (9) had BU stage IIIb cardiac disease at baseline. The cardiovascular comorbidities included 51% (49) with a history of hypertension, 47% (46) with hyperlipidaemia, 20% (19) with chronic kidney disease, 18% (17) with clinical heart failure, and 9% (9) with coronary artery disease. The median troponin I level was 0.05 ng/mL, and the median BNP was 280 pg/mL, with 36% (35) of patients having a BNP ≥ 400 pg/mL.

Table 1.

Baseline clinical characteristics (N = 97)

Male	60 (62)
Age, years	62 (57–69)
BMI, kg/m2	26.3 (23.0–30.4)
SBP, mmHg	116 (103–133)
DBP, mmHg	73 (64–79)
HR, b.p.m.	82 (71–90)
Troponin I, ng/mL	0.05 (0.05–0.14)
BNP, pg/mL	280 (167–504)
Serum creatinine, mg/dL	1.0 (0.8–1.3)
BU
II	60 (62)
IIIa	28 (29)
IIIb	9 (9)
History of hypertension	49 (51)
Hyperlipidaemia	46 (47)
Chronic kidney disease	19 (20)
Clinical heart failure	17 (18)
Coronary artery disease	9 (9)
dFLC, mg/dL	18 (7–45)
BNP ≥ 400, pg/mL	35 (36)

Values are n (%) or median (interquartile range).

BU, Boston University; SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate; BNP, brain natriuretic peptide; dFLC, difference between involved and uninvolved light chains.

The median (IQR) creatinine was 1.0 (0.8–1.3) mg/dL. Forty-six patients (47%) received high dose melphalan with autologous stem cell transplant and the remaining 51 patients (53%) received bortezomib based therapy. The baseline echocardiographic findings, which are listed in Table 2, included a median LVEF of 65% (IQR 59, 70), GLS of −14.9% (IQR −12.1, −17.7), and septal thickness of 1.3 cm (IQR 1.1, 1.5).

Table 2.

Baseline echocardiographic characteristics

	n	Median (interquartile range)
GLS%	97	−14.9 (−12.1, −17.7)
LVEF %	101	65 (59, 70)
IVS thickness, cm	96	1.3 (1.1, 1.5)
Mitral E/A ratio	89	1.0 (0.8, 1.5)
Lateral e′, cm/s	82	6.4 (5.2, 8.0)
Septal e′, cm/s	80	5.3 (4.2, 6.9)
Average E/e′	84	14.9 (12.0, 18.9)
Deceleration time, s	78	0.19 (0.16, 0.24)
LA volume index, mL/m2	90	31.8 (23.4, 39.3)
TAPSE, mm	73	2.0 (1.7, 2.3)
RV TDI, cm/s	53	14.0 (12.0, 15.7)
Stroke volume, ml	81	65.3 (48.6, 80.9)
Stroke volume index, mL/m2	81	35.2 (27.8, 41.2)
Cardiac output, L/min	81	4.9 (4.0, 5.9)
Cardiac index, L/min/m2	81	2.6 (2.2, 3.0)

GLS, global longitudinal strain; LVEF, left ventricular ejection fraction; IVS, interventricular septal thickness; LA, left atrial volume; TAPSE, tricuspid annular plane systolic excursion; RV TDI, right ventricular tissue Doppler imaging.

Assessment at 1 year after treatment

Haematologic and cardiac response

At the 1-year mark, all patients underwent a follow-up evaluation to assess haematologic and cardiac response, as well as an echocardiogram. The haematologic response included 38 (39%) CR, 32 (33%) VGPR, 16 (16%) PR and 11 (11%) NR, as well as 39 (40%) DR. A cardiac response or a BNP response (BNP+), defined by a 30% reduction from baseline, was seen in 49 (51%) patients.

GLS improvement

GLS improvement (GLS+), defined by an absolute 2.0%-point increase from baseline, was seen in 35 (36%) patients. Table 3 compares the clinical characteristics of patients with GLS improvement (GLS+) and those without (GLS−). The GLS(+) patients compared to GLS(−) were younger (60 vs. 64 years; P = 0.034), were more frequently women (54% vs. 29%, P = 0.014), and had a lower baseline GLS (−13.5% vs. −16.1%; P = 0.003). There was no difference in the BU stage between the two groups. The dFLC at 1 year was lower in the GLS(+) group compared to the GLS(−) group (1.10 mg/dL vs. 1.79 mg/dL; P = 0.081), and the CR rate was close to 50% in the GLS(+) group compared to 34% in the GLS(−) group. However, these differences did not reach statistical significance. A cardiac response, or BNP(+), was significantly higher in the GLS(+) than the GLS(−) group. We further evaluated the patients based upon a combination of BNP response and GLS improvement (Table 4). Twenty-nine (30%) patients had both GLS improvement and BNP response (GLS+/BNP+), and 42 (43%) patients had no GLS improvement or BNP response (GLS−/BNP−). Patients with both BNP response and GLS improvement (GLS+/BNP+) had a lower dFLC at 1 year (1.01 mg/dL) compared to patients with GLS+ or BNP+ response (1.51 mg/dL) or no GLS improvement and BNP response (GLS−/BNP−) (2.50 mg/dL; P = 0.045).

Table 3.

Comparison of clinical characteristics of patients based upon GLS improvement

Parameter	GLS+ N = 35	GLS− N = 62	P-value
Age (years)	60 (55, 65)	64 (59, 69)	0.034
Female	19 (54)	18 (29)	0.014
BU
Stage II	24 (69)	36 (58)	0.324
Stage IIIA	7 (20)	21 (34)
Stage IIIB	4 (11)	5 (8)
dFLC (mg/dL) baseline	12.84 (2.71, 52.06)	20.89 (9.26, 44.86)	0.194
Baseline GLS (%)	13.5 (11.4, 16.4)	16.1 (13.3, 18.5)	0.003
Baseline LVEF (%)	66.0 (61.1, 69.6)	64.3 (58.3, 71.0)	0.677
Baseline troponin (ng/mL)	0.05 (0.05, 0.13)	0.05 (0.05, 0.16)	0.856
Baseline BNP (pg/mL)	336 (219, 611)	257 (162, 467)	0.122
Autologous SCT	20 (57)	26 (42)	0.15
dFLC (mg/dL) 1 year	1.10 (0.31, 1.98)	1.79 (0.62, 5.66)	0.081
Complete response	17 (49)	21 (34)	0.154
Deep response	15 (43)	24 (39)	0.689
BNP response	29 (83%)	20 (32%)	<0.001

Values are n (%) or median (interquartile range).

GLS+, GLS improvement defined by a 2%-point increase; GLS−, no GLS improvement defined by <2%-point increase; BU, Boston University; dFLC, difference between involved and uninvolved light chains; LVEF, left ventricular ejection fraction; BNP, brain natriuretic peptide.

Table 4.

Comparison of clinical characteristics of patients based upon GLS and BNP response

Parameter	GLS+/BNP+; N = 29	GLS+ or BNP+; N = 26	GLS− and BNP− N = 42	P-value
Age (years)	60 (55, 65)	61.5 (58, 69)	64 (59, 69)	0.192
Female	14 (48)	11 (42)	12 (29)	0.214
BU
Stage II	21 (72)	13 (50)	26 (62)	0.265
Stage IIIA	5 (17)	9 (35)	14 (33)
Stage IIIB	3 (10)	4 (15)	2 (5)
dFLC (mg/dL) baseline	12.84 (2.71, 52.06)	19.36 (6.37, 43.25)	20.25 (10.28, 56.50)	0.472
dFLC (mg/dL) 1 year	1.01 (0.31, 1.75)	1.51 (0.62, 3.64)	2.50 (0.75, 5.83)	0.045
Complete response	14 (48)	11 (42)	13 (31)	0.325
Deep response	14 (48)	10 (38)	15 (36)	0.602
Baseline GLS (%)	14.2 (11.4, 16.4)	14.6 (11.9, 17.9)	16.4 (13.9, 19.0)	0.010
Baseline LVEF (%)	66.2 (61.1, 69.0)	62.5 (57.0, 70.0)	64.8 (60.0, 71.0)	0.511
Baseline troponin (ng/mL)	0.05 (0.05, 0.11)	0.09 (0.05, 0.14)	0.05 (0.05, 0.16)	0.675
Baseline BNP (pg/mL)	336 (219, 562)	323 (194, 498)	212 (148, 431)	0.066

Values are n (%) or median (interquartile range).

GLS+, GLS improvement defined by a 2%-point increase; GLS−, no GLS improvement defined by <2%-point increase; BNP+, cardiac response defined by a 30% reduction from pre-treatment; BNP−, no cardiac response or <30% reduction from pre-treatment; BU, Boston University; dFLC, difference between involved and uninvolved light chains; LVEF, left ventricular ejection fraction; BNP, brain natriuretic peptide.

Survival analysis

The median follow-up time after the baseline echocardiogram was 64.7 months (IQR: 37.1–91.8). Among survivors with AL amyloidosis at one year following treatment, the median overall survival (OS) was 113.4 months, with no significant difference between patients with baseline BU stage II and III (a, b combined) disease (OS 105.3 months and 114.6 months, respectively P = 0.7). Median OS was greater in patients who achieved complete response (CR) or deep response (DR) compared to those who did not achieve CR or DR (120.2 vs. 90.2 months, respectively; P = 0.02) (Figure 1). The median OS was also greater in the GLS−positive (GLS [+]) group compared to the GLS-negative (GLS [−]) group (not reached for GLS [+] vs. 91.8 months for GLS [−]; P = 0.02) (Graphical Abstract). Similarly, the median OS was greater in the BNP-positive (BNP [+]) group compared to the BNP-negative (BNP [−]) group (not reached for BNP [+] vs. 90.2 months for BNP [−]; P = 0.006) (Figure 2). The hazard ratio (HR) for OS was 0.42 [95% confidence interval (CI): 0.20–0.89] in the GLS [+] group and 0.46 (95% CI: 0.23–0.91) in the BNP [+] group after adjusting for DR. Adjusting for age had no effect on any of the models. Patients with either GLS [+] or BNP [+] (HR = 0.25; 95% CI: 0.09–0.73; P = 0.011) or both GLS [+] and BNP [+] (HR = 0.42; 95% CI: 0.19–0.89; P = 0.024) had significantly improved survival compared to those without GLS improvement or BNP response (Table 5). From the likelihood-ratio test, Model 4, which included both BNP and GLS, demonstrated significantly better goodness-of-fit compared to Model 3 with BNP only (P = 0.016) and Model 1 with DR only (P = 0.020), supporting the incremental value of GLS in predicting survival.

Figure 1.

Kaplan–Meier survival curves based on haematologic response at 1 year following treatment. dFLC, difference between involved and uninvolved light chains. Patients who achieved deep response showed improved survival than patients who did not (median overall survival 120.2 vs. 90.2 months, respectively, P = 0.02). Product-limit survival estimates with number of subjects at risk and 95% confidence limits.

Figure 2.

Kaplan–Meier survival curves based on BNP response at one year following treatment. Patients with a positive BNP response showed significantly better survival than patients with a negative BNP response (median overall survival 90.2 months for BNP(−) and not reached for BNP(+), P = 0.006), Product-limit survival estimates with number of subjects at risk and 95% confidence limits. BNP, B-type natriuretic peptide.

Table 5.

Multivariable Cox proportional hazards models of survival with haematologic response and cardiac response as dependent covariates

	Model 1 Hazard ratio 95% CI	P-value	Model 2 Hazard ratio 95% CI	P-value	Model 3 Hazard ratio 95% CI	P-value	Model 4 Hazard ratio 95% CI	P-value
Deep response	0.44 (0.22, 0.89)	0.022	0.46 (0.23, 0.92)	0.028	0.52 (0.26, 1.06)	0.071	0.50 (0.25, 1.02)	0.055
GLS+/−			0.42 (0.20, 0.89)	0.024
BNP+/−					0.46 (0.23, 0.91)	0.025
GLS and BNP
−/−							Ref	0.011
−/+ or +/−							0.25 (0.09, 0.73)	0.024
+/+							0.42 (0.19, 0.89)

With overall survival as the outcome, Model 1 included deep response as the dependent covariate, Model 2 included deep response and GLS improvement as the dependent covariates, Model 3 included deep response and BNP improvement as the dependent covariates, and Model 4 included deep response and integrated GLS and BNP improvement (GLS+ and BNP+ vs. GLS+ or BNP+ vs. GLS− and BNP−) as the dependent covariates.

CI, confidence interval; GLS+, GLS improvement defined by a 2%-point increase; GLS−, no GLS improvement defined by <2%-point increase; BNP+, cardiac response defined by a 30% reduction from pre-treatment; BNP−, no cardiac response or <30% reduction from pre-treatment.

Discussion

In this single-centre retrospective cohort analysis of patients with AL amyloidosis and cardiac stage II, IIIA, and IIIB disease, GLS improvement at 1 year following plasma cell-directed therapy was shown to be a strong predictor of survival. Among survivors at 1-year post-treatment, GLS improvement was observed in 36% of patients, occurring across all three cardiac stages. This improvement was associated with a 60% reduction in the risk of death, independent of haematologic response and age.

Global longitudinal strain (GLS) is a measure of the longitudinal contraction of cardiac motion. It serves as a marker for subendocardial function and can detect subclinical dysfunction at an early stage, as longitudinally oriented fibres, primarily located in the subendocardium, are highly sensitive and vulnerable to myocardial disease.^10,12 GLS has been shown to be superior to LVEF and wall motion score in predicting all-cause mortality among patients undergoing an echocardiogram for suspected or known left ventricular (LV) impairment in the general population, as well as in specific cardiovascular conditions.^13,14 The role of GLS as a strong and independent prognostic marker in patients with newly diagnosed AL amyloidosis has been well established.^5,15 The findings of this study further expand the role of GLS by demonstrating the strong prognostic value of GLS improvement following treatment. Cohen et al.⁶ reported GLS improvement at 12 months following plasma cell-directed therapy in 32% of patients with cardiac involvement who achieved CR, which provided incremental prognostic value beyond the BNP response. In the current study, GLS improvement was observed in 36% of the patients, and it was more common in patients with greater haematologic response. The GLS(+) group had a lower dFLC at 1 year than the GLS(−) group, which is consistent with the prevailing notion that improvement in organ function is correlated with the quality of haematologic response. However, among patients with GLS+, no significant difference was observed between those who achieved CR and those who did not. These results suggest that lowering serum FLC, even without reaching the defined threshold of complete remission, may contribute to improved cardiac function. Supporting this observation, a previous study demonstrated a simultaneous drop in serum FLCs and NT-proBNP after three cycles of chemotherapy.¹⁶ There is evidence suggesting that soluble pre-fibrillar amyloidogenic light chains themselves exert direct cytotoxic effects on cardiomyocytes, and the ultimate cardiac damage may result from the combination of amyloid burden and/or direct toxicity caused by the light chains.^17,18 In addition, there is likely heterogeneity in the proteotoxicity of amyloidogenic light chains, which may contribute to the variability in the association between light chain levels and the degree of cardiac dysfunction observed among AL amyloidosis patients.^16,19 Thus, it is conceivable that reducing circulating light chains could lead to GLS improvement, even in cases where the haematologic response is less than complete remission.

Another remarkable finding of the study is the impressive observed survival rate among patients who made it to 1 year, especially those who showed GLS improvement or BNP response, with a respective reduction in the risk of death by 58% and 54%. While this study was unable to demonstrate an additional prognostic benefit of GLS improvement when combined with BNP response due to the small sample size of patients exhibiting both BNP and GLS improvement, Cohen et al.⁶ demonstrated an incremental value when GLS was combined with NT pro BNP. Given the association of GLS improvement with improved survival, further investigation is needed to determine whether GLS improvement could guide the intensity and duration of plasma cell-directed therapy, particularly for patients at risk of treatment-related toxicity.

It is interesting to note that among patients who reached 1 year on treatment, baseline biomarker-based staging no longer predicted their survival. While there were only nine patients with cardiac stage IIIb disease, GLS improvement was noted across all three stages suggesting that recovery of cardiac function is possible even among patients with advanced disease. The baseline GLS was lower in the GLS(+) group compared to the GLS(−) group. This difference in baseline GLS may be attributed to the fact that patients with low GLS succumbed to their condition before the 12-month assessment, while only those who showed improvement in GLS survived to the 1-year follow-up. Another possible explanation for this finding is that patients with normal or near-normal GLS at baseline had little room for improvement. As a result, when comparing those who improved vs. those who did not, they may not appear to have improved. Since the same criteria were applied to individuals with normal baseline values, the effect size on mortality for GLS(+) vs. GLS(−) may, in fact, be underestimated, as some of these baseline-normal individuals would be classified as GLS(−).

The findings of this study support and expand upon the current data regarding the role of GLS improvement as a prognostically significant marker following plasma-directed therapy.^6,20 This study is distinct from prior publications in that the assessment of GLS improvement included all patients with a prognostically significant increase in circulating cardiac biomarker levels, as determined by the conventional staging system commonly used for risk stratification. Furthermore, the utilization of a BNP-based staging system in this study enhanced its overall applicability, considering that some centres do not provide NT-proBNP testing.

Study limitations

The study is limited by its single centre and retrospective design, with missing data points at 1 year due to patients lost to follow-up. However, the baseline characteristics of those lost to follow-up were similar to those included in the study. Patients who died before reaching 1 year following treatment were excluded, given that the focus of the paper is examining the significance of the GLS at one year.

Given the lack of GLS standardization and the inter-vendor variability in strain measurements, the cut-off value used in the present study to define GLS improvement may not be applicable when using a different vendor system. However, TomTec is platform-neutral software used by many centres, which reduces variation resulting from different vendor platforms. Similar to the study by Cohen et al.,⁶ our study also utilized a 2.0% change in GLS as a meaningful cut-off, which was also found to be prognostic, despite variations in GLS measurement techniques and software used. This study was unable to assess the effects of the treatment regimen on the study outcome, as there was a higher usage of SCT compared to other studies and the lack of specific data, such as dosage, on the regimens patients received. Additionally, this study was conducted prior to the advent of more recent, effective therapies, such as daratumumab-based treatment. It is conceivable that the predictive value of GLS on outcomes observed in this study may differ in the era of contemporaneous treatment. Further evaluation of determinants of GLS improvement and validation of the correlation between GLS improvement and clinical outcomes in large cohorts of patients treated with contemporary therapy would be warranted.

Conclusions

In summary, GLS improvement following plasma cell-directed therapy among patients with AL amyloidosis conferred a significant survival benefit, even in those with advanced disease, supporting its role as an important prognostic marker. GLS improvement was more likely to occur in patients with lower dFLC levels after treatment; however, further investigation is needed to define other determinants of GLS improvement. These findings suggest that GLS improvement may serve as an important marker for risk stratification and possibly treatment decision-making in AL amyloidosis patients undergoing therapy. Further investigation through a large multicentre trial is warranted.

Lead author biography

Jennifer Liu is the Chief of Cardiology at the Memorial Sloan Kettering Cancer Center and a Professor of Medicine at Weill Cornell Medical College. She is a recognized Cardio-Oncology specialist with expertise in advanced echocardiographic imaging. Her clinical and research endeavours focus on the role of advanced imaging in diagnosing and managing cancer therapy-related cardiac dysfunction and systemic amyloidosis with cardiac involvement. She has led several expert consensus documents that establish practice standards for the use of echocardiography in cardiotoxicity monitoring. She has served on the ACC Cardio-Oncology Leadership Council and the editorial board of JACC: CardioOncology. Currently, she is a member of the Board of Directors of the American Society of Echocardiography.

Data availability

The datasets generated and/or analysed during this study are available from the corresponding author upon reasonable request.

Supplementary material

Supplementary material is available at European Heart Journal Open online.

Funding

National Cancer Institute Cancer Center Support Grant P30CA008748 (A.F.Y., H.L., C.L.C., J.E.L.).