Andrew Staron

IntroductionIgD-associated AL amyloidosis is a rare subtype, accounting for 1–2% of cases, with fewer than 100 reported. Prior studies show inconsistent findings on organ involvement, progression, and survival, underscoring the need for real-world data.MethodsWe performed a retrospective review of patients with IgD-associated AL amyloidosis at a tertiary referral center.ResultsTen patients (0.6% of systemic AL cases) were identified. All evaluable patients had lambda light chain predominance; nine had detectable IgD lambda monoclonal protein. Cardiac involvement occurred in six patients and renal involvement in four; two had both. Most received upfront combination therapy, including autologous stem cell transplantation. Hematologic responses were favorable, though organ responses were less frequent. Median overall survival was 9.7 years.DiscussionIgD-associated AL amyloidosis is rare but clinically significant, with organ involvement patterns similar to other AL subtypes. Despite frequent deep hematologic responses, organ responses remain limited, particularly in advanced disease. Diagnosis is challenging and requires a high index of suspicion. Long-term survival is achievable, with mortality primarily driven by amyloidosis-related complications.

Survival in AL amyloidosis is strongly influenced by the severity of cardiac involvement. The recently proposed AL International Staging System (AL-ISS) incorporates echocardiographic global longitudinal strain (GLS) to subdivide biomarker-defined stage IIIb disease into stages IIIb and IIIc; however, its prognostic relevance in the daratumumab era remains uncertain. We evaluated the AL-ISS GLS cutoff of 9% in 53 patients with newly diagnosed stage IIIb AL amyloidosis. Patients classified as proposed stage IIIc (GLS 0-9%) had higher baseline difference between involved and uninvolved free light chains (dFLC; 300 vs 167 mg/L; p=0.08), similar left ventricular wall thickness (14.5 vs 15.0 mm; p=0.57), and lower left ventricular ejection fraction (LVEF; 45% vs 55%; p=0.02) compared with those with GLS >9%. GLS correlated moderately with LVEF (ρ=0.47; p<0.001). On multivariable analysis, LVEF <50% (HR 3.18; p=0.006) and dFLC ≥180 mg/L (HR 3.26; p=0.003) independently predicted overall survival, whereas GLS did not. Median overall survival was longer in proposed stage IIIc disease (31 vs 13 months), reflecting greater use of daratumumab-based therapy (82% vs 25%). Among daratumumab-treated patients, survival did not differ by GLS category. These findings suggest limitations of GLS-based sub-staging in advanced cardiac AL amyloidosis in the daratumumab era.

Congo red (CR) staining of surrogate tissues, such as the abdominal fat pad (FP) or bone marrow (BM), provides a minimally invasive approach to diagnosing systemic amyloidosis. This study evaluated the diagnostic yield of surrogate tissue biopsies across amyloidosis classes. We retrospectively analyzed 4,027 patients with systemic amyloidosis (1968-2023) who underwent CR staining of FP aspirates (n = 3,873) and/or BM core biopsies (n = 2,598). Detection rates were compared by amyloidosis class and biopsy site. AL amyloidosis had the highest CR positivity rates (FP: 73%; BM: 53%), whereas ATTRwt amyloidosis had the lowest (FP: 22%; BM: 26%). CR positivity in BM was not exclusive to AL amyloidosis; 74 CR-positive BM biopsies were in non-AL cases. Among 2,213 patients with AL amyloidosis who underwent both FP and BM sampling, combined testing increased detection to 85% (40% positive in both; 32% FP-only; 13% BM-only). Higher CR positivity grades in FP aspirates correlated with shorter survival in AL amyloidosis but not in other amyloidosis classes. The diagnostic yield of CR-stained surrogate tissue biopsies varies by amyloidosis class and biopsy site. In AL amyloidosis, combining FP and BM sampling enhances detection, and FP CR positivity grade offers prognostic insight.

Cardiac dysfunction in AL amyloidosis is thought to be partly related to the direct impact of AL LCs on cardiomyocyte function, with the degree of dysfunction at diagnosis as a major determinant of clinical outcomes. Nonetheless, mechanisms underlying LC-induced myocardial toxicity remain unclear. We identified gene expression changes correlating with human cardiac cell exposure to cardiomyopathy-associated AL LCs. We then confirmed these findings in a clinical dataset focusing on clinical parameters associated with pathways dysregulated at the gene expression level. Upon exposure to cardiomyopathy-associated AL LCs, cardiac cells exhibited gene expression changes related to myocardial contractile function and inflammation, leading us to hypothesise that there could be clinically detectable changes in global longitudinal strain (GLS) on echocardiogram and serum inflammatory markers in patients. Thus, we identified 29 patients with normal interventricular septum diameter (IVSd) but abnormal cardiac biomarkers, suggestive of LC-induced cardiac dysfunction. These patients display early cardiac biomarker staging, abnormal GLS, and significantly reduced serum inflammatory markers compared to patients with clinically evident amyloid fibril deposition. Collectively, our findings highlight early molecular and functional signatures of cardiac AL amyloidosis, with potential impact for developing improved patient biomarkers and novel therapeutics.