IgD-related AL amyloidosis: Clinical features and outcomes Free

Background: Immunoglobulin D (IgD)-related AL amyloidosis is a rare subtype, representing approximately 1% of AL amyloidosis cases, with fewer than 100 cases described in the literature to date. Prior case series from the Mayo Clinic (N=53) and UK National Amyloidosis Centre (N=20) had conflicting findings regarding organ involvement and prognosis: the former reported lower incidence of cardiac and renal involvement but similar overall survival compared to other AL subtypes, whereas the latter observed higher cardiac and renal involvement, along with greater risk of progression to symptomatic myeloma. As such, the clinical features and outcomes of IgD-related amyloidosis remain poorly defined.

Methods: We conducted a retrospective review of all patients diagnosed with IgD-related AL amyloidosis between 2000 and 2024 at the Boston University Amyloidosis Center. Data on presenting symptoms, organ involvement, biomarker levels, treatments and outcomes were collected. Hematologic and organ responses were assessed according to the International Society of Amyloidosis consensus criteria.

Results: Among 1,798 patients with AL amyloidosis, 11 (0.6%) patients had an IgD monoclonal protein. The median age at diagnosis was 58.3 years (range 17.4–75.7); 64% were male and 91% were White. Common presenting symptoms included lower extremity edema (55%), dyspnea on exertion (55%), fatigue (45%), and skin discoloration (45%). Cardiac involvement was present in 7 (64%) patients and renal involvement in 4 (36%) patients; 2 patients had both. All cases with cardiac involvement showed diastolic dysfunction, with a median septal thickness of 14 mm, troponin level of 0.118 ng/mL (range 0.030–0.549), and NT-proBNP level of 230 pg/mL (range 58–1649). Cases with renal involvement had a median serum creatinine of 1.18 mg/dL (range 0.83–2.11) and 24-hour urine total protein excretion of 5.13 g (range 0.26–9.99).

All cases demonstrated lambda light chain predominance, with a median serum free lambda level of 146.1 mg/L (range, 64.5–745). IgD levels were measured in two patients, with an average of 741.5 mg/L (normal <179). IgD lambda monoclonal protein was identified by serum immunofixation electrophoresis in all but one patient; in that case, IgD expression was confirmed by immunohistochemistry on the tissue biopsy. Urine immunofixation detected lambda monoclonal protein in eight patients. Bone marrow biopsies showed a median of 7% lambda-restricted plasma cells (range, 5–30). FISH cytogenetic analysis was normal in the three patients tested.

Nine patients received treatment, with three requiring more than one line of therapy (up to a maximum of three). Two patients died before therapy could be initiated. Most were treated with upfront combination regimens that included an alkylating agent, with or without an immunomodulatory agent, anti-CD38 monoclonal antibody, proteasome inhibitor, or autologous stem cell transplantation. Hematologic response to first-line therapy was high, with 86% achieving a very good partial response or better. However, organ-specific responses were less frequent: 29% achieved a cardiac response and 50% a renal response of very good partial response or better. During follow-up, seven patients (64%) died, with six deaths attributed to amyloidosis-related complications. The median overall survival was 9.7 years. Over the course of disease, four patients developed clinical heart failure, and one progressed to end-stage renal disease requiring dialysis.

Conclusions: IgD-related AL amyloidosis frequently involves the heart and kidneys, often resulting in complications such as heart failure or renal dysfunction. In our cohort, hematologic responses to therapy were robust; however, organ responses were less common. Despite a median overall survival approaching a decade, most deaths were due to disease-related complications. These findings align with and extend prior case series, indicating that IgD-related amyloidosis shares clinical features and outcomes similar to other AL amyloidosis subtypes.