Role of Daratumumab in Cardiac AL Amyloidosis

Corresponding Author

Immunoglobulin light chain amyloidosis (AL) is the disease that results when clonal plasma cells in the bone marrow produce light chains that misfold, rendering them insoluble, leading to deposition in tissues, leading to organ dysfunction and death. The myocardium is involved clinically in 70% of newly diagnosed patients. Cardiac AL amyloidosis represents a classic form of heart failure with preserved ejection fraction, but the diagnosis is often delayed due to its nonspecific presentation. The most common symptoms are fatigue, weakness, dyspnea, and lower extremity fluid retention.¹ In a community-based survey of patients, 49% visited 4 or more physicians before the diagnosis was established. Symptoms were present for >1 year in 37%. The diagnosis was established by a cardiologist in 19%.² Echocardiographic features show thickening of the septum and left ventricular free wall, which can easily be misinterpreted as hypertrophy secondary to hypertension or valvular disease or hypertrophic cardiomyopathy.

Morbidity and mortality in AL amyloidosis are driven by progressive restrictive cardiomyopathy and heart failure, with a median overall survival of 3.5 years and 30% to 40% mortality within 1 year of diagnosis. The diagnosis of AL amyloidosis always requires biopsy verification. Once amyloid deposits are recognized, accurate typing is required to avoid confusion with the more common transthyretin (TTR) cardiac amyloidosis.³

Amyloidosis is staged by measuring the N-terminal pro–B-type natriuretic peptide (NT-proBNP) and assigning 1 point for a level >332 ng/L and 1 point for cardiac troponin T >0.035 ng/mL. The median overall survival rates for patients with 0 points, 1 point, or 2 points, corresponding to stage I, II, and III, are 57% alive at 10 years, 67 months, and 15 months, respectively, if the NT-proBNP was also <8,500 pg/mL (NYHA functional class IIIA). The outcome for amyloidosis patients could be markedly improved if the knowledge gap leading to delayed diagnosis could be overcome.⁴

The ANDROMEDA study (A Randomized Phase 3 Study to Evaluate the Efficacy and Safety of Daratumumab in Combination With Cyclophosphamide, Bortezomib and Dexamethasone [CyBorD] Compared to CyBorD Alone in Newly Diagnosed Systemic AL Amyloidosis) randomized patients with biopsy-proven AL amyloidosis, all of whom received chemotherapy designed to destroy the amyloid-producing plasma cells. The control arm received bortezomib, cyclophosphamide, and dexamethasone, a standard chemotherapy regimen for AL amyloidosis. The treatment arm added daratumumab, a monoclonal antibody directed against the CD38 antigen found on all plasma cells, the source of the light chain in AL amyloidosis. Daratumumab was given weekly for 8 weeks, biweekly for an additional 16 weeks, and maintenance every 4 weeks for an additional 18 months, totaling 96 weeks of therapy. Patients with NT-proBNP levels >8,500 ng/L or New York Heart Association functional class IIIB and class IV were excluded from participation. The primary endpoint was complete hematologic response, which is defined as normalization of the involved free light chain and free light chain ratio. The presumption is that elimination of circulating amyloidogenic light chains from the serum will prevent any further deposition of amyloid, and this might allow for improvement in organ function. This trial met its primary endpoint of hematologic complete response, which was achieved in 59% in the daratumumab arm compared with 19% in the control arm. Hematologic response is only a surrogate for the desired outcome, which is an improvement in organ function. In cardiac amyloidosis, this is defined as a 30% reduction in the NT-proBNP levels with a magnitude of reduction of at least 300 ng/L. At 12 months, the cardiac response rate was 57% in the daratumumab arm compared with 28% in the control arm.⁵ The results of this trial lead to daratumumab becoming the first Food and Drug Administration–approved agent for the management of AL amyloidosis.

In this issue of JACC: CardioOncology, Minnema et al⁶ in an unplanned post hoc analysis compared the rates of complete hematologic response and cardiac response at 6 months, as well as median organ progression-free survival across cardiac stages I, II, and III (NT-proBNP >8,500 ng/L ineligible). The key findings of the study are that hematologic and organ response rates were higher and major organ progression-free survival rates were longer with the daratumumab-containing regimen across all cardiac stages. There was no difference between arms in mortality within the first 6 months of initiating therapy. This likely reflects the inability of even highly effective chemotherapy to achieve rapid reversal of severe cardiac dysfunction and emphasizes the need for earlier diagnosis. It also suggests that it is important, however, for all patients to receive a trial of daratumumab-containing chemotherapy, given the hematologic response rates ranging from 51.1 (stage I) to 61.1% (stage IIIA) and the cardiac response rates of 50.9 and 33.3% in cardiac stage II and IIIA, respectively. These rates are significantly higher than non–daratumumab-based chemotherapy (29.6% and 15.9% cardiac response, respectively).

What are the unmet needs in AL amyloidosis currently? It remains unclear what benefits daratumumab-containing chemotherapy regimens have for patients with NT-proBNP levels >8,500 ng/L at diagnosis. This will need to be the subject of future trials. The second unmet need is the lack of an amyloid-specific imaging agent. Ideally agents currently under investigation could be useful when a cardiologist suspects the presence of cardiac amyloidosis, but echocardiographic and magnetic resonance imaging findings are equivocal.⁷ It also could be used to monitor for organ response and progression. Finally, all currently available treatments short of cardiac transplantation focus on the clonal plasma cell production of the amyloidogenic light chain. There are currently no agents approved that can dissolve tissue amyloid deposits in situ. There are currently 2 phase 3 trials accruing actively in advanced cardiac amyloidosis that are randomizing patients to anti–plasma cell chemotherapy with or without antibodies that are capable of dissolving amyloid deposits in vitro.^8,9 This would offer the potential to benefit patients who present with advanced organ deposition. The future for patients with cardiac AL amyloidosis is bright, and the diagnosis should be kept in mind for all patients seen with heart failure and preserved ejection fraction, unexplained interventricular septal thickening or cardiomyopathy associated with proteinuria, or peripheral neuropathy.

Funding Support and Author Disclosures

Dr Gertz has received personal fees from Ionis/Akcea, Prothena, Sanofi, Janssen, Aptitude Healthgrants, Research to Practice, Physicians Education Resource, Johnson & Johnson, Celgene, and Ashfield; honorarium from Alnylam; personal fees for meetings from Juno and Sorrento; data safety monitoring board fees from AbbVie; fees from i3Health for development of educational materials.