Outcomes by Cardiac Stage in Patients With Newly Diagnosed AL Amyloidosis

Background Patients with amyloid light chain amyloidosis and severe cardiac dysfunction have a poor prognosis. Treatment options that induce rapid and deep hematologic and organ responses, irrespective of cardiac involvement, are needed. Objectives The aim of this study was to evaluate the impact of baseline cardiac stage on efficacy and safety outcomes in the phase 3 ANDROMEDA trial. Methods Rates of overall complete hematologic response and cardiac and renal response at 6 months and median major organ deterioration–progression-free survival and major organ deterioration–event-free survival were compared across cardiac stages (I, II, or IIIA) and treatments (daratumumab, bortezomib, cyclophosphamide, and dexamethasone [D-VCd] or bortezomib, cyclophosphamide, and dexamethasone [VCd]). Rates of adverse events (AEs) were summarized for patients with and without baseline cardiac involvement and by cardiac stage. Results Median follow-up duration was 15.7 months. The proportions of stage I, II, and IIIA patients were 23.2%, 40.2%, and 36.6%. Across cardiac stages, hematologic and organ response rates were higher and major organ deterioration–progression-free survival and major organ deterioration–event-free survival were longer with D-VCd than VCd. AE rates were similar between treatments and by cardiac stage; serious AE rates were higher in patients with cardiac involvement and increased with increasing cardiac stage. The incidence of cardiac events was numerically greater with D-VCd vs VCd, but the rate of grade 3 or 4 events was similar. The exposure-adjusted incidence rate for cardiac events was lower with D-VCd than VCd (median exposure 13.4 and 5.3 months, respectively). Conclusions These findings demonstrate the efficacy of D-VCd over VCd in patients with newly diagnosed amyloid light chain amyloidosis across cardiac stages, thus supporting its use in patients with cardiac involvement. (NCT03201965)

S ystemic amyloid light chain (AL) amyloidosis is a rare clonal plasma cell disease associated with amyloid deposition within vital organs (particularly the heart and kidneys), leading to progressive organ dysfunction and death. 1 Cardiac involvement in AL amyloidosis manifests as a restrictive cardiomyopathy resulting in congestive heart failure and arrhythmias. The extent of cardiac involvement at baseline is the most important predictor of clinical outcomes, [2][3][4][5][6][7][8] with median survival of <1 year in untreated patients with severe cardiac involvement vs about 8 years in those without. 5,9 Approximately one-third of early deaths (ie, within 90 days of diagnosis) among patients with AL amyloidosis are attributed to cardiac involvement. 10 Mayo Clinic researchers established a staging system for AL amyloidosis on the basis of the prognostic biomarkers serum high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP). 7 Patients are classified in stage I if levels of both hs-cTnT and NT-proBNP are less than their respective thresholds (54 ng/L for hs-cTnT and 332 pg/mL for NT-proBNP), stage II if the level of either biomarker is greater than its threshold, and stage III if levels of both biomarkers are greater than their respective thresholds. 11 Median overall survival for patients in stages I, II, and III was 69, 29, and 6 months, respectively. The European modification of the Mayo staging system further stratified stage III into subgroups: NT-proBNP levels of <8,500 ng/L (stage IIIA) and >8,500 ng/L (stage IIIB). [4][5][6] Stage III patients are considered at high risk and have an especially poor prognosis, with high rates of early death within months of diagnosis. 2,[4][5][6] Until recently, standard treatment for AL amyloidosis included off-label use of modified bortezomib-based regimens approved for the treatment of multiple myeloma, 1,6,12,13 including the combination of bortezomib, cyclophosphamide, and dexamethasone (VCd), which has led to improved outcomes compared with earlier treatment options. 6,14,15 A recent study suggests that patients with severe cardiac involvement at baseline have not experienced the same level of benefit as the overall population of patients with AL amyloidosis, 16 and there is a need for additional treatment options that will improve outcomes in this high-risk group. and more rapid hematologic responses and higher rates of organ responses than those treated with VCd alone. 17 The safety profile was consistent with previous studies of daratumumab and VCd. 17 On the basis of these results, D-VCd became the first treatment for AL amyloidosis to receive regulatory approval. 18 Here, we evaluate the impact of patients' cardiac stage on efficacy and safety outcomes in patients from ANDROMEDA.
METHODS PATIENTS AND DESIGN. The primary report of ANDROMEDA has been published. 17   Values are median (IQR) or n (%). a Includes 8 patients (2 in the D-VCd group, 6 in the VCd group) who were in stage IIIA at screening and converted to stage IIIB at cycle 1, day 1 (results determined by central laboratory were made available only after cycle 1, day 1). b ECOG PS is scored on a scale from 0 to 5, with 0 indicating no symptoms and higher scores indicating increasing disability. c Patients who were comfortable at rest; less than ordinary physical activity resulted in fatigue, palpitation, dyspnea, or anginal pain.
AL ¼ amyloid light chain; CrCl ¼ creatinine clearance; D-VCd ¼ daratumumab, bortezomib, cyclophosphamide, and dexamethasone; dFLC ¼ difference between involved and uninvolved free light chain; ECOG PS ¼ Eastern Cooperative Oncology Group performance status; NYHA ¼ New York Heart Association; VCd ¼ bortezomib, cyclophosphamide, and dexamethasone.   Given the observed difference in treatment duration between the D-VCd and VCd arms (13.4 months vs 5.3 months), we analyzed the exposure-adjusted AE incidence rates and found that the incidence of all reported AEs was lower for D-VCd vs VCd (Table 5). In the intent-to-treat population and in patients who were evaluable for cardiac response, NT-proBNP levels increased during the first treatment cycles, followed by a decline over time, which was more pronounced and occurred earlier with D-VCd vs VCd ( Figure 3). Mean high-sensitivity troponin remained stable during initial treatment; thereafter, it gradually decreased over time in both treatment arms.

DISCUSSION
Earlier studies have explored the use of high-dose melphalan and autologous stem cell transplantation in patients with AL amyloidosis. Although this treatment combination induced good hematologic and organ response in patients, it was associated with a high rate of mortality if patients were not carefully selected and thus was not recommended for high-risk patients, especially those with advanced cardiac involvement. 22 The advent of novel agents has improved long-term outcomes in AL amyloidosis overall, but few studies highlight such benefits in high-risk patients. 16    Values are n (%). Cycles 1 to 6 and cycles 7 and later groups are not mutually exclusive. a Fine and Gray's method was used to assess the cumulative incidence rate of cardiac events (including cardiac failure, atrial fibrillation, and palpitations) by considering death as a competing event for the first cardiac event. b Includes cardiac failure and cardiac failure congestive.
Abbreviations as in Table 1.  a Patient-months at risk is the sum of the exposure times at the occurrence of the first TEAE for each subject. A patient's duration of exposure is given either by the time when the event occurred (noncensored data) or by the total duration of treatment if the patient does not show the AE in question (censored data). b EAIR represents the number of subjects with the event divided by the 100 patient-months at risk for that event. If a patient has multiple occurrences of an event, the patient is counted only once in the numerator.
EAIR ¼ exposure-adjusted incidence rate; TEAE ¼ treatment-emergent adverse event; other abbreviations as in Tables 1 and 3. Severe cardiac involvement at baseline is associated with poor prognosis in patients with AL amyloidosis.
Patients treated with D-VCd experienced better clinical outcomes than those treated with VCd, irrespective of the severity of cardiac involvement, supporting its use in a broad range of patients.
TRANSLATIONAL OUTLOOK: Future research should examine efficacy and safety outcomes of treatment, including D-VCd, among the most highrisk patients (stage IIIB), with special attention to cardiac outcome parameters.