A total of 81 patients were included. The median age of all patients was 56 years and 51% were male. The majority of patients (97.5%) had renal involvement with a median estimated glomerular filtration rate (eGFR) of 78.1 mL/min/1.73 m2 and a median 24-h urinary protein of 3.36g. Cardiac involvement was present in 61 (75.3%) patients, and Mayo stage distribution was 39.5%, 25.9%, 25.9% and 8.6% for stages I, II, III, and IV, respectively. Of the 81 patients included, 42 were treated with CTD and 39 with BDex (Table 1). The median number of cycles received in each group was similar (8.0 for CTD group and 6.0 for BDex group, P = 0.235). Most of the parameters were comparable between the two treatment groups but variables associated with cardiac involvement, N-terminal pro-B-type natriuretic peptide (NT-proBNP), troponin T (TnT), and intraventricular septum (IVS), and clonal depth measured as the difference between involved and uninvolved free light chain (dFLC) were significantly higher in the BDex group (Table 1). All of the above variables are known to be independent prognostic factors of OS. Therefore, we matched patients by Mayo stage 2012, which includes NT-proBNP, TnT, and dFLC.
There were 26 patients in each treatment group in the matched cohort. After matching, there were no significant differences in patients’ characteristics in terms of any clinical or biochemical characteristic, including NT-proBNP, TnT, IVS, dFLC, and the distribution of organ involvement (Table 2). There were also no differences in the median follow-up time (22.5m for the CTD group vs 15.0m for the BDex group, P = 0.210) and the number of cycles received (5.0 vs 7.5 respectively, P = 0.761) between two groups.
Hematologic and organ response
In the ITT analysis, the overall hematologic response (OHR) rates in the CTD and BDex group were 86% vs 91% (P = 0.77), including a complete response (CR) rate in 56% vs 71% (P = 0.19) of the primary cohort (Table 3). Given that rapid clonal control is strongly associated with better OS and preservation of organ function,22 3-month and 6-month hematologic responses were also evaluated among the evaluable patients. There were no differences in OHR between treatment groups at either 3 or 6 months. However, there was a significant improvement in the rate of CR in patients treated with BDex (47% vs 19% at 3 months, P = 0.02; 69% vs 38% at 6 months, P = 0.02).
In the ITT analysis of the matched sub-cohort, the OHR rates was 75% in the CTD group vs 96% in the BDex group (P = 0.13). The rate of CR was 45% and 74%, respectively (P = 0.053) (Table 3). A significantly higher CR rate was observed at 6 months in the BDex group compared to the CTD group (75% vs 27%, P = 0.007), with a trend for a higher CR rate at 3 months (44% vs 16%, P = 0.053). The median time to initial response was 2.0 months in both treatment groups (P = 0.209) and median time to best response was 8.0 in the CTD group vs 2.25 months in the BDex group (P = 0.014).
During the follow-up period, a total of 4 (4.9%) patients progressed to dialysis (3 in the CTD group and 1 in the BDex group), although two of them achieved a hematologic CR. Renal and cardiac responses were recorded in 63% and 40% of patients treated with CTD, whereas for BDex-treated patients the response rates were 72% and 46%, respectively (P > 0.05 for all comparisons). Results in matched sub-cohort showed an advantageous tendency toward preserving renal function in the BDex group (68% vs 44% in the CTD group, P = 0.09), with similar cardiac response rates in both groups (27% vs 50% for CTD and BDex, respectively, P = 0.43).
Survival
The median follow-up time in the whole cohort was 25.8 months for the CTD group and 11.0 months for the BDex group. Among the 81 patients, twelve patients died (8 in the CTD group and 4 in the BDex group) during the follow-up period, of whom ten were Mayo stage III or worse at diagnosis. Median OS was not reached in either group and there was no significant difference in OS (P = 0.763, Figure 1A). One- and two-year OS was 90.2%, 81.7%, respectively in patients who received the CTD regimen, vs 87.6% and 82.7% in patients who received the BDex regimen. In the 6-month landmark analysis that excluded patients whose follow-up time were less than 6 months, there were 37 patients in the CTD group and 27 in the BDex group and no significant differences in OS were observed (P = 0.780, Figure 1B). For the matched cohort, median OS was not reached in either group based on the ITT analysis or the 6-month landmark analysis, and no correlation between longer survival and treatment was observed (P = 0.238 for ITT analysis and P = 0.476 for 6-month landmark analysis, Figure 2A and 2B).
In the ITT analysis we next tested the effect of treatment regimen on patients with Mayo stage ≤ II or > II to find out if the two regimens had different effects in treating patients with different risk levels. The results indicated that subjects with advanced (Mayo stage > II) AL amyloidosis who received BDex survived significantly longer than those who received CTD (median survival not reached vs. 11.5 months, P = 0.009, Figure 3, c vs d). While OS was similar following BDex or CTD in patients with Mayo stage ≤ II (P = 0.318, Figure 3, a vs b), although the small sample size limits interpretation.
Univariate and multivariate analyses with Cox regression were used to predict factors closely associated with survival. The variables predicting OS by univariate analysis in the whole cohort were alkaline phosphatase (ALP) level, eGFR, Mayo stage 2012, IVS, and dialysis. After adjustment for these factors in the multivariate analysis, the BDex regimen showed a protective effect on survival (hazard ratio [HR] = 0.19, 95% CI, 0.05-0.67; P = 0.01) compared to CTD regimen in treating AL amyloidosis (Table 4). In addition, Mayo stage III (HR = 25.6, 95% CI, 2.7-241.9; P = 0.05) and Mayo stage IV (HR = 23.3, 95% CI, 1.1-498.8; P = 0.044) were independently associated with poor OS (Table 4).
Toxicity
Overall, 76.9% of patients treated with BDex and 64.3% of patients treated with CTD reported at least one adverse event during the study (P = 0.213) (Table 5). There were more reports of any and grade ≥ 3 hematologic symptoms (anemia, thrombocytopenia or neutropenia) in patients treated with BDex than in those treated with CTD. Among non-hematologic toxicities, reports of diarrhea and herpes zoster were more common in the BDex than the CTD group (30.8% vs 2.4%, respectively for diarrhea and 23.1% vs 4.8% for herpes zoster). In the CTD group, fluid retention (16.7%) and fatigue (14.3%) were the most common non-hematologic toxicities. Few patients reported peripheral neuropathy (12.8% in the BDex group and 9.5% in the CTD group) and no grade ≥3 peripheral neuropathy was observed.
Grade ≥ 3 adverse events were reported significantly more frequently by patients in the BDex group than the CTD group (33.3% vs 14.3%, P = 0.043) (Table 5). Diarrhea (10.3%) and hematologic toxicities were the most commonly reported toxicities of grade ≥3 severity in the BDex group, and an acute kidney injury event occurred in one patient due to severe diarrhea. In the CTD group, one patient reported severe gastrointestinal bleeding that required admission to hospital for blood transfusion.