Abstract
Mayo 2004 stage IIIB primary light chain amyloidosis (AL) patients exhibit poor outcomes and were excluded from most clinical trials. To investigate the efficacy and safety of daratumumab in combination with bortezomib and dexamethasone (Dara-VD) for newly diagnosed Mayo 2004 stages IIIA and IIIB patients, we conducted a phase 2 trial and had reported the 24-month median follow-up results (NCT04474938, Shen et al. Haematologica, 2024). We now present the long-term outcome data after a median 46-month follow-up and highlight the favorable outcomes of stage IIIB patients.
A detailed study protocol had been published previously. We enrolled newly diagnosed, Mayo 2004 stage IIIA and IIIB AL patients. Dara-VD regimen was given as previously reported. The hematologic and organ responses were evaluated as per current validated criteria. Stringent free light chain (FLC) response was defined as a reduction of dFLC to <10mg/L or involved FLC ≤20mg/L. Minimal residual disease (MRD) was measured at the end of treatment. The primary endpoint was CR and VGPR at 3 months after treatment initiation. Patients who died and did not have a post-baseline assessment were categorized as the no-response group.
Twenty (50.0%) Mayo stage IIIA and 20 (50.0%) stage IIIB patients were enrolled from May 2021 to March 2022. Twelve patients discontinued treatment due to cardiac events, and 1 patient discontinued due to adverse events. The 24-month hematologic CR and VGPR rate were 52.5% (95%CI 36.3-68.7%) and 12.5% (95%CI 1.8%-23.2%), respectively. The 24-month stringent FLC response rate was 47.5% (95%CI 31.3-63.7%). The 24-month cardiac CR, VGPR, and PR rate were 15.0% (95%CI 3.4-26.6%), 35.0% (95%CI 19.6-50.4%), and 10.0% (95%CI 2.0-15.8%), respectively. Compared with the 12-month cardiac response, 3 (7.5%) VGPR patients achieved CR, and 5 (12.5%) PR patients achieved VGPR, whereas 1 VGPR and 1 PR patients had progression disease. The 24-month hepatic response rate reached 80.0%, compared with the 12-month response rate of 20.0%. The 24-month renal response rate was 33.3%, whereas the best response rate was 50%, and the decrease in renal response rate was due to 2 patients' death from cardiac events.
Twelve patients had died due to sudden cardiac death or heart failure exacerbation after infection, as reported before. After a median follow-up of 46 months (range 0.3-50.8), another 2 patients died from cardiac progression, 1 patient died from rectal cancer, and 1 patient died due to an unknown cause.
Ten of the 27 patients who completed treatment had a disease progression. Five patients had hematologic progression and 3 patients had renal progression. Two patients had both cardiac and renal progressions, and 1 patient had both renal and hepatic progressions. Three patients received venetoclax plus dexamethasone as a salvage treatment. Two patients with cardiac progression died before salvage therapy. Three patients with only hematologic progression and 2 patients with only renal progression are under close follow-up.
The median OS had not been reached. The median PFS was 33.5 months (95% CI 21.0-46.0). The estimated 3-year OS and PFS rate was 61.6% (95%CI 46.5%-76.7%) and 47.5% (95% CI 32.0%-63.0%), respectively. In subgroup analysis, there was neither a significant difference in OS between Mayo stage IIIA and IIIB patients (median OS not reached in both groups, p=0.406), nor a significant difference in PFS (Mayo stage IIIA vs. IIIB, 33.5 months vs. 32.8 months, p=0.383).
Notably, 28 (70%) patients had ever achieved a stringent FLC response. Five (25%) stage IIIA and 10 (50%) stage IIIB patients had reached negative MRD. At last follow-up, ten (35.7%) patients lost stringent FLC response, and only 3 of them ever had negative MRD. Twelve (42.9%) patients still stayed in a stringent FLC response state, 10 of them ever had negative MRD. Six (21.4%) patients died before loss of stringent FLC response. In a competing risk analysis, the stage IIIB patients had a significantly longer median duration of stringent FLC response than stage IIIA patients (not reached vs. 40.0 months, p=0.048), possibly due to a high MRD negative rate in the IIIB subgroup in our study.
This study presents the long-term follow-up results of the first clinical trial including Mayo stage IIIB AL amyloidosis patients. The strong anti-plasma cell regimen Dara-VD provided a comparable prognosis for Mayo stage IIIB patients compared with IIIA patients.
