ANDROMEDA: Addition of daratumumab showed superior efficacy in patients with AL amyloidosis

Addition of daratumumab to standard-of-care treatment in patients with amyloid light-chain (AL) amyloidosis showed superior efficacy to standard-of-care treatment alone, according to updated results of the ANDROMEDA trial. Based on these results, this combination therapy has become the first approved therapy for AL amyloidosis.

Systemic AL amyloidosis is a rare plasma cell disease characterised by the deposition of insoluble amyloid fibrils causing organ dysfunction and death. Patients have a poor prognosis: about 30% die within the first year of diagnosis and the 4-year survival rate is 54% [1]. Median overall survival in patients with Mayo stage IIIB at baseline is 2.5–3.5 months [2].

Prof. Efstathios Kastritis (National and Kapodistrian University of Athens, Greece) presented updated results of the ongoing, open-label, randomised, phase 3 ANDROMEDA study (NCT03201965) [3,4]. The study included 388 patients with newly diagnosed AL amyloidosis who had ≥1 organs impacted. They were randomised to receive 6 cycles of either bortezomib, cyclophosphamide, and dexamethasone (VCd) plus 1,800 mg of subcutaneous daratumumab (D-VCd) followed by daratumumab every 4 weeks for up to 24 weeks (n=195) or VCd alone (n=193). The primary results after a median follow-up of 11.4 months showed that addition of subcutaneous daratumumab (D-VCd) to the standard-of-care combination (VCd) was superior to VCd alone [5].

Prof. Kastritis presented the updated results after a median 20.3-month follow-up (D-VCd n=193; VCd n=188) [3]. In the D-VCd arm, 40% of participants were still receiving daratumumab monotherapy and the median duration of therapy was 18.5 months versus 5.3 months for VCd. There were 31 deaths in the D-VCd group and 40 deaths in the VCd group.

The primary endpoint was complete haematologic response (CR) defined as normalisation of free light chain (FLC) levels and FLC ratio, and negative serum and urine immunofixation. Rates of CR were significantly higher with D-VCd (P<0.0001), the median time to CR was 2.0 versus 2.8 months, and CR rates were high across all pre-specified subgroups (see Figure). Haematologic overall response was 92% in the D-VCd group versus 77% of VCd-treated patients (P<0.0001).

Figure: Haematologic CR rates in pre-specified subgroups favour D-VCd treatment [3]



Cardiac response rate, defined as a baseline NT-proBNP of ≥650 ng per litre or baseline NYHA class of III or IV, was higher in D-VCd at 6 (42% vs 22%; P=0.0029) and 12 months (57% vs 28%; P<0.0001), improving with longer follow-up. The same was true for renal response rate at 6 (54% vs 27%; P<0.0001) and 12 months (57% vs 27%; P<0.0001). The safety profile of the 2 treatment arms was comparable.

In conclusion, longer follow-up data support the benefit of adding daratumumab to VCd treatment. With D-VCd now approved in the United States and Brazil, these data support D-VCd as the new standard of care for patients with AL amyloidosis.

1. 
   
   1. Muchtar E, et al. Blood 2017;129(15):2111–9.
   2. Palladini G, et al. Blood 2020;136(Suppl.1):50–1.
   3. Kastritis E, et al. Updated results from phase 3 ANDROMEDA study of patients with newly diagnosed AL amyloidosis treated with bortezomib, cyclophosphamide, and dexamethasone plus subcutaneous daratumumab. P417-5, EHA 2021 Virtual Congress, 9–17 June.
   4. Kastritis E, et al. N Engl J Med 2021;385:46–58.
   5. Kastritis E, et al. LB2604, EHA 2020, 11–21 June.

 

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Posted on 5 August 202127 March 2024