Page 341 - Haematologica Vol. 109 - July 2024

LETTER TO THE EDITOR
Efficacy and safety of daratumumab plus bortezomib and dexamethasone in newly diagnosed Mayo 2004 stage IIIA or IIIB light-chain amyloidosis: a prospective phase II study
Immunoglobulin light-chain (AL) amyloidosis has shown a rapid and high rate of response to daratumumab, but Mayo stage IIIB patients are excluded from most trials.1 We aimed to prospectively evaluate the efficacy of daratumumab plus bortezomib and dexamethasone (Dara-VD) in Mayo stage III, especially IIIB, AL through this phase II study (clinicaltrials gov. Identifier: NCT04474938). The treatment scheme was intravenous daratumumab at 16 mg/kg weekly in cycles 1-2, every 2 weeks for cycles 3-6 and every 4 weeks for cycles 7-12, 1.3 mg/m2 bortezomib and 20 mg dexamethasone once weekly for six cycles of 28 days each. The primary outcome was hematologic response ≥ very good partial response (VGPR) at 3 months. A total of 40 patients were enrolled, including 20 with IIIB disease. The percentage of patients with response ≥ VGPR at 3 months was 67.5%, including 47.5% complete response (CR). The percentage who had a cardiac response at 6 months was 47.5%. After a median follow-up of 24.0 months, the 2-year overall survival (OS) estimate reached 69.8%. The response ≥ VGPR at 3 months (70.0%) and cardiac response at 6 months (50.0%) in the IIIB subgroup were comparable to those in the IIIA sub- group. The 2-year OS rate was 65.0% in IIIB patients. Grade ≥3 treatment-related adverse events occurred in 40.0% of patients. Dara-VD had favorable efficacy and safety in advanced AL amyloidosis, including IIIB disease.
As is known, the benefits of bortezomib in severely advanced AL amyloidosis have not been demonstrated definitively.2,3 In the ANDROMEDA trial, the combination of daratumumab with bortezomib, cyclophosphamide and dexamethasone (Dara-VCD) achieved a deeper hematologic response and longer survival across cardiac stages.4,5 Unfortunately, pa- tients with stage IIIB disease were excluded from the above study. Agents targeting the deposited amyloid fibrils on affected organs are appealing, but not ready for routine clinical practice.6,7 Thus, the management of advanced cardiac AL amyloidosis remains a major unmet medical need. The ongoing EMN22 study is evaluating daratumumab monotherapy in stage IIIB patients.8 Yet past experience has indicated that there might be only one chance to start effective treatment in patients with advanced heart involve- ment, who have low probability of receiving salvage therapy. Aside from monotherapy, a combination regimen followed by de-escalation is also worth prospective investigation. Therefore, we conducted this phase II, single-arm study to evaluate the efficacy and safety of front-line Dara-VD in both IIIA and IIIB AL amyloidosis patients (Online Sup- plementary Figure S1). The exclusion criteria included a
co-diagnosis of multiple myeloma (patients whose only myeloma defining event was serum free light chain ratio ≥100 could be included) or Waldenström’s macroglobulin-
Table 1. Baseline demographic and clinical characteristics of the patients (N=40).
Characteristics
N=40
Male, N (%)
30 (75.0)
Age in years, median (range)
59 (40-77)
Amyloid light-chain type λ, N (%)
31 (77.5)
Mayo 2004 stage IIIB, N (%)
20 (50.0)
Mayo 2012 stage, N (%)
II III IV
0 (0.0)
1 (2.5) 17 (42.5) 22 (55.0)
NYHA stage, N (%)
II III IV
2 (5.0) 14 (35.0) 23 (57.5) 1 (2.5)
Symptom-diagnosis interval in months, median (range)
8 (2-43)
Involved organs Kidney
Liver
12 (30.0) 10 (25.0)
Number of organs involved, N (%)
2 (1-4)
Laboratory values, median (range) cTnI, μg/L
NT-proBNP, ng/L
IVS, mm
LVEF, %
24hUP, g
eGFR, mL/min/1.73 m2 ALP, U/L*
dFLC, mg/L
BMPC, %
0.17 (0.07-3.07) 7,801 (803-35,000) 15 (11-23)
56 (32-83) 0.24 (0.03-12.57) 77 (12-124) 106 (38-643) 274 (72-2,966)
5 (0-25)
FISH, N (%) t(11;14), N†=39 Gain 1q21, N†=29 Del 17p, N†=29
14 (35.9) 4 (13.8) 2 (6.9)
Haematologica | 109 July 2024
2355
*The upper limit of normal is 135 U/L. †Number of patients evaluated. 24hUP: 24-hour urine protein; ALP: alkaline phosphatase; BMPC: bone marrow plasms cell; cTnI: cardiac troponin-I; dFLC: difference between involved and uninvolved free light chain; eGFR: estimated glomerular filtration rate; FISH: fluorescence in situ hybridization; IVS: intraven- tricular septum; LVEF: left ventricular ejection fraction; NT-proBNP: N-terminal pro-brain natriuretic peptide; NYHA: New York Heart Asso- ciation.