Bortezomib added to standard therapy confers survival benefit in light-chain amyloidosis
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The addition of bortezomib to oral melphalan and dexamethasone improved hematologic response rates and OS among patients with systemic light-chain amyloidosis, according to phase 3 study results published in Journal of Clinical Oncology.
The regimen should become a new standard of care for patients with this rare disease, researchers noted.
“Systemic light-chain (AL) amyloidosis is caused by monoclonal light chains misfolding and aggregating into fibrils that deposit in tissue, causing progressive organ dysfunction that is fatal if diagnosis is delayed or treatment is ineffective,” Efstathios Kastritis, MD, clinical researcher at National and Kapodistrian University of Athens in Greece, and colleagues wrote. “Presently, treatment is aimed at reducing the availability of the precursor protein, using chemotherapy to target the plasma cell clone producing the amyloid light chains.”
Oral melphalan and dexamethasone have been considered a standard of care in AL amyloidosis. However, the proteasome inhibitor bortezomib (Velcade, Millennium/Takeda) has been used increasingly in combination with alkylating agents and dexamethasone.
In the multicenter, open-label trial, Kastritis and colleagues randomly assigned 109 patients with AL amyloidosis (median age, 66 years; 56% men) to oral melphalan and dexamethasone in combination with bortezomib (n = 53) or oral melphalan and dexamethasone alone (n = 56) to compare responses and survival.
Patients with advanced cardiac-stage amyloidosis were not eligible.
All patients received at least one dose of therapy.
Hematologic response rate at 3 months served as the primary endpoint.
Results showed a higher hematologic response rate among patients who received the bortezomib regimen vs. oral melphalan and dexamethasone only (79% vs. 52%; P = .002).
The bortezomib group also demonstrated higher rates of very good partial or complete response (64% vs. 39%; HR = 2.47; 95% CI, 1.3-4.71) and longer OS (median, not reached vs. 34 months), with a decrease in mortality rate (HR = 0.5; 95% CI, 0.27-0.9).
Grade 3 and grade 4 adverse events, including cytopenia, peripheral neuropathy and heart failure, occurred twice as frequently in the bortezomib group (20% vs. 10%).
The authors deserve to be congratulated for establishing this regimen as a new standard of care for most patients with AL amyloidosis who are not suitable for stem cell transplantation, Guy Pratt, MD, consultant hematologist at University Hospitals Birmingham in the U.K., wrote in an accompanying editorial.
“In common with practice in multiple myeloma, daratumumab [Darzalex, Janssen] and other monoclonal antibodies are rapidly being incorporated in clinical trials for patients with AL amyloidosis on the basis that these antibodies will provide augmented clinical activity with minimal patient toxicity,” Pratt wrote. “The current [bortezomib] regimen would be a natural backbone for trials with daratumumab and other monoclonal antibodies.”
References:
- Kastritis E, et al. J Clin Oncol. 2020;doi:10.1200/JCO.20.01285.
- Pratt G. J Clin Oncol. 2020;doi:10.1200/JCO.20.01904.
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