What is the role of bortezomib in the treatment of light-chain deposition disease (LCDD)?

Updated: Sep 26, 2019
  • Author: Swapna Boppana, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Answer

In light-chain deposition disease (LCDD), monoclonal light chains interact with the receptors in mesangial cells and activate many pathways including the nuclear factor (NF)kB pathway. This results in increased cytokine production leading to cell proliferation and activation of genes responsible for collagen and tenascin production. These changes lead to changes in the mesangial matrix ,causing glomerulosclerosis. [11, 15] Bortezomib inhibits the NFkB pathway, decreases cytokine production, and decreases collagen production. [44, 45] The downstream cascade is interrupted by bortezomib preventing rapid progression of glomerulosclerosis and proteinuria and improving the renal function. [45, 46]

Bortezomib has been used in small series of patients with LCDD, including as induction therapy. [42, 47, 48] In one series, 3 patients were treated with bortezomib as induction therapy. This led to rapid hematologic response after a mean of 2 cycles based on decrease in serum free light-chain levels. [47] Another series reported the use of bortezomib with dexamethasone as induction therapy prior to autologous stem cell transplantation (ASCT) in 4 patients, which lead to rapid response with 50% of patients with complete hematologic response. [48] A Canadian group reported the use of bortezomib and dexamethasone as induction therapy in 2 patients prior to ASCT, and both achieved partial response after 3 cycles and organ response 6 months after ASCT. [41]

The Canadian group also reported the only randomized study of 6 patients with LCDD. Patients were randomized to either dexamethasone alone or bortezomib with dexamethasone prior to high-dose chemotherapy with melphalan followed by ASCT. After completion of induction therapy 4 of 6 patients achieved partial response based on the decrease in serum free light-chain ratio and 2 of 6 achieved stable disease and both were in dexamethasone alone group.

At day 100, the post-ASCT overall response rate was 100%; 4 patients achieved complete hematological response, 1 exhibited near-complete response, and 1 attained partial response. All patients derived clinical benefit, including those who achieved less than complete response. At 6 months post-ASCT, all 6 patients showed organ response manifested mainly by decreased proteinuria of greater than 50%. Patients receiving bortezomib and dexamethasone induction showed a median time of kidney response of 3 months versus 6 months for the group receiving only dexamethasone. All 6 patients are alive after a median follow up of 2 years and have remained dialysis free. [49]

Based on the limited available data, induction with bortezomib helps improve renal function. This may possibly lead to more high-dose chemotherapy followed by ASCT, enabling for a better outcome. With bortezomib-based therapy, hematologic responses are rapid and are normally accompanied by rapid and significant reduction of proteinuria and improvement of renal function. The measurement of serum free light chains was useful in the follow-up of patients with LCDD, and the reduction of involved light chains was associated with significant improvement of proteinuria. High dose chemotherapy followed with ASCT is a safe and well-tolerated treatment for LCDD, showing a good overall response rate.


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