Light-Chain Deposition Disease Treatment & Management

Updated: Oct 26, 2021
  • Author: Eric J Vick, MD, PhD; Chief Editor: Emmanuel C Besa, MD  more...
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Treatment

Medical Care

Treatment of light-chain deposition disease (LCDD) is indicated for patients who present with systemic involvement, kidney dysfunction, and the associated presence of multiple myeloma. The goal of treatment in these patients is to suppress the production of light chains and damage to other organs. Appropriate medical management must be provided for organ dysfunction as needed, such as the use of angiotensin-converting enzyme (ACE) inhibitors or dialysis.

Unlike in multiple myeloma, the plasma cell burden is quite low (< 5%) and the genetic abnormalities associated with adverse prognosis in multiple myeloma are generally absent. In patients with LCDD associated with multiple myeloma, the prognosis is quite poor and they should be treated per multiple myeloma guidelines. [42] In these patients, there is little evidence to support maintenance therapy, [43]  except in cases where the patients would otherwise be receiving therapy for multiple myeloma. LCDD is a rare disease; hence, no placebo-controlled trials have been performed, there are no established guidelines, and management remains controversial. [18]

Treatment options include the following [44] :

  • Autologous stem cell transplantation (ASCT)
  • Bortezomib
  • Immunomodulatory drugs
  • Daratumumab
  • Kidney transplantation

Autologous stem cell transplantation

Autologous stem cell transplantation (ASCT) can produce durable responses in patients with LCDD. [18, 45, 46] Stem cells are mobilized using granulocyte colony-stimulating factor (G-CSF), and high-dose chemotherapy with melphalan is given. The dose of melphalan is adjusted to the patient's kidney function, to decrease morbidity.

A long-term analysis of 6 patients with LCDD who underwent ASCT demonstrated that this is an effective therapy for patients with kidney dysfunction due to LCDD. [18] Proteinuria was reduced by 92% and the glomerular filtration rate improved by 95% in these patients. The authors also suggest that if kidney dysfunction persists after ASCT, a hematologic response may permit successful kidney transplantation with improved graft viability and decreased risk of recurrence. Another study of patients with LCDD treated with high-dose melphalan followed by ASCT also demonstrated that patients with kidney dysfunction have improvement in kidney function following ASCT. [47] Of the 5 evaluable patients with hematologic response, one had a complete response and four had a partial response.

The use of high-dose chemotherapy followed by ASCT is associated with toxicities such as mucositis, sepsis, bacteremia, and diarrhea. In general, LCDD patients are younger; thus, ASCT should be considered in these patients. However, associated comorbidities, cardiac involvement, concomitant multiple myeloma, and number of organs affected may predict for a worse outcome. Therefore, age and comorbidities should be considered prior to ASCT. Multiorgan failure following ASCT has been reported in patients with extrarenal disease. [18]

Bortezomib

In LCDD, monoclonal light chains interact with the receptors in mesangial cells and activate many pathways, including the nuclear factor (NFkB) 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. [12, 19] Bortezomib inhibits the 26S proteasome, and through secondary effectors modulates the NFkB pathways, decreases cytokine production, and decreases collagen production. [48, 49, 50]  Interruption of the downstream cascade by bortezomib prevents rapid progression of glomerulosclerosis and proteinuria and improves kidney function. [49, 51]

Bortezomib has been used in small series of patients with LCDD, including as induction therapy. [46, 52, 53] 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. [52] Another series on the use of bortezomib with dexamethasone as induction therapy prior to ASCT in 4 patients reported rapid response, with 50% of patients achieving a complete hematologic response. [53] A Canadian group reported on the use of bortezomib and dexamethasone as induction therapy in 2 patients prior to ASCT; both achieved partial response after 3 cycles and organ response 6 months after ASCT. [45]

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 benefits, 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 were alive after a median follow-up of 2 years and have remained dialysis-free. [54]

Based on the limited available data, induction with bortezomib helps improve kidney function. This may possibly permit 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 kidney 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 a significant improvement of proteinuria. High-dose chemotherapy followed by ASCT is a safe and well-tolerated treatment for LCDD, showing a good overall response rate.

Immunomodulatory agents

Thalidomide and its analogs lenalidomide and pomalidomide are immunomodulatory drugs that have been extensively studied in amyloid light-chain (AL)–amyloidosis and multiple myeloma. They have shown promise in LCDD, but their use has been limited and their role needs to be further explored in prospective studies. Case reports have included the following:

  • In a young patient in whom conventional chemotherapy had failed, demonstrated that thalidomide with dexamethasone provided a complete hematologic response after 8 months. The patient had a sustained hematologic response with improvement in kidney function that lasted 31 months. [55]
  • A patient with multiple myeloma was given lenalidomide with melphalan and prednisone. However, lenalidomide was discontinued as the patient unfortunately developed intrahepatic ischemic cholangitis. Histopathological analysis revealed LCDD of the hepatic arteries. [56]
  • In a patient with severe nephrotic syndrome and anemia (which had failed to respond to treatment with bortezomib, cyclophosphamide, and dexamethasone), lenalidomide plus prednisolone successfully reduced proteinuria and hematuria. [57]
  • In a kidney transplant recipient who was experiencing allograft failure and gastrointestinal dysfunction due to LCDD, and who was unable to tolerate bortezomib-based therapy, treatment with lenalidomide and dexamethasone led to a reduction of light chains for 10 months. [15]

A case report describes a patient in whom melphalan and prednisolone therapy was started upon diagnosis of LCDD and continued for 10 years. Serial evaluations of kidney histology revealed that nodular lesions resolved and the glomeruli became nearly normal. [58]  

Daratumumab

Daratumumab is a monoclonal antibody targeting CD38 that has become a cornerstone in the treatment of multiple myeloma and can be used with both lenalidomide and bortezomib-based regimens. Milani et al described successful use of daratumumab in the treatment of eight patients with LCDD. All eight had bone marrow involvement of > 10% with disease confined to the kidney and had been heavily pretreated (most having had more than 2 lines of therapy). Mean time from diagnosis to initiation of daratumumab was 57 months. Daratumumab was administered at 16 mg/kg weekly for 8 weeks, followed by every other week for 8 doses, and then every 4 weeks as maintenance. [59]

Seven of the eight patients achieved a partial response, defined as a > 50% decrease in serum free light chains. Two patients achieved a renal response, and four had improvement or stabilization of kidney function. Responses were durable to 20 months. [59]  These promising results suggest that daratumumab represents a fresh option for treatment of LCDD, although the study population was small.

Kidney transplantation

A few patients with LCDD with end-stage renal disease (ESRD) have undergone kidney transplantation. [60]  Long-term benefits are seen, but allograft survival is significantly reduced in this patient population. [61] LCDD patients who have detectable light chains in urine or serum have worse outcomes, with early recurrences despite pretransplantation treatment. [62] Thus, transplantation should be reserved for select patients with a relatively slow course in whom light-chain production can be controlled by directed therapy.

Despite careful consideration, LCDD may recur in kidney transplant recipients. Recurrences sometimes can be confused with acute rejection. A case report suggests that bortezomib can successfully reverse the early recurrence of LCDD in the allograft. [63] Rituximab could also be considered for delaying early LCDD recurrence in patients in whom treatment of the underlying bone marrow disorder failed or is contraindicated, but maintenance therapy is apparently necessary to consolidate this response. [64] The possibility of maintenance with bortezomib, thalidomide, or daratumumab needs to be further explored.