Myeloma-Related Renal Impairment Management Update

Kidney impairment is a frequent and prognostically relevant complication in multiple myeloma (1). Up to 50% of patients with multiple myeloma present with kidney dysfunction at diagnosis, and 2%–4% require dialysis (2). In addition, kidney dysfunction is associated with shorter overall survival and increased risk of early mortality in patients with multiple myeloma. The average survival of patients with renal dysfunction is approximately 20 months. On the other hand, with current therapies, only a small percentage of patients experience a significant decline in renal function within the first 12 months. Because kidney dysfunction in patients with multiple myeloma is reversible (especially in the early stages), a multidisciplinary approach to diagnosis and management is required (3). In recent years, the introduction of novel agents for multiple myeloma has expanded its treatment options, and the International Myeloma Working Group (IMWG) has updated its clinical practice recommendations for managing renal dysfunction associated with multiple myeloma (4) (Table 1).

Table 1

Summary of IMWG recommendations

View Table

First, for the diagnosis of kidney dysfunction in multiple myeloma, it is recommended that measurements of serum creatinine, estimated glomerular filtration rate (eGFR), electrolytes, and free light chain (FLC), as well as 24-hour urine total protein, electrophoresis, and immunofixation, be performed. Kidney biopsy is not recommended if proteinuria is light chain-dominant, and serum FLC levels are elevated because these findings indicate the presence of cast nephropathy, the most common and important kidney pathology in patients with multiple myeloma. On the other hand, a kidney biopsy is justified if the patient shows nonselective proteinuria (primarily albuminuria) or serum FLC levels less than 500 mg/L when there is no known cause of worsening kidney function.

Next, the IMWG criteria were recommended to define the renal response concerning treating kidney dysfunction due to multiple myeloma. This criterion is superior because it has already been validated in several studies. As for treatment details, all patients require high-dose dexamethasone and supportive care (hydration, correction of hypercalcemia, and avoidance of nephrotoxic agents such as nonsteroidal anti-inflammatory drugs). Bortezomib-based regimens are fundamental to managing patients with multiple myeloma and kidney dysfunction, but the potency and drug resistance of bortezomib have been therapeutic limitations, leading to the development of a new generation of agents. Studies have shown that prolonged persistence of light chains after diagnosis of myeloma worsens kidney prognosis and that rapid reduction of serum light chain levels increases the likelihood of kidney function recovery. Therefore, extracorporeal removal of FLC using high-cutoff dialysis or plasma exchange in addition to standard therapy may improve the rate of dialysis independence.

Furthermore, dialysis is indicated in acute kidney injury (AKI) with severe fluid overload and electrolyte abnormalities, regardless of myeloma status. The new four- and three-drug regimens, including proteasome inhibitors, immunomodulators, and anti-CD38 monoclonal antibodies, have improved kidney function and survival outcomes in patients who are newly diagnosed and relapsed or refractory. The panel recommended intensified therapy with daratumumab, bortezomib, dexamethasone, weekly FLC response assessment, and a second cycle of immunomodulatory agents, particularly for patients who are newly diagnosed. Notably, the report mentioned kidney adverse effects with carfilzomib, including thrombotic microangiopathy, albuminuria, and grade 3 AKI. If kidney damage due to carfilzomib is suspected, a re-biopsy of the kidney may be considered. Additionally, the dose adjustment of renally excretable anti-myeloma drugs in patients with kidney dysfunction is discussed. Antibody-drug conjugates, chimeric antigen receptor T cells, and bispecific T cell engagers are well-tolerated and effective in patients with moderate kidney dysfunction. Although the level of evidence is low, kidney transplantation can be considered for patients with end stage kidney disease (ESKD) and persistent myeloma control (i.e., minimal residual disease-negative for 2 years) (5).

The shortcomings of prior research encompass varied and inconsistent methodologies for evaluating kidney dysfunction, the omission of patients with severe kidney impairment from clinical trials, and the application of chronic kidney disease equations for estimating kidney function in patients with AKI. A differential diagnosis of kidney dysfunction in patients with multiple myeloma needs to be implemented appropriately. The optimal treatment for myeloma in patients with impaired kidney function has yet to be established and requires further study.