Predicting Survival in MM With Renal Impairment and Light Chain Cast Nephropathy

The quality of renal response to therapy was associated with survival in patients with multiple myeloma (MM) with renal impairment and light chain cast nephropathy (LCCN), according to a study published in Blood. These results suggest that adding renal biopsy findings to clinical assessment may assist in predicting patient outcomes associated with MM and renal impairment.

Few studies have investigated the prognostic value of histologic findings in LCCN, and most were conducted before the era of currently used antimyeloma agents, said study author Virginie Royal, MD, of the University of Montreal in Québec. Dr. Royal and her colleagues retrospectively identified an international cohort of 178 patients with biopsy-proven LCCN who had follow-up data and pathology material available for analysis.

Patients were included in the study if they met the following criteria:

  • diagnosis of MM
  • ≥1 renal tubular cast with typical appearance for a light chain cast by light microscopy
  • ≥1 cast staining for anti-κ or anti-λ by immuno-fluorescence or immunohistochemistry
  • sufficient follow-up data to examine hematologic response

In patients who presented prior to 2006, the hematologic response was evaluated retrospectively using International Myeloma Working Group criteria. Hematologic response was based on protein electrophoresis and serum and urine immunofixation when free light chain (FLC) assay was not available.

Approximately 82% of patients received bortezomib- or immunomodulatory drug-based regimens as initial therapy for their MM. All patients received these therapies as either first- or secondline approaches.

Overall, the mean age of the cohort was 66±11 years, and the median time between diagnosis of MM and LCCN was 2 days (range = 0-25). The mean estimated glomerular filtration rate (eGFR) at presentation was 13±11 mL/min/1.73 m2. Approximately 82% of patients had stage III acute kidney injury at presentation. The mean number of casts was 3.2/mm2 in the cortex and 2.2/mm2 in the medulla.

The following histologic patterns were observed on pathology review:

  • acute tubular injury (94%)
  • tubulitis (82%)
  • tubular rupture (62%)
  • giant cell reaction (60%)
  • cortical inflammation (95%)
  • medullary inflammation (75%)

The investigators observed correlations between eGFR value at LCCN diagnosis and medullary inflammation (p=0.04), giant cell reaction around casts (p=0.003), and extent of cast formation (p<0.001).

After a median of 5 months (range = 3-8), approximately 69% of patients had a very good partial response or better (≥VGPR). Over a median follow-up period of 22 months, the mean eGFR increased from 13±11 mL/min/1.73 m2 at presentation to 43±30 mL/min/1.73 m2. Factors independently associated with a higher eGFR during this follow-up period included younger age, β2-microglobulin, higher quality hematologic response, lower number of cortical casts/mm2, and less interstitial fibrosis/tubular atrophy.

A strong association was observed between overall survival (OS) and the best eGFR value (hazard ratio [HR] of death = 1.6 per every 15-mL/min/1.73 m2 drop in eGFR <45 mL/min/1.73 m2; 95% CI 1.3-1.9; p<0.001). In the multivariate Cox regression analysis, the association between OS and the best eGFR persisted.

“Our results strongly support the added value of performing a renal biopsy, as pathology findings correlate with the best estimated glomerular filtration rate, which is associated with the OS.”

—Virginie Royal, MD

Dr. Royal explained that these results are insufficient to recommend treatment adaptation based on renal pathology findings. “However, we believe that future interventional studies dedicated to renal outcomes in LCCN should consider stratification based on the extent of casts and, to a lesser extent, degree of interstitial fibrosis and tubular atrophy,” she said. “It is possible that investigational treatments for light chain removal, such as high cutoff dialysis membranes or plasma exchange, have benefits that may depend on the underlying pathology – something that has not been addressed in recent randomized controlled trials.

“In our observational study, when considering those who required hemodialysis at presentation,” she added, “the best eGFR was higher in patients who received extracorporeal removal of FLC, in line with results from the recent MYRE randomized controlled trial.”

Not all patients enrolled in the study survived long enough to be included in follow-up analyses. According to Dr. Royal, this limitation may have resulted in the selection of individuals with a better outcome. Despite this study being the largest ever published about outcomes in MM-associated LCCN, she noted, the modest sample size represents another limitation.

“Our results strongly support the added value of performing a renal biopsy, as pathology findings correlate with the best eGFR, which is associated with the OS,” said Dr. Royal. “In light of this, we believe that a pathology assessment should be considered in future studies dedicated to renal outcomes in LCCN.”

Reference

Royal V, Leung N, Troyanov S, et al. Clinicopathologic predictors of renal outcomes in light chain cast nephropathy: A multicenter retrospective study. Blood. 2020 Mar 11. [Epub ahead of print]