ARF Can Be First Sign of Myeloma

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NEW ORLEANS—Acute renal failure (ARF) induced by pathogenic light chains can be the first presenting sign of multiple myeloma, and prompt treatment of the malignancy is critical to reversing renal damage, according to a study presented by European investigators at the American Society of Hematology 51st annual meeting.

“This is an oncologic emergency and you need very active myeloma treatment to correct it. You must get rid of the toxic light chain to treat the renal failure as fast as possible,” said principal investigator Heinz Ludwig, MD, of the Center for Oncology and Hematology, Wilhelminenspital, Vienna, Austria.

In the study, a regimen of bortezomib, doxorubicin and dexamethasone (BDD) resulted in high tumor and renal response rates.

ARF is a frequent and serious complication in patients with multiple myeloma. It is associated with an increased risk of permanent renal dysfunction and dependence on chronic hemodialysis, and it is a prognostic marker for shortened survival. In most cases, renal failure is caused by accumulation of pathogenic light chains in the distal tubules that induces tubular extension, obstruction, and destruction (cast nephropathy).

Reversal of renal failure due to cast nephropathy can only be achieved by rapid, substantial, and permanent suppression of pathogenic light chain production, according to Dr. Ludwig. The involvement of an oncologist is critical to the treatment of this condition, he said.

The prospective study included 58 patients with advanced multiple myeloma and light chain-induced acute renal failure. For 46 (79%) patients, renal failure was their first presentation of the malignancy. Only 12 (21%) had progressive, previously treated disease. The median baseline glomerular filtration rate (GFR) was 20 mL/min/1.73 m2.

Patients were treated with bortezomib 1.0-1.3 mg/m2, doxorubicin 9 mg/m2 and dexamethasone 40 mg in a 21-day cycle for a median of eight cycles.

The overall renal response rate was 72%, with 36% achieving a complete response (GFR of 60 or greater). Median time to response was 38 days and median time to best renal response was 132 days. Three of nine dialysis-dependent patients (33%) were able to discontinue dialysis, Dr. Ludwig reported.

“The value of bortezomib in this setting is you do not have to adjust the dose,” he said. “It has a very short half life and is not excreted by the kidneys, so you can give full doses in patients with good performance status. It has high activity and induces remission rapidly.”

Tumor response to BDD initiation was observed in 84% of patients. Of the 12 previously treated patients, seven (58%) achieved a complete or near-complete response, one (8%) achieved a very good partial response or better, and one (8%) had a minor response. The median time to first tumor response was 31 days.

At a median follow-up of 20 months, median time before the malignancy progressed was 13.7 months and median overall survival had not been reached. In the intention-to-treat population, one-year survival was 72% and two-year survival was 60%, which improved in the response-evaluable population to 84% and 70%, respectively. Overall survival was significantly shorter in the 12 patients with previously treated disease, he added.

In a multivariate analysis, baseline GFR and tumor response correlated significantly with marked improvement in renal function, with higher GFR and better responses raising the odds of improved renal function about fourfold.

“Timely diagnosis and treatment may prevent further GFR deterioration and reverse the destructive process of renal failure,” Dr. Ludwig noted.

He added: “Improvement in renal function was seen more often in patients achieving a substantial tumor response. And time to first tumor response was just 31 days, which emphasizes the high activity of the treatment regimen.”

The results of this study and other retrospective and post hoc studies substantiate bortezomib-based regimens as an excellent treatment option for myeloma in patients with renal impairment, he said.

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