Effect of Bortezomib on the Autonomic Nervous System.

Background

Peripheral neuropathy is one of the most frequent adverse events associated to bortezomib therapy; among neuropathic syndromes, postural hypotension is described as well. However, information on disautonomic toxicity are limited and there are no studies addressed to this particular issue so far.

Before starting this study we had observed a case of dramatic acute autonomic failure during bortezomib treatment in a patient with advanced multiple myeloma, who developed severe orthostatic hypotension, tachycardia and impairment to tolerate the sitting and orthostatic posture for several weeks.

Methods

We prospectively studied 12 consecutive patients, treated with bortezomib at our Institution between February 2005 and July 2006. Assessment included neurological examination, INCAT Disability scale, INCAT sensory sum score, MRC sum score, nerve conduction studies, and standard cardiovascular autonomic tests including Lying to standing, Deep breathing and Postural hypotension. These tests were conducted baseline and after each bortezomib 21-days cycle up to three consecutive cycles.

Results

Two pts showed a clinically evident autonomic involvement with orthostatic hypotension; a change to a pathological score in 2 out of 3 tests anticipated clinical disautonomic signs in 1 and 11 weeks respectively. Clinical impairment showed to be reversible in both cases. Four pts presented only 1 pathological test (without any clinical sign or symptom of postural hypotension) and 6 patient had normal results. There was no apparent correlation between autonomic impairment and disease response to therapy or patients baseline characteristics (disease stage, Ig class, previous anti-myeloma therapies, concomitant thalidomide or anti-hypertensive treatment); furthermore, none had evidence of amyloidosis.

Conclusions

Our prospective study confirms that autonomic dysfunction is a potential adverse effect of bortezomib. Autonomic, non invasive, cardiovascular testing may reveal subclinical involvement and precede clinical evidence of disautonomic neuropathy. Further studies in larger cohorts of patients are needed to clarify the interactions between proteasome inhibitor activity and autonomic nervous system, in order to assess the frequency, the ability of available test in early pre-clinical diagnosis and the potential of the reversibility of neuropathic signs after drug discontinuation.