Neuropathy In Multiple Myeloma Research Articles

Neuropathy in multiple myeloma treated with thalidomide

Thalidomide is effective as a first-line therapy for the treatment of multiple myeloma (MM), but its use is limited by peripheral neurotoxicity. To study the occurrence of both myeloma-related neuropathy and thalidomide-induced neuropathy in 31 patients with newly diagnosed MM. Clinical and electrophysiologic examinations were performed in 31 patients with newly diagnosed MM before and after 4 months of therapy with thalidomide (200 mg/day, total dose: 21 g) aimed at debulking MM, before autologous transplantation. After transplantation, the patients took thalidomide, 200 mg/day for another 3 months (total dose over three months: 18 g) and then underwent a final clinical and electrophysiologic checkup. At baseline, four patients presented a mild sensorimotor peripheral neuropathy related to MM, which tended to worsen slightly during treatment with thalidomide. At the end of treatment, 83% of the patients had clinical and electrophysiologic evidence of a mild sensory rather than motor, axonal, length-dependent polyneuropathy, whereas 100% of the patients showed improvement to the basic pathology (>or=partial response). Peripheral neuropathy, sometimes subclinical, and mild in our patients, is a common, early side effect of thalidomide therapy. The high doses (21 g) used in all patients for a relatively short time (4 months) rule out any correlations between neuropathy, total dose, and duration of treatment.

Use of Immunoglobulin Infusions in the Management of Bortezomib-Induced Peripheral Neuropathy in Multiple Myeloma.

Bortezomib (VELCADE) is a novel proteasome inhibitor that has shown tremendous clinical efficacy in Asian patients with multiple myeloma (MM). Prior studies have found that about a third (35%) of Caucasian patients develop bortezomib-induced peripheral neuropathy (PNY); and 12% and 5% of these patients require dose-reduction or discontinuation of bortezomib, respectively. Moreover, it has anecdotally been reported that a greater proportion of Asian patients receiving bortezomib develop PNY, and we are concerned that this unwanted effect of bortezomib would greatly limit the use of a drug that would otherwise be highly-effective for Asian MM patients. We therefore analyzed 20 Asian patients with MM who were treated with bortezomib, and found that up to 75% (15 out of 20) of patients developed bortezomib-induced PNY - sensory (75%) and/or motor (50%); confirming the observation that Asian patients are more prone to developing bortezomib-induced PNY. The majority of sensory PNY were mild. Grades 1 or 2 sensory PNY was seen in 45%, grade 3 in 15%, and grade 4 in another 15% of patients. Of these, 80% of patients reported painful neuropathies - 53% requiring dose reduction, and 27% requiring discontinuation of bortezomib. By contrast, motor PNY was more severe - 5% of patients reported grades 1 or 2, 15% with grade 3, and 30% with grade 4 motor PNY. In other words, if PNY develops in an Asian patient with MM, it is more likely to be a mild painful sensory PNY. However, if motor PNY occurs, it is more likely to be severe. For the treatment of PNY, all patients received gabapentin (600 mg to 1,400 mg per day), and 9 patients received L-carnitine (2 or 3 tablets a day). Gabapentin-treated patients reported only minimal effectiveness of this drug in relieving their symptoms, whereas no objective improvements were observed in all L-carnitine-treated patients. Similarly, amitriptyline was given to 3 patients with severe painful PNY and only a non-sustained modest improvement was reported in all these patients. In contrast, improvements of at least 1 grade in both symptoms and function were reported by all 9 patients who received intravenous immunoglobulins (IVIG). In the most significant of these, a patient who was bed-ridden because of grade 4 combined sensorimortor PNY, dramatically recovered (became pain-free, and improved to grade 2 motor weakness) within 2 days of completing IVIG 2.0 gm/kg divided over 4 days. In conclusion, Asian MM patients have indeed significantly higher rates of bortezomib-induced PNY, which unfortunately often leads to dose-reduction and/or discontinuation of bortezomib. Our data demonstrate that IVIG may be a useful agent for the management of these patients; and for facilitating the continued administration of bortezomib.

Thalidomide‐associated neuropathy in multiple myeloma

Thalidomide is a neurotoxic immunomodulating agent currently used in Multiple Myeloma (MM). We prospectively evaluated the frequency and characteristics of peripheral neuropathy in a continuous series of 25 patients (13 M, 12 F; age 38–60, median 55 yrs) treated with thalidomide for MM. Patients underwent a neurological and neurophysiological evaluation before starting thalidomide therapy and monthly throughout duration of treatment. Sixteen patients (5 M, 11 F) developed neurophysiological characteristics of axonal sensitive damage and/or clinical peripheral neuropathy with distal sensory symptoms; treatment duration ranged between 95 and 572 days (median 298) in patients with neuropathy, and 49–264 days (median 162) in patients without neuropathy; the total amount of thalidomide taken ranged between 26 and 169 g (median 83 g) for patients with neuropathy and 13–170 g (median 51 g) for those without. In four patients, ENG alterations appeared before clinical symptoms, while in two patients they were not followed by clinical symptoms. In the remaining three patients, clinical symptoms preceded neurophysiological alterations. Age at onset of MM, disease duration before thalidomide therapy was started, total dose, duration of therapy and previous treatments were not correlated with neuropathy (multivariate logistic regression analysis). Female gender was a risk factor for developing neuropathy (OR 7.7).

Peripheral neuropathies associated with monoclonal proteins: a clinical review.

Over the last decade, the increasing use of serum and urine protein electrophoretic screening of patients with idiopathic peripheral neuropathy has led to greater recognition of peripheral neuropathy syndromes that are associated with monoclonal proteins and plasma cell dycrasias. After careful evaluation, most of these patients have benign monoclonal gammopathy, followed in frequency by primary systemic amyloidosis and osteosclerotic myeloma, with occasional cases associated with osteolytic multiple myeloma, Waldenstrom's macroglobulinemia, gamma heavy chain disease, and other rare disorders. Several of these syndromes have distinctive presentations and are recognizable clinically, whereas others (especially multiple myeloma neuropathy) are diverse clinically and are not clearly distinguishable from other chronic neuropathies. The discovery of IgM-kappa monoclonal proteins directed at myelin antigens in some patients with benign monoclonal gammopathy and the delineation of the syndrome of neuropathy and multiorgan involvement in osteosclerotic myeloma are important developments which may shed light on the mechanism of the remote effects of malignancies on the nervous system.

Amyloid neuropathy in multiple myeloma and other plasma cell dyscrasias: A hypothesis of the pathogenesis of amyloid neuropathies

The development of amyloid neuropathy is an uncommon complication of multiple myeloma. The clinical, electrophysiological and pathological features of 3 such patients are described. The small fiber neuropathy in these 3 cases was similar to that in patients with primary amyloidosis and with the Andrade-type of familial neuropathy, and differed from the large fiber neuropathy which more commonly develops in patients with multiple myeloma. We advance the hypothesis that the absence of the blood-nerve barrier in the dorsal root and sympathetic ganglia allows the access of amyloidogenic proteins to these ganglia, and that these ganglia are the primary site of damage to the peripheral nervous system in the amyloid neuropathies.