A group of multiple myeloma experts from the International Myeloma Working Group recently published a review of management strategies for drug-induced peripheral neuropathy in patients with multiple myeloma.

This Beacon article, the first in a three-part series describes peripheral neuropathy and summarizes the symptoms of drug-induced neuropathy as well as the risk of developing neuropathy associated with myeloma therapies.

A second Beacon article ^[1] will discuss the experts’ recommendations for the treatment of drug-induced peripheral neuropathy, and a third article ^[2] will summarize their recommendations for prevention of peripheral neuropathy as well as future steps toward better management of the condition.

What Is Peripheral Neuropathy?

Peripheral neuropathy is a disorder of the nervous system in which nerve damage causes sensations of pain, tingling, and numbness in the hands and feet.

It affects up to 20 percent of multiple myeloma patients at diagnosis but appears more frequently during the course of therapy. Many of the most commonly used treatments for multiple myeloma, such as Velcade ^[3] (bortezomib) and thalidomide ^[4] (Thalomid), damage the body’s nerve cells and can cause peripheral neuropathy in up to 75 percent of myeloma patients.

Although the biological causes of peripheral neuropathy are not fully understood, it is evident that the disorder may be a result of both myeloma-related and drug-related factors.

“Peripheral neuropathy is a feature of chemotherapy’s side effects in many different settings [such as lung and breast cancer], and not just multiple myeloma. In myeloma, it is also part of the underlying disease as well,” said Dr. Paul Richardson of the Dana Farber Cancer Institute in Boston and the lead author of the review.

The current review focuses specifically on drug-induced peripheral neuropathy in myeloma patients.

Symptoms Of Drug-Induced Peripheral Neuropathy

Symptoms of Velcade-induced peripheral neuropathy are usually mild and include burning, tingling, prickling, and other abnormal sensations predominantly in the feet, excessive or reduced physical sensitivity, discomfort, and weakness. It can be alleviated or eliminated through dose reductions or discontinuation of Velcade.

Thalidomide-induced peripheral neuropathy may cause tingling or painful sensations in the hands and feet, sensory loss in the lower limbs, muscle weakness, and tremor. Thalidomide has also been reported to cause permanent nerve damage, and symptoms may persist after treatment has stopped.

Myeloma patients treated with vincristine ^[5] (Oncovin) can also experience peripheral neuropathy.  Vincristine-induced peripheral neuropathy can cause symptoms similar to Velcade- or thalidomide-induced peripheral neuropathy. In addition, prolonged exposure to vincristine can cause additional nerve pain and motor difficulties.

Occurrence

The most common forms of drug-induced peripheral neuropathy are caused by neurotoxic drugs, or drugs that damage the body’s nervous system. These frequently include the novel agents Velcade and thalidomide, although other neurotoxic drugs such as vincristine and cisplatin may also lead to peripheral neuropathy.

Velcade-Induced Peripheral Neuropathy

Studies have shown that peripheral neuropathy can occur in 64 percent to 70 percent of newly diagnosed myeloma patients treated with twice-weekly, intravenous Velcade, with up to 16 percent of patients experiencing severe neuropathy.               

These rates are similar for myeloma patients treated with Velcade in the relapsed setting.

Recent studies, however, have shown that administering Velcade once weekly ^[6] or subcutaneously ^[7] (injected into the fat just below the skin) significantly reduces the rate and severity of neuropathy without affecting the drug’s efficacy. They have shown 8 percent severe neuropathy when Velcade is administered weekly and 6 percent when administered subcutaneously.

The experts pointed out that although combinations of neurotoxic drugs might be expected to cause higher rates of peripheral neuropathy, combinations including Velcade and thalidomide were not associated with higher rates of neuropathy.

In addition, Velcade plus Revlimid ^[8] (lenalidomide) and dexamethasone ^[9] (Decadron) resulted in lower-than-expected rates of neuropathy, with 2 percent to 3 percent of patients experiencing severe symptoms in most studies.  The experts suggested that the anti-inflammatory effects of Revlimid or dosing of Velcade and dexamethasone on the same days may reduce the risk of Velcade-induced neuropathy.

Velcade-induced peripheral neuropathy generally begins to occur after 15 weeks when the patient has received a total of approximately 26 mg/m² of Velcade.  The risk increases until the patient has received 42 mg/m² to 45 mg/m² Velcade, at which point the risk tapers off.

The only known risk factor for Velcade-induced peripheral neuropathy is a history of peripheral neuropathy prior to the start of Velcade therapy.  Studies have shown that prolonged exposure to Velcade or retreatment with Velcade does not increase a patient’s risk of developing peripheral neuropathy.

Thalidomide-Induced Peripheral Neuropathy

Most studies indicate that peripheral neuropathy develops in up to 55 percent of newly diagnosed myeloma patients treated with thalidomide (10 percent severe), and up to 27 percent of relapsed myeloma patients (6 percent severe).

However, studies have shown that up to 75 percent of myeloma patients treated with thalidomide for more than 12 months develop peripheral neuropathy.

The rate and severity of thalidomide-induced peripheral neuropathy also depends on the duration of therapy. Although it usually occurs after several months of thalidomide therapy, it has also been shown to affect patients within 14 weeks of therapy and occasionally after treatment has been stopped.

Results have been mixed regarding the factors that predispose a myeloma patient to thalidomide-induced peripheral neuropathy. The results of one study indicated that age, sex, and prior thalidomide therapy do not increase the risk of developing thalidomide-induced peripheral neuropathy. However, another study found that patients over 65 years of age were more likely to develop the disorder than patients under 65 years of age.

Other Drug-Induced Peripheral Neuropathy

Myeloma patients treated with vincristine-based combinations have been shown to develop moderate to severe peripheral neuropathy in 10 percent to 15 percent of cases, although peripheral neuropathy may emerge in up to 24 percent of patients who receive large doses of vincristine.

Much lower rates of peripheral neuropathy have been reported in myeloma patients treated with Revlimid (up to 2 percent severe neuropathy) and pomalidomide ^[10] (preliminary data suggests low to intermediates rates).

Moreover, recent studies have shown patients taking carfilzomib ^[11] (Kyprolis ^[12]), marizomib ^[13], and MLN9708 ^[14] (ixazomib ^[15]) – which belong to the same class of drugs as Velcade, called proteasome inhibitors – may also experience lower rates of peripheral neuropathy.

“Second generation proteasome inhibitors such as carfilzomib, marizomib, and MLN9708 are significantly less neurotoxic and also show considerable therapeutic promise, especially carfilzomib and MLN9708,” said Dr. Richardson.

However, the experts acknowledged that larger studies are needed to confirm the rate of peripheral neuropathy in patients receiving these newer proteasome inhibitors.

For more information, please see the article in the journal Leukemia ^[16] (abstract).