Many multiple myeloma patients are afflicted by tingling and pain in the hands, arms, feet, and legs (known as peripheral neuropathy). Treatments for myeloma can make this neuropathy worse. Dr. Paul Richardson of the Dana-Farber Cancer Institute discussed the prevention and management of peripheral neuropathy (PN) during an education session on June 7 at the annual American Society of Clinical Oncology (ASCO) meeting.

Dr. Richardson explained that myeloma, itself, causes nerve damage that leads to the pain and tingling. Up to 20 percent of patients experience some PN prior to treatment.

Myeloma patients can experience prickling or tingling, numbness, sensitivity to touch, and muscle weakness in the extremities. The neuropathy typically affects both sides of the body, and it progressively gets worse.

Patients with Vitamin B-12 deficiencies are at increased risk of developing PN, and 17 percent of newly diagnosed patients are Vitamin B-12 deficient. Dr. Richardson said that Vitamin B-12 deficiency needs to be corrected to avoid PN.

Many of the novel agents cause further PN, particularly thalidomide ^[1] (Thalomid) and Velcade ^[2] (bortezomib). Vincristine ^[3] (which is no longer commonly used to treat myeloma) and platinum-based chemotherapy (used in the DCEP regimen under the drug name cisplatin) also cause neuropathy.

“Management of peripheral neuropathy requires close monitoring and regular assessments,” said Dr. Richardson. “Prompt dose reduction and schedule change is essential, even with mild symptoms.”

Up to 75 percent of patients receiving thalidomide have some form of PN. The longer a patient is on thalidomide, the more likely they are to develop PN. In particular, there is an increased risk of developing PN after six months of treatment—an even higher risk after one year.

Although thalidomide-induced PN is typically mild to moderate, it is often irreversible even after discontinuation of therapy.

With such a high risk of a patient developing PN while on thalidomide, a cumulative neurotoxicity assessment should be performed monthly for the first three months, then at each exam or consult while on therapy.

As soon as PN develops, a patient should discuss it with their physician. A dose reduction is necessary, and if possible, thalidomide treatment should be discontinued. Revlimid presents much less risk than thalidomide and may be a suitable replacement.

Velcade often causes sensory and sometimes painful neuropathy and often begins in the legs and feet before affecting the arms and hands. PN caused by Velcade tends to be different than PN caused by thalidomide.

Velcade-induced PN most commonly occurs by cycle five of treatment. As PN develops, it can be managed by reducing the dose and frequency of Velcade. Unlike thalidomide, Velcade-related PN is usually reversible.

About 35 percent of patients using Velcade develop PN. Fortunately, the symptoms fade for 71 percent of those patients.

“PN dose modification did not appear to affect time to progression,” said Dr. Richardson. “This is a very important thing to understand. It reflects the fact that we were then able to continue therapy for longer.”

Patients who had PN before treatment are at high risk of their PN getting worse during treatment. However, age apparently does not affect the risk of developing PN.

Combination approaches can significantly impact the risk of PN. Combinations of drugs associated with PN can greatly increase the risk. However, other combinations may decrease the risk of PN. For instance, the addition of an HSP inhibitor (e.g. tanespimycin ^[4]) or an HDAC inhibitor (e.g. panobinostat ^[5]) to Velcade has been shown to reduce the rate of PN as compared to Velcade alone.

“Very importantly, as we now have combination strategies that work. It is perfectly reasonable to move to weekly schedules and lower doses [of Velcade] because you have other drugs in your combination that are likely to keep the myeloma under control.”

Additionally, Dr. Richardson said, “New agents, in particular, second-generation proteasome inhibitors (e.g. carfilzomib ^[6]) may hold real answers for us because their degree of neurotoxicity appears dramatically less, and I think that’s a very important consideration going forward.”

Dr. Richardson also recommended a list of vitamins and supplements ^[7] and cocoa butter massages to help reduce PN.  He pointed out, though, that clinical trials are needed to confirm the efficacy. He also recommended gabapentin (Neurontin) and Lyrica (pregabalin) to help manage PN-associated pain.

For more information, see a related Beacon ^[8] article about the causes of PN and how to treat it.