Peripheral neuropathy results from damage to the peripheral (e.g. arms and legs) nervous system. This system sends signals between the central nervous system (the brain and spinal cord) and the rest of the body. When a myeloma patient experiences peripheral neuropathy (PN), it occurs as a change in feeling in the hands, fingers, legs, feet, toes, or lips. PN is often described as pain, numbness, tingling, or burning.

Multiple myeloma patients may experience peripheral neuropathy as a result of the disease itself or its treatments.

According to the 2011 publication in Leukemia by Dr. Paul Richardson of the International Myeloma Working Group (IMWG), “Management of treatment-emergent peripheral neuropathy in multiple myeloma,” up to 20% of myeloma patients have PN at diagnosis. Additionally, PN symptoms can occur in up to 75% of myeloma patients after exposure to treatments that are toxic to nerve tissue. 

The nervous system is made up of the central nervous system (CNS), which includes the brain and the spinal cord, and the peripheral nervous system (PNS), which includes all the nerves in the body beyond the brain and spinal cord. 

The term “peripheral neuropathy” commonly describes damage to the nerves at the body’s periphery, or outer areas. These areas are often the arms, hands, fingers, feet, and legs.  

However, the peripheral nervous system also includes the autonomic nervous system, which regulates the function of organs over which we have no conscious control.  

The autonomic nerves connect the spinal cord to the internal organs. These organs include the blood vessels, stomach, intestine, liver, kidneys, bladder, genitals, lungs, pupils, heart, as well as  the sweat, salivary, and digestive glands. 

Which Peripheral Pathways Are Affected by Peripheral Neuropathy? 

PN can affect each of the peripheral nerve pathways: 

Sensory nerves. These nerves carry messages from receptors all around the body to the brain. 

Motor nerves. These nerves carry messages from the brain to the muscles to cause movement. 

Autonomic nerves. These nerves carry messages from the spinal cord to the organs to stimulate such functions as blood pressure control, body temperature control, breathing, digestion, heart rate, dilation and contraction of the pupils, urination, and sexual arousal. 

What Are the Symptoms of Peripheral Neuropathy? 

PN occurs  

  1. when the nerves are damaged or inflamed, or 
  2. when degeneration of nerve tissue has occurred, leading to changes in how nerves function. 

The symptoms of nerve damage depend on the type of nerves affected (sensory, motor, or autonomic). In myeloma patients, symptoms of PN occur symmetrically, or rather, on both sides of the body. For example, PN may occur in both hands and both feet. 

Symptoms of sensory peripheral neuropathy include: 

  • numbness 
  • tingling 
  • a prickling sensation 
  • sensitivity to touch 
  • lack of temperature sensation 
  • a burning, freezing, jabbing and/or throbbing sensation in the hands and feet 
  • the sensation of wearing gloves and stockings 
  • feeling of sand or gravel in the shoes 
  • the loss of proprioception, which is the feeling of knowing where your feet are on the ground 
  • loss of balance with the eyes closed 
  • loss of reflexes 
  • tinnitus (ringing in the ears) or trouble hearing 

Symptoms of motor peripheral neuropathy include: 

  • numbness 
  • tingling 
  • a prickling sensation 
  • sensitivity to touch 
  • lack of temperature sensation 
  • a burning, freezing, jabbing and/or throbbing sensation in the hands and feet 
  • the sensation of wearing gloves and stockings 
  • feeling of sand or gravel in the shoes 
  • the loss of proprioception, which is the feeling of knowing where your feet are on the ground 
  • loss of balance with the eyes closed 
  • loss of reflexes 
  • tinnitus (ringing in the ears) or trouble hearing 
  • Symptoms of motor peripheral neuropathy include: 
  • weakness 
  • muscle cramping 
  • loss of muscle mass 
  • decrease in reflexes 
  • difficulty writing 
  • difficulty manipulating and feeling small objects 
  • lack of coordination and falling 

Symptoms of autonomic neuropathy include: 

  • intolerance of heat, usually from decreased sweating 
  • difficulty adjusting to the dark (pupils not dilating enough) 
  • changes in blood pressure causing dizziness or light-headedness when sitting up or standing up 
  • digestive problems (diarrhea and/or constipation; bloating, reflux) 
  • a feeling of being full after eating very little 
  • urinary/bladder issues (urinating too frequently or too infrequently, or not being able to empty the bladder) 
  • erectile dysfunction 

What Causes Neuropathy in Patients with Multiple Myeloma?

  • Approximately 20% of patients present with peripheral neuropathy (PN) symptoms concurrent with the diagnosis of myeloma. 
  • PN may arise from pre-existing diabetes in some patients. 
  • Others may experience PN due to autoimmune diseases. 
  • Many individuals with PN developed it during the precursor stage of myeloma, known as monoclonal gammopathy of undetermined significance (MGUS). 

Myeloma-related peripheral neuropathy 

  • The ways in which PN occurs in MGUS and myeloma are complex and are not well understood. The general theory is that monoclonal protein secreted by myeloma cells directly damages motor and sensorimotor nerve cells  
    • by stripping their myelin sheaths and 
    • by causing degeneration of axons, the long threadlike parts of nerve cells along which impulses are conducted from the cell body to other cells. 
  • Myeloma can also cause PN when a fractured vertebra directly compresses nerve roots in the spinal cord. 
  • PN caused by myeloma may improve with treatment that controls the myeloma. Yet, some treatments may be toxic to nerve tissue. 
  • In addition to MGUS, PN occurs in patients with other disorders related to myeloma, including amyloid light-chain (AL) amyloidosis and the rare POEMS syndrome. 

Treatment-related neuropathy 

In myeloma, the chance and seriousness of nerve issues from treatment increase  

  • with the dose of treatment and 
  • the duration of treatment.  

Nerve issues can even happen after treatment ends. 

Proteasome inhibitors affect how myeloma cells recycle proteins, like a "garbage disposal" for proteins. Without this process, myeloma cells get overloaded with protein "garbage" and die. 

Unfortunately, these broken-down proteins can build up in and harm special nerve cell clusters called dorsal nerve root ganglia. These clusters help send messages of pain and touch from the spinal cord to the skin, muscles, and more. 

Myeloma drugs that may cause peripheral neuropathy 

Proteasome inhibitors 

Kyprolis (carfilzomib) does not cause PN. 

Yet, Velcade (bortezomib) and Ninlaro (ixazomib) can cause significant peripheral neuropathy. 

Velcade and PN 
  • Velcade primarily affects sensory nerves and can lead to painful neuropathy. 
  • Subcutaneous (SC or SQ) Velcade injections cause significantly less sensory peripheral neuropathy compared to intravenous (IV) Velcade. 
  • SC Velcade also results in fewer autonomic nerve side effects, such as gastrointestinal upset (diarrhea, constipation, nausea), low blood pressure (hypotension), and irregular heartbeat, compared to IV Velcade. 
  • Risk factors for peripheral neuropathy in Velcade patients include obesity and pre-existing neuropathy. 
  • Peripheral neuropathy induced by Velcade is at least partially reversible in most patients. 
Ninlaro and PN
  • Ninlaro, an oral proteasome inhibitor, is used alongside Revlimid® and dexamethasone (Rd). 
  • Like Velcade, the combination of Ninlaro + Rd can lead to peripheral sensory neuropathy (PN). 
  • However, the incidence of PN is lower with Ninlaro + Rd compared to Velcade + Rd. 
  • Severe cases of PN with Ninlaro + Rd are as frequent as with Rd alone, affecting 2% of patients. 
  • In a large study submitted to the U.S. Food and Drug Administration (FDA) for Ninlaro + Rd approval, 28% of patients reported PN. 
  • Of the reported PN cases, 18% were mild (grade 1 on a scale of 1–4). 

Immunomodulatory drugs 

Revlimid, Pomalyst, & Thalomid and PN 
  • Revlimid® (lenalidomide) and Pomalyst® (pomalidomide) are oral medications that regulate the immune system and have both anti-inflammatory and anti-cancer properties. 
  • They work by blocking cytokine activity, activating T cells and natural killer (NK) cells, and inhibiting the growth of blood vessels that support cancer cells. 
  • Thalomid (thalidomide) is associated with peripheral neuropathy (PN) as a common side effect, likely due to its effects on the dorsal root ganglia (DRG) and myelinated nerve fibers, as well as its impact on the autonomic nervous system. 
  • PN occurs in about 70% of patients treated with Thalomid for 12 months or longer, and symptoms can persist even after treatment ends. The risk increases if nerve damage exists before treatment. 
  • PN from Thalomid can be permanent, with some cases not resolving at all. 
  • Patients treated with Revlimid and Pomalyst have a significantly lower risk and less severe PN compared to Thalomid. 
  • Clinical trial data show PN rates of 23% for Revlimid and dexamethasone (Rd) and 17% for Pomalyst and dexamethasone (Pd), with no reports of severe (grade 3 or 4) PN for either medication. 

Other factors that may worsen peripheral neuropathy 

  • Smoking interferes with circulation of the blood in the hands and feet, and blood flow is therefore cut off to nerve cells in these areas. Patients with PN should not smoke. 
  • Diabetes can cause chronically elevated blood sugar, as can treatment with such steroids as dexamethasone. A high blood sugar level can damage the peripheral circulation and peripheral nerves. 
  • Narrowing of the arteries from high blood pressure or atherosclerosis (fatty deposits on the inside of the blood vessels) can decrease oxygen supply to the peripheral nerves and lead to nerve tissue damage. 
  • Infections that affect the nerve cells can pose additional risk of neuropathy for myeloma patients.  
  • Shingles, a reactivation of the virus that causes chicken pox (the zoster virus), can cause painful peripheral neuropathy.
    • Patients receiving treatment with a proteasome inhibitor (Velcade, Kyprolis, or Ninlaro) should be taking an anti-viral medication such as acyclovir or valacyclovir to prevent shingles. 
  • Bacterial infections, like the ones that cause Lyme disease, can also cause peripheral neuropathy. Discuss preventive use of antiviral and antibacterial medications with your doctor

Some drugs not used to treat cancer can also cause PN, including the following: 

  • amiodarone, which controls heart rhythm (brand names Nexterone® and Pacerone®) 
  • hydralazine (Apresoline®, BiDil®), a vasodilator that relaxes the blood vessels to lower blood pressure 
  • isoniazid (Nidrazid®), used as part of combination therapy to treat tuberculosis 
  • the anti-malarial medication chloroquine (Aralen Phosphate®) 
  • the anti-bacterial drug metronidazole (Flagyl®) 
  • drugs used to treat autoimmune diseases such as etanercept (Enbrel®), infliximab 
  • (Remicade®), and leflunomide (Arava®) 
  • anti-seizure medications such as carbamazepine (Tegretol®), phenytoin (Dilantin®, Phenytek®), and phenobarbital (Luminal®, Solfoton®).  

Make sure that you consult your doctor or a pharmacist about drugs you may be taking for other medical conditions that may cause or worsen peripheral neuropathy. 

  • Vitamin B12 deficiency can cause peripheral neuropathy (PN). 
    • In the United States, B12 deficiency is common, especially among the elderly, with estimates of 10%–25% in those over age 80. 
    • A vegan diet can lead to B12 deficiency as animal-based foods are the primary sources of B12. 
    • Before starting treatment, a medical evaluation should include assessing the baseline level of vitamin B12. 
    • Vitamins E, B1, and B6 are also crucial for nerve health and function.

Preventing peripheral neuropathy or lessening its impact 

  • Assessment for signs of sensory or motor nerve damage is crucial before starting treatment with any drug that can cause peripheral neuropathy (PN). 
  • Early assessment helps establish a baseline for comparing new symptoms of PN. 
  • If early PN is detected, reducing the dose or adjusting the treatment schedule can help manage it. 
  • Early recognition of PN is vital as early neuropathy is often reversible. 
  • Keep records of any symptoms and report them promptly to facilitate timely intervention. 

Managing peripheral neuropathy 

Modifying dosages and schedules of medications 

  • If symptoms of peripheral neuropathy (PN) arise during treatment, your doctor can adjust the dose and/or schedule of the medication. 
  • More severe PN symptoms may lead to referral to a neurologist or discontinuation of the treatment causing PN. 
  • Velcade dosing can be adjusted by reducing the standard dose from 1.3 mg/m2 to 1.0 mg/m2 or 0.7 mg/m2. It can also be given once weekly instead of twice weekly without losing effectiveness. Subcutaneous injection of Velcade is preferred over intravenous infusion due to lower PN rates. 
  • For Ninlaro, dosing can be withheld or reduced until PN symptoms improve. It comes in 4 mg, 3 mg, and 2.3 mg capsules for dose adjustments. 
  • Thalomid, Revlimid, and Pomalyst are oral medications available in various dosages. Dose reductions may be made with these medications to manage PN. Revlimid may be adjusted to provide breaks in the treatment cycle or prescribed at lower doses, such as 5 mg daily.

Medications for painful neuropathy 

The pain associated with PN can vary in intensity and is often described as “sharp,” “burning,” or “jabbing.” 

  • Mild pain from PN can be controlled with a simple over-the-counter (non-prescription) pain-reliever such as acetaminophen (Tylenol®). 
  • In general, myeloma patients should not use non-steroidal anti-inflammatory drugs (NSAIDs) such as naproxen or ibuprofen because NSAIDs can cause kidney damage. 
  • Common medications prescribed to treat neuropathic pain are antiseizure medications gabapentin (Neurontin®) and pregabalin (Lyrica®). 
  • Duloxetine (Cymbalta®) and some of the tricyclic antidepressant drugs, like amitriptyline (Elavil®) and nortriptyline (Pamelor®), can also be effective for nerve pain. 
  • A neurologist may be able to give you a prescription that combines topical versions of several drugs for nerve pain mixed into a neutral gel or ointment that can be made at a compounding pharmacy. 
  •  A lidocaine patch or lidocaine ointment can offer local relief to a particular area of pain, as can capsaicin cream, which is a very inexpensive numbing agent made from the active ingredient in chili peppers.  
  • Other patients have reported success in reducing PN pain with a menthol cream. 
  • Gently massaging cocoa butter into an affected area can be soothing. 

Supplements that are neuroprotective 

  • Vitamin B6, not to exceed 100 mg per day. (More than that can be toxic to the nerves.) If you’re already taking a multi-vitamin or a B vitamin complex that includes B1, B6, B12, and folic acid, make sure that the total daily dose of B6 is nor more than 100 mg. 
  • Vitamin B12, at least 400 micrograms daily (can be part of the B complex vitamin) 
  • L-glutamine, 500 mg per day 
  • L-carnitine, 500 mg per day 
  • Alpha lipoic acid (ALA), 400–600 mg per day. ALA comes in 200-mg capsules.
    • Take one capsule with a meal. If no improvement is seen with 400 mg, you can take a third capsule with food.
    • ALA is especially effective for leg cramping associated with peripheral neuropathy. 
    • A caveat: ALA can prevent Velcade from working. To be absolutely safe, patients who are being treated with Velcade should NOT TAKE ALA the day before, the day of, and the day after a Velcade treatment. 
  • HIgh-dose vitamin C and green tea can also interfere with the action of Velcade, reducing its anti-myeloma effect. 

Dealing with cramps and muscle twitching 

  • Nocturnal leg cramps can be caused by peripheral neuropathy. 
  • To lessen the likelihood of leg cramps, stretch and lengthen the calf and leg muscles a bit before bed. 
  • Loosen the sheet and blanket from the corners and bottom of the bed to relieve pressure on the feet and legs. A pillow at the end of the bed can lift the sheets off the legs. 
  • Drink plenty of fluids to stay hydrated. 
  • A warm towel, heating pad, or warm bath can soothe tight muscles. 
  • There is scientific evidence to support the claim that drinking pickle juice helps alleviate leg cramps. The acid in pickle juice triggers a reflex in the back of the throat that decreases activity in the alpha motor neurons, which causes muscle relaxation. You don’t even have to swallow the pickle juice to trigger the reflex, which can relieve cramps in 3–4 minutes. 
  • A warm towel, heating pad, or warm bath can soothe tight muscles. 
  • There is scientific evidence to support the claim that drinking pickle juice helps alleviate leg cramps. The acid in pickle juice triggers a reflex in the back of the throat that decreases activity in the alpha motor neurons, which causes muscle relaxation. You don’t even have to swallow the pickle juice to trigger the reflex, which can relieve cramps in 3–4 minutes. 

Other strategies for dealing with peripheral neuropathy 

  • Studies show that aerobic exercise can stabilize or partially reverse neuropathy. Swimming is an excellent way for myeloma patients to get aerobic exercise. It safely offers resistance to the muscles without the potential harm of impact. Even putting on a floatation belt and treading water can raise the heart rate and strengthen muscles in the arms and legs. 
  • Acupuncture is thought to stimulate the nervous system by causing the release of endorphins, the body’s natural painkillers. Acupuncture can complement the use of pain-relieving drugs. A list of doctors who practice acupuncture is available from the American Academy of Medical Acupuncture. 
  • Transcutaneous electrical nerve stimulation (TENS) machines can sometimes help reduce pain by delivering tiny electrical impulses to specific nerve pathways at or near the site of pain through small electrodes placed on the skin. These electrical impulses prevent pain signals from reaching the brain. 
  • CBD (cannabidiol), the non-psychoactive compound in marijuana, and THC (tetrahydrocannabinol), the principal psychoactive compound, may be helpful in managing neuropathic pain. Animal tests have shown that both THC and CBD are neuroprotective antioxidants. CBD has particularly strong anti-inflammatory and anti-seizure properties; as we saw above, anti-seizure medications are also effective for the treatment of neuropathy. If you live in a state where you can obtain medical marijuana legally, you may want to discuss this option with your doctor. 
  • Reduce alcohol intake. Alcohol consumption can increase nerve damage. 

Strategies to help manage autonomic symptoms 

  • Feeling dizzy or light-headed after standing up (orthostatic hypotension) 
  • Compression stockings that go above the knees can help prevent pooling of blood in the legs. Your doctor may prescribe these for you. 
  • Have your doctor monitor your blood pressure regularly. 
  • Fluid intake of 2–3 liters daily can help. 
  • Unless you have a heart condition that limits your salt intake, get a normal amount of salt in your diet to help keep water in your blood vessels. 
  • Sit up or stand up slowly and move the feet and legs to allow the blood pressure to adjust. 
  • In cases of severe hypotension, your doctor may prescribe a medication. 

Gastrointestinal problems: constipation and/or diarrhea 

  • Eat small, more frequent meals that don’t contain insoluble fiber (beans, whole wheat or bran products, green beans, potatoes, cauliflowers, and nuts). 
  • Liquids are easier to digest than solids, so supplement with protein shakes. 
  • Avoid carbonated beverages and alcohol and stay well hydrated. 
  • Your doctor may need to recommend a medication that you can take before eating to get your gut moving. 
  • Urinary frequency may be caused by neuropathy. Your doctor may recommend a medication to help with urinary frequency. Yet, caution must be taken because some of these medications also cause lightheadedness. There are drugs for this problem that do not make hypotension worse. 

Sexual dysfunction 

  • Men who have a change in their ability to get or sustain an erection should report the problem their doctor, who can prescribe a medication (like Viagra® or Cialis®) or a medical procedure. 
  • Some women may notice vaginal dryness. The doctor can recommend a lubricant or cream. 

Maintaining good general health 

  • A well-balanced diet with freshly prepared ingredients and ample sources of vitamins B6, B12, and folate, vitamins D and E, and healthy fats helps protect the nervous system. Eat lots of fresh fruits and vegetables, whole grains, and fish rich in omega 3 fatty acids. 
  • Drink plenty of water and other non-alcoholic drinks. 
  • Limit sugar intake. High blood sugar increases damage to peripheral circulation and peripheral nerves. 
  • Make regular, daily exercise for 20–30 minutes a part of your life. If swimming is not convenient or possible, a brisk walk outdoors or on a treadmill or a ride on a stationary exercise bike are other good options. 
  • Maintain healthy skin in areas of sensory neuropathy. Reduced sensation can result in injuries that leave sores or blisters. Moisturize the hands and feet daily and keep toenails carefully trimmed and filed smooth. 
  • Reduce accident risk by
    • turning the lights on before entering a dark room 
    • removing small rugs and loose floor mats 
    • wiping up spills immediately 
    • removing clutter near walkways, and  
    • using skid-free shower and bathmats. 

Download the IMF Publication Understanding Peripheral Neuropathy as listed in Related Content. 

The International Myeloma Foundation medical and editorial content team

Comprised of leading medical researchers, hematologists, oncologists, oncology-certified nurses, medical editors, and medical journalists, our team has extensive knowledge of the multiple myeloma treatment and care landscape. Additionally, Dr. Brian G.M. Durie reviews and approves all medical content on this website.

Last Medical Review: April 19, 2024

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