Drug-Induced Peripheral Neuropathy In Multiple Myeloma Patients – Part 2: Treatment
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 second in a three-part series, summarizes the experts’ recommendations for the treatment of drug-induced peripheral neuropathy.
The first article in the 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 third article will summarize the experts’ recommendations for prevention of peripheral neuropathy as well as future steps toward better management of the condition.
The authors of the International Myeloma Working Group review concede that there is limited data regarding the treatment of drug-induced peripheral neuropathy specifically in myeloma patients.
For this reason, drug dose reduction is currently the “gold standard” when it comes to helping myeloma patients with Velcade (bortezomib)- or thalidomide (Thalomid)-induced peripheral neuropathy.
Velcade
Based on the findings of several Phase 2 studies, dose-modification guidelines have been developed for the management of Velcade-induced peripheral neuropathy. These guidelines are also included in the prescribing information for Velcade.
The guidelines state that patients who develop mild peripheral neuropathy without pain or loss of function should continue to receive the same dose of Velcade.
Patients who develop mild peripheral neuropathy with pain, or moderate peripheral neuropathy, should have their dose reduced to 1.0 mg/m2 of Velcade.
Patients who develop moderate peripheral neuropathy with pain, or severe peripheral neuropathy, should discontinue Velcade until their condition improves. Then, they should begin to receive Velcade at a reduced dose of 0.7 mg/m2 and once-weekly administration.
Patients with life-threatening peripheral neuropathy should discontinue Velcade.
In their review, the experts also agreed on a separate set of evidence-based dose modification guidelines for the management of Velcade-induced peripheral neuropathy.
“This is a proposed improvement on existing guidelines to reflect the role of combinations [of therapy] and the establishment of weekly Velcade as effective when indicated,” commented Dr. Paul Richardson of the Dana Farber Cancer Institute in Boston and the lead author of the review.
These consensus guidelines state that patients who develop mild or moderate peripheral neuropathy should receive Velcade either once per week or at a reduced dose. Patients who are already receiving Velcade once per week should further reduce their dose, or temporarily discontinue treatment and restart treatment at a reduced dose once their condition improves.
Patients who have moderate peripheral neuropathy with pain, severe peripheral neuropathy, or life-threatening peripheral neuropathy should discontinue Velcade.
In addition, the experts stated that patients may improve by switching from intravenous Velcade to subcutaneous Velcade.
“[Subcutaneous Velcade] is clearly less neurotoxic, reduces overall rates of peripheral neuropathy by 50 percent, and appears to be as effective as intravenous Velcade. However, it is not without its own challenges, including skin reactions,” said Dr. Richardson.
“Thus, strategies to reduce peripheral neuropathy with intravenous Velcade remain very important,” he added.
Thalidomide
Currently, there are no official dose modification guidelines for thalidomide-induced peripheral neuropathy.
For patients with mild peripheral neuropathy, the experts recommended cutting their thalidomide dose in half.
They further recommended that patients with moderate peripheral neuropathy discontinue treatment until their condition improves. Then, patients may restart with half of their original dose of thalidomide.
Based on current clinical practice, the experts noted that thalidomide should be discontinued in patients with severe or life-threatening peripheral neuropathy.
Other Treatment Measures
Several studies have shown positive results for the treatment of chemotherapy-induced peripheral neuropathy. However, these treatments have not yet been assessed in patients receiving anti-myeloma therapies.
According to the experts, anti-seizure medications such as gabapentin (Neurontin) and Lyrica (pregabalin) and anti-depression medications such as amitriptyline (Elavil) and Cymbalta (duloxetine) are commonly used for the treatment of drug-induced peripheral neuropathy.
Moreover, the amino acid acetyl-L-carnitine has shown activity in the treatment of drug-induced peripheral neuropathy.
Recent studies have also shown promising results for the treatment of drug-induced peripheral neuropathy with skin creams containing baclofen, amitriptyline, and ketamine.
Similarly, one study showed that menthol cream was effective in treating a patient with Velcade-induced nerve pain.
The experts warned that physicians who prescribe treatments for a myeloma patient with drug-induced peripheral neuropathy should keep in mind the patient’s current dosing schedule. The effectiveness of the potential treatments for peripheral neuropathy may be compromised if the patient continues to receive the same dose of neurotoxic anti-myeloma therapy.
For more information, please see the article in the journal Leukemia (abstract).
Related Articles:
- Eyelid-Related Complications Of Velcade Therapy: New Insights And Recommendations
- Adding Clarithromycin To Velcade-Based Myeloma Treatment Regimen Fails To Increase Efficacy While Markedly Increasing Side Effects
- Nelfinavir-Velcade Combination Very Active In Advanced, Velcade-Resistant Multiple Myeloma
- Revlimid, Velcade, and Dexamethasone, Followed By Stem Cell Transplantation, Yields Deep Responses And Considerable Overall Survival In Newly Diagnosed Multiple Myeloma
- Stem Cell Transplantation May Be Underutilized In Multiple Myeloma Patients In Their 80s
I know I sound like a old record but this approach of dose reduction "AFTER" peripheral neuropathy is realized is so archaic and downright patient hostile. Especially since PN is frequently reversible such as I have experienced after thalidomide.
Somehow we need to convince the medical community that the one-size-fits all approach to dosing velcade and thalidomide is simply unacceptable. Lets individualize the dose and minimize the possibility of ever contracting PN. That's my soap box for today.
You mentioned gabapentin as an analgesic for PN. We have just completed our work on this medicine and can provide optimal individualized dosing guidelines. Now all we have to do is sell our engineering based results to the medical community.
Patients who experience severe peripheral neuropathy with bortezomib and then switch to lenalidomide are likely to experience neuropathy with the new drug, and it is likely that the onset will occur more quickly and in the same category of severity.
It's still new enough that only limited data is available, but it appears that a switch from intravenous to subcutaneous bortezomib only marginally reduces the symptoms of neuropathy in those patients severely affected. For the greatest benefit, patients need to start with subcutaneous treatment.
Gabepentin and other drugs are usually only partially effective and more often have little or no effect --and sadly have their own side effects more often than not.
Those who experience severe peripheral neuropathy are basically left with no treatment alternatives because, as this article explains, the sole alternative is to abort therapy. This doesn't leave any alternative except for drugs like doxorubicin, which is tremendously toxic and has severe risk of cardiac and digestive tract damage.
These things cause me to question the idea of high dose chemotherapy in any but profoundly threatened by Multiple Myeloma. I think that treatment should begin with low dose regimens, and in the case of Velcade, subcutaneously. Only when a tolerance is demonstrated should a dosage be increased and a combination therapy tried. Considering the stakes, it makes more sense for a reluctant approach than a zealous one.
Thanks to the Beacon staff for this series of articles, which are very relevant to many MM patients. Gary, it sounds like you work in the field of treating neuropathy....would you like to elaborate more on the work? Bob, you have personal experience that cautions us to take neuropathy into account when taking treatments. As a patient, I think this shows that one shouldn't try to be too stoic about pain, because maybe dosages or treatments can be changed to avoid nerve damage. When I was treated, all the medical staff, including doctors, nurses and pharmacists, constantly queried me about neuropathy and other side effects. My dosages and duration on drugs were adjusted accordingly. i was indeed fortunate to escape with only mild neuropathy in my feet so far. Bob, when you say 'those profoundly threatened', I think that would include a lot of us who started treatment in what was Stage 3, but maybe for patients with a lower tumour burden treatments can be more gradually started.
Hi Nancy:
Yes, I think you're precisely right. I'm alarmed by the physicians who advocate immediate institution of high dose therapies; a recent interview here at the Beacon quoted the physician advocating large dose therapy even for MGUS/smoldering MM patients. Given the published research that low dose treatment has essentially the same effectiveness as large dose, I think the smart approach is reluctance; moving to treatment only when the MM is symptomatic and actually threatening, and then to approach treatment with low dose therapy. In the case of Bortezomib, try subcutaneous injection unless infusion becomes indicated, and even then in low dosage treatments.
Peripheral Neuropathy is like Pandora's Box, once the contents are released, you can never fully put them back in the box.
My teams were actually quite vigilant; my cycles were interrupted to permit the PN to wane. But it returned faster and faster with each resumption of treatment. Even changing from Velcade to Revlimid after a lengthy break failed to be helpful. That's why I am so supportive of the drug analogs which reduce side effects and alternate delivery (injection vs infusion) methods too. Even though they may not be better at stemming the Myeloma than their predecessors, a reduction in side effects permits greater latitude and time in treatment. That offers a greater opportunity for treatment success.
Thanks Bob...that is an excellent, logical summary of how to try to avoid neuropathy. Also, I get the impression that the drug thalidomide is worse for causing PN than some of the newer drugs available.
Nancy: The pharmacokinetics of gabapentin vary dramatically from patient to patient. For example, the bioavailability of the medicine ranges from 5% to 75% (i.e. the amount of gaba that enters the blood is 5% to 75% of the administered dose. Yet, we use a one-size-fits all approach to dosing (300mg day 1, two 300mg doses day 2 and three 300mg doses day 3 and then continuing at this level until clinical effects are observed). If the pain is not reduced, the dose is increased generally in 300 mg increments until it is or side effects are observed. Never does the doctor even examine the amount of gaba in the blood even though therapeutic window is known. Giving the same dose to two different people could give widely different results. Thankfully, the toxicities for gaba are mild. Can't say the same about our chemo agents. It is really frightening that we start each patient with same dose of velcade, melphalan, thalidomide, and dex. Each of these compounds have dramatically different Pharmacokinetic profiles. We need determine the concentration of the medicine in the blood of each patient first and then determine the best starting dosage regimen so we don't overdose. Just starting everyone at a low dose such as was suggested is not a good approach either. We simply have to use advances in personalized medicine to individualize the dosing to the patient. It is simple, cheap and minimizes the toxicities.
All we have to do is apply it.
Hi Gary, thanks for your scientific reply! Although I do not know enough about pharmacokinetics to make an informed reply, I would just guess that these tests for the levels of gabapentin, and velcade, melphalan, thalidomide and dex, are not widely available through the usual testing labs. Some of these drugs are so very expensive that one might propose that the manufacturers bear the cost of testing the levels in the blood of patients. Would that make sense to you?
Also, I realize that just starting patients who are not in an emergency situation with their myeloma problems, with a lower level of prescriptions, might not work at all times, due to the possiblility of drug resistance occurring.
Of course, one hopes just to rid themselves of all of the cancer cells quickly. However, there are other considerations such as neuropathy to be considered, since unfortunately it seems that the possibility of an indefinite period of CR is an unknown quantity for us patients, if we do get to that place.
Wishing you all the best with your interesting and important research!
Hi Again...when you say that the testing for drug levels in the blood is inexpensive, how is it done and is that widely available for the drugs in question?
I asked my oncologist this morning why the testing Gary suggested wasn't being used. It seemed like an easy way to predetermine Gabapentin effectiveness. He said that Gabapentin was an analog of GABA (gamma-aminobutyric acid) and chemically different. It did not use the same receptors as GABA nor did it cause an increase in GABA levels. According to him, no one really knows for sure why Gabapentin has the relieving effects on some people it does. As such, the only way to see if Gabapentin helps is to try it.
I also learned that the drug is known to cause edema in seniors and it also results in suicidal or violent thinking. It needs to be used with caution and monitoring according to NIH and Wikipedia.
my wife is in great pain from the velcade chemo drug ? she has been on all the pain drugs oxycodin oxycotin morphine etc . she is due to have another last round of a chemo drug diff from velcade . to get ready for a autologous transplant .my question is as my wife has been suffering for 2 months no change in this pain ,i think called (peripheral neuropathy)how long will pain last ????? as a loving husband it pains me to see her in this pain and her doctors do not seem to address it to stop it even after to stays in hospital . we are desperate for answers .. sincerly husband jim