Managing Bortezomib-Induced Neuropathy

Burning, tingling, squeezing, pinching, numbness, aching, and pain--these are all words patients use to describe how a common side effect such as chemotherapy-induced peripheral neuropathy (CIPN) feels to them. This is a common side effect related to administering platinum and taxane drugs, but is this something that patients are experiencing with targeted therapy drugs as well?

As an example, for those with multiple myeloma being treated with proteasome inhibitors such as bortezomib (Velcade), it definitely can be.

Multiple myeloma (MM) accounts for almost 1% of all cancers and there are over 20,000 new cases annually, with half of that number resulting in death in the United States. MM is one of the most common of the plasma cell disorders. Accumulation of monoclonal plasma cells within the bone marrow secrete immunoglobulins or light chains and can have a harmful effect on kidneys, bones or cause systemic dysfunction due to the tumor-released humoral factors.

Bortezomib is usually administered as a first-line therapy, often part of a prednisone and melphalan combination. In the past, bortezomib was only available via intravenous route. However, by 2012, results from a phase III clinical trial that compared intravenous vs subcutaneous administration of bortezomib, demonstrated that after 10 cycles of this medication, near-complete responses were just about the same, as well as time to progression.

The bonus finding here was that peripheral neuropathy incidences were significantly lower overall (38% vs 53%) with subcutaneous administration. Even higher-graded peripheral neuropathy side effects were also decreased significantly with the subcutaneous route (≥grade 2 at 24% vs 41% and ≥grade 3 at 6% vs 16%). Reason being is that the subcutaneous route reduces the incidence of high peak medication levels often seen with intravenous use. Therefore, there could be less direct damaging effects on the dorsal root ganglion (sensory) aspect of CIPN. And as for the motor skills that could be altered, demyelinated or a mixed axonal-demyelinated neuropathy may also have less of an impact. Overall weakness (7% compared to 16%) is also less with the subcutaneous route.

Many factors go into the incidence of this common side effect from occurring: Comorbidities (e.g., diabetes), a preexisting baseline neuropathy, those receiving treatment longer, repeatedly, or at higher doses, and even genetic factors. When someone is receiving bortezomib, symptoms of peripheral neuropathy are usually seen within the first few cycles of treatment, or when the cumulative dose reaches about 26 mg/m².

On exam, distal sensory loss is exhibited, as well as possible changes in proprioception. Deep tendon reflexes may be diminishes or absent. Motor skills may also be affected with distal weakness being seen in the lower extremities. This weakness may manifest as being mild to severe.

Many patients have asked me, “Will this go away?”, and usually it does. By 3 months (after the completion or discontinuation of bortezomib treatment), resolution may be seen. However, it could take up to a couple of years, or in less common cases, it could be a sequela from treatment.

Another question I am often asked before treatment begins and side effects are discussed, is if there is any way to prevent CIPN from happening. In addition to my usual recommendation of good habits (adequate sleep, managing stress techniques, proper nutrition, hydration, and exercise) there are no established ways to prevent it. However, weekly administration of subcutaneous bortezomib rather than the standard twice per week treatment schedules has demonstrated less frequent and severe neurotoxicity--dose reduction may be an option too.

If patients do actually experience this troublesome side effect, management of the symptoms are just as important as the disease management itself. Duloxetine (Cymbalta) is one medication known to lessen these symptoms. These findings were shared from the April 2013 issue of the Journal of American Medical Association (JAMA) and the British Medical Journal (BMJ).

The results from this clinical trial demonstrated that duloxetine helped to reduce pain in people with peripheral neuropathy after chemotherapy. However, this study only included chemotherapy protocols that contained taxane or platinum drugs in their regimen. The trial studied the effects over 5 weeks, starting the first week dose at 30 mg per day, and then increasing to 60 mg per day for a month. At the end of 5 weeks, the duloxetine group reported a decrease in pain over 10% to 30% from baseline. The sample size was small, only 231 patients in this study. Additional recommendations from the American Society for Clinical Oncology (ASCO) for treating CIPN include using gabapentin or pregabalin for a few weeks. Also, tricyclic antidepressants such as, nortriptyline or desipramine, can be used short-term and are known to help with other types of neuropathic pain.

Topical gels containing baclofen, amitriptyline HCI, and ketamine can be trialed, but keep in mind that these formulas can only be created by a compounding pharmacy. Topical menthol (e.g., calamine lotion) may also help those being treated for postherpetic neuralgia. Remember, there are no medications that have been proven to prevent CIPN--the above recommendations may only help to lessen the symptoms associated with CIPN.

It is also thought that bortezomib may cause an immune-mediated neuropathy with both motor and sensory involvement, in addition to the usual neurotoxicity that this may be responsive to immunotherapy. Some limited studies have shown some relief with the administration of IV immunoglobulin or glucocorticoids.

It is always enlightening to witness ongoing advances, not only with targeted therapy drugs such as bortezomib, but also in the management of side effects from these novel new therapies.

How do you manage treatment-induced neuropathy?

References:

• Arnulf B, Pylypenko H, Grosicki S, et al. (2012). Updated survival analysis of a randomized phase III study of subcutaneous versus intravenous bortezomib in patients with relapsed multiple myeloma. Haematologica. 2012 Dec; 97 (12): 1925-8. Epub 2012 Jun 11.
• BMJ 2013; 345: f2199. Duloxetine reduced chemotherapy-induced peripheral neuropathy. British Medical Journal. Retrieved from epocrates.com via Doc Alert.
• Lee EQ, Wen PY. (2014). Overview of neurologic complications of non-platinum cancer chemotherapy. Updated on May 27, 2014.
• Lexicomp (2014). Bortezomib: Drug information.
• Loprinzi CL. (2014). Prevention and treatment of chemotherapy-induced peripheral neuropathy. Updated on June 10, 2014.
• Smith EM, Pang H, Cirrincione C, et al. (2013). Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: a randomized clinical trial. The Journal of the American Medical Association (JAMA), 2013 April 3;309 (13): 1359-67. Doi: 10.1001/jama.2013.2813.