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Treating Peripheral Neuropathy in Multiple Myeloma

Value-Based Care in Myeloma - Multiple Myeloma
Caroline Helwick

In a recent article, the International Myeloma Working Group reviewed the latest information and management strategies for treatment-emergent peripheral neuropathy (PN) in multiple myeloma, and made recommendations (Richardson PG, et al. Leukemia. 2012;26:595-608). The key points are summarized here, with commentary by the lead author, Paul G. Richardson, MD, Clinical Director, Jerome Lipper Center for Multiple Myeloma and Associate Professor of Medicine, Harvard Medical School at Dana-Farber Cancer Institute in Boston.

Understanding the Condition

PN is common in patients with multiple myeloma, both as a disease-related complication in newly diagnosed patients and as a side effect of treatment. Although the exact etiology of disease-related PN is unknown, mechanisms are thought to include amyloid deposition, immunoglobulin M antibodies against myelin-associated glycoprotein (a glycoconjugate component of nerves that interacts between Schwann cells and axons), and cytokine-mediated neuronal damage, which possibly involves microvascular and small fiber injury as part of this process.

PN can also present in the form of radiculopathy from direct compression as a result of bone damage and plasmacytoma. In particular, however, PN can develop with the use of certain drugs, the most important being bortezomib and thalidomide, as well as vincristine, cisplatin, certain alkylating agents when used in combination with other neurotoxic drugs (eg, melphalan and thalidomide or bortezomib), and, much less common, lenalidomide.

Symptoms of Peripheral Neuropathy

Myeloma-associated PN predominantly occurs in the form of sensory or sensorimotor disturbances that are distal and progressive. Symptoms are usually symmetric and mild and include paresthesias, numbness, burning sensations, and weakness, although they can, in the rare patient, be disabling.

Symptoms caused by bortezomib versus thalidomide can be somewhat different, according to Dr Richardson, who spoke to Value-Based Care in Myeloma about the group’s report. “These drugs produce different types of symptoms,” he said. “Bortezomib usually affects the lower extremities first, then the hands. Thalidomide affects different people in different ways, and can have more central effects as well as present more proximally first.”

The article by Richardson and colleagues describes the differences this way: Bortezomib-induced PN “is predominantly sensory and mild (though severe sensory and motor PN have been reported in up to 15% of patients). Symptoms include a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort and neuropathic pain or weakness, which may start distally and progress proximally….Thalidomide is reported to cause a primarily sensory/sensorimotor, length-dependent axonal neuropathy, typically with tingling or painful distal paresthesia affecting the feet and sometimes the hands, as well as sensory loss in the lower limbs. Motor changes may affect patients with [thalidomide-induced PN] and can present as muscle weakness or, more frequently, tremor.”

Interesting Findings Regarding Incidence

Experience with bortezomib suggests that once PN plateaus, extending therapy does not usually increase the rate or severity of PN, and retreatment does not result in more toxicity, although the authors suggest that this may be in part because of a bias in patient selection.

Studies also indicate that lower doses and/or a weekly dosing schedule results in less risk from bortezomib, with subcutaneous administration (vs intravenous) being especially advantageous. With thalidomide, the incidence and severity are both dose- and duration-related, with the actuarial incidence increasing over the course of treatment and even worsening after treatment stops.

Although administration of neurotoxic agents in combination is a logical consideration to increase PN risk, clinical evidence suggests that this is not always so. Studies of bortezomib plus thalidomide alone or with dexamethasone, prednisone, or melphalan/prednisone do not show a notable increase in rate or severity of PN, and lower-than-expected rates of PN are observed with combinations of bortezomib plus lenalidomide, with grade 3 PN rates of 2% to 3% seen with bortezomib/lenalidomide/dexamethasone. Low rates of bortezomib-induced PN have also been reported when bortezomib is given with pegylated liposomal doxorubicin (4% vs 9% for bortezomib alone), or with some other experimental agents, such as histone deacetylase inhibitors.

“Neuropathy is probably reduced with these combinations because we are able to use less of each drug versus the single-agent approach where we have to maximize dose to ensure efficacy. It is also important to note that we may be seeing neuropathy from actual disease in some patients, rather than just drugs alone,” Dr Richardson suggested.

Finally, an important new area of investigation is the emergence of less-neurotoxic agents, including the second-generation proteasome inhibitors, such as carfilzomib, marizomib, and MLN9708.

Clinical Recommendations

Prevention of PN is important to preserve quality of life and future treatment options. All patients who are scheduled to receive neurotoxic drugs should be assessed for signs and symptoms of PN before starting treatment, particularly those with baseline PN, and should be monitored throughout therapy, ideally with each dose. This is particularly important for patients who develop severe, early-onset, bortezomib-induced PN, which may respond to high-dose steroids and require prompt dose reduction or treatment cessation. Regular monitoring is also important after transplant in patients with prior PN. The use of neuropathy-specific patient-completed questionnaires may help identify symptoms early, although these are not specific to myeloma, the authors noted.

“Neuropathy should be carefully monitored through direct questioning of the patient,” Dr Richardson emphasized. “Patient-reported symptoms are the most important clues, in my experience, with objective findings often being more difficult to routinely obtain.”

A neurologist’s clinical assessment can be useful in determining whether PN is treatment-related or disease-related; can distinguish motor neuropathy from other entities, such as steroid-induced myopathy; and may accurately determine the severity of the condition. Input from a neurologist can also be helpful for monitoring the benefit of symptomatic treatment with antiepileptic or antidepressant medications.

Prophylaxis and Treatment

On the basis of some prospective data from clinical trials and also anecdotal evidence, the authors suggested a number of prophylactic approaches, including the use of vitamin supplements (multi-B complex plus folic acid and vitamin E); magnesium replacement; increased dietary potassium intake; other supplements, including certain amino acids, fish oil, and omega-3 fatty acids; specific medications as indicated, including gabapentin, pregabalin, amitriptyline, and duloxetine; and topical creams, such as cocoa butter, which may help as part of regular therapeutic massage.

For patients receiving bortezomib, dose-modification guidelines have been developed and are included in the prescribing information for the drug. Early monitoring and prompt use of these guidelines can improve or resolve bortezomib-induced PN, while maintaining therapeutic efficacy. According to the article by Richardson and colleagues, the use of weekly bortezomib dosing in combination regimens may also help prevent grade 1/2 PN. It is important that supplements should not be taken on the day of bortezomib administration, because theoretical evidence, at least, suggests they may block the activity of the drug.

Reversibility of bortezomib-induced PN has been repeatedly demonstrated. In patients with prior bortezomib treatment, clinicians could commence subsequent treatment using a lower dose or once-weekly schedule, escalating as tolerated. As mentioned previously, subcutaneous bortezomib, which is now approved by the US Food and Drug Administration, is associated with a much lower incidence of PN and is viewed as an important new strategy, Dr Richardson noted.

For thalidomide, dose modification and discontinuation should also be used, but there is no prospectively validated dose-modification guideline. The authors suggested that thalidomide be limited to <200 mg/day, have a dose reduction by 50% in the case of grade 1 or 2 toxicity, and be stopped if grade 3 develops. Dose modification and discontinuation are important with low doses (eg, 50 mg daily), for example, during maintenance, once patients achieve the desired response.

The full publication contains details of the guidelines, which will be useful to all clinicians treating patients with multiple myeloma.

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Last modified: May 20, 2015
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