Managing Peripheral Neuropathies Associated With Waldenström Macroglobulinemia

At the 2022 Lymphoma, Leukemia & Myeloma Congress in New York, Norman Latov, MD, Weill Cornell Medicine, Irvington, NY, outlined the types of peripheral neuropathies associated with Waldenström macroglobulinemia and IgM monoclonal gammopathies and discussed available therapies for managing these complications.

Transcript:

My name is Norman Latov. I'm a professor of Neurology at Weill Cornell Medicine with an interest in peripheral neuropathies. I spoke at the Lymphoma, Leukemia & Myeloma Congress on peripheral neuropathies associated with Waldenström macroglobulinemia and IgM monoclonal gammopathies. The neuropathy occurs in about 5% of patients with macroglobulinemia. It's important to screen patients for the presence of neuropathy, because it can remain asymptomatic until late when there's considerable amount of damage. So, it's good to diagnose it early and start treatment to prevent progression of the neuropathy.

Many of the patients don't have macroglobulinemia. They have what's called MGUS, monoclonal gammopathy of uncertain significance, because it's precancerous, which may or may not develop into cancer. But normally such patients aren't treated. In some cases, the abnormal proteins secreted by these cells bind to peripheral nerve and cause neuropathy, in which case it's important to treat them even at the early stage before they become cancerous.

This condition can be easily screened for, by checking sensation at the toes with a tuning fork to see if there's a sensory decrement. Also, blood tests can be ordered for antibody binding to peripheral nerves. Most commonly the antibodies are directed at MAG or Myelin-associated Glycoprotein. Some less commonly, again, is gangliosides or sulfatides, and those tests are also available. So probably early in the course of investigation of the neuropathy, these should be tested for.

The diagnosis sometimes is missed because patients present early not because of the tumor load, but because of the peripheral neuropathy. The monoclonal gammopathy could be very small and requires testing by immunofixation electrophoresis rather than by serum protein electrophoresis. Also, the neuropathy can remain mild for long periods of time and patients compensate for the loss, but then precipitously progress. It's important to make a diagnosis before this progressive stage, when there's still time to prevent significant damage.

There are 3 main types of neuropathy associated with Waldenström macroglobulinemia. One is MAG neuropathy. It affects predominantly the distal portions of the nerves or the feet, and then the hands, and causes numbness and loss of sensation, and eventually ataxia or a loss of balance in coordination, and if allowed to progress, also weakness. Again, it's a slow progressive neuropathy, but after about 10 or 15 years, about 50% of the patients become disabled if not treated.

Another type of neuropathy is multifocal motor neuropathy, which presents predominantly with weakness in the hands, and progresses to involve the feet. It's associated with antibodies to GM1 ganglioside. A third type of neuropathy is predominantly sensory neuropathy, which presents only with sensory loss in hands and feet, and it's associated with antibodies to GD1 ganglioside or to sulfatide. And these can be tested for.

There's good evidence that the neuropathies caused by the IgM paraproteins that can cause disease in experimental animals, and if treated to reduce the antibody concentration, the neuropathy improves. The mainstay of therapy is rituximab, which reduces the concentration of the IgM. The aim is to reduce the concentration by at least 50%. And usually if that's done, the neuropathy improves or stops progressing. In some cases when the condition is premalignant, the abnormal protein can be eradicated and the treatment could be discontinued without recurring. Again, if caught early, significant neuropathy can be disabled and prevented.

The treatments which are available include rituximab, which is the mainstay, and more recently Ibrutinib, which is a BTK pathway inhibitor, which can help reduce the IgM concentration. And even more recently, BCL-2 inhibitors such as venetoclax which also reduces IgM concentration. Prior to that, we used chemotherapeutic reagents, but the neuropathies are a chronic condition and these have cumulative toxicity, so they're not favored.

One problem is [that] the newer drugs are only approved for the malignant conditions for Waldenström, not for MGUS, so it is sometimes difficult to get insurance approval based on the lack of large study showing efficacy and FDA approval. We need these types of studies to show benefit, in order to make treatment more accessible to more patients.

Source:

Latov, N. WM Associate Neuropathy. Presented at Lymphoma, Leukemia & Myeloma Congress; October 18-22, 2022. New York, NY.