What is central nervous system (CNS) myeloma and how is it treated? Is there a difference between a plasmacytoma located in the brain and central nervous system (CNS) myeloma?

What is Central Nervous System (CNS) Myeloma and how is it treated?

CNS myeloma of the brain is very, very rare and most of what we look at is involvement of the covering of the brain with plasma cells usually become thickened and the CSF, which is fluid covering the brain, will have plasma cells in it. And that's what constitutes most of the serious disease.

Most of those patients will present with headache, blurred vision. Some of them present with nerve palsy, meaning paralysis of some of the nerves in the brain or paralysis in the legs, or what's called cauda equina syndrome, which affects the lower part of the spinal cord. Those patients usually have significant indication to actually look for CNS myeloma, we do not routinely look for CNS myeloma like some other diseases, like lymphoma and leukemia. They routinely put needles around the brain to see if this malignant cells are there or not. And myeloma, we do not do that.

Some studies suggest that patients with plasma cell leukemia, which is a very aggressive form of myeloma, will benefit from screening or routine evaluation of the CSF. But we have not adopted that approach in our center and I don't think other centers do that.

If a patient is diagnosed with CNS myeloma, how is it treated?

So unfortunately, the outcome for CNS myeloma patients is not great. The best treatment we have can be divided into three parts. The first one is called craniospinal radiation. When we do radiation to the brain and to the spine to try to clear as many plasma cells as we can. And this has been shown to be effective in good number of patients.

The second part is delivering the chemotherapy directly into the brain, covering, which is called the CSF. It's called intrathecal chemotherapy. This usually is given almost every other day. And then we cleared the CSF from the malignant cells and then we give them prophylactic doses every week and every month after that.

The intrathecal chemotherapy goal of it is to overcome what's called the blood brain barrier. The brain is protected from the different toxins in the blood by the blood brain barrier. And the same barrier can actually in prevent, some of the systemic treatments from concept to the blood to the brain to kill those plasma cells. And that's what is the benefit of giving the chemotherapy directly into the CSF.

The systemic treatment that has been tried has not been very successful. That said, there are some studies that suggest that IMiDs like REVLIMID and Pomalidomide can cross the blood-brain barrier, but I think the concentrations are usually very low and they do not kill enough myeloma cells. So, by themselves, they're not very effective.

There are some case reports we actually did one of those studies looking at what's called third generation proteasome inhibitors, not the Bortezomib or Velcade, or Carfizomib or Kyprolis, but it is a new one called the Marizomib. Marizomib is a new proteasome inhibitor that appears to have lipophilic properties, meaning it likes to bind to the lipids and it actually have a property to cross the blood brain barrier. So it has been tried in some brain tumors with some success.

And we did have a trial in our center of this particular and actually from Dana-Farber. Looking at combination of bortezomib and pomalidomide. And we have used this drug in a few cases with CMS myeloma in our center, and we have been able to clear the CSF.

So that is a new interest and finding those systemic patients that can cross the blood brain barrier. But in general, the outcome is not great and this is an area of great need or unmet need in myeloma.

What is intrathecal chemotherapy and is it used to CNS myeloma?

It's actually different types of chemotherapy. We do not usually use them in multiple myeloma. One is called methotrexate, Ara-C and prednisone. That's the three drugs we use in our center. There are other chemotherapies activity given intrinsically, but this is this triple into a peak of chemotherapy is more or less standard for any malignant or hematologic malignancies that affects the CNS, whether it's lymphoma, leukemia, or myeloma.

And as I said, we give it more frequent in the first few weeks until we clear the CSF of the cerebrospinal fluid from the plasma cells and then we give it once a week and then once a month of that.

So, central nervous system in myeloma is something that we certainly do worry about. So the central nervous system for one is referring to the brain and spinal cord specifically is different from the peripheral nervous system, which is really all the other nerves and nervous organs of the body. CNS myeloma and CNS plasmacytomas are manifestations of the abnormal plasma cells within the brain and spinal cord. And that can happen in a couple of different flavors.

One is, is a solitary plasmacytoma, similar to what can happen with bone, it technically can present in the central nervous system, and that is not defined as myeloma. But if someone was to have multiple plasmacytomas within the central nervous system, that would be considered myeloma, extramedullary myeloma, as it's called, which is multiple myeloma outside of the main space of the bone marrow, can technically occur anywhere within the body, including the central nervous system.

When this does occur, we do consider it an unfortunate finding prognostically this is not a great thing to see. And that's because, as with a lot of cancers that enter into that CNS space, they're just harder to treat. A lot of the drugs don't cross that blood brain barrier quite as well. And so the efficacy of these drugs that we otherwise would rely on and are successful, they just don't have the same efficacy.

We tend to rely more on radiation and some subsets of drugs do still have efficacy. Some of those include the immunomodulatory drugs, the IMiDs, things like lenalidomide or pomalidomide. But then the other mainstay of drugs such as the proteasome inhibitors, unfortunately don't penetrate the blood brain barrier quite as well. It's important to have a multimodal approach when we do see any evidence of plasma cell disease within the central nervous system. And so that usually involving also the radiation oncology team, in addition to your typical medical oncology and hematology teams.