Is there a difference between a plasma cytome in the brain and CNS myeloma? The 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 the fluid covering the brain, will have plasma cells in it. And that's what really constitutes most of the CNS 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 Coda Aquina 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 there is malignant cells there or not. In 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 a lot of centers do that. What does CSF stand for? Sleprospinal fluid, which is a fluid that protects the brain, and that's also part of the normal covering of the brain to make sure that the brain and the spinal cord are intact. If a patient is diagnosed with CNS myeloma, how is it treated? So unfortunately, the outcome for CNS myeloma patients is not great. The total number of people actually is counted in months, and the treatment has not been very effective. The best treatment we have can be divided into three parts. The first one is called craniospinal radiation. Will 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 a good number of patients. The second part is delivering the chemotherapy directly into the brain, coverings which is called the CSF. It's called intrathecal chemotherapy. This usually is given almost every other day until we clear 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 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 prevent some of the systemic treatments from crossing to the brain to kill those plasma cells. And that's what is the benefit of giving the chemotherapy directly into the CSF. What intrathecal chemotherapy is used? It's actually different types of chemotherapy. We do not usually use them in multiple myeloma. One is called methotrexate, RSC, and prednisone. That's the three drugs we use in our center. There are other chemotherapies that can be given intrathecally, but this is this triple intrathecal chemotherapy is more or less standard for any malignant or hematologic malignancy 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, the serpospinal fluid from the plasma cells, and then we give it once a week and then once a month after that. Has any systemic myeloma therapy been used to treat CNS myeloma? The systemic treatment that has been tried has not been very successful. That said, there are some studies that suggest that the imides 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. They are 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 Portazumab or Velcade or Carflozumab or Kyprolas, but there is a new one called Merazumab. Merazumab is a new proteasome inhibitor that appears to have lipophilic property, meaning it likes to bind to the lipids, and it actually has 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 with Paul Richardson actually from Dana-Farber looking at combination of Merazumab with pomalidomide. And we have used this drug in few cases with CNS myeloma in our center, and we have been able to clear the CSF. So there is a new interest in finding those systemic agents 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.