Anastasios Raptis, MD, PhD, Hematology Oncologist at UPMC Hillman Cancer Center talks about a new method of treatment for multiple myeloma patients.
Many of our viewers may have heard of multiple myeloma and they have a real understanding of it’s a type of blood cancer. But just for those who are not as familiar, can you tell me what multiple myeloma is?
RAPTIS: So multiple myeloma is a blood cancer that originates from the plasma cells. Plasma cells usually are normal cells presently in our bone marrow that are responsible for producing the antibodies. So, when we get infected, there are different types of plasma cells that they are activated, and they produce the antibodies that will fight whatever infection the patient encounters. In multiple myeloma, what happens is that one specific plasma cell starts proliferating at the expense of the other normal plasma cells. And as a result, one clone of plasma cells that dominates the plasma cell population in the marrow and produces one type of antibody, which we used to call it M protein. And that is the M protein that we monitor in order to assess the status of the disease at the beginning but also to assess the response to any treatment that we initiate for the patients.
What’s the standard treatment? What’s the gold standard right now?
RAPTIS: The standard treatment varies. It depends on the age of the patient or the physical condition of the patient. It depends whether the patient is a stem cell transplant candidate or he is not a stem cell transplant candidate. So usually it varies from patient to patient. But I would say that the majority of the patients will be treated with a combination of three drugs the Bortezomib, Revlimid and Dexamethasone. The so-called VRD regimen.
You had mentioned stem cell transplant for younger patients. Is that the most common treatment? Is that an effective treatment?
RAPTIS: So for younger patients, the high dose chemotherapy and a stem cell transplant still today is considered the standard of care. And that is because we have several studies, even in the context of the newer drugs that are available for patients with myeloma, that has offered longer disease-free survival, deeper response rates compared to patients who do not take the transplant. Now this most likely is going to change in the next few years, particularly after assessing the minimal residual disease status with the newer modalities that we have available and possibly patients who are in minimal residual disease negative status, we could avoid transplant and keep the transplants for later on when the patient will have recurrent disease.
If a patient can’t have a stem cell transplant, either they’re older or they have other mitigating circumstances where they’re just not good candidates. Has there been much that you’ve been able to offer them?
RAPTIS: Oh, yes. Yes. There has been significant improvement not only for patients who undergo a stem cell transplant, but also for patients who do not take the transplant we have several options these days to treat these patients. So suffice to say that generally speaking, all comers, we have been able to improve the survival of our patients. The media survival is to now nine to 10 years compared to approximately two to three years a decade ago.
Let’s talk a little bit about the CAR T therapy. Can you tell me, first of all, what this is that we’re talking about?
RAPTIS: The CAR T therapy is a form of immunotherapy. So, the basis of this approach is the utilization of a patient’s own lymphocytes. So, we harvest that lymphocytes from the peripheral blood. And we send them to a manufacturing facility where they genetically engineer the T lymphocytes in such a way that when we infuse them back into the patient, they will recognize a specific antigen that is expressed by the myeloma cells. And this antigen is called BCMA. That is the most common target of the current CAR T cells. Now, there is a significant also interest in trying to identify other possible targets like the SLAMF7, BRAF or APRIL. So these are the targets that most of the CAR T cells will target and possibly a combination of two targets. For example, BCMA with APRL or BCMA with BRAF. So after we infuse the CAR T cells to the patient, there is a significant interaction between the infused CAR T cells and the patient. And that interaction results in the killing of the myeloma cells but can also result into toxicity. And what is that toxicity? It is the CRS and neurotoxicity. The CRS stands for cytokine release syndrome. Fortunately in the myeloma field, the CRS and the neurotoxicity in the majority of patients are grade I-II, in other words mild forms, as opposed to the experience of the CAR T cell treatment in acute lymphoblastic leukemia or diffuse large B cell lymphoma where the CRS and the neurotoxicity are higher grades than one and two, three to four. We have been fortunate in the myeloma field that we have not had a grade three or four for either CRS or neurotoxicity. It’s probably in the single digits the rate of grade three or four of these toxicities in myeloma patients.
Doctor, how many patients have you had? How many multiple myeloma patients have you had on the CAR T therapy? And how do you explain to them how it’s working in their system?
RAPTIS: So personally, from my clinic, I had one patient who participated in the clinical trial. And this patient was refractory to all three classes of the most effective drugs, was refractory to immunomodulators like Revlimid or Pomalidomide, was refractory to proteasome inhibitors like Carfilzomib or Velcade, and refractory to monoclonal antibodies like Daratumumab that targets the CD38. So, this patient population has an expected disease-free survival of three months. With the CAR T cell, particularly from the KarMMA trial, we have been able to extend in these heavily pretreated patients the disease-free survival to 10.7 months compared to three. And those patients from the KarMMA trial that they have achieved a complete remission, the disease-free survival is 20 months. So imagine that we go from three months that is expected for survival in this heavily pretreated population up to 20 months for those who achieve a complete remission. My patient, as I said before, he was triple refractory.
So, nothing was working?
RAPTIS: Nothing was working and we gave her the CAR T cell in September of ’09 and – I’m sorry, September ’19. And she achieved immediate response, as you will seeing in the graph that I have prepared. And she stayed in remission for one year, which is expected according to their trials. Now, slowly, I have seen again a rising of the light chain, of the M protein that I described to you in the beginning. What can we do now? We can give a second course of treatment. And we hope that with a second infusion of CAR T cells, we will probably have a longer duration of remission because now we have to deal with a lower tumor barden. It is not like in the beginning, as you will see the graph, that the M protein was up in 13000 and we brought it down to nothing. Now the M protein is like 200. So at this level, if we give another infusion of CAR T cells, hopefully the patient will enjoy a longer duration of remission.
Can you give it more than that? Is this a treatment that can grow?
RAPTIS: That is not known yet. We don’t know that yet. And that is going to be answered with the results of clinical trials undergoing at this point. But another point I would like to bring is that during that year that the patient is in remission from September a year ago to this September, she was not receiving any treatment, which is important for the patients with myeloma because this will translate into a better quality of life. Compared to the other modality of treatments like chemotherapy, that we keep treating the patient continuously, that the patient has to come into the clinic to get the treatment, with the CAR T cells we give one treatment. The patient goes into remission and they come into a clinic just to monitor them to see how they are doing. They don’t receive any treatment, which is, again, very important for the quality of life of the patient. Unfortunately, we don’t have a curative approach. Even with the CAR T cells, the patients do relapse. And there are significant efforts made at this point to try to improve the outcome of these patients, to try to improve the effectiveness of the CAR T cells. And as I mentioned before, investigators now they generate CAR T cells that they target two molecules, BCMA and APRIL and so on. Or they are the so-called biepitopic. So, the CAR T cell binds on one target, for example, BCMA, but it binds in two epitopes. So, the binding is stronger compared to the CAR T cells that they bind in one epitope. Another effort that has been made is also to use healthy T cells and healthy T cells from donors, from normal donors. So there are investigations going on that they collect T cells from normal donors. They genetically engineer the same way that the autologous can be infused them to the patient, hopefully to have better results by utilizing normal, healthy T cells.
What are the implications, I know you said it’s not curable, but you’re buying from a patient basically having a month to having potentially you said 10 to 20 months. Is that what you said?
RAPTIS: So, patients who achieve a complete remission based on the KarMMA study, they have 20 months disease free survival compared to the expected three months of disease-free survival for this patient. Patients, as I said before, they’re heavily pretreated. And they are refractory to three classes of drug, modulators, immunomodulators, proteasome inhibitors and monoclonal antibodies.
So, what are the implications of having this tool for you and your colleagues to use with patients?
RAPTIS: Well, we are very excited. We are very excited because we feel that we can prolong the survival of our patients. But most importantly, we can improve the quality of life of our patients.
Is there anything I didn’t ask you about this particular trial that you’re working on that you would want to make sure that people know?
RAPTIS: No, I think we have covered every possible topic on this.
Interview conducted by Ivanhoe Broadcast News.
END OF INTERVIEW
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