CAR T-cell Therapy & MRD Negativity in Myeloma: What Patients Need to Know 
 

Dr. Joseph Mikhael: 

Can you have CAR T-cell therapy after a stem cell transplant? Do doctors hesitate to make the diagnosis in older patients? Is MRD negativity connected to long-term survival? Hi, everyone. Dr. Joseph Mikhael here, chief medical officer of the International Myeloma Foundation. On a regular basis, I host a Facebook Live and we encourage people to send in their questions. So today I'm going to do my best to catch up on the loads of questions that have been sent in for me to answer. 

But just before I do, I want to share something very special with you. September is Blood Cancer Awareness Month, and lots of activities are going to be going on with our campaign Know Myeloma, K-N-O-W Myeloma. So look out for that hashtag Know Myeloma and please use it throughout the whole of the month. We're here for you as the IMF and we want to encourage you to ask questions. Send them to us through every social media possible that you have access to. But also remember if it's of a more personal nature, feel free to reach out to us through the info line or at myeloma.org. All right, let's get into our questions that we have for the day. 

"Can you have CAR T-cell therapy after a stem cell transplant or do you lose the option forever?" Well, the short answer is absolutely you can have a CAR T-cell therapy after transplant. In fact, for the first several years of our treatments with CAR T-cell therapy, most of our patients had had a stem cell transplant. There has been some work looking at how transplant that is soon thereafter followed by a CAR T-cell therapy may be challenging in some patients, but don't feel at all that having a stem cell transplant is going to prevent the option of a CAR T-cell therapy later. 

Here's another great question, "CAR T is groundbreaking, so why isn't it used right at the start?" Well, thanks for this commentary, which actually I agree with, that CAR T is groundbreaking. We have seen incredible outcomes with CAR T-cell therapy. Not only the percent of patients that respond to it, but for how long they respond to it. Now we're not quite ready to use it upfront, and I'll explain why. Typically, in drug development we have to use drugs after everything else has been used to prove that it's valuable, and that's what we did with CAR T-cell therapy. When it was first approved several years ago, it was only to be given in patients who had had four prior lines of therapy. But then as the evidence mounted and we did clinical trials, we can use CAR T-cell therapy as soon as second-line therapy. And the clinical trials are now ongoing to use it even frontline. So even though we're not quite ready for it, I'm going to predict that we are soon going to be able to use CAR T-cell therapy even in frontline. Great question. 

Here's another question about CAR T-cell therapy, "If a new CAR T-cell therapy," and they specifically highlighted one called Anito-cel, "Works incredibly well, can it get FDA approval faster?" And again, the short answer is yes. The FDA has a program called accelerated approval, where drugs that show tremendous promise can indeed be approved more quickly based on a smaller study and typically based on the response rate in that study. That has to later be confirmed in a more comprehensive study when it's compared to others. But we do anticipate a drug like Anito-cel, which I do believe has been very promising, will likely go through this accelerated approval process and we hope to have it available to us in the near future. 

Here's a great question from Veronica, "Why would doctors wait on treatment when there's a plasmacytoma? You're literally watching cancer grow." Veronica, you really bring out an important concept here in multiple myeloma. That there are forms of myeloma, typically the precursors of myeloma as we call them, something called smoldering myeloma or MGUS, monoclonal gammopathy of undetermined significance, I know that's a mouthful, but those are situations where there actually may be a very, very low level of cancer cells. But they're so small, we sometimes actually don't treat them, we just wait and watch. One, because it's extremely common. And often, those very cells will actually never become truly cancerous cells or never grow to a level that is going to hurt someone. 

Now, in your question you referenced a plasmacytoma, which is typically a collection of plasma cells together. Those we tend not to watch, those we actually do tend to treat. Now, obviously, depends on the scenario. Sometimes if someone's had a larger plasmacytoma and it's shrunk down to a smaller size, we may wait to give more treatment depending on the scenario. But you highlight a very important point about myeloma being a disease where we have to carefully decide when to treat and when to watch. 

Here's another great question from Tammy, who wrote, "My husband watched MGUS for 10 years, then it flipped to myeloma. Do doctors hesitate to diagnose older patients? He's in his 80s." I don't think doctors are trying to hesitate to make the diagnosis, I think that there are lots of things at play here. I think at times the general medical community is not as aware of multiple myeloma and may not think about it or think that it's growing in a patient. One of the reasons why we have so many educational efforts at the IMF. 

Also, I think there may be a hesitation when it comes to treating, to know is the treatment more aggressive than the disease? And this is always a discussion we have to have as we get older and as our bodies acquire new, what we call comorbidities or other diseases. We have to make sure, as I often say, we don't treat disease, we treat people, and that we choose the right treatment. I hope that your husband does well with the treatment that he'll be given. And I think it's very important to highlight the importance of watching MGUS, so that if it does grow into myeloma, we can intervene as quickly as possible. 

Here's a great question from Ginger, "I'm MRD-negative after transplant and I'm on Revlimid maintenance. Would adding Daratumumab give me longer remission?" Well, this tells me, Ginger, that you've been listening to our videos and that you're very in tune with what's happening in the myeloma community. For the longest time after transplant, we would typically give someone Revlimid maintenance to keep them in that remission for longer periods of time. But some recent clinical trials have demonstrated a potential benefit of adding daratumumab. So this is a conversation, of course, you have to have with your doctor. But I will note, if you're already MRD-negative, it may not be necessary to add more to the Revlimid. It may be also a function of whether or not the disease is what we call high risk or standard risk. Because typically, in high-risk situations, even if they're MRD-negative, we may decide on two maintenance therapies instead of just a single therapy. 

Here's another question from Bonnie, "Is steady MRD negativity tied to longer survival? What does the latest data show?" Well, Bonnie, you've also been listening in and watching very carefully. And just to make sure we're on the same page here with everyone, MRD or minimal residual disease refers to the testing that we do typically on the bone marrow to see if there's any tiny amounts of myeloma left. And sometimes we can't find any, and we call that MRD-negative. 

Quick answer to your question, yes, MRD negativity is linked to longer term survival, which is not a surprise. Because if we can truly eradicate the disease or at least reach to a point where we can't see it anymore, we actually still think there may be still some of it hiding in a place that we can't see, but if we can get rid of it down to that level, it is going to keep people in remission for longer and, indeed, alive for longer. Now, there are some exceptions to the rule because myeloma is a very complicated disease. Paradoxically, we have some patients that actually get into MRD negativity really quickly but, sadly, don't stay there for very long. That's typically high-risk myeloma. But overall, yes, getting into MRD negativity is a great thing and predicts for longer survival. And I hope you stay in MRD negativity for a very long time and can enjoy your quality and quantity of life. 

Kathleen asks a question, "Is it common to stop treatment if there's no detectable M protein, or is that risky?" Kathleen, you highlight one of the most important challenges have as a myeloma community and an area of intense work and research, and indeed, part of the work that we do at the IMF and our Black Swan Research initiative, which is to help determine when can we stop treatment. I sometimes joke and say, I love giving patients my favorite drug, nada, nothing. It's great to be able to stop treatment. And we've learned that MRD negativity is a powerful tool in helping us to predict when we can stop treatment. But it can also be risky, just like you noted, if indeed patients have so-called high-risk disease or have features that the disease can come back more quickly. So again, a conversation that has to be had with your provider, but we do believe that we are doing the clinical trials now that are going to help us know when we can stop maintenance therapy or certain treatments so that we can give patients treatment-free intervals. 

"When diagnosed with myeloma, does your disease burden change your prognosis?" Well, the short answer to this is yes. We know that lots of things influence prognosis, meaning if people will get into remission and how long they'll stay in remission, and indeed, their overall survival. And one of those can be the burden of disease, which is measured in different ways. How much of myeloma is infiltrating the bone marrow? Do people have myeloma outside of the bone marrow, what we call extramedullary disease? And then a particular blood test called beta-2 microglobulin, which in our new high-risk category does retain itself as an important prognostic marker. So indeed, disease burden can influence prognosis. 

"What happens if you're allergic to steroids used in transplant recovery?" Well, thankfully, it's not very common to be allergic to steroids, and thankfully, there are other kinds of steroids that can be used. So typically, if someone does have a reaction to one of the types of steroids, like dexamethasone or cortisone or prednisone, there are other options, and typically we can switch from one to another. 

Karen writes, "I'm a veteran," and let me first say thank you, Karen, for your service, "With no family history of cancer. Could myeloma be linked to toxic exposure at work?" We don't fully understand or appreciate what causes multiple myeloma. Over the years, we have noted that there are certain things linked to myeloma, things like our veterans who are exposed to Agent Orange, firefighters who've been exposed to repeated fires. Our other first responders, even after 9/11, for example, we saw a rise, a spike in the diagnosis of multiple myeloma. So depending on your service, Karen, it is possible that there may be a link, and I would discuss this further with your healthcare team and indeed with military services, as there may be an opportunity here to ensure that you have the right access to therapies and that you have the right coverage. 

Papineau writes, "My mother and half sister both died of myeloma." I'm sorry to hear that. "Am I at higher risk? Is there anything I can do to stop it?" Well, Papineau, you bring an important question to the myeloma community, which is when should we test family members when someone has myeloma? And typically, we don't routinely screen family members because it does not generally run in families. However, if there are two first-degree relatives that have myeloma, most of us will suggest this, as indeed is the situation here. So I would review this with your physician as it may be reasonable to consider being tested to look for the possibility of multiple myeloma. 

"What are the long-term side effects of these drugs if you're on them for life?" Well, thank you for asking this, Stratos. We recognize that every drug comes with a challenge. We want to, as much as possible, hit the myeloma, but spare the patient. And, depending on the kinds of drugs that you're referring to, we know that, sadly, every drug comes with some side effects. Thankfully, now, as we've seen patients live longer and longer with myeloma, we've had many of our patients on certain regimens for 2, 5, 10, and even over 15 years. So there can be feasibly given drugs over many, many years. But of course, this has to be discussed with your healthcare team, because we always want to strike the balance with giving people enough therapy but not too much therapy to put them at risk of other side effects or effects. 

Here is a great last question to end with, "If there are still some myeloma cells left, why isn't that treated like residual disease?" That's such a great question, where we're often in a situation where we treat patients and we want to get rid of the disease, but sometimes there's that little bit left. And we may be tempted to say, "Well, let's just treat more and let's treat more aggressively, and get rid of that last little bit." And sometimes, we actually may decide to do that. In particular, when patients have high-risk disease, that tiny little bit left puts them at high risk of it growing back. 

But interestingly, there are some patients who have a tiny amount of disease left that will actually just sit there very quietly. Once, at a conference, I describe that little bit of residual disease left as being either Rambo or Bambi, meaning we need to know is this aggressive or is this not aggressive? So this has to be discussed with your healthcare team and what the history of the myeloma has been, because again, we don't want to over-treat nor under-treat our patients, so we can give them the right treatment that's going to keep their disease down and give them the quality of life that they need. 

Well, that's all we have time for today for questions. We trust that this has been helpful to you in your myeloma journey, and I do want to encourage you to keep the questions coming. Use social media, with the hashtag #AskTheIMF. Join our future Facebook Lives, when you can. Call the info line, go to myeloma.org, and don't forget to subscribe to our YouTube channel so you can be in touch with the latest and greatest in myeloma, because we want to empower you through knowledge, through education to go through your myeloma journey.