Activity Transcript

Joseph Mikhael, MD, MED, FRCPC: Hello and welcome to this Medscape Oncology program titled "Risk-Adapted Management of Multiple Myeloma in the Era of Modern Therapy." My name is Dr Joseph Mikhael. I'm a professor at the Translational Genomics Research Institute and the chief medical officer of the International Myeloma Foundation.

I'm particularly privileged today to be joined by 2 colleagues and very dear friends: Dr Sandra Kurtin, who is an assistant professor of clinical medicine and assistant professor of nursing in the University of Arizona Cancer Center; and Dr Kathryn Maples, who is a clinical pharmacy specialist in multiple myeloma at the Winship Cancer Institute of Emory University in Atlanta, Georgia.

Welcome to both of you. It's always a pleasure to have you with us.

Sandra Kurtin, PhD, ANP-C, AOCN: Thanks for having us.

Kathryn Maples, PharmD, BCOP: Yes, very happy to be here today, thank you.

Dr Mikhael: Well, we have the privilege today to talk about multiple myeloma (MM), which really has gone through a tremendous evolution over the last several years. When we go back in time when many of you were still in utero, back into the 1970s, we really didn't have a lot of choices in myeloma where we used standard historical chemotherapies. Ultimately, we were able to introduce the concept of autologous stem cell transplant in the 1990s. Really, we had a rather significant transition around 2015, when a whole series of new agents started to make their way into MM. With this, we saw significant improvements in 5-year overall survival exceeding 50%.

Now we're launching into an even more exciting era, maybe even a golden era of MM, where not only have we built on the platform of monoclonal antibodies, we're now introducing a whole series of novel agents, some of which we will discuss today, which include nuclear export inhibitors, antibody drug conjugates, CAR T-cell therapy, and indeed, bispecific antibodies, with indeed, even more yet to come.

What this has led to, of course, in a marvelous way, is that our patients with MM are living longer than they've ever lived before. As a myeloma physician in the clinic, it is tremendously encouraging to see that patients can live longer. But it also has implications for the pragmatic use of these novel therapies. Patients are getting older while on therapies and this means that they carry more comorbidities. We know that they're therefore being exposed to more therapies; even though we haven't truly cured myeloma, we're controlling it in many patients. So, many patients see multiple lines of therapy. As they go through, they're receiving different mechanisms of action, each of which comes with different toxicities that we're going to be addressing today and require different methods of supportive care -- through the patient themselves, through their care partners, and indeed, through the healthcare team that we'll be discussing extensively today.

Let's take a look at some of these newer treatments that are in this golden age of MM. The first of which is selinexor. Selinexor is a first-in-class agent, often called an XPO1 inhibitor, or a nuclear export inhibitor. This drug works in a very unique way by blocking the XPO1 pathway. The XPO1 pathway is a pathway that many of our good tumor suppressors would naturally leave in the nucleus, things like p53, that we want to have preserved in the nucleus. Because when they disappear from the nucleus, the cell can become more malignant and resistant. So, by blocking that pathway, those tumor suppressors remain within the nucleus.

So we use this agent typically after someone has progressed on a proteasome inhibitor (PI) or an immunomodulatory drug (IMiD) with now 2 specific FDA indications: in patients who have had at least 1 prior therapy in combination with bortezomib and also simply with dexamethasone alone in patients who have had 4 or more prior therapies and are penta-drug refractory. Now that being said, we also know that there are National Comprehensive Cancer Network (NCCN) guidelines that can recommend other combinations with selinexor, including with carfilzomib, with daratumumab, and indeed, with pomalidomide.

This is an oral drug that's given typically now through the combination strategy in the BOSTON protocol on a weekly basis, where the starting dose is typically 100 mg. When we give it through the STORM protocol when it was given just with dexamethasone in very heavily relapsed patients, it was given in a twice weekly format at 80 mg. But again, we've learned over time that we tend to use this drug at lower doses, as you're going to hear.

At this point I'm going to transition over to Dr Kurtin to tell us a little bit more about the pragmatic and practical uses of selinexor.

Dr Kurtin: Thanks very much for that. I think this does offer a good option for these very heavily pretreated patients, but there are some very specific considerations in being able to keep people on therapy and continue that drug exposure. One of the most prevalent adverse events (AEs) are gastrointestinal (GI) toxicities. This is not if it's going to happen; it's going to happen. Just as you would not give one of those highly emetogenic intravenous drugs without having adequate pre-medication, that same principle applies here. So, very common GI symptoms including nausea, anorexia, diarrhea, fatigue, and then hyponatremia that comes both as a result of those, but also due to other processes that are a result of how the drug works.

The other thing I think that is really important, and we'll talk more about this, is this proactive approach. It's an oral compound, so not only do you need to make sure that you have the drug itself, but all of the supportive medications need to be in the patient's hands before they take their first dose of selinexor. We'll come back to some of that in a moment.

Then, really optimizing the dose. Dr Mikhael just mentioned some of the changes that have occurred over time in the various studies. Dr Maples is going to go through that in more detail here. But really understanding the data and who is your patient in front of you, what are their other comorbidities? As we just heard, most of these people are older, they have been heavily treated, they may have some GI symptoms that are a result of prior therapy or a prior transplant, for instance. Understanding who your patient is and what their vulnerabilities are is also critically important.

It takes communication between you and the patient. Again, this is an oral compound that people are self-administering. We need to have them tell us. I always tell my patients, "I can't help you if you don't tell me what you're feeling." We count on what I call the truth squad, the caregivers. I'll come back to that in a moment to really talk about how they're tolerating or not tolerating a drug. Keeping a journal is a really good idea. Keeping an eye on their weight, vital signs, even at home in between visits and reporting those changes so that we can act on them in the best way to maintain them on therapy.

Diet and hydration, this sounds self-explanatory, but people often don't truly understand what you mean. Being as specific as possible: how much fluid do they need? Eating, reviewing small frequent meals, avoiding highly spicy foods, all the things that may aggravate those symptoms. Then really, including salt. Some of these patients have opted on their own to be off salt in their diet completely because of other comorbidities, but they do need some sodium in their diet.

Then, really, that persistence, understanding that a lot of these symptoms are front-loaded, that they do get better with time. I know in my practice I have people coming in more frequently so that I can intervene right up front and not allow any of these to get too severe and make those adjustments that we're going to talk about in a moment.

One of the most critical things in prevention of these GI symptoms is having dual anti-emetic prophylaxis before starting. So, you order the selinexor, you order your 5-HT3 antagonist, and you order your low-dose olanzapine. You can adjust as needed, understanding each of these drugs and what their side effect profile is also really important.

Then again, hydration. Both Dr Mikhael and I are here in Arizona. We do not have the humidity that Dr Maples has. Our humidity is I think -5%. You can be dehydrated just without even going outside. I am very specific. I tell people if it's 2 liters, you fill up 2 1-liter bottles in the morning and if they're not empty at the end of the day, you did not drink them. So being very specific in what you mean.

As far as electrolyte solutions, I really try very hard to get them not to drink the sugar-laden sports drinks because we already are dealing with people that often have borderline diabetes or diabetes from all the steroids we've used over the course of their disease. That also is not good for diarrhea. So, trying to get some of those [drinks] that are not heavily sugar-laden is important.

I'm going to turn it over to Dr Maples now to talk more about some of the other strategies for continued dosing.

Dr Maples: Yes, thank you for that. We sure do have the humidity down here enough for both of you.

As Dr Mikhael mentioned, when selinexor was originally approved, it was just as a dual therapy in combination with dexamethasone. So, the dosing with this was a biweekly dosing strategy at 80 mg twice a week. We really saw that this is very hard for patients to tolerate, mostly from the nausea, vomiting, and fatigue standpoint. But you can see that in the various combinations that we have available right now, the recommended dose of selinexor is different. When combined with bortezomib, the recommended dose currently is 100 mg weekly. When combined with carfilzomib, it's recommended at 80 mg weekly. Then with pomalidomide, the recommended current dose is to start at 60 mg weekly.

The reason for this is that we do need to tailor the recommendation to the other side effects of the combined medication. For example, pomalidomide, we know we're going to see some more cytopenias with that agent, so we might need to start at that lower dose of selinexor. We want to tailor to both agents and use the synergy that we're going to get with the combination therapy, even in patients who might be refractory to some of these combined agents. If they're refractory to carfilzomib or refractory to pomalidomide, combining it with selinexor might be able to restore some of that sensitivity.

Notably, I think the biggest takeaway for me is that with the once-weekly dosing, we see less grade 3-4 toxicities. You can see the percentages of grade 3-4 nausea, grade 3-4 fatigue, and grade 3-4 thrombocytopenia are much better when we dose it at once weekly. I would say in my practice, we really don't use that twice-weekly dosing anymore and we might need to start low on the dose and you can always go up if they are tolerating it.

In terms of some other monitoring and management, it's good to consider weekly office visits when you first start selinexor to check blood counts, check in on their symptoms, check in on their weight, as Dr Kurtin mentioned. Thrombocytopenia is one thing we haven't mentioned yet in detail and it is a very common side effect in selinexor-based regimens. Especially in patients that might have a low platelet count at baseline, you really want to make sure that you're checking their platelet count frequently, holding if that platelet count gets less than 25,000. Then you can consider adding something like romiplostim or eltrombopag to help reduce the need for transfusions and reduce the need for holding therapy in patients that have thrombocytopenia.

We also want to monitor closely for any neutropenia and anemia that can also occur. We can use our growth factor filgrastim to support for neutropenia and then of course use blood transfusions as needed for anemia.

In terms of the impact on dose modification and how that impacts the ability to stay on therapy, dose reductions in the BOSTON trial did allow patients to remain on selinexor for a much longer period. They could stay on therapy, which then translated to a longer improved progression-free survival, which is what we want for these patients.

Typically, you're going to think about reducing in 20 mg increments. If they start at 100 mg weekly, you would drop down to 80 mg weekly and then 60 mg weekly. You want to allow for time to those cytopenias to recover, watching their weight very closely, and listening to the patient and making sure that they're letting you know what's going on with their symptoms.

Lastly, just to round out selinexor, we've mentioned some of these non-pharmacologic management strategies already, but some that I really like to talk with patients and caregivers about is considering dosing selinexor at bedtime. You can take your anti-nausea medication like olanzapine at bedtime, take your selinexor at bedtime, and possibly sleep through some of those nausea/vomiting side effects. Using meal replacement shakes is a really good thing for patients to consider, especially if they're losing weight. Sports drink, salty snacks, as Dr Kurtin mentioned, but making sure that they get the sugar-free ones when they can. Then making sure that they are just moderating their exercise, not pushing themselves too hard, doing what feels right for them and engaging with their family and their community.

I think that rounds out selinexor and I'll bring it back to Dr Mikhael for his closing thoughts on that.

Dr Mikhael: Thank you both so much for that. We've heard some great themes today that we'll reiterate at the end, but of ensuring that we typically plan to give selinexor on a weekly basis, that it can have multiple partners, and that we have to be very deliberate in particular in that first few weeks. As I often say, "the worst month is the first month", as we ensure that we overcome the potential nausea and vomiting and fatigue with a proactive approach.

Well, let's now move on to some of the other novel agents. Perhaps one of the most exciting areas of advance in myeloma and, frankly, in all malignancies and specifically hematologic malignancies, has been CAR T-cell therapy, or chimeric antigen receptor T-cell therapy. This is where, of course, we collect T cells from patients and then genetically modify them so that they can express a receptor that binds, presently, at least to B-cell maturation antigen (BCMA), although others are being explored as the target so that we can, by immune methods, destroy that cell.

These are now typically being used later in the disease course and, indeed, we actually have 2 separate CAR T cell strategies that have been approved, both ide-cel and cilta-cel. They have, essentially, the identical indication in patients who have had at least 4 prior lines of therapy that include a PI, an IMiD, and an anti-CD38 antibody.

This is a very exciting feature that we have now in MM. Part of the excitement is, first of all, that this is really a 1-and-done, single infusion approach; whereas many of our treatments patients have to stay on therapies indefinitely, here with CAR T-cell therapy, patients are given a single dose.

Now again, these both come with a Risk Evaluation and Mitigation Strategies (REMS) program because there are toxic concerns primarily through the initial administration, where patients are at risk of cytokine release syndrome (CRS). But we're going to be hearing much more about these toxicities from Dr Kurtin. Sandy, I'm going to pass it off to you to walk us through some of these practical, logistical, and toxicity issues related to CAR T-cell therapy.

Dr Kurtin: Sure. I think the basic concept here is this is not something you just go do. It takes a lot of planning. It's very similar in terms of the planning and logistics that we see with an autologous transplant. It requires a coordinated effort between the specialty center and the referring provider or practice and very much requires full participation of the patient and their caregiver.

I think the other thing about CAR T, and we're going to talk about a different drug here in a moment, is really maintaining eligibility. These are generally, at this point anyway, people who have had a lot of therapy. They may have very aggressive disease that's difficult to keep under control and keep them well enough to actually be eligible for CAR T. Another reason to really get the CAR T centers involved early and considering how to get a patient effectively to this treatment.

The immune-related toxicities are common but manageable. I think we've really gotten so much better at this, both in terms of the CRS and the neurotoxicity that may be seen. But it does, again, require coordination. Really, what it takes is a 24/7 caregiver and this means what it means. These people become an extension of our team. They need to be able to monitor and report and mitigate these symptoms in real time. Because if a person does develop CRS or some of the neurotoxicity symptoms, interventions need to be made very, very quickly. They often require a central line. Most of these people have one by now, they may have lost it over time and have to have it replaced.

We do, for these patients, admit them for the first week of CAR T infusion. We need them to stay near the center for those first 4 weeks because of how some of these symptoms linger. In the short term, they come every single day to the clinic and the amount of time they spend there may vary, but that is a conversation to be had upfront with the patient and their caregiver, so they know really what the commitment is. Honestly, that caregiver may be a caregiver team just to allow that flexibility.

Avoiding sources of infection, which is pretty hard to do these days because there's so many of them out there. But we do have to remind people about what that means.

Most of you are familiar with this scenario and so I'll just touch on it briefly, but that early referral, as I mentioned, is really important so that we can get the logistics in motion. They then get their cells collected, much like you would do for an autologous stem cell collection: same process, really. But that then is going to be sent off to be basically manufactured for that individual patient and that manufacturing process can vary by product and take time.

You need to then do the bridging therapy while you're waiting to receive that product and this is where that balance of keeping them eligible while we wait becomes so key and critical. Understanding that they will have lymphodepletion before a delivery of the CAR T cells is also really important in considering what you're doing to bridge. That's where the collaboration between the treating center and the referring provider or practice is so critical so that we are working as a team to maintain eligibility and reduce the potential for toxicity for those patients.

Then it's really about monitoring for CRS and the neurotoxicity. Cytokine release is just what it sounds like. You think about people who are septic or infected, you have cytokine release and you see the typical hallmarks of fever, hypotension, hypoxia can occur. It very much mimics the scenario of someone who has febrile neutropenia or sepsis. This is generally early in the phase of treatment but sometimes can be delayed, so being vigilant and that's why we keep them close for those first few weeks. The ICANS, or immune effector cell neurotoxicity, is a very specific phenomenon. These people almost look stroke-like. They may have aphasia, mental status changes, cognitive impairment, weakness. Then we very specifically are going to monitor that every single day that they come to the clinic. We do labs to evaluate for CRS, things like a C-reactive protein, and other measures.

Then we're going to actually do a neuro check on the patients every single day. That includes this immune effector cell associated encephalopathy (ICE) scoring system. There are little cheat sheets and cards that the nurses use to do this or the providers use to do this. Looking at something as simple as checking their handwriting over time, that fine motor skill.

I'm going to let Dr Maples take on the hematologic toxicity as she goes through some of the other strategies here.

Dr Maples: Great, thank you so much. Just to briefly touch on the acute toxicity management as an overview and a guideline. As Dr Kurtin mentioned, patients can have CRS, ICANS, and cytopenias in that immediate period following CAR T cells and based off of the grading of that toxicity, we would use things like tocilizumab and corticosteroids to manage these patients.

When we think about how these patients are going to transition back into the community, patients will be discharged when all of their non-hematologic toxicities have resolved to a grade 1 or better and they do need to remain close to the site of care where they've received their CAR T cells for at least 4 weeks.

How do we want to manage these patients once they're past that acute 4-week period? Really the biggest toxicity that we see for these patients is prolonged cytopenia and that translates into a high risk for infection. This can be bacterial infections, viral, fungal, we have seen some crazy opportunistic infections. So really monitoring these patients' counts, using growth factor support if they need it. That could be twice weekly, 3 times weekly growth factor for a period of time. Then using intravenous immunoglobulin (IVIG) for someone who has hypogammaglobulinemia or a recurrent infection that's happening over and over again. CRS and ICANS really shouldn't persist much longer than that acute period, but you always want to keep it in the back of your mind. Then managing some of the other rare side effects as they come up would be something we want to think about.

I will turn it back over to Dr Mikhael for any final thoughts on CAR T cells.

Dr Mikhael: Great, thanks so much Kathryn. Yeah, I think what you said at the end there was just so critical. It ultimately just requires so much good communication between the treating center and if they're making it back into the community. Because some of these toxicities we're still learning about and they can be concerning, especially the infections.

Well, we've talked so far about CAR T-cell therapy. But let's talk now about the whole concept of  bispecific antibodies. The first approved in myeloma was teclistamab. This is also BCMA-driven. But as the name would imply, a bispecific antibody has 2 arms, 1 that adheres to the myeloma cell through BCMA, but the other has an arm that binds to the CD3 antigen on a T-cell and immediately engages that T-cell to help destroy the MM. It saves, if you will, the challenge of having to collect T-cells as Dr Kurtin described, and all the challenges of manufacturing and re-infusing them. This is directly off the shelf to the patient.

It also has a very similar indication to CAR T, being used significantly later in the disease course, at least now, where it's approved in patients who have had at least 4 prior lines of therapy that include a PI, an IMiD, and a monoclonal antibody.

This is, for teclistamab specifically, a subcutaneous injection. Again, it has a REMS program associated with it because even though we may not see it to the same degree, there is a significant risk of CRS that was described earlier. To help mitigate that, we give it in step-up dosing.  We start with lower doses at day 1 and then move up to day 4 and day 7 and then ultimately the treatment dose of 1.5 mg per kilogram is met.

I going to turn it over to Dr Kurtin to talk to us a little bit more about those transitions and the practical management of teclistamab.

Dr Kurtin: Sure, thank you. You already mentioned that this is very similar to CAR T, so the concepts that we just described apply here in terms of communication, getting the caregivers involved, having that planning ahead of time. But because it is off the shelf, you don't have that wait, as you just mentioned, for sending the cells off for manufacturing and then waiting for them to get back. So that whole idea of bridging may not really be necessary, but you do need to plan ahead so that they maintain their eligibility.

The risk of infection I think we've talked about, and Dr Maples is going to come back to that more specifically. These are directly targeting B-cells, B-cell development and maturation, plasma cells which produce antibodies. So, these patients can be very vulnerable, particularly to atypical infections.

We do admit for that ramp-up dosing, so generally days 1, 4, 7, the ramp-ups are those first 2 doses and then what's considered the first therapeutic dose is day 7. That is where the bulk of these treatment-related AEs occur and so that's why they're in the hospital setting. I think this does reduce some of that caregiver burden in the early phase. But we still need caregivers to be available and they still may experience some of those neurotoxicities such that they aren't able to drive. Ninety-eight percent of CRS and ICANS occur in that step-up, so we premedicate: that reduces the incidence significantly. Just as you would with CAR T, confirming that you have available doses of tocilizumab before you initiate treatment is part of the logistics that the treatment center needs to follow.

Then I'm going to send this off to Kathryn to talk more specifically about the infectious prophylaxis and the incidence of some of those infections, specifically.

Dr Maples: Great, thank you. Just like our CAR T-cell patients, the long-term complications with teclistamab really revolve around infections. Patients can experience bacterial, fungal, and viral infections while on teclistamab. For our viral prophylaxis, we do always want to make sure myeloma patients are on their herpes simplex virus (HSV) prophylaxis, so they should likely already be on that coming into teclistamab and we would continue it. For bacterial and fungal, we would want to initiate prophylaxis anytime the absolute neutrophil count (ANC) is less than 500. But we also want to consider using things like granulocyte colony-stimulating factor (G-CSF) to help prevent those prolonged periods of neutropenia when we can.

Then very similar to CAR T cells, we would consider the use of IVIG for anybody who has hypogammaglobulinemia or recurrent infections. Just 1 quick study to highlight from the Medical College of Wisconsin. This really showed us how the cumulative risk of infections grows as they're on bispecifics. This is not something that they're only at risk when you first start. It's something that their cumulative risk will grow as they are on prolonged bispecific therapy. So that cumulative risk they identified as high as 70%. Immunoglobulin G (IgG) was undetectable in 28%. I think that's really profound and something to keep your eye on closely.

Another thing to consider with teclistamab was that the MajesTEC-1 study was conducted in the peak of our COVID-19 era. So, 63% of the AE-related deaths on MajesTEC-1 were due to COVID-19. We want to be very vigilant about making sure our patients are on the up-to-date vaccines for COVID-19. We can consider the pre-exposure monoclonal antibodies as well, although they don't have as great activity against the current strains of COVID-19, but that may change and be ever-evolving. But what we do want to make sure we do is initiate immediate antiviral therapy for anybody who is diagnosed with COVID-19 while they're on teclistamab. You may want to consider holding their therapy. You can hold teclistamab for up to 28 days without having to restart that step-up dosing that Dr Kurtin and Dr Mikhael were talking about. You have some room there to let them quiet down and recover from their COVID.

Lastly, the neurotoxicity that we talked about. While ICANS is rare after those step-up doses, we can have some other neurological type of side effects that persist. This could be headache, motor weakness, loss of coordination. We want to make sure that we continue to monitor for those. We've talked about the hematologic toxicity already, but I think really being mindful of that and initiating the growth factor support when needed can really help patients stay on this therapy.

But really exciting time and a really exciting drug to have available for our patients. I will bring it back to Dr Mikhael to close us out.

Dr Mikhael: Great. Well, thank you so much, both of you for your input. I mean, I learned from the 2 of you every time we speak, so I really appreciate it.

We've learned a lot today about this golden era of myeloma therapies. In selinexor, how we're using it weekly and being very careful whether antiemetic use. With CAR T-cell therapies, with unprecedented response rates, but with significant logistical challenges that we have to work through. It is a 1-and-done treatment, but it requires that collection, the manufacturing, and a particularly important communication between the treating center and the community as there are those later effects of infections and cytopenias and neurological effects. Lastly, we saw very similarly with bispecific therapies, despite the fact that they can be immediately off the shelf and we may be able to avoid all of the collection and manufacturing challenges we have with CAR T, but that cumulative risk of infection is really something to watch carefully and requires a very careful monitoring of the patient and communication between the primary center and the community or wherever it is that a patient is being treated.

We hope that this has been helpful to you as you care for your patients with myeloma in these changing times. There are many, many more CAR Ts and bispecifics and other agents on their way, so keep attuned to what is coming because some of them have different toxicity profiles. But we're very excited to be able to care for our patients in different ways now.

I'd like to take a moment again to thank Drs Kurtin and Maples for joining us today for their tremendous insight into this topic and we trust this has been helpful to you. Thank you very much for your attention.

This transcript has not been copyedited.