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Spotlight

This roundtable series considers the operationalization of care for patients with relapsed/refractory multiple myeloma, as discussed by key opinion leaders and participants at virtual live events.

Operationalization of Cancer Care in R/R Multiple Myeloma

Targeted Oncology: Which bispecific T-cell engagers [BiTEs] are now available for use in hematologic malignancies?

There are 6 BiTEs currently on the market; we didn’t include blinatumomab [Blincyto], though technically that is a BiTE, but that is a continuous infusion…and has been around for quite some time.

The first 3 are elranatamab-bcmm [Elrexfio], teclistamab-cqyv [Tecvayli], and talquetamab-tgvs [Talvey], [which are] multiple myeloma drugs.

Epcoritamab-bysp [Epkinly] and glofitamab-gxbm [Columvi] are for patients with diffuse large B-cell lymphoma and more aggressive lymphomas, then mosunetuzumab-axgb [Lunsumio] is a follicular lymphoma drug.

 Those last 3 all have the same target; they’re all anti-CD20, but they do have differences.

Epcoritamab and glofitamab have the same indication but mosunetuzumab is for that indolent lymphoma.

 Then of the first 3, elranatamab and teclistamab are essentially the same drug, a B-cell maturation antigen–targeting bispecific, [whereas] talquetamab targets GPRC5D, so it is different.

What risks and mitigation strategies are present for each of the BiTEs?

All of them have risk of CRS [cytokine release syndrome] and ICANS [immune effector cell–associated neurotoxicity syndrome], but only the myeloma drugs have the REMS [Risk Evaluation and Mitigation Strategy] requirement.

If you look at the package inserts, pretty much all of them with the exception of mosunetuzumab have some type of recommendation for hospital admission or observation.

 For elranatamab, it is for the first 2 doses; for teclistamab, it’s for the first 3; for talquetamab, it is the first 3 or 4 depending on which dosing regimen you look at.

 For epcoritamab, it’s for day 15 of cycle 1, which is the first full treatment dose.

 Then for glofitamab, it is cycle 1, day 8, which is the first dose because with glofitamab, cycle 1, day 1 is [only] a dose of obinutuzumab [Gazyva], which they get for B cell depletion.5 For glofitamab, it’s for the first dose of the drug that inpatient observation is recommended.

There are a lot of ways to approach that, and investigators have looked at trying to move these patients into the outpatient setting. But that does make things a little bit more resource-intensive. However, in our experience, we’re going to be doing our first fully outpatient use of teclistamab next week. We’ll see how that goes. But so far [I believe we’ve treated] 5 patients with epcoritamab, and of the ones that have made it up to cycle 1, day 15, we haven’t had to admit any of them yet. Even with that recommendation, we’re able to manage these patients in an outpatient setting with appropriate monitoring.

All of these products have financial assistance available through the manufacturers and preferences. In terms of [requiring availability of] tocilizumab [Actemra], if you look at some of the CRS guidelines, that is a recommendation for management of CRS. Unlike chimeric antigen receptor T-cell therapy, which requires you to have 2 doses of tocilizumab on hand at all times, none of these products require that,

 so it’s up to your clinic on whether or not you would consider giving tocilizumab in the outpatient setting. Now, for inpatients it is obviously a little bit different. But the thing to consider is that if you are going to use this and build tocilizumab into your treatment protocols, I would make sure that you’re authorizing the tocilizumab upfront [with insurance], because you don’t want to get into a situation where the patient needs it and you want to give it but then you don’t have that authorization for it. If you’re going to build into your protocols, the use of tocilizumab in the outpatient setting, [get that authorized] at the same time that your [treatment] is authorized.

Have you used tocilizumab in the outpatient setting?

We prefer dexamethasone as our primary treatment for CRS…so we don’t routinely use tocilizumab. But I know there are a lot of centers that prefer tocilizumab over dexamethasone, for reasons similar to their using CAR [chimeric antigen receptor] T-cell therapy. Only if you plan to give tocilizumab on the clinic side or the outpatient side, would you require that prior authorization.

We have not on the outpatient side. If a patient on any of these products required tocilizumab, they’re usually in the hospital by that point. But I know there are centers that I’ve talked to that use tocilizumab in the outpatient setting for grade 1 CRS. Just make sure you’re thinking about the cost and that prior authorization. Luckily, there should be a biosimilar tocilizumab coming out, which will hopefully reduce some of the costs.

Who should be involved in management of adverse events related to BiTEs administered in the community practice setting?

For protocol development, making sure you have that outline. Next is making sure you’re educating your staff on everything that’s important. How do we identify these patients? [When] they come into clinic, is it all on the physicians to be able to identify this or are we relying on our support staff to help us identify these patients? And if so, what do they do about it? It’s not only our staff…we have to think about the emergency department as well. So if we have an association, we’re telling our patients to go to a specific emergency department, your emergency department if your practice has one, making sure that they are aware of what these drugs are, and what to do if a patient comes through that. That education process is important.

Third is educating not only your patients, but their caregivers. I think caregivers are essential to successful treatment of these patients, especially up front in the outpatient setting, and making sure that we’re educating our patients on what symptoms to report, and when and who to call. A lot of times, patients will be told to call an after-hours line and they may get hold of an on-call oncologist who may not know the patient or hasn’t used this particular drug. For us, we instruct our patients when they call to make sure on the after-hours line, they specifically ask for the on-call bone marrow transplant/hematology physician who manages that patient. And [tell the patient] when to go to the emergency department.

1. Elrexfio. Prescribing information. Pfizer, Inc, 2023. Accessed November 30, 2023. 

2. Tecvayli. Prescribing information. Janssen Pharmeceutical Companies, 2022. Accessed November 30, 2023. 

3. Talvey. Prescribing information. Janssen Pharmaceutical Companies; 2023. Accessed November 30, 2023. 

4. Epkinly. Prescribing information. Genmab A/S, 2023. Accessed November 30, 2023. 

5. Columvi. Prescribing information. Genentech, Inc, 2023. Accessed November 30, 2023. 

6. Lunsumio. Prescribing information. Genentech, Inc, 2022. Accessed November 30, 2023. 

During a Targeted Oncology™ Case-Based Roundtable™ event, Robert Mancini, PharmD, BCOP, FHOPA, discussed the various approved bispecific T-cell engagers and gave guidance for healthcare professionals, patients, and caregivers related to adverse event management. This is the second of 2 articles based on this event. 

Understanding Risks and Training Needs for Outpatient Bispecific Usage

Targeted Oncology: How were standard operating procedures (SOPs) for bispecific T-cell engagers developed at your institution?

 At our institution, I wrote all the protocols and I sent them to our physicians who signed off and made the changes that they wanted to see. I helped develop that base. As physicians, we have enough on our plates, but if you can have someone who helps develop those [SOPs] to at least give you a starting point, then you can weigh in on it, so that becomes a good option.

If you can find someone to…reach out to those institutions, and then help take that back and say, “What are we going to do with that?” That's one option. We also have a working group that developed this, sat down together, included all of those key stakeholders…to hash that out. But in the end, you're still going to have to have one person who is actually writing the protocols and initiating. If you're in the process, or you haven't yet started, it’s an important thing to consider who's going to be that one person that's going to write the protocol.

What was your experience at your institution setting up a bispecific administration program?

What happened was, we had our first patient and we flailed in the water. [We weren’t sure] what we were supposed to do with this patient. Luckily, the first patients were those receiving mosunetuzumab [Lunsumio]—patients who did not require inpatient administration. The risks and the tolerability were a little bit easier.

We knew how to manage cytokine release syndrome [CRS] and neurotoxicity. We have those pieces down. Now we need to think about where this patient can be treated with the mosunetuzumab. It does not require inpatient administration. We set that up, and we use EPIC, so we had to build our treatment plans and get that prepared for when the patient came in. Having gone through it with that first patient, we realized we need to formalize this process, because everyone's asking different questions [concerning] why we did this or that. The physician may see him with the first dose but an advanced practice provider may see him with the second dose and they don't necessarily know what the process is.

The [first] thing that we found that we needed was deciding how these patients are going to be selected. Is a patient a good patient for a bispecific agent? Is this a drug that requires inpatient vs outpatient administration? Is the patient capable of managing this? If not, do you need a caregiver? We developed caregiver requirements into our protocols…because what we found is the most important thing, especially if you're dealing with ICANS [immune effector cell–associated neurotoxicity syndrome] or neurotoxicity, is you can't rely on a patient knowing that they're having ICANS, or even some degrees of CRS.

We looked at how we are going to…determine what setting they're going to be treated in. Then, what are you requiring of the patients? This is a 2-way street. We as providers need to determine how we're going to treat these patients and give them those resources. But patients also have to take some of that responsibility on their own to have success with their treatment. What are those components they're going to require? And last, what are the caregiver requirements? Those are the pieces that we looked at in terms of how to develop [an SOP].

How do you initiate the first doses of a bispecific T-cell engager in your practice?

We are a larger community [cancer] center. We have our main site in Boise, Idaho, and then we have multiple clinics across Idaho. All of our patients will come to our primary site in Boise for initiation. They'll get referred to 1 of our bone marrow transplant/CAR [chimeric antigen receptor] T-cell therapy physicians who are familiar with this ramp-up toxicity profile, and then we have to decide if we going to keep them the whole time, or send them back. We face…issues with travel; our clinics are 2 and a half to 3 hours away, so are we going to make some of these patients drive up to 3 hours every week? At what point are we comfortable sending them back to that community institution?

If you look at the data for most of these products, once you get them through that first full treatment dose, or potentially the second full treatment dose, the risk of these toxicities drop off very rapidly and very extensively. [At the first doses], there is the risk. Then you get past that second treatment dose, and your risks are basically in the single-digit percentages for those acute, more difficult toxicities.

What we did is similar to a [patient receiving] CAR T-cell therapy or even an autologous [stem cell] transplant. We require them to get treated at the main institution site in Boise for the first month of therapy. Depending on the product, some of those are 4 doses if they're weekly, like teclistamab [Tecvayli], or 3 doses, if you're looking at one of the B-cell lymphoma products.

During a Case-Based Roundtable event, Robert Mancini, PharmD, BCOP, FHOPA, discusses his experience setting up procedures for administering bispecific T-cell engagers for a large community oncology practice. This is the first of 2 articles based on this event. 

Developing Standard Operating Procedures for Using Bispecific Agents

David Dingli, MD, PhD, professor of medicine, consultant in the division of hematology in the department of internal medicine and department of molecular medicine at Mayo Clinic, discusses the tolerability of teclistamab for patients with relapsed/refractory multiple myeloma (RRMM) and dosing practices with the bispecific antibody.

Teclistamab was approved by the FDA based on the phase 1/2 single-arm, multi-cohort, open-label, multicenter MajesTEC-1 study (NCT03145181), which showed heavily pretreated patients with RRMM had deep and durable responses to the drug. 

The main outcome was looking at the overall response rate (ORR) in 165 patients who were pretreated with at least 3 lines of therapy. Patients were given a weekly subcutaneous injection of teclistamab at a dose of 1.5 mg/kg based on body weight after they received step-up dosing of 0.06 mg/kg to 0.3 mg/kg.

After a median follow up of 14.1 months, the ORR in the entire population was 63.0% with 65 patients achieving a complete response or better with the drug. Further, 44 patients had no minimal residual disease (MRD) at the time of follow-up, with a MRD negativity rate of 46% among those patients who had a complete response or better. 

A median progression-free survival of 11.3 months (95% CI, 8.8-17.1) was also observed. The most common adverse events (AEs) were cytokine release syndrome (72.1%), neutropenia (70.9%), anemia (52.1%), and thrombocytopenia (40.0%). According to Dingli, these were manageable through step-up dosing methods and were not seen at a high grade, along with being able to use G-CSF (granulocyte-colony stimulating factor) to treat these patients.

With step-up dosing, the incidence of toxicities is quite mild. Cytokine release syndrome occurs, typically, after the first few injections. We give the lowest dose on day 1, subsequently another dose on day 3, and by day 5 or day 7 we will give the third dose, which is the 1.5-mg/kg dose. And patients then go on to weekly therapy, as per the label. As I mentioned, the patients tolerate the drug quite well. Where I practice, [we] typically treat patients in the outpatient setting. If the patient develops fever, [we] presume it's cytokine release syndrome, and that can be treated, and we'll address that in a little bit [for them].

Apart from the risk of cytokine release syndrome, the risk of neurotoxicity appears to be quite low and generally short-lived; it's typically grade 1 or grade 2 at most. There are some other toxicities as reported in this study, and most of these are hematologic. Typically [they are] cytopenias, whether it's anemia, neutropenia, or thrombocytopenia. The [AEs] are reversible, either by holding therapy for some time, and of course, it's important to always look for other potential causes of cytopenias, in particular, CMV [cytomegalovirus] reactivation. The neutropenia also responds very nicely with the use of G-CSF.

In a discussion with Targeted Oncology, David Dingli, MD, PhD, looks at how the use of step-up dosing with tecalistimab helped avoid many serious adverse events. 