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Optimizing Bispecific Antibody Safety and Care Coordination From the Pharmacy in RRMM

Multiple Myeloma

Multiple myeloma is an incurable hematologic malignancy that is defined by a clonal proliferation of immunoglobulin-secreting malignant plasma cells. These cells will produce a monoclonal M-protein that is then secreted into the serum and/or the urine.

We have really seen the treatment landscape of myeloma rapidly evolve.

Unmet Needs in Patients With MM

Although we have had this rapid progress, we still have a lot of unmet needs for patients with myeloma.

Bispecific Therapy Options for R/R MM

Bispecific antibodies really offer a novel mechanism of action that might help us overcome some of these unmet needs. These products are often referred to as "off-the-shelf" immunotherapy, and they have dual binding domains, one on an antigen on the myeloma cell, and then the other for CD3 on T-cells.

In myeloma, we have four FDA-approved agents, including teclistamab, elranatamab, and linvoseltamab, that all target that B cell maturation antigen, and then talquetamab that targets GPRC5D on the malignant plasma cell.

Cevostamab and etentamig are investigational therapies that are currently only available through clinical trial, and all of these agents do require step-up dosing and premedication to mitigate the risks of cytokine release syndrome, or CRS, and ICANS.

Most of these therapies are administered subcutaneously, but linvoseltamab does offer an intravenous option.

Safety of Approved Bispecific Antibodies for Multiple Myeloma

Toxicities of greatest concern with the bispecifics include our two T-cell redirecting toxicities, which are cytokine release syndrome or CRS, as well as immune effector cell-associated neurotoxicity syndrome or ICANS. The incidence of CRS ranged from 46% with linvoseltamab to 76% with talquetamab. But I do want to note that the majority of these events were grade one, and less than 1% of the events were grade three or higher. ICANS is really quite uncommon with these therapies with reported ranges from 3% to 7%.

Infection is one of our greatest ongoing concerns with these therapies due to the B cell and T cell suppression. Infections, particularly those grade three or higher, occur in about a third of patients receiving BCMA-directed therapy and about 17% of patients that receive talquetamab in the trials. Talquetamab also carries a unique side effect profile due to the expression of GPRC5D on keratinized tissues, particularly in the mouth and on the skin. We see a lot of dysgeusia, as well as dry mouth, dysphagia, and then rash and non-rash-related skin changes.

Dr. Syeda Saba Kareem (Moffitt Cancer Center): Thank you, Sara. We will be talking about assessing and managing adverse effects associated with bispecific antibody therapy in multiple myeloma.

The first one we will go into is cytokine release syndrome. CRS is a supra physiological response following immune therapy that activates your immune effector T cell. There is a lot of symptoms and clinical manifestations associated with CRS. Many of these include organ toxicities, these are graded using your typical CTCAE grading criteria.

CRS: Grading and Treatment

For CRS specifically, these are some of the hallmark symptoms that we look for in regards to grading. If a patient only presents with a fever greater than 100.4, then we would consider this grade 1. If a patient has hypertension that is not requiring vasopressors, or if they have hypoxia where they have oxygen less than six-liter requirement, then that would be considered grade 2. As you go higher with the intensity and severity, that is where the grading gets higher as well. When you have higher grades of hypotension or hypoxia, you can get grade 3. If you are requiring multiple vasopressors or have to have positive pressure for hypoxia, it would be considered grade 4.

Accordingly, the treatment is managed per that grading criteria. For grade 1 CRS, as you see here, your mainstay is supportive care. At this point you can consider steroids, PO or IV dex, and patients that have high risk CRS, you can consider tocilizumab as well. Of course, you want to hold the treatment, hold your bispecific until resolution. For grade 2 CRS, as you see here, we do symptomatic or supportive care with IV fluids and oxygen supplementation. At this point you definitely want to start steroids, so you can start it at Q 12-hour dosing.

You can also consider tocilizumab for patients that have high-risk or prolonged CRS. If it is an IV infusion like a linvoseltamab, then when we are resuming after a patient has resolved CRS, we can decrease the infusion rate by up to 50%. If a patient is experiencing grade 3 CRS, you definitely want to consider ICU-level care. We increase the frequency of the steroids, you definitely want to give tocilizumab at this point and even consider other alternatives if needed. As mentioned with all of these, if you are experiencing CRS, you want to hold your bispecific until resolution.

If a patient is experiencing grade 4 or more severe CRS, you want to increase your dose and frequency of your steroids by giving high-dose methylprednisolone. Again, at this point, you would definitely give tocilizumab for this patient. Some of the things that I want to point out is that if a patient was given an antipyretic or an anti-cytokine agent when you are grading for CRS, then a fever is no longer required to grade subsequent severity. If an antipyretic agent was given for grade 1 CRS, if a patient after a few hours starts having hypotension, they do not need to have fever again. We would consider that a grade 2 CRS.

Other things to be mindful of if a patient does experience CRS is you always want to be evaluating for an infection, because a lot of these symptoms can present as an infection as well. So, you want to initiate empiric antibiotics if a patient is neutropenic as well. High-risk features where you would consider giving tocilizumab early, like I mentioned previously, would be higher tumor burden, rapid tumor progression, if they have high inflammatory markers like high CRP or ferritin, older age, and multiple comorbidities, those would be considered high-risk patients.

Looking at incidence and timing, most of the CRS occurs during the first two step-up doses. By the time we get to the full treatment dose, the CRS rates are much lower. Another thing I wanted to point out is that the route of agent can also affect the duration and onset of CRS. Linvoseltamab that you see here, the median onset is about 0.46 or 11 hours versus the other agents, which is about one to two days where you have a longer onset when you are giving a Sub-Q route.

MajesTEC-1 looked at a cohort of patients that received prophylactic tocilizumab for CRS. In this trial, the rates overall were higher for CRS, 72.1%. However, most of them were grade 1 to 2. This prophylactic tocilizumab cohort used tocilizumab eight mg/kg about within four hours prior to the first step-up dose, along with the standard premedication. The incidence of CRS dramatically decreased to about 25% for patients that did have prophylactic tocilizumab.

One of the things that I also want to point out is rates of infection or neurotoxicity. Between the two cohorts of patients that did have tocilizumab and that did not, the rates of infections were fairly similar, rates of neutropenia were fairly similar as well, about 63% for the Toci group and then 64% for the patients without Toci. Rates of ICANS were similar, and then the efficacy as well was not compromised by giving tocilizumab.

MonumenTAL-1: Prophylactic Tocilizumab for CRS With Talquetamab in R/R MM

The MonumenTAL Trial looked at giving prophylactic tocilizumab before talquetamab about three hours before the first step-up dose of talquetamab, along with the standard premeds. Another additional nuance of this trial was that they also gave prophylactic dexamethasone, so they gave additional doses of dexamethasone two days after each step-up dose.

In this case, you also see a dramatic decrease in the incidence of CRS going from 75%, with patients that did not have any tocilizumab to about 18.5%. Infection rates were similar in the cohorts between tocilizumab and without Toci. Neutropenia, and ICANS were similar as well. Dysgeusia and oral toxicity were also similar in patients that did have tocilizumab versus without. The efficacy rate was not compromised either.

Neurotoxicity

The next thing we will talk about is neurotoxicity.

Neurologic Toxicity

Three main types of neurotoxicity we see for bispecifics are headaches, peripheral neuropathy, and immune effector cell-associated neurotoxicity syndrome or ICANS. It is relatively lower, it is much less common with bispecifics compared to our CAR T counterparts. We will see what that means regarding the specific ICANS.

ICANS: Clinical Manifestation

The manifestations of ICANS, the way that we assess it, is using the ICE score, and ICE score is the immune effector cell-associated encephalopathy score. Here, patients are asked a series of questions to look at their orientation to be able to name objects, follow commands, write a sentence. Those are specifically asked to a patient every single time to assess their level of neurotoxicity. The grading for ICANS is using that ICE score, as well as other parameters like looking at their level of consciousness, seeing if they have a seizure, any motor findings, or if they have elevated cerebral oedema. Those are some things that we look at when we are grading for ICANS.

If a patient has grade 1 ICANS, the management or treatment is steroids. You can start off with steroids with grade 1 and increase to Q6 hours if it is unresolved. If a patient does experience ICANS regardless of any grade, you always want to consider seizure prophylaxis as well. As with CRS, if a patient is experiencing ICANS toxicity, you want to hold a bispecific agent. For grade 2 toxicity, you can increase your steroids to every six hours. With grade 3, you again increase your steroids to a higher-grade high dose methylprednisolone about 1000mg, which can go up to Q12 hours if refractory. Again, for grade four, increasing your methylprednisolone to 1000mg every 12 hours is something that we want to consider.

Another thing we want to make sure is we have neuro consult, especially if a patient is refractory to dex. Neuroimaging is something that is recommended as well for these patients if they have consistent or persistent ICANS toxicity. Aspiration precautions should be taken if a patient is being admitted for ICANS toxicity, ensuring that withholding oral intake, ensuring that medications are converted to IV, doing a swallow eval are important. Then regarding tocilizumab, the only time that we would ever consider tocilizumab if a patient is having ICANS, is if they have concurrent CRS only.

Infection

BsAb Therapy's Infection Risk

The next thing we want to talk about is infection. Bispecific therapy inherently has an infection risk. This could be patient-related, it could be disease-related from the myeloma, or it could be treatment-related. When we talk about bispecifics, the targets do matter. BCMA agents do have a higher, more significant hypogammaglobulinemia and impaired humoral immunity. These patients tend to have a higher incidence of infection. The treatment itself, the mechanism of action being T cell redirecting, so you do have T cell dysfunction exhaustion. This can have impaired cellular immunity. Also, the previous toxicity that we just talked about with CRS and ICANS, you are giving them concomitant immunosuppressive agents with anti-cytokines and steroids. That also can increase your risk of infection.

With bispecifics you have the cumulative exposure. You are giving these agents every week every other week, every month, so it is a continuous exposure. This can also increase the risk of infection as you are having a longer duration of therapy.

Class Effect: Incidence of Infection With BsAbs in MM

The incidence, as you see, there is a class effect like we talked about with BCMA agents you definitely have a higher risk of infection, a higher rates of grade 3 infection to 45%, GPRC5D is lower, about 20% for grade 3 or more infection. I did want to point out about the redirect trial, where you have the combination of teclistamab and talquetamab. This does have a higher rate of grade 3 infection, so something to be mindful of as we are seeing this combination more in practice.

Effect of IVIG Prophylaxis on Infection-Free Survival in Recipients of BCMA-Directed BsAb for MM

A study was done by Mohan and colleagues. They looked at the effect of IVIg prophylaxis to see whether this will improve the rates of infection in patients with BCMA-directed therapy.  As soon as patients started a bispecific therapy, they received monthly doses of IVIg, and they had much better infection-free survival higher, about 7.7 months for any infection, and about 14 months for grade 3 or higher infection. This is something that we do recommend for patients regarding getting IVIg.

Consensus Guideline Recommendations for BsAb Therapy-Related Infections

I did want to point out we have some differences between NCCN and IMWG, consensus guideline recommendation for bispecific therapy with our antivirals.

We have our antiviral prophylaxis. Technically per NCCN, it should be given indefinitely or at least through the duration of the treatment of bispecifics and at least three months off treatment per IMWG. For antibacterial, we only really prophylax for that if a patient has neutropenia or ANC less than 500. Similar with an antifungal yeast antifungal where you would give it only if a patient is neutropenic.

Regarding multiple prophylaxis, we only would consider that in patients that are a high risk for infection with prolonged high-dose steroids or if they have prolonged neutropenia. For PJP prophylaxis, we do continue that greater than six months after duration of therapy, or until their CD4 counts are above 200, whichever is longer per NCCN. For IVIG, as we saw with our previous study, it does have the benefit of decreasing rates of infection. We do want to consider that throughout the duration of their bispecific therapy. When they are off therapy, then we can look at their IGG counts, and when it is less than 400 we can do the IVIG supplementation. For Hep B and HIV screenings, those should be done at baseline because of the risk of reactivation. Then for CMV, we really only monitor viral load if you have suspected CMV-related disease. We would not just do it, normally. You could do it if you have unexplained fever or cytopenias or those patients with a higher risk. For all these patients, you really want to maintain their updated vaccination status as well.

GPRC5D-Specific Toxicities

Next, we are going to go into the GPRC5D-specific toxicities.

Talquetamab: On-Target, Off-Tumor Effects

Like Sara mentioned earlier, talquetamab is unique. It has these on-target off-tumor effects. The GPRC5D is expressed in our keratinized tissue, so you do see the type of side effect profile for oral toxicity as well as dermatological toxicity. Most of the grading is grade 1 to 2. However, something to point out is dysgeusia only comes in two grades of severity. If a patient has grade 2 severity of dysgeusia, they do have an altered taste, it changes their diet, they could have weight loss, so this can get very difficult for the patients, and we do see a high percentage of patients that end up with oral toxicity.

Talquetamab Toxicity Management

Some of the management or toxicity recommendations is, when it comes to nail or dermatological toxicities, supportive care is recommended. Steroids are also used. You could do topical steroids for grade 1 to 2, dermatological toxicities or oral steroids for higher more severe toxicity. Of course you can always do dose modifications. Decreasing the frequency and decreasing the dose of talquetamab has been shown to help with these effects. Also, for oral toxicity, again, increasing hydration, you want to make sure you have a nutrition consult early on, dietary modifications, same as the other management dose modifications does help on this side as well.

Care Coordination With BsAb Therapy

The next thing we are going to talk about is care coordination when we think about bispecifics.

Current Recommendations for Step-up Dosing When Beginning Bispecific Antibody Therapy

We have four commercially available bispecific agents with a variety of step-up doses, anywhere from every two to four days to weekly. Hospitalization is recommended by the PIs to mitigate these severe toxicities of CRS ICANS, which do occur within the first step-up periods.

Outpatient Models for BsAb Step-up Dosing

Some institutions have started looking at outpatient models. How do we consider when we are thinking about doing step-up dosing on the outpatient side? The first thing you want to think about is criteria. Does the patient have caregiver support? Do they have patient comorbidities that can increase their risk? Do they have an appropriate performance status? Do they have local lodging? Just starting off with making sure this patient is appropriate for an outpatient treatment is important.

The next thing is looking at prophylactic strategies. As we saw in the studies previously, prophylactic tocilizumab can be given. Also, we can do prophylactic dexamethasone after each step-up dose. Different institutions will be looking at different strategies that they can use to have outpatient bispecific therapy.

The third thing we want to think about is patient monitoring. It is very important that these patients are closely monitored. However, how it is done really varies depending on the different institutions. Some institutions do remote monitoring 24 over seven, some do self-monitoring where patients check their own temperature and vital signs every four to eight hours and report to the clinical team. The important thing is to have frequent assessments, whether it is virtual or in person, to make sure the patient is tolerating therapy.

The next thing is outpatient treatment strategies. We talked about prophylactic strategies. What do we do when a patient does develop toxicity? Does your institution want to treat grade 1 CRS on the outpatient side which can be done with the use of dexamethasone or tocilizumab, or do they do observation and just monitor these patients? Or the other thing is, are all patients that have any toxicity admitted? Having an inpatient admission criterion is also important to understand the concept of if a patient does have toxicity.

Some institutions will admit patients if they have any grade CRS or ICANS, and some institutions will wait if it is grade 2 or higher or if they have persistent grade 1. You can have some sort of stratification depending on your institution.

Framework for Care Coordination and REMS

Another part I want to talk about is the framework for care coordination. Once you have looked into the outpatient structure and it really is a whole framework, regardless of whether a patient is getting bispecifics outpatient, inpatient, or continuing their care, some of the important things to highlight is education and training. That needs to be done regardless of what area you are looking at. Looking at the REMS requirements for each of these different agents, is important for the institution as well. Having some standardized documentation. How are we documenting CRS? Making sure we are grading, giving the ICE scores, having an appropriate standardized documentation regardless of whether it is happening in the clinic or whether the patient is getting admitted. Then having an appropriate triage or on call process is extremely important.

When are we giving prophylactic treatment? When are we doing management? All of those things should be standardized for the patients. Making sure we are connecting with our community emergency center and acute care facilities. This is important if your institution is looking to start bispecific therapy, it is important to engage to all the different institutions around you as the patients can go to the different ERs.

Making sure those communities have access and availability to tocilizumab, which is really important for the treatment and management of this toxicity. Making sure we have appropriate patient education resources. All of these patients, not just the patients, but caregivers should be educated on this treatment. This is a complete multidisciplinary care, so you have patient care navigators that should be involved in these complex regimens and complex treatments, side effects that can happen for these patients, as well as making sure we have social workers on board looking at local lodging, and of course, involving our financial insurance teams.

From the inpatient side, making sure we have an appropriate admission pathway. When these patients get admitted, they are flagged in the system that these patients are on bispecific, because a lot of these toxicities can just present as an infection in the emergency room, so making sure we have an appropriate triage process. Again, having some standardized protocols and management guidelines is important. Having standardized order sets is really helpful on the inpatient side for having CRS and ICANS protocols, making sure these patients are getting vital signs and ICE scores, getting at an appropriate standardized way.

Of course, even here you want to engage your multidisciplinary specialties, educating emergency department, critical care, neurology, hospitalists on some of these side effects and symptoms is really key.

Once we are done with the step-up dosing, you always have to think about continued care. With all the side effects we discussed, the infection risk is real and high rates of infection, so having frequent assessments and visits continues to be a priority even after a patient has completed step up dosing. Making sure we have appropriate supportive care protocols, as we saw with our GPRC5D toxicity. Making sure that we are assessing and monitoring these patients. Again, having a multidisciplinary multispecialty care with the involvement of GI, ENT, dietician, infectious disease and working together because of the unique toxicities of bispecifics.

Now I will pass it off to Sara to talk about education.

Patient and Caretaker Education

Dr. Scott: Thank you. As Saba mentioned, these therapies are complicated, and so I think one of our greatest roles as a pharmacist is taking these complicated regimens and breaking them down and helping a patient understand what they are about to experience. Not only educating the patient, but also the caretaker, particularly if you are going to be doing outpatient step-up dosing. I do not know any institutions that are doing that without the support of a caretaker. The first step is evaluating where these patients are getting step up dosing and that will allow you to help tailor the CRS ICANS monitoring and recognition education, whether that responsibility is falling on the patient and their family or caretaker, or if that is something that they just need to be aware of why the monitoring is happening on the inpatient side, but nothing they actively need to do.

With this, as well, is not only recognition, but what to do if it happens. Providing very clear, patient friendly language and patient friendly guidance, if you have a fever, do X, Y, Z, whether that is taking a pocket dexamethasone, calling the triage line, coming into the care center, whatever that might be. Then once they get through the step-up dosing, infection is going to be our biggest concern across the board. What prophylaxis are they getting? Many of these patients have not had IVIg before, and that is not a benign therapy, so discussing with them what that looks like, what the risks of IVIG are, options for home administration of either IV or subcutaneous immune globulin if that is something the patient is interested in.

Then recognizing infections. I think we as oncology providers always just talk about fever but there are a lot of ways these infections can present, especially when these infections are more unique, we see opportunistic infections. Any sort of infectious symptom to make sure the patients can recognize those.

Then agent specific adverse effects, really honing in on those GPRC5D associated toxicities. I think an important piece of education here is being realistic with the patients. As we have both mentioned, Saba and myself, the dysgeusia should just be expected. It is going to happen for these patients, and so resetting those expectations, engaging the dietitian so they can also educate the patients on how to navigate that really challenging toxicity in regard to quality of life.

Then discussing with them and giving, we provide a tips and tricks tip sheet because there really is no home run as far as treatment for these toxicities at this time. Providing them with when to call us again, but also things they can do at home as far as moisturization, saliva stimulants, all of the options that they could have.

Then last but not least, talking about their treatment schedule and duration. These are ongoing therapies. At this time, we do not have data to support fixed duration therapy. Though I do think that data is coming, we just do not have it right now. That is a question you always get from patients is, how long am I going to be on this? Discussing with them what their schedule is going to look like, when is that frequency going to change? Do you as an institution, follow the label, or do you have an adopted practice where you are maybe changing that frequency much sooner? Then how long they can expect to be on the therapy.

Bispecific Antibody REMS Programs

The other piece of it, from a pharmacy perspective, is taking into account that all of these products unfortunately carry a REMS program due to the risk of CRS and neurotoxicity. Oftentimes a pharmacist will be the authorized representative for these programs, and so we need to be intimately familiar with these programs. Prescribers must be certified. They enroll and they complete training. It is a really straightforward 10 question quiz. Then the prescribers are responsible for the counselling of patients on these risks and providing the patients with a wallet card. They can designate somebody to do this for them, but the patient must be given that wallet card prior to starting therapy.

Then pharmacies and healthcare facilities that are going to dispense these drugs also have to be certified. The pharmacy has to be enrolled; you cannot order drug until you are enrolled. Then there are SOP requirements and other pieces that are required within the pharmacy as far as appropriate documentation and maintenance of records.

Role of the Pharmacist

Last but not least, just summing up the role of the pharmacist that we have alluded to throughout this presentation. When these drugs come to market, formulary management is going to be the first step you can take as a pharmacist and really evaluating if you want all of these drugs on formulary, critically evaluating if you need them, or if you are going to have them all, how you make that clinical decision amongst those products.

At our institution, we have them all. We also have a decision tree for how we use them all. Those are pieces that we have managed within formulary, and that has really been a pharmacy-driven process. Protocol development, again, alluding to those REMS SOPs, but also discussing outpatient step-up dosing versus inpatient step-up dosing, developing protocols for the management of toxicities, patient and caretaker education that we just stepped through, coordination and administration of the step-up dosing, so playing a role not only on the clinic side, but also the operational side and supporting that administration and the safety of that supportive care.

Saba talked about CRS prophylaxis, and really pharmacists can drive the implementation of that. Infection prophylaxis and ensuring those patients have everything they need, including that IVIG, and then developing protocols for toxicity management to try to help standardize this as much as possible. Developing those order sets for CRS and ICANS management should the patient present to the ED or be inpatient and need management. All of those things that can be really pharmacy-driven.

One big counselling point we have talked about a lot is the CRS and ICANS management and what the roles are for the patient and their caregiver with this. A secondary question is what strategies has your institution adopted to operationalize outpatient step-up dosing if you have, and do you use any prophylaxis, whether that is dexamethasone post-dose or tocilizumab pre-dose?

Dr. Kareem: What does your institution do, Sara?

Dr. Scott: We do have a 100% outpatient program with the only exceptions really being patients without caregiver support. We were early adopters of the prophylactic tocilizumab, and one of the questions I get from a lot of pharmacists is, how do you manage the cost of that? I would like to reassure everyone that we get reimbursed for every single one of those doses. It is now integrated into the NCCN guidelines we do have to appeal this pretty often, and we have not yet had like a denial held up. That is our approach.

Then we do have pocket dex as well. We have pocket dex and Tylenol. We have that, and then patients come in at any sign of CRS or ICANS. We handle most of them in the outpatient setting. As you mentioned, we will admit people should they have grade 2 or persistent grade 1 toxicities, which is very rare.

Dr. Kareem: That is interesting. We do the same. We have adopted prophylactic tocilizumab as well. We do majority, almost 90%, of our all of our myeloma bispecifics outpatient and only admit them if needed for social reasons. The only other difference I would say from your institution is that we do admit for any grade CRS. If they are having any grade, we bring them in observation or an admission if needed. Next phase is to do pocket dex and outpatient triage.

Dr. Scott: Yeah. It is helpful. It is helpful with bed space, and I think that is what most institutions are finding that, as we learn more about these therapies, the inpatient admission is probably not necessary for step-up dosing unless, like you said, they are having toxicity and then of course, we need to take care of those patients.

Then the next piece for counselling points is the infection prophylaxis. Saba, have you all integrated primary prophylaxis with IVIG?

Dr. Kareem: We have. We actually have created order sets, and it is included in all our SOPs and guidelines to do primary prophylaxis for IVIG.

Dr. Scott: I think most institutions are adopting that based on some of the recent data. We do that as well. It is built right into our bispecific treatment plans.