Ajai Chari, MD, director, clinical research, Multiple Myeloma Program, UCSF Helen Diller Family Comprehensive Cancer Center, discusses important patient factors to consider when selecting between currently approved BCMA-targeted therapies for the treatment of patients with multiple myeloma.

Of the recent BCMA-directed therapies that have been approved in multiple myeloma treatment, many have an indication for patients who received 4 or more lines of therapy and are triple-class exposed to a proteasome inhibitor, immunomodulatory agent, and anti-CD38 therapy, Chari begins. If a patient meets those criteria, the next biggest determinant aside from insurance approval is the rate of their disease progression, he says.

The biggest differentiation between bispecific antibodies and CAR T-cell therapy is the infusion wait time for CAR T-cell therapy, Chari explains. Manufacturing CAR T-cell therapy is a lengthy procedure in which T cells are collected from the patient through apheresis. Logistical challenges associated with this process can often result in manufacturing delays, longer wait-times for patients, or a complete lack of access to this therapy, Chari details. Conversely, bispecific antibodies are off-the-shelf and are more readily available for administration, Chari adds.

Another key factor to consider is the selection bias that arises from the patient enrollment process in early-phase clinical trials, Chari continues. Historically, CAR T-cell trials involving CAR T-cell therapy were often conducted in heavily pretreated populations and had limited slots, Chari describes, leading institutions to carefully choose their patients. The resulting selection bias has influenced real-world decision-making and reflects the difficulty many patients experience when attempting to access CAR T-cell therapy, Chari says.

In order to receive CAR T-cell therapy, patients with rapidly progressing disease must remain stable for apheresis, while awaiting insurance approval, Chari states. After obtaining this approval many patients must wait several more weeks for their scheduled time slot. Patients’ stability must be maintained for a minimum of 4 to 6 weeks after apheresis, which can be a challenge, he adds. Chari also notes that some of the most recent CAR T-cell products have data that do not meet the predefined efficacy cutoffs agreed upon by health authorities. This complicates long-term follow-up data for these patients, he says.

Ultimately, patients with rapidly progressing disease may benefit more from treatment with a bispecific antibody, as this is a more immediate treatment option, Chari advises. Conversely, patients with indolent disease who are considered fit, are far from academic centers that administer ongoing bispecific therapy and can tolerate potential treatment-related neurotoxicity may be better candidates for CAR T-cell therapy, Chari concludes.

Videos

Ajai Chari, MD,  discusses important patient factors to consider when selecting between currently approved BCMA-targeted therapies for the treatment of patients with multiple myeloma.

Dr Chari on the Selection of BCMA-Targeted Therapies Within Multiple Myeloma

Ajai Chari, MD, director, clinical research, Multiple Myeloma Program, UCSF Helen Diller Family Comprehensive Cancer Center, discusses the significance of the FDA approval of talquetamab-tgvs (Talvey) in patients with relapsed/refractory multiple myeloma.

granted accelerated approval to talquetamab for adult patients with relapsed/refractory multiple myeloma

 who have received at least 4 prior therapies, including an immunomodulatory agent, an anti-CD38 antibody, and a proteasome inhibitor. This approval was supported by findings from the phase 2 MonumenTAL-1 trial (NCT04634552), in which patients who had received 4 or more prior lines of therapy and had no prior T-cell redirection therapy (n = 187) who were treated with subcutaneous talquetamab at 0.8 mg/kg every 2 weeks achieved an overall response rate (ORR) of 73.6% (95% CI, 63.0%-82.4%). Furthermore, patients with no prior exposure to T-cell redirection therapy who received the agent at 0.4 mg/kg weekly achieved an ORR of 73.0% (95% CI, 63.2%-81.4%). Moreover, MonumenTAL-1 included 32 patients with at least 4 prior lines of therapy including prior bispecific antibody or CAR T-cell exposure who received talquetamab at 0.4 mg/kg weekly. In these patients, the ORR was 72% (95% CI, 53%-86%).

In the current arena of advances with T-cell redirection therapy in patients with multiple myeloma, CAR T-cell therapy and bispecific antibodies are eliciting deep and durable responses, Chari says. Prior to the approval of talquetamab, all approved treatments for patients with multiple myeloma targeted BCMA, Chari explains. The bispecific antibody talquetamab is the first agent to target GPRC5D, Chari notes.

In addition, talquetamab is an off-the-shelf bispecific antibody, which increases its accessibility to patients, according to Chari. Furthermore, its adverse effect profile is unique compared with those of other bispecific antibodies and opens the door to potential combinations with other agents, Chari concludes.

Ajai Chari, MD, discusses the significance of the FDA approval of talquetamab in patients with relapsed/refractory multiple myeloma.

Dr Chari on the FDA Approval of Talquetamab in Relapsed/Refractory Multiple Myeloma

Ajai Chari, MD, professor of medicine, director of clinical research in the multiple myeloma program, and hematologic oncologist at Mount Sinai Hospital, discusses recommendations for minimal residual disease (MRD) testing in patients with multiple myeloma.

It is important to ensure that serologic tests are negative in the blood and urine, radiologic tests are negative, bone marrow tests are good quality, and other analytic characteristics are accurate, according to Chari. Additionally, the sensitivity of these tests needs to be adequate, at either 10-5 or 10-6. Suboptimal tests should not be used to inform treatment decisions, Chari says. Furthermore, if there no predictive data are available, these tests will often not impact the management of patients, except for in extreme cases, Chari adds.

Additionally, sustained MRD status is crucial in making treatment decisions for patients, and adequate follow-up is needed, Chari adds. For example, the phase 2 FORTE trial (NCT02203643), which examined induction with the combination of carfilzomib (Kyprolis), lenalidomide (Revlimid), dexamethasone followed by maintenance with either carfilzomib plus lenalidomide or lenalidomide alone, showed that the study arms were not as comparable as originally reported. This emphasizes the need for longer follow-up to make appropriate therapeutic decisions, Chari concludes. 

Ajai Chari, MD, discusses recommendations for minimal residual disease testing in patients with multiple myeloma.

Dr. Chari on the Role of MRD Testing in Multiple Myeloma 

I think from a physician’s point of view and a practice management point of view, one of the biggest barriers to getting DARA [daratumumab] has been that first dose issue, that long infusion, the 1:1 nursing staffing, the chair time. All of those barriers I think are challenging. Danny, what do you think, we hope daratumumab subQ [subcutaneous] will be approved very soon. What do you think might be helpful for community doctors to know about this new formulation?

I think it is safe to give, the efficacy is there, and the low adverse events, infusion-related events are extremely low compared to the intravenous [IV]. I think for them, because most communities have limited time availability, that I feel that it’s a great option that their patients, instead of coming to a big institution, bringing them in. Yes, Mount Sinai Health System is in the city, or even other institutions in the community—they travel very far. So, if there’s a community physician who can give this drug instead of the patient driving 2 hours in each direction, it’s also saving them the wear and tear, even emotionally, of driving to the institution. I think if they’re nervous about it, if your community physicians and practices are nervous, then maybe give the drug in the beginning of the week, Monday, Tuesday, Wednesday, because if patients do have a delayed effect, then they can still manage them up front. But I think in the whole, it’s going to revolutionize how patients are treated.

I think it’s interesting. In some ways, comparing IV and subQ, probably the people who are affected the least are the physicians because we write the order, but then it’s everybody else who benefits, right? The pharmacists are mixing this small vial of fluid, the nurses clearly are benefitting from much less chair time and 1:1 monitoring, and patients. But I’m curious if you could expand a little bit more on the nursing involvement in terms of how long this drug is infused over, daratumumab subQ, and logistics of premedications, monitoring. What are your thoughts? What would you instruct community nurses about this drug?

The premedications are again the same standard of 1 to 3 hours prior to getting the infusion. And definitely, in the community, once they’ve received their first dose and they’ve tolerated it, most of the premedications can go to an oral formulation. You can instruct your patients to take them 1 to 3 hours prior, so now you’ve even freed up an extra hour of time of chairs, excluding having laboratory monitoring that might be necessary per week. And again, the drug is given over 3 to 5 minutes, the first dose within the first 5 minutes, and then if tolerated, can go over 3 minutes. I think in the community, a follow-up phone call might be an insight on patients to see how well they tolerate it. If it was in the morning, are they feeling OK that evening? And then having another phone call, having a nurse navigator follow up with the patient the next day to see if they had any kind of infusion reaction for tolerability. But again, it’s maybe more phone call driven, or maybe on the side of administration, but again the patients will enjoy it.

A couple of other things that came to mind are of course, here we have a flat dosing, so 1800 mg. That’s nice because most likely that dose will be targeted to, the typical patient will be 80 kg, so obviously they want to avoid underdosing patients because we’re trying to go for myeloma disease control. So it will be a flat dose, which is convenient and nice for everyone. You don’t have to keep re-signing orders because of weight changes. And I think as you very well outlined for first dose in getting things going, this is pretty clear in terms of same premedications and administration.

Some of the things I guess that we need to discuss a little bit more are how long to keep somebody in the clinic. That first dose, we have a 5 minute injection, but then how long do you have to keep the patient around? The rates of allergic reaction we said are quite low, but the median time to allergic reaction or infusion-related reaction was about 3.4 hours. It is slightly delayed. So, depending on how folks want to do it, whether they want to keep them in the waiting area of just be around in case of issues, check vital signs, etc. Maybe for those patients with respiratory issues, keep them around for sure and be getting the vital signs. That maybe something to consider on a case-by-case and infusion center-by-infusion center basis.

I think if you compare the first subQ versus the IV, asking a patient to remain in your clinic for 4 hours versus 8 hours, I think they still would be happy to wait to see in 4 hours, no adverse effects, go home, versus leaving at 8 o’clock at night.

And again, most of these were grade 1 and 2 as well. I think as we get more experience with this in the community, that may change or we may even be doing phone calls, as you suggested, especially for those patients who are young, healthy, compliant, no respiratory issues. I think the other thing that we will need to think about is it’s easy to get somebody started on subQ daratumumab, but there may be also the issue of transitioning patients.

People who are on their umpteenth dose of daratumumab, part of their maintenance once monthly, transitioning those people to subQ, because some of those, as you said, at our center we’ve weaned off a lot of the premedications. And we’ll need to look into the guidance on that, whether at least for 1 dose we need to give those premedications just because there is this hyaluronidase being mixed in. So I think we’ll have to stay tuned for that, but I think again it will be very minor issues.

And again, these patients will all have been tolerating IV daratumumab, which is much more likely to cause infusion-related reactions. And the likelihood of that after you’ve been on it for a long time should be pretty low. That's another concern or issue that we may have to think about with the transition. I think daratumumab subQ is going to be great for everyone, and I would say in particular probably, as I said, the patient, the nurse, the pharmacist more so than the physician. Danny, any final thoughts?

I agree. I think it really embodies the quality of life when you talk about therapy and the patient with myeloma themselves. Convenience, efficacy, and then to still be able to do their own daily living and not be trapped, like you said earlier, chained to the infusion chair for 8 hours and stare at us when they can at least stare at their grandkids, I think is a great asset to the myeloma paradigm.

Great. Well, thank you, Danny, for joining me, and we hope this has been helpful to everyone and that you enjoyed this session. Thank you very much.

*Note: Subcutaneous daratumumab is now approved in the US and Europe.*

Community Advice: SQ Formulation of Daratumumab

Danny, maybe you can walk us through what it’s like to give subQ [subcutaneous] DARA [daratumumab] in clinic.

Absolutely. The premeds, or the premedication, and testing would be identical to what we would do for a patient who was actually going to receive the intravenous [IV] version of the daratumumab, except the administration of the drug is different. You’re going to give it subQ like Dr Chari said earlier. It’s better in the belly because there’s a lot more subQ tissue in there, and it’s given over 3 to 5 minutes. It’s a very small needle; it’s about a 5/8-inch needle, so patients don’t experience much discomfort. Even though it sounds like a lot of volume, 15 cc, because we all learned in school that we’re only allowed to give 2 cc at the maximum, but you can literally give them 15 cc. They tolerate it extremely well. Usually the first 4 doses are 5 minutes, and if they tolerate it well, it’s given over 3 minutes. I think it adds an extra convenience for our population, instead of staying 7 hours or a minimum of 4 hours.

Yes. I think to emphasize, maybe Danny, you can talk about the nursing implications in terms of the staffing of a nurse to first dose monoclonal antibody for IV versus subQ, and how that impacts the staffing.

Absolutely. It allows staff to be freer. Instead of a 1:1 for your stay, for your first 4 to 7 hours of intravenous fluids, you’re with them maybe an hour the most. So now the increase in chair time in your institution, in the clinical trials the patients were monitored for 4 hours, and if it does become commercially available, the monitoring will be a little bit different on patients. But again, your chair time is no more than maybe 1 to 3 hours maximum instead of 7 hours maximum. And the nurses then can move from one patient to the next.

Danny, I still remember when daratumumab was first coming on, we had that expanded access program, we started 50 patients on IV daratumumab in the span of 2 months. So talk about chair time in the infusion center, each patient is getting blocked not only for that long first day, but multiple hours every week after that. It really put a big damper on the infusion turnover time.

Even other institutions, they were starting them inpatient, actually. Many institutions were starting their first doses inpatient to see if they were tolerating the drug and then moved them to outpatient. So you’re exposing a patient to an inpatient environment, or taking up an inpatient bed, just for a monoclonal antibody, and then again coming out to the infusion center, blocking at least 5 hours of a chair.

I think another interesting question that folks who have not given daratumumab subQ, can you talk about what the injection site looks like, especially, let’s say, in comparison to bortezomib and what that looks like, the day of, the day after? What does it look like in somebody who’s gotten daratumumab subQ?

Interestingly enough, there is some slight swelling. It’s a little bit different than bortezomib, where sometimes patients would get a redness or an irritation of the skin. You still would get some types of irritation. Some people do get a red blotchy kind of discoloration at the infusion site, but it’s very fleeting. It usually lasts about a day and it dissipates over that, but again a minimal amount of effects to the skin or discomfort to the patient themselves.

I’ve shown up to a bedside after a patient got daratumumab subQ, and I can’t even find where the nurse injected. And I’m like, where did it go? It’s really hard to see. I think it’s really well tolerated. I think these are the sum of what we covered between COLUMBA, PLEIADES, and your bedside experience description. I always say that when we compare daratumumab IV and subQ, actually when you compare any medical treatments, we think about risk, benefit, and convenience, right? So risk here, we see lower rates of infusion-related reactions, significantly, as low as 4% in DRd [daratumumab, lenalidomide, dexamethasone] in PLEIADES and 9% in the other arms in COLUMBA, so less than 10% infusion-related reactions versus as high as 40% to 50% for IV.

Efficacy seems to be comparable, both by the response rates that we’ve seen in COLUMBA as well as PLEIADES, but also that important pharmacokinetic parameter called C trough was comparable. And of course the convenience is really unbeatable. I always say that when I’ve been consenting patients to daratumumab subcutaneous clinical trials, the discussion goes like this. “We have a drug that’s basically as efficacious, better risk profile, and is more convenient.” Very few patients have had any issues. I think it’s the easiest study to get patients consented on because who wants to spend more time in the infusion center? Danny, what do you think?

I think it’s a great idea. Even though our patient population is the more mature adult, the average age is 69, they’re still working, or even if they’re not working they still have other extracurricular activities. They’re active, they’re seeing their grandkids. And to spend time in an infusion center for 7 hours, compared with, “I’m going to come in for my shot, I’m going to spend an hour or 2 in the infusion center, and I can still go back to work, I can still go on a trip, I can still enjoy my life.” I think when you look at patient satisfaction and convenience, that outweighs having the intravenous therapy.

Yes, I always say what’s the point of having your myeloma be in remission but you’re chained to the infusion center all the time.

It’s a great liberation from the infusion center.

Real-World Experience With SQ Monoclonal Antibodies

I think this is a great segue into a very new way of giving DARA [daratumumab]. We talked about the infusion-related reactions, the time of infusion, the volume, the management of all of these things, the concentration. So a lot of factors to consider but a good segue into giving daratumumab subcutaneously [subQ]. We know that, for example, rituximab was recently approved to be given subcutaneously; IVIg [intravenous immunoglobulin], which is commonly used, to be given subcutaneously. And of course, the question is what about daratumumab? So daratumumab can be given subcutaneously, but one of the limitations of giving antibodies is the volume of the antibody would not necessarily diffuse through the subcutaneous compartment.

In order to give daratumumab subcutaneously, it’s mixed with hyaluronidase, and what this does is it allows the drug to be given subcutaneously in a relatively small volume of 15 mL, and it can be given in the abdominal site. The important study that led to this, the phase III study that compared subcutaneous IV daratumumab, it’s called the COLUMBA study, and that was recently published in 

 by Maria-Victoria Mateos, MD. The eligibility criteria were patients with at least 3 lines of prior therapy, including a PI [proteasome inhibitor] and an IMiD [immunomodulatory drug], or they had to be refractory to PI and an IMiD. Patients were stratified by 3 different criteria, body weight being less than or greater than 85 kg, less than or greater than 4 lines of therapy, and IgG [immunoglobulin G] versus non-IgG subtype.

The randomization was 1:1, and about 260 patients got daratumumab subcutaneously. Importantly, this is a flat dose, 1800 mg, and it was given subcutaneously, as I mentioned, in 15 mL, and it was given at the same schedule that Danny just outlined for IV. And the comparator group was standard daratumumab IV at the standard dose and schedule, 16 mg/kg.

There were 2 co-primary end points. One was the response rate, and the second is the maximum C trough. C trough is basically the dose concentration of daratumumab after you finish those 8 weekly doses. That’s cycle 3, day 1, if you will, because that C trough level has been correlated to efficacy in other studies. In this study, obviously one of the most important and interesting findings is that the median duration of infusion in the first administration was 421 minutes for the IV versus 5 minutes for the subQ. And that goes to 255 minutes and 5 minutes for the second dose; and 205 minutes and remains of course 5 minutes. So we’re looking at 7, 4, and a little over 3 hours for the IV, whereas the subQ remains flat at 5 minutes.

That primary end point was response rate with a median follow-up of 7.46 months, response rate of subQ 41% versus 37%; VGPR [very good partial response] and better, 19% versus 17%, so looking comparable or noninferior. The co-primary end point of C trough was also very comparable. The 107.93%, so C trough, if anything, was slightly higher with daratumumab subQ than IV. But really, again, this was noninferior and that criteria were met.

When we looked at the patient, their cancer treatment satisfaction, it continually improved with daratumumab subQ. Who wants to spend more time in the infusion center? And importantly, I think one of the things that we’ve been talking about with the IV[daratumumab is the infusion-related reactions [IRRs]. When we look at the so-called IRRs, subQ daratumumab, the rate was only 13% compared to 34% for IV. And most of these infusions occurred during that first dose, as we would expect, even with IV. Grade 3 was very uncommon, 2% versus 5%. There were no grade 4 or 5 [IRRs]. And the infusion-related reactions are what you would expect in IV as well—chills 5% versus 12%, pyrexia 5% and 3%, dyspnea 1% versus 7%.

One difference is the median time to infusion-related reactions. With daratumumab, the subQ was 3.4 hours. Again, the drug is being diffused slowly, versus intravenous, which was 1.5 hours. I think that was an important study to show the benefits of intravenous versus subcutaneous daratumumab. The primary end point of response rate was comparable—C trough comparable. So we have basically comparable efficacy with what appears to be an improved safety profile, with lower rates of infusion-related reaction, obviously way more convenient, and then finally the rates of infusion-related reactions were lower.

Moving to the other study, which is important because this was a single-agent noninferiority study, this was a phase III. There’s also the PLEIADES study, which I’ve updated at ASH [the American Society of Hematology 2019 annual meeting]. Basically, this was a slightly different study because it’s daratumumab in combination with some of our standard backbones that we covered. So daratumumab in combination with VRd [bortezomib, lenalidomide, dexamethasone], as was done in the GRIFFIN study, so it’s subcutaneous daratumumab. Daratumumab in combination with VMP [bortezomib, melphalan, prednisone] as was done in ALCYONE with subQ. And finally in DRd [daratumumab, lenalidomide, dexamethasone] as per MAIA, but again the subQ daratumumab. So subQ daratumumab given with the backbones.

The primary end points were different for these 3 arms. The primary end point for the D/VRd [daratumumab with bortezomib, lenalidomide, dexamethasone] was VGPR and better because this was only 4 cycles of administration. Whereas the D/VMP [daratumumab with bortezomib, melphalan, prednisone] and DRd [daratumumab, lenalidomide, dexamethasone] were overall response rate. There were some key secondary end points. But each group had about 67 patients in each arm, what you would expect for the patient populations. The response rate for D/VRd [daratumumab with bortezomib, lenalidomide, dexamethasone] was 97%; 89.6% for D/VMP [daratumumab with bortezomib, melphalan, prednisone]; and finally 94% for DRd [daratumumab, lenalidomide, dexamethasone]. So kind of comparable to what you would expect for the intravenous regimens.

Importantly, the rates of infusion-related reactions were very low, 9% for D/VRd [daratumumab with bortezomib, lenalidomide, dexamethasone]and D/VMP [daratumumab with bortezomib, melphalan, prednisone], and only 4.6% for DRd [daratumumab, lenalidomide, dexamethasone]. So really very low rates, very easy to administer. And again, most of these occurred in that first dose, very little in subsequent doses.

Study Overview: COLUMBA and PLEIADES

Speaking to the infusion reaction, maybe you can tell us a little bit about what that looks like, when you see them, and what kinds of reactions have you seen?

I think in the healthcare industry, we’ve been working with monoclonal antibodies for many years, over 25 years now. It’s a lot of anaphylaxis or hypersensitivity reactions. You’re going to see patients get nasal congestion, which I think is not as captured. Many patients may blame the nasal congestion on allergies or they feel like they’re coming on with a cold, but it was something that was really driven by the antibody. You’ll see them get chills, rigors, shortness of breath. Some people will complain of tingling of the throat or of the lips themselves.

One of the big adverse effects that was slightly different than with most antibodies that I have seen in my experience is that patients on the first infusion would complain about severe bone pain, whether it was in the long bones—the hip, the back, the chest—or they would have this diarrhea experience compared to other antibodies. Those are things they we’ll see. Usually about 30% to 40% of patients will have some type of adverse event or some type of adverse effect. But I will say after they’re exposed to the monoclonal antibody, to daratumumab, by the time they get to their second week, that second infusion, they will not have another adverse event. It drops down actually to 2%.

To clarify, the usual adverse events that we see in oncology and myeloma from this initial dose issue, or the first few doses, we really try in clinical trials, they’re often described and categorized as infusion-related reaction, or IRR, to distinguish from other, say, adverse events, such as neutropenia, fevers, etcetera. So IRR, it’s a first few doses effect. For somebody who hasn’t given a lot of monoclonal antibodies, or perhaps may not be used to the nature of DARA [daratumumab], sometimes people do get a little concerned. If somebody does have a reaction, like bronchospasm or some shortness of breath, what do you do at the bedside?

Those adverse effects, to go back, can happen within 5 minutes; typically we’ve been seeing the adverse effects occur within the first 90 minutes. And we’ll talk about how the infusion goes. Usually when the infusion rate changes from 50 cc to 100 cc, within 20 minutes you’ll see some adverse effects occur. But it can be up to 7 hours before the first reaction can occur. For your new exposure, your new healthcare provider who’s not seen monoclonal antibodies, you want to assure them that these are very typical adverse effects, they’re very common with monoclonal antibodies as a group. You want them to stop the infusion, you want to call your healthcare provider, and you want to give the appropriate medication, depending on the adverse effect that you’re dealing with.

If they’re feeling very short of breath, you may want to give them a little more steroid at that time to help mediate. You could also, if they feel very itchy or have a rash, some patients have developed rashes, you may want to give them some Benadryl to help, again, that particular adverse effects. We’ve used Demerol in the past for rigors or chills, too, which can help mitigate that, very small doses and the patients resolve very quickly.

The goal is at the time of adverse effect, you want to wait about a half hour to 40 minutes and see if the adverse effects resolves, and then reinitiate the medication, the daratumumab, but you want to start it at half the rate of when their reaction occurred. So, if it was at 100 cc an hour, you’re going to restart them back at 50 cc, wait an hour, and then escalate it.

Perfect. I think you covered a lot of the bedside management issues with daratumumab. Some of the other things to be mindful of are, especially in somebody who is practicing perhaps in a community center, the infusion time may be quite limited. By the time somebody comes in, they often need laboratory tests, the drug has to be mixed, and then they give the premedications. These infusion-related reactions, if the median infusion time of the first dose is 6 to 8 hours, you can run into trouble. Some of the things people have done in the community are to do split dosing, so day 1 and day 2, so to mix half the bag the first day and then second half the next day.

That’s also important we learned in the inpatient setting because often, and we’ll talk more about this later in the discussion about the nursing implications, but often in an inpatient, if a nurse has a patient who has an allergic reaction and they’ve decided to pause and run it slowly, the stability of daratumumab is about 15 to 16 hours. It’s not like some of the other monoclonals, which can be run slowly over a day if they’re an inpatient. So I think 1 important bedside issue is time of infusion, and so sometimes people do split dosing.

And there are also some emerging data of rapid daratumumab, which is 90-minute infusion after they finish those first 3 doses, and that’s been published and done in a lot of settings. But it still again requires an IV [intravenous infusion] and has that 90-minute duration. I think the other important thing is in spite of all of this discussion about infusion-related reactions, I’m curious to see if Danny agrees. Even if patients have had significant reactions, I have never not been able to give daratumumab after getting through those initial few doses because of allergic issues or hypersensitivity. I think these infusion-related reactions are typically manageable, and eventually well tolerated, and we can resume standard dosing. Danny?

Absolutely, I agree. I think sometimes you may have more than 1 reaction within the first infusion, depending on each reaction, but absolutely. Sometimes we’ve actually dose reduced it. So instead of being 16 mg/kg, what the indicated dose is, we’ve started patients at 4 mg/kg in fluid to see if they can almost desensitize them to the daratumumab to escalate it up, so that they can receive the drug at full dose. The other thing that we’ve done here, at Mount Sinai Health System too, is that we can concentrate the volume. Besides split dosing, which is a great option for the communities that do not have long infusion bed/chair time, this allows our patients who have severe renal insufficiency or congestive heart failure to still limit their fluids.

Can you tell us a little bit more about that? Standard volume versus concentrated.

The standard volume in healthy individuals is a liter for the first dose, and if they tolerate it well, then the fluid is decreased to 500 cc, so you double the concentration of the medication but the same dosage. And it stays at 500 mL throughout their entire time experiencing it. It’s given weekly for 8 weeks in a row, and then on the ninth week, it goes for every other week for another 8 doses, and then monthly, for our patients. So it’s 8 doses weekly, 8 doses every 2 weeks, and then monthly as long as they tolerate it or they don’t have progression of disease. But when we start talking about patients for concentrated volume, you’re really looking at the best dosage for the volume by their weight, and pharmacy will calculate by their weight to see if they get the right volume.

Infusion-Related Adverse Events

I think another important thing before starting DARA [daratumumab] is the premeds [premedications]. Danny, what are the premeds that you typically like to give in patients before they start daratumumab?

Usually up front, absolutely. But going back to your question of, if they don’t receive it at your center with the daratumumab, Janssen Pharmaceuticals Inc has also developed a card for patients to carry with them to let them know they are taking a monoclonal antibody. Because even if they were traveling somewhere else out of state and they had an emergency, that it states that they are on a monoclonal antibody.

Premeds, I think, what are the adverse effects up front and we’re trying to mediate many of them going forward. With infusions, patients will get usually in the first dose, they’ll have everything pretty much IV, intravenously—corticosteroids, we’ll give them acetaminophen, and IV oral antihistamines up front. At our institution, we did use Singulair in our premeds to help prevent the cytokine release and the shortness of breath of bronchospasms. But we also use Pepcid, like an H2 [histamine type 2] inhibitor; that could be done. But in the clinical trials, they only really use the corticosteroid, the Tylenol, and the antihistamine. IV is appropriate for up front, but if the patient truly tolerates the medication, then they can all go to oral. Generally it’s given 1 hour prior to the starting of the daratumumab. I know in many institutions and in the community, if they’re taking oral, the option is 1 to 3 hours, so patients can actually take the medications at home and then go to their infusion center and receive the daratumumab. But I think that’s something you have to know, if the patient is oral adherent, and you know they’re really going to take those drugs up front.

Premeds are super important. Maybe you could comment on, a lot of myeloma regimens obviously contain DEX [dexamethasone] already. You have these steroid premeds that are part of the daratumumab label, but then you’re also asking patients to get dexamethasone. How do you manage that?

It is interesting that, yes, steroids are the backbone of what myeloma does. We will use them as premeds. Usually in the clinical trials they did use methylprednisolone. It was 100 mg for the first dose, and it dropped down to 60 mg. I think when patients are on long-term daratumumab, and if they’re in complete remission, we then at our institution are starting to pull the steroid out of the regimen if there’s no need for it. Because a lot of times our patients are much more mature in age and they have other comorbidities, so you’re dealing with hyperglycemia or other issues. So you can remove the steroids up front. They use methylprednisolone up front, but they also use dexamethasone because it was the backbone of the other medications, whether it was bortezomib or lenalidomide, so dexamethasone was substituted for it. Again, that’s also an option to switch from methylprednisolone to it.

An interesting thing to keep in mind, whether it’s premeds after their infusion, it was recommended to give steroids post-daratumumab because there was seen some delayed hypersensitivity up to 48 hours. So patients were given methylprednisolone for 2 days or dexamethasone the day after it. Again, in our institution, to be truly honest, if the patient truly does not have any adverse effects from it, we’ve removed the post-daratumumab dexamethasone, again, decreasing their exposure to it.

Yes, I agree. I think the only caveat I would add would be that if somebody has a significant respiratory history, be it asthma or COPD [chronic obstructive pulmonary disease], since a lot of those patients may not have always been included in clinical trials, that’s probably the one subgroup of patients where, at least for the first dose, it may not be a bad idea to do the post-dose. But I think to be giving it for everyone, for the most part we don’t really see a lot of delayed reactions, and I think it’s probably not needed.

Medication Supplements Prior to IV Administration

Danny, you bring up some important points. Starting with hepatitis, what’s your approach if somebody does have, say, not just hepatitis B surface antibody, which is more consistent with a vaccination, but perhaps hepatitis B core antibody present as well, suggestive that they’ve been exposed before? How do you approach that patient if you’re thinking about DARA [daratumumab]?

That’s important. I think on a patient’s list, sometimes they don’t even know they were exposed and have the actual virus themselves. So number 1, is explaining to them that they were probably past exposed and they never knew or had any symptoms from it. We would treat them with upfront medication, but it would not hinder us from treating them with the daratumumab.

Another factor with daratumumab, which you also mentioned in combination with other drugs, is that besides hepatitis B, it can reactivate the herpes zoster or shingles virus. So patients should be put on an antiviral medication prior to starting the drug itself. And if they are in combination with the IMiDs [immunomodulatory drugs], you would want them to be on some type of baby aspirin or something a little bit stronger.

Yes, and I think going back to the hepatitis point, I completely agree if somebody has been exposed to hepatitis and is about to start daratumumab, we could start drugs like tenofovir or entecavir, depending on your local hepatology preference, to suppress the reactivation of hepatitis B. But the other thing that’s important is to also monitor the hepatitis B PCR [polymerase chain reaction] to ensure that we’re staying ahead of that. Danny, can you speak to the ways that we do it at Mount Sinai Health System—because one might forget to order the type and screen or do the hepatitis serology&mdash;are there some practical recommendations for those in the community for not forgetting to do those things?

I think one of the challenges is whether you’re using paper versus electronic record keeping. At Mount Sinai, we have incorporated in all first use of daratumumab that they have the hepatitis serology panels drawn plus a type and screen as a control factor. We also have as a practice initiated, whether we do it every 6 months or up to 1 year, we check their hepatitis. If their antibodies surface, we will recheck them within a year, but if they do have a positive, we monitor them every 6 months to make sure that it is under better control.

And then in clinical trials, it is actually every 3 months, hepatitis B PCR. One other point relating to your testing, the question is if a patient, let’s say, has been getting daratumumab, but they have an emergency, let’s say they may be in a car accident and show up at an emergency room or they’ve started daratumumab in an outside hospital and they’re coming to you for subsequent care. It’s important that we know how to deal with that because if you don’t have that baseline type and screen pre-daratumumab, some of the strategies to deal with that are you can use trypsin or other enzymes to strip away the daratumumab and then type the red cell without the daratumumab coating, keeping in mind that it can also denature the Kell antigen, so you have to give Kell-negative blood. But also at baseline some centers do full genotypic or phenotypic characterization of the red cell.

Intravenous Administration and Hepatitis

Hi, my name is Ajai Chari. I’m a professor of medicine at the Icahn School of Medicine at Mount Sinai in New York. Today I’m privileged to have joining us one of our most seasoned NPs [nurse practitioners], Daniel Verina. Together we’re going to be covering daratumumab, the intravenous and subcutaneous formulations, and what’s new and exciting. Daniel, welcome. Thanks for joining me.

Let’s get things started. I think to set the stage, obviously we know daratumumab is a CD38 monoclonal antibody. It’s approved for myeloma in several different indications and combinations. In the newly diagnosed setting for transplant-eligible patients, it’s actually approved in combination with VTd, or bortezomib, thalidomide, and DEX [dexamethasone], so DARA/VTd [daratumumab with bortezomib, thalidomide, dexamethasone]. For the transplant-ineligible population, it’s also been approved in combination with lenalidomide and dexamethasone as part of the MAIA study, and also with VMP [bortezomib, melphalan, prednisone] as part of the ALCYON study. All of these have shown that the addition of daratumumab has led to significant improvement in not only response rate but progression-free survival [PFS].

I think one of the other interesting things about this front-line setting is there’s always this question of if you use your drug early, what might happen? And I think an important additional statement to that point is the ALCYON data from ASH [the American Society of Hematology annual meeting] 2019 was updated to show that the addition of daratumumab not only improved response and PFS [progression-free survival], but also overall survival. So I think this concern about using drugs early and potentially getting more aggressive relapse has not been borne out, particularly for the transplant-ineligible population, where you don’t always get a chance to salvage these patients.

And then briefly, in the relapsed setting, daratumumab is also approved in combination with lenalidomide and dexamethasone, and bortezomib and dexamethasone as part of the POLLUX and CASTOR studies. This is with at least 1 line of prior therapy. And then it’s approved in combination with pomalidomide and dexamethasone for at least 2 prior lines of therapy, including a PI [proteasome inhibitor] and an IMiD [immunomodulatory drug]. And finally it’s approved as monotherapy for patients who’ve had at least 3 lines of therapy, which include a PI or IMiD. Those are the current uses of daratumumab, and there are a lot of other exciting studies.

Now I’ll throw this to Danny. So, Danny, you agree, a lot of options to use daratumumab, and maybe you could walk us through what it’s like to give daratumumab currently, which is in the intravenous formulation.

Absolutely, thank you. Yes, I think it’s a great option for many of our patients, starting even in newly diagnosed, and like Dr Chari said, even salvage and in the relapsed setting. Because it is a monoclonal antibody, I think many of our patients are concerned about different testing and different adverse effects that they’re going to see. When we speak to our patients up front, we really talk to them about doing normal laboratory tests. You’re going to get your complete blood checked, your CBC [complete blood count], your CMPs [comprehensive metabolic panels]. Interestingly enough, they did find in later data that there was a reactivation of hepatitis B, so now we are testing all patients for hepatitis panel and hepatitis C up front before starting daratumumab, if they need any type of medical interventions prior to starting the medication itself.

Also, we can talk about it a little bit later, is that because daratumumab is a monoclonal antibody, it does adhere to the CD38 receptor that’s located on erythrocytes, and you can interfere with some type and screening of blood. So most patients should have a type and screen drawn prior to their first dose, so that their blood banks can monitor, and know that to be in their control, and if they have antibodies in the past.

Interesting also is because it is an IgG [immunoglobulin G] kappa, it can cause interference with immunofixation electrophoresis [IFE]. Why that becomes important down the line is when you’re trying to say if a patient truly is in complete remission or in a very good partial remission, vgPR, knowing this up front is important. So patients who are IgA or IgM, it really has no bearing on it. But really you’re IgG kappa. So there are 2 tests available. There’s a daratumumab interference assay that is available and also mass spec [spectrometry] on the local level. So if the IFE is there and we want to find out whether it is interference from the drug itself, or does the patient still have a very fine amount of disease, that’s also important.

Ajai Chari, MD

Articles