Ola Landgen, MD, PhD

Ever-Expanding Indications for Daratumumab in MM

Practical Management of IV Daratumumab in MM

Exciting Subcutaneous Formulation Approval in MM

Clinical Impact of SubQ Daratumumab for Multiple Myeloma

The Impact of COVID-19 on Patients With Multiple Myeloma

Videos

How the recent FDA approval of the subcutaneous formulation of daratumumab in multiple myeloma will affect patients and oncologists from practical and clinical standpoints.

Role of Novel Subcutaneous Daratumumab in Multiple Myeloma

The COVID-19 [coronavirus disease 2019] pandemic has clearly impacted everything, including the care of patients with multiple myeloma. The changes are more practical. We don’t really see that the prognosis is very different for patients with myeloma compared with what we have seen in the general population. That’s very good news. We have been very cautious and careful across the board. All the institutions, we talk to one another all the time. We have been using fewer doses. Instead of giving weekly doses and then dosing every other week, if the regimen has such a dosing schedule, we have tried to move to monthly infusions more quickly to try to skip a few steps. If possible, we have tried to use more oral drugs versus IV [intravenous] or subcutaneous [SQ] drugs. Of course, for newly diagnosed patients or patients who have an active relapse, combination therapy is still much more powerful, so we obviously would prefer that. But then we will go toward a less intense regimen to spare the patients from unnecessary visits.

We have cut back on biopsies; there are no bone marrow biopsies. And also imaging; there are no PET [positron emission tomography] or CT [computed tomography] scans or other types of imaging, unless there is really a strong reason. Typically, in newly diagnosed patients, we would check for MRD [minimal residual disease] status after 6 cycles. Now we would hold off with that. We are waiting for COVID-19 to calm down before we start doing these things again. We also stay away from those combination therapies that are highly cytopenic, and that’s typically in the relapsed/refractory setting. Using all the chemotherapy drugs that would make the patient a candidate for transfusions is not what we want.

The patients would be immunosuppressed, exposed to a lot of risks, and there would be need for platelet and blood transfusions, which we try to save because there is a shortage of blood products.

I think very importantly, we have stopped the entire program for transplantation. This is supported by the ASH [American Society of Hematology] Guidelines that very clearly state no more bone marrow transplants in the setting of COVID-19 for patients with myeloma. This is with the exception of patients who have a lot of aggressive disease, for whom there are no other options. But those patients are few and far between given all the other options we have. ASH says to hold off on the collection of stem cells, so that’s also implemented across the board.

Using modern combination therapy and switching to maintenance, we use carfilzomib, we use bortezomib, we use lenalidomide, we use pomalidomide, we use daratumumab, and we use dexamethasone. We use all those drugs, but we are just cautious and try to minimize the unnecessary visits. We do most of their care, I would say 99% of their care, with telemedicine at the current time, but we are also planning to go back and start seeing patients in the clinic in the coming weeks.

In the current setting of COVID-19, daratumumab is becoming an established standard of care in the newly diagnosed setting in combination with lenalidomide and dexamethasone for nontransplant patients and emerging in combination with RVd [lenalidomide, bortezomib, dexamethasone] or KRd [carfilzomib, lenalidomide, dexamethasone] for transplant candidates. This is already an established standard of care for patients with relapsed disease given CASTOR, POLLUX, and other studies. We already have it in that setting, but the SQ administration of daratumumab would make it an even more attractive regimen. It will increase its use in all these different settings because it’s quicker and easier to give.

Access to a subcutaneous [SQ] version of daratumumab will make daratumumab even more attractive for any indication. I could see that it could be partnered even more so with drugs for up-front therapy, given that it is FDA and/or NCCN [National Comprehensive Cancer Network] Guidelines–approved. In the relapsed setting, it also gives daratumumab an upper leg compared with other drugs because it’s so easy and so well tolerated. It also is efficacious. I think that the use of daratumumab as an extended dosing regimen in the fashion of a maintenance therapy will probably become more popular. It’s not being developed as a maintenance drug, but it’s very likely that daratumumab could take the role of a continued injection over time where patients could come in and get an injection and that would be all. We will see exactly where that’s going to land. But I think the SQ route really gives daratumumab a very strong upper leg.

With daratumumab being FDA approved as a subcutaneous drug, I think that should be immediately implemented and should replace the intravenous [IV] drug. It really has a role in any setting, anything from the newly diagnosed and early disease to later stages of disease, based on the NCCN Guidelines and the FDA label. It just gives us access to a good drug for more patients because it’s easier to administer and we can pretty much use it anywhere. You don’t have the long infusion at the beginning, which we used to have with the IV formulation.

How will the subcutaneous administration route impact patients and the whole clinical procedure compared with the IV formulation? It’s quite obvious. If you have a drug that can be given as a shot, everyone likes it. The patient loves it. It’s a much shorter visit. The chemotherapy nurses like it because the patient can sit in the chair, you give an injection, and then you’re done. The overall institution likes it because you can reduce the number of chemotherapy chairs and get the work done. Of course, you still must take care of the patient. You have to monitor and make sure everything is safe, but it is a much more feasible way of using this drug.

The administration schedule for the subcutaneous version of daratumumab is the same as the IV administration. According to the FDA label, it’s once a week for 8 doses, then every other week for 8 doses, then once a month, or every 28 days to be exact. It’s the same for both of them. The subcutaneous administration has a fixed dose. The IV dose is 16 mg/kg body weight.

Daratumumab being approved for administration as a subcutaneous [SQ] drug is a huge step forward for the myeloma field. This really gives every patient access to daratumumab. There has been some hesitation in smaller offices that don’t treat so many patients with daratumumab, given that the administration of the monoclonal antibodies as infusions took an extended window of time, at least with the first dose. There was a little bit of a barrier, but once you got up and going, it could be done in a few hours or even as rapid infusions in 90 minutes. With the subcutaneous administration, you start off really fast. It’s only an injection, so it’s a 5-minute procedure. You still will have to monitor the patient afterward, but the fact that it’s a very quick injection is of course fantastic for patients. It makes it much more feasible for doctors’ offices.

The data show, from the studies that have been presented so far, that the efficacy seems to be virtually identical compared with the IV [intravenous] drug. These are single-drug studies comparing SQ with IV. We don’t yet have a lot of data from combination strategies, but there’s no reason to believe that they wouldn’t be the same. I assume that once the drug is approved as a subcutaneous drug, it will move on in all the combinations. I think another huge benefit with the subcutaneous drug is the fact that the drug has fewer infusion-related reactions. With the intravenous drug, around 50% of the patients had an infusion reaction for the first dose and after that, it typically would never happen again.

With the subcutaneous drug, the data suggest that maybe 10% of the patients experience this. I do think there will be continued development when it comes to the premedication. It’s not fully known, but my prediction—based on my clinical experience for many years treating patients with myeloma with different types of drugs, and also treating other hematologic malignancies—is that premedication with steroids can probably be cut back. I think the antihistamine premedication can probably be cut back. The overall experience with daratumumab will be even more gentle beyond the fact that it’s now an injection. We can cut back on the premedication, I would think. We will need a little more data to fully hammer this out, but that’s my prediction.

At our program at Memorial Sloan Kettering Cancer Center, we have used daratumumab extensively with the intravenous administration. This goes back years before it was FDA approved, on clinical trials. We have used it extensively after it was FDA approved as a standard-of-care drug. We are just about to open investigator-initiated studies using the subcutaneous administration. With the FDA approval for the drug, we will obviously switch the entire program from IV to subcutaneous administration within days after the FDA signs off on all the papers.

The subcutaneous dose will definitely reduce patient time in the office, although we don’t know to what degree we need to monitor patients after the first dose with the subcutaneous drug. The data suggest that instead of 50% infusion-related reactions, which we see with IV administration, the SQ administration has about 10% infusion-related reactions. We don’t fully know what the time window should be for monitoring. I think our practice, located in the heart of New York City, will maybe let patients stroll around the city rather than sitting and waiting for many hours. But I could also see that we could potentially have patients waiting in the building instead of sitting in the chemotherapy suite and waiting for hours, as we have done when we have given the intravenous infusion. I think we will learn as we go. I do predict that we probably will loosen up on these rules and procedures going forward. To begin with, we will probably have the patient around for a few hours. After the first cycle, I could see that it will probably be a very short visit. But this is to be investigated further.

My personal experience with daratumumab is that it’s a very efficacious drug. It can be combined with literally every drug that is FDA approved, to my knowledge. All the established combinations work very well in addition to daratumumab. You don’t see any strong adverse effects, except for the fact that with the intravenous administration, around 50% of patients experience an infusion reaction. With the subcutaneous administration, less than 10% of patients experience that. Over time, patients who had a reaction in the beginning don’t seem to have recurrent reaction. Those patients who did not have it in the beginning don’t develop it later. There are some laboratory abnormalities that we see over time. We see there could be drops in the IgG levels, and sometimes that could lead to infections. Infection is 1 of the adverse effects that has been reported. In some individual cases, we consider giving patients IVIG [intravenous immunoglobulin] for these reasons. But overall, it’s a very well-tolerated drug.

Beyond the fact that this is a very well-tolerated drug and highly efficacious, when the Ohio State University group presented at ASH [American Society of Hematology Annual Meeting] a couple of years ago in Atlanta, they showed that you could give daratumumab as a rapid infusion from dose 3 onward unless there were problems during the first and second infusion. I think everyone has implemented that, at least the larger centers. That has really made the drug even easier to give. You can give it intravenously for 90 minutes in a rapid infusion from dose 3 onward. That will also help deliver the drug.

The role of daratumumab in the setting of multiple myeloma continues to move forward almost every month. It was initially FDA approved in November 2015 for the indication of relapsed/refractory myeloma. Initial approval was as a single drug. In less than 12 months, the first trials read out for combination therapy with lenalidomide [Revlimid]–dexamethasone and bortezomib-dexamethasone. After that, pomalidomide-dexamethasone was added. It kept on coming, and now we have an approval for the newly diagnosed patients. In mid-2019, daratumumab was approved by the FDA for patients with a new diagnosis of myeloma who are nontransplant candidates, in combination with lenalidomide and dexamethasone, as the up-front treatment. This comes from the MAIA study.

There have been additional approvals after that. The combination of thalidomide, bortezomib, dexamethasone, and daratumumab was approved in 2019. This is not the combination we typically use in the United States. It’s more of an ex-US treatment combination. Just a few weeks ago, the GRIFFIN study was published in 

. This is a combination of bortezomib, lenalidomide, dexamethasone, and daratumumab showing superiority over the traditional VRd [bortezomib, lenalidomide, dexamethasone] regimen.

There are ongoing phase 3 trials for newly diagnosed patients with and without transplantation. There are ongoing studies using the KRd [carfilzomib, lenalidomide, dexamethasone] regimen with or without daratumumab. I think daratumumab has already established itself as a great treatment as a single drug and in combination in the relapsed/refractory setting, now moving up to earlier lines. It has already moved up to the newly diagnosed setting, and it’s expanding with more established US combinations up front. As a consequence of these studies, there is also ongoing work to look at it as an extended dosing option in the maintenance setting with or without Revlimid, so that will be very exciting to see. It’s literally everywhere.

We use daratumumab very frequently in our clinical program, and we use it for the indications provided by the FDA and supported by the NCCN [National Comprehensive Cancer Network] Guidelines, both in the newly diagnosed setting with lenalidomide-dexamethasone—the MAIA indication—as well as in the relapsed/refractory setting. We use it commonly for patients who relapse on lenalidomide maintenance therapy. We commonly would partner it with pomalidomide-dexamethasone. Some of us combine it with the bortezomib and dexamethasone. We have ongoing trials using KRd with daratumumab versus KRd without daratumumab; there is a control arm with VRd as part of that study, so it’s a 3-arm study. This is in the newly diagnosed setting, and we’re just about to open a maintenance study where we will investigate daratumumab as a single drug with subcutaneous administration. It’s a randomized study comparing it with lenalidomide on the other arm.