As we begin to see multiple agents that will target BCMA with multiple mechanisms of action, the obvious question comes up about sequencing. How do you choose which one to use when? The reality is that, while many of the cell therapy enthusiasts may say, “CAR [chimeric antigen receptor] T cells are the answer. That is the only way we should go,” we know that certain patients cannot wait 6 to 8 weeks to get CAR T-cell therapy. We know, for instance, that not every patient wants to go in the hospital and experience the potential risk of cytokine release syndrome [CRS], or even be in the hospital at all. Each of these 3 mechanisms that target BCMA have their own relative advantages or disadvantages.

For instance, belantamab mafodotin is an easy off-the-shelf administered approach that does not require hospitalization, but it does require partnering with an eye care professional, and it can be associated with some keratopathy or ocular toxicity. There are pros and cons of each of those drugs.

CAR T cells require a manufacturing period and a strategy for bridging for many patients who may have refractory myeloma. They also require admissions to the hospital, chemotherapy for lymphodepletion therapy, and potential complications associated with CRS, including ICU [intensive care unit] stays or other potential prolonged hospitalizations as well.

The bispecifics or T-cell engagers, while they may not be as intense as the CAR T cells, they may often require hospital stays as well, and many patients, again, do not necessarily want to do that. There is a risk of CRS, but again, it is an immune-based therapy that appears to be potentially easier to give than a CAR T cell. It is a decision and a discussion that we are going to have with our patients about where they are in their specific journey as to which agent we choose at which different time.

I cannot tell you that I have an ideal patient for each of these drugs, but we make those decisions. It is unlike other drugs where, if you target 1 antigen, such as CD19 or CD20, you do not necessarily come back with a different drug. As I mentioned earlier, we do not lose BCMA expression with progression in most cases. If one drug does not work, you may be able to go to a second class or a third. You are not precluding exposure to one of these different mechanisms by using one of them earlier or later.

When we talk about the ultimate goal, it is to bring these treatments to earlier and earlier lines of therapy and eliminate the need for treatment for relapsed disease. Understanding how CAR T cells, bispecifics or T-cell engagers, and antibody-drug conjugates may be best used in the newly diagnosed setting will require us to revisit a total therapy-like approach. It may be that the ultimate treatment is an IMiD [immunomodulatory drug], a PI [proteasome inhibitor], and BCMA-directed therapy for a few cycles, then consolidation with an anti-CD38 antibody, then consolidation with high-dose melphalan, and a maintenance approach to get patients to MRD [minimal residual disease]-negativity. These may all involve different drugs, so by using these different noncross-reactive drugs, we may ultimately be able to get patients to MRD-negativity and cure them earlier in the disease course. How do we bring all of these approaches into earlier lines of therapy? This is the challenge for me and many others who deal in myeloma, and it is a challenge I look forward to because more treatment options are always better than fewer.

 As researchers, we would always recommend that a patient be considered for a clinical trial of some BCMA-targeting agent if it is available. If it is not, then how people end up making some of these decisions has to do with the state of the patient. Most of the available CAR T products need some time for the manufacture of the cell, so if a person has an aggressive relapse and is not particularly stable, then an off-the-shelf product is probably a better approach, and right now, that is belantamab, so that is what a lot of people would turn to. 

What we do not yet know is if there is an ideal order for these different BCMA-targeting therapies. Should you use one before another, or will that make a difference? Because of the way CAR T is being used in earlier lines of therapy, we are going to soon have an opportunity to find out if that BCMA-targeting approach does not last, or if we can use another BCMA-targeting agent if a patient relapses. There are data that BCMA can be downregulated on myeloma cells but that they come back. This has been researched a bit in patients who have received CAR T-targeting BCMA, and it has been shown that, over time, their myeloma cells will lose BCMA. But with further observation, that antigen comes back again, so that means that another BCMA-targeting drug would be useful, we would hope.

Everybody is interested in getting into that area of using BCMA for newly diagnosed patients. As I mentioned, there is a belantamab mafodotin trial that is looking at VRd [bortezomib, lenalidomide, dexamethasone] for patients with newly diagnosed myeloma. There is the KarMMa-2 study that is looking to incorporate CAR T for patients who have high-risk myeloma who we know are subject to relapse fairly quickly after an autologous transplant. The BMT CTN [Blood and Marrow Transplant Clinical Trials Network] is planning to use CAR T for either an early biochemical progression after an autologous transplant, or lack of having more than a VGPR [very good partial response].

We are hopefully going to have a high-risk trial as well, so that question is going to be answered. We are ultimately hoping to have a design where one of the bispecific engagers like teclistamab could be incorporated as an additional consolidation step following treatment either with or without an autologous stem-cell transplant. I suspect that, for all of those areas, we are going to see lots of research in the next couple of years.

With this whole area of specifically targeting antigens on myeloma cells, we have had 2 already available. We have had anti-CD38 drugs, and anti-SLAMF7, which are daratumumab, isatuximab for CD38, SLAMF7 for elotuzumab respectively. We now have belantamab mafodotin for BCMA. You are going to be seeing other targets emerging. There is GPRC5D, which is being developed as a CAR T target, and some others. We are going to see more and more of this kind of immunotherapy. It is not going to replace some of our good drugs like IMiD drugs or proteasome inhibitors, but more and more, this is going to be a step that patients receive treatment, either in the first line or early after a progression.

Videos

Influencing Factors to Initially Targeting BCMA in MM

As we have discussed, targeting BCMA through an antibody-drug conjugate is certainly an exciting treatment approach for which we now have an FDA approved drug to go after. To me, this is important and exciting because, as I mentioned, BCMA is in many ways an ideal target in the context of multiple myeloma. One of the challenges for us in the near future is how do we bring belantamab mafodotin into earlier lines of therapy so that we can partner it with other drugs? There are combination trials that are being evaluated. My colleague Ajay Nooka, MD, MPH, FACP, has reported on combining belantamab mafodotin with bortezomib and has demonstrated safety and efficacy. There are additional data combining belantamab mafodotin with pomalidomide. Figuring out the dose and schedule of an antibody drug conjugate in combination with other known active agents in myeloma is part of our typical strategy for bringing drugs that are approved in the refractory myeloma setting to earlier and earlier lines of therapy.

Now, the other targets for BCMA that are exciting are the CAR [chimeric antigen receptor] T cells, and we have several of them that are in development. These include idecabtagene vicleucel or bb2121. Orvacabtagene autoleucel is another one, or ciltacabtagene autoleucel, which is part of the CARTITUDE-1 study. There are a number of trials evaluating each of these 3, and there are up to 7 or 8 different BCMA-directed CAR T cells that are being done in phase 1 and phase 2 studies in myeloma. What is quite interesting is that we know, for instance, that the rates of grade 3/4 cytokine release syndrome [CRS] or neurotoxicity are significantly lower than what we have seen with CD19-directed CAR T cells in lymphoma or diffuse large B-cell lymphoma.

That is one difference between CD19 and BCMA. We also know, however, that there does not as yet appear to be a plateau on the treatment curve. This is unlike CD19 where, if you achieve a CR [complete response], and that CR is durable for 6 to 9 months, the likelihood of relapse drops significantly. In BCMA-directed therapy, it is not clear that that necessarily happens, so we need to learn more about the biology of CAR T cells in myeloma to understand how to maximize persistence and duration of response in many of these patients because the median progression-free survival looks to be somewhere around 11 to 12 months, at least for bb2121, which is the furthest along that we have.

Now, the third area that we are excited about when we target BCMA is the area of bispecific antibodies or T-cell engagers. These are antibodies that have been engineered to express CD3 and BCMA, and their function is to bring a T cell next to a myeloma cell by bringing BCMA-expressing, T-cell expressing, or CD3-expressing cells in close proximity. We know with CD19 and blinatumomab that this can be a highly effective strategy. We have seen in phase 1 studies, whether it is CC269, Amgen-402, or daclizumab, that these agents can be quite effective at the maximum tolerated dose. In many anecdotal situations, we are hearing that patients who progress on BCMA-directed CAR T cells may respond to the T-cell engagers, so this is an important next step in the biology and treatment approach for patients with myeloma. It certainly represents an important step forward for treatment of refractory myeloma.

At ASH [the American Society of Hematology 2020 annual meeting], there were updates on a lot of belantamab mafodotin data that continued to show high response rates. There were some interesting presentations about quality of life, where patients who responded to belantamab mafodotin reported increased quality of life with less bone pain and less fatigue. The ocular toxicity that people are aware of with belantamab mafodotin seemed to improve over time as patients got more drug exposure, which is great.

There is also another antibody-drug conjugate that Shaji Kumar, [MD,] presented: MEDI2228. This also had high response rates, but it has some interesting toxicities that have to do with the PBD [pyrrolobenzodiazepine] payload. They saw a fairly high incidence of photophobia in about 50% of patients. They also saw some trouble with pleural effusions, and rashes were pretty common in about a third of patients. Although they had very high response rates, they discontinued the agent after about a median of 3 cycles. I suspect that there is going to be more investigation about how to use that drug to capture its effectiveness and try to minimize toxicity.

There was a lot of CAR T action at both ASCO [the American Society for Clinical Oncology annual meeting 2020] and at ASH. There was a big presentation at ASCO by Nikhil Munshi, MD, looking at the update of the KarMMa trial where they had 128 patients. It had high response rates in the 75% range, 83% in those getting the highest doses, with manageable CRS. The most common toxicities ended up being hematologic, but the CRS that was serious was grade 1 or less. It was grade 1 in about 75% of patients, but beyond that, it very well tolerated and had low rates of neurotoxicity.

The CARTITUDE-1 trial was updated here at ASH by Deepu Madduri, MD. They had a large number of patients to present as opposed to a year ago. They also saw high response rates of about 97% with the CARTITUDE-1 trial. They are showing a bit of a different toxicity profile for a couple of reasons. One is that there was a slightly higher incidence of neurotoxicity that was significant compared to the bb2121 product. The onset of CRS is later, interestingly; instead of day 1, which is the median with bb2121, it ends up being more likely day 7. 

Some of the other updates on CAR T: the Poseida Therapeutics product looks good. The Chinese investigators here at ASH had a couple of presentations on different manufacturing methods and a dual-targeted CAR T targeting CD19 and BCMA, so that is a lot of action. It remains to be seen if one appears to be superior to the other. Of course, all these are being moved up earlier in the line of therapy to see whether there can be greater persistence of CAR T because that is one thing that has been a bit disappointing. As opposed to lymphoma, it does not yet look that there is a plateau in response in some of the heavily pretreated patients. Patients are still relapsing, so we obviously have to figure out how to make these products work better and work longer.

There was an update by Adam Cohen, MD, here at ASH on teclistamab, which has high response rates. That drug is already getting combined with other drugs. He presented data using this drug intravenously but also subcutaneously at a fixed dose. Their data looked very interesting.

The CRS was manageable: it occurred mostly with the first doses, and it then started to go down, so we are hoping that, perhaps after initial hospitalization when you receive this drug, you will be able to receive it as an outpatient. It has manageable CRS with just a low use of steroids. It has high response rates in the range of over 80% in heavily pretreated patients.

There is also the Celgene Corp product that was updated at ASCO, and it looks promising as well. Right now, that is still intravenous administration. They also had a presentation at ASH on Amgen [AMG]-701. AMG-701 is another bispecific engager that looks promising; it builds on their original data with AMG-401, which was a 4-week infusion. This is a weekly infusion, and it looks promising with high response rates and manageable toxicity.

Ongoing Approaches Toward Targeting BCMA

What we are probably going to be seeing more and more with belantamab mafodotin is that it is going to be combined with other agents and used earlier in the lines of therapy. There are some exciting phase 3 trials that are going to get underway shortly. One is being led by Robert Rifkin, MD, FACP, where he is using belantamab mafodotin in combination with Velcade [bortezomib] and dexamethasone and comparing that to daratumumab, Velcade [bortezomib], and dexamethasone. That is going to be a large international trial for people who have had previous treatment. There is a large study called DREAMM-9 where up front, patients are going to be randomized to receive Velcade [bortezomib], Revlimid [lenalidomide], and dexamethasone with or without belantamab mafodotin. Right now, that study is going to open to try to figure out what the ideal dosing is for the agent. It is probably likely that the Q3 [every 3] week schedule of belantamab mafodotin is going to change with some of these combinations where there might be some other toxicity issues. Lots of different drugs are going to be combined.

Right now, it is essentially for triple-refractory disease after 4 lines of therapy, but in at least some of the preliminary studies, like the study done by Ajay Nooka, MD, MPH, FACP, who presented some updated data on his combination of belantamab mafodotin with Velcade [bortezomib] and dexamethasone, it looks promising with high response rates. A combination like that would be carried forward a bit earlier. Particularly, it is going to be moving up because as daratumumab and other CD38 antibodies like isatuximab are going to be used in the frontline setting, there is going to be a consideration to use an anti-BCMA antibody much earlier in the lines of therapy, particularly if someone is on a CD38 agent when they progress since there are several maintenance trials going on looking at anti-CD38 antibodies post-transplant.

There are now going to be any number of agents that are targeting BCMA for obvious reasons; BCMA is a great target. One of the things that we do not know is about the sequencing of this agent, belantamab mafodotin, compared to a CAR T [chimeric antigen receptor T-cell] transplant that is BCMA directed, or a bispecific engager that is BCMA directed. There is a small study that was published looking at the use of belantamab mafodotin after some CAR T progressions. That looks interesting. We are going to be trying to figure out in the next year or two what sequencing is appropriate, or if you can go back and retreat patients with a different BCMA agent.

One of the most interesting trials that we [at the University of Wisconsin] have been able to be involved in is called DREAMM-5. This is a study that is combining belantamab mafodotin with some interesting agents that are essentially T-cell agonists to try to help with some immune response. We are interested in those drugs. One is combining ICOS [inducible T-cell costimulators], and there is also going to be a PD-L1 inhibitor. We are interested in looking at some of those combinations that are moving away a bit from the less traditional type of chemotherapy and more into the immunomodulatory type of drugs. We are interested in that.

Next Steps for Use of Belantamab in Clinical Practice

The poster that was presented at the American Society of Hematology annual meeting 2020 was focused on patient-reported outcomes with belantamab mafodotin. The interesting point to take home from this poster was that patients who had a good response to the drug—in other words, they had relapsed and refractory multiple myeloma, and they were placed on belantamab and had a drug response—had a very high degree of satisfaction with the drug despite that many of them had some types of adverse effects, including ocular and visual adverse effects. This is important for both oncologists as well as ophthalmologists to understand: every patient will have a different level of tolerance for drug adverse effects.

For example, for a patient who is otherwise doing well and is healthy, if you all of a sudden tell them, “Your vision is going to be blurry at least temporarily while you are on a certain treatment,” that would probably be difficult to accept for the patient. For the particular patient population in whom belantamab is being used at present, they have tried multiple different antimyeloma drugs, and those drugs have not worked. If they are having a response to the drug, they then have a greater degree of tolerance for those types of [adverse] effects. Of course, as an ophthalmologist, I have an interest in mitigating and relieving those [adverse] effects as much as possible, but even for myself, I have to put that into the context of the patient’s overall well-being and what their goals are with therapy.

The impact on prolonged dose delays of belantamab is an area that is being investigated by the drug manufacturer. As far as the data in the DREAMM-2 study, there did not appear to be, to my knowledge, any adverse effects of the dose delays and dose reductions that occurred as a result of ocular toxicity.

With that being said, as patients are treated for longer periods, if and when they develop degrees of ocular toxicity that may require multiple dose holds, that information will be informative in telling us what the long-term effects of these ocular-related dose holds on the efficacy of the drug are, more so for my oncology colleagues. That is an active area of investigation as doses and treatment schedules are being looked into.

My advice for community oncologists in terms of managing toxicities that are occurring, specifically the ocular toxicity, is No. 1, to try to become familiar with the ocular toxicity. A good resource is the manuscript that we [at the University of Chicago Medical Center] wrote that was published in the journal 

, that showed the ocular findings from the DREAMM-2 study.

In addition, if you are going to place patients on this drug, it is imperative to find an ophthalmology or optometry partner who is willing to take this on, because they are going to be vital in providing that pre-treatment evaluation throughout the course of therapy for these patients. That is key to making sure that the process is smooth, and that the patient and you both have a positive experience. It has to be a team approach.

Oftentimes, the patients themselves are important lines of communication. For myself, for example, it is relatively easy because I am in an academic center. The oncology team and I are on the same electronic medical record. I can simply send my notes or a message to the oncology team, but that may not be the case in the community setting. That direct line of communication with the eye care provider is important, but so is making sure that the patient knows what to communicate to the oncologist as well as the eye care provider about what they are experiencing with their vision and what their expectations and hopes are for this drug and their quality of life while they are on therapy.

DREAMM-2 Trial Regimen: Safety Updates and Dose Delay

As with any monoclonal antibody, we know that there can be other adverse events in addition to the keratopathy I just mentioned. If we look at data in terms of other adverse events, the second most common after keratopathy was hematologic toxicity, which is not a surprise. Thrombocytopenia was noted as well as neutropenia, and in some cases, anemia. We know that, unlike other monoclonal antibodies that have been administered in myeloma, the rate of infusion-related reactions is quite low. They tend to occur with the first dose, but it can be reduced significantly with the use of steroids and antihistamines. It is a relatively low event, especially considering what we see with daratumumab or with elotuzumab for first event infusion-related reactions.

In terms of the long-term follow-up of ocular events, as a result of the fact that this drug, belantamab mafodotin, has not been available, you do not have data for it for multiple years. We do not know what the potential long-term adverse effects are going to be. However, for those patients who were followed beyond the limitations of the trial, we saw that these lesions tended to resolve and that their visual acuity returned back to baseline.

The key point is that a significant percentage of patients develop these lesions, but once there is either a dose hold followed by dose reduction or if the treatment is stopped due to completion of therapy or another reason, those patients went back to baseline.

The optimal management and monitoring strategy of ocular events requires a degree of coordination between the ophthalmologist or optometrist and the hematology-oncology specialist. This is, in part, due to the fact that patients need to have an eye exam at baseline and then prior to every infusion, which is generally scheduled once every 3 weeks.

This requires some cooperation on the part of the ophthalmologist to agree to take on these patients. I would argue as an ophthalmologist and for my ophthalmology colleagues that this is an opportunity to have an impact on patients that is somewhat unique compared to what we normally do in our clinical practice because we hope to facilitate a reasonable quality of vision and quality of life for patients with multiple myeloma who are on belantamab, which they may be getting after having failed 3, 4, or 5 other agents. Our examination and our reporting back to the oncologist is critical for the patient to either get their next dose of the medication or for us to recommend a dose hold because of the impact that it is having on their cornea and on their vision.

That coordination and communication is important because once the patient is scheduled and an ophthalmologist agrees to take on this patient, each time that patient has an appointment, the ophthalmologist will follow the grading and dose modification guidelines that are provided in the prescriber information for belantamab and then report back to the oncologist about what they see. As an example, in my practice at the University of Chicago Medical Center, there is pretty frequent and regular communication between myself and the oncology team, which includes the nurses as well as the attending physician, in terms of what the patient is experiencing both subjectively and objectively as well as the grading of corneal lesions and what my ultimate assessment is about whether a dose hold would be recommended based on the criteria.

With that being said, as an ophthalmologist, I also understand that my job is basically to perform the grading and assessment of the corneal changes and relay that information both to the patient as well as the oncologist. The decision to treat or to do a dose hold is up to them, so that communication link has to be strong to make this all work in the best interest of the patient.

The specific management of keratopathy at the present time, with the knowledge that we have, is most heavily reliant on dose holds and dose modification. The reason for this is that we have seen in the DREAMM-2 study as well as from seeing patients post-FDA approval that when the drug is held, the corneal changes seem to resolve. In some patients, they resolve faster than in others, but we think that this is a dose-dependent phenomenon.

This is why, in the package insert in the prescriber information, the guidance in terms of management is this: once there is grade 2 or higher keratopathy, meaning microcyst-like epithelial changes, the presence of those lesions or decrease in visual acuity associated with those lesions will warrant a hold of the dose. Once the dose is held and the cornea and vision go back to baseline, then the medication will be resumed at a lower dose.

Another aspect of treatment for these patients that has been recommended is eye lubrication, preferably with preservative-free artificial tears. The reason for that is that we have seen patients with dry eye, and the DREAMM-2 study data showed that patients with a history of dry eye had a greater chance of developing grade 2 or higher microcyst-like changes within the epithelium. Because of this relationship, we as ophthalmologists have encouraged patients to be on lubricated eyedrops, preferably preservative-free artificial tears, as frequently as 4 to 6 times a day.

If I look to the future, I hope and suspect that there will be more directed therapies that will become available for the type of corneal changes that we are seeing as the exact pathophysiology of the changes are confirmed and once directed therapies are developed.

Management of Ocular Events From DREAMM-2 Regimen

One of the unique adverse events associated with belantamab mafodotin is an ocular toxicity: keratopathy. Functionally, what that means is that patients develop microcysts in the cornea, and those microcysts cannot be seen by you or me unless we have a slit lamp examination. To give belantamab mafodotin, it is important that you partner with an eye care professional so that they can do slit lamp exams before each dose of belantamab mafodotin is administered. One may say, “This sounds complicated. Do you have to have a specific ophthalmologist to work with?” One of the important take-home messages is this: if you can find an ophthalmologist to work with, that is great, but even an optometrist can see and grade the keratopathy as evidenced by microcysts using a routine slit lamp exam.

If you look at all the patients who were treated at the 2.5 mg/kg dose, roughly 70% of patients had some form of keratopathy as demonstrated by an exam from an ophthalmologist. It is important to recognize that every exam finding does not correlate to clinical findings, so finding that intersection between exam and clinical findings is what you do in partnership with your eye care professional before you give a dose of belantamab mafodotin. As an example, if we look at the DREAMM-2 study, in the 2.5 mg/kg group, as I mentioned, 70% of patients may have keratopathy as measured by an exam finding, but only 50% have any true symptoms at all. The most common symptoms that we see are dry or itchy eyes, which can sometimes be alleviated through lubricating eye drops, which are recommended at the time you start belantamab mafodotin therapy. 

If you drill further down in the data, only 18% of patients had changes in visual acuity, which means a reduction greater than 20/50 in their best eye. While you may see 50% of patients who had some symptoms like dry or itchy eyes, only 1 out of 5 patients will have any true changes in visual acuity. In the DREAMM-2 study, only 3%, or 3 patients, had to discontinue belantamab mafodotin because of ocular issues. The keys to managing ocular issues are dose holding or dose modification. This is unlike other medications where, when you hold the dose, you have this fear that you are going to lose control, particularly in the context of refractory myeloma. Because the half-life of belantamab mafodotin can be so long in some patients, only 10% to 15% of patients lost control of their disease during dose holding or dose modification. It is OK to hold the dose until the keratopathy or symptoms improve such that you can reinitiate therapy. In some patients, the dose was held 6 weeks or longer, so that is OK. Allow the keratopathy to resolve with dose holding and dose modifications.

We know from longer-term follow-up that almost no patients had irreversible ocular changes: they almost all recovered. The ones for whom we cannot say that with clarity are because they progressed or came off study and had other treatments that were administered to them at that point. It is not like there are patients who have irreversible ocular toxicity. From what we know about the data, that is not a significant concern with appropriate dose holding, dose modification, and partnerships with eye care professionals.

The DREAMM-2 trial for belantamab mafodotin showed us the ocular adverse effects. In terms of ocular safety, it was important to develop an understanding of what the rate of ocular toxicity that occurs with this drug is, as well as what the impact on visual acuity and visual function is. What are the short-term and long-term implications for patients?

In general, the DREAMM-2 study showed from an ocular safety standpoint that a significant proportion of patients develop ocular adverse effects. Most predominantly, this includes the finding of microcyst-like changes within the corneal epithelium, which in our University of Chicago Medical Center recent paper, we have called microcyst-like epithelial changes, or MECs. Roughly 70% of patients in the DREAMM-2 study developed these MECs.

We also know, based on looking at both the location data, meaning location within the cornea that these lesions were present, as well as the impact on visual acuity, that in a significant number of patients who develop these microcyst-like changes, there is no impact on visual acuity. That is reassuring. In other words, for a number of patients who will develop these lesions within the cornea, they will continue to have their baseline vision or vision to pursue their activities of daily living. However, a significant portion of patients, closer to about 50%, had some decrease in vision associated with these lesions.

We have some parameters by which that decrease in visual acuity was defined. For anyone with a decrease of greater than 1 line of visual acuity, we would pick them up using our visual acuity metrics in the DREAMM-2 study. With that being said, the patients who developed both MECs and a decrease in visual acuity, at the time of data cutoff for all those patients for whom there was adequate follow-up, these lesions and their visual acuity returned. The lesions resolve and visual acuity returned back to baseline.

From a safety standpoint, what we are seeing with belantamab and what we saw in the DREAMM-2 study was that a significant majority of patients developed cornea lesions, which we call microcyst-like epithelial changes. A significant portion, although not all of them, roughly 50%, also had some level of decrease in visual acuity, but the patients for whom we had follow-up at the time of data cutoff, they resolved. We also saw that, with a number of patients—and I have seen on my own anecdotal experience—with dose holds and dose reductions, these lesions also tend to recover. That was valuable information that was provided as a result of the DREAMM-2 study.

DREAMM-2 Trial Regimen Safety Profile

One of the exciting areas of new development in myeloma was the recent approval of belantamab mafodotin. Belantamab mafodotin was approved in a randomized phase 2 trial called the DREAMM-2 study, and in the DREAMM-2 study, we at the Winship Cancer Institute randomized patients between 3.4 mg/kg of belantamab mafodotin, which was the MTD [maximum tolerated dose] from the phase 1 trial, and 2.5 mg/kg of belantamab mafodotin, which was a dose recommended by the FDA to see whether the adverse event profile was different.

In that trial, we looked at the primary end point, which was overall response rate, which was about 30% to 32%, and it was similar between the 2 different doses of belantamab mafodotin. We then looked at the progression-free survival [PFS], and it was about 3 months, which is not dissimilar from what we saw with pomalidomide/dexamethasone in the same patient population, for daratumumab in the same population, and for carfilzomib in the same population of patients with refractory myeloma. We then began to look at DOR [duration of response], and we noted that the DOR for patients who achieved MR [minimal response] or better, was somewhere around 11 months, which now puts it at one of the longest durations of response of any approved drug in the refractory myeloma setting. This is important because DOR, in my mind, speaks to a balance between efficacy, as measured by overall response rate, and safety.

For drugs that do not have a great safety profile but can induce a response, the DOR and the PFS are similar, but in drugs that can be managed, and responders can be kept on therapy, you see that the DOR is substantially longer than the median progression-free survival. We saw this for daratumumab, for which the DOR was somewhere between 9 and 10 months, and in belantamab mafodotin, we see this as well: the PFS was 3 months, but the DOR was closer to 11 months. We know that, in these responders, the median overall survival is likely in excess of 13 months, which is significantly longer than the 6 to 11 months that I mentioned earlier as the median expected survival for patients with triple-class refractory myeloma.

Now, we also did some subanalyses from the DREAMM-2 study evaluating patients with high-risk genetics vs everybody without high-risk genetics. We demonstrated that the PFS and overall response rate were similar between those 2 groups of patients. We also looked at patients who had a renal insufficiency or were older, and we saw similar results: they were balanced between the 2, and there was no detriment in PFS or overall response rate between those groups.

We then looked at patients who had earlier treatment, meaning relapsing on 5 or fewer lines of therapy vs 6 or more prior lines of therapy. The overall response rate and DOR appeared to hold up in that patient population as well. This suggests to me that belantamab mafodotin is an important new treatment approach for patients with triple-class refractory myeloma. It being dosed once every 3 weeks is a reasonable approach in partnership with an eye care professional to treat patients with refractory myeloma.

DREAMM-2 Trial Efficacy Data and Recent FDA Approval

 One of the exciting, important developments in the context of myeloma is the realization that 

, or B-cell maturation antigen, is an important target in multiple myeloma. We are excited about this target as opposed to others, such as 

 CD38, because BCMA is much more narrowly expressed on plasma cells. There may be some mature phenotypes of B cells that express 

, but their expression numbers are much lower, and it is almost exclusively expressed on mature plasma cells. The target we’re going after is more selective than other targets we have in multiple myeloma.

 is also important for a number of points. A number of things occur to a myeloma cell that has been transformed, including proliferation, drug resistance, and overall survival of myeloma cells, all of which are governed by a 

 through ligation with its ligands, BAFF and APRIL, which are often circulating in the blood. When 

 is blocked with a receptor, whether it’s an antibody-drug conjugate, a T-cell engager, or a CAR [chimeric antigen receptor] T cell, you take out 1 of the major resistance factors for malignant plasma cells and potentially may resensitize them to other agents. Additionally, there’s very little expression at all on stem cells and nonhematopoietic cells. The 

 is in many ways an ideal target in multiple myeloma because of its more selective expression on plasma cells and the role 

The Rationale for Targeting BCMA in Multiple Myeloma

 Of the challenges we have struggled with in caring for patients who have seen multiple lines of therapy, of particular note are patients who are triple-class refractory or resistant to the proteasome inhibitors, immunomodulatory agents, and CD38 antibodies. Our treatment options are fairly limited at that point. Often, we will recycle previous agents in different combinations and hope we can get responses. Alkylator-based therapy, such as cyclophosphamide or melphalan, may be agents that we bring into play in this context. Combination chemotherapy approaches such as VDT-PACE [bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide] or DCEP [dexamethasone, cyclophosphamide, etoposide, cisplatin], may be treatments that we use as well, but unfortunately all those recycling or chemotherapy-based approaches have a limited life span. In all likelihood, you usually get 30 to 60 days of those treatment approaches. It has been new drug approvals and access to clinical trials that have really made a difference for patients with refractory myeloma.

What we know about patients who have reached the triple-class refractory stage of myeloma is that their median expected prognosis or survival is somewhere between 6 and 11 months. This has been demonstrated in a couple of retrospective analyses looking at daratumumab-resistant patients, such as in the MAMMOTH study as well as in the work of Dr Ajay Nooka from our group at Winship Cancer Institute, who demonstrated that the median overall survival for patients in this category is quite short. That is where we begin to look at the efficacy of new drugs. Can they really push the boundary of median overall survival in addition to response?

When we begin to think about what the treatment options are for patients who have had 4 or more prior lines of therapy, functionally, their condition is triple-class refractory. They are resistant to proteasome inhibitors, they are resistant to IMiDs [immunomodulatory drugs], and they are resistant to anti-CD38 antibodies. There are potential options in addition to recycling previously used agents or chemotherapy-based approaches. One approach that was recently approved is belantamab mafodotin, or belamaf, and this is 1 recent approach using an antibody-drug conjugate targeting BCMAs [B-cell maturation antigens] that provides significant potential benefit for patients. 

The other agent in this situation is the use of selinexor, which is a first-in-class XPO1 inhibitor. Selinexor was combined with dexamethasone in the STORM trial and was FDA approved for a similar pretreated patient population. There are some challenges to both of these medications, but with appropriate supportive care this can be used. It is important to recognize that the ongoing, unmet medical needs include management of patients who are frail, patients who have renal insufficiency, and patients who developed oligo-secretory myeloma, because unfortunately many of these patients are not eligible for clinical trials. Their treatment options in the refractory myeloma setting can be quite limited.

One of the things that we do when we try to assess what treatment approach might be suitable for a patient with refractory myeloma is to understand what their current symptom burden is and how much of that symptom burden is related to myeloma vs comorbid conditions that may or may not get better. What other specific issues such as travel, co-pays, and distance from the clinic impact patients’ treatment? All those things play into those decision-making processes. It is important to recognize that not all patients with 4 or more prior lines of therapy are going to be able to take aggressive therapy. Trying to understand how you tailor the treatment approach to what they need is 1 of the clinical challenges we struggle with in this situation.

Sagar Lonial, MD, FACP, Winship Cancer Institute of Emory University

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