Belantamab mafodotin-blmf (Blenrep) has elicited significant responses in patients with relapsed/refractory multiple myeloma, but the corneal toxicities associated with its use will require a multidisciplinary effort between ophthalmologists and hematologist/oncologists, according to Sanjay V. Patel, MD, FRCOphth.

 in August 2020 for use in patients with relapsed/refractory multiple myeloma who have received 4 prior therapies, including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody. The decision was based on data from the DREAMM-2 study, in which the antibody-drug conjugate elicited an overall response rate of 31% in those who received the recommended dose of 2.5 mg/kg.

The most common grade 3/4 AE reported by those who received the agent was keratopathy; this occurred in 27% of those who received the 2.5-mg/kg dose and in 21% of those who were given the 3.4-mg/kg dose. Because of this incidence rate, the FDA requires that patients, physicians, and infusion centers alike to participate in a Risk Evaluation and Mitigation Strategy (REMS) program to ensure the appropriate use of the treatment.

“There are several medications that can affect the cornea, but uncommonly, and so, a REMS program is not in place for those medications,” said Patel. “What's different here is that most patients on belantamab mafodotin are going to experience corneal toxicity [and some patients will be symptomatic]. As such, [this agent] really [requires] a new partnership between ophthalmology and hematology/oncology [to develop] a new way of trying to manage these patients.”

, Patel, emeritus chair of ophthalmology at Mayo Clinic, discussed the corneal-associated toxicities that can occur with belantamab mafodotin and the need for multidisciplinary management to optimally administer this agent.

: How has the FDA approval of belantamab mafodotin impacted the treatment of patients with relapsed/refractory multiple myeloma?

As an ophthalmologist, I don't see patients with [myeloma] primarily, but I did see those on the DREAMM-2 trial because of their eye toxicities. Based on the patients I have seen, and with getting to know this drug, my understanding is that it offers those with relapsed/refractory myeloma an opportunity for prolonged survival. It sounds like it is an option that is very beneficial for patients.

Could you speak about the corneal toxicities that occur with this agent?

Some of the adverse effects (AEs) associated with this medication are very similar to other oncologic agents. However, this [agent] has a unique toxicity that is quite common: keratopathy, which is an abnormality of the cornea. This drug [can demonstrate] a toxicity in the corneal epithelium, so we would [refer to that] as a corneal epitheliopathy. I would say the majority of patients receiving this treatment will develop [deposits] in their cornea. For some patients, it can be a limiting factor to either further treatment if a dose reduction is not possible.

What we see is that these patients develop microcyst-like deposits in the cornea, many of [which] are scattered around the edge of the cornea. The cornea itself is an 11-mm circle; we do most of our seeing through the central 4 mm or 5 mm. These little deposits tend to occur in the periphery of the cornea early on and most patients wouldn't know that they're there because they're not symptomatic. However, we, as cornea specialists, can see them with a microscope.

Some patients will become symptomatic because if these deposits extend towards the center of the cornea where they cross the line of vision; [this results in] impaired vision or visual acuity. If they move to the center, that's when [a patient will] require an ophthalmologist or an optometrist to [advise] the hematologist or the oncologist on the grade of keratopathy which could result in the next dose being withheld.

Also, many patients will get dry eye syndrome, which is dryness in the tear film that covers the cornea and that can upset their vision or comfort; that is also something that you see with many other [cancer and non-cancer] medications. There are a couple of things happening here, but it's really those cyst-like deposits that are unique to this [agent].

What multidisciplinary effort will be required to adequately manage these AEs?

It's definitely [going to require] a multidisciplinary effort. With the agent only just being FDA approved, we haven't yet seen anyone on the drug yet [referred from our oncologists here]; the only ones I have seen were on the DREAMM-2 trial. However, I'm expecting them to be showing up any day now. Certainly, here at Mayo Clinic, we're fortunate because this is what we do; we work collaboratively with our colleagues in other specialties to coordinate patient care.

When a patient is put on this medication by a hematologist or oncologist, or if they're being considered for the medication, they need to be sent to an ophthalmologist or an optometrist for a baseline eye exam. We would see them to evaluate their whole eye: What factors are affecting their vision? What's the baseline? [Are there] other specific [factors] that already affect their cornea? What's the visual acuity?

Then, they'll be prescribed the drug, receive the drug on a 3-week cycle. Before each subsequent administration of the drug, they will need to see their eye care provider again. Each time we see them in subsequent visits, we're going to be checking the visual acuity, assessing their cornea primarily, and then grading any vision loss or corneal findings. We’re probably not going to see many findings in the first subsequent visit. [This effect is] more likely to [present] during the second subsequent visit, just based on what we saw in the DREAMM-2 trial.

We would assess our findings, and here, at Mayo Clinic, can electronically communicate that through the patient record to the hematologist and oncologist. In the rest of the world, that could be a bit of a challenge because you may have private groups of oncologists who need to work with private or independent ophthalmologists or optometrists who are going to be a little less familiar. [Therefore], they will need to establish chains of communication. That is essentially what needs to happen, per the FDA.

Could you expand more on what these eye exams look like?

The first exam would be a comprehensive eye exam, like when patients go to get their eyes tested. They’re going to have their vision measured on an eye chart. If they wear glasses or contacts, they often get a refraction. We would be doing a refraction in these patients to determine what their best corrected vision is with a pair of glasses.

The ophthalmologist or optometrist would then examine their eyes [through the use of] a slit lamp microscope. That provides us with a magnified view of the front of the eye, which is really where these [deposits] are going to be, in the cornea or the front window of the eye. At the initial examination, we would also look at other factors that may be influencing vision or other findings that may be important for us to know. We want to understand what their baseline looks like. The first exam could take a little longer than the others because we typically dilate the patients and then examine the front and back of the eye.

However, the subsequent exams will really be checking their best corrected vision; we want to know if their visual acuity has changed [since baseline]. We then assess their cornea, which is done with a slit lamp examination; there's no dilation involved there. Let's say a patient has no change or findings, then that's probably the end of the exam. If a patient has decreased vision and corneal findings are observed, they're probably related. If a patient has decreased vision, but the cornea looks good, we would [look further into this] by dilating them to see whether something changed in the back of the eye. We do not expect that with this medication, but other things can happen to patients. That's our role in this: To figure out whether it's a problem related to the drug or if there's something else happening that's unrelated to the medication.

Could you provide an overview of the REMS program?

As part of the DREAMM-2 trial, it became obvious that corneal toxicity is a common AE; [therefore], the FDA asked that a REMS program be implemented. Basically, this medication cannot be prescribed unless a patient has undergone a baseline eye examination. Subsequent treatments also cannot be given unless patients have an eye examination.

This is going to be new for this population of patients, but also for the physicians who manage them. Patients will be required to have eye examinations to receive this treatment. It will require communication and coordination between the eye care professional and the hematologist/oncologist. There's a structure in place that we, as the eye care professionals, don't get involved in, but my hematology colleagues need to be registered in that REMS program, [along with] the administering institution. As long as there's an eye examination on file and an order from the hematology specialists, then infusion center can administer the drug, but that's all coordinated through the REMS program. It's a coordinating mechanism to ensure these patients are getting their safety evaluation and not running into trouble with their vision.

Is there anything else you would like to touch on that we haven't discussed?

The vast majority of patients do not have permanent vision changes. Therefore, stopping the medication will result in improvement of the cornea and, if patients did experience a vision change, a return to baseline vision. Any changes that we see are reversible, but we do need to dose them according to what we see in the cornea.

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Sanjay V. Patel, MD, FRCOphth, discusses the corneal-associated toxicities that can occur with belantamab mafodotin and the need for multidisciplinary management to optimally administer this agent.

Belantamab Mafodotin in Relapsed/Refractory Myeloma Requires Multidisciplinary Effort

BCMA-directed therapies, such as bispecific monoclonal antibodies, CAR T-cell therapy, and antibody-drug conjugates (ADCs), are in the midst of transforming the treatment paradigm of relapsed/refractory multiple myeloma to get closer to a cure for patients, said David H. Vesole, MD, PhD.

“We keep striving for a cure. Right now, we have the option to make this a chronic disease in the same way high blood pressure or diabetes [are chronic diseases]. We didn’t have that option when I started. We can control a patient’s disease for an unbelievably extended period of time. Even if we don’t cure patients, we can make it a chronic disease,” said Vesole. “This is exciting for patients and their families. most of these therapies can be given with the prolongation of life, without negatively impacting QOL a great deal.”

, Vesole, director of the Myeloma Program at MedStar Georgetown University Hospital, professor of medicine at Georgetown University, co-director of the Myeloma Division and director of Myeloma Research at John Theurer Cancer Center at Hackensack University Medical Center, discussed the evolution of multiple myeloma treatment, and explained how other BCMA-therapies are poised to impact clinical practice.

: What makes BCMA a logical target in multiple myeloma?

: All patients with multiple myeloma are BCMA positive. BCMA stands for B-cell maturation agent, and all myeloma cells have some expression of BCMA on their cell surface. The extent of BCMA positivity may be higher or lower for individual patients, but because they are all positive, BCMA serves as a very efficient target for BCMA-directed therapies.

How has the treatment of multiple myeloma evolved?

I’ve been caring for patients with multiple myeloma for over 30 years, and treatments have evolved tremendously over the years. Back in the day, all of our drugs were chemotherapies, which have a lot of bystander effects and can cause nausea and vomiting.

It wasn’t until proteasome inhibitors (PIs), which were enzyme-specific pathway inhibitors that were first approved in 2003, that we started [using] targeted therapies for specific pathways and cells. These [agents] had significantly fewer bystander effects on normal cells. Therefore, since 2003, [multiple drugs have been] approved for the treatment of myeloma. Most of the [newer treatments] are more sensitive and specific to myeloma cells with much less bystander effect. They are tolerated better and their efficacy is better than conventional chemotherapy.

Over the course of the past few years, we found that giving combination therapies with multiple mechanisms of action results in superior activity, such that triplets appear to be the standard of care for newly diagnosed patients. [These triplets] are based on different categories of drugs such as PIs, immunomodulatory drugs (IMiDs), and corticosteroids. Many trials have looked at triplets versus doublets, and essentially all of them show that triplets are superior to doublets in the frontline and relapsed/refractory settings.

Currently, triplet therapy seems to be the standard of care, but what is evolving is whether we should give quadruplet regimens with monoclonal antibodies in addition to those same 3 classes of drugs I mentioned. Emerging data indicate that [quadruplets] are even more efficacious without a significant increase in toxicity. Although they are not currently the standard of care, I anticipate within the next 5 years that they will become the standard of care potentially up front, as well as in the relapsed/refractory settings for patients with multiple myeloma.

It is exciting to know that we have these monoclonal antibodies, which target specific surface components of myeloma cells. They [cause] very few bystander effects on other cells in the body. Although [these agents] are not completely devoid of other toxicities, they focus predominantly on myeloma cells.

[Historically], we would see, at most, a 20% likelihood of achieving a complete remission (CR). Now, we are approaching potentially achieving CRs in 80% or more of patients depending on the regimen that we utilize. Overall survival (OS) [rates] have improved as well [compared with] when I first started more than 30 years ago. Currently, patients with stage I disease have a life expectancy that exceeds 10 to 15 years versus 2.5 years [when I first started].

What challenges remain with regard to treatment in multiple myeloma?

The biggest hurdle that we still have in multiple myeloma is [treating] patients with high-risk disease based on [their] cytogenetics and staging. We’ve certainly made major headway, but their OS remains in the 4- to 6-year range, which is much lower than what we see with those patients who do not have adverse cytogenetic features.

Belantamab mafodotin-blmf (Blenrep) received regulatory approval in August 2020. How does this agent compare with others in the space?

The first BCMA-directed therapy that has been FDA approved is belantamab mafodotin. It is an ADC where the antibody is directed against BCMA and is conjugated to a chemotherapy drug. Biologically, the monoclonal antibody attaches to the myeloma cell, which is endocytosed into the cell. Then, lysozymes break down the link between the chemotherapy drug and the antibody, which allows the chemotherapy drug to kill the cell [from within]. Other diseases have ADCs as well, but [belantamab mafodotin] is the first approved in multiple myeloma.

For patients who respond [to belantamab mafodotin], the duration of response exceeds 11 months. This is quite impressive for a group of patients whose lifespan would be shorter than patients who have not received 4 prior lines of therapy. This opens up a wide avenue of patients with multiple myeloma who may have exhausted all other potential treatments.

The drug does not [elicit] an overly robust response rate as a single agent. [The rates are] about 30% to 35% depending on which DREAMM study you look at. As a single agent, belantamab mafodotin is currently approved for patients who have been heavily pretreated with 4 or more prior lines of therapy—which is a lot of chemotherapy.

Could you describe the unique safety profile of belantamab mafodotin?

Yes, there are some bystander effects with [belantamab mafodotin]. From a hematologic standpoint, it can lower white [blood cell] counts and platelet counts, but that is usually not a major consequence.

However, for reasons that we do not know, [belantamab mafodotin] can cause problems with the eye, [namely] keratopathy. In the vast majority of patients, this is very minor and presents as blurred vision or dry, scratchy eyes. Although this occurs in about 80% of patients treated with the drug, severe reactions occur in about 10% of patients. To the best of my knowledge, most of these abnormalities are completely reversible with time. The time sequence of the reversibility depends on how severe [the toxicity] is. There is a grading system from 1 to 4 with regard to how involved the ophthalmologic abnormalities are.

Before each dose of [belantamab mafodotin], which is administered every 3 weeks, patients have to be seen by an ophthalmologist or optometrist to be cleared before receiving the next dose of therapy. If a patient meets certain grades of severity, the drug is either dose reduced or held.

Although this is the first approved [BCMA-directed] drug, there are a lot of other therapies directed against BCMA that have different toxicity profiles than belantamab mafodotin.

 for patients who have had 4 prior lines of therapy. Selinexor is an [oral] pill given once or twice a week, depending on the schedule. It is not a BCMA-directed agent. Instead, selinexor is directed against a specific mechanism in the nucleus of the myeloma cells [called XPO1]. Selinexor has a completely different toxicity profile; gastrointestinal toxicities are mainly seen with this agent.

The FDA approval of belantamab mafodotin was based on data from the DREAMM-2 trial. How has the DREAMM series evolved since the approval?

The DREAMM-1 study essentially [evaluated whether] belantamab mafodotin had any activity [in patients with relapsed/refractory multiple myeloma]. DREAMM-2 is the phase 2 trial that led to the FDA approval for the drug. DREAMM-3 through DREAMM-16 [are trials] that are evaluating a variety of other agents to be added to belantamab mafodotin. Additionally, DREAMM-12 and DREAMM-13 are evaluating belantamab mafodotin in patients with renal failure and liver abnormalities, [respectively].

Essentially, [the trials] are taking all the known drugs that we currently use to treat patients with multiple myeloma and adding them to belantamab mafodotin in some form. The DREAMM series is an ongoing effort to improve the outcome of single-agent belantamab mafodotin. DREAMM-6 was presented at [the 2020 ASCO Virtual Scientific Program] in June, showing response rates north of 30% with the addition of bortezomib (Velcade), [which is] far superior [than what we’ve seen with belantamab mafodotin alone]. When we combine belantamab mafodotin with other active agents with different mechanisms of action, we can see superior response rates and remission durations.

How do you approach sequencing in your own practice? Where does belantamab mafodotin fit into the paradigm?

Although quadruplets are quite effective up front, they are not FDA approved at this point in time. We are not sure if they will be covered by third-party carriers. Therefore, we generally use triplet regimens for initial therapy.

Our group is heavily biased toward stem cell transplants, which is considered standard of care throughout the world. For patients who have multiple myeloma and adequate physiologic organ function, and agree to [undergo] transplant, transplant is considered standard. We would give a triplet regimen, followed by transplant. Our group is a bit unique because we are not particularly in favor of maintenance therapy. On average, patients stay in remission for 2.5 to 5 years. Then we come back with salvage therapy, usually with triplet regimens, of which there are a number approved by the FDA for patients who have had 1 to 3 prior lines of therapy.

Belantamab mafodotin was approved in kind of a niche sense in that it is approved for patients who had 4 prior lines of therapy. [The FDA] doesn’t specify lines of therapies, so it is an interpretation of what that means. The agent was only tested in patients who had 4 or more lines of therapy. It is a little bit confusing because, in theory, we could use [belantamab mafodotin] in the second- or third-line settings.

There will likely be a lot of competing options for BCMA-directed therapy. CAR T-cell therapy is likely going to be approved sometime in the first quarter of 2021. Two companies are neck-and-neck with the FDA submission for CAR T-cell therapy approval. [Both] are BCMA-directed therapies.

Bispecific antibodies are a little bit further away from receiving regulatory approval, but are also BCMA-directed therapies.

There will certainly be a lot of competition for belantamab mafodotin in this niche [setting of patients who received at least 4 prior therapies]. These other agents have different toxicities profiles and different response rates. Similar to the DREAMM studies, these agents are being combined with many of the standard therapies that we currently use. We are going to have a whole list of additional options with these BCMA-directed therapies in the very near future.

Where would you like to see future research efforts focused?

Right now, belantamab mafodotin is being given as a single agent. We are not going to control multiple myeloma with single agents. We need combination therapies that have different mechanisms of action. That is ultimately going to be the goal of treatment.

The future is going to have personalized medicine. There is a trial by the Multiple Myeloma Research Consortium that is using standard therapies and then doing next-generation sequencing to find out if there are specific gene mutations for which specific drugs can be directed toward. The investigators are giving individual drugs, based on the patient’s DNA sequencing, that will attack specific abnormalities.

Ultimately, this is what is going to happen. We are going to be individualizing precision medicine and treating patients’ specific DNA abnormalities in their myeloma cells.

Yes, we could have a BCMA-directed target, but if we add that with a targeted agent against some specific enzyme deficiency or genetic abnormality, it [will be a valuable] addition to these other mechanisms. I imagine that in the future, patients are going to get 4 or 5 different drugs, some specific to enzyme pathways, others specific to their individual DNA sequencing. That is, in addition to targets that are widely expressed on the myeloma cells themselves such as BCMA.

How do you see CAR T-cell therapy impacting the landscape of multiple myeloma?

CAR T-cell therapy is an exciting area now. CAR T cells are patients’ own lymphocytes that are genetically modified to improve their activity in targeting their own myeloma cells. Unlike belantamab mafodotin, which, as we mentioned, needs to be combined with other agents to improve efficacy, CAR T-cell therapy alone has a response rate of 75% to 100%.

Further, CAR T-cell therapy is [a] one-and-done [approach]. Patients get CAR T cells on day 1 and they may not need therapy for 1 or 2 years, perhaps longer. All the other BCMA-directed therapies require continuous and indefinite therapy until they no longer work. With CAR T cells, patients get their therapy, get their response, and may not require treatment for an extended period of time. Ultimately, this will result in superior quality of life (QOL) for those patients who are going to get continuous therapy.

The CAR T-cell technology continues to improve. There are probably over 30 different companies that are trying to [manufacture] CAR T cells in multiple myeloma. The vast majority of them are using BCMA as the target, but that is not the only target that is available.

Right now, CAR T cells are predominantly made using a patient’s own cells, which takes 2 to 4 weeks to generate, genetically modified, and engineered before being returned to the patient. In the future, there will also be what we call off-the-shelf CAR T cells that are made in a laboratory and can be given the day after ordering them. Studies evaluating these allogeneic

CAR T cells are just beginning, but they could save a lot of time. Some patients cannot generate good CAR T cells if they have been heavily pretreated or if they don’t generate the number of cells needed for the infusion. Allogeneic CAR T-cell therapy opens [the option] up for those patients, as well as for the patients who need treatment sooner rather than later; some patients cannot wait 2 to 4 weeks for the cells to be generated.

To me, this is the most exciting area because it is a one-and-done [approach] versus continued therapy. CAR T-cell therapy can cause toxicities, but in contrast to lymphoma and leukemia, most of them are minor in multiple myeloma. [Moreover,] there is at most a 10-day window in which these abnormalities occur, after which patients are essentially home free for the duration of time the cells are effective.

David H. Vesole, MD, PhD, discusses the evolution of multiple myeloma treatment, and explained how other BCMA-therapies are poised to impact clinical practice.

Monoclonal Antibodies, ADCs, and CAR T Cells Invigorate the Myeloma Paradigm

Ophthalmologists are filling a critical role in the collaborative management of patients with relapsed/refractory multiple myeloma who are receiving belantamab mafodotin-blmf (Blenrep), said Shaily Shah, MD, who added that the potential ocular toxicities that can occur with the antibody-drug conjugate (ADC) require consistent screening and management.

“As a junior attending, what opened my eyes has been how incredible the field of medicine is in general, and how eager people are to work together to do what is best for the patient,” Shah said. “It is very exciting, in general, [that] oncology is a multidisciplinary specialty.”

 for use in patients with relapsed/refractory multiple myeloma who have received 4 prior therapies, including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 agent.

Findings from the DREAMM-2 trial, which served as the basis for the approval, demonstrated a 31% overall response rate (ORR) with the recommended 2.5 mg/kg dose of belantamab mafodotin (n = 97).

 The ORR was 34% among patients who received the 3.4-mg/kg dose (n = 99).

Grade 3/4 keratopathy was observed in 27% of patients who received the 2.5 mg/kg dose versus 21% of patients who received the 3.4 mg/kg dose.

At 13 months of follow-up, deep responses were seen; more than half of responders in the 2.5 mg/kg (58%) and 3.4 mg/kg groups (66%) achieved a very good partial response or better.

No new safety signals were identified with longer-term follow-up. Although keratopathy was common, only 6 patients discontinued treatment due to corneal events, suggesting that they were well managed with dose modifications.

According to Shah, with this ocular safety signal, patients treated with belantamab mafodotin should receive prophylactic treatment for dry eye, as well as have routine eye examinations to ensure ocular changes are identified early.

“There is still a lot to be learned here,” said Shah. “Of course, the studies have been done, but now that belantamab mafodotin is going to be prescribed on a larger scale, there is going to be so much that we learn specifically regarding that agent, as well as how we can improve collaborative management for these patients.”

, Shah, an assistant attending ophthalmologist at NewYork-Presbyterian Hospital and an assistant professor of ophthalmology at Weill Cornell Medicine, discussed disease and treatment-related ocular toxicities that can arise in patients with cancer, specific management strategies for patients receiving belantamab mafodotin who develop ocular toxicities, and the importance of collaborative management of these patients.

: What is the frequency of disease-related ocular toxicities among patients with cancer?

: I don’t have an exact percentage offhand, but [ocular toxicities] are more common than one may think. Oftentimes, it is not related to the cancer itself but, there are certain types of cancers that manifest with ocular findings, such as some lymphomas and leukemias. Multiple myeloma in itself can produce crystalline keratopathy, but it is uncommon that we see that.

How frequently are treatment-related ocular toxicities observed in oncology?

Treatment-related adverse effects (TRAEs) are fairly common to see. At Cornell, we are right next to Memorial Sloan Kettering Cancer Center, so we see quite a few patients with graft-versus-host disease (GVHD), as well as patients who have received bone marrow transplants for leukemia. Those patients will often develop significant ocular toxicity from their systemic GVHD. Patients will sometimes come in with severe dry eye, lack of tear production, corneal haze, or corneal opacities. Patients could eventually develop limbal stem cell deficiency and go down a path of significantly decreased quality of life and visual acuity.

We have gotten good at having a protocol in place for our patients with GVHD. We know that patients may not respond to typical dry eye management, so we have steps to help them.

There are also certain medications such as chemotherapeutic agents that can cause cancer treatment-related ocular toxicities. We know that treating breast cancer with tamoxifen can cause retinopathy—changes in the retina of the eye where crystal-type deposits [form] in the macula.

We may also see radiation-related toxicities in patients who had radiation near the face or around the chest and neck. Oftentimes, these patients will have problems with their tear ducts, tear drainage system, and sometimes, their tear production glands. They may develop significant dry eye either from scarring of the eyelids where they can’t blink easily and the eyes dry out from exposure, or from a problem with tear production or drainage.

What ocular toxicities have been observed with belantamab mafodotin specifically? What sort of issues could arise if these AEs are not managed correctly?

Certainly, now with [the approval of] belantamab mafodotin, we have been seeing corneal toxicities [in patients with myeloma]. Throughout the clinical [trial] process for belantamab mafodotin with the DREAMM-1 and DREAMM-2 studies, the ocular toxicities [observed were] specific to the ocular surface. When [investigators] studied that further, they found that it [has] a corneal epithelial pathology. The cornea is the most superficial layer of the eye, and the epithelium is the most superficial layer of the cornea. Therefore, it is really [on] the most superficial layer of the ocular surface that we are seeing the majority of these toxicities.

Even just being confined to 1 portion of the tissue, the range of symptoms that the patient can feel is broad. Patients could be completely asymptomatic [although] the [ocular] changes are seen on the exam from the physician’s standpoint, or the exam may not show changes, but the patient could have significant ocular surface-related complaints.

In general, these complaints will be similar to dry eye–related complaints, including burning, grittiness, a foreign body or sandy sensation, an achy sensation, redness, and significant tearing. Oftentimes, patients may experience decreased visual acuity, so they may come in with complaints of blurred vision.

Our exam findings can range from no findings at all, to mild or moderate dry eye. We would see signs of dryness on the surface exam where a dye used to stain the surface of the cornea can pick up changes that correlate with dry eye and highlight dry spots in the corneal epithelium.

In terms of parameters, we look at whether there are any staining patterns. Are there any punctate epithelial erosions? An interesting finding that we have seen, and that was reported after the DREAMM-1 and DREAMM-2 studies, is microcystic keratopathy. These are small microcysts that we can see just underneath the surface layer of the epithelium.

[Microcysts] usually start in the periphery of the cornea and work their way in toward the center. That is consistent with what the studies had shown. Initially, the 2 patients I had seen who developed microcysts were completely asymptomatic. They came in for a routine follow-up with no visual complaints and their vision hadn’t changed on their exams. It was an incidental finding.

Corneal exams [can also show] corneal haze. Again, this very fine opacity starts around the edges of the cornea and can eventually progress to the center. Sometimes the exam findings are correlated with patient symptoms such as blurred vision or discomfort, but again, patients may be completely asymptomatic.

It is important to screen these patients. If they do not have symptoms, they won’t necessarily come in of their own accord. We have a great system in place where right before every infusion, we see patients for screening exams.

If a patient on belantamab mafodotin does develop ocular toxicities, what are some of the management strategies that can be used to treat these AEs?

With this expanded access [program] that I have been part of at Cornell through GlaxoSmithKline, the protocol that we have in place is to treat our patients prophylactically with artificial tears. We will start patients on preservative-free artificial tears anywhere from 4 to 6 times a day, or more if patients get [relief] from them. The idea is to lubricate the eyes and keep them as healthy and wet as possible to try to minimize discomfort and surface level toxicity.

One of the proposed pathophysiologic mechanisms for why corneal toxicity occurs is that some of the drug may be carried in through the tear film of the patient. Then every time that patient blinks and produces tears, the drug sits on the surface of their eye. In addition to keeping patients comfortable and preventing dry eye symptoms, artificial treats help to dilute their natural tear film and potentially prevent toxicity from building up.

Even if patients don’t have dry eye, but they have any other eye conditions that can contribute to dry eye such as meibomian gland dysfunction (MGD), I will oftentimes have them start treatment for that ahead of time. The treatment [for MGD] is simple. At home, patients are asked to use warm compresses to try to open up the glands to increase oil production and improve the quality of their natural tears.

At this point, most treatment is preventative, and we try to maximize patients’ ocular health before they even start treatment. As soon as I see them for screening, I will go over the details of what the [potential] toxicities are and why it is so important to start these preventative treatments.

Additionally, some studies have shown that putting a cold compress on the eye during the time of infusion can increase patients’ comfort levels and potentially improve the ocular toxicity profile. That is also something that is built into our protocol.

How do these ocular toxicities affect the use of belantamab mafodotin?

It depends on the level of toxicity the patient is experiencing. If patients have mild toxicity with a little bit of dry eye on the exam, no significant haze, no microcysts, and they are asymptomatic, we would call that grade 1 toxicity. Patients can usually continue with their treatment as planned.

If they start to develop peripheral microcystic changes or corneal haze, with or without changes in their visual acuity, oftentimes we will dose reduce or halt the next dose of belantamab mafodotin until they resolve back to grade 1 or baseline.

If a patient has cysts in the central portion of their cornea, their vision has [declined] significantly, or they have haze in the center of their cornea, those are definite indications to hold the next treatment. If patients get back to a certain healthy baseline, we can start belantamab mafodotin at either a decreased dose or full dose depending on the patient’s corneal health.

In the DREAMM-2 study, [investigators] evaluated whether the use of corticosteroids would help in [preventing the] development of these changes. The toxicities associated with a drug are often thought to be related to the inflammation that they induce in a certain tissue.

However, it was found that prophylactic corticosteroid use did not make a difference in the ocular toxicity profile, so that is no longer recommended for patients starting on belantamab mafodotin.

Could you speak to the collaborative efforts required between oncologists and ophthalmologists to manage patients receiving belantamab mafodotin?

One of the really beautiful things about the expanded access protocol, as well as the DREAMM-1 and DREAMM-2 studies and the FDA approval, is that it encourages and requires collaborative management of patients. It is about collaborating with the patient, their oncology team, including the infusion specialist, nurses, pharmacists, and the ophthalmology team.

With the FDA approval, [we have seen] a lot of outreach into the community [regarding this agent and this collaboration]. Community oncologists are going to be prescribing this medication now, so community oncologists and community ophthalmologists [need to be educated on] what these toxicities are, how frequently patients should be screened, and how frequent follow-ups should be. The lines of communication between the ophthalmology team and the oncology team need to be kept open.

What are some of the challenges that remain in this space?

In an academic center, it is much easier to collaborate with other departments. For example, the ophthalmology department is in full collaboration with the oncology department [at Cornell] so that we can get these patients seen quickly and get the [treatment] decision over to the oncology department. Once community doctors are prescribing belantamab mafodotin more, the challenge will be getting patients quickly to an ophthalmologist or having ophthalmologists ready to see these patients. Additionally, making sure that the ophthalmologists are communicating efficiently, quickly, and clearly to the oncology team could become a challenge as well.

What would you like to emphasize regarding the management of ocular toxicities among patients receiving belantamab mafodotin?

The most important thing is to make sure that all parties are equally aware of the importance of communication with one another, as well as communication with the patient. Oftentimes, patients [receiving belantamab mafodotin] may feel like this drug is their last resort. Patients may ignore certain AEs that they are having or may not be aware of what AEs are important [to report]. Keeping those lines of communication open, not just among providers, but with the patient, as well as educating patients on the potential toxicities that could manifest is important. Additionally, making sure that patients follow up with the ophthalmologist, even if they are asymptomatic, is important.

It is a really exciting time because it affords us, as ophthalmologists, the opportunity to collaborate on a truly systemic disease. It is also exciting to be able to be part of a larger treatment team and to work within other specialties.

FDA approves GSK’s BLENREP (belantamab mafodotin-blmf) for the treatment of patients with relapsed or refractory multiple myeloma. News release. August 5, 2020. Accessed September 23, 2020. https://bit.ly/3gxEXB1

Lonial S, Lee HC, Badros A, et al. Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study [published online December 16, 2019]. 

. https://doi.org/10.1016/S1470-2045(19)30788-0.

Lonial S, Lee HC, Badros A, et al. Pivotal DREAMM-2 study: single-agent belantamab mafodotin (GSK2857916) in patients with relapsed/refractory multiple myeloma (RRMM) refractory to proteasome inhibitors (PIs), immunomodulatory agents, and refractory and/or intolerant to anti-CD38 monoclonal antibodies (mAbs). 

. 2020;38(suppl 15):8536. doi:10/1200/JCO.2020.38.15_suppl.8536

Shaily Shah, MD, discusses disease and treatment-related ocular toxicities that can arise in patients with cancer, specific management strategies for patients receiving belantamab mafodotin who develop ocular toxicities, and the importance of collaborative management of these patients.

From the Ophthalmologist’s Eye: Managing Ocular Toxicities With Belantamab Mafodotin in Myeloma

The relapsed/refractory multiple myeloma treatment landscape is in the process of undergoing a major revolution, with the emergence of novel BCMA-targeted approaches comprised of antibody-drug conjugates (ADCs), bispecific T-cell engagers (BiTEs), and CAR T-cell therapies, according to Elisabet E. Manasanch, MD.

“I really feel that the way we treat [patients with] myeloma will be completely different 5 years from now because many of these [new] drugs will be on the market,” said Manasanch. “There was a big revolution in this disease when we started to use proteasome inhibitors (PIs). When bortezomib (Velcade) came along, that was another revolution [because] there were not many medications that were effective. Right now, we are [witnessing] another revolution with CAR T-cell therapies, BiTEs, and ADCs.”

 (Blenrep) demonstrated an overall response rate (ORR) of 31% (97.5% CI, 20.8-42.6) when given at a dose of 2.5 mg/kg in patients with relapsed/refractory multiple myeloma who had previously received 4 therapies, including an immunomodulatory drug (IMiD), a PI, and an anti-CD38 antibody. The ORR was even higher, at 34% (97.5% CI, 23.9-46.0), when patients received the higher dose of 3.4 mg/kg. These data led to the August 2020 FDA approval of the agent in this patient population.

BiTEs are also generating excitement in the relapsed/refractory treatment setting. AMG 701, a half-life–extended anti-BCMA BiTE demonstrated encouraging preclinical in vitro antitumor activity and characteristics suitable for once-weekly dosing in patients with multiple myeloma.

Additionally, the agent REGN5458 elicited responses in 57% of heavily pretreated patients (n = 4/7) who received a dose of 3 mg; 75% (n = 3/4) who received a higher dose of 6 mg achieved a response.3 Moreover, 50% of those who received the higher dose also achieved minimal residual disease negativity. Participants had received a median of 7 prior lines of systemic therapy and had all progressed on anti-CD38 treatment.

“One of the main advantages [with BiTEs] is that you can just give [the drug to the patient]. You could be in the hospital and see a patient who has relapsed myeloma and if BiTEs are approved, you can give them that agent in the same afternoon,” added Manasanch. “That’s very attractive because you get immediate access to [an efficacious drug]. That will be one of the potential advantages of BiTEs over CAR T-cell therapies.”

, Manasanch, an associate professor in the Department of Lymphoma/Myeloma and Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discussed novel modalities that are emerging in relapsed/refractory multiple myeloma.

: How do you identify patients with BCMA expression? Are you testing for this to decide who should receive BCMA-targeted agents?

 I don't think that it’s important to check whether the patient expresses BCMA because most of them will have it. Plus, there's a lot of data saying that the response to BCMA-targeted agents is not directly related to the BCMA expression. You can test for BCMA through immunohistochemistry and flow cytometry, but it’s not something that we do clinically; we do this in a clinical trial setting, if anything. Also, for belantamab mafodotin, for example, you don’t need to do BCMA staining.

Belantamab mafodotin is an antibody-drug conjugate. In just 3 to 4 years, they [brought] the drug from a phase 1 study to an FDA approval. [Investigators have] done an excellent job and this drug is very good; it has a response rate of approximately 30% as a single agent without steroids in patients who have received many [prior] therapies. The patients who do respond [to the agent] seem to respond very well. These patients also seem to have a prolonged response; it's not just that they respond and it lasts for a couple of months. These patients can experience responses that last for 1 or 1.5 years. This is very valuable for these patients [who are so heavily pretreated].

Belantamab mafodotin is approved for patients who have relapsed myeloma and who have had at least 4 prior therapies. There is nowhere in the approval that you have to test for BCMA expression. Any patient who has relapsed myeloma and received 4 prior lines of therapies, you can start on belantamab mafodotin. We don’t really check for BCMA clinically.

I asked a couple months ago [about obtaining] validated tests to test for BCMA because if there's any relationship, we want to know about it. [That test is also] good at identifying plasma cells and so on. They’re now doing a test to validate this, so that we can test for it clinically but this it’s not ready; it’s very new. I don’t believe that [something like this] will be available in smaller centers [anytime soon].

Could you expand on the approval of belantamab mafodotin in this setting?

The FDA approval of belantamab mafodotin is a major one in the field of myeloma because it is the first BCMA-targeted agent approved and it had a response rate of about 30%. Patients who do respond can have a duration of response that is quite long. I don’t know if this has been talked about too much, but based on some of the data that have been [reported], we see some of the patients can be on this treatment for 1 year or longer. That’s very important.

[However], this approval has several limitations. The main limitation is that this drug [can cause] corneal changes because the payload of the ADC can deposit in the cornea. When this happens, some patients can be very uncomfortable. I don’t know that it’s necessarily painful, but it’s definitely annoying. Patients can also have dry eyes. However, the FDA has implemented an ocular risk evaluation and mitigation strategy (REMS) program, so that this drug can be given safely.

The REMS program requires the physician and the patient to sign up along with the infusion center. An ophthalmologist or optometrist is also needed to do an eye exam. These are very detailed examinations [pertaining to the cornea and visual acuity] that have to be done within 2 weeks of receiving the drug.

In the clinic, the physician looks at the evaluations from the optometrist and ophthalmologist. If [results fall] within [an acceptable] range, then the physician prescribes the medication. It's only when you go on the website and [input the necessary information] that you get a code that indicates to the infusion center that you can infuse the drug.

Beyond the program, how do you suggest that these toxicities be mitigated in practice?

The drug is effective as a single agent in the relapse [setting]; it’s going to help a lot of patients. There are going to be some patients with myeloma who don’t have many treatment options who can go on this medication and do really well for quite some time. This is very important despite the limitations that I have mentioned. As we get used to giving this medication outside of clinical trials, it will become easier and easier [to manage]. As long as we follow the REMS program and patients undergo evaluations and go to the ophthalmologist, these [AEs] should not be a real issue. It also very important to know that the corneal changes that we have seen usually resolve within a couple of months.

Some patients are going to have symptoms and some may not even though they have some changes in the cornea. There could be an incident where the ophthalmologist says that you have to halt the drug because there are some changes [even though] the patient's vision may be perfectly fine; that can happen. The other thing important [to note] is that even if you hold the medication, that doesn't mean the patient is going to relapse right away.

You give a patient a couple of doses, which is a dose every 3 weeks; they receive cycle 1, day 1 and cycle 2, day 1. Then, if they come for cycle 3, day 1 and they have some epithelial cornea changes or a little bit of blurry vision and it's determined that they cannot receive the drug that day because those ocular need to be watched, you can hold the drug. If the patient has a response within the first 2 doses, it's very possible that you can carry this response through for the next 2 to 6 weeks and you can dose the patient later, once these changes have resolved. You may be able to put the patient on the medication again [at that time].

Depending on the severity of the changes in the cornea, you can also [reduce] the [dose of the] drug. If the patient has very high-grade changes in the cornea or severe diminishing of visual acuity, then you can decrease the dose of the medication, as well. [We have a lot to] learn [about] how to manage the drug. Overall, I'm very happy that we have this drug on the market right now.

Is there anything you would like to add on the Driving Excellence in Approaches to Multiple Myeloma (DREAMM) program?

It’s a nice program. I haven't used it personally yet, but it doesn't seem very difficult to use. We have support staff in our clinic who can help patients work closely with an ophthalmologist or optometrist to get the scores that we need, and the nurses and infusion centers can call us. I don’t think it’s going to be a big issue; I just think it’s going to need some logistical setup to get it up and running. However, once it starts, I don’t believe it’s going to be [problematic]. I think it was really well set up. It’s very functional, and it’s online, so it’s easy to access. The [program has] a lot of information available for patients, which is good. It’s all for the safety of the patients.

Shifting to other BCMA-targeted agents, could you speak to some of the recent developments that have been made with BiTEs?

AMG 420 was 1 of the first [BiTEs] that had data presented in a past medical meetings and the efficacy was really good, but I don’t think this drug is [still] being developed by Amgen. AMG 420 was a medication that was [given as] a continuous intravenous infusion and the half-life of the drug was very short. The development of AMG 701 followed. This agent does not have such a short half-life; it can be given once a week. This is still [under] development so there are not a lot of data [with regard to its efficacy], but the expectation is that the response will be very good. [AMG 701] is under evaluation in a phase 1 trial.

One of the nice things about this study is that there's an escalation of the dose. As you know, BiTEs can have similar toxicities to that of CAR T cells. Cytokine release syndrome is 1 of the dangerous toxicities that can occur. One of the things that we have realized in drug development is that perhaps some of the studies can start with a very low dose in the first week, then they can ramp up the dosage each week if a patient doesn't experience AEs. That probably makes the drug much easier to give, but it's still early.

Another BiTE [is being developed] by Regeneron Pharmaceuticals: [REGN5458]. Some of the data on that drug were presented and looked very promising in terms of efficacy. BiTEs are most likely going to move forward in development for multiple myeloma; it could be another revolution. There’s definitely going to be a market for this approach because these drugs can be given off-the-shelf. You don't have to do T-cell collection; with CAR T, you have to collect T-cells and then you have to manufacture the cells.

What is some of the work that is being done with CAR T-cell therapies? Are there benefits to this modality over BiTEs?

The good thing about CAR T-cell therapy is that usually it's given once and a patient could achieve a very good response from it; it is then followed with observation. Patients usually like this because they get a break from treatment. With BiTEs, you really need continuous dosing. Usually [patients] get repeated dosing either every week or every couple of weeks, so they’re not going to receive a treatment once and then be done. That would be 1 of the [reasons] why CAR T-cell therapy may be preferable [to BiTEs] for patients.

Are any other agents under exploration that you are excited about?

 (formerly CC-220), which is a drug from Bristol Myers Squibb and it is a new generation of IMiD that looks very promising. The phase 1 study of the agent focused on [establishing] the toxicity and efficacy [of the agent]. The response rate was around [30%], which is very good, especially in patients who [have progressed on] almost all of the therapies [available to them]. The agent was also found to be safe. The [patients] went through dose escalation without [experiencing] toxicities; it took a while for them to find [the recommended] dose. That's a good thing.

Lonial S, Lee HC, Badros A, et al. Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study. Published online December 16, 2019. 

Cho S-F, Lin L, Xing L, et al. AMG 701, a half-life extended anti-BCMA BiTE, potently induces T cell-redirected lysis of human multiple myeloma cells and can be combined with IMiDs to overcome the immunosuppressive bone marrow microenvironment. Presented at: The 17th International Myeloma Workshop; Sept. 12-15, 2019; Boston, MA. AB169.

First clinical data for REGN5458 (BCMAxCD3) show positive preliminary results in multiple myeloma. News release. Regeneron Pharmaceuticals, Inc. December 8, 2019. Accessed September 24, 2020. 

Elisabet E. Manasanch, MD, discusses novel BCMA-targeted modalities that are emerging in relapsed/refractory multiple myeloma.

BCMA-Targeted Approaches Revolutionize Relapsed/Refractory Myeloma Treatment

The approval of belantamab mafodotin-blmf (Blenrep) addressed an unmet need in relapsed/refractory multiple myeloma, according to Sagar Lonial, MD, FACP, and to build off the efficacy observed with the agent, research efforts are dedicated to examining its use in other novel combinations and moving it earlier on in the treatment journey.

“BCMA is the ‘it’ target of 2020,” said Lonial, a professor and chair of the Department of Hematology and Medical Oncology at Emory University School of Medicine. “Belantamab mafodotin provides an off-the-shelf [opportunity] to target BCMA; the agent not only elicits responses in a highly-resistant patient population, but these responses are also durable. The agent also has a reasonable safety profile.”

(NCT03525678) served as the basis for the August 2020 FDA approval of the antibody-drug conjugate (ADC) in the treatment of patients with relapsed/refractory disease who have received 4 prior therapies, including an immunomodulatory drug (IMiD), a proteasome inhibitor (PI), and an anti-CD38 antibody.

Updated data from a 13-month follow-up analysis presented during the 

showed an overall response rate (ORR) of 32% (97.5% CI, 21.7%-43.6%) in patients who received the recommended 2.5 mg/kg dose of belantamab mafodotin and an ORR of 35% (97.5% CI, 23.9%-46.0%) in those who received the 3.4 mg/kg dose of the agent.

“Several combination studies [with belantamab mafodotin] will emerge,” said Lonial, who is also the chief medical officer of Emory University’s Winship Cancer Institute. “The is whether we should use a different dose or schedule to be able to combine [the ADC] with additional agents. There is also a big push to use the agent up front in combination with the 3-drug induction regimen of lenalidomide, bortezomib, and dexamethasone (RVd).”

, Lonial discussed the role of belantamab mafodotin in relapsed/refractory multiple myeloma and emerging BCMA-targeted agents that are generating excitement in this setting.

What is the significance of the regulatory approval of belantamab mafodotin in multiple myeloma?

 Belantamab mafodotin provides patients with a new treatment modality, particularly those who have exhausted most [available] treatment approaches. Despite all the great advances that we've seen, with median overall survivals now exceeding 10 to 12 years, there are patients who become triple-class refractory; these patients are resistant to IMiD, PIs and anti-CD38 antibodies and. For these patients, treatment options are relatively limited.

Could you shed light on findings from the

phase 2 DREAMM-2 trial that served as the basis for the approval of this agent?

In this randomized phase 2 trial, [investigators] evaluated 2 different doses of belantamab mafodotin. The lower dose of 2.5 mg/kg, which is now the FDA-approved dose, was requested by the [regulatory agency] to see whether it would have a different safety profile.

Although on the surface it appeared that the response rates were somewhat similar, and the adverse effects (AEs) were somewhat similar [between the doses], results showed that more patients had grade 1/2 AEs versus grade 3/4 AEs [with the lower dose]. The ORR was 32% with a median progression-free survival (PFS) of 2.9 months and a DOR of 11 months [in those who received this dose]. The DOR truly showed that in the patients for whom this therapy appears to be working, you can safely keep them on this agent despite the AEs that occur.

Could you speak to the administration of this agent along with the safety profile?

Belantamab mafodotin is an intravenous BCMA ADC. The agent is administered intravenously, and it is very well tolerated from an infusion reaction perspective. The ADC is much easier to give with acetaminophen and Benadryl prophylaxis; it doesn’t require steroid premedication. The agent doesn't take very long to administer and is given every 3 weeks.

The safety profile has 2 [notable toxicities]. The first is hematologic toxicity; we have seen suppression of the white blood count and some level of anemia; a lot of that is often disease related but it can be attributed to belantamab mafodotin, as well. The second is keratopathy, which is the development of microcysts within the cornea. Notably, microcysts occur in about 70% of patients who receive belantamab mafodotin.

Notably, only about 50% of patients are symptomatic and the most common AE was dry or itchy eyes, which can be addressed with lubricating eyedrops. People are most worried about changes in visual acuity; however, only approximately 20% of patients on the trial experienced these changes. The optimal way to administer belantamab mafodotin is by partnering with an ophthalmologist, who can see the patient before each dose is given to ensure that the keratopathy is not significant or severe enough that it does warrant adjustment or holding of to allow for that [toxicity] to improve.

Are there any other elements of the trial that you wanted to elaborate on? What was the significance of this research?

This trial addressed the unmet medical need in myeloma. Patients had received a median of 6 prior lines of therapy, and both 100 patients were on each arm [of the trial]; thus, it provided a fairly robust experience.

I believe it reflects the real-world practice of seeing patients with triple-class refractory multiple myeloma. It’s important to remember that, just because patients develop keratopathy, doesn't mean it will always impact their vision. In patients who have changes in visual acuity, the median time to recovery is about 22 days, so missing a dose could allow for them to recover back to baseline.

Moreover, in the majority of patients who had to miss a dose or reduce their dose, the disease actually didn't grow out of proportion. Over 80% of these patients maintained their disease response or deepened their response, likely because of the very long half-life of the antibody. It's a different drug in a number of different ways than most are used to dealing with.

What are the next steps for research with this agent?

As with every drug that we use in myeloma, we often try to move these agents [to examine their use] earlier on in the course of disease; these trials are currently ongoing. For example, the DREAMM-6 study combined bortezomib (Velcade) with belantamab mafodotin and demonstrated a significantly high ORR with a similar keratopathy rate to what was shown in the DREAMM-2 study. 

Other ongoing are trials examining belantamab mafodotin in combination with new immunologic targets. Some are looking at belantamab mafodotin in combination with 

With quadruplet therapies emerging in the frontline setting, have sequencing strategies been impacted? Do you foresee the ADC being used in second-line setting?

Quadruplet therapies are being used more frequently in the newly diagnosed setting, particularly for patients who are transplant eligible. I do foresee antibody strategies, other than daratumumab, potentially moving into the second-line setting.

The strategy at Emory University’s Winship Cancer Institute is to use daratumumab with RVd in the first 4 cycles of therapy, but not after transplant. In those cases, the use of daratumumab after transplant, is a reasonable approach, especially in the context of relapse. If you’re giving continuous daratumumab, [investigators will start to examine] belantamab mafodotin, isatuximab (Sarclisa), or other antibodies more frequently in first relapse.

What are some of the other BCMA-targeted therapies that are currently under investigation?

Belantamab mafodotin is an ADC and others are currently under development. Additionally, we have seen a lot of data on BiTEs. [With regard to BiTEs], AMG 420 led the way early on, but there are now 

targeting BCMA that have a longer half-life. Also, [data with] bispecifics have been reported by several companies. At higher doses, there seems to be ORRs ranging anywhere from 60% to 90%; this is very exciting, especially for relapsed/refractory multiple myeloma where we have been worried about T-cell health being a limiting factor for the efficacy of these bispecifics. However, this does not appear to be the case in small phase 1 studies.

Compared with lymphoma and chronic lymphocytic leukemia, we have been behind with regard to CAR T-cell therapy. [We know that] CAR T cells elicit high ORRs and minimal residual disease negativity rates along with longer DOR and PFS. The product that is furthest along in research is probably idecabtagene vicleucel. We're hoping that [this product] will be approved in the next few months based on results from the 

. Right behind this are other products that seem to have similar efficacy. We’ll have to see more information on PFS to determine which of these CAR T-cell products are optimal.

One of the differences between myeloma CARs and CD19 CARs has to do with both efficacy and toxicity. We see much less grade 3/4 cytokine release syndrome with myeloma CARs as well as less grade 3/4 neurotoxicity. This is great, because those toxicities are challenging to deal with; this differentiates CD19 from BCMA as a target.

Sagar Lonial, MD, FACP, discusses the approval of belantamab mafodotin-blmf and how it addressed an unmet need in relapsed/refractory multiple myeloma.

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BCMA-Targeted Approaches Revolutionize Relapsed/Refractory Myeloma Treatment

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