 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.

Treatment Approach for R/R Multiple Myeloma

 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

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 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.

BCMA as a Target in Heavily Pre-Treated RRMM | Insights

Treatment Approach for R/R Multiple Myeloma

The Rationale for Targeting BCMA in Multiple Myeloma

DREAMM-2 Trial Efficacy Data and Recent FDA Approval

DREAMM-2 Trial Regimen Safety Profile