Roundtable Discussion: Manasanch Explores BMCA-Targeted Management of Relapsed/ Refractory Multiple Myeloma

Elisabet E. Manasanch, MD

During a Case-Based Roundtable event, Elisabet E. Manasanch, MD, MHSc diccused the case of 55-year-old Black man in a rural community who had relapsed or refractory multiple myeloma.

YEAGER: The fact that he now has a del(17p) abnormality and has had prior therapies with similar mechanisms of action would be 2 things that make me favor belantamab. But given his rural residence and previous autologous transplant, follow-up and close monitoring give me some concerns.

MCKENNEY: I think of the same factors that Dr. Yeager mentioned. He appears to be developing more resistant disease to the IMiDs [immunomodulatory imide drugs], and the transplant is increasing cells with del(17p), so I was going more directly to the BCMA [B-cell maturation antigen]-directed therapy.

MANASANCH: Would you consider, for example, belantamab mafodotin [Blenrep] as an infusion given every 3 weeks? Sometimes we give it less frequently vs carfilzomib [Kyprolis], which is [given] at minimum once a week. Do you think that could influence your decision in a patient like this?

MCKENNEY: Yes, he is going to need more targeted treatment. He has had the IMiDs and is becoming more refractory to that treatment.

REDDY: I did not choose belantamab because we do not have good support. I do not have an ophthalmologist [the patients] are going to see every 3 weeks. So that is not an option, but the 3 options we have are not the best because we have used all [effective] drugs [for] this patient already. Is belantamab better than a carfilzomib combination, even though the patient already had bortezomib?

MANASANCH: I am sorry you do not have the option to give belantamab in your practice, but for a patient like this, you could do carfilzomib with cyclophosphamide [Cytoxan], and as the patient is progressing on daratumumab, you could always switch to isatuximab-irfc [Sarclisa]. But they are similar antibodies.

Selinexor [Xpovio] could be another option. There are no head-to-head comparison studies. What would the efficacy be? The toxicity of carfilzomib and selinexor may be a little more overall than just belantamab, especially if you monitor the patient [who receives belantamab] and have the ophthalmologist do assessments. We do not see a lot of toxicity. Of course, there are other treatment options you could select, but belantamab would be a good option for this patient at this stage of their treatment. So what do you think if the patient had cataracts? Would this affect you giving belantamab [to] this patient?

YEAGER: If they had cataract surgery, they have an implantable lens. It is not biologic, and the keratopathy [associated with belantamab] is not lenticular in nature, is it? So I would [suggest] ophthalmologic evaluation and close ophthalmologic follow-up. But I stand to be corrected on this because I do not have as much experience with belantamab. I do not think that cataracts would be an absolute contraindication.

MANASANCH: Yes. that is correct. Cataracts are very common in [patients with] multiple myeloma because they receive dexamethasone. Cataracts are like sores for myeloma, and patients get a lot of them. This is a real issue, but it is very easy to have the cataracts removed and new lenses implanted. The patient could have cataract surgery before and then proceed to belantamab without any problems.

GOROUHI: If you have a patient who had 4 different classes of medication, is belantamab the only option left? Because it is recommended for patients with more than 3 prior treatments [based on the NCCN (National Comprehensive Cancer Network) guidelines].¹

MANASANCH: Well, one could use any of the recommended medicines the patient has not received. So everything not used in the prior lines could still be used. Belantamab is usually for late relapses [and] is considered after 3 prior therapies, but you could give it after a second relapse. But you would not be able to give idecabtagene vicleucel [Abecma] or ciltacabtagene autoleucel [Carvykti] for a second relapse because their approval is for patients with 4 prior lines of therapy. So the patient would have had an anti-CD38 antibody, a PI [proteasome inhibitor], and an IMiD.

YEAGER: I think it is important that these are guidelines. We like consistency, but we appreciate that there is a uniqueness to patients in these guidelines for late relapse therapies. We need not be limited to what is listed in the guidelines. We must be sensitive to that.

YEAGER: Because my practice is largely limited to transplant, I have sent patients back to their primary oncologist [whether] they were referred [to me] for transplant or had a transplant with progression of myeloma, and we might make recommendations for therapies including belantamab. That is why I do not have direct experience.

MCKENNEY: I have not had a patient who has been an appropriate candidate [for belantamab] because they are still on IMiDs and PIs. But we do have ophthalmologists, and we would not be opposed to using it; we just have not had the right patient.

GOROUHI: When my patient gets to the significant level of refractory or relapsed disease, I usually get a second opinion from The University of Texas MD Anderson Cancer Center or a similar organization. For my last patient, [the center] suggested the next line of treatment be the clinical trial option. There is 1 trial that is not FDA approved, so we have not started it. So far I have not had a patient for whom belantamab was suggested, and I have not had that opportunity to start, but I am not against it. If there is a case that is indicated, I am for it.

REDDY: As I commented earlier, we do not have an ophthalmologist. I have found one who is interested to see patients [who receive belantamab]. Maybe with the next patient who meets these criteria I will probably use it, but…it is one thing to have cytopenia or cardiac adverse [events] [AEs], but ophthalmologic ones scare me. If I had other options, I would prefer not to go there.

CHU: I have the same impression. Because of the eye-related AE, I had to coordinate with the ophthalmologist, and sometimes it gets the treatment delayed. I do not think it is more toxic than the other ones, but it will put a damper on my enthusiasm.

MANASANCH: Have you used selinexor-based treatment for relapsed/refractory multiple myeloma? If so, can you share how that went?

GOROUHI: I currently have a patient on this medication. The consultant who gave us the second opinion asked us [whether] the patient was heavily treated before and was weak. [Based on this] he asked me to start from the second dose reduction. He said that if you can go up on that, then you can try. I started the medication, and the patient was tolerating it, so I went 1 dose up and then another dose up. Then the patient was feeling bad, so we eventually had to go down to the same dose originally requested. He is tolerating that dose and we [have] had a great response so far.

Interestingly, the physician who sent the patient to me was under the impression it was not going to work. He was [preparing to enroll him in] a clinical trial after that, but when I told him how good the response was, he crossed that out.

MANASANCH: Good. I am happy for the patient.

REDDY: I have used [selinexor] only once. It was a couple [of] years ago, but this patient had already received all other drugs. We [used selinexor] for 1 or 2 months, but he [died]. It was the last attempt.

YEAGER: It is about the AEs and their frequency, and that includes the treating physician’s and patient’s willingness to tolerate them. I realize there are other AEs that occur with sufficient frequency in patients receiving selinexor. [With] keratopathy being the main concern of belantamab, knowing one can have these dose delays without a pronounced loss of effect indicates to me that there is good tolerability. I realize the comparison of belantamab vs selinexor in terms of efficacy, responses, duration of response, OS [overall survival], and PFS [progression-free survival] is a large discussion [From the Data].²

MANGAT: Belantamab looks effective, but we must deal with the obvious visual toxicities compared with selinexor, which is presumably more convenient orally. But I am sure it comes with its own AEs like neurotoxicity and hyponatremia. So you must weigh the AEs and discuss with patients to see what they are willing to tolerate, and we can manage [AEs] along the way.

REDDY: Based on the mechanism [of action], this is a different drug compared with the 3 other classes of drugs, which is exciting. Only 3% of patients had toxicities that caused discontinuation.2 But the [high rate of] grade 3 toxicity of keratopathy…is my concern.

MANASANCH: That is a valid concern. Does anyone else have this concern as well, knowing the keratopathy [is not necessarily] symptomatic and [can be] resolved? In my experience, because I have given a lot of belantamab to 30 patients or so, it is well tolerated. We usually do not see high-grade keratopathy suddenly; it is gradual. So if you reduce the dose and follow the patients, you do not need steroids. It is very well tolerated. They can get visual changes, but it is reversible. Most patients do not have visual changes, so you must monitor them and be careful, but that has been my experience.

MANGAT: What is the longest time your patients have had to delay treatment?

MANASANCH: I would say 4 months or so. I have a patient who [participated in] the DREAMM 2 study [NCT03525678], and he has been on belantamab mafodotin for more than 3 years, [considering] this study is from 2019 or 2018. I delayed treatment for 3 or 4 months. He [left] the study because they closed it, but he is still on belantamab. It has been a long time, [approximately] 3 to 4 years. I have a couple of patients who have been on it for a long time. They are doing well.

SUD: How long do you [normally] need to delay before you resume [treatment] after the [patient has] keratopathy?

MANASANCH: You can delay it 3 to 4 weeks. I have a patient who has been on it for 1 year, and I told them to come back in 6 weeks. We will check their eyes because I can tell based on how long it takes to resolve the keratopathy. But I have had patients who delayed treatment for 3 or 4 months, [and] they still have deep remissions. Many times, they can get good remissions. [As] with other chemotherapies, if the cell counts do not recover, we tend to discontinue treatment.

SUD: Do you ever decide to stop belantamab mafodotin if the patient does not have a resolution of the keratopathy from grade 2 to grade 1?

MANASANCH: Usually the patient comes in and they have grade 2 keratopathy, which is usually easy to resolve. Because you do not know when you check; it could be on the way to grade 3 or it could be resolving. But for most patients, [it takes] up to a couple of months to resolve. When they come back and [it is] not resolved, you have them come back the next month. After 2 or 3 months, it resolves, but myeloma could progress in the meantime, and you try to keep [withholding treatment]. If they are in remission, the myeloma is not worsening, and these patients feel great. For most who have visual changes, the visual changes seem to go away a little faster than keratopathy. But you can have them keep coming back until [the keratopathy resolves], and if you [need] a lot of [interruptions], then you reduce the dose or you extend the frequency of the infusions.

MANASANCH: This drug [is in] a lot of trials right now, even a frontline study. What are your thoughts on using this medication in combination with [an agent like] pomalidomide? A trial with good data has been reported with pomalidomide.3 Do any of you have thoughts on whether you would use this in combination with other agents [for] myeloma?

YEAGER: I would like to see some preliminary data with combination therapies. We have discussed extensively how keratopathy might be a reason for delay or discontinuation of the agent. So I would like to know [whether] there could be additive toxicities. I would be interested in trials evaluating its use with other agents, but I would not be the one to empirically try combinations.

MCKENNEY: It seems belantamab has a relatively high AE rate, and when you add more drugs, you are going to increase the toxicity. With multiple myeloma, the push has been to give multiple agents as opposed to other solid tumors where you usually give a single agent, so I would want to see what the data show when used in combination. I would think the toxicity would be much worse.

MANASANCH: That is valid. The good thing with this agent is [no other agent it could be combined with is associated with] the keratopathy.

MCKENNEY: Right, no overlapping [toxicity].

MANASANCH: Yes, so what could get worse are thrombocytopenia and AEs like that, but because the toxicity profile is so different from other drugs [used for] myeloma, in combination it seems to be fine. We have used it with pomalidomide, and there are other combinations out there [in trials]. We will have to see what everything looks like, but I think it is a concern when you add other medicines in combinations.

_REFERENCES:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Multiple myeloma, version 5.2022. Accessed July 22, 2022. https://bit.ly/3JZWq3p}

_{2. 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. Lancet Oncol. 2020;21(2):207-221. doi:10.1016/S1470-2045(19)30788-0}

_{3. Trudel S, McCurdy A, Sutherland HJ, et al. Part 1 results of a dose-finding study of belantamab mafodotin in combination with pomalidomide and dexamethasone for the treatment of relapsed/refractory multiple myeloma (RRMM). Blood. 2021;138(suppl 1):1653. doi:10.1182/blood-2021-147101}