Roundtable Discussion: Berdeja and Participants Cover When and How to Treat Patients With Late- Stage Multiple Myeloma

Jesus G. Berdeja, MD

Director, Myeloma Research Sarah Cannon Research Institute/

Tennessee Oncology Nashville, TN

GHAZAL: This patient [has] already had 2 recurrences and now he has del(17p), which carries a worse prognosis and more resistance to other agents. So I think some form of B-cell maturation antigen [BCMA]-targeted therapy would be helpful instead of therapies like selinexor [Xpovio]1 or belantamab mafodotin-blmf [Blenrep],2 which are indicated in this space. But I think the benefit of these 2 agents,^3-6 compared with what we are seeing with CAR [chimeric antigen receptor] T-cell therapy,^7,8 is rather limited. So if you have access to CAR T-cell therapy, [which is] now approved,⁹ I would say the sooner the better, rather than wait for more lines of therapy. Because from now on, you know that the patient’s responses to other agents are going to be limited.

CARR: Yes, I agree. The patient has had 3 prior lines of therapy, so CAR T-cell therapy is a very attractive option here.

BERDEJA: Does the location of the patient help you determine [whether] he would be eligible or not? Rural vs in the city, for example?

LIN: The patient is still young and has reasonable performance status. If the patient is motivated, I think certain obstacles can be overcome. A lot is up to the patient. If the patient understands that this is the only chance for putting him in durable remission, I think [he] would agree to go for CAR T-cell therapy.

GHANEM: I don’t think the location or the distance is a big factor, as Dr Lin said, if the patient is a candidate and especially [if he is] young. I live 2 hours from Nashville, and when I was in Michigan, I used to be 5 hours from the Mayo Clinic. In the right situation, most patients will travel if it’s indicated. If I have a young patient in their 50s or even 60s, [who] has good functionary status, I recommend the treatment and they know that’s probably their best shot at the disease. I believe most patients will travel for it. Distance is probably a factor in some cases, but in a younger population it’s not the main thing. At this late stage of the disease, it’s usually comorbidities and patient functionary status [that matter].

LIN: I inherited a patient [in Knoxville], a woman who is only 55 years old, and she was [exhibiting] progressive elevation of M protein. Her previous oncologist put her on lenalidomide alone because she refused any other infusion. [Even] with the persistent progression, she kept declining to see physicians at Sarah Cannon in Nashville, even though they do come to Knoxville regularly. She wouldn’t do anything, so I [said], “Maybe we should start. You’re young. It’s progressing.” But she didn’t like what I told her, and I wasn’t forcing her; I was just trying to explain to her. So she went to see 1 of my younger, junior partners, who just did what the patient liked; [she], who had progressed on lenalidomide, was put on pomalidomide, another pill.

So I think it’s not just location, it has a lot to do with the person. [This patient] just didn’t want the infusion, she just didn’t want to come here. Some people are just like that. It’s not uncommon in east Tennessee; I’m learning the culture here. I practiced 15 years in Ohio and Illinois combined, mainly in Ohio.

BERDEJA: You’re hitting on something that’s very imporant. You’re right, it’s not just about being rural or urban, it’s also about the wishes of the patient. Some people have very particular needs or goals.

I’m curious: would you change your mind if this patient were frail?

LIN: Yes. A frail patient is not able to go through CAR T-cell therapy.

BERDEJA: So what would you choose if you couldn’t choose CAR T-cell therapy?

LIN: Another agent, just for palliation.

GHAZAL: There are degrees of frailty. Frailty [needs to be] defined better because I know the criteria to be accepted for CAR T-cell therapy are certainly easier to meet than, for example, [those that must be met to receive] stem cell transplantation. This situation is not [suitable for the patient to have] a transplant.

From the data we have seen, even the adverse event [AE] potential appears to be better tolerated [in patients with multiple myeloma] than anti-CD19–directed CAR T for patients with lymphoma.¹⁰ It’s a judgement call. You have to evaluate your patient; [you have to ask] how frail is frail. Because if you look at the other options, like selinexor or belantamab mafodotin, they all have their own AEs. They are certainly not easier to use. And the beauty of CAR T-cell therapy is that it is a one-time procedure [vs] the bispecifics and antibody-drug conjugates that we have on the market. So you have to evaluate on a case-by-case [basis].

BERDEJA: Would you say the same if this patient had moderate renal insufficiency but was not frail?

GHAZAL: Yes, probably. Again, with the AE potential being on the low side, that doesn’t bother me. [Moderate renal insufficiency] used to be a contraindication for transplantation in patients with myeloma, but I think that as the care for these patients has improved, people with renal insufficiency are being accepted even [for] transplant.

BERDEJA: [Let’s consider] the National Comprehensive Care Network [NCCN] guidelines for patients who’ve had at least 3 prior lines of therapy, particularly [the guidelines for those who have received] 4 prior therapies: remember, prior therapies and prior lines of therapy are not always the same. For patients who have received at least 4 prior therapies, belantamab mafodotin is an NCCN [recommendation], as is the CAR T-cell therapy idecabtagene vicleucel [Abecma], also known as ide-cel. Selinexor plus dexamethasone is an option as well.¹¹

CARR: The thing that comes to my mind is the ocular toxicity.2 That’s what I’ve heard about in regard to this agent, [but] I haven’t used it yet.

BERDEJA: Do you think it works?
GHAZAL: Yes, it works. It’s on the market right now; it’s FDA labeled.¹²

BERDEJA: If you haven’t used it, how do you know?

GHAZAL: Well, we know the data. When you look at the data, the progression-free survival is modest.⁶ The problem is [that it’s] short acting. Don’t expect to have over a year of response; the median [duration of response] is limited. It’s not the easiest drug [to use]. You need to check with the ophthalmologist before almost every treatment.²

BERDEJA: In a patient who’s triple refractory—that is, refractory to a proteasome inhibitor, to an immunomodulatory drug, and to an anti-CD38 antibody—what would be a good response rate for a new single-agent myeloma therapy that would excite you [and make] you think that the therapy is an active agent in myeloma?

Would you expect an overall response rate of 80%? 50%? 20%? Obviously, we’re all wowed by the data supporting CAR T-cell therapy.^7,8

CARR: In the patient population that you’re describing, I would say anything above 35% is probably a good objective response rate; then you add the stable disease [rate] or the clinical benefits on top of that. That’s a heavily pretreated population that you’re asking about.

GHAZAL: I’d say 50% or higher would certainly be exciting.

BERDEJA: Many treatments are tested and only a few go [beyond phase 1]. Traditionally, for the relapsed/refractory myeloma, we [have considered] an overall response rate of 20% [to be indicative of] an active agent. That just shows things have changed, because that’s how pomalidomide, daratumumab, selinexor, and other therapies got approved.^13-15

GHAZAL: In the face of other agents coming up, the only main advantage is that you can use belantamab mafodotin at your own office. I think the exciting part is the [potential for] combination therapy. If the single agent is good, why not combine it? [This is similar to] what happened with pomalidomide⁴ and even lenalidomide.^16-18 I think belantamab mafodotin, [likewise], has the potential to be combined with other agents and offer better efficacy in combination.

BERDEJA: That’s an excellent point.

the therapy is an active agent in myeloma?

Would you expect an overall response rate of 80%? 50%? 20%? Obviously, we’re all wowed by the data supporting CAR T-cell therapy.^7,8

CARR: In the patient population that you’re describing, I would say anything above 35% is probably a good objective response rate; then you add the stable disease [rate] or the clinical benefits on top of that. That’s a heavily pretreated population that you’re asking about.

GHAZAL: I’d say 50% or higher would certainly be exciting.

BERDEJA: Many treatments are tested and only a few go [beyond phase 1]. Traditionally, for the relapsed/refractory myeloma, we [have considered] an overall response rate of 20% [to be indicative of] an active agent. That just shows things have changed, because that’s how pomalidomide, daratumumab, selinexor, and other therapies got approved.^13-15

GHAZAL: In the face of other agents coming up, the only main advantage is that you can use belantamab mafodotin at your own office. I think the exciting part is the [potential for] combination therapy. If the single agent is good, why not combine it? [This is similar to] what happened with pomalidomide⁴ and even lenalidomide.^16-18 I think belantamab mafo- dotin, [likewise], has the potential to be combined with other agents and offer better efficacy in combination.

BERDEJA: That’s an excellent point.

ZAYDAN: [I am familiar with keratopathy]. My best understanding is that we have to check for corneal lacerations prior to therapy and before each treatment, am I correct?

BERDEJA: Yes, you have to have an ophthalmologist do an exam before you treat. The good thing is that you don’t have to do [the exam].

ZAYDAN: Basically, what we are doing is looking at this corneal laceration [and] not looking at [anything else]?

BERDEJA: That’s one [among] several things. You’re looking for any kind of eye toxicity, usually [involving] the cornea. According to the Risk Evaluation and Mitigation Strategy [REMS] program,¹⁹ you have to do a baseline exam before you [begin] treatment and then [repeat the exam] before each treatment.

Giving belantamab does seem a little bit daunting. However, the first time I sent a patient to an optometrist, the patient came back with a [stack] of business cards from the optometrist and [a message that I should] feel free to send all of my patients to their practice. So, [though] we think of it as an encumbrance for [the optometrist], I think your local eye doctors are more than happy to see these patients.

GHAZAL: Yes. If [there is limited] access to an ophthalmologist, that could be a problem, because the patient has to be examined frequently.

BERDEJA: [Are you bothered by] the fact that you have to send the patient to the ophthalmologist or that this is a scary toxicity? Or both?

GHAZAL: I think both. When you tell patients that they may have some vision trouble [or] corneal problems, it’s not easy for them to accept. But also, if there is no ophthalmologist around you, and the patient would have to travel to another town or something, then that puts the patient in more jeopardy.

ZAYDAN: There’s another way of looking at it. If they are on Medicare, ophthalmology [services] are covered, but if they are private-insurance patients, [the services] might not be covered, especially if they need to be seen every 3 weeks.

BERDEJA: This is part of the REMS program,¹⁹ so I think, in general, it should be covered. The FDA is mandating that this be done.

ZAYDAN: If a patient has blurred vision, keratopathy, or lacerations, [are these] reversible if we stop the drug?

BERDEJA: The short answer is yes.⁶

GHAZAL: For the most part, yes, but in some [instances these] could be irreversible.

HANEM: My concern is that the percentage of patients that have a grade 3 AE is around [80%, and 30%] of those patients will have ocular toxicity; this is according to the data from the DREAMM 2 study [NCT03525678].6 That’s a high percentage. And then [one needs to consider] the logistics: when you send the patient to ophthalmology, do you need a clearance letter every time they are seen? A lot of patients are not [adherent to treatment], and when the patient comes to get the treatment, do you have to call ophthalmology to be sure the patient was really seen? The logistics also make it more difficult to choose [this] drug when you’re thinking about your options. Because it’s not [enough] to establish [the situation] with ophthalmology and get clearance, you have to have it every 3 weeks. And if the patient saw the ophthalmologist but you don’t have a letter [of clearance], you have to call the office to be sure [the exam] was done appropriately. All of this makes me anxious to use [this drug].

BERDEJA: That’s fair. There is a learning curve. [The process is similar to implementing] the REMS program for the immu- nomodulatory drugs lenalidomide^20,21 and pomalidomide^;22,13 you have to have staff that help you navigate [the process, including administering] patient questionnaires, pregnancy tests, and so on. We assigned a person who deals with all that. I agree, if you haven’t done it, it can be a little daunting.

But when the patient goes to see the ophthalmologist, the [ophthalmologist] has a form that they fill out for you. The patient brings it back, and you have to sign off saying that you saw it and that the patient can proceed with the next dose. This [form] has to be submitted before the patient can get the next dose. I think as you do it more, it becomes easier.

GHAZAL: The pro is the efficacy. We have an agent that’s effective. Again, we’re talking about late lines of therapies, so we don’t expect very high responses. But as a single agent, [belantamab mafodotin at] 31% is certainly higher than what we saw with single-agent pomalidomide or daratumumab. It is an [intravenous drug], but it is administered every 3 weeks² so it is not a huge [inconvenience] in terms of frequency.

You cannot help but think of the ocular toxicity because it’s something new for us. If a complication occurs, you have to be prepared.

The good news is that we have [this drug] available if we need to use it. [And other than the ocular toxicity], all other AEs are much lower. If you look at grade 3 and grade 4 AEs, including gastrointestinal and hematologic AEs, they’re minimal. They are certainly very manageable and acceptable. Compared with selinexor, if you don’t develop higher-grade keratopathy, you will be doing very well in terms of tolerability.^1,2,6

It is important at this stage of disease to maintain good quality of life; that’s one thing patients ask for when they are in their third or fourth line. They want to make sure [the treatment] is not going to make them too ill. They realize they are getting more toward the end of the line, so to speak, if other options have been exhausted.

BERDEJA: One of the things I always [neglect to] mention is that this is a steroid-free treatment, which is rare for myeloma. In your patients, [in whom] steroids wreak havoc with their diabetes, edema, and other things, this is another thing to consider.

LIN: I haven’t had experience using belantamab mafodotin, but [it seems like this regimen requires] coordination among 3 parts: the patient, the ophthalmologist, and us. I don’t think it’s for everyone—I’m talking about my patient population here—but if a patient is motivated and has good family support, the AEs are definitely manageable.

HANNA: The data look good, especially in heavily pretreated patients.⁶ I’ve never used [this drug], but when I have a patient who has no other options, I think we’ll use it. We have to be very selective and careful with the ocular toxicity. But the data speak [for themselves].

BERDEJA: I agree; we’re all concerned about the ocular toxicity, and we don’t know much about it. Even though the comment was made that AEs are [not always] reversible, for most patients, once you stop the drug, all the changes in the eye are reversed. By the end of the study, even the people whose AEs had not [been completely] reversed were improving; they just hadn’t been completely reversed by that time.⁶

GHAZAL: This is a BCMA-directed drug.² We don’t see this particular toxicity in other BCMA-directed drugs. Mechanistically, is this [toxicity caused by] the mafodotin? Do we know what is happening?

BERDEJA: Yes, this is definitely from the mafodotin component, the microtubule-disrupting monomethyl auristatin F [MMAF].² Among antibody-drug conjugates, the most commonly attached toxins are MMAE and MMAF. The MMAE toxin is notorious for causing peripheral neuropathy; as you can imagine, that wasn’t good [for patients with myeloma]. So MMAF was used, but unfortunately, [ophthalmologic toxicity] is not unusual with this agent. So yes, most of the toxicity is because of the toxin.

_REFERENCES

_{1. Xpovio. Prescribing information. KaryopharmTherapeutics Inc; 2022. Accessed April 7, 2022. https://bit.ly/3v0pHoE}

_{2. Blenrep. Prescribing information. GlaxoSmithKline; 2022. Accessed April 7, 2022. https://bit.ly/3DYljur}

_{3. Chari A, Vogl DT, Gavriatopoulou M, et al. Oral selinexor-dexamethasone for triple-class refractory multiple myeloma. N Engl J Med. 2019;381(8):727-738. doi:10.1056/NEJMoa1903455}

_{4. Chen CI, Bahlis N, Gasparetto C, et al. Selinexor, pomalidomide, and dexamethasone (SPd) in patients with relapsed or refractory multiple myeloma. Blood.2019;134(suppl 1):141. doi:10.1182/blood-2019-122907}

_{5. Grosicki S, Simonova M, Spicka I, et al. Once-per-week selinexor, bortezomib, and dexamethasone versus twice-per-week bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a randomised, open-label, phase 3 trial. Lancet. 2020;396(10262):1563-1573. doi:10.1016/S0140-6736(20)32292-3}

_{6. Lonial S, Lee HC, Badros A, et al. Longer term outcomes with single-agent belantamab mafodotin in patients with relapsed or refractory multiple myeloma: 13-month follow-up from the pivotal DREAMM2 study. Cancer. 2021;127(22):4198-4212. doi:10.1002/cncr.33809}

_{7. Munshi NC, Anderson LD Jr, Shah N, et al. Idecabtagene vicleucel in relapsed and refractory multiple myeloma.N Engl J Med. 2021;384(8):705-716. doi:10.1056/NEJMoa2024850}

_{8. Anderson LD Jr, Munshi NC, Shah N, et al; KarMMa Study Investigators. Idecabtagene vicleucel (ide-cel, bb2121), a BCMA-directed CAR T cell therapy, in relapsed and refractory multiple myeloma: updated KarMMa results. J Clin Oncol. 2021;39(suppl 15):8016. doi:10.1200/JCO.2021.39.15_suppl.8016}

_{9. FDA approves idecabtagene vicleucel for multiple myeloma. FDA. Updated March 29, 2021. Accessed April 7, 2022. https://bit.ly/3DPtSHX}

_{10. Zhou X, Rasche L, Kortüm KM, Danhof S, Hudecek M, Einsele H. Toxicities of chimeric antigen receptor Tcell therapy in multiple myeloma: an overview of experience from clinical trials, pathophysiology, and management strategies.Front Immunol. 2020;11:620312. doi:10.3389/fimmu.2020.620312}

_{11. NCCN. Clinical Practice Guidelines in Oncology. Multiple myeloma, version 5.2022. Accessed April 7, 2022. https://bit.ly/3LNPp6v}

_{12. FDA granted accelerated approval to belantamab mafodotin-blmf for multiple myeloma. FDA. Updated August 6, 2020. Accessed April 7, 2022. https://bit.ly/35VK3ag}

_{13. Pomalyst. Prescribing information. CelgeneCorporation; 2021. Accessed April 7, 2022. https://bit.ly/3DSjYoV}

_{14. FDA approves daratumumab and hyaluronidase-fihj for multiple myeloma. FDA. May 1, 2020. Accessed April 7, 2022.https://bit.ly/3O6ldpo}

_{15. FDA approves selinexor for refractory or relapsed multiple myeloma. FDA. December 18, 2020. Accessed April 7, 2022. https://bit.ly/3ujzya5}

_{16. Gay F, Musto P, Rota-Scalabrini D, et al. Carfilzomib with cyclophosphamide and dexamethasone or lenalidomide and dexamethasone plus autologous transplantation or carfilzomib plus lenalidomide and dexamethasone, followed by maintenance with carfilzomib plus lenalidomide or lenalidomide alone for patients with newly diagnosed multiple myeloma (FORTE): a randomised, open-label, phase 2 trial. Lancet Oncol. 2021;22(12):1705-1720. doi:10.1016/S1470-2045(21)00535-0}

_{17. Bahlis NJ, Dimopoulos MA, White DJ, et al. Daratumumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: extended follow-up of POLLUX, a randomized, open-label, phase 3 study. Leukemia. 2020;34(7):1875-1884. doi:10.1038/s41375-020-0711-6}

_{18. Jakubowiak A, Usmani SZ, Krishnan A, et al. Daratumumab plus carfilzomib, lenalidomide, and dexamethasone in patients with newly diagnosed multiple myeloma. Clin Lymphoma Myeloma Leuk. 2021;21(10):701-710. doi:10.1016/j.clml.2021.05.017}

_{19.Risk Evaluation and Mitigation Strategy (REMS) document: Blenrep (belantamab mafodotin) REMS program. FDA. Accessed April 7, 2022. https://bit.ly/3jyt5lz}

_{20. Revlimid. Prescribing information. CelgeneCorporation; 2021. Accessed April 7, 2022. https://bit.ly/3DRJXN921.Risk Evaluation and Mitigation Strategy (REMS) document: Lenalidomide REMS program. FDA. Accessed April 7, 2022. https://bit.ly/3ujzBmh}

_{21. Risk Evaluation and Mitigation Strategy (REMS) document: Pomalyst (pomalidomide) REMS program. FDA. Accessed April 7, 2022. https://bit.ly/3jhDO3w}