Roundtable Discussion: Vogl Discusses Targeted Treatment Choices in Relapsed/Refractory Multiple Myeloma

Dan Vogl, MD, MSCE (Moderator)

Director, Abramson Cancer Center Clinical Research Unit (CRU)

Associate Professor of Medicine

Hospital of the University of Pennsylvania

Philadelphia, PA

VOGL: What are the key factors that influence your decision-making for a patient like this? There’s a long list of possibilities there, so tell me what your thoughts might be if the patient had mild or moderate renal impairment and if that would change your decision. Or if they had a history of cataracts or other ocular comorbidity, and…presented with an infection this time, how do you all think about these choices?

MEWAWALLA: I think their prior therapy is a big concern, and the patient was already refractory to lenalidomide, bortezomib, and daratumumab, so adding carfilzomib [Kyprolis] and pomalidomide [Pomalyst] just made sense, depending on what they [had] already [received] and what they’re refractory to.

VOGL: Are there any other regimens that you all would consider giving?

RIZVI: One that was not present was elotuzumab [Empliciti]. Sometimes if your disease is not extremely progressive then elotuzumab [can be] effective, but generally not after daratumumab.

VOGL: I think that an elotuzumab combination, in this case in a lenalidomide-refractory patient, probably with pomalidomide would be a reasonable option to choose. I’d probably be a little less likely to do it in a patient with a del(17p) because I don’t think of elotuzumab as one of our more powerful drugs, but on an occasional basis for an individual patient, I’ve sometimes been impressed [with the results].

If this were a patient who, for instance, had a history of heart failure and [to whom we] were worried about giving carfilzomib, I could imagine doing an elotuzumab-pomalidomide combination. I think the switch from daratumumab to elotuzumab still allows for some activity because they have different targets. Any other ideas?

SOTIRESCU: Certainly, the prior therapies and previous adverse events [AEs] matter, [and] preference for the patient matters. I’m still struggling with the young patients. In fact, I recently saw a 24-year-old patient and I don’t think she’s a good candidate for transplant because of non-adherence and how she would go to the center when she makes time but forgets to take the pills and has poor support at home. So certainly you put all of this into consideration.

I have another patient who has neuropathy and…she is doing so well on bortezomib for so many years, but back in Puerto Rico she was receiving bortezomib intravenously and she came with a severe neuropathy that I have to deal with. I’m thinking now to switch her to carfilzomib. I like the option with elotuzumab because of its AE profile but I would [have to consider] the 20- to 30-year-old patients…because I don’t think it has a good response.

I had a couple of patients with a very long response. I didn’t try to match young patients unless I [had] run out of options, and it was very late in therapy. Certainly now I’m gaining a lot of experience with selinexor [Xpovio], which is a fantastic drug but also is used later in the treatment. I had a flop with the newest melphalan, and I dosed it as low as possible; I used it in a very late stage.…I wish to [gain] some experience with belantamab [Blenrep], but for this specific patient, I think carfilzomib would be my choice for the depth of the response.

If you…added daratumumab to the first line and the response [was] deeper before bone marrow transplant, do you think this relapse would occur later? This is the biggest question when I’m designing first-line treatment. Certainly, I’m using daratumumab for high-risk patients; there are not so many, but the response is so great and deep, so these are things that come into my mind.

VOGL: I agree with you, and I do think that we’re struggling right now to decide whether and when to include daratumumab in first-line therapy for myeloma. There are some trials that clearly show better response rates, and even progression-free survival in certain contexts, but no trial yet that shows an improved overall survival advantage, especially when we consider that we could just as easily use it in second-line therapy.

There are certainly centers in the country that are using upfront daratumumab for basically every patient, either with VRd or carfilzomib Rd or just Rd for the older patients. Our style here at the University of Pennsylvania, right now, is still to [have] most patients start with VRd and add in daratumumab only for insufficient response, acknowledging that there are no big trials showing long-term benefit from the early daratumumab. However, we do use daratumumab for all our patients who are sick at presentation, especially [with] acute renal failure, very severe bone disease, or hypercalcemia, and patients who, like you said, have very adverse cytogenetic profiles, especially [those with] del(17p).

SOTIRESCU: We had the same experience when carfilzomib showed deep response and certainly didn’t make the cut to take over VRd, and now we have [it] again, so it’s déjà vu.

VOGL: One other combination that I’ll throw out here, just because I like thinking about treating [patients with] relapsed myeloma, is that cyclophosphamide can be a well-tolerated, effective drug. It combines nicely with carfilzomib. So for a patient like this, [receiving] a cyclophosphamide-carfilzomib combination with weekly carfilzomib dosing…you don’t have to worry about [adherence] with what the patient’s taking at home.

RIZVI: You were all having a conversation about using daratumumab up front. I get a little nervous using all the good drugs up front, as I would like to keep something in my back pocket for relapses.

SOTIRESCU: Here I would like to…react to the points and counterpoints because I’m struggling every day. I’ve [been] doing this for 20 years, and at least 2 times…each decade the specialists in academics in multiple myeloma try to [tell] us, where we used to have only 8 or 9 drugs, [to use] as many drugs as you can upfront, and the response is deeper and longer. You go [to the] second line and it’s shorter and not so deep, and then you go to the third line.

I saw another slide with the newest approved drug not long ago where it shows several drugs, or 4 drugs, or 5 drugs at the beginning, and after that you go on fewer lines [of therapy]. I would like to have a national interest trial to see sequential treatment followed by daratumumab with upfront quadruplet [therapy]. So build on the MAIA trial [NCT02252172], it’s transplant noneligible, and follow up with doctor’s choice. This would be a fantastic way to prove [efficacy] prospectively.

Another thing we are struggling with in the community is the cost containment. Our practice participated in the OCM [Oncology Care Model] and we found out that myeloma is one of the highest costs [to] society. But certainly, patient interest is foremost, so we have to sometimes do 3 or 4 drugs up front, regardless of the cost. However, it’s multidimensional, and don’t forget we use a lot of oral drugs.

VOGL: I would like to see a randomized trial of an upfront quadruplet therapy vs a triplet therapy and see what the long-term benefits are. I think it’s going to be a while before we have those results, so we’re going to be forced to make it up as we go along.

I don’t think I’ve ever been truly convinced that we should be saving drugs for later so much [as] I think we should have a reason to give a drug earlier. To add more complexity, potentially more risk of infection, [and] more cost in the initial therapy in earlier lines of therapy, I like to have a reason to do it. Right now, [I’m not sure] whether we truly have a reason to add in daratumumab that’s proved to be fully beneficial to the patient. I think we come at it from slightly different directions but come to the same conclusion that we’re mostly sticking with a triplet initial therapy using lenalidomide and bortezomib.

SOTIRESCU: Another aspect of long-term survival is exposure to as many agents and mechanisms of action as possible. I’m frustrated I couldn’t put patients on belantamab because I don’t know where to put it.

VOGL: What have you all heard about [belantamab mafodotin]? What are your perceptions of [this medication]?

VARADI: It’s a very promising drug. It has a new mechanism of action but a disturbing AE profile that you have to pay attention to. [But addressing that, I would be eager to use it].

ROTKOWITZ: I think the key data from the DREAMM-2 trial

[is the concern of the] that 30% overall response rate.¹ My one question is how do I sequence these BCMA [B-cell maturation antigen] therapies. I kind of look at it like lymphoma where it’s…tafasitamab [Monjuvi] vs CAR T-cell therapy. Do I want to exhaust the BCMA mechanism? I’m probably more inclined to refer a patient for an idecabtagene vicleucel [Abecma] treatment before I would consider belantamab, and I think my number one rule, especially in the community, is don’t volunteer for anything, don’t get involved in anything that’s going to make your life more difficult. However, I think we’re a little bit reluctant due to a lack of ability to…get the patients in rapidly, and maybe we should…be referring these patients for CAR T-cell therapy, which is…going to offer more durability, before we consider belantamab.

VOGL: I was a subinvestigator at Penn Medicine while my colleague Adam Cohen, [MD], was running part of the phase 1 [trial] and then the pivotal phase 2 trial of belantamab, DREAMM-1 and DREAMM-2 [NCT02064387, NCT03525678], respectively.

In a space of 2 months, I think I put 9 of my own patients in the DREAMM-2 trial, so I’ve had a lot of experience treating patients with belantamab in clinical trials and I’ve become a big fan of this agent. There are a lot of questions about how to sequence these drugs, but I will say that although we have some increasing evidence that loss of BCMA expression is part of progression on CAR T-cell therapies, and maybe bispecific T-cell–engaging therapies, it doesn’t seem to be a consistent feature of progression on belantamab. We certainly have had experience treating patients first with belantamab and then with CAR T cells and seeing CAR T-cell responses when belantamab had previously stopped working; either [it has] never been effective or [patients] had a response and then progression. I’m not sure that we should be holding off on using belantamab to get patients to CAR T-cell therapy first, especially given that right now, getting patients to CAR T-cell therapy—and we can…talk about the manufacturing difficulties that Bristol Myers Squibb has been having—is tough. So I have become a big fan of using belantamab.

SOTIRESCU: Selinexor is a very interesting drug, and it’s very interesting how I started to use it. I started to read about it because it came with the same approval in large cell lymphoma and I was chatting with colleagues about the patients [on this treatment]. They shared [information about the results of patients with] very refractory large cell lymphoma and said it doesn’t look as good as [it is] in myeloma.

We had a very active dispensary here, and we have a coordinator, and…I said, you know what? [For] this lovely 84-year-old mother of a doctor who could be my mom, why don’t I start her on level minus 1? And…we tried to go to level minus 1, but she said she felt tired.

[The patient has been] on this drug for several months and she has been very well and has a good quality of life. She’s carrying on without a problem. I offered it to another patient, but there is a problem with the insurance. So I’m just getting traction. …I tried [it in] another patient with large cell lymphoma [but] it doesn’t work so well. But that’s my experience.

VOGL: I have both a lot of experience with selinexor and… an extensive relationship with Karyopharm. I’ve done a lot of consulting work for them, and I was the lead author on the initial phase trial of selinexor and then second author on the pivotal phase 2 trial that led to its initial approval.² [I was also] part of the response assessment committee for their randomized BOSTON trial [NCT03110562] of selinexor, bortezomib, and dexamethasone vs bortezomib and dexamethasone. Although I am a big fan of selinexor, and use it quite frequently, I’m also very aware of the limitations, although an oral agent does have a challenging AE profile. I think [when] starting it, even though it’s oral and the patient takes it at home, you have to be prepared to have the patient come in each week for the first month, check their blood count, and see whether they’re able to keep up with hydration because the gastrointestinal AEs can be pretty intense. Be prepared to hold doses and lower doses or start at a lower dose and try to increase the dose as the patient tolerates it.

I’m also using selinexor primarily in combination treatments and there are several excellent combinations. Bortezomib, carfilzomib, daratumumab, and pomalidomide have all been looked at extensively, so there are good dosing recommendations for all of those.

When I have a patient whose alternative is infusion chemotherapy or salvage ASCT, I’m often willing to try selinexor because it’s outpatient, given orally, and because I have seen a few amazing results of patients who were able to tolerate it well and got good durable responses out of it. I would say that’s not most patients, but it’s enough that it makes it worth trying at some point.

SOTIRESCU: I’ve certainly been having an eye problem [in my patients who are taking belantamab mafodotin]. It’s a profoundly emotional issue not only for patients but for the doctors. …We occasionally see uveitis in immunotherapy, but again, it impacts the use of belantamab. First, I was more reassured by doctors like you, academics, that it’s usually reversible, and that’s the first [thing in my] mind that we can do. Second, it’s not easy to find an ophthalmologist, and if you find somebody and you bond with somebody who you trust, you can do it.

[Perhaps] the drug companies can band together, especially with these ocular [issues] which are rare. But when you cluster together it can give enough work and a lot of interest to a local ophthalmologist, especially if you can convince them, instead of charging [$100 for] the injection of bevacizumab [Avastin], [that they] can do a better job to help us to do that. I think that would be a tremendous help to the communities just by [putting out] this idea, because other drug [companies] can come together to help us to find the local resources.

_References

_{1. 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 DREAMM-2 study. Cancer. 2021;127(22):4198-4212. doi:10.1002/cncr.33809}

_{2. Jakubowiak AJ, Jasielec JK, Rosenbaum CA, et al. Phase 1 study of selinexor plus carfilzomib and dexamethasone for the treatment of relapsed/refractory multiple myeloma. Br J Haematol. 2019;186(4):549-560. doi:10.1111/bjh.15969}