Benefits of Utilizing CAR-T in Later Lines of Therapy for Patients With Multiple Myeloma

At the 2024 Great Debates & Updates (GDU) in Hematologic Malignancies meeting in Los Angeles, California, Rahul Banerjee, MD, Fred Hutchinson Cancer Center, Seattle, Washington, participated in a debate in which he argued against the use of chimeric antigen receptor (CAR) T-cell in earlier lines of therapy among patients with multiple myeloma (MM), instead arguing for their use in third-line and beyond.

“[First], we have good, solid other second-line therapies, if they're more convenient for the patient for where they are, I think they make sense. [Second], I think CAR-T therapy is still in its teenage years. I think we have better therapies that are constantly emerging and being studied, and an argument really could be made to say, "Look, why rush to CAR-T now and give up your best BCMA therapy, when in 2 years even better BCMA therapy is becoming available. And [third], CAR-T for everybody's second-line, I think is not sustainable for our health care system and would exacerbate disparities,” explained Dr Banerjee.

Transcript:

My name is Rahul Banerjee. I'm an assistant professor of medicine at the Fred Hutchinson Cancer Center in Seattle, Washington and at the University of Washington in Seattle, Washington. I specialize in multiple myeloma (MM) and other plasma cell precursor disorders, for example, AL amyloidosis and (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and dermopathy) POEMS syndrome.

I'll be debating Dr. [Jeffrey] Matous from Colorado about the topic of CAR-T therapy in earlier lines of therapy, whether it should be used or should not be used. I'm arguing against it. Obviously in real life the answer is quite nuanced, but I think overall for patients who are starting second-line treatment, I am not a big proponent of CAR-T for them, at least not yet.

I think there's a couple reasons why you can break that down and say so. [First], I think there are standard therapies that work quite well for patients who have had their initial relapse, so have been on front-line therapy, plus or minus transplant maintenance and now [the] myeloma is coming back for the first time. Importantly, many of those other therapies are available to be given closer to home, have fewer toxicities, don't require a caregiver, and don't require the logistics that CAR-T entails.

The example, and I tell patients this upfront, truly, is that unless CAR-T versus [daratumumab plus a combination of carfilzomib and dexamethasone] DARA-KD or [daratumumab plus pomalidomide and dexamethasone] DARA-PD would mean no difference to you logistically, then I think it's reasonable to talk about CAR-T [in the] second line for everybody.

Where I practice in Seattle, [most of] my patients live more than 30 minutes away. Many of them live several hours away. Several of them live in other states like Alaska, Idaho, [and] Hawaii. Can I truly look them in the eye after first line relapse and say you need CAR-T second-line therapy when you can easily—which probably has a [progression-free survival] PFS in CARTITUDE-1 about 3 years or so, when using DARA-KD or (isatuximab in combination with carfilzomib-dexamethasone) ISA-KD can also get you 2 to 3 years if not more with your local doctor, without having to move? It's a tricky sell for patients.

A lot of patients are excited about CAR-T, and I agree completely CAR-T has less time toxicity, pound for pound, less time in clinic compared to DARA-KD, but for that patient who [has] to uproot their life, stop working, have their caregiver stop working and move, it's a big decision. That's the first reason I would say that: Yes, CAR-T may outperform standard therapies, but standard therapies may outperform CAR-T logistically, for where the patient lives.

I don't want to come across giving the vibe that everyone only gets 1 shot at CAR-T therapy because certainly it is possible to use a different epitope, or re-challenge them with a different CAR-T product later. However, in general, we find that it's best to [pick] your best [B-cell maturation antigen] BCMA-targeted therapy and give it at once, rather than giving something that works for a little bit and then moving to a different BCMA CAR-T therapy.

Why does that matter? The CAR-T therapy we have available in 2024, here on July 28th, 2024, are great. We have [idecabtagene vicleucel] ide-cel and we have [ciltacabtagene autoleucel] cilta-cel. They're great, but they're not perfect, right? [With] ide-cel, the median PFS is typically a little bit less than cilta-cel if you kind of compare between studies. But cilta-cel, for example, does have some real rare, but delayed toxicities like Guillain-Barré syndrome, parkinsonism, [and] other delayed neurological or multi-organ toxicities.

Newer CAR-Ts are on the horizon. We have (anitocabtagene autoleucel) anito-cel; we have [ ]; we have GCO12F. If you had to choose between rushing the CAR-T second line [with] what we have right now or getting a different therapy closer to home, and in 2028 when it's time for your next therapy have the best CAR-T available in 2028, I might vote for the latter. CAR-T therapy is still what I would say is like a teenager—we've gotten a lot of progress with how to make it work better and work more safely, but [there is] just a lot of recklessness with some of our commercial CAR-T therapies currently. I'm hoping in [the] coming years that gets better. I would say that if you “waste” your shot at BCMA CAR-T therapy with the therapy now, a second-line treatment, that might make third-line BCMA CAR-T not work as well.

There's a rationale to be said to wait. The third, moving back from the individual patient lens to a broad patient lens here, would be that I think if we were to try to do second line CAR-T for everybody, we would both bankrupt the system and create more healthcare disparities. Why do I say that? [First], CAR-T therapy costs about half a million dollars for the actual infusion itself. If you add all the indirect costs around staffing and the cell therapy lab and nursing and apheresis, easily you're coming close to 1 million dollars in the [United States]. People are trying to work on ways to make that work better and make it happen more cheaply and more efficiently for patients, but it's a lot. If we asked everybody or insisted that, hey, if your doctor doesn't recommend second-line CAR-T for you, find a new doctor—again—we would bankrupt the system, we would make wait times terribly long.

Right now, even for our patients who truly need CAR-T, we're talking at least a brain to vein time—from the day that I decide to talk about CAR-T to when they get the cells infused—about 4 to 6 months. That includes 2 months of manufacturing, typically, and other logistics, but also you have to make sure to get a spot, get insurance clearance, and so forth. That wait time will go up dramatically because we have a fixed number of slots and health care insurance companies may not be willing to pay for everything.

The other part of it I would argue is that every center is doing their own method of trying to determine who needs CAR-T therapy first versus last. I think there is actually some triage that goes into it where patients who've had 3 prior lines or 4 prior lines of therapy, if they feel like they need CAR-T, even if they aren't the best candidate in terms of frailty or don't have a good strong caregiver or so forth, we figure it out because the patient needs CAR-T, versus if we say everybody second line and up gets CAR-T therapy regardless of their unique situations, I feel like people who don't truly need CAR-T, that their disease might do well no matter what, will get CAR-T—and those who truly need it might get pushed at the back of the line just because there's so many people rushing for it.

To summarize there, why I don't think CAR-T should be for everybody as second-line therapy. [First], we have good, solid other second-line therapies, if they're more convenient for the patient for where they are, I think they make sense. [Second], I think CAR-T therapy is still in its teenage years. I think we have better therapies that are constantly emerging and being studied, and an argument really could be made to say, "Look, why rush to CAR-T now and give up your best BCMA therapy when in 2 years even better BCMA therapy is becoming available. And [third], CAR-T for everybody's second-line, I think is not sustainable for our health care system and would exacerbate disparities.

To be fair, there are some patients where I absolutely will recommend second line CAR-T and those would be the patients who are very young, who have functional high-risk myeloma—early relapse within 18 months of frontline therapy or then 1 year transplant—those patients do poorly with commercial therapies. Disproportionately so, I would rush those patients towards CAR-T. Perhaps patients with visceral extramedullary disease where the disease biology is behaving aggressively, we know that those patients won't do as well with DARA-KD or ISA-KD, meaning a CD30 monoclonal antibody plus carfilzomib plus dexamethasone, [is] just as a very good second-line regimen. For those patients, I completely agree with CAR-T, but I don't think that CAR-T should be second line for everybody. [For the] third line, I think yes. [For the] fourth line, yes.

I think we have a lot of work to do in the [United States] to make that possible, even third line for everybody. Obviously, globally, most patients of myeloma in the world do not have access remotely to CAR-T therapy. I think we have to work on those things first, before we start saying second-line CAR-T for all.

Source:

Banerjee R. Debate - CAR T Cell Therapy Should Be Used As Early As Possible – NO. July 27-28, Los Angeles, California.