Expanded Indications for CAR T-Cell Therapies Shepherd in New Era of Myeloma Care

Expanded indications for the CAR T-cell therapies idecabtagene vicleucel (Abecma; ide-cel) andciltacabtagene autoleucel (Carvykti; cilta-cel) in earlier treatment settings have provided additional options for patients with relapsed/refractory multiple myeloma, according to David R. Oveisi, MD, who emphasized the need for increased awareness about the availability of these therapies in early-relapse settings.

On April 5, 2024, the FDA approved ide-cel for the treatment of adult patients with relapsed or refractory multiple myeloma after 2 or more prior lines of therapy, including an immunomodulatory agent (IMiD), a proteasome inhibitor (PI), and an anti-CD38 monoclonal antibody.¹ On the same day, the regulatory agency approved cilta-cel for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least 1 prior line of therapy, including a PI and an IMiD, and who are refractory to lenalidomide (Revlimid).²

With both CAR T-cell therapies approved in earlier indications, Oveisi noted that counseling eligible patients about these options is a crucial step toward selecting a treatment.

“Think about referral [to CAR T-cell therapy] for these patients early in the course of relapse. [Refer patients] if you think that they're robust and might benefit from CAR T-cell therapy,” Oveisi detailed in an interview with OncLive®.

In the interview, Oveisi discussed the implications of the expanded indications for ide-cel and cilta-cel; how these have impacted the real-world treatment of multiple myeloma; and long-term management strategies after administering CAR T-cell therapy.

Oveisi serves as an assistant professor of Hematology Oncology and is a staff physician at the Regenerative Medicine Institute of Cedars-Sinai in Los Angeles, California.

OncLive: How have the expanded indications for ide-cel and cilta-cel in earlier lines of therapy impacted your treatment decision-making for patients with multiple myeloma?

Oveisi: This is an important question, and it's sometimes not the easiest one to answer. What we're good at is determining when someone's eligible for an autologous stem cell transplant [ASCT]. Usually, it's straightforward; if [patients are] of reasonable age and fitness without a lot of comorbidities, most are transplant eligible. However, for patients who are frail or anyone over 80 years of age, we're saying no to [ASCT] and leaning on the other drugs we use.

For CAR T-cell therapy, [treatment decision-making] gets a bit more complicated. Patient input is certainly a factor, as is how far patients are traveling to see us. We generally view CAR T-cell therapy as a bit easier to administer than high-dose melphalan. We have given CAR T-cell therapy to some older patients in their 80s, provided that they are still fit and functional.

The prior label indications [for ide-cel and cilta-cel] of 4 or more prior lines of therapy resulted in most of our patients [who received CAR T-cell therapy] being fairly beat up from treatment, and outcomes were not always the best if we were using [CAR T-cell therapy] at the end of the [treatment] road.

In the earlier-relapse setting, [I’m most excited about CAR T-cell therapy] for patients who may not get another chance for [this] treatment down the road. I always tell other community providers, who may not have as much experience with multiple myeloma, that we want to prioritize giving our best treatments early. We want to give 4 drugs before ASCT and refer them for a transplant if you think they're eligible.

I’m most enthusiastic about earlier use of CAR T-cell therapy in patients who I'm worried about being alive 2 years down the roach, [such as those with] high-risk cytogenetic features, with extramedullary disease, or who relapsed very soon after ASCT. Based on the current label indications, that would be cilta-cel for anyone who's refractory to lenalidomide [Revlimid]. Ide-cel is certainly a reasonable option in the early-relapse setting, although the label indication is a little bit less liberal. You would have to wait until a patient is refractory to [at least] 2 prior lines of therapy.

Has increased experience with these CAR T-cell therapies in clinical practice helped expand which patients you are comfortable recommending for 1 of these treatments?

A lot of the hesitation in the community and even at academic centers is acknowledging that there are some adverse effects [(AEs) associated with CAR T-cell therapy] can be quite serious or even fatal. Neurocognitive and movement disorders are of particular concern, mostly because they're quite challenging to manage. I have had patients and family members tell me that [neurocognitive and movement AEs] are worse than the multiple myeloma, which you never want to hear. However, we're getting much better at understanding which patients are at higher risk for those AEs and how to mitigate them.

We've gotten a lot more successful at bridging patients from leukapheresis to the start of lymphodepletion by using our most effective treatments to get the myeloma disease burden to a low level, where we worry less about the high-grade cytokine release syndrome [CRS] and immune effector cell–associated neurotoxicity syndrome [ICANS]; we worry less about unusual things like hemophagocytic lymphohistiocytosis and neurocognitive movement disorders if the disease burden can be reduced going into the [CAR T-cell therapy] process.

We’re quite comfortable managing CRS and ICANS at this point; that part I don't worry about so much. However, I might be more concerned if it was an older patient. In the right patient, I might still have some hesitation if they're older or frailer, but we have a lot more confidence taking more people to CAR T-cell therapy [by] getting their disease burden down and knowing how to identify those unusual AEs, which are thankfully rare.

Within the phase 3 CARTITUDE-4 (NCT04181827) and KarMMa-3 (NCT03651128) studies, which supported the earlier indications for cilta-cel and ide-cel, respectively, how did these patient populations differ? How does that potentially influence treatment selection in the clinic?

What we saw in CARTITUDE-4 and KarMMa-3 mirrors the earlier key studies using both of those agents. Just looking at the raw numbers, such as objective response rate, progression-free survival, and overall survival, it seems like cilta-cel has a higher rate of response and works longer than ide-cel. Perhaps in the real world, we're seeing that the outcomes are probably a little bit closer than in the clinical trials. However, in the cilta-cel study, patients were a little bit less refractory and had fewer prior lines of therapy. They were allowed to have 1 to 3 prior lines [in CARTITUDE-4], as opposed to 2 to 4 [prior lines in KarMMa-3]. The median number of prior therapies was less with cilta-cel, so perhaps [CARTITUDE-4 included] more robust patients who were not so beat up from [prior] treatment. We do have to interpret the results with a little bit of caution and try not to cross-compare these trials too much because the populations were a touch different.

Additionally, the bridging therapy was different [between the 2 trials]. [Bridging therapy] was mandated in the cilta-cel study, whereas it was optional in the ide-cel study, although most patients did end up getting bridging therapy. The [bridging therapy] options were slightly different [between the studies] due to the patients being a little bit more refractory in KarMMa-3.

The results [from CARTITUDE-4 and KarMMA-3] echo what we saw in the later-line setting, which is that both CAR T-cell therapies appear to work well. What I thought was interesting about KarMMa-3 and CARTITUDE-4 was that [patients who were] randomly assigned to [1 of the] CAR T-cell therapies had an early mortality safety signal. Some patients were dying within 9 months of infusion, whereas they may not have had such an outcome in the standard-of-care [SOC] arm. Despite the small number of patients who had early death, the overall outcomes were superior with both ide-cel and cilta-cel. The overwhelming majority of patients benefited from these therapies as opposed to SOC. The FDA’s decision was that the benefits outweigh the risks [with cilta-cel and ide-cel], and that's generally agreed upon in the myeloma community.

For patients who receive CAR T-cell therapy and are in remission for a long period of time, what are the long-term management and monitoring strategies?

The big question is: how do we improve upon these outcomes from CAR T-cell therapy? With our current strategy of watchful waiting and doing nothing, some patients love that. They like being off treatment. They like not having to come into the clinic so often. Many of them commute from quite far away and are happy to do virtual visits with me, and I think that's great. However, I have other patients who are constantly anxious about when [the multiple myeloma] is going to come back. An area of unmet need is maintenance after CAR T-cell therapy, and we're all excited about some of the investigational things that could improve upon that.

From a pure supportive standpoint, we've become better at understanding how to keep patients safe. First and foremost, [we must ensure] that they're having hematopoietic recovery after lymphodepletion and that they're not having a delayed worsening of their counts later, which we think is directly related to the CAR T-cell therapies. I haven't had to do a lot of stem cell boosts, but I like having stem cells available just in case patients are not recovering their hematopoiesis. Generally, I can get by with use of growth factors and periodic transfusions; most patients are achieving transfusion independence by 3 months.

Another thing that we're vigilant about is keeping patients out of the woods from infection and keeping them on prophylactic IVIg until their immunoglobulins can recover; for most patients, that's about 6 to 12 months after CAR T-cell therapy. We keep an eye on their CD4 counts and keep them on pneumocystis jirovecii pneumonia prophylaxis until the [CD4] count is well above 200 cells/mm3. We make sure they're on antiviral suppression, and when they're neutropenic, we're thinking about bacterial and fungal prophylaxis as well.

In most patients, once they get more [removed] from lymphodepletion and CAR T-cell therapy infusion, they tend to get better and better with each visit. [Visits involve] mostly just reviewing the [hematologic] numbers

For community colleagues treating patients with multiple myeloma, if they have a patient who may be a candidate for CAR T-cell therapy, what advice would you give in terms of counseling those patients?

It's important for a patient to understand what the [CAR T-cell therapy] process involves; sometimes patients arrive in my clinic and are surprised to hear that chemotherapy is involved with an immune therapy. Some patients are completely turned off from that and don't want even a small chance of losing their hair. Therefore, it's a good idea to counsel patients that this is an immune-based treatment, but this doesn't mean that it's free of AEs or free from chemotherapy. There is a need to give lymphodepleting chemotherapy to make room for these engineered CAR T cells, and AEs can happen from both the chemotherapy and the [CAR T-cell therapy]. It does involve some time in the hospital and close monitoring afterward.

It's important to understand the patient's social situation, such as where they live and who lives with them. Can there be someone reliable to make sure that they're safe, particularly in the first 30 days or perhaps longer if it's an older patient?

[You can also start considering referral for CAR T-cell therapy before relapse] if you have a patient who you think is at high-risk for early relapse. If a high-risk patient has either had an ASCT or started first-line therapy if transplant ineligible, and you think they could be a candidate for CAR T-cell therapy at first relapse, it's always best to meet with [speak with a CAR T-cell therapy center] first to get some of the legwork done. When those high-risk patients relapse, it tends to be in an aggressive fashion over a shorter period of time.

When I see patients for ASCT, I keep close contact with them afterward. Some providers say, 'Okay, you made it to 3 months [post-ASCT]. Go back to your community provider, and I'm here if you need me.' However, I like to keep tabs on them at least once or twice per year to make sure that things are going well. If there is a sign of a relapse, particularly an early one, we can have that conversation about whether they would benefit from going straight to CAR T-cell therapy, perhaps when things are only growing slowly and we don't have to bother with bridging therapy.

I share the responsibility with the community providers. The community doctors often know patients for much longer and have that good relationship with them, but once I see them for transplant, I try to maintain the relationship myself and work together [with the community provider].

We're certainly getting more referrals for CAR T-cell therapy earlier and earlier, but [with] the new label indications, we could have more. The word needs to get out to oncologists that CAR T-cell therapy is now an earlier option in the treatment paradigm.

[CAR T-cell therapy] is not the best treatment for every single patient. There are some patients [who get turned off to CAR T-cell therapy] when you talk to them about some of the risks, including secondary myeloid cancers, movement disorders, being in the hospital, or getting chemotherapy. We have a lot of other drugs [to pick from], but I think conversations [about treatment post-relapse] are best had with a doctor who does a lot of CAR T-cell therapy so that patients are as informed as they can be. There are some patients who are extremely enthusiastic about having time off treatment. They have a lot of plans, they want to travel, they still have a lot of things they want to do in their life, and being tied down to an infusion center is not as desirable. I'm enthusiastic having the conversation. I'm not [giving CAR T-cell therapy] to every [eligible] patient [under the indications], but it's a great option.

References

1. US FDA approves Bristol Myers Squibb and 2seventy bio’s Abecma for triple-class exposed relapsed or refractory multiple myeloma after two prior lines of therapy. News release. Bristol Myers Squibb and 2seventy bio, Inc. April 4, 2024. Accessed November 19, 2024. https://news.bms.com/news/corporate-financial/2024/U.S.-FDA-Approves-Bristol-Myers-Squibb-and-2seventy-bios-Abecma-for-Triple-Class-Exposed-Relapsed-or-Refractory-Multiple-Myeloma-After-Two-Prior-Lines-of-Therapy/default.aspx
2. Carvykti is the first and only BCMA-targeted treatment approved by the US FDA for patients with relapsed or refractory multiple myeloma who have received at least one prior line of therapy. News release. Johnson & Johnson. April 5, 2024. Accessed November 19, 2024. https://www.jnj.com/media-center/press-releases/carvykti-is-the-first-and-only-bcma-targeted-treatment-approved-by-the-u-s-fda-for-patients-with-relapsed-or-refractory-multiple-myeloma-who-have-received-at-least-one-prior-line-of-therapy