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Rafael Fonseca, MD, breaks down the integration of CAR T-cell therapy as a treatment for early relapsed multiple myeloma.
As treatment options in initial relapsed/refractory settings expand for patients with multiple myeloma, longer-term follow-up data for CAR T-cell therapies have helped support this modality as a standard-of-care approach for this population, according to Rafael Fonseca, MD.
“The results [with CAR T-cell therapy at early relapse] are quite good,” Fonseca said. “The clinical trial data support this [approach].”
In an interview with OncLive®, Fonseca broke down how the CAR T-cell therapies
Fonseca is director for Innovation and Transformational Relationships at Mayo Clinic in Phoenix, Arizona. He was also the winner of the
Fonseca: The results that we have seen with CAR T-cell therapies in the area of myeloma are impressive, and I was pleased when we had the results of the [phase 3] CARTITUDE-4 clinical trial [NCT04181827] that allowed us to use cilta-cel [after] that first relapse, and subsequently, the [phase 3] KarMMA-3 study [NCT03651128] looking at ide-cel. In practice, I have [used] that [cilta-cel] approval to make it pretty much the standard therapy for patients who come into clinic and are unfortunately experiencing a first relapse. I have found that in doing so, it provides us with extra time and flexibility on how we plan things.
There has been some difficulty reaching consensus [on the best treatment approach at first relapse], and I presume that’s going to go on for some time, mostly because of good news. Given what we know from all the recent published and presented clinical trials, in my mind, there is no question that any patient who is experiencing a first relapse in 2026 should be choosing between either a CAR T-cell therapy or a bispecific antibody[–based regimen]. There are many other treatments that we have used for many years as myeloma doctors that proved to be useful, but [they] now fall short, given the results of these clinical trials. Combinations of anti-CD38 antibodies and some of the traditional agents, which again were useful, don’t stand a chance when it comes down to results as they are compared with CAR T-cell therapy and bispecific antibodies. People are still coming around to that, but I would say it’s still a relatively small fraction.
There are still patients who receive some of those other treatments, and then they are later considered for CAR T-cell therapy. CAR T-cell therapy or a bispecific antibody should not be considered for later. The more scientifically interesting part is whether one should use a bispecific antibody or CAR T-cell therapy first. We have excellent results with the clinical trials, and we could take a long time to talk about all the nuances and details. I favor the idea of doing CAR T-cell therapy before doing a bispecific antibody for a number of reasons, but we will see a significant lack of consensus for the foreseeable future in that regard.
When we’re [treating] a patient in that first relapse and we’re heading toward second-line therapy, we ask: Is there a particular way of doing patient segmentation? It’s difficult to do that. Many patients can be considered candidates for CAR T-cell therapy, including patients of more advanced age and frailty status. There’s a bias, or a bit of a selection process, that for patients of more advanced age, more and more [hematologists] are comfortable proposing one of the bispecific antibodies as a single agent or in a combination, but short on that, it’s hard for me to think about patient segmentation [for treatment selection].
CAR T-Cell Therapy in Early-Relapsed Myeloma
I start with the assumption [that patients] are [candidates for CAR T-cell therapy], and then we work through the details. The issue of access is no longer relevant. We can collect [T cells] and then administer [treatment] as soon as we can feasibly coordinate that with the patient, so there’s no process of waiting or prioritizing. [The process has] changed quite a bit in favor of the patients, where they can more freely make that decision [to use CAR T-cell therapy]. My general stance is that any patient who’s a reasonable candidate will be first considered for CAR T-cell therapy.
One of the nice things is that as time goes by, we are getting maturity in the follow-up periods [for these trials]. Having seen the results from the [phase 1/2] CARTITUDE-1 trial [NCT03548207], where approximately one-third of patients were out from their CAR T-cell therapy for 5 years and had not relapsed, was quite encouraging. That [outcome] can be considered common and routine, and the results, as we get the longer-term follow-up for CARTITUDE-4, [could be] even better. I don’t think it’s far-fetched that as we think about the results of CARTITUDE-1, but now in the CARTITUDE-4 population, we might see that [survival] percentage go up, perhaps as high as 50% of patients. We [could be] talking about a treatment that is administered once that [might have] a 50% chance of not being associated with a subsequent relapse.
Only time will tell [regarding longer-term follow-up for CARTITUDE-4], but [CAR T-cell therapy] is also attractive when we look at other outcomes we don’t talk about as much, such as quality of life, time in the treatment center, and requirements for other medications. CAR T-cell therapy can be a life-changing experience for patients. I can’t tell you how many times I’ve seen patients come to us and say, ‘I wish [CAR T-cell therapy] was available earlier. I wish I had done this earlier, and I’ve never felt as good as I feel in this phase of my life, since I had been receiving treatment for such a long period of time.’
Bridging therapy is devised as a way to control the disease before a patient goes to CAR T-cell therapy, but my one of my sayings is that the ideal patient for CAR T-cell therapy does not need bridging therapy. What I mean by that is, if we use CAR T-cell therapy for that first relapse, we can anticipate with plenty of time which patients are relapsing way before they have a sizeable monoclonal protein or a significant elevation of the light chains, as we monitor these patients closely after the first line. We often will use tools such as minimal residual disease detection, [as well as] the measurement of the monoclonal proteins and light chains. We also track abnormal proteins by mass spectrometry analysis of the blood. We can [potentially] tell well in advance, a month or sometimes even years, that the patient is going to experience a relapse. If we do that, then we can propose to start the process for CAR T-cell therapy at the proper time. Once we have the numbers and the certainty that [relapse] will occur, we start collecting cells. Oftentimes we don’t even have to give bridging therapy.
[That said], it’s important to give bridging therapy if a patient has a sizable number of myeloma cells in their body, because it’s increasingly clear that giving a CAR T-cell therapy to a patient who has a large number of myeloma cells in the body will possibly result in hyperreactivity of the infused CAR T cells, which ultimately can also lead to toxicities. We try to take patients with minimal disease to the CAR T-cell infusion, and that’s why I say the ideal patient does not need bridging therapy.
Will there ever be consensus on what to use [as bridging therapy]? The answer is no. Whatever works for patients [is the answer]. It can be through a reuse of some of the drugs [from an earlier line], bispecific antibodies, combination chemotherapy, etc. To me, that specific question is one of the reasons why it’s so attractive to do CAR T-cell therapy on the first relapse, because a patient who’s received, for example, a quadruplet induction, had a transplant, and then relapses several years later are likely to respond to therapy if they need therapy. However, it’s better to detect [relapse] at the point that they don’t even need that bridging therapy. The immunotherapy consortium has shown that response to bridging therapy is critical for CAR T-cell therapy recipients, but it is not the therapy but the disease control that matters.
The advent of CAR T-cell therapy options opens all sorts of new doors toward the management of myeloma. Our audience knows that [these agents] are being tested as frontline therapy; they’re even being tested in the pre-malignant stages, such as in smoldering myeloma. The good news is that all of this has to be done under the rigor of a clinical trial. I wouldn’t be surprised if CAR T-cell therapy forms part of an already-structured initial approach that leads to great control of the disease for a vast majority of patients. I see that happening.
CAR T-cell therapies are moving into other hematological malignancies, so hopefully, we’ll soon see expansion in other areas that are in desperate need of additional treatments, such as T-cell lymphomas. Subsequent to that, we’ll see [these therapies] in solid tumors, and that is going to be married with the development of bispecific antibodies. I think CAR T-cell therapy and bispecific antibodies will become bread and butter for most oncology practices, so you have to start becoming familiar with them.
There are new developments, such as the in vivo CAR T-cell therapy, that will make [the modality] far more accessible. The in vivo CAR T-cell therapies would drop the cost of goods significantly, so at a global level, many more patients would be able to receive CAR T-cell therapy because [manufacturing and administration] would be more of a gradual process. You also don’t see as much cytokine release syndrome [with in vivo CAR T-cell therapies], so there is a future where CAR T-cell therapy will [undergo] widespread adoption for the management of malignancies and beyond, including autoimmune disorders.
