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Sundar Jagannath, MBBS, discusses the significance of the FDA approval of ciltacabtagene autoleucel, important adverse effects to be aware of, and shared his thoughts on where the treatment fits into the current and future treatment paradigms.
The FDA approval of ciltacabtagene autoleucel (cilta-cel; Carvykti) in relapsed/refractory multiple myeloma is nothing short of a breakthrough, said Sundar Jagannath, MBBS, who added that findings from the pivotal phase 1b/2 CARTITUDE-1 trial (NCT03548207) exceed historical responses with previously approved treatments, such as selinexor (Xpovio) and belantamab mafodotin-blmf (Blenrep), bringing the field one step closer to cure.
On February 28, 2021, the FDA approved cilta-cel for the treatment of adult patients with relapsed/refractory multiple myelomafollowing 4 or more prior lines of therapy, including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 monoclonal antibody. The approval for cilta-cel was based on findings from the CARTITUDE-1 trial, in which cilta-cel led to an objective response rate (ORR) of 98% (95% CI, 92.7%-99.7%) in this patient population. Additionally, the stringent complete response (sCR) rate was 78% (95% CI, 68.8%-86.1%). The median duration of response (DOR) was 21.8 months at a median 18 months of follow-up.1
Updated findings from the study, which were presented at the 2021 ASH Annual Meeting and Exposition, demonstrated 2-year progression-free survival (PFS) and overall survival (OS) rates of 60.5% and 74.0%.2
In an interview with OncLive®, Jagannath, director of the Center of Excellence for Multiple Myeloma and a professor of medicine (hematology and medical oncology) at The Tisch Cancer Institute, Mount Sinai, discussed the significance of the FDA approval of cilta-cel, important adverse effects to be aware of, and shared his thoughts on where the treatment fits into the current and future treatment paradigms.
Jagannath: The approval comes at an incredible time of progress in the treatment of patients with multiple myeloma. Right now, multiple myeloma is not a curable cancer, although we have a lot of drugs [that have] improved life expectancy. The median life expectancy in the SEER [Surveillance, Epidemiology, and End Results] Program database for all patients, including elderly patients, has crossed the 5-year mark, which is a major milestone. For younger patients, it has crossed the 7-year mark. [Because of that], the prevalence of myeloma has increased, so we want to make a breakthrough for our patients.
The approval of this CAR T-cell therapy has been a breakthrough. Usually, the new drugs that are approved, especially [those receive] accelerated approvals, have shown meaningful benefit for patients who have failed all currently approved treatment. The past couple drugs that have been approved in multiple myeloma, such as selinexor and belantamab mafodotin, have response rates around 30% and the PFS may be 3 months, with a DOR of 9 months and OS of 1 year to 15 months––something to that effect. With cilta-cel, we have an ORR of 98% and an sCR rate of around 80%. Most importantly, [the responses are] durable. At the 2021 ASH Annual Meeting and Exposition [updated findings from CARTITUDE-1 showed that at a] median follow-up of 22.5 months, 60% of patients were still progression free at about 2 years, and the OS was even better. That kind of response, the durability of response and depth of response, and improvement in survival expectancy in patients who would have gone for hospice if this drug was not made available is game changing. This now gives me the confidence that we will no longer keep on saying “Myeloma is not a curable cancer.”
Bispecific antibodies are also in clinical trials, showing response rates in the 70% range, not the traditional 30% range. The [responses] are also durable [out to] 1 year [according to data from] the 2021 ASH Annual Meeting and Exposition. These [agents] are phenomenal and they are off the shelf, so you can give them right away. Multiple myeloma is finally entering the era where, like lymphoma, we will be able to say that the disease is curable.
Similar to when the idecabtagene ciloleucel [ide-cel; Abecma] program opened 1 year ago, [Janssen] will likely open [their program] at a few centers, then they will open additional centers, and so on and so forth. More than likely, Janssen will take a similar approach to [Bristol Myers Squibb] and open some of the centers who have already participated in the clinical trial and have experience [with cilta-cel] so there are no glitches in the initial [rollout]. [Then, they will likely] broaden [the program] to almost all transplant centers in the country.
CAR T-cell therapy, like autologous transplant or other transplant, [can be tricky] during the first 2 weeks [of treatment]. The patient must be monitored closely. Thus far, CAR T-cell treatments have been administered and monitored as an inpatient therapy, even if it can be given as an outpatient treatment, which has been shown with cilta-cel. Most of the treatment in this country, even in diseases like leukemia and lymphoma and other diseases, has been in the cellular therapy arena. [The rollout will] be more in the transplant area. That is how I foresee this program moving forward.
CRS [cytokine release syndrome] is a toxicity that occurs with all CAR T-cell therapies; it happens in almost 97% of patients. In myeloma, the CRS is well tolerated; usually grade 1 and 2 events are seen. The occurrence of grade 3 and 4 events is much lower. HLH (hemophagocytic lymphohistiocytosis) is one of the things that we must watch for [if the] CRS gets very severe.
The [FDA label also mentions] neurotoxicity or ICANS [immune effector cell–associated neurotoxicity syndrome] and the fact that a case of Guillain-Barré Syndrome happened in the program development—not necessarily in the CARTITUDE-1 trial, but in another ongoing trial. The FDA also [lists a] Parkinson-like syndrome, which has also been reported with ide-cel. The FDA has included those 4 things in their Blackbox warning. Centers should be experienced; they need to know how to take care of CRS and how to prevent macrophage activating syndrome or HLH syndrome. They are to be cognizant of potential neurotoxicity. That’s the key. There could also be low blood counts, which happens because we give cyclophosphamide and fludarabine, so every patient experiences a low blood count phase, then they recover. There have been cases of delayed low blood counts too. [We] must be cognizant about delayed low blood counts. All of this has been put out by the FDA in their package insert.
The most exciting part is the durability of response. The very first patient we put on the clinical trial, that patient is now 4 years out in complete minimal residual disease [MRD]–negative remission, which is unheard of. We would be excited if that happened in a newly diagnosed patient with myeloma because we might think we are curing that patient. There are 2 patients who will soon be crossing the 3-year mark. I’m pretty sure there is going to be an update of CARTITUDE-1 at the 2022 ASCO Annual Meeting with long-term follow-up. I have a feeling that more than likely since about 60% of patients were progression free at the 2-year mark that chances are the [median] PFS is going to be beyond the 2-year mark, which would be very exciting.
[We don’t have those data yet], but I can speak to our experience. At the 2021 ASH Annual Meeting and Exposition, our group at Mount Sinai gave an oral presentation, where we showed that patients can go from one bispecific antibody to another bispecific antibody or go from a bispecific antibody to a CAR T-cell therapy or from CAR T-cell therapy failure can go to a bispecific antibody. Typically, we have tried to switch the target from BCMA to GPRC5D or FcRH5, but there have been patients who have failed the antibody-drug conjugate belantamab mafodotin who have gone onto CAR T-cell therapy, and they have responded very well.
We have also noticed that the patients who have failed CAR T-cell therapy or bispecifics, especially BCMA-directed CAR T-cell therapy, that the BCMA target when they relapse is still expressed. As long as the target is expressed in the myeloma cells, I have a feeling that [we] can still go for [a BCMA-directed approach]. [These days, you can check for BCMA with] immunohistochemistry in any pathology [lab]. Just like CD138 on the myeloma plasma cells, you can also look for BCMA expression. It’s a very easy, ubiquitously available test [that you can order] and decide accordingly. [Ultimately, I do not believe prior BCMA-directed therapy] does not preclude you going from one [such approach] to another.
There are treatment opportunities with CAR T-cell therapy and now bispecific antibodies where you redirect the patient’s own T cells against the myeloma cells. These agents are eliciting such wonderful results in such a late stage of the disease. Now my feeling is they will all start moving forward, because ultimately, we want to cure myeloma. It cannot be that these treatments are restricted to relapsed and refractory patients with myeloma who have become frail or who have organ damage and are not eligible [for these agents].
The next important aspect will be cure, but to say somebody is cured, you must follow them for at least 10 years, so we will probably look at MRD negativity using next-generation sequencing by molecular clonoSEQ, which has been FDA approved. [We’re going to see] clinical trials that employ clonoSEQ every year for 5 consecutive years, showing that the patient has achieved MRD-negative complete remission [CR] every year for at least 5 years.
There will be randomized trials in patients with 1 to 3 relapses comparing currently approved treatment with daratumumab [Darzalex]-based treatment with an IMiD and PI with CAR T-cell therapy, and, similarly, in the frontline setting comparing transplant with CAR T-cell therapy.
These are all clinical trials that are being designed and implemented not only in the United States, but also in Europe. I’m excited that these are all trials that must happen. However, the readout will be longer. The readout will be slow because people want to see whether the approach is curative, which begs the question: How do we define cure in myeloma—because relapses can happen even 8 years later?
Another important question is: If a patient fails one modality, let’s say they fail a T-cell redirection therapy with a bispecific antibody and the cancer comes back, what happens? Can [we] use a different bispecific antibody with a different target, or can the patient go to a CAR T-cell therapy? If a patient has failed a CAR T-cell therapy directed against BCMA, can they go to a BCMA- and if not a BCMA- GPRC5D/CD3-directed bispecific antibody? Even with CAR T-cell therapy, we are coming up with targets other than BCMA like CS1 and GPRC5D, so those [agents] will also be coming in a clinical trial.
How to select patients for therapy and treatment sequencing is going to be an important area of research. Patients should feel empowered that such treatment options are coming. Researchers are not stopping here. Even better treatments and combinations are coming. We are now striving to cure myeloma. That is the excitement for the myeloma field.
Community oncologists have been exposed to CAR T-cell therapy because of [the approvals in] lymphoma and leukemia. In myeloma, the approvals right now for ide-cel and cilta-cel are similar. Patients should have received at least 4 lines of therapy and been exposed to a PI, an IMiD, and an anti-CD38 monoclonal antibody, either daratumumab or isatuximab-irfc [Sarclisa]. The important question is whether they can find a center to send patients to at an appropriate time. The other question is: If a patient is given a choice of getting ide-cel right away in one center or waiting for cilta-cel in another center, the decision will depend on the patient’s clinical situation. If a patient’s disease is progressing, and they need CAR T-cell therapy immediately, right now, because it’s not so ubiquitously available, if they have access to ide-cel, they should get ide-cel right away, because both products are able to put the patient into CR at a high rate, and they are all alive.
It is conceivable that some of the patients who have received ide-cel also have durable responses, but in case the disease comes back, there are bispecific antibodies. You must be alive to participate in the next treatment option. You don’t want to lose your fight. You don’t have to pick and choose and say “I want that” and then lose your life because you couldn’t get access to one product. Any CAR T-cell therapy is lifesaving, and if you’re alive and in remission later, your future is getting better, because next year bispecifics will become commercially available. The future is good. The dilemma should not be a major issue for the oncologists.
In terms of whether people should choose ide-cel or cilta-cel, my feeling is either one of them [would be the right choice because both products can] get [patients] into remission. The beauty is, even in the case of recurrence, the future is still very good because the bispecifics are available [in clinical trials]. One more thing I want community oncologists to know is that there are many T-cell engagers in clinical trials, and all drug companies want their clinical trial done quickly [because] they want their approval.
As a result, they have to diversify the centers in which they open their trials. You would find that you have access to one or the other bispecific antibody, anywhere in the country, almost in every state. That should be known because the options that are available are really lifesaving treatment options. In addition to the excitement of cilta-cel getting [getting approved], [we also have to be mindful that] the whole treatment paradigm of myeloma is changing, and treatment options are available ubiquitously across the country. Oncologists should be aware of that.