CAR T-Cell Therapies Improve Treatment Landscape in Relapsed/Refractory Multiple Myeloma

Barry Paul, MD

The increasing integration of CAR T-cell therapies into the treatment paradigm for adult patients with relapsed or refractory multiple myeloma addresses several unmet needs and improves outcomes for this historically limited patient population, according to Barry Paul, MD. He added that improvements in manufacturing times, T-cell expansion and persistence, and treatment sequencing will be vital to their continued success.

On March 26, 2021, the FDA approved idecabtagene vicleucel (Abecma; ide-cel) as the first BCMA-directed chimeric antigen receptor (CAR) T-cell therapy for patients with relapsed/refractory multiple myeloma after 4 or more prior lines of therapy. The approval was based on findings from the phase 2 KarMMa trial (NCT03361748), which showed an objective response rate (ORR) of 72% (95% CI, 62%-81%) and a stringent complete response (sCR) in 28% (95% CI, 19%-38%) of patients receiving ide-cel.¹

Almost a year later, on February 28, 2022, ciltacabtagene autoleucel (Carvykti; cilta-cel) was approved for the same patient population, based on results from the phase 1/2 CARTITUDE-1 trial (NCT03548207). Patients receiving cilta-cel demonstrated an ORR of 98% (95% CI, 92.7%-99.7%), and an sCR rate of 78% (95% CI, 68.8%-86.1%). Both ide-cel and cilta-cel elicited a durable response in these patients.²

“The [treatment] paradigm has changed [for this] patient population,” said Paul, who is an assistant professor in the Division of Plasma Cell Disorders in the Department of Hematologic Oncology and Blood Disorders, at Atrium Health in Durham, North Carolina. “Traditionally, [these patients] had poor prognoses [because of] limited [treatment] options [that] were not tremendously effective and had lots of toxicities. Now, [they] have agents that are incredibly effective. While the toxicities shouldn’t be taken lightly, [they] are manageable, especially when administered in the right setting with people who have experience in this space.”

In an interview with OncLive^® following an Institutional Perspectives in Cancer (IPC) webinar on multiple myeloma, Paul expanded on the emerging benefits of ide-cel and cilta-cel in this patient population, areas for improvement within CAR T-cell delivery and production, and future efforts to optimize the efficacy of CAR T-cell therapy in clinical practice.

OncLive^®: What distinguishes BCMA-directed CAR T-cell therapy from historical options for patients with relapsed/refractory myeloma?

Paul: I reviewed what BCMA is, why it’s an appropriate target for myeloma, what the downstream effects of targeting BCMA are, and the CAR T-cell therapies that target BCMA. I focused on commercially available CAR T-cell therapies [like] ide-cel and cilta-cel, both of which are now FDA approved for patients with relapsed/refractory myeloma. Both [agents] have excellent efficacy in this patient population, which is a very challenging population to treat at baseline. [These are] very exciting [options] for patients that are being [increasingly] integrated into our treatment paradigm for myeloma.

Could you elaborate on the recent FDA approvals for ide-cel and cilta-cel and describe what the effects have been on patient outcomes?

Ide-cel is the first of these agents that was FDA approved in February of 2021 for patients with refractory myeloma who had previously been treated with [4] or more prior lines of therapy. The median number of prior lines of therapy patients received in [the KarMMa trial] was 6. These are heavily pretreated patients, most of [whom] are triple-class refractory, and this patient population typically does not do well after they are refractory to an IMiD [immunomodulatory drug], a PI [proteasome inhibitor] and a CD38-targeting antibody. Patients in this population who were treated with the therapeutic dose of ide-cel had a response rate of [approximately] 70%. [This is] very exciting information for a patient population that previously had very few effective options.

Cilta-cel is the second agent in this class and was approved in March of 2022. [Its approval] was based on the CARTITUDE-1 trial, which looked at about 98 patients [who had received] at least 3 or 4 prior lines [of therapy]. [Patients] had to be refractory to a PI, an IMiD, and a CD38 antibody, and this patient population, again had a remarkable response rate [around] 98% which is previously [unheard] of in this patient population. Both these agents have very exciting profiles in a patient population that typically has limited options [that] are not tremendously effective.

What important adverse effects can result from CAR T-cell therapy?

Any T cell-mediated regimen has the potential to cause cytokine release syndrome [CRS], or immune effector cell–associated neurotoxicity syndrome, otherwise known as ICANS. CRS is a systemic inflammatory response. It’s thought to be secondary to the activation of bystander immune and non-immune cells. When these cells get activated, you get a significant increase in IL1 and IL6 levels in patients, and that causes an immune response. [Symptoms] include fever, fatigue, headaches, arthralgias, myalgias, and patients often feel like they have a bad flu virus. [However,] it can progress to a more severe presentation, including things like hypotension, shock, and multi-organ system failure. [These toxicities are] manageable with an anti-IL6 antibody called tocilizumab [Actemra]. Traditionally, management would be [initially] supportive, [employing] antipyretics or acetaminophen, IV fluids, if necessary, supplemental oxygen and then tocilizumab if the symptoms do not improve or are progressing.

ICANS symptoms [have a] similar pathophysiology. The difference is [that with ICANS], the blood brain barrier is disturbed, and these agents can traverse into the CNS [central nervous system]. When that happens, the cytokines can cause more pronounced CNS symptoms, including headache, confusion, and impaired fine motor skills. It can then progress to more concerning things like aphasia, seizures, cerebral edema, even coma. The treatment here is high-dose corticosteroids. This is not an area where tocilizumab is particularly effective, because it does not cross the blood-brain barrier.

What is the advantage of incorporating CAR T-cell therapies into the current treatment paradigm?

One of the attractive things about this type of therapy is that it’s a [single] infusion. When patients get their CAR T-cell product, [the drugs] expand on their own and there is no need to [continually] reinfuse. That’s relatively unheard of in myeloma [treatment.] Traditionally, myeloma [requires] continuous chemotherapy treatments until disease progression or intolerance. So, a one-and-done type of therapy is very attractive for patients and physicians.

What unmet needs may still exist in the administration of CAR T-cell therapy, and how could these be mitigated?

One area of concern for CAR T-cell therapy is that the manufacturing of these products takes time. In general, [it takes] about 4 weeks [to manufacture these products] but it can [sometimes take] between 10 and 12 weeks. [Moreover,] there’s always the [possibility] that the CAR T-cell manufacturing process doesn’t go well, in which case the product [cannot] be delivered or released because it may not be appropriate or safe. Oftentimes, these patients are highly refractory to commercially available treatments, yet [clinicians] still have to maintain their disease while they’re waiting for their CAR T-cell therapy to be manufactured. Depending on how long that can be, [clinicians may] have to keep their disease under control for several months.

We’re learning more about the best ways to control the disease [while not] interfering with the activity of the CAR T [T-cell therapy] or allowing [the disease to progress] to such an extent that CAR T-cell [administration occurs too late to be effective.] Better manufacturing [could increase] the [speed] of CAR T-cell therapy [delivery], so that [both] patients and physicians know exactly when their CAR T-cell therapy is going to be available.

Similarly, the way that these agents are delivered is somewhat problematic. While they all have relatively well-understood toxicities, the timing and the ability to get treatment for that toxicity is crucial. It is somewhat counterintuitive to keep patients in the hospital for prolonged periods of time, [despite] understanding [at what point] the toxicities are going to manifest. There’s an opportunity for outpatient administration of these agents in the right setting. Also, [utilizing] prophylaxis against some of these CRS and ICANS symptoms could potentially allow this [administration] to be a little bit safer and delivered in a non-tertiary facility.

What future developments still need to occur to maximize CAR T-cell efficacy in the relapsed/refractory setting?

We need to figure out ways to optimize CAR T-cell therapies. We may find adjunctive therapies that can allow the CAR T-cell therapies to persist longer and [achieve] better expansion at infusion, which often leads to a more robust response.

Similarly, we need to figure out how to sequence these agents and [determine] where they fit in [the treatment paradigm], especially with other cell-mediated therapies. [We also need to determine] which patients would be best served with a CAR T-cell product vs a bispecific antibody vs an antibody-drug conjugate. Those are areas that we’re still actively trying to figure out [through continued] research.

What ongoing research are you excited about in this field?

[Researchers are] currently investigating [the use of] these therapies in earlier lines of therapy for newly diagnosed patients with myeloma who are less refractory. We [hope to] see an even more robust, long-lasting response in these patients who are less heavily pretreated than we are seeing in this relapsed/refractory patient population.

References

1. Munshi NC, Anderson LD Jr, Shah N, et al. Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N Engl J Med. 2021;384(8):705-716. doi:10.1056/NEJMoa2024850
2. Martin T, Usmani S, Berdeja J, et al. Updated Results from CARTITUDE-1: phase 1b/2 study of ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T cell therapy, in patients with relapsed/refractory multiple myeloma. Blood. 2021;138(suppl 1):549. doi:10.1182/blood-2021-146060