Cilta-Cel Allows for Treatment-Free Period in Early R/R Multiple Myeloma

Saad Z. Usmani, MD, MBA, FACP, FASCO, discusses the significance of the FDA approval of cilta-cel in relapsed/refractory multiple myeloma.

Saad Z. Usmani, MD, MBA, FACP, FASCO

Saad Z. Usmani, MD, MBA, FACP, FASCO

The FDA’s approval of ciltacabtagene autoleucel (Carvykti; cilta-cel) represents a significant advancement in relapsed/refractory multiple myeloma, potentially allowing patients to experience a treatment-free period following administration, according to Saad Z. Usmani, MD, MBA, FACP, FASCO. However, he noted that patient preference must be considered as there are logistical barriers associated with this modality.

In the phase 3 CARTITUDE-4 trial (NCT04181827), patients treated with cilta-cel (n = 208) achieved a 59% reduction in the risk of disease progression or death vs those treated with standard-of-care (SOC) regimens (n = 211).1 With a median follow-up of 15.9 months, the median progression-free survival (PFS) was not evaluable (NE; 95% CI, 22.8-NE) with cilta-cel vs 12 months (95% CI, 9.8-14.0) with SOC (HR, 0.41; 95% CI, 0.30-0.56; P < .0001). The median overall survival (OS) with cilta-cel was not NE (95% CI, NE-NE) vs NE (95% CI, 22.97-NE) for the SOC arm (HR, 0.57; 95% CI, 0.40-0.83).

On March 15, 2024, the FDA’s Oncologic Drugs Advisory Committee (ODAC) raised concerns regarding the OS rates during the first 10 months of treatment. In this time period, 14% of patients who received the CAR T-cell therapy had died vs 12% of those who were given SOC.2 Janssen, the sponsor for cilta-cel, attributed the early OS imbalance to patients who experienced disease progression or death prior to receiving the CAR T-cell therapy. Ultimately, the committee voted 11 to 0 that the benefits of cilta-cel outweigh its risks in the treatment of adult patients with relapsed/refractory multiple myeloma who have received at least 1 prior line of therapy, including a proteasome inhibitor and an immunomodulatory drug, and are refractory to lenalidomide (Revlimid). On April 5, 2024, the FDA approved cilta-cel for this indication.3

“Cilta-cel will play an important role for patients with functional, high-risk and/or lenalidomide-refractory multiple myeloma who experience early relapse within the first 2 years of diagnosis,” said Usmani, who serves as chief of the Myeloma Service at Memorial Sloan Kettering Cancer Center in New York, New York.

In an interview with OncLive®, Usmani highlights key data from the CARTITUDE-4 trial supporting the approval of cilta-cel in pretreated multiple myeloma, provides insight on the FDA’s ODAC review of the therapy’s risk-benefit profile, and expands on the role for the agent in the paradigm.

OncLive: What was the design of the CARTITUDE-4 trial?

Usmani: Patients had received 1 to 3 prior lines of treatment. They were randomly assigned to cilta-cel in the intervention arm [or physician’s choice of] pomalidomide [Pomalyst], bortezomib [Velcade], and dexamethasone or daratumumab [Darzalex], pomalidomide, and dexamethasone in the SOC [arm.]

What key data from the trial supported the approval of cilta-cel in pretreated multiple myeloma?

The primary end point of the study was PFS, and it was met in favor of cilta-cel, with a median PFS [that] has not been reached. In the SOC arm, [the median PFS is] approximately 1 year. The hazard ratio was quite impressive for this clinical trial. As expected, cytokine release syndrome and infection were observed with cilta-cel. For that whole population, the data were quite impressive. The prespecified subgroup analyses [showed that] high-risk patients and those with higher burden of disease also benefitted [from treatment with the CAR T-cell therapy;] that’s the group where an intervention [may] have the most impact.

Prior to approval of cilta-cel, the FDA’s ODAC voted in favor of the benefit-risk profile of cilta-cel in patients with early relapsed/refractory myeloma. Please expand on your key takeaways from the data they discussed regarding OS in the CARTITUDE-4 trial.

The key issue that the FDA wanted to make sure that the ODAC was comfortable with in terms of regulatory approval was the early deaths that were observed during that period when patients randomly assigned to cilta-cel were on bridging therapy with a triplet regimen that the patients [assigned to the SOC arm] were receiving. There was some imbalance [between the experimental and control arms, with] 7 vs 1 patient, respectively, dying from their disease during that period. These were [patients with] progressive disease.

Therefore, the ODAC [wanted to assess whether] this was in any way connected to cilta-cel, but clearly it was not. It highlights the heterogeneity we have in this disease and the aggressive nature of those progression events. That was clearly stated in the whole discussion and alleviated some of the concerns that the panel had. [Moreover], the OS signal favored cilta-cel even after those events. [These data] haven’t gained statistical significance [to] satisfy the FDA, but [regardless], OS does not [appear to be] worse in the cilta-cel arm.

The key takeaway [from this decision] was that there was more assurance for physicians. We heard a lot of patient voices [in favor of] having this option available for them and allowing them to have those discussions with their physicians at the opportune time during the course of their disease. Ultimately, the ODAC came to a unanimous decision in favor of cilta-cel’s risk-benefit profile.

Where do you see cilta-cel being used within the myeloma treatment paradigm, and are there any patient populations in which you would hesitate to use this therapy?

[When considering the use of cilta-cel] I would think about the risk of infection, disease biology, and the pace of the disease as the determining factors [for treatment selection], as well as patient preference for continuous treatment with a triplet vs [a single infusion of] cilta-cel.

This would be a discussion with functional, high-risk, and/or lenalidomide-refractory patients. That group tends to include patients who already have documented high-risk disease, as well as standard-risk patients, who may have had high-risk clones sitting outside of the pelvic bone that were not [identified as] part of their early diagnostic workup. [If] that clone survives, it can proliferate and lead to disease relapse; that’s where we will see cilta-cel being used more often.

What is the overall significance and impact of cilta-cel’s approval in this disease?

One thing that we have to recognize is the [limited] accessibility of CAR T-cell therapy as it stands, as well as the capacity at transplant cellular therapy centers. [We] also [should] appreciate the fact that we do have some triplet regimen options for patients in that early-relapsed setting.

Having said all that, cilta-cel would be a very good option for the patients who are functionally high risk and who did not have a good first or even second PFS period. We saw this in small cohorts of patients in the phase 2 CARTITUDE-2 trial [NCT04133636]. The phase 3 [CARTITUDE-4 trial data] certainly validate [the phase 2 findings]. Having those conversations with the patients [about this agent] is going to be important.

The other important piece is that patients who do choose cilta-cel as an option [typically experience] a drug-free period after they’ve recovered from the CAR T-cell therapy. There are so many advantages, but we have to present those options with the caveat that logistics will be an issue.


  1. Carvykti. Prescribing information. Janssen Biotech, Inc; 2024. Accessed April 11, 2024.
  2. March 15, 2024, Meeting of the Oncologic Drugs Advisory Committee (ODAC). FDA. Accessed April 11, 2024.
  3. 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 April 11, 2024.
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